SUMMARY OF PRODUCT CHARACTERISTICS

• 1. NAME OF THE MEDICINAL PRODUCT

Imatinib Teva B.V. 100 mg film-coated tablets

Imatinib Teva B.V. 400 mg film-coated tablets

• 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Imatinib Teva B.V. 100 mg film-coated tablets

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

Imatinib Teva B.V. 400 mg film-coated tablets

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

For the full list of excipients, see section 6.1.

Film-coated tablet.

Imatinib Teva B.V. 100 mg film-coated tablets

Dark yellow to brownish orange round film-coated tablets with a score line on one side. The tablet is debossed with “IT” and “1” at each side of the score line. The diameter of the film-coated tablet is approximately 9 mm.

The tablet can be divided into equal doses.

Imatinib Teva B.V. 400 mg film-coated tablets

Dark yellow to brownish orange oblong film-coated tablets with a score line on one side. The tablet is debossed with “IT” and “4” at each side of the score line. The length of the film-coated tablet is approximately 20 mm and the width is approximately 10 mm.

The tablet can be divided into equa

• 4. CLINICAL PARTICULARS

  • 4.1 Therapeutic indications

Imatinib Teva B.V. is indicated for the treatment of

• Paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic

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

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

Adult patients with Ph+ CML in blast crisis.

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

Adult patients with relapsed or refractory Ph+ ALL as monotherapy.

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

Adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIPILl-PDGFRa rearrangement.

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

Imatinib Teva B.V. 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 patients with recurrent and/or metastatic DFSP who are not eligible for surgery.

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

• 4.2 Posology and method of administration

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

For doses of 400 mg and above (see dosage recommendation below) a 400 mg film-coated tablet is available.

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

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 dose of Imatinib Teva B.V. is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts > 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.

Posology for CML in 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 Imatinib Teva B.V. is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management of this disease should supervise the therapy throughout all phases of care.

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

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

Posology for Ph+ ALL in 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).

a B.V. is 400 mg/day for adult patients with MDS/MPD.

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

Posology for HES/CEL

The recommended dose of Imatinib Teva B.V. 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.

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

Posology for GIST

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

Dose adjustment for adverse reactions

Non-haematological adverse reactions

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

If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day.

Haematological adverse reactions

Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.

Dose adjustments for neutropenia and thrombocytopenia:

HES/CEL (starting dose 100 mg)	ANC < 1.0 × 109/1 and/or platelets < 50 × 109/1	1. Stop imatinib until ANC > 1.5 × 109/l and platelets > 75 × 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction).
MDS/MPD and GIST (starting dose 400 mg) HES/CEL (at dose 400 mg)	ANC < 1.0 × 109/l and/or platelets < 50 × 109/l	1. Stop imatinib until ANC > 1.5 × 109/l and platelets > 75 × 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 x109/l and/or platelets < 50 × 109/l, repeat step 1 and resume imatinib at reduced dose of 300 mg.
Paediatric chronic phase CML (at dose 340 mg/m2) & /	ANC < 1.0 × 109/l and/or platelets < 50 × 109/l	1. Stop imatinib until ANC > 1.5 × 109/l and platelets > 75 × 109/l. 2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction). 3. In the event of recurrence of ANC < 1.0 × 109/l and/or platelets < 50 × 109/l, repeat step 1 and resume imatinib at reduced dose of 260 mg/m2.
CML in blast crisis and Ph+ ALL (starting dose 600 mg)	a ANC < 0.5 × 109/l and/or platelets < 10 × 109/l	1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 400 mg. 3. If cytopenia persists for 2 weeks, reduce further to 300 mg. 4. If cytopenia persists for 4 weeks and is still

		unrelated to leukaemia, stop imatinib until ANC > 1 × 109/1 and platelets > 20 × 109/l, then resume treatment at 300 mg.
Paediatric accelerated phase CML and blast crisis (starting dose 340 mg/m2)	a ANC < 0.5 × 109/1 and/or platelets < 10 × 109/1	1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy). 2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 260 mg/m2. 3. If cytopenia persists for 2 weeks, reduce further to 200 mg/m2. 4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Imatinib until ANC > 1 × 109/1 and platelets > 20 × 109/l, then resume treatment at 200 mg/m2.
DFSP (at dose 800 mg)	ANC < 1.0 × 109/1 and/or platelets < 50 × 109/1	1. Stop imatinib until ANC > 1.5 × 109/l and platelets > 75 × 109/l. 2. Resume treatment with imatinib at 600 mg. 3. In the event of recurrence of ANC < 1.0 × 109/l and/or platelets < 50 × 109/l, repeat step 1 and resume imatinib at reduced dose of 400 mg.
ANC = absolute neutrophil count a occurring at least after 1 month of treatment

Special populations

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

The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less than 18 years of age have not been established in clinical trials. Currently available published data are summarised in section 5.1 but no recommendation on a posology can be made.

Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2).

Liver dysfunction classificatio

Liver dysfunction	Liver function tests
Mild N	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

LN = upper limit of normal for the institution ST = aspartate aminotransferase

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

Older people: Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in older people.

• 4.3 Contraindi­cations

  
  

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

• 4.4 Special warnings and precautions for use

When imatinib is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals, certain macrolide (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide,

tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomi quinidine) or warfarin and other coumarin derivatives (see section 4.5).

Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum , also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see section 4.5).

Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidecto replacement during treatment with imatinib (see section should be closely monitored in such patients.

Hepatotoxicity

Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment.

Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see section 4.5 and 4.8).

Fluid retention

Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with cardiac dysfunction.

^Patients with cardiac disease

Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib.

As cardiac adverse events have been reported uncommonly with imatinib, a careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation.

Myelodysplastic/my­eloproliferati­ve diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids (1–2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy.

Gastrointestinal haemorrhage

In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra-tumour haemorrhages were reported (see section 4.8). Based on the available data, no predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for the monitoring and management of haemorrhage in all patients should be applied.

In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 4.8). When needed, discontinuation of Imatinib Teva B.V. treatment may be considered.

Tumour lysis syndrome

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

Hepatitis B reactivation

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

Patients should be tested for HBV infection before initiating treatment with Imatinib Teva B.V. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib Teva B.V. 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 imatinib. Treatment of CML patients with imatinib has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as recommended in section

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

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

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

Paediatric population

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

• 4.5 Interaction with other medicinal products and other forms of interaction

Active substances that may increase imatinib plasma concentrations:

Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir, lopinavir/rito­navir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and

40%, respectively) in healthy subjects when it was co-administered with

CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family.

Active substances that may decrease imatinib plasma concentrations:

Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum , also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-v, by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic 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 imatinib

Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2– and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e.

statins, etc.).

Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives such as warfarin.

In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23% (90%CI [1.16–1.30]). Dose adjustments do not seem to be necessary when imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol clinical monitoring should be considered.

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

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

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown.

In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy ( 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 i has been reported that concomitant use with L-asparaginase could be associated with increas hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires specia

• 4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

Breast-feeding

There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed.

Fertility

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

• 4.7 Effects on ability to drive and use machines

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

Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products.

In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of patients.

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

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

Miscellaneous adverse reactions such as pleural effusion, ascites ary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life-threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials.

Adverse reactions

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.

Adverse reactions and their frequencies are reported in Table 1.

Table 1 Tabulated summary of adverse reactions

Infections and infestations
Uncommon: c?	Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sep­sis
Rare:	Fungal infection
Not known:	Hepatitis B reactivation*
Neoplasm benign, malignant and unspecified (including cysts and polyps)
Rare:	Tumour lysis syndrome
Not known:	Tumour haemorrhage/tumour necrosis*
Immune system disorders
Not known:	Anaphylactic shock*
Blood and lymphatic system disorders

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

• 2 Headache was the most common in GIST patients.

• 3 On a patient-year basis, cardiac events including congestive heart failure were more commonly

  4

  5

  6+7

  8

  9

  10

  11

  
  

  observed in patients with transformed CML than in patients with chronic CML.

  Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC).

  Pleural effusion was reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML.

  Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.

  
  

  Some fatal cases of hepatic failure and of hepatic necrosis have been reported.

  Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed post-marketing.

  Musculoskeletal pain and related events were more commonly observed in patients with CML

  
  
  
  

  in

  
  

  an in

  
  

  GIST patients.

  Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia

  
  

and other serious concomitant conditions.

Laboratory test abnormalities

Haematology

In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all

studies, with the suggestion of a higher frequency at high doses > 750 mg (phase I study). However, the

occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 × 109/l) and thrombocytopenias (platelet count < 50 × 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 × 109/l) and thrombocytopenia (platelet count < 10 × 109/l) were observed in 3.6% and < 1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy.

In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter.

Biochemistry

Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3%.

There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol.

Description of selected adverse reactions

Hepatitis B reactivation

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

♦ c

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

Adult population

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointesti­nal pain.

6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.

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

Paediatric population

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

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

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1 Pharmacody­namic properties

Pharmacotherapeutic group: Protein kinase inhibitors, 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 imatinib is based on overall haematological and cytogenetic response rates and progression-free survival. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

A large, international, open-label, non-controlled phase II study was conducted in patients with Philadelphia chromosome positive (Ph+) CML in blast crisis phase of the disease. 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.

Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg.

The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. In this study, 31% of patients achieved a haematological response (36% in previously untreated patients and 22% in previously treated patients). The rate of response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively.

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

Table 2 Response in adult CML studies

	Study 0102 38-month data Myeloid blast crisis (n=260)
	% of patients (CI95%)
Haematological response1 Complete haematological response (CHR) No evidence of leukaemia (NEL) Return to chronic phase (RTC)	31% (25.2–36.8) 8% 5% 18%
Major cytogenetic response2 Complete (Confirmed3) [95% CI] Partial	15% (11.2–20.4) 7% (2%) [0.6–4.4] 8%

• 1 Haematological response criteria (all responses to be confirmed after > 4 weeks):

CHR: In study 0102 [ANC > 1.5 × 109/1, platelets > 100 × 109/1, no blood blasts, BM blasts < 5% and no extramedullary disease]

NEL Same criteria as for CHR but ANC > 1 × 109/l and platelets > 20 × 109/l

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

BM = bone marrow, PB = peripheral blood

• 2 Cytogenetic response criteria:

A major response combines both complete and partial responses: complete (0% Ph+ metaphases), partial (1–35%)

• 3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at least one month after the initial bone marrow study

Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), 340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77%.

A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.

The European Medicines Agency has waived the obligation to submit the results of studies with imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use).

Clinical studies in Ph+ ALL

Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a complete haematological response. This clinical effect was associated with a higher reduction in bcr-abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free survival (p=0.02).

he results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled clinical udies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with chemotherapy induction (see Table 3) resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in two studies (AJP01 and AUS01).

