Ezetimibe: The First Cholesterol Absorption Inhibitor

Transcription

1 PHARMACEUTICAL SPOTLIGHT Ezetimibe: The First Cholesterol Absorption Inhibitor Beata M. Domagala, PharmD, Michelle Leady, PharmD, and Daniel S. Streetman, PharmD OVERVIEW Ezetimibe (Zetia TM, Merck/Schering-Plough) is the first agent in a new drug class known as selective cholesterol absorption inhibitors (CAIs), which have been found to be useful in the treatment of hyperlipoproteinemias. The Food and Drug Administration has approved this drug for the following indications: 1 Reduction of low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and apolipoprotein B (apob) