Gleevec
INDICATIONS
Newly Diagnosed Philadelphia Dositive Chronic Myeloid Leukemia (Ph+ CML)
Newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase. Follow-up is limited to 5 years.
Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy
Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
Pediatric Patients with Ph+ CML in Chronic Phase
Pediatric patients with Ph+ CML in chronic phase who are newly diagnosed or whose disease has recurred after stem cell transplant or who are resistant to interferon-therapy. There are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Ph+ Acute Lymphoblastic Leukemia (ALL)
Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia
Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)
Adult patients with myelodysplastic/ myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements
Aggressive Systemic Mastocytosis (ASM)
Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL)
Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown
Dermatofibrosarcoma Protuberans (DFSP)
Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans
Kit+ Gastrointestinal Stromal Tumors (GIST).
Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. The effectiveness of Gleevec in GIST is based on objective response rate [see Clinical Studies]. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
DOSAGE AND ADMINISTRATION
Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies or malignant sarcomas, as appropriate. 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.
In children, Gleevec 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 Gleevec treatment in children under 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).
For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron.
Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.
Adult Patients with Ph+ CML CP, AP and BC
The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis.
In CML, 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 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.
Pediatric Patients with Ph+ CML
The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg). The recommended Gleevec dose is 260 mg/m2/day for children with Ph+ chronic phase CML recurrent after stem cell transplant or who are resistant to interferon-alpha therapy.
Ph+ ALL
The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
MDS/MPD
The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.
ASM
The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Gleevec 400 mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological 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.
HES/CEL
The recommended dose of Gleevec is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, 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.
DFSP
The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.
GIST
The recommended dose of Gleevec is 400 mg/day or 600 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.
Dose Modification Guidelines
Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Gleevec should be increased by at least 50%, and clinical response should be carefully monitored. [see DRUG INTERACTIONS]
Hepatic Impairment: 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. [See Use in Specific Populations]
Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Gleevec should be withheld until bilirubin levels have returned to a < 1.5 x IULN and transaminase levels to < 2.5 x IULN. In adults, treatment with Gleevec may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day or from 260 mg/m2/day to 200 mg/m2/day, respectively.
If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Gleevec should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
Dose Adjustment for Hematologic Adverse Reactions
Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.
Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia
| ASM associated with eosinophilia (starting dose 100 mg) | ANC < 1.0 x109/L and/or platelets < 50 x109/L | 1. Stop Gleevec until ANC ≥ 1.5 x109/L and
platelets ≥ 75 x109/L. 2. Resume treatment with Gleevec at previous dose (i.e. dose before severe adverse reaction). |
| HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) | ANC < 1.0 x 109/L and/or platelets < 50 x109/L | 1. Stop Gleevec until ANC ≥ 1.5 x109/L and platelets ≥
75 x109/L. 2. Resume treatment with Gleevec at previous dose (i.e. dose before severe adverse reaction). |
| Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose either 400 mg or 600 mg) |
ANC < 1.0 x 109/L and/or platelets < 50 x 109/L | 1. Stop Gleevec until ANC ≥ 1.5 x 109/L and platelets ≥ 75
x 109/L 2. Resume treatment with Gleevec at the original starting dose of 400 mg or 600 mg 3.If recurrence of ANC < 1.0 x 109/L and/or platelets < 50 x 109/L, repeat step 1 and resume Gleevec at a reduced dose (300 mg if starting dose was 400 mg, 400 mg if starting dose was 600 mg) |
| Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL(starting dose 600 mg) |
ANC < 0.5 x 109/L and/or platelets < 10 x 109/L | 1. Check if cytopenia is related to leukemia (marrow aspirate or biopsy)
2. If cytopenia is unrelated to leukemia, reduce dose of Gleevec 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 Gleevec until ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L and then resume treatment at 300 mg |
| DFSP(starting dose 800 mg) | ANC < 1.0 x109/L and/or platelets < 50 x109/L | 1. Stop Gleevec until ANC ≥ 1.5 x109/L and platelets ≥
75 x109/L. 2. Resume treatment with Gleevec at 600 mg 3. In the event of recurrence of ANC < 1.0 x109/L and/or platelets < 50 x109/L, repeat step 1 and resume Gleevec at reduced dose of 400 mg. |
| Pediatric newly diagnosed chronic phase CML(starting dose 340 mg/m2) | ANC < 1.0 x109/L and/or platelets < 50 x109/L | 1. Stop Gleevec until ANC ≥ 1.5 x109/L and platelets ≥
75 x109/L. 2. Resume treatment with Gleevec at previous dose (i.e. dose 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 Gleevec at reduced dose of 260 mg/m2 |
| Pediatric patients with chronic phase CML recurring after transplant or resistant to Interferon (starting dose 260 mg/m2) | ANC < 1.0 x109/L and/or platelets < 50 x109/L | 1. Stop Gleevec until ANC ≥ 1.5 x109/L and platelets ≥
75 x109/L. 2. Resume treatment with Gleevec at previous dose (i.e. dose 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 Gleevec at reduced dose of 200 mg/m2 |
Dosage Forms And Strengths
100 mg film coated tablets
Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side
400 mg film coated tablets
Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score
HOW SUPPLIED
Storage And Handling
Each film-coated tablet contains 100 mg or 400 mg of imatinib free base.
100 mg Tablets
Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with “NVR” on one side, and “SA” with score on the other side.
Bottles of 100 tablets..............NDC 0078-0401-05
400 mg Tablets
Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with “400” on one side with score on the other side, and “SL” on each side of the score.
Bottles of 30 tablets..............NDC 0078-0438-15
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP.
Manufactured by: Novartis Pharma. Stein, AG Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation., East Hanover, New Jersey 07936. FDA Rev date: 9/13/2007
Generic Name: Imatinib Mesylate
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