Gleevec (imatinib mesylate), marketedby Novartis, has received FDA approvalfor multiple disorders in bothpediatric and adult patients. Gleevec'sindications include newly diagnosedchronic-phase Philadelphia chromosomepositive chronic myeloid leukemia(Ph+ CML) in pediatric and adult patients;patients in blast crisis, acceleratedphase, or chronic phase Ph+ CMLwho have already failed interferon therapy;adults with relapsed or refractoryPh+ acute lymphoblastic leukemia;adults with myelodysplastic/myeloproliferativedisease associated withplatelet-derived growth factor receptor(PDGFR) gene rearrangements; adultswith aggressive systemic mastocytosiswithout mutation of the D816V c-Kit orunknown mutation status of the c-Kit;adults with hypereosinophilic syndromeand/or chronic eosinophilic leukemiawith positive, negative, or unknownFIP1L1-PDGFRafusion kinase; adultswith dermatofibrosarcoma protuberansthat is unresectable, recurrent, and/ormetastatic; and patients with malignantgastrointestinal stromal tumors that areunresectable and/or metastatic.1
Mechanism of Action
Gleevec exerts its effect as a proteintyrosinekinase inhibitor. In CML, thePhiladelphia chromosome abnormalitycreates the BCR-ABL tyrosine kinase.Gleevec's inhibition of this enzymeinhibits proliferation and promotesapoptosis in both BCR-ABL-positiveand leukemic cells.Other enzymes inhibited by Gleevecinclude the receptor tyrosine kinasesfor platelet-derived growth factor(PDGF), stem cell factor (SCF), and c-Kit. Gleevec has also been shown toinhibit cellular events mediated byPDGF and SCF.1
Gleevec is contraindicated in patientswith a known hypersensitivity toany of its components. Gleevec is aPregnancy Category D drug; womenwho are pregnant or may becomepregnant should not use Gleevec.1Patients with concomitant cardiac diseaseshould be carefully monitoredbefore and during treatment withGleevec for signs of cardiac failure.2
Fluid retention and edema of thebrain, eye, pericardium, abdomen, andlung have been associated with the useof Gleevec.2 Cases of hepatotoxicityhave occurred with Gleevec; liver functionshould be assessed prior to the initiationof treatment and either monthlyor as clinically appropriate during therapy.Should hepatotoxicity occur, adose reduction may be appropriate.1
Rare but serious adverse reactions toGleevec include sepsis, pneumonia,depression, convulsions, thrombosis,embolism, ileus, pancreatitis, hepaticfailure, exfoliative dermatitis, angioedema,Stevens-Johnson syndrome, renalfailure, fluid retention, hemorrhage,diverticulitis, gastrointestinal perforation,tumor hemorrhage or necrosis, hiposteonecrosis, and avascular necrosis.2
Coadministration of Gleevec withinhibitors of the CYP3A4 family mayresult in increased plasma concentrationsof Gleevec. Examples of CYP3A4inhibitors include ketoconazole, itraconazole,erythromycin, and clarithromycin.
Inducers of the CYP3A4 family mayresult in decreased plasma concentrationsof Gleevec when the agents areadministered together. Examples ofCYP3A4 inducers include phenytoin,carbamazepine, rifampin, phenobarbital,or St. John's wort.
Concomitant use of Gleevec withCYP3A4 substrates may cause decreasedlevels of the substrate. Examplesof CYP34 substrates includecyclosporine and simvastatin. Becausewarfarin is a CYP3A4 substrate, its useshould be avoided in patients usingGleevec.1
Gleevec is available as 100-and 400-mg tablets. Individual doses aredependent upon the diagnosis andprotocol for each condition. Gleevecshould be taken with food.
In clinical trials, the most commonside effects from Gleevec included nausea,vomiting, muscle cramps, musculoskeletalpain, diarrhea, and rash. Theoccurrence of edema was usually manageablethrough treatment with diuretics;edema can be more serious in somepatients, however. Patients should beeducated on the signs of edema andfluid overload and should immediatelyreport any sudden weight gain to theirhealth care professional.1
Dr. Holmberg is a pharmacist withPhoenix 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 ofpatients with chronic myeloid leukemia. Available at:www.novartis.com/newsroom/index.shtml. Accessed February 2007.