March 2, 2004

Thank you for providing us with the opportunity to respond to the letter by Heller that raises questions about the safety and tolerability of ezetimibe. We fail to understand Dr. Heller’s conclusions that the “Tolerability and Safety” section of our article is “radically different” from the CCOHTA newsletter (1). The issue of a small increase in liver enzyme abnormalities associated with the combination of ezetimibe and statin in the pooled data analysis was outlined in our article. The clinical significance of this increase remains unclear. Therefore, in the “Clinical Use” section, we state that “When ezetimibe is used in combination with a statin, monitoring should be performed according to the recommendations for the statin.” This is totally consistent with the product monographs for ezetimibe in both Canada and the United States. Regarding the issue of long-term safety, the study lengths were cited in the text of our article. Therefore, we feel that our conclusions are once again compatible with those of the CCOHTA newsletter. In addition, a recent abstract reported the results of a 48-week extension of a double-blind, placebo-controlled study of combination therapy with ezetimibe and simvastatin. There were no difference in the incidence of adverse events between the groups and the incidence of consecutive elevations in liver transaminases ≥ 3 times the upper limit of normal was low (0% vs. 0.3%, placebo+simvastatin vs. ezetimibe+simvastatin) (2). Finally, we thank Dr. Heller for raising the issue of angioedema and rash. The postmarketing experience of ezetimibe has included rare reports of hypersensitivity reactions including angioedema and rash – the frequency of which is not known. information was not available at the time our manuscript was submitted to the Journal.