Posology : מינונים

4.2 Posology and method of administration
Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate.
For doses other than 400 mg and 800 mg (see dosage recommendation below) a 100 mg divisible tablet is available.
For doses of 400 mg and above (see dosage recommendation below) a 400 mg tablet (not divisible) is available.
The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in the evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
Treatment should be continued as long as the patient continues to benefit.
Monitoring of response to Glivec therapy in Ph+ CML patients should be performed routinely and when therapy is modified, to identify suboptimal response, loss of response to therapy, poor patient compliance, or possible drug-drug interaction. Results of monitoring should guide appropriate CML management.

Posology for CML in adult patients
The recommended dosage of Glivec is 400 mg/day for adult patients in chronic phase CML. Chronic phase CML is defined when all of the following criteria are met: blasts < 15% in blood and bone marrow, peripheral blood basophils < 20%, platelets > 100 x 109/l. The recommended dosage of Glivec is 600 mg/day for adult patients in accelerated phase. Accelerated phase is defined by the presence of any of the following: blasts ≥ 15% but < 30% in blood or bone marrow, blasts plus promyelocytes ≥30% in blood or bone marrow (providing < 30% blasts), peripheral blood basophils ≥20%, platelets < 100 x 109/l unrelated to therapy.
The recommended dose of Glivec is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.


Treatment duration: In clinical trials, treatment with Glivec was continued until disease progression.
The effect of stopping treatment after the achievement of a complete cytogenetic response has not been investigated.
Dose increases from 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to GLI FCT API May23 V17                                                                      EU SmPC March 2022

achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved hematological 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.
See section on special populations for children.

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 600 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).
Glivec is not indicated for children under 3 years of age.

Posology for Ph+ ALL in adult patients
The recommended dose of Glivec is 600 mg/day for adult patients with Ph+ ALL.
Haematological experts in the management of this disease should supervise the therapy throughout all phases of care.
Treatment schedule: On the basis of the existing data, Glivec has been shown to be effective and safe when administered at 600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly diagnosed Ph+ ALL. The duration of Glivec therapy can vary with the treatment programme selected, but generally longer exposures to Glivec have yielded better results.
For adult patients with relapsed or refractory Ph+ALL Glivec monotherapy at 600 mg/day is safe, effective and can be given until disease progression occurs.

Posology for MDS/MPD
The recommended dose of Glivec is 400 mg/day for adult patients with MDS/MPD.
Treatment duration: In the only clinical trial performed up to now, treatment with Glivec was continued until disease progression (see section 5.1). At the time of analysis, the treatment duration was a median of 47 months (24 days - 60 months).

Posology for ASM
The recommended dose of Glivec is 400 mg/day for adult patients with ASM without the D816V KIT mutation. or mutational status unknown or not responding satisfactorily to other therapies.
For patients with ASM associated with eosinophilia, a clonal haematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

Posology for HES/CEL
The recommended dose of Glivec is 400 mg/day for adult patients with HES/CEL.
For HES/CEL patients with demonstrated FIP1L1-PDGFR-alpha fusion kinase, a starting dose of 100 mg/day is recommended. 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.


GLI FCT API May23 V17                                                                    EU SmPC March 2022

Posology for GIST
The recommended dose of Glivec is 400 mg/day for adult patients with unresectable and/or metastatic malignant GIST.
Limited data exist on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing at the lower dose (see section 5.1).
Treatment duration: In clinical trials in GIST patients, treatment with Glivec was continued until disease progression. At the time of analysis, the treatment duration was a median of 7 months (7 days to 13 months). The effect of stopping treatment after achieving a response has not been investigated.
The recommended dose of Glivec is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the clinical trial supporting this indication was 36 months (see section 5.1).

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

Dose adjustment for adverse reactions
Non-haematological adverse reactions
If a severe non-haematological adverse reaction develops with Glivec use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with Glivec may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg, or from 600 to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m2/day.

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

Dose adjustments for neutropenia and thrombocytopenia:
ASM      associated      with ANC < 1.0 x109/l 1. Stop Glivec until ANC ≥ 1.5 x109/l and eosinophilia                  and/or              platelets ≥ 75 x109/l.
HES/CEL(starting         dose platelets < 50 2. Resume treatment with Glivec at 100mg)                        x109/l              previous dose (i.e. before severe adverse reaction).

Chronic      phase     CML,     ANC < 1.0 x109/l 1. Stop Glivec until ANC ≥ 1.5 x109/l and MDS/MPD, ASM and GIST           and/or               platelets ≥ 75 x109/l (starting dose 400 mg)          platelets < 50 2. Resume treatment with Glivec at HES/CEL(at dose 400mg)          x109/l               previous dose (i.e. before severe adverse reaction)
3. In the event of recurrence of ANC < 1.0 x109/l and/or platelets < 50 x109/L,
repeat step 1 and resume Glivec at reduced dose of 300 mg
GLI FCT API May23 V17                                                                      EU SmPC March 2022

Paediatric   chronic phase ANC < 1.0 x109/l 1. Stop Glivec until ANC ≥ 1.5 x109l and CML                        and/or              platelets ≥ 75 x109/l.
(at dose 340 mg/m2)        platelets < 50 2. Resume treatment with Glivec at x109/l              previous dose (i.e. before severe adverse reaction).
3. In the event of recurrence of ANC < 1.0 x109/l and/or platelets < 50 x109/L,
repeat step 1 and resume Glivec at reduced dose of 260 mg/m2.
Ph+CML:Accelerated Phase aANC < 0.5 1. Check whether cytopenia is related to and blast crisis and         x109/l                leukaemia (marrow aspirate or biopsy).
Ph+ ALL                     and/or            2. If cytopenia is unrelated to leukaemia, (starting dose 600 mg)       platelets < 10        reduce dose of Glivec to 400 mg.
9 x10 /l            3. If cytopenia persists for 2 weeks, reduce further to 300 mg.
4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC ≥ 1 x109/l and platelets ≥ 20 x109/l, then resume treatment at 300 mg.
a
Paediatric accelerated phase ANC               1.Check whether cytopenia is related to 9
CML and blast crisis < 0.5 x 10 /l                   leukaemia (marrow aspirate or 2
(starting dose 340 mg/m )    and/or                  biopsy).
platelets< 10 x 1 2.If cytopenia is unrelated to leukaemia,
09/l                    reduce dose of Glivec to 260 mg/m2.
3.If cytopenia persists for 2 weeks, reduce further to 200 mg/m2.
4.If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop Glivec until ANC ≥ 1 x 109/l and platelets
≥ 20 x 109/l, then resume treatment at
200 mg/m2.
DFSP                            ANC < 1.0 x109l 1. Stop Glivec until ANC ≥ 1.5 x109/l and (at dose 800 mg)                and/or             platelets ≥ 75 x109/L.
platelets < 50 2. Resume treatment with Glivec at 600 x109/l             mg
3. In the event of recurrence of ANC < 1.0 x109/l and/or platelets < 50 x109/l,
repeat step 1 and resume Glivec at reduced dose of 400 mg.
ANC = absolute neutrophil count a occurring after at least 1 month of treatment

Special populations:
Paediatric use: Glivec is not indicated for children with CML under 3 years of age.
For all other indications, Glivec is not indicated for children and adolescents under 18 years old.
The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less GLI FCT API May23 V17                                                                      EU SmPC March 2022

than 18 years of age have not been established in clinical trials.

Hepatic insufficiency:
Imatinib is mainly metabolized 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)
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.