Source: FDA, National Drug Code (US) Revision Year: 2020
Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.
Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.
Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.
Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown.
Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.
Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.
Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
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 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.
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 to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response.
The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m²/day (not to exceed 600 mg). Gleevec treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening. There is no experience with Gleevec treatment in children under 1 year of age.
The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
The recommended dose of Gleevec to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m²/day (not to exceed 600 mg). Gleevec treatment can be given as a once daily dose.
Determine PDGFRb gene rearrangements status prior to initiating treatment.
The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.
Determine D816V c-Kit mutation status prior to initiating treatment.
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.
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.
The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP.
The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. 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.
The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of Gleevec and three years of Gleevec were studied. In the patient population defined in Study 2, three years of Gleevec is recommended [see Clinical Studies (14.8)]. The optimal treatment duration with Gleevec is not known.
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 coadministered 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 (7.1)].
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 (8.6)].
Renal Impairment: Patients with moderate renal impairment (creatinine clearance [CrCL] = 20-39 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 = 40-59 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 was tolerated in two patients with severe renal impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.7)].
If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, Gleevec should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the 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.
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 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 less than 1.0 × 109/L and/or platelets less than 50 × 109/L | • Stop Gleevec until ANC greater than or equal to 1.5 × 109/L and platelets greater than or equal to 75 × 109/L • 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 less than 1.0 × 109/L and/or platelets less than 50 × 109/L | • Stop Gleevec until ANC greater than or equal to 1.5 × 109/L and platelets greater than or equal to 75 × 109/L • 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 400 mg) | ANC less than 1.0 × 109/L and/or platelets less than 50 × 109/L | • Stop Gleevec until ANC greater than or equal to 1.5 × 109/L and platelets greater than or equal to 75 × 109/L • Resume treatment with Gleevec at the original starting dose of 400 mg • If recurrence of ANC less than 1.0 × 109/L and/or platelets less than 50 × 109/L, repeat step 1 and resume Gleevec at a reduced dose of 300 mg |
| Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg) | ANC less than 0.5 × 109/L and/or platelets less than 10 × 109/L | • Check if cytopenia is related to leukemia (marrow aspirate or biopsy) • If cytopenia is unrelated to leukemia, reduce dose of Gleevec to 400 mg • If cytopenia persists 2 weeks, reduce further to 300 mg • If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Gleevec until ANC greater than or equal to 1 × 109/L and platelets greater than or equal to 20 × 109/L and then resume treatment at 300 mg |
| DFSP (starting dose 800 mg) | ANC less than 1.0 × 109/L and/or platelets less than 50 × 109/L | • Stop Gleevec until ANC greater than or equal to 1.5 × 109/L and platelets greater than or equal to 75 × 109/L • Resume treatment with Gleevec at 600 mg • In the event of recurrence of ANC less than 1.0 × 109/L and/or platelets less than 50 × 109/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 less than 1.0 × 109/L and/or platelets less than 50 × 109/L | • Stop Gleevec until ANC greater than or equal to 1.5 × 109/L and platelets greater than or equal to 75 × 109/L • Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) • In the event of recurrence of ANC less than 1.0 × 109/L and/or platelets less than 50 × 109/L, repeat step 1 and resume Gleevec at reduced dose of 260 mg/m² |
Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; DFSP, dermatofibrosarcoma protuberans; HES, hypereosinophilic syndrome; MDS/MPD, myelodysplastic/myeloproliferative diseases; PDGFR, platelet-derived growth factor receptor; Ph+ CML, Philadelphia chromosome positive chronic myeloid leukemia; Ph+ ALL, Philadelphia chromosome positive acute lymphoblastic leukemia.
Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment.
1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.
1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, GI pain.
6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.
8 to 10 g (single dose): Vomiting and GI pain have been reported.
A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.
One 3 year old male exposed to a single dose of 400 mg experienced vomiting, diarrhea, and anorexia; and another 3 year old male exposed to a single dose of 980 mg experienced decreased white blood cell (WBC) count and diarrhea.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Protect from moisture.
Dispense in a tight container, USP.
Do not crush Gleevec tablets. Avoid direct contact of crushed tablets with the skin or mucous membranes. If such contact occurs, wash thoroughly as outlined in the references. Avoid exposure to crushed tablets.
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