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Drugs List
Therapeutic Indications
Dosage
Administration
Contraindications
Precautions and Warnings
Pregnancy and Lactation
Side Effects
Monograph

Therapeutic Indications

Uses

Advanced hypereosinophilic syndrome
Chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFR alpha rearrangement
Kit(CD117)+ve unresectable and/or metastatic GI stromal tumours (GIST)
Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements
Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia
Philadelphia chromosome positive (Ph+) chronic myeloid leukaemia (CML)
Unresectable dermatofibrosarcoma protuberans (DFSP)

Treatment of 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.

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

Treatment of patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy.

Treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.

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

Treatment of adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with FIP1L1-PDGFR-alpha rearrangement.

Treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST).

Adjuvant treatment of adult patients at risk of relapse following resection of Kit (CD 117) positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant treatment.

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

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

Dosage

Adults
Children
Patients with Renal Impairment
Patients with Hepatic Impairment
Additional Dosage Information

Chronic myeloid leukaemia

Patients in chronic phase CML

The recommended dose is 400mg/day, increasing if necessary up to a maximum of 800mg/day (as 400mg twice a day).

Chronic phase CML is defined when all of the following criteria are met: blasts less than 15% in blood and bone marrow, peripheral blood basophils less than 20%, platelets more than 100 x 10 to the power of 9 per litre.

Patients in accelerated phase CML

The recommended dose is 600mg/day, increasing if necessary up to a maximum of 800mg/day (as 400mg twice a day).

Accelerated phase is defined by the presence of any of the following: blasts equal to or more than 15% but less than 30% in blood or bone marrow, blasts plus promyelocytes equal to or more than 30% in blood or bone marrow (providing less than 30% blasts), peripheral blood basophils equal to or more than 20%, platelets less than 100 x 10 to the power of 9 per litre unrelated to therapy.

Patients in blast crisis

The recommended dose is 600mg/day, increasing if necessary up to a maximum of 800mg/day (as 400mg twice a day).

Blast crisis is defined as blasts equal to or more than 30% in blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Dose increases for chronic phase CML, accelerated phase CML and blast crisis

Increases above the initial recommended dose 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
Loss of a previously achieved haematological/cytogenetic response

Patients should be monitored closely following dose escalation given the potential for an increased incidence of adverse events at higher dosages.

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.

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL)

The recommended dose is 600mg/day when used in combination with chemotherapy for newly diagnosed Ph+ALL (in induction, consolidation and maintenance phase) or as monotherapy for relapsed or refractory Ph+ALL.

Treatment duration varies, however, longer treatment duration is associated with better treatment results.

Myelodysplastic / myeloproliferative diseases (MDS/MPD)

The recommended dose is 400mg/day continued until disease progression.

Advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL)

The recommended dose is 100mg/day increasing to a maximum of 400mg/day in the absence of adverse reactions if assessments demonstrate an insufficient response to therapy. Treatment should continue for as long as the patient continues to benefit.

Gastro-intestinal stromal tumours (GIST)

The recommended dose is 400mg/day for patients with unresectable and/or metastatic malignant gastro-intestinal stromal tumours.
In clinical trials treatment with imatinib was continued until disease progression and the median treatment duration was 7 months. The effect of stopping treatment after the achievement of a response has not been investigated.

The recommended dose is 400mg/day for adjuvant treatment of adults following resection of GIST. Optimal duration of treatment has not been established. Treatment duration was 36 months in clinical trials.

Dermatofibrosarcoma protuberans (DFSP)

The recommended dose is 800mg/day (as 400mg twice a day).

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 more than 3 x institutional upper limit of normal (ULN) or in liver transaminases more than 5 x ULN occur, imatinib should be withheld until bilirubin levels have returned to less than 1.5 x ULN and transaminase levels to less than 2.5 x ULN. Treatment with imatinib may then be continued at a reduced daily dose:
800mg reduced to 600mg for adults OR
600mg reduced to 400mg for adults OR
400mg reduced to 300mg for adults OR
340mg reduced to 260mg/metre squared BSA for children

Haematological adverse reactions

HES/CEL (starting dose 100mg in adults only)

Absolute neutrophil count (ANC) less than 1.0 x 10 to the power of 9 per litre and/or platelets less than 50 x 10 to the power of 9 per litre

Chronic phase CML (starting dose 400mg in adults or 340mg/metre squared for children), MDS/MPD, GIST and HES/CEL (at dose 400mg in adults only)

ANC less than 1.0 x 10 to the power of 9 per litre and/or platelets less than 50 x 10 to the power of 9 per litre

1. Stop imatinib until ANC is equal to or more than 1.5 x 10 to the power of 9 per litre and platelet count is equal to or more than 75 x 10 to the power of 9 per litre.
2. Resume treatment with imatinib at the previous dose before the adverse reaction.
3. In the event of recurrence of ANC less than 1.0 x 10 to the power of 9 per litre and/or platelet count less than 50 x 10 to the power of 9 per litre, repeat step 1 and resume imatinib at reduced dose of 300mg in adults or 260mg/metre squared in children.

