Background and Objective In the recently reported Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, the combination of ezetimibe/simvastatin (E/S) was associated with a significantly increased risk of cancer compared to placebo, causing widespread public concern. We examined the rates of cancer adverse event reports filed with the US Food and Drug Administration (FDA) of patients on ezetimibe or E/S, and compared these to reports with other potent cholesterol-lowering drugs. Alsheikh-Ali and Karas JCL 3(2): , 2009

Methods We tabulated all adverse event reports listing ‘‘cancer’’ or ‘‘malignancy’’ filed with the FDA (July 2004 to March 2008) of patients taking ezetimibe or E/S, and compared those to reports of patients taking simvastatin, atorvastatin, or rosuvastatin. We calculated rates for such reports per million prescriptions. A secondary analysis examined cancer reports as a proportion of all reported adverse events for each medication. Alsheikh-Ali and Karas JCL 3(2): , 2009

Results Prescriptions for all drugs totaled 559 million (approximately 52 and 55 million prescriptions of ezetimibe and E/S, respectively), and cancer adverse event reports totaled There were 2.9 and 1.3 cancer-associated adverse event reports per million ezetimibe or E/S prescriptions, respectively, compared to a range of 3.1 to 5.1 per million prescriptions for the other drugs. Alsheikh-Ali and Karas JCL 3(2): , 2009

Results Findings were similar when only reports listing the drug as ‘‘suspect’’ were considered. The proportions of reports listing cancer relative to all adverse event reports were 2.0% and 1.9% for ezetimibe and E/S, respectively, compared to a range of 1.3% to 3.9% for the other drugs. Alsheikh-Ali and Karas JCL 3(2): , 2009

Results Alsheikh-Ali and Karas JCL 3(2): , 2009 EzetimibeSimvastatinEzetimibe/ Simvastatin AtorvastatinRosuvastatin Total prescriptions (millions) Total cancer adverse event reports Age65 ± 1167 ± 1064 ± 1166 ± 11 Gender (% male) Fatal outcome (%) Cancer site (%) Breast Lung GI Renal Skin11 87 Blood Other Table 1: Characteristics of cancer associated adverse event reports.

Results *P < 0.01 versus ezetimibe/simvastatin †P < 0.01 versus ezetimibe Alsheikh-Ali and Karas JCL 3(2): , 2009

Results *P < 0.01 versus ezetimibe/simvastatin †P < 0.01 versus ezetimibe Alsheikh-Ali and Karas JCL 3(2): , 2009

Results Alsheikh-Ali and Karas JCL 3(2): , 2009 EzetimibeSimvastatinEzetimibe/ Simvastatin AtorvastatinRosuvastatin All cancer adverse event reports Suspect only Non-suspect only Excluding first year of E/S approval in US (7/ /2008) Excluding first year of E/S approval in US and 2008 (7/ /2007) Table 2: Rates of cancer associated adverse event reports in patients treated with the combination ezetimibe/simvastatin and other potent cholesterol lowering drugs (rate per million prescriptions).

Conclusions This large-scale post-marketing analysis of reported adverse events does not support that ezetimibe or E/S increase the risk of cancer. Alsheikh-Ali and Karas JCL 3(2): , 2009