Imatinib

Gleevec is a kinase inhibitor indicated for the treatment of: 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 (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) 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 (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events.

Adults with Ph+ CML CP: 400 mg/day Adults with Ph+ CML AP or BC: 600 mg/day Pediatrics with Ph+ CML CP: 340 mg/m 2 /day Adults with Ph+ ALL: 600 mg/day Pediatrics with Ph+ ALL: 340 mg/m 2 /day Adults with MDS/MPD: 400 mg/day Adults with ASM: 100 mg/day or 400 mg/day Adults with HES/CEL: 100 mg/day or 400 mg/day Adults with DFSP: 800 mg/day Adults with metastatic and/or unresectable GIST: 400 mg/day Adjuvant treatment of adults with GIST: 400 mg/day Patients with mild to moderate hepatic impairment: 400 mg/day Patients with severe hepatic impairment: 300 mg/day All doses of Gleevec should be taken 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. Gleevec can be dissolved in water or apple juice for patients having difficulty swallowing.

None. None.

Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics. Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction, dose interruption, or discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter. Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Monitor and treat patients with cardiac disease or risk factors for cardiac failure. Severe hepatotoxicity, including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated.

The following serious adverse reactions are described elsewhere in the labeling: Fluid Retention and Edema Hematologic Toxicity Congestive Heart Failure and Left Ventricular Dysfunction Hepatotoxicity Hemorrhage Gastrointestinal Disorders Hypereosinophilic Cardiac Toxicity Dermatologic Toxicities Hypothyroidism Growth Retardation in Children and Adolescents Tumor Lysis Syndrome Impairments Related to Driving and Using Machinery Renal Toxicity The most frequently reported adverse reactions (greater than or equal to 30%) are edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain.

CYP3A4 inducers may decrease Gleevec C max and area under curve (AUC). CYP3A4 inhibitors may increase Gleevec C max and AUC. Gleevec is an inhibitor of CYP3A4 and CYP2D6 which may increase the C max and AUC of other drugs. Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin. Gleevec may delay the clearance of methotrexate when methotrexate is used at high doses (> 500 mg/m 2 ).

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). Protect from moisture.