Accelerated phase CML and blast crisis (starting dose 600mg in adults or 340mg/metre squared for children) and Ph+ALL (starting dose 600mg in adults only)

ANC (occurring after at least 1 month of treatment) less than 0.5 x 10 to the power of 9 per litre and/or platelets less than 10 x 10 to the power of 9 per litre

1. Check whether cytopenia is related to leukaemia (marrow aspirate or biopsy).
2. If cytopenia is unrelated to leukaemia, reduce dose of imatinib to 400mg for adults or 260mg/metre squared for children.
3. If cytopenia persists for 2 weeks, reduce further to 300mg for adults or 200mg/metre squared for children.
4. If cytopenia persists for 4 weeks and is still unrelated to leukaemia, stop imatinib until ANC is equal to or more than 1 x 10 to the power of 9 per litre and platelet count is equal to or more than 20 x 10 to the power of 9 per litre, then resume treatment at 300mg for adults or 200mg/metre squared for children.

DFSP (dose of 800mg in adults only)

ANC less than 1.0 x 10 to the power of 9 per litre and/or platelets less than 50 x 10 to the power of 9 per litre

1. Stop imatinib until ANC is equal to or more than 1.5 x 10 to the power of 9 per litre and platelet count is equal to or more than 75 x 10 to the power of 9 per litre.
2. Resume treatment with imatinib at dose of 600mg.
3. In the event of recurrence of ANC less than 1.0 x 10 to the power of 9 per litre and/or platelet count less than 50 x 10 to the power of 9 per litre, repeat step 1 and resume imatinib at reduced dose of 400mg.

Precautions and Warnings

Children under 18 years
Neutrophil count below 1.0 x 10 to the power of 9 / L
Platelet count below 50 x 10 to the power of 9 / L
Predisposition to cardiac failure
Cardiac disorder
Dehydration
Galactosaemia
Glucose-galactose malabsorption syndrome
Hepatic impairment
Hereditary fructose intolerance
History of cardiac failure
History of hepatitis B
Lactose intolerance
Renal impairment

Post thyroidectomy: Monitor TSH if using replacement therapy
Advise ability to drive/operate machinery may be affected by side effects
Before initiating screen all patients for hepatitis B infection
Consider premedication with hypouricaemic agent
Hepatitis B: Refer prior to initiation to liver disease specialist
Maintain adequate hydration of patient prior / during treatment
Monitor growth of children during treatment
Not all available products are licensed for all age groups
Not all available products are licensed for all uses
Treatment to be initiated and supervised by a specialist
Oral solution with maltitol unsuitable in hereditary fructose intolerance
Some formulations contain lactose
Consult local policy on the safe use of oral anti-cancer drugs
Must be taken with food and water
Consider echocardiogram before treatment
Monitor renal function before treatment and regularly during treatment
Monitor blood counts regularly
Monitor closely patient at risk of cardiovascular disorders
Monitor for active hepatitis B during therapy and for several months after
Monitor for bleeding during treatment
Monitor for signs of rapid weight gain may indicate severe fluid retention
Monitor hepatic function regularly
Monitor patients for signs of tumour lysis syndrome
Monitor patients with cardiac disorders
Monitor urine output & renal function in patients at risk of renal failure
Risk of gastrointestinal haemorrhage
May cause growth retardation in children
Reactivation of hepatitis B may occur in chronic carriers
Consider discontinuing if gastric antral vascular ectasia (GAVE) occurs
Discontinue at first signs of thrombotic microangiopathy
Interrupt or reduce dose if significant leucopenia/thrombocytopenia occur
Interrupt therapy if elevations in bilirubin of > 3 x ULN occur
Interrupt therapy if hepatic transaminases > 5 times upper limit of normal
Interrupt therapy if severe non-haematological reaction occurs
Advise patient not to take St John's wort concurrently
Female: Contraception required during and for 15 days after treatment
Breastfeeding: Do not breastfeed during and for 15 days after treatment
Advise patient on appropriate sun protection methods
Advise patient to avoid exposure to direct sunlight

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib. TSH levels should therefore be closely monitored in such patients.

Presentation

Oral formulations containing imatinib (as mesilate)

Drugs List

GLIVEC 100mg tablets

GLIVEC 400mg tablets

imatinib 100mg capsules

imatinib 100mg tablets

imatinib 400mg capsules

imatinib 400mg tablets

imatinib 80mg/ml oral solution sugar-free