Imatinib Dosage

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Usual Adult Dose for Chronic Myelogenous Leukemia

Chronic phase: 400 mg orally once a day.
Accelerated phase: 600 mg orally once a day.

Disease progression chronic phase: 600 mg orally once a day.
Disease progression accelerated phase: 400 mg orally twice a day.

A dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least three months of treatment, failure to achieve a cytogenetic response after six to twelve months of treatment, or loss of a previously achieved hematologic or cytogenetic response.

Dose adjustments for Chronic Phase CML (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg or 600 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg).

Dose adjustments for Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg)
ANC less than 0.5 x 10(9)/L and/or Platelets less than 10 x 10(9)/L:
1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy).
2. If cytopenia is unrelated to leukemia, reduce dose of imatinib to 400 mg.
3. If cytopenia persists 2 weeks, reduce further to 300 mg.
4. If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib until ANC greater than or equal to 1 x 10(9)/L and platelets greater than or equal to 20 x 109/L and then resume treatment at 300 mg.

Usual Adult Dose for Gastrointestinal Stromal Tumor

For adult patients with unresectable and/or metastatic, malignant GIST:
Recommended dose: 400 mg/day
A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions.

For the adjuvant treatment of adult patients following complete gross resection of GIST:
Recommended dose: 400 mg/day
In the clinical study, imatinib was administered for one year. The optimal treatment duration with imatinib is not known.

Dose adjustments for GIST (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose of 300 mg.

Usual Adult Dose for Acute Lymphoblastic Leukemia

For use in the treatment of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL):

Recommended dose: 600 mg/day for adult patients with relapsed/refractory Ph+ ALL

Dose adjustments for ALL (starting dose 600 mg)
ANC less than 0.5 x 10(9)/L and/or Platelets less than 10 x 10(9)/L:
1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy).
2. If cytopenia is unrelated to leukemia, reduce dose of imatinib to 400 mg.
3. If cytopenia persists 2 weeks, reduce further to 300 mg.
4. If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib until ANC greater than or equal to 1 x 10(9)/L and platelets greater than or equal to 20 x 109/L and then resume treatment at 300 mg.

Usual Adult Dose for Systemic Mastocytosis

Recommended dose: 400 mg/day for patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with imatinib 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies.

Dose adjustments for ASM (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg or 600 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg).

For patients with ASM associated with eosinophilia (a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRalpha):
Recommended starting dose: 100 mg/day
A 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.

Dose adjustments for ASM associated with eosinophilia (starting dose 100 mg)
ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction).

Usual Adult Dose for Hypereosinophilic Syndrome

For patients with hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL):
Recommended dose: 400 mg/day

Dose adjustments for HES/CEL (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg or 600 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg).

For patients with HES/CEL patients with demonstrated FIP1L1-PDGFRalpha fusion kinase:
Recommended starting dose: 100 mg/day
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.

Dose adjustments for HES/CEL with FIP1L1-PDGFRalpha fusion kinase (starting dose 100 mg)
ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction).

Usual Adult Dose for Chronic Eosinophilic Leukemia

For patients with hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL):
Recommended dose: 400 mg/day

Dose adjustments for HES/CEL (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg or 600 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg).

For patients with HES/CEL patients with demonstrated FIP1L1-PDGFRalpha fusion kinase:
Recommended starting dose: 100 mg/day
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.

Dose adjustments for HES/CEL with FIP1L1-PDGFRalpha fusion kinase (starting dose 100 mg)
ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction).

Usual Adult Dose for Dermatofibrosarcoma Protuberans

Recommended dose: 800 mg/day for patients with dermatofibrosarcoma protuberans (DFSP)

Dose adjustments for DFSP (starting dose 800 mg)
ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 X 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at 600 mg.
3. In the event of recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at reduced dose of 400 mg.