Table 3 Chemotherapy regimen used in combination with imatinib

Study ADE10
Prephase	DEX 10 mg/m2 oral, days 1–5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX 12 mg intrathecal, day 1
Remission induction	DEX 10 mg/m2 oral, days 6–7, 13–16; VCR 1 mg i.v., days 7, 14; IDA 8 mg/m2i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2i.v.(1 h) day 1; Ara-C 60 mg/m2 i.v., days 22–25, 29–32
Consolidation therapy I, III, V	MTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1–20
Consolidation therapy II, IV	Ara-C 75 mg/m2 i.v. (1 h), days 1–5; VM26 60 mg/m2 i.v. (1 h), days 1–5
Study AAU02
Induction therapy (de novo Ph+ ALL)	Daunorubicin 30 mg/m2 i.v., days 1–3, 15–16; VCR 2 mg total dose i.v., days 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; Prednisone 60 mg/m2 oral, days 1–7, 15–21; IDA 9 mg/m2 oral, days 1–28; MTX 15 mg intrathecal, days 1, 8, 15, 22; Ara-C 40 mg intrathecal, days 1, 8, 15, 22; Methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22
Consolidation (de novo Ph+ ALL)	Ara-C 1,000 mg/m2/12 h i.v.(3 h), days 1–4; Mitoxantrone 10 mg/m2 i.v. days 3–5; MTX 15 mg intrathecal, day 1; Methylprednisolone 40 mg intrathecal, day 1
Study ADE04
Prephase	DEX 10 mg/m2 oral, days 1–5; CP 200 mg/m2 i.v., days 3–5; MTX 15 mg intrathecal, day 1
Induction therapy I	DEX 10 mg/m2 oral, days 1–5; VCR 2 mg i.v., days 6, 13, 20; Daunorubicin 45 mg/m2 i.v., days 6–7, 13–14
Induction therapy II <r	CP 1 g/m2 i.v. (1 h), days 26, 46; Ara-C 75 mg/m2 i.v. (1 h), days 28–31, 35–38, 42–45; 6-MP 60 mg/m2 oral, days 26–46
Consolidation therapy	DEX 10 mg/m2 oral, days 1–5; Vindesine 3 mg/m2 i.v., day 1; MTX 1.5 g/m2 i.v. (24 h), day 1; Etoposide 250 mg/m2 i.v. (1 h) days 4–5; Ara-C 2× 2 g/m2 i.v. (3 h, q 12 h), day 5
Study AJP01
Indu…	CP 1.2 g/m2 i.v. (3 h), day 1; Daunorubicin 60 mg/m2 i.v. (1 h), days 1–3; Vincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21; Prednisolone 60 mg/m2/day oral
Consolidation therapy	Alternating chemotherapy course: high dose chemotherapy with MTX 1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2–3, for 4 cycles
Maintenance	VCR 1.3 g/m2 i.v., day 1; Prednisolone 60 mg/m2 oral, days 1–5
Study AUS01
Induction-consolidation therapy	Hyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days

	1–3; Vincristine 2 mg i.v., days 4, 11; Doxorubicine 50 mg/m2 i.v. (24 h), day 4; DEX 40 mg/day on days 1–4 and 11–14, alternated with MTX 1 g/m2 i.v. (24 h), day 1, Ara-C 1 g/m2 i.v. (2 h, q 12 h), days 2–3 (total of 8 courses)	À
Maintenance	VCR 2 mg i.v. monthly for 13 months; Prednisolone 200 mg oral, 5 days per month for 13 months
All treatment regimens include administration of steroids for CNS prophylaxis.
Ara-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6MP: 6-mercaptopurine VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous

Paediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from 1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, non-randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination with intensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts 1–5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the lowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days with continuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily exposure to imatinib early in the course of treatment in combination with chemotherapy in cohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls (n=120), who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The estimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 out of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant.

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

Consolidation block 1 (3 weeks)	VP-16 (100 mg/m2/day, IV): days 1–5 Ifosfamide (1.8 g/m2/day, IV): days 1–5 MESNA (360 mg/m2/dose q3h, x 8 doses/day, IV): days 1–5 G-CSF (5 ^g/kg, SC): days 6–15 or until ANC > 1500 post nadir IT Methotrexate (age-adjusted): day 1 ONLY Triple IT therapy (age-adjusted): day 8, 15
Consolidation block 2 (3 weeks)	Methotrexate (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2 and 3 Triple IT therapy (age-adjusted): day 1 ARA-C (3 g/m2/dose q 12 h x 4, IV): days 2 and 3 G-CSF (5 ^g/kg, SC): days 4–13 or until ANC > 1500 post nadir
Reinduction block 1 (3 weeks)	VCR (1.5 mg/m2/day, IV): days 1, 8, and 15 DAUN (45 mg/m2/day bolus, IV): days 1 and 2 CPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4 PEG-ASP (2500 IUnits/m2, IM): day 4 G-CSF (5 ^g/kg, SC): days 5–14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1–7 and 15–21
Intensification block 1 (9 weeks)	Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: Days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22–26 CPM (300 mg/m2/day, IV): days 22–26 MESNA (150 mg/m2/day, IV): days 22–26 G-CSF (5 ^g/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 gg/kg, SC): days 5–14 or until ANC > 1500 post nadir Triple IT therapy (age-adjusted): days 1 and 15 DEX (6 mg/m2/day, PO): days 1–7 and 15–21
Intensification block 2 (9 weeks)	Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2, 3, 16, and 17 Triple IT therapy (age-adjusted): days 1 and 22 VP-16 (100 mg/m2/day, IV): days 22–26 CPM (300 mg/m2/day, IV): days 22–26 MESNA (150 mg/m2/day, IV): days 22–26 G-CSF (5 gg/kg, SC): days 27–36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44 _____________­_____________________
Maintenance (8-week cycles) Cycles 1–4	MTX (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3 Triple IT therapy (age-adjusted): days 1, 29 VCR (1.5 mg/m2, IV): days 1, 29 DEX (6 mg/m2/day PO): days 1–5; 29–33 6-MP (75 mg/m2/day, PO): days 8–28 Methotrexate (20 mg/m2/week, PO): days 8, 15, 22 VP-16 (100 mg/m2, IV): days 29–33 CPM (300 mg/m2, IV): days 29–33 MESNA IV days 29–33 G-CSF (5 gg/kg, SC): days 34–43
Maintenance (8-week cycles) Cycle 5	Cranial irradiation (Block 5 only) 12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis 18 Gy in 10 fractions for patients that are CNS3 at diagnosis VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1–5; 29–33 6-MP (75 mg/m2/day, PO): days 11–56 (Withhold 6-MP during the 6–10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP the 1st day after cranial irradiation completion.) Methotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50
Maintenance (8-week cycles) Cycles 6–12	VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1–5; 29–33 6-MP (75 mg/m2/day, PO): days 1–56 Methotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50

G-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG asparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 ^M, q6h = every 6 hours, Gy= Gray

Study AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients (1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study seem to be in line with the safety profile of imatinib in Ph+ ALL patients.

Relapsed/refrac­tory Ph+ ALL: When imatinib was used as single agent in patients with relapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a haematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. (Of note, out of the 411 patients, 353 were treated in an expanded access program without primary response data collected.) The median time to progression in the overall population of 411 patients with relapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include only those patients age 55 or older.

Clinical studies in MDS/MPD

Experience with imatinib in this indication is very limited and is based on haematological and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased survival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were treated with imatinib 400 mg daily. Three patients presented a complete haematological response (CHR) and one patient experienced a partial haematological response (PHR). At the time of the original analysis, three of the four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years.

patients suffering from myeloproliferative neoplasms with PDGFR- ß rearrangement and who were treated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose of 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to the observational nature of this registry, haematologic, cytogenetic and molecular assessment data were available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming conservatively that patients with missing data were non-responders, CHR was observed in 20/23 (87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When the response rate is calculated from patients with at least one valid assessment, the response rate for CHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively.

In addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were treated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 11 patients revealed that all these patients remained in cytogenetic remission (range 32–38 months). The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic responses have been sustained for a median of 49 months (range 19–60) and 47 months (range 16–59), respectively. The overall survival is 65 months since diagnosis (range 25–234). Imatinib administration to patients without the genetic translocation generally results in no improvement.

There are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD associated with PDGFR gene re-arrangements were reported in 4 publications. The age of these patients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging from 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic response and/or clinical response.

One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to 1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case reports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic abnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients FIPILl-PDGFRa fusion kinase was identified. An additional four HES patients were found to be FIP1L1-PDGFRa-positive in other 3 published reports. All 65 FIP1L1-PDGFRa fusion kinase positive patients achieved a CHR sustained for months (range from 1+ to

44+ months censored at the time of the reporting). As reported in a recent publication 21 of these 65 patients also achieved complete molecular remission with a median follow-up of 28 months (range 13–67 months). The age of these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports. Improvements were reported in cardiac, nervous, skin/subcutaneous tissue, respiratory/tho­racic/mediasti­nal, musculoskeletal/con­nective tissue/vascular, and gastrointestinal organ systems.

There are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and CEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging from 200 to 400 mg daily. All patients achieved complete haematological response, complete cytogenetic response and/or complete molecular response.

Clinical studies in unresectable and/or metastatic GIST

One phase II, open-label, randomised, uncontrolled multinational study was conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumours (GIST). In this study 147 patients were

In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of imatinib was escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg. The daily dose was escalated to 800 mg in a total of 103 patients; 6 patients achieved a partial response and 21 stabilisation of their disease after dose escalation for an overall clinical benefit of 26%. From the safety data available, escalating the dose to 800 mg daily in patients progressing at lower doses of 400 mg or 600 mg daily does not seem to affect the safety profile of imatinib.

Clinical studies in adjuvant GIST

In the adjuvant setting, imatinib was investigated in a multicentre, double-blind, long-term, placebo-controlled phase III study (Z9001) involving 773 patients. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histological diagnosis of primary GIST expressing Kit protein by immunochemistry and a tumour size > 3 cm in maximum dimension, with complete gross resection of primary GIST within 14–70 days prior to registration. After resection of primary GIST, patients were randomised to one of the two arms: imatinib at 400 mg/day or matching placebo for one year.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date of randomisation to the date of recurrence or death from any cause.

Imatinib significantly prolonged RFS, with 75% of patients being recurrence-free at 38 months in the imatinib group vs. 20 months in the placebo group (95% CIs, [30 – non-estimable]; [14 – non- estimable], respectively); (hazard ratio = 0.398 [0.259–0.610], p<0.0001). At one year the overall RFS was significantly better for imatinib (97.7%) vs. placebo (82.3%), (p<0.0001). The risk of recurrence was thus reduced by approximately 89% as compared with placebo (hazard ratio = 0.113 [0.049–0.264]).

The risk of recurrence in patients after surgery of their primary GIST was retrospectively assessed based on the following prognostic factors: tumour size, mitotic index, tumour location. Mitotic index data were available for 556 of the 713 intention-to-treat (ITT) population. The results of subgroup analyses according to the United States National Institutes of Health (NIH) and the Armed Forces Institute of Pathology (AFIP) risk classifications are shown in Table 6. No benefit was observed in the low and very low risk groups. No overall survival benefit has been observed.

Table 6 Summary of Z9001 trial RFS analyses by NIH and AFIP risk classifications

Risk criteria	Risk level	% of patients	No. of events / No. of patients	Overall hazard ratio (95% CI)	RFS rates (%)
					12 month	24 month
			Imatinib vs placebo f		Imatinib vs placebo	Imatinib vs placebo
NIH	Low	29.5	0/86 vs. 2/90	N.E.	100 vs. 98.7	100 vs. 95.5
	Intermediate	25.7	4/75 vs. 6/78	0.59 (0.17; 2.10)	100 vs. 94.8	97.8 vs. 89.5
	High	44.8	21/140 vs. 51/127	0.29 (0.18; 0.49)	94.8 vs. 64.0	80.7 vs. 46.6
AFIP	Very low	20.7	0/52 vs. 2/63	N.E.	100 vs. 98.1	100 vs. 93.0
	Low	25.0	2/70 vs. 0/69	N.E.	100 vs. 100	97.8 vs. 100
	Moderate	24.6	2/70 vs. 11/67	0.16 (0.03; 0.70)	97.9 vs. 90.8	97.9 vs. 73.3
	High	29.7	16/84 vs. 39/81	0.27 (0.15; 0.48)	98.7 vs. 56.1	79.9 vs. 41.5

Full follow-up period; NE – Not estimable

A second multicentre, open label phase III study (SSG XVIII/AIO) compared 400 mg/day imatinib 12 months treatment vs. 36 months treatment in patients after surgical resection of GIST and one of the following: tumour diameter > 5 cm and mitotic count > 5/50 high power fields (HPF); or tumour diameter > 10 cm and any mitotic count or tumour of any size with mitotic count > 10/50 HPF or tumours ruptured into the peritoneal cavity. There were a total of 397 patients consented and randomised to the study (199 patients on 12-month arm and 198 patients on 36-month arm), median age was 61 years (range 22 to 84 years). The median time of follow-up was 54 months (from date of randomisation to data cut-off), with a total of 83 months between the first patient randomised and the cut-off date.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date of randomisation to the date of recurrence or death from any cause.

