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Gleevec (imatinib mesylate), marketed by Novartis, has received FDA approval for multiple disorders in both pediatric and adult patients. Gleevec's indications include newly diagnosed chronic-phase Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in pediatric and adult patients; patients in blast crisis, accelerated phase, or chronic phase Ph+ CML who have already failed interferon therapy; adults with relapsed or refractory Ph+ acute lymphoblastic leukemia; adults with myelodysplastic/myeloproliferative disease associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements; adults with aggressive systemic mastocytosis without mutation of the D816V c-Kit or unknown mutation status of the c-Kit; adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia with positive, negative, or unknown FIP1L1-PDGFRafusion kinase; adults with dermatofibrosarcoma protuberans that is unresectable, recurrent, and/or metastatic; and patients with malignant gastrointestinal stromal tumors that are unresectable and/or metastatic.1
Mechanism of Action
Gleevec exerts its effect as a proteintyrosine kinase inhibitor. In CML, the Philadelphia chromosome abnormality creates the BCR-ABL tyrosine kinase. Gleevec's inhibition of this enzyme inhibits proliferation and promotes apoptosis in both BCR-ABL-positive and leukemic cells. Other enzymes inhibited by Gleevec include the receptor tyrosine kinases for platelet-derived growth factor (PDGF), stem cell factor (SCF), and c- Kit. Gleevec has also been shown to inhibit cellular events mediated by PDGF and SCF.1
Gleevec is contraindicated in patients with a known hypersensitivity to any of its components. Gleevec is a Pregnancy Category D drug; women who are pregnant or may become pregnant should not use Gleevec.1 Patients with concomitant cardiac disease should be carefully monitored before and during treatment with Gleevec for signs of cardiac failure.2
Fluid retention and edema of the brain, eye, pericardium, abdomen, and lung have been associated with the use of Gleevec.2 Cases of hepatotoxicity have occurred with Gleevec; liver function should be assessed prior to the initiation of treatment and either monthly or as clinically appropriate during therapy. Should hepatotoxicity occur, a dose reduction may be appropriate.1
Rare but serious adverse reactions to Gleevec include sepsis, pneumonia, depression, convulsions, thrombosis, embolism, ileus, pancreatitis, hepatic failure, exfoliative dermatitis, angioedema, Stevens-Johnson syndrome, renal failure, fluid retention, hemorrhage, diverticulitis, gastrointestinal perforation, tumor hemorrhage or necrosis, hip osteonecrosis, and avascular necrosis.2
Coadministration of Gleevec with inhibitors of the CYP3A4 family may result in increased plasma concentrations of Gleevec. Examples of CYP3A4 inhibitors include ketoconazole, itraconazole, erythromycin, and clarithromycin.
Inducers of the CYP3A4 family may result in decreased plasma concentrations of Gleevec when the agents are administered together. Examples of CYP3A4 inducers include phenytoin, carbamazepine, rifampin, phenobarbital, or St. John's wort.
Concomitant use of Gleevec with CYP3A4 substrates may cause decreased levels of the substrate. Examples of CYP34 substrates include cyclosporine and simvastatin. Because warfarin is a CYP3A4 substrate, its use should be avoided in patients using Gleevec.1
Gleevec is available as 100-and 400-mg tablets. Individual doses are dependent upon the diagnosis and protocol for each condition. Gleevec should be taken with food.
In clinical trials, the most common side effects from Gleevec included nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, and rash. The occurrence of edema was usually manageable through treatment with diuretics; edema can be more serious in some patients, however. Patients should be educated on the signs of edema and fluid overload and should immediately report any sudden weight gain to their health care professional.1
Dr. Holmberg is a pharmacist with Phoenix Children's Hospital, Phoenix, Ariz.
1. Gleevec. Complete prescribing information. Available at: www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf. Accessed February 2007.
2. Glivec demonstrates highest five-year overall survival rate in history of treatment of patients with chronic myeloid leukemia. Available at: www.novartis.com/newsroom/index.shtml. Accessed February 2007.