Usual Adult Dose for Myeloproliferative Disorders

Recommended dose: 400 mg/day for patients with myelodysplastic/myeloproliferative diseases (MDS/MPD)

MDS/MPD (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg or 600 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg).

Usual Adult Dose for Myelodysplastic Diseases

Recommended dose: 400 mg/day for patients with myelodysplastic/myeloproliferative diseases (MDS/MPD)

MDS/MPD (starting dose 400 mg)
ANC less than 1.0 x 10(9)/L and/or Platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at the original starting dose of 400 mg or 600 mg.
3. If recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg).

Usual Pediatric Dose for Chronic Myelogenous Leukemia

Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase:

340 mg/m2 orally once a day or 170 mg/m2 orally twice a day

Maximum Dose: 600 mg daily

Duration of therapy: Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Comments: There is no experience with imatinib treatment in children under 1 year of age.

Dose adjustments for newly diagnosed pediatric chronic phase CML (starting dose 340 mg/m2):

ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L:
1. Stop imatinib until ANC greater than or equal to 1.5 x 10(9)/L and platelets greater than or equal to 75 x 10(9)/L.
2. Resume treatment with imatinib at previous dose (i.e. before severe adverse reaction).
3. In the event of recurrence of ANC less than 1.0 x 10(9)/L and/or platelets less than 50 x 10(9)/L, repeat step 1 and resume imatinib at reduced dose of 260 mg/m2.

Usual Pediatric Dose for Acute Lymphoblastic Leukemia

Newly diagnosed Ph+ ALL in combination with chemotherapy:

340 mg/m2 orally once a day

Maximum Dose: 600 mg once a day

Duration of therapy: Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

Comments: There is no experience with imatinib treatment in children under 1 year of age.

Renal Dose Adjustments

Patients with moderate renal impairment (CrCl = 20 to 39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCl = 40 to 59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day has been tolerated in two patients with severe renal impairment.

Liver Dose Adjustments

Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

If severe hepatotoxicity develops, the dose should be withheld until condition resolves. If elevations in bilirubin greater than 3 times the upper limit of normal (ULN) or liver transaminases greater than 5 times the ULN occur, the dose should be withheld until bilirubin returns to less than 1.5 ULN and transaminases to less than 2.5 ULN, at which time treatment may be resumed with a reduced dose (i.e. 400 mg reduced to 300 mg; 600 mg reduced to 400 mg).

Precautions

Imatinib has often been associated with edema and occasionally serious fluid retention. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. Unexpected rapid weight gain should be carefully investigated and appropriate treatment should be provided.

Cases of cardiogenic shock / left ventricular dysfunction have been associated with the initiation of imatinib therapy in patients with hypereosinophilic syndrome and cardiac involvement. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1 to 2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy.

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

Thrombocytopenia, neutropenia and anemia often occur during treatment and are more frequent in accelerated phase CML and blast crisis. Complete blood counts should be obtained weekly during the first month, biweekly during the second month, and thereafter as clinically appropriate.

Imatinib has occasionally been associated with severe hepatotoxicity. Liver function tests (transaminases, bilirubin, and alkaline phosphatase) should be monitored at baseline and at monthly intervals or as clinically appropriate. Abnormal results may be managed by interrupting treatment or decreasing the dose.

Growth retardation occurring in children receiving imatinib has been reported. Close monitoring of growth in children under imatinib treatment is recommended. Growth retardation occurring in children receiving imatinib has been reported. Close monitoring of growth in children under imatinib treatment is recommended.

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

Tumor Lysis Syndrome, including fatal cases, have been reported. Close monitoring is recommended.

Safety and efficacy have not been established in children less than 2 years old.

Dialysis

Data not available

Other Comments

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

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. For daily dosing of 800 mg and above, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.

In children, imatinib treatment can be given as a once-daily dose or alternatively the daily dose may be split into two, once in the morning and once in the evening. There is no experience with imatinib treatment in children less than 2 years of age.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of 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).

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