Thirty-six (36) months of imatinib treatment significantly prolonged RFS compared to 12 months of imatinib treatment (with overall Hazard Ratio (HR) = 0.46 [0.32, 0.65], p<0.0001) (Table 7, Figure 1).

In addition, thirty-six (36) months of imatinib treatment significantly prolonged overall survival (OS) compared to 12 months of imatinib treatment (HR = 0.45 [0.22, 0.89], p=0.0187) (Table 7, Figure 2).

Longer duration of the treatment (> 36 months) may delay the onset of further recurrences; however the impact of this finding on the overall survival remains unknown.

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

Treatment with imatinib for 36 months was superior to treatment for 12 months in the ITT analysis, i.e. including the entire study population. In a planned subgroup analysis by mutation type, the HR for RFS for 36 months of treatment for patients with mutations of exon 11 was 0.35 [95% CI: 0.22, 0.56]. No conclusions can be drawn for other less common mutation subgroups due to the low number of observed events.

There are no controlled trials in paediatric patients with c-Kit positive GIST. Seventeen (17) patients with GIST (with or without Kit and PDGFR mutations) were reported in 7 publications. The age of these patients ranged from 8 to 18 years and imatinib was given in both adjuvant and metastatic settings at doses ranging from 300 to 800 mg daily. The majority of paediatric patients treated for GIST lacked data confirming c-kit or PDGFR mutations which may have led to mixed clinical outcomes.

Clinical studies in DFSP

One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients with DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to 75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of study entry. The primary evidence of efficacy was based on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and 8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. A further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages ranging from 18 months to 49 years. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. Five (5) patients responded, 3 completely and 2 partially. The median duration of therapy in the published literature ranged between 4 weeks and more than 20 months. The translocation t(17:22)[(q22­:q13)], or its gene product, was present in nearly all responders to imatinib treatment.

There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 520 mg/m2 daily. All patients achieved partial and/or complete response.

acokinetics of imatinib

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

Absorption

Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated.

Distribution

At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to lipoprotein.

Biotransformation

The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of the parent compound.

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

The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC50 5 0 pM) and fluconazole (IC 50 118 pM) showed inhibition of imatinib metabolism which could have clinical relevance.

Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 pmol/l, respectively. Maximal plasma concentrations of imatinib in patients are 2–4 pmol/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 pM). This K i 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 t./2 was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily.

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 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing.

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

Organ function impairment

Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5– to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4).

Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8).

• 5.3 Preclinical safety data

  The preclinical safety profile of im

  
  

as 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

veral of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the inary bladder was observed at doses > 6 mg/kg in the 13-week study, without changes in serum or urinary rameters. An increased rate of opportunistic infections was observed with chronic imatinib treatment.

In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on body surface.

Treatment resulted in worsening of normally suppressed malarial infections in these animals.

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

In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses < 20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses > 30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-implantation foetal loss and a reduced number of live foetuses. This was not seen at doses < 20 mg/kg.

In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg).

Imatinib was teratogenic in rats when administered during organogenesis at doses > 100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. These effects were not seen at doses < 30 mg/kg.

No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, effects upon growth, delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at approximately 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2.

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.

Tablet core

Calcium hydrogen phosphate, anhydrous

Crospovidone

Magnesium stearate

Tablet coat

Polyvinyl alcohol partially hydrolysed

Macrogol

Iron oxide yellow (E172)

Talc

Titanium dioxide (E171)

Iron oxide red (E172)

• 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

• 6.5 Nature and contents of container

PVC/PE/PVdC/P­E/PVCAl blisters OPA/Al/PVCAl blisters

Imatinib Teva B.V. 100 mg film-coated tablets

Pack sizes of 60 or 120 film-coated tablets in blisters.

Pack sizes of 20×1, 60×1, 120×1 or 180×1 film-coated tablets in perforated unit dose blisters.

Imatinib Teva B.V. 400 mg film-coated tablets

Pack sizes of 30 or 90 film-coated tablets in blisters.

Pack sizes of 30×1 or 90×1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

• 6.6 Special precautions for disposal

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

• 7. MARKETING AUTHORISATION HOLDER

Teva B.V.

Swensweg 5 2031GA Haarlem

Netherlands

• 8. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1243/001–012 (100 mg)

EU/1/17/1243/025–032 (400 mg)

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATI

  
  

Date of first authorisation:

• 10. DATE OF REVISION OF THE TEXT

  
  

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

• 1. NAME OF THE MEDICINAL PRODUCT

Imatinib Teva B.V. 100 mg hard capsules

Imatinib Teva B.V. 400 mg hard capsules

• 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Imatinib Teva B.V. 100 mg hard capsules

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

Imatinib Teva B.V. 400 mg hard capsules

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

For the full list of excipients, see section 6.1.

Hard capsule.

Imatinib Teva B.V. 100 mg hard capsules

Non transparent orange capsules with black marking 7629 on capsule body and black marking TEVA on capsule cap. The content of the capsule is white to light yellow granulated powder.

The length of the capsule is from 19.1 mm to 19.7 mm

Imatinib Teva B.V. 400 mg hard capsules

Non transparent orange capsules with black marking 7630 on capsule body and black marking TEVA on capsule cap. The content of the capsule is white to light yellow granulated powder.

The length of the capsule is from 23.0 mm to 23.6 mm and the width is 8.53 mm.

• 4.1 Therapeutic indications

Imatinib Teva B.V. is indicated for the treatment of

• Paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.
• Paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in

accelerated phase or blast crisis.

• Adult patients with Ph+ CML in blast crisis.

♦

• Adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.
• Adult patients with relapsed or refractory Ph+ ALL as monotherapy.
• Adult patients with myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD) associated with platelet-

derived growth factor receptor (PDGFR) gene re-arrangements.

• Adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFRa rearrangement.

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

Imatinib Teva B.V. 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 imatinib is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on recurrence-free survival in adjuvant GIST. The experience with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased survival for these diseases.

• 4.2 Posology and method of administration

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

The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening. For patients (children) unable to swallow the capsules, their content may be diluted in a glass of either still water or apple juice. Since studies in animals have shown reproductive toxicity, and the potential risk for the human foetus is unknown, women of child-bearing potential who open capsules should be advised to handle the contents with caution and avoid skin-eye contact or inhalation (see section 4.6). Hands should be washed immediately after handling open capsules.

Posology for CML in adult patients

The recommended dose of Imatinib Teva B.V. is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts > 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.

dogy 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 Imatinib Teva B.V. is 600 mg/day for adult patients with Ph+ ALL.

Haematological experts in the management of this disease should supervise the therapy throughout all phases of care.

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

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

Posology for Ph+ ALL in 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 Imatinib Teva B.V. is 400 mg/day for adult patients with MDS/MPD.

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

Posology for HES/CEL

The recommended dose of Imatinib Teva B.V. 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 Imatinib Teva B.V. 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).

♦ J

tment duration: In clinical trials in GIST patients, treatment with imatinib was continued until disease ssion. At the time of analysis, the treatment duration was a median of 7 months (7 days to 13 months).

e effect of stopping treatment after achieving a response has not been investigated.

The recommended dose of Imatinib Teva B.V. 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 Imatinib Teva B.V. is 800 mg/day for adult patients with DFSP.

Special populations

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

The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less than 18 years of age have not been established in clinical trials. Currently available published data are summarised in section 5.1 but no recommendation on a posology can be made.

Hepatic insufficiency : Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). .

Liver dysfunction classification:

Liver dysfunction	Liver function tests
Mild	Total bilirubin: = 1.5 ULN AST: >ULN (can be normal or < ULN if total bilirubin is > ULN)
Moderate	Total bilirubin: > 1.5–3.0 ULN AST: any
Severe	Total bilirubin: > 3–10 ULN AST: any

ULN = upper limit of normal for the institution AST = aspartate aminotransferase

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

Older people : Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65 and older. No specific dose recommendation is necessary in older people.

3 Contraindica­tions

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

• 4.4 Special warnings and precautions for use

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

Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum , also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided (see section 4.5).

Hypothyroidism

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

Hepatotoxicity

Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment.

Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see section 4.5 and 4.8).

Fluid retention

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

those with a prior history of cardiac disea 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 imatinib therapy should be considered in the HES/CEL population before treatment initiation.

odysplastic/my­eloproliferati­ve diseases with PDGFR gene re-arrangements could be associated with gh 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 needed, discontinuation of Imatinib Teva B.V. treatment may be considered.

Tumour lysis syndrome

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

Hepatitis B reactivation

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

Patients should be tested for HBV infection before initiating treatment with Imatinib Teva B.V. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib Teva B.V. 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 imatinib. Treatment of CML patients with imatinib has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase

rupted or the dose may be reduced, as recommended in section

Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients

In patients with i al function, imatinib plasma exposure seems to be higher than that in patients

with normal rena tion, 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).

• 4.5 Interaction with other medicinal products and other forms of interaction

Active substances that may increase imatinib plasma concentrations

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

Active substances that may decrease imatinib plasma concentrations Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum , also known as St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-v, by at least 54% and 74%, of the respective values without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic 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 imatinib

Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2– and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.).

Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives such as warfarin.

In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23% (90%CI [1.16–1.30]). Dose adjustments do not seem to be necessary when imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprolol clinical monitoring should be considered.

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

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

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. However, the mechanism of the observed interaction is presently unknown.

In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see section 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well

characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase could be associated with increased hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special precaution.

• 4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

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

spontaneous abortions and infant congenital anomalies from women who have taken imati udies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk foetus is unknown. Imatinib should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding

There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not breast-feed.

Fertility

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

• 4.7 Effects on ability to drive and use machines

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

• 4.8 Undesirable effects

Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the co-administration of numerous medicinal products.

• ♦ Ç Ji

In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of patients.

The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious and sometimes fatal.

The most commonly reported (> 10%) drug-related adverse reactions in both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib.

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

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may be serious or life-threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials.

Adverse reactions

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency categories are defined using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.

Adverse reactions and their frequencies are reported in Table 1.

Common:	Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction
Uncommon:	Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions
Rare:	Acute febrile neutrophilic dermatosis (Sweet’s syndrome), nail discolouration, angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis (AGEP)
Not known:	Palmoplantar erythrodysesthesia syndrome, lichenoid keratosis*, lichen planus*, toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders
Very common:	Muscle spasm and cramps, musculoskeletal pain including myalgia9, arthralgia, bone pain10
Common:	Joint swelling
Uncommon:	Joint and muscle stiffness
Rare:	Muscular weakness, arthritis, rhabdomyolysis/my­opathy
Not known:	Avascular necrosis/hip necrosis, growth retardation in children*
Renal and urinary disorders
Uncommon:	Renal pain, haematuria, renal failure acute, urinary frequency increased
Not known:	Renal failure chronic
Reproductive system and breast disorders
Uncommon:	Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema
Rare:	Haemorrhagic corpus luteum/haemorrhagic ovarian cyst
General disorders and administration site conditions
Very common:	Fluid retention and oedema, fatigue
Common:	Weakness, pyrexia, anasarca, chills, rigors
Uncommon:	Chest pain, malaise
Investigations
Very common:	Weight increased
Common:	Weight decreased
Uncommon:	Blood creatinine increased, blood creatine phosphokinase increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased
Rare:	Blood amylase increased

These types of reactions have been reported mainly from post-marketing experience with imatinib. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved indications. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure. Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.

