Active Ingredient and Strength	IMATINIB MESYLATE 119.47 MG EQV IMATINIB - 100 MG
Dosage Form	CAPSULE
Manufacturer and Country	ADAMED PHARMA S.A. - POLAND
Registration Number	SIN15107P
Licence Holder	APEX PHARMA MARKETING PTE. LTD.
Forensic Classification	PRESCRIPTION ONLY MEDICINES
Anatomical Therapeutic Chemical (ATC) code	L01EA01

2 INDICATIONS

Imatinib – AFT is indicated for:

treatment of adult and paediatric patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukaemia (Ph+ CML) (for paediatric use see section DOSAGE REGIMEN AND ADMINISTRATION).
treatment of adult and paediatric patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy (for paediatric use see section DOSAGE REGIMEN AND ADMINISTRATION).
treatment of paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) integrated with chemotherapy.
treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
treatment of adult patients with Kit+ (CD117) unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).
adjuvant treatment of adult patients following complete gross resection of Kit+ GIST.

The effectiveness of Imatinib – AFT is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in relapsed or refractory adult Ph+ ALL, on objective response rates in unresectable and/or metastatic GIST and on recurrence free survival in adjuvant GIST (see PHARMACODYNAMICS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). Except in newly diagnosed chronic phase CML there are no controlled trials demonstrating increased survival.

3 DOSAGE REGIMEN AND ADMINISTRATION

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

The prescribed dose should be administered orally with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances. 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 capsules, their content may be dispersed in a glass of either still water or apple juice. The suspension should be administered immediately after preparation.

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

Monitoring of response to Imatinib – AFT 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.

3.1 DOSAGE IN CML

The recommended dosage of Imatinib – AFT is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis. The prescribed dose should be administered orally, once daily with a meal and a large glass of water.

Dose increase from 400 mg to 600 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg 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 achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response.

Dosing in pediatric patients should be on the basis of body surface area (mg/m²). The recommended dose of Imatinib – AFT for children with newly diagnosed Ph+ CML is 340 mg/m²/day (not to exceed 600 mg). Doses of 260 mg/m²/day and 340 mg/m²/day are recommended for children with chronic phase CML and advanced phase CML respectively, after failure of interferon-alpha therapy. However, the total daily dose in children should not exceed adult equivalent doses of 400 mg and 600 mg respectively. 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. There is no experience with the treatment of children below 2 years of age.

3.2 DOSAGE IN PH+ ALL

The recommended dose of Imatinib – AFT is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. See section on special populations for pediatric patients.

Dosing in pediatric patients should be on the basis of body surface area (mg/m²). The recommended dose of Imatinib – AFT to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m²/day (not to exceed 600 mg). Treatment can be given as a once daily dose. The dose recommendation is currently based on a small number of paediatric patients. See section on special populations for pediatric patients.

3.3 DOSAGE IN GIST

The recommended dose of Imatinib – AFT is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.

A dose increase from 400 mg to 600 mg or 800 mg for patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.

Treatment with Imatinib – AFT in GIST patients should be continued until disease progression.

The recommended dose of Imatinib – AFT 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.

3.4 DOSE ADJUSTMENTS FOR ADVERSE DRUG REACTIONS

Non-haematological adverse drug reactions

If a severe non-hematological adverse drug reaction develops with Imatinib – AFT 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 – AFT should be withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with Imatinib – AFT 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 pediatric patients from 260 to 200 mg/m²/day or from 340 to 260 mg/m²/day.

Haematological adverse drug reactions

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

3.5 SPECIAL POPULATION

Pediatric patients (below 18 years)

There is no experience with the use of Imatinib – AFT in pediatric patients with CML below 2 years of age and with Ph+ ALL below 1 year of age.

Dosing in pediatric patients 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 and advanced phase CML and Ph+ ALL (not to exceed the total dose of 600 mg daily). Treatment can be given as a once daily dose in CML and Ph+ ALL. In CML, alternatively the daily dose may be split into two administrations – one in the morning and one in the evening (see section Clinical Pharmacology – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Hepatic impairment

Imatinib is mainly metabolized by the liver. Patients with mild or moderate liver impairment should be given the minimum recommended dose of 400 mg daily, and patients with severe liver dysfunction should start at 300 mg daily. The dose can be reduced if not tolerated (see sections WARNINGS AND PRECAUTIONS, ADVERSE DRUG REACTIONS, AND CLINICAL PHARMACOLOGY – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Renal insufficiency

Imatinib and its metabolites are not significantly excreted via the kidney. Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg daily as starting dose (see section CLINICAL PHARMACOLOGY – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information). 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 section WARNINGS AND PRECAUTIONS – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information).

Geriatric patients (65 years or above)

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 the elderly.

4 CONTRAINDICATIONS

Use in patients with a hypersensitivity to the active substance or to any of the excipients is contraindicated.