Slide 1 EZT 2003-W SS Mechanism of Action and Pharmacology of Ezetimibe Copyright © 2003 MSP Singapore Company, LLC. All rights reserved.

Slide 2 EZT 2003-W SS Chemical Structure of Ezetimibe Adapted from Catapano AL Eur Heart J Suppl 2001;3 (suppl E):E6-E10. OH O F N F

Slide 3 EZT 2003-W SS Mechanism of Action of Ezetimibe Localizes at the brush border of the small intestine to prevent and decrease the delivery of intestinal cholesterol to the liver The reduction of hepatic cholesterol stores leads to an increase in clearance of cholesterol from the blood Adapted from van Heek M et al Br J Pharmacol 2000;129:

Slide 4 EZT 2003-W SS Metabolism of Ezetimibe Rapidly metabolized to an active glucuronide metabolite Both parent drug and metabolite inhibit cholesterol absorption Glucuronide metabolite more potent than parent drug in inhibiting cholesterol absorption Repeated enterohepatic circulation results in long duration of action Adapted from Catapano AL Eur Heart J Suppl 2001;3(suppl E):E6-E10; van Heek M et al Br J Pharmacol 2000;129: ; Patrick JE et al Drug Metab Dispos 2002;30: ; Ezzet F et al Clin Ther 2001;23: OH OGluc O F N F Glucuronidation Glucuronide OH O F N F Ezetimibe

Slide 5 EZT 2003-W SS Pharmacokinetics of Ezetimibe Elimination half-life of ezetimibe approximately 22 hours Enterohepatic recirculation of glucuronide metabolite extends duration of action Long half-life –Permits once-daily dosing –Increases convenience –May improve compliance Adapted from Bays HE et al Clin Ther 2001;23: ; Kirsten R et al Clin Pharmacokinet 1998;34:

Slide 6 EZT 2003-W SS Adapted from Patrick JE et al Drug Metab Dispos 2002;30: ; Ezzet F et al Clin Ther 2001;23: Ezetimibe: Summary of Pharmacokinetic Parameters Absorption –Rapid after oral administration –Peak plasma concentration in an average of 2–3 hours Distribution –Relative volume of distribution L –20% reabsorbed due to enterohepatic recirculation Elimination –Primarily in feces after extensive enterohepatic recirculation –Half-life 22 hours

Slide 7 EZT 2003-W SS Adapted from Data on file, MSD. Factors Influencing Pharmacokinetics of Ezetimibe Food –No significant effect on oral bioavailability of ezetimibe Elderly –Plasma concentration of ezetimibe in elderly (  65 years) two-fold higher than in young (18–45 years) –Differences observed with age not clinically significant –Dosage adjustment not necessary Gender –Plasma concentration of ezetimibe slightly higher (<20%) in women than in men –LDL-C reduction and safety profile comparable between men and women –Dosage adjustment not necessary

Slide 8 EZT 2003-W SS Drug Interactions of Ezetimibe Ezetimibe does not induce cytochrome P450 enzymes Statins: no significant pharmacokinetic interactions with atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin Other drugs: no effect on pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives, glipizide, tolbutamide, midazolam, or warfarin Cimetidine: no effect on bioavailability of ezetimibe Antacids: decreased absorption rate of ezetimibe—not clinically significant Cholestyramine: decreased mean AUC of ezetimibe ~55% –May lessen incremental LDL-C reduction Fibrates: safety and efficacy of fibrate co-administration not established

Slide 9 EZT 2003-W SS Ezetimibe and Plasma LDL-C: Dose Response SEM=standard error of the mean *p<0.01 vs. placebo Adapted from Bays HE et al Clin Ther 2001;23: Mean % change in LDL-C Time (wk) 5 –5 –10 –15 –20 Baseline246810Endpoint (±SEM) 0 12 Ezetimibe 0.25 mg (n=47) Ezetimibe 1 mg (n=49) Ezetimibe 5 mg (n=49) Ezetimibe 10 mg (n=46) Placebo (n=52) * * * *

Slide 10 EZT 2003-W SS Ezetimibe and Plasma LDL-C: Morning versus Evening Dosing Mean % change in LDL-C from baseline at week 12 AM dosing 5 –5 –10 –15 –20 0 *p<0.01 vs. placebo Adapted from Bays HE et al Clin Ther 2001;23: ; Data on file, MSD. Placebo (n=36) +4.9 Ezetimibe 5 mg (n=36) –16.7* Ezetimibe 10 mg (n=39) –17.5* Ezetimibe 5 mg (n=40) –13.8* PM dosing Ezetimibe 10 mg (n=38) –18.2*

Slide 11 EZT 2003-W SS Key Benefits of Ezetimibe: Summary Unique mechanism of action inhibits absorption of dietary and biliary cholesterol Complements mechanism of action of cholesterol synthesis inhibitors (statins) Has additive LDL-C lowering effects with statins Pharmacokinetics –Long half-life permits once-daily dosing –No known clinically significant pharmacokinetic interactions were seen with statins Provides greater lipid control when used in co-administration with statins

Slide 12 EZT 2003-W SS Before prescribing any of the products mentioned in this presentation, please consult the manufacturers’ full prescribing information.