Headache was the most common in GIST patients.

• 3 On a patient-year basis, cardiac events including congestive heart failure were more commonly

observed in patients with transformed CML than in patients with chronic CML.

• 4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most common in patients with GIST and with transformed CML (CML-AP and CML-BC).

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

6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.

• 8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported.

• 9. Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-marketing

• 10 Musculoskeletal pain and related events were more commonly observed in patients with CML than in GIST patients.

• 11 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions.

Laboratory test abnormalities

Haematology

In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses > 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3 or 4 neutropenias (ANC < 1.0 × 109/l) and thrombocytopenias (platelet count < 50 × 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 × 109/l) and thrombocytopenia (platelet count < 10 × 109/l) were observed in 3.6% and < 1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy.

In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly during the first six weeks of therapy, with values remaining relatively stable thereafter.

Biochemistry

Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were observed. Bilirubin elevation was below 3%.

There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal, including one patient on high dose paracetamol.

Description of selected adverse reactions:

Hepatitis B reactivation

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

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

Adult population

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointesti­nal pain.

6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vo abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.

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

Paediatric population

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

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

• 5. PHARMACOLOGICAL PROPERTIES

• 5.1 Pharmacody­namic properties

Pharmacotherapeutic group: Protein kinase inhibitors, 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 imatinib is based on overall haematological and cytogenetic response rates and progression-free survival. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

A large, international, open-label, non-controlled phase II study was conducted in patients with Philadelphia chromosome positive (Ph+) CML in the blast crisis phase of the disease. In addition, children 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.

Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg.

The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase CML. In this study, 31% of patients achieved a haematological response (36% in previously untreated patients and 22% in previously treated patients). The rate of response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively.

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

p_____

Study 0102 38-month data Myeloid blast crisis _____________­____(n=260) ________ ___________% of patients (CI95%) 31% (25.2–36.8) 8% 5%

_____________­__18% ________ 15% (11.2–20.4) 7%

(2%) [0.6–4.4] 8%

Paediatric patients : A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), 340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77%.

A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.

The European Medicines Agency has waived the obligation to submit the results of studies with imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use).

Clinical studies in Ph+ ALL

Newly diagnosed Ph+ ALL : In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a complete haematological response. This clinical effect was associated with a higher reduction in bcr-abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after induction and the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free survival (p=0.02).

The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with chemotherapy induction (see Table 3) resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in two studies (AJP01 and AUS01).

Table 3 Chemotherapy regimen used in combination with imatinib

Study ADE10
Prephase	DEX 10 mg/m2 oral, days 1–5; CP 200 mg/m2i.v., days 3, 4, 5; MTX 12 mg intrathecal, day 1
Remission induction	DEX 10 mg/m2 oral, days 6–7, 13–16; VCR 1 mg i.v., days 7, 14; IDA 8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15; CP 500 mg/m2i.v.(1 h) day 1; Ara-C 60 mg/m2 i.v., days 22–25, 29–32
Consolidation therapy I, III, V	MTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1–20

	MESNA (150 mg/m2/day, IV): days 22–26 G-CSF (5 gg/kg, SC): days 27–36 or until ANC > 1500 post nadir ARA-C (3 g/m2, q12h, IV): days 43, 44 L-ASP (6000 IUnits/m2, IM): day 44
Maintenance (8-week cycles) Cycles 1–4	MTX (5 g/m2 over 24 hours, IV): day 1 Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii: days 2 and 3 Triple IT therapy (age-adjusted): days 1, 29 VCR (1.5 mg/m2, IV): days 1, 29 DEX (6 mg/m2/day PO): days 1–5; 29–33 6-MP (75 mg/m2/day, PO): days 8–28 Methotrexate (20 mg/m2/week, PO): days 8, 15, 22 VP-16 (100 mg/m2, IV): days 29–33 CPM (300 mg/m2, IV): days 29–33 MESNA IV days 29–33 G-CSF (5 gg/kg, SC): days 34–43
Maintenance (8-week cycles) Cycle 5	Cranial irradiation (Block 5 only) 12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis 18 Gy in 10 fractions for patients that are CNS3 at diagnosis VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1–5; 29–33 6-MP (75 mg/m2/day, PO): days 11–56 (Withhold 6-MP during the 6–10 days of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP the 1st day after cranial irradiation completion.) Methotrexate (20 mg/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50
Maintenance (8-week cycles) Cycles 6–12	VCR (1.5 mg/m2/day, IV): days 1, 29 DEX (6 mg/m2/day, PO): days 1–5; 29–33 6-MP (75 mg/m2/day, PO): days 1–56 Methotrexate (20 mg/m2/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50

G-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV = intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine, CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP = 6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG asparaginase, MESNA= 2-mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 gM, q6h = every 6 hours, Gy= Gray

Study AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients (1 to < 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study seem to be in line with the safety profile of imatinib in Ph+ ALL patients.

Relapsed/refrac­tory Ph+ ALL: When imatinib was used as single agent in patients with relapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a haematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. (Of note, out of the 411 patients, 353 were treated in an expanded access program without primary response data collected.) The median time to progression in the overall population of 411 patients with relapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include only those patients age 55 or older.

Clinical studies in MDS/MPD

Experience with imatinib in this indication is very limited and is based on haematological and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increased survival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD who were treated with imatinib 400 mg daily. Three patients presented a complete haematological response (CHR) and one patient experienced a partial haematological response (PHR). At the time of the original analysis, three of the four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years.

An observational registry (study L2401) was conducted to collect long-term safety and efficacy data in patients suffering from myeloproliferative neoplasms with PDGFR- p rearrangement and who were treated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose of 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to the observational nature of this registry, haematologic, cytogenetic and molecular assessment data were available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming conservatively that patients with missing data were non-responders, CHR was observed in 20/23 (87%) patients, CCyR in 9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When the response rate is calculated from patients with at least one valid assessment, the response rate for CHR, CCyR and MR was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively.

In addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were treated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 11 patients revealed that all these patients remained in cytogenetic remission (range 32–38 months). The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic responses have been sustained for a median of 49 months (range 19–60) and 47 months (range 16–59), respectively. The overall survival is 65 months since diagnosis (range 25–234). Imatinib administration to patients without the genetic translocation generally results in no improvement.

There are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD associated with PDGFR gene re-arrangements were reported in 4 publications. The age of these patients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging from 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogenetic response and/or clinical response.

Clinical studies in HES/CEL

One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to 1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case reports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic abnormalities were evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients FIPILl-PDGFRa fusion kinase was identified. An additional four HES patients were found to be FIP1L1-PDGFRa-positive in other 3 published reports. All 65 FIP1L1-PDGFRa fusion kinase positive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at the time of the reporting). As reported in a recent publication 21 of these 65 patients also achieved complete molecular remission with a median follow-up of 28 months (range 13–67 months). The age of these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports. Improvements were reported in cardiac, nervous, skin/subcutaneous tissue, respiratory/tho­racic/mediasti­nal, musculoskeletal/con­nective tissue/vascular, and gastrointestinal organ systems.

There are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and CEL associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses ranging from 200 to 400 mg daily. All patients achieved complete haematological response, complete cytogenetic response and/or complete molecular response.

Clinical studies in unresectable and/or metastatic GIST

One phase II, open-label, randomised, uncontrolled multinational study was conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumours (GIST). In this study 147 patients were enrolled and randomised to receive either 400 mg or 600 mg orally once daily for up to 36 months. These patients ranged in age from 18 to 83 years old and had a pathologic diagnosis of Kit-positive malignant GIST that was unresectable and/or metastatic. Immunohistoche­mistry was routinely performed with Kit antibody (A-4502, rabbit polyclonal antiserum, 1:100; DAKO Corporation, Carpinteria, CA) according to analysis by an avidin-biotin-peroxidase complex method after antigen retrieval.

The primary evidence of efficacy was based on objective response rates. Tumours were required to be measurable in at least one site of disease, and response characterisation based on Southwestern Oncology Group (SWOG) criteria. Results are provided in Table 5.

Table 5 Best tumour response in trial STIB2222 (GIST)

Best response	All doses (n=147) 400 mg (n=73) 600 mg (n=74) n (%) />?
Complete response	1 (0.7)
Partial response	98 (66.7)
Stable disease	23 (15.6)
Progressive disease	18 (12.2)
Not evaluable	5 (3.4)
Unknown	2 2 (1.4)

There were no differences in response rates between the two dose groups. A significant number of patients who had stable disease at the time of the interim analysis achieved a partial response with longer treatment (median follow-up 31 months). Median time to response was 13 weeks (95% C.I. 12–23). Median time to treatment failure in responders was 122 weeks (95% C.I 106–147), while in the overall study population it was 84 weeks (95% C.I 71–109). The median overall survival has not been reached. The Kaplan-Meier estimate for survival after 36-month follow-up is 68%.

In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of imatinib was escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg. The daily dose was escalated to 800 mg in a total of 103 patients; 6 patients achieved a partial response and 21 stabilisation of their disease after dose escalation for an overall clinical benefit of 26%. From the safety data available, escalating the dose to 800 mg daily in patients progressing at lower doses of 400 mg or 600 mg daily does not seem to affect the safety profile of imatinib.

Clinical studies in adjuvant GIST

In the adjuvant setting, imatinib was investigated in a multicentre, double-blind, long-term, placebo-controlled phase III study (Z9001) involving 773 patients. The ages of these patients ranged from 18 to 91 years. Patients were included who had a histological diagnosis of primary GIST expressing Kit protein by immunochemistry and a tumour size > 3 cm in maximum dimension, with complete gross resection of primary GIST within 14–70 days prior to registration. After resection of primary GIST, patients were randomised to one of the two arms: imatinib at 400 mg/day or matching placebo for one year.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date of randomisation to the date of recurrence or death from any cause.

Imatinib significantly prolonged RFS, with 75% of patients being recurrence-free at 38 months in the imatinib group vs. 20 months in the placebo group (95% CIs, [30 – non-estimable]; [14 – non- estimable], respectively); (hazard ratio = 0.398 [0.259–0.610], p<0.0001). At one year the overall RFS was significantly better for imatinib (97.7%) vs. placebo (82.3%), (p<0.0001). The risk of recurrence was thus reduced by approximately 89% as compared with placebo (hazard ratio = 0.113 [0.049–0.264]).

The risk of recurrence in patients after surgery of their primary GIST was retrospectively assessed based on the following prognostic factors: tumour size, mitotic index, tumour location. Mitotic index data were available for 556 of the 713 intention-to-treat (ITT) population. The results of subgroup analyses according to the United States National Institutes of Health (NIH) and the Armed Forces Institute of Pathology (AFIP) risk classifications are shown in Table 6. No benefit was observed in the low and very low risk groups. No overall survival benefit has been observed.

