Medication Adverse Effect Alert

October 20, 2006

MEDICATION: imatinib mesylate (Gleevec®)

Description:	Initially approved for use in treating Philadelphia chromosome-positive chronic myeloid leukemia and gastrointestinal stromal tumors. On October 19, 2006, the manufacturer, Novartis, announced that imatinib has also been granted approval to treat Philadelphia chromosome-positive acute lymphoblastic leukemia, hypereosinophilic syndrome, aggressive systemic mastocytosis and certain forms of myeloproliferative disorders.
Dosage:	Available as tablets and capsule
Manufacturer:	Novartis
Strength:	Tablets 100mg, 400mg and capsule 100mg

Event Description: Under FDA direction, Novartis has revised the PRECAUTIONS section of the prescribing information for imatinib and has sent out a "Dear Healthcare Professional" letter to warn about the potential for severe congestive heart failure and left ventricular dysfunction that has been reported in patients taking imatinib.

Description of Adverse Events A recent online article by Nature Medicine (Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Kerkela R, Grazette L, Yacobi R, et al., Nature Medicine; advance online publication, July 23, 2006) reports that 10 imatinib treated patients had developed severe congestive heart failure and left ventricular dysfunction. Prior to imatinib treatment, all 10 of these patients had New York Heart functional class 1 and normal left ventricular ejection fractions. However, most of these patients has pre-exiting conditions such as hypertension, diabetes and coronary artery disease. This same article also describe about preclinical studies in which mice developed left ventricular dysfunction when treated with imatinib and in vitro imatinib-induced cardiomyocyte cell-death. The article's authors hypothesize that the mechanism for imatinib's cardiotoxicity is through the inhibition of the Abl tyrosine kinase enzyme and they suggest that all agents working through the same mechanism would be expected to have the similar side effects.

Novartis' Response to the Information: After the publication of the article, Novartis performed a comprehensive review of data from clinical trials and voluntary adverse drug reaction reports and concluded that "While cardiac events remain uncommon, severe congestive heart failure and left ventricular dysfunction have occasionally been reported. As such we believe any patients with known cardiac disease or risk factors for cardiac failure should be monitored carefully…" As indicated above, Novartis has revised the prescribing information PRECAUTION section to include information about possible adverse cardiac event during treatment with imatinib. In particular, the revised labeling warn that patients with predisposing risk factors such as advanced age and history of cardiac disease should be closely monitored.

Recommendations: The current available data suggest that if cardiotoxicity occurs from imatinib treatment, it is more likely to do so in patients with predisposing risk factors such as advanced age or history of cardiac disease. Vigilant monitoring for cardiotoxicity should be focused on this particular group of patients. As more experience with imatinib is accumulated, elucidation of whether this drug can cause cardiotoxicity in the previously healthy patient should provide more clinical direction in this issue.