Gleevec (imatinib mesylate) 100mg scored tablets, 400mg tablets

Manufacturer:  Novartis (Gleevec hotline 1-877-GLEEVEC or 1-877-453-3832)

Indication(s):  Treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) in chronic phase.  Also for treatment of Philadelphia chromosome positive CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.  Also for pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon alpha therapy.  Also indicated for treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).

Dosage & Administration :  Therapy should be initiated by a physician experienced in the treatment of patients with chronic myeloid leukemia.

Chronic Phase:  400mg/day for adult patients in chronic phase

Accelerated Phase or Blast Crisis Adults:  600mg/day

Pediatric Ph+ CML recurrent after stem cell transplant or resistant to interferon alpha therapy: 260mg/m2/day

Treatment should be continued as long as the patient continues to benefit.  Dosage may be increased by 200mg 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; loss of a previously achieved hematologic response.

Pharmacological Mechanism of Action: 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 chronic myeloid leukemia (CML).  It inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.  In colony formation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows inhibition of Bcr-Abl positive colonies from CML patients. 

In vivo, it 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.

In vitro studies demonstrate imatinib is not entirely selective; it also inhibits 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.

WebRx Editorial Notes:  The manufacturer states, "It should be noted that the effectiveness of Gleevec is based on overall hematologic and cytogenetic response rates.  There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival."  While this is true, the expectation is that there would be clinical benefit when controlled study results become available.

The cost of one month of Gleevec therapy can be several thousand dollars.

Gleevec seems to be metabolized, in large part by the CYP3A4 liver isoenzyme and is an inhibitor of CYP3A4, CYP2D6, and CYP2C9.  Gleevec increased the mean Cmax and AUC of simvastatin by 2- and 3.5 fold respectively.  Co-administration with ketoconazole can increase Cmax of Imatinib by 26% and AUC by 40%.  Drug interactions such as these are generally tried to be avoided.  However, due to the high price tag of imatinib, it seems that the time has come to explore the exploitation of such drug interactions as a means of reducing medication cost.  Perhaps ketoconazole is not the ideal candidate for such use but it seems that a drug that is otherwise inert, that inhibits CYP3A4, could have a major role in reducing costs of drug therapy in general when co-administered with another CYP3A4 metabolized entity.

2002-3 WebRx Pharmacy Palace

Page last updated 7/2003

The information contained on this page is abridged.  For more information about Gleevec (imatinib mesylate) please see the manufacturer's documentation.