Table 6 Summary of Z9001 trial RFS analyses by NIH and AFIP risk classifications

Risk criteri a	Risk level	% of patients	No. of events / No. of patients	Overall hazard ratio (95% CI)	RFS rates (%)
					12 month	24 month
			Imatinib vs placebo		Imatinib vs placebo	Imatinib vs placebo
NIH	Low	29.5	0/86 vs. 2/90	N.E.	100 vs. 98.7	100 vs. 95.5 J
	Intermediate	25.7	4/75 vs. 6/78	0.59 (0.17; 2.10)	100 vs. 94.8	97.8 vs. 89.5
	High	44.8	21/140 vs. 51/127	0.29 (0.18; 0.49)	94.8 vs. 64.0	80.7 vs. 46.6
AFIP	Very low	20.7	0/52 vs. 2/63	N.E.	100 vs. 98.1	100 vs. 93.0
	Low	25.0	2/70 vs. 0/69	N.E.	100 vs. 100	97.8 vs. 100
	Moderate	24.6	2/70 vs. 11/67	0.16 (0.03; 0.70)	97.9 vs. 90.8	97.9 vs. 73.3
	High	29.7	16/84 vs. 39/81	0.27 (0.15; 0.48)	98.7 vs. 56.1	79.9 vs. 41.5

Full follow-up period; NE – Not estimable

A second multicentre, open label phase III study (SSG XVIII/AIO) compared 400 mg/day imatinib 12 months treatment vs. 36 months treatment in patients after surgical resection of GIST and one of the following: tumour diameter > 5 cm and mitotic count > 5/50 high power fields (HPF); or tumour diameter > 10 cm and any mitotic count or tumour of any size with mitotic count > 10/50 HPF or tumours ruptured into the peritoneal cavity. There were a total of 397 patients consented and randomised to the study (199 patients on 12-month arm and 198 patients on 36-month arm), median age was 61 years (range 22 to 84 years). The median time of follow-up was 54 months (from date of randomisation to data cut-off), with a total of 83 months between the first patient randomised and the cut-off date.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date of randomisation to the date of recurrence or death from any cause.

Thirty-six (36) months of imatinib treatment significantly prolonged RFS compared to 12 months of imatinib treatment (with overall Hazard Ratio (HR) = 0.46 [0.32, 0.65], p<0.0001) (Table 7, Figure 1).

In addition, thirty-six (36) months of imatinib treatment significantly prolonged overall survival (OS) compared to 12 months of imatinib treatment (HR = 0.45 [0.22, 0.89], p=0.0187) (Table 7, Figure 2).

Longer duration of the treatment (> 36 months) may delay the onset of further recurrences; however the impact of this finding on the overall survival remains unknown.

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

Treatment with imatinib for 36 months was superior to treatment for 12 months in the ITT analysis, i.e. including the entire study population. In a planned subgroup analysis by mutation type, the HR for RFS for 36 months of treatment for patients with mutations of exon 11 was 0.35 [95% CI: 0.22, 0.56]. No conclusions can be drawn for other less common mutation subgroups due to the low number of observed events.

Table 7 12-month and 36-month imatinib treatment (SSGXVIII/AIO Trial)

RFS	12-month treatment arm % (CI)	36-month treatment arm % (CI)
12 months	93.7 (89.2–96.4)	95.9 (91.9–97.9)
24 months	75.4 (68.6–81.0)	90.7 (85.6–94.0)

36 months	60.1 (52.5–66.9)	86.6 (80.8–90.8)
48 months	52.3 (44.0–59.8)	78.3 (70.8–84.1)
60 months	47.9 (39.0–56.3)	65.6 (56.1–73.4)
Survival
36 months	94.0 (89.5–96.7)	96.3 (92.4–98.2)
48 months	87.9 (81.1–92.3)	95.6 (91.2–97.8)
60 months	81.7 (73.0–87.8)	92.0 (85.3–95.7)

Figure 1

Kaplan-Meier estimates for primary recurrence-free survival endpoint (ITT population)

There are no controlled trials in paediatric patients with c-Kit positive GIST. Seventeen (17) patients with GIST (with or without Kit and PDGFR mutations) were reported in 7 publications. The age of these patients ranged from 8 to 18 years and imatinib was given in both adjuvant and metastatic settings at doses ranging from 300 to 800 mg daily. The majority of paediatric patients treated for GIST lacked data confirming c-kit or PDGFR mutations which may have led to mixed clinical outcomes.

Clinical studies in DFSP

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

DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to 75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of study entry. The primary evidence of efficacy was based on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and 8 partially. Three of the partial responders were subsequently rendered disease free by surgery. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. A further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their ages ranging from 18 months to 49 years. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. Five (5) patients responded, 3 completely and 2 partially. The median duration of therapy in the published literature ranged between 4 weeks and more than 20 months. The translocation t(17:22)[(q22­:q13)], or its gene product, was present in nearly all responders to imatinib treatment.

There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 520 mg/m2 daily. All patients achieved partial and/or complete response.

• 5.2 Pharmacoki­netic properties

Pharmacokinetics of imatinib

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

Absorption

Mean absolute bioavailability for the capsule formulation is 98%. There was high between-patient variability in plasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated.

Distribution

At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to

• lipoprotein.

o

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 5 0 pM) and fluconazole (IC 50 118 pM) showed inhibition of imatinib metabolism which could have clinical relevance.

Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 pmol/l, respectively. Maximal plasma

concentrations of imatinib in patients are 2–4 pmol/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 pM). This K i 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, approxima 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 t./2 was approximately 18 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed once daily.

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 presen 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 e, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. ysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m2 once daily (not eding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to ose in adult patients who received imatinib 400 mg or 600 mg once daily.

Organ function impairment

Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5– to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4).

Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8).

• 5.3 Preclinical safety data

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

Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs an 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 species. No

histopathological changes were seen in rat liver. Severe liver toxicity was observed in do ated for 2

weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.

Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses > 6 mg/kg in the 13-week study, without changes in serum or urinary parameters. An increased rate of opportunistic infections was observed with chronic imatinib treatment.

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

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

In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses < 20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses > 30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-implantation foetal loss and a reduced number of live foetuses. This was not seen at doses < 20 mg/kg.

In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg).

Imatinib was teratogenic in rats when administered during organogenesis at doses > 100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. These effects were not seen at doses < 30 mg/kg.

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 i statistically significant reduction in the longevity of males at 60 mg/kg/day and females at >30 mg/kg/c Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressiv nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifi 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 so mals.

an environmental risk for sediment organisms.

Capsule content

Mannitol

Crospovidone

Magnesium stearate Silica colloidal, anhydrous

Capsule shell

Gelatin

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Iron oxide, red (E172)

Printing ink

Shellac

Iron oxide black (E172)

10. DATE OF REVISION OF THE TEXT

MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

• B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

• C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE

E USE OF THE MEDICINAL PRODUCT

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release Teva Czech Industries s.r.o.

Ostravská 29, c.p. 305

CZ-74770 Opava – Komárov

Czech Republic

Merckle GmbH

Graf-Arco-Str. 3, 89079 Ulm

Germany

TEVA UK Ltd

Brampton Road, Hampden Park, Eastbourne, East Sussex, BN22 9AG

United Kingdom

Teva Operations Poland Sp. z.o.o ul. Mogilska 80. 31–546, Krakow Poland

TEVA Pharmaceutical Works Private Limited Company

Pallagi út 13, 4042 Debrecen

Hungary

TEVA PHARMA S.L.U.

C/C, n. 4, Poligono Industrial Malpica, 50016 Zaragoza Spa­in

Teva Pharma B.V.

Swensweg 5, 2031GA Haarlem Netherlands

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25 10000 Zagreb

Croatia

The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch.

OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2).

OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

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

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

Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

At the request of the European Medicines Agency;

Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Teva B.V.

Swensweg 5 2031GA Haarlem

Netherlands

EU/1/17/1243/001 20×1 film-coated tablets

EU/1/17/1243/002 60 film-coated tablets

EU/1/17/1243/003 60×1 film-coated tablets

EU/1/17/1243/­004 120 film-coated tablets

EU/1/17/1243/­005 120×1 film-coated tablets

EU/1/17/1243/­006 180×1 film-coated tablets

EU/1/17/1243/007 20×1 film-coated tablets

EU/1/17/1243/008 60 film-coated tablets

EU/1/17/1243/009 60×1 film-coated tablets

EU/1/17/1243/­010 120 film-coated tablets

EU/1/17/1243/­011 120×1 film-coated tablets

EU/1/17/1243/­012 180×1 film-coated tablets

__xV___

• 16. INFORMATION IN BRAILLE

—

imatinib teva b.v. 100 mg film-coated tablets

• 17. UNIQUE IDENTIFIER – 2D BARCODE

barcode carrying the unique identifier included.

• 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

Outer carton

• 5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

Oral use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

  
  

• 9. SPECIAL STORAGE CONDITIONS

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

  11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

  
  

Teva B.V.

Swensweg 5 2031GA Haarlem

Netherlands

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1243/025 30 film-coated tablets

EU/1/17/1243/026 30×1 film-coated tablets

EU/1/17/1243/027 90 film-coated tablets

EU/1/17/1243/028 90×1 film-coated tablets

EU/1/17/1243/029 30 film-coated tablets

EU/1/17/1243/030 30×1 film-coated tablets

EU/1/17/1243/031 90 film-coated tablets

EU/1/17/1243/032 90×1 film-coated tablets

14. GENERAL CLASSIFICATION FOR SUPPLY

16. INFORMATION IN BRAILLE imatinib teva b.v. 400 mg film-coated tablets

Teva B.V.

Swensweg 5 2031GA Haarlem

Netherlands

• 12. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1243/013 20×1 hard capsules

EU/1/17/1243/014 60 hard capsules

EU/1/17/1243/015 60×1 hard capsules

EU/1/17/1243/­016 120 hard capsules

EU/1/17/1243/­017 120×1 hard capsules

EU/1/17/1243/­018 180×1 hard capsules

EU/1/17/1243/019 20×1 hard capsules

EU/1/17/1243/020 60 hard capsules

EU/1/17/1243/021 60×1 hard capsules

EU/1/17/1243/­022 120 hard capsules

EU/1/17/1243/­023 120×1 hard capsules

EU/1/17/1243/­024 180×1 hard capsules

• 17. UNIQUE IDENTIFIER – 2D BARCODE |^^^l*2D barcode carrying the unique identifier included.

• 18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

Outer carton

• 5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use. Oral use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING(S), IF NECESSARY

  
  

9. SPECIAL STORAGE CONDITIONS

17. UNIQ

ENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

UNIQUE IDENTIFIER – HUMAN READABLE DATA

Package leaflet: Information for the patient

Imatinib Teva B.V. 100 mg film-coated tablets Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

Imatinib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general informati this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor without taking Imatinib Teva B.V

If you think you may be allergic but are not sure, ask your doctor for advic

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart p

• – if you are taking the medicine levothyroxine because your thyroid has been removed.

• – if you have ever had or might now have a hepatitis B infection. This is because Imatinib Teva B.V.

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

• – If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

• – Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

  
  

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious condition. Imatinib Teva B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Chec your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor t medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many tablets of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as 4 tablets once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to the treatment. If your daily dose is 800 mg (8 tablets), you should take 4 tablets in the morning and 4 tablets in the evening.

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as 4 tablets once a day.

If you are being treated for HES/CEL:

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

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many tablets of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

  
  

• - Swallow the tablets whole with a large glass of water.

If you are unable to swallow the tablets, you can dissolve them in a glass of still water or apple juice:

• Use about 50 ml for each 100 mg tablet.
• Stir with a spoon until the tablets have completely dissolved.
• Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved tablets may be left behind in the glass.

The tablet can be divided into equal doses.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many tablets, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon skip the missed dose.

• – Then continue with your normal sc

Do not take a double dose to make up a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

• 4. Possible side effec

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention). Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can reduce the number of white blood cells, so you might get infections more easily.

Unexpected bleeding or bruising (when you have not hurt yourself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

• Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).
• Feeling light-headed, dizzy or fainting (signs of low blood pressure).

Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems).

Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain).

Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red blood cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellulitis).

Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).

atitis B infection when you have had hepatitis B in the past (a liver

If you get any of the above, tell your doctor straight away.

Other side effects may include:

Very common (may affect more than 1 in 10 people):

Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

Muscle cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you have stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.
• Feeling dizzy or weak.

Difficulty in sleeping (insomnia).

Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.

Nose bleeds.

Pain or swelling in your abdomen, flatulence, heartburn or constipation.

Itching.

Unusual hair loss or thinning.

Numbness of the hands or feet.

Mouth ulcers.

Joint pain with swelling.

Dry mouth, dry skin or dry eye.

Decreased or increased skin sensitivity.

Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.ach of children.Keep this medicine out of the sight andDo not use this medicine after the expir

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

This medicine does not require any special storage conditions.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each film-coated tablet of Imatinib Teva B.V. contains 100 mg imatinib (as mesilate).

• – The other ingredients are calcium hydrogen phosphate anhydrous, crospovidone and magnesium stearate.

• – The tablet coating is made of polyvinyl alcohol partially hydrolysed, macrogol, iron oxide yellow (E172), talc, titanium dioxide (E171) and iron oxide red (E172))

What Imatinib Teva B.V. looks like and contents of the pack

Imatinib Teva B.V. 100 mg film-coated tablets are dark yellow to brownish orange round film-coated tablets with a score line on one side. The tablet is debossed with “IT” and “1” at each side of the score line. The tablets are approximately 9 mm in diameter.

Imatinib Teva B.V. 100 mg film-coated tablets are available in pack sizes of 60 or 120 film-coated tablets in blisters.

Imatinib Teva B.V. 100 mg film-coated tablets are available in pack sizes of 20×1, 60×1, 120×1 or 180×1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder Teva B.V.

Swensweg 5 2031GA Haarlem

Netherlands

Manufacturer

Teva Pharmaceutical Works Private Limited Company

Pallagi ut 13

Debrecen H-4042

Hungary

TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

Teva Czech Industries s.r.o.

Ostravska 29, c.p. 305, 74770

Opava-Komarov

Czech Republic

TEVA PHARMA, S.L.U.

C/C, n. 4, Poligono Industrial Malpica 50016 Zaragoza Spa­in

Teva Operations Poland Sp. z o.o. ul. Mogilska 80, 31–546 Krakow Poland

Teva Pharma B.V. Swensweg 5, 2031GA Haarlem Netherlands

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25 10000 Zagreb

Croatia

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgie/Belgiqu­e/Belgien

Teva Pharma Belgium N.V./S.A./AG

Tél/Tel: +32 3 820 73 73

Efc^rapufl

TeBa OapMacromuKMC Etnrapua EOOfl

Tea: +359 2 489 95 82

Česká republika

Teva Pharmaceuticals CR, s.r.o.

Tel: +420 251 007 111

Lietuva

UAB “Sicor Biotech”

Tel: +370 5 266 0203

Luxembourg/Lu­xemburg

Teva Pharma Belgium N.V./S.A./AG,

Belgique/Belgien

Tel/Tel: +32 3 820 73 73

Magyarorszag

Teva Gyogyszergyar Zrt.

Tel.: +36 1 288 64 00

Malta

Teva Pharmaceuticals Ireland, L-Irlanda

Tel: +353 51 321740

Nederland

Teva Nederland B.V.

Tel: +31 800 0228 400

Eesti

UAB “Sicor Biotech“ Eesti filiaal

Tel: +372 661 0801

España

Teva Pharma, S.L.U.

Tél: +34 91 387 32 80

France

Teva Santé

Tél: +33 1 55 91 78 00

Norge

Teva Norway AS

Tlf: +47 66 77 55 90 ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1 97 0070

Polska

Teva Pharmaceuticals Polska Sp. z o.o.

Tel.: +48 22 345 93 00

Romania

Teva Pharmaceuticals S.R.L

Tel: +40 21 230 65 24

Slovenija

Pliva Ljubljana d.o.o.

Tel: +386 1 58 90 390

Slovenská republika

TEVA Pharmaceuticals Slovakia s.r.o.

Tel: +421 2 57 26 79 11

Suomi/Finland

ratiopharm Oy

Puh/Tel: +358 20 180 5900

Kûnpoç

Teva EMôç A.E., EMôôa

Tql: +30 210 72 79 099

Latvija

UAB “Sicor Biotech” filiale Latvijâ

Tel: +371 673 23 666

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency

website:

Package leaflet: Information for the patient

Imatinib Teva B.V. 400 mg film-coated tablets Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

• - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

Imatinib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general informati this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor without taking Imatinib Teva B.V.

If you think you may be allergic but are not sure, ask your doctor for advic

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart p

• – if you are taking the medicine levothyroxine because your thyroid has been removed.

• – if you have ever had or might now have a hepatitis B infection. This is because Imatinib Teva B.V.

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

• – If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

• – Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

  
  

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious condition. Imatinib Teva B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Chec your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor t medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight

away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many tablets of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as one tablet once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to the treatment. If your daily dose is 800 mg (2 tablets), you should take one tablet in the morning and a second

tablet in the evening.

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as one tablet once a day.

If you are being treated for HES/CEL:

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

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many tablets of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

  
  

• - Swallow the tablets whole with a large glass of water.

If you are unable to swallow the tablets, you can dissolve them in a glass of still water or apple juice:

• Use about 200 ml for each 400 mg tablet.
• Stir with a spoon until the tablets have completely dissolved.
• Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved tablets may be left behind in the glass.

The tablet can be divided into equal doses.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many tablets, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose.

• – Then continue with your normal schedule.

• – Do not take a double dose to make up a forgotten dose.

  If you have any further qu

  
  

n the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can

reduce the number of white blood cells, so you might get infections more easily.

• Unexpected bleeding or bruising (when you have not hurt yourself).
• Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).

Feeling light-headed, dizzy or fainting (signs of low blood pressure).

Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel pro Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red bloo cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellu Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).
• Chronic renal failure.
• Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection).

If you get any of the above, tell your doctor straight away.

Other side effects may include:

• Very common (may affect more than 1 in 10 people): Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

Muscle cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you have stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.

Feeling dizzy or weak.

Difficulty in sleeping (insomnia).

Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.

Nose bleeds.

Pain or swelling in your abdomen, flatulence, heartburn or constipation.

Itching.

Unusual hair loss or thinning.

Numbness of the hands or feet.

Mouth ulcers.

Joint pain with swelling.

Dry mouth, dry skin or dry eye.

Decreased or increased skin sensitivity.

Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

This medicine does not require any special storage conditions.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each film-coated tablet of Imatinib Teva B.V. contains 400 mg imatinib (as mesilate).

• – The other ingredients are calcium hydrogen phosphate anhydrous, crospovidone and magnesium stearate.

• – The tablet coating is made of polyvinyl alcohol partially hydrolysed, macrogol, iron oxide yellow (E172), talc, titanium dioxide (E171) and iron oxide red (E172))

What Imatinib Teva B.V. looks like and contents of the pack

Imatinib Teva B.V. 400 mg film-coated tablets are dark yellow to brownish orange oblong film-coated tablets with a score line on one side. The tablet is debossed with “IT” and “4” at each side of the score line. The tablets are approximately 20 mm long and 10 mm wide.

Imatinib Teva B.V. 400 mg film-coated tablets are available in pack sizes of 30 or 90 film-coated tablets in blisters.

Imatinib Teva B.V. 400 mg film-coated tablets are available in pack sizes of 30×1or 90×1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Manufacturer

Teva Pharmaceutical Works Private Limited Company

Pallagi ut 13

Debrecen H-4042

Hungary

TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

Teva Czech Industries s.r.o. Ostravska 29, c.p. 305, 74770 Opava-Komarov Czech Republic

TEVA PHARMA, S.L.U.

C/C, n. 4, Poligono Industrial Malpica 50016 Zaragoza Spa­in

Merckle GmbH Graf-Arco-Str. 3, 89079 Ulm Germany

Teva Operations Poland Sp. z o.o. ul. Mogilska 80, 31–546 Krakow

Teva Pharma B.V. Swensweg 5, 2031GA Haarlem Netherlands

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25

10000 Zagreb Croatia

België/Belgiqu­e/Belgien

Teva Pharma Belgium N.V./S.A./AG

Tél/Tel: +32 3 820 73 73

Efc^rapufl

TeBa OapMacromuKMC Etnrapua EOOfl

Ten: +359 2 489 95 82

Česká republika

Teva Pharmaceuticals CR, s.r.o.

Tel: +420 251 007 111

Danmark

Teva Denmark A/S

Tlf: +45 44 98 55 11

Deutschland

TEVA GmbH

Tel: +49 731 402 08

Lietuva

UAB “Sicor Biotech”

Tel: +370 5 266 0203

Luxembourg/Lu­xemburg

Teva Pharma Belgium N.V./S.A./AG,

Belgique/Belgien

Tél/Tel: +32 3 820 73 73

Magyarország

Teva Gyógysze

Tel.: +36 1 288

Malta

Teva Pharmaceuticals Ireland, L-Irlanda

Tel: +353 51 321

Slovenija

Pliva Ljubljana d.o.o.

Tel: +386 1 58 90 390

Slovenská republika

TEVA Pharmaceuticals Slovakia s.r.o.

Tel: +421 2 57 26 79 11

Suomi/Finland

ratiopharm Oy

Puh/Tel: +358 20 180 5900

Kûnpoç

Teva EMôç A.E. , EMôSa

Tql: +30 210 72 79 099

Latvija

UAB “Sicor Biotech” filiale Latvijâ

Tel: +371 673 23 666

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency

website:

Package leaflet: Information for the patient

Imatinib Teva B.V. 100 mg hard capsules

Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information.

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia

is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

Imatinib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general informati this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor without taking Imatinib Teva B.V.

If you think you may be allergic but are not sure, ask your doctor for advic

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart p

• – if you are taking the medicine levothyroxine because your thyroid has been removed.

• – if you have ever had or might now have a hepatitis B infection. This is because Imatinib Teva B.V.

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

• – If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask your doctor for advice before taking this medicine.

• – Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

  
  

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious condition. Imatinib Teva B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Chec your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor t medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight

away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many capsules of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as 4 capsules once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (8 capsules), you should take 4 capsules in the morning and 4 capsules in the evening.

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as 4 capsules onc e a day.

If you are being treated for HES/CEL:

The starting dose is 100 mg, to be taken as one capsule once a day. Your doctor may decide to

increase the dose to 400 mg, to be taken as 4 capsules once a day, depending on how you respond to

treatment.

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many capsules of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

• - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless

you have difficulty in swallowing (e.g. in children).

• – If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice.

• – If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose.

• – Then continue with your normal schedule.

• – Do not take a double dose to make up a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can

reduce the number of white blood cells, so you might get infections more easily.

• Unexpected bleeding or bruising (when you have not hurt yourself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

• Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).
• Feeling light-headed, dizzy or fainting (signs of low blood pressure).
• Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver

problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain) Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels o cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellulitis).

Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).

Very common (may affect more than 1 in 10 people):

Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

le cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.
• Feeling dizzy or weak.
• Difficulty in sleeping (insomnia).
• Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.
• Nose bleeds.
• Pain or swelling in your abdomen, flatulence, heartburn or constipation.
• Itching.
• Unusual hair loss or thinning.
• Numbness of the hands or feet.
• Mouth ulcers.
• Joint pain with swelling.
• Dry mouth, dry skin or dry eye.
• Decreased or increased skin sensitivity.
• Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

Store below 30°C.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each hard capsule of Imatinib Teva B.V. contains 100 mg imatinib (as mesilate).

• – The other ingredients are mannitol, crospovidone, magnesium stearate and silica colloidal anhydrous.

The capsule shell is composed of gelatin, titanium dioxide (E171), iron oxide yellow (E172) and iron oxide red (E172). The printing ink is composed of shellac, iron oxide black (E172) and propylene glycol.

What Imatinib Teva B.V. looks like and contents of the pack

Imatinib Teva B.V. 100 mg hard capsules are non-transparent orange capsules with black marking 7629 on capsule body and black marking TEVA on capsule cap. The content of the capsule is white to light yellow granulated powder. The capsules are approximately 19 mm long and 7 mm wide.

