Ezetimibe Overall Conclusions

Overall Conclusions Ezetimibe, with its unique mechanism of action, is the first innovation in cholesterol management since the introduction of statins Plasma cholesterol is derived from two sources Absorption from the intestine Synthesis in the liver and extrahepatic tissue Ezetimibe coadministered with a statin provides greater LDL-C reduction through dual inhibition of both cholesterol absorption and synthesis than a statin alone Ezetimibe is the first member of a new class of lipid-lowering drugs that inhibit absorption of dietary and biliary cholesterol and the first major innovation in cholesterol management since the introduction of statins. Coadministration of ezetimibe and a statin provides greater low-density lipoprotein cholesterol (LDL-C) lowering, through dual inhibition of cholesterol absorption and synthesis, than a statin alone.1,2 Adapted from Bays H Expert Opin Investig Drugs 2002;11:1587–1604; Darkes MJM et al Am J Cardiovasc Drugs 2003;3:67–76.

Overall Conclusions: Efficacy Coadministration of ezetimibe with ongoing statin therapy lowered LDL-C by an additional 21% vs. statin alone Coadministration of ezetimibe with atorvastatin or simvastatin Lowered LDL-C by 46%–61% Lowered TG by 25%–40% Raised HDL-C by 5%–11% Coadministration of ezetimibe with a statin further enhanced the reduction in CRP achieved with a statin alone For statin-treated patients not at NCEP ATP II goal, coadministration of ezetimibe increased percentage achieving LDL-C goal to 72% vs. 19% with coadministration of placebo Coadministration of ezetimibe with ongoing statin therapy in patients requiring further LDL-C reduction to meet the NCEP ATP II goal resulted in an additional 21% reduction in LDL-C.3 Coadministration of ezetimibe with atorvastatin or simvastatin in patients with hypercholesterolemia lowered LDL-C by 46% to 61% and triglycerides by 25% to 40% and raised high-density lipoprotein cholesterol (HDL-C) by 5% to 11%.4,5 Coadministration of ezetimibe with a statin further enhanced the reduction in C-reactive protein (CRP) achieved with statin alone.3,6 At the final assessment, 72% of patients with baseline LDL-C levels above the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP II) target attained goal LDL-C with coadministration of ezetimibe with ongoing statin therapy as compared with 19% assigned to coadministration of placebo.3 Adapted from Gagné C et al Am J Cardiol 2002;90:1084–1091; Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Sager PT et al Am J Cardiol 2003;92:1414–1418.

Overall Conclusions: Safety Profile In clinical trials, ezetimibe had a safety and tolerability profile comparable to placebo Ezetimibe is not metabolized by the CYP 450 pathway Ezetimibe does not inhibit the absorption of fat-soluble vitamins Ezetimibe coadministered with a statin has a safety profile comparable to that of the statin alone Ezetimibe has a safety and tolerability profile comparable to placebo.7 Ezetimibe is not metabolized by the CYP 450 pathway.8 Pharmacokinetic interactions of note include those with cholestyramine, fibrates, and cyclosporine. Administration of ezetimibe should occur two or more hours before or four or more hours after administration of a bile acid sequestrant. Concomitant administration of ezetimibe with fibrates is not recommended and caution is needed when ezetimibe is given in the setting of cyclosporine. Ezetimibe does not inhibit the absorption of fat-soluble vitamins. Ezetimibe coadministered with a statin has a safety profile comparable to the statin alone.7 Rates of serious drug-related adverse events reported in controlled clinical trials were low, and drug therapy was seldom discontinued due to adverse events. Adapted from Data from Registration File, MSP; Summary of Product Characteristics, EZETROL™, MSP.

Ezetimibe: Dosage and Administration Recommended ezetimibe dosage: 10 mg once daily, coadministered with a statin or as monotherapy No dosage adjustment required in children and adolescents 10 years or in the elderly May be taken at any time of day, with or without food May be taken at same time as statin Ezetimibe is indicated for primary hypercholesterolemia, homozygous familial hypercholesterolemia, and homozygous sitosterolemia.8 The dosing regimen of ezetimibe is easy and convenient. The recommended dosage is 10 mg once daily, coadministered with a statin or as monotherapy. No dosage adjustment is required in children older than age 10 years or in the elderly. Ezetimibe may be taken at any time of day, with or without food. Because of the lack of clinically significant pharmacokinetic interactions with rosuvastatin, atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin, ezetimibe may be taken at the same time as a statin.8,9 Adapted from Summary of Product Characteristics, EZETROL™, MSP.

References Please see notes page. References 1. Bays H. Ezetimibe. Expert Opin Investig Drugs 2002;11:1587–1604. 2. Darkes MJM, Poole RM, Goa KL. Ezetimibe. Am J Cardiovasc Drugs 2003;3:67–76. 3. Gagné C, Bays HE, Weiss SR et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol 2002;90:1084–1091. 4. Ballantyne CM, Houri J, Notarbartolo A et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia. A prospective, randomized, double-blind trial. Circulation 2003;107:2409–2415. 5. Davidson MH, McGarry T, Bettis R et al. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–2134. 6. Sager PT, Melani L, Lipka L, et al. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414–1418. 7. Data from Registration File, MSP. 8. Summary of Product Characteristics, EZETROL™, MSP. 9. Kosoglou T, Statkevich P, Yang B et al. Pharmacodynamic interaction between ezetimibe and rosuvastatin. Presented at the European Atherosclerosis Society Meeting, Seville, Spain, April 18–20, 2004. Please see notes page.

Ezetimibe Overall Conclusions Before prescribing, please consult the manufacturers’ prescribing information. MSP does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2004 MSP Singapore Company, LLC. All rights reserved. 6-05 EZT 2004-W-6161-SS Printed in USA VISIT US ON THE WORLD WIDE WEB AT http://www.ezetrol.com Before prescribing, please consult the manufacturers’ prescribing information. MSP does not recommend the use of any product in any different manner than as described in the prescribing information. Copyright © 2004 MSP Singapore Company, LLC. All rights reserved. 6-05 EZT 2004-W-6161-SS Printed in USA VISIT US ON THE WORLD WIDE WEB at http://www.ezetrol.com