"The U.S. Food and Drug Administration today approved Iclusig (ponatinib) to treat adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), two rare blood and bone marrow diseases."...
Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML)
Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferonalpha (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.
Adult patients with Ph+ Acute Lymphoblastic Leukemia (ALL)
Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia.
Pediatric patients with Ph+ Acute Lymphoblastic Leukemia (ALL)
Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.
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)
Kit+ Gastrointestinal Stromal Tumors (GIST)
Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.
Adjuvant Treatment of GIST
Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
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 in CML and Ph+ ALL. Alternatively, in children with CML 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.
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 CP
The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m²/day (not to exceed 600 mg).
Adults Patients with Ph+ ALL
The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL.
Pediatric Patients with Ph+ ALL
The recommended dose of Gleevec to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340mg/m²/day (not to exceed 600mg).
The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD.
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.
Metastatic or Unresectable GIST
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]. The optimal treatment duration with Gleevec is not known.
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].
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].
Patients with moderate renal impairment (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, 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.
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
|ASM associated with eosinophilia (starting dose 100 mg)||ANC < 1.0 x 109/L
platelets < 50 x 109/L
|HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg)||ANC < 1.0 x 109/L
platelets < 50 x 109/L
|Chronic Phase CML (starting dose 400 mg)
MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg)
|ANC < 1.0 x 109/L
platelets < 50 x 109/L
|Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg)||ANC < 0.5 x 109/L
platelets < 10 x 109/L
|DFSP (starting dose 800 mg)||ANC < 1.0 x 109/L
platelets < 50 x 109/L
|Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m²)||ANC < 1.0 x 109/L
platelets < 50 x 109/L
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
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 90 tablets .NDC 0078-0401-34
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
Storage and Handling
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.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4
Gleevec tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets [see Nonclinical Toxicology].
Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. January 2013
Last reviewed on RxList: 2/21/2013
This monograph has been modified to include the generic and brand name in many instances.
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