Imatinib Teva B.V. 100 mg hard capsules are available in pack sizes of 60 or 120 hard capsules in blisters. Imatinib Teva B.V. 100 mg hard capsules are available in pack sizes of 20×1, 60×1, 120×1 or 180×1 hard capsules in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Manufacturer

Teva Pharmaceutical Works Private Limited Company

Pallagi ut 13

Debrecen H-4042

Hungary

TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

Teva Czech Industries s.r.o.

Ostravska 29, c.p. 305, 74770

Opava-Komarov

Czech Republic

TEVA PHARMA, S.L.U.

C/C, n. 4, Poligono Industrial Malpica 50016 Zaragoza Spa­in

Merckle GmbH Graf-Arco-Str. 3, 89079 Ulm Germany

Teva Operations Poland Sp. z o.o. ul. Mogilska 80, 31–546 Krakow Poland

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25 10000 Zagreb

Croatia

Khnpoç

Teva EXXaç A.E., EXXaSa

Tql: +30 210 72 79 099

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

Package leaflet: Information for the patient

Imatinib Teva B.V. 400 mg hard capsules

Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information.

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

• - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia

is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

inib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general information conta this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (liste

  
  

If this applies to you, tell your doctor without taking Imatinib Teva B.V.

If you think you may be allergic but are not sure, ask your doctor for advice.

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart proble

  id has been removed.

  . This is because Imatinib Teva B.V.

  
  

• – if you are taking the medicine levothyroxine because yo

if you have ever had or might now have a hepatitis B in

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be

carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask your doctor for advice before taking this medicine.

Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious c B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many capsules of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as one capsule once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (2 capsules), you should take one capsule in the morning and a second capsule in the evening.

• ♦ < N

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as one capsule once a day.

If you are being treated for HES/CEL:

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

you respond to treatment.

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many capsules of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

• - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children).

• – If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice.

• – If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose.

• – Then continue with your normal schedule.

• – Do not take a double dose to make up a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can

reduce the number of white blood cells, so you might get infections more easily.

• Unexpected bleeding or bruising (when you have not hurt yourself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

• Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).
• Feeling light-headed, dizzy or fainting (signs of low blood pressure).
• Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver

problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain) Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels o cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellulitis).

Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).
• Chronic renal failure.
• Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection).

Very common (may affect more than 1 in 10 people):

Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

le cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.
• Feeling dizzy or weak.
• Difficulty in sleeping (insomnia).
• Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.
• Nose bleeds.
• Pain or swelling in your abdomen, flatulence, heartburn or constipation.
• Itching.
• Unusual hair loss or thinning.
• Numbness of the hands or feet.
• Mouth ulcers.
• Joint pain with swelling.
• Dry mouth, dry skin or dry eye.
• Decreased or increased skin sensitivity.
• Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

Store below 30°C.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each hard capsule of Imatinib Teva B.V. contains 400 mg imatinib (as mesilate).

• – The other ingredients are mannitol, crospovidone, magnesium stearate and silica colloidal anhydrous.

What Imatinib Teva B.V. looks like and contents of the pack

Imatinib Teva B.V. 100 mg film-coated tablets are dark yellow to brownish orange round film-coated tablets with a score line on one side. The tablet is debossed with “IT” and “1” at each side of the score line. The tablets are approximately 9 mm in diameter.

Imatinib Teva B.V. 100 mg film-coated tablets are available in pack sizes of 60 or 120 film-coated tablets in blisters.

Imatinib Teva B.V. 100 mg film-coated tablets are available in pack sizes of 20×1, 60×1, 120×1 or 180×1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder Teva B.V.

Swensweg 5 2031GA Haarlem

Netherlands

Manufacturer

Teva Pharmaceutical Works Private Limited Company

Pallagi ut 13

Debrecen H-4042

Hungary

TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

Teva Czech Industries s.r.o.

Ostravska 29, c.p. 305, 74770

Opava-Komarov

Czech Republic

TEVA PHARMA, S.L.U.

C/C, n. 4, Poligono Industrial Malpica 50016 Zaragoza Spa­in

Teva Operations Poland Sp. z o.o. ul. Mogilska 80, 31–546 Krakow Poland

Teva Pharma B.V. Swensweg 5, 2031GA Haarlem Netherlands

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25 10000 Zagreb

Croatia

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgie/Belgiqu­e/Belgien

Teva Pharma Belgium N.V./S.A./AG

Tél/Tel: +32 3 820 73 73

Efc^rapufl

TeBa OapMacromuKMC Etnrapua EOOfl

Tea: +359 2 489 95 82

Česká republika

Teva Pharmaceuticals CR, s.r.o.

Tel: +420 251 007 111

Lietuva

UAB “Sicor Biotech”

Tel: +370 5 266 0203

Luxembourg/Lu­xemburg

Teva Pharma Belgium N.V./S.A./AG,

Belgique/Belgien

Tel/Tel: +32 3 820 73 73

Magyarorszag

Teva Gyogyszergyar Zrt.

Tel.: +36 1 288 64 00

Malta

Teva Pharmaceuticals Ireland, L-Irlanda

Tel: +353 51 321740

Nederland

Teva Nederland B.V.

Tel: +31 800 0228 400

Eesti

UAB “Sicor Biotech“ Eesti filiaal

Tel: +372 661 0801

España

Teva Pharma, S.L.U.

Tél: +34 91 387 32 80

France

Teva Santé

Tél: +33 1 55 91 78 00

Norge

Teva Norway AS

Tlf: +47 66 77 55 90 ratiopharm Arzneimittel Vertriebs-GmbH Tel: +43 1 97 0070

Polska

Teva Pharmaceuticals Polska Sp. z o.o.

Tel.: +48 22 345 93 00

Romania

Teva Pharmaceuticals S.R.L

Tel: +40 21 230 65 24

Slovenija

Pliva Ljubljana d.o.o.

Tel: +386 1 58 90 390

Slovenská republika

TEVA Pharmaceuticals Slovakia s.r.o.

Tel: +421 2 57 26 79 11

Suomi/Finland

ratiopharm Oy

Puh/Tel: +358 20 180 5900

Kûnpoç

Teva EMôç A.E., EMôôa

Tql: +30 210 72 79 099

Latvija

UAB “Sicor Biotech” filiale Latvijâ

Tel: +371 673 23 666

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency

website:

Package leaflet: Information for the patient

Imatinib Teva B.V. 400 mg film-coated tablets Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

– If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

• - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

Imatinib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general informati this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor without taking Imatinib Teva B.V.

If you think you may be allergic but are not sure, ask your doctor for advic

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart p

• – if you are taking the medicine levothyroxine because your thyroid has been removed.

• – if you have ever had or might now have a hepatitis B infection. This is because Imatinib Teva B.V.

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

• – If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

• – Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

  
  

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious condition. Imatinib Teva B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Chec your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor t medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight

away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many tablets of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as one tablet once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to the treatment. If your daily dose is 800 mg (2 tablets), you should take one tablet in the morning and a second

tablet in the evening.

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as one tablet once a day.

If you are being treated for HES/CEL:

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

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many tablets of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

  
  

• - Swallow the tablets whole with a large glass of water.

If you are unable to swallow the tablets, you can dissolve them in a glass of still water or apple juice:

• Use about 200 ml for each 400 mg tablet.
• Stir with a spoon until the tablets have completely dissolved.
• Once the tablet has dissolved, drink everything in the glass straight away. Traces of the dissolved tablets may be left behind in the glass.

The tablet can be divided into equal doses.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many tablets, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose.

• – Then continue with your normal schedule.

• – Do not take a double dose to make up a forgotten dose.

  If you have any further qu

  
  

n the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can

reduce the number of white blood cells, so you might get infections more easily.

• Unexpected bleeding or bruising (when you have not hurt yourself).
• Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).

Feeling light-headed, dizzy or fainting (signs of low blood pressure).

Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel pro Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red bloo cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellu Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).
• Chronic renal failure.
• Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection).

If you get any of the above, tell your doctor straight away.

Other side effects may include:

• Very common (may affect more than 1 in 10 people): Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

Muscle cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you have stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.

Feeling dizzy or weak.

Difficulty in sleeping (insomnia).

Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.

Nose bleeds.

Pain or swelling in your abdomen, flatulence, heartburn or constipation.

Itching.

Unusual hair loss or thinning.

Numbness of the hands or feet.

Mouth ulcers.

Joint pain with swelling.

Dry mouth, dry skin or dry eye.

Decreased or increased skin sensitivity.

Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

This medicine does not require any special storage conditions.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each film-coated tablet of Imatinib Teva B.V. contains 400 mg imatinib (as mesilate).

• – The other ingredients are calcium hydrogen phosphate anhydrous, crospovidone and magnesium stearate.

• – The tablet coating is made of polyvinyl alcohol partially hydrolysed, macrogol, iron oxide yellow (E172), talc, titanium dioxide (E171) and iron oxide red (E172))

What Imatinib Teva B.V. looks like and contents of the pack

Imatinib Teva B.V. 400 mg film-coated tablets are dark yellow to brownish orange oblong film-coated tablets with a score line on one side. The tablet is debossed with “IT” and “4” at each side of the score line. The tablets are approximately 20 mm long and 10 mm wide.

Imatinib Teva B.V. 400 mg film-coated tablets are available in pack sizes of 30 or 90 film-coated tablets in blisters.

Imatinib Teva B.V. 400 mg film-coated tablets are available in pack sizes of 30×1or 90×1 film-coated tablets in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Manufacturer

Teva Pharmaceutical Works Private Limited Company

Pallagi ut 13

Debrecen H-4042

Hungary

TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

Teva Czech Industries s.r.o. Ostravska 29, c.p. 305, 74770 Opava-Komarov Czech Republic

TEVA PHARMA, S.L.U.

C/C, n. 4, Poligono Industrial Malpica 50016 Zaragoza Spa­in

Merckle GmbH Graf-Arco-Str. 3, 89079 Ulm Germany

Teva Operations Poland Sp. z o.o. ul. Mogilska 80, 31–546 Krakow

Teva Pharma B.V. Swensweg 5, 2031GA Haarlem Netherlands

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25

10000 Zagreb Croatia

België/Belgiqu­e/Belgien

Teva Pharma Belgium N.V./S.A./AG

Tél/Tel: +32 3 820 73 73

Efc^rapufl

TeBa OapMacromuKMC Etnrapua EOOfl

Ten: +359 2 489 95 82

Česká republika

Teva Pharmaceuticals CR, s.r.o.

Tel: +420 251 007 111

Danmark

Teva Denmark A/S

Tlf: +45 44 98 55 11

Deutschland

TEVA GmbH

Tel: +49 731 402 08

Lietuva

UAB “Sicor Biotech”

Tel: +370 5 266 0203

Luxembourg/Lu­xemburg

Teva Pharma Belgium N.V./S.A./AG,

Belgique/Belgien

Tél/Tel: +32 3 820 73 73

Magyarország

Teva Gyógysze

Tel.: +36 1 288

Malta

Teva Pharmaceuticals Ireland, L-Irlanda

Tel: +353 51 321

Slovenija

Pliva Ljubljana d.o.o.

Tel: +386 1 58 90 390

Slovenská republika

TEVA Pharmaceuticals Slovakia s.r.o.

Tel: +421 2 57 26 79 11

Suomi/Finland

ratiopharm Oy

Puh/Tel: +358 20 180 5900

Kûnpoç

Teva EMôç A.E. , EMôSa

Tql: +30 210 72 79 099

Latvija

UAB “Sicor Biotech” filiale Latvijâ

Tel: +371 673 23 666

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency

website:

Package leaflet: Information for the patient

Imatinib Teva B.V. 100 mg hard capsules

Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

– If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information.

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia

is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

Imatinib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general informati this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (listed in section 6).

If this applies to you, tell your doctor without taking Imatinib Teva B.V.

If you think you may be allergic but are not sure, ask your doctor for advic

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart p

• – if you are taking the medicine levothyroxine because your thyroid has been removed.

• – if you have ever had or might now have a hepatitis B infection. This is because Imatinib Teva B.V.

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

• – If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask your doctor for advice before taking this medicine.

• – Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

  
  

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious condition. Imatinib Teva B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Chec your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor t medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight

away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many capsules of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as 4 capsules once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (8 capsules), you should take 4 capsules in the morning and 4 capsules in the evening.

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as 4 capsules onc e a day.

If you are being treated for HES/CEL:

The starting dose is 100 mg, to be taken as one capsule once a day. Your doctor may decide to

increase the dose to 400 mg, to be taken as 4 capsules once a day, depending on how you respond to

treatment.

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many capsules of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

• - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless

you have difficulty in swallowing (e.g. in children).

• – If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice.

• – If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose.

• – Then continue with your normal schedule.

• – Do not take a double dose to make up a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can

reduce the number of white blood cells, so you might get infections more easily.

• Unexpected bleeding or bruising (when you have not hurt yourself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

• Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).
• Feeling light-headed, dizzy or fainting (signs of low blood pressure).
• Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver

problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain) Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels o cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellulitis).

Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).

Very common (may affect more than 1 in 10 people):

Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

le cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.
• Feeling dizzy or weak.
• Difficulty in sleeping (insomnia).
• Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.
• Nose bleeds.
• Pain or swelling in your abdomen, flatulence, heartburn or constipation.
• Itching.
• Unusual hair loss or thinning.
• Numbness of the hands or feet.
• Mouth ulcers.
• Joint pain with swelling.
• Dry mouth, dry skin or dry eye.
• Decreased or increased skin sensitivity.
• Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

Store below 30°C.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each hard capsule of Imatinib Teva B.V. contains 100 mg imatinib (as mesilate).

• – The other ingredients are mannitol, crospovidone, magnesium stearate and silica colloidal anhydrous.

The capsule shell is composed of gelatin, titanium dioxide (E171), iron oxide yellow (E172) and iron oxide red (E172). The printing ink is composed of shellac, iron oxide black (E172) and propylene glycol.

What Imatinib Teva B.V. looks like and contents of the pack

Imatinib Teva B.V. 100 mg hard capsules are non-transparent orange capsules with black marking 7629 on capsule body and black marking TEVA on capsule cap. The content of the capsule is white to light yellow granulated powder. The capsules are approximately 19 mm long and 7 mm wide.

Imatinib Teva B.V. 100 mg hard capsules are available in pack sizes of 60 or 120 hard capsules in blisters. Imatinib Teva B.V. 100 mg hard capsules are available in pack sizes of 20×1, 60×1, 120×1 or 180×1 hard capsules in perforated unit dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Teva B.V.

Swensweg 5

2031GA Haarlem

Netherlands

Manufacturer

Teva Pharmaceutical Works Private Limited Company

Pallagi ut 13

Debrecen H-4042

Hungary

TEVA UK Ltd Brampton Road Hampden Park Eastbourne, East Sussex BN22 9AG United Kingdom

Teva Czech Industries s.r.o.

Ostravska 29, c.p. 305, 74770

Opava-Komarov

Czech Republic

TEVA PHARMA, S.L.U.

C/C, n. 4, Poligono Industrial Malpica 50016 Zaragoza Spa­in

Merckle GmbH Graf-Arco-Str. 3, 89079 Ulm Germany

Teva Operations Poland Sp. z o.o. ul. Mogilska 80, 31–546 Krakow Poland

PLIVA Croatia Ltd.

Prilaz baruna Filipovica 25 10000 Zagreb

Croatia

Khnpoç

Teva EXXaç A.E., EXXaSa

Tql: +30 210 72 79 099

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

Package leaflet: Information for the patient

Imatinib Teva B.V. 400 mg hard capsules

Imatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• – Keep this leaflet. You may need to read it again.

• – If you have any further questions, ask your doctor, pharmacist or nurse.

• – This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even i

their signs of illness are the same as yours.

– If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

• 1. What Imatinib Teva B.V. is and what it is used for

• 2. What you need to know before you take Imatinib Teva B.V.

• 3. How to take Imatinib Teva B.V.

• 4. Possible side effects

• 5. How to store Imatinib Teva B.V.

• 6. Contents of the pack and other information.

1. What Imatinib Teva B.V. is and what it is used for

Imatinib Teva B.V. is a medicine containing an active substance called imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed below. These include some types of cancer.

Imatinib Teva B.V. is a treatment for:

• - Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white cells

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

In adult patients, Imatinib Teva B.V. is intended for use in the most advanced phase of the disease (blast crisis). In children and adolescents, Imatinib Teva B.V. can be used in different phases of the disease (chronic, accelerated phase and blast crisis).

Imatinib Teva is also a treatment for adults and children for:

• - Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). Leukaemia

is a cancer of white blood cells. These white cells usually help the body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells.

inib Teva B.V. is also a treatment for adults for:

Myelodysplastic/my­eloproliferati­ve diseases (MDS/MPD). These are a group of blood diseases in which some blood cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL). These are blood diseases in which some blood cells (named eosinophils) start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells in a certain subtype of these diseases.

Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It arises from uncontrolled cell growth of the supporting tissues of these organs.

Dermatofibrosar­coma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin in which some cells start growing out of control. Imatinib Teva B.V. inhibits the growth of these cells. In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Teva B.V. works or why this medicine has been prescribed for you, ask your doctor.

2. What you need to know before you take Imatinib Teva B.V.

Imatinib Teva B.V. will only be prescribed to you by a doctor with experience in medicines to treat cancers or solid tumours.

Follow all your doctor’s instruc­tions carefully, even if they differ from the general information conta this leaflet.

Do not take Imatinib Teva B.V.

• – if you are allergic to imatinib or any of the other ingredients of this medicine (liste

  
  

If this applies to you, tell your doctor without taking Imatinib Teva B.V.

If you think you may be allergic but are not sure, ask your doctor for advice.

Warnings and precautions

Talk to your doctor before taking Imatinib Teva B.V.:

• – if you have or have ever had a liver, kidney or heart proble

  id has been removed.

  . This is because Imatinib Teva B.V.

  
  

• – if you are taking the medicine levothyroxine because yo

if you have ever had or might now have a hepatitis B in

could cause hepatitis B to become active again, which can be fatal in some cases. Patients will be

carefully checked by their doctor for signs of this infection before treatment is started.

If any of these apply to you, tell your doctor before taking Imatinib Teva B.V.

During treatment with Imatinib Teva B.V., tell your doctor straight away if you put on weight very quickly. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).

While you are taking Imatinib Teva B.V. your doctor will regularly check whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Teva B.V. is also a treatment for children with CML. There is no experience in children with CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

Some children and adolescents taking Imatinib Teva B.V. may have slower than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Teva B.V.

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

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby ask your doctor for advice before taking this medicine.

Imatinib Teva B.V. is not recommended during pregnancy unless clearly necessary as it may harm your baby. Your doctor will discuss with you the possible risks of taking Imatinib Teva B.V. during

pregnancy.

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

Do not breast-feed during the treatment with Imatinib Teva B.V.

Patients who are concerned about their fertility while taking Imatinib Teva B.V. are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, or use any tools or machines until you are feeling well again.

3. How to take Imatinib Teva B.V.

Your doctor has prescribed Imatinib Teva B.V. because you suffer from a serious c B.V. can help you to fight this condition.

However, always take this medicine exactly as your doctor or pharmacist has told you. It is important that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or pharmacist if you are not sure.

Do not stop taking Imatinib Teva B.V. unless your doctor tells you to. If you are not able to take the medicine as your doctor prescribed or you feel you do not need it anymore, contact your doctor straight away.

How much Imatinib Teva B.V. to take

Use in adults

Your doctor will tell you exactly how many capsules of Imatinib Teva B.V. to take.

If you are being treated for CML:

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

If you are being treated for GIST:

The starting dose is 400 mg, to be taken as one capsule once a day.

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your daily dose is 800 mg (2 capsules), you should take one capsule in the morning and a second capsule in the evening.

• ♦ < N

If you are being treated for Ph-positive ALL:

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

If you are being treated for MDS/MPD:

The starting dose is 400 mg, to be taken as one capsule once a day.

If you are being treated for HES/CEL:

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

you respond to treatment.

If you are being treated for DFSP:

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

Use in children and adolescents

The doctor will tell you how many capsules of Imatinib Teva B.V. to give to your child. The amount of Imatinib Teva B.V. given will depend on your child’s condition, body weight and height. The total daily dose in children must not exceed 800 mg with CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be split into two administrations (half in the morning and half in the evening).

When and how to take Imatinib Teva B.V.

• - Take Imatinib Teva B.V. with a meal. This will help protect you from stomach problems when taking Imatinib Teva B.V.

• - Swallow the capsules whole with a large glass of water. Do not open or crush the capsules unless you have difficulty in swallowing (e.g. in children).

• – If you are unable to swallow the capsules, you can open them up and pour the powder into a glass of still water or apple juice.

• – If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, you should handle the contents with caution in order to avoid skin-eye contact or inhalation. You should wash your hands immediately after opening the capsules.

How long to take Imatinib Teva B.V.

Keep taking Imatinib Teva B.V. every day for as long as your doctor tells you.

If you take more Imatinib Teva B.V. than you should

If you have accidentally taken too many capsules, talk to your doctor straight away. You may require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Teva B.V.

• – If you forget a dose, take it as soon as you remember. However if it is nearly time for the next dose, skip the missed dose.

• – Then continue with your normal schedule.

• – Do not take a double dose to make up a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the following:

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people):

• Rapid weight gain. Imatinib Teva B.V. may cause your body to retain water (severe fluid retention).
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Teva B.V. can

reduce the number of white blood cells, so you might get infections more easily.

• Unexpected bleeding or bruising (when you have not hurt yourself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

• Chest pain, irregular heart rhythm (signs of heart problems).
• Cough, having difficulty breathing or painful breathing (signs of lung problems).
• Feeling light-headed, dizzy or fainting (signs of low blood pressure).
• Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of liver

problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of gastrointestinal disorders).

Severely decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel problems). Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain) Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels o cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in your hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syn­drome).

Sudden swelling and redness of the skin (signs of a skin infection called cellulitis).

Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and calcium levels and low phosphorous levels in the blood).

Not known (frequency cannot be estimated from the available data):

• Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic reaction).
• Chronic renal failure.
• Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a liver infection).

Very common (may affect more than 1 in 10 people):

Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

le cramps or joint, muscle or bone pain, during treatment with Imatinib Teva B.V. or after you stopped taking Imatinib Teva B.V.

Swelling such as round your ankles or puffy eyes.

Weight gain.

If any of these affects you severely, tell your doctor.

Common (may affect up to 1 in 10 people):

• Anorexia, weight loss or a disturbed sense of taste.
• Feeling dizzy or weak.
• Difficulty in sleeping (insomnia).
• Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or having blurred vision.
• Nose bleeds.
• Pain or swelling in your abdomen, flatulence, heartburn or constipation.
• Itching.
• Unusual hair loss or thinning.
• Numbness of the hands or feet.
• Mouth ulcers.
• Joint pain with swelling.
• Dry mouth, dry skin or dry eye.
• Decreased or increased skin sensitivity.
• Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

• Reddening and/or swelling on the palms of the hands and soles of the feet which may be accompanied by tingling sensation and burning pain.
• Slowing of growth in children and adolescents.

If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Imatinib Teva B.V.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of the month.

Store below 30°C.

Do not use any pack that is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Imatinib Teva B.V. contains

• – The active substance is imatinib (as mesilate).

• – Each hard capsule of Imatinib Teva B.V. contains 400 mg imatinib (as mesilate).

• – The other ingredients are mannitol, crospovidone, magnesium stearate and silica colloidal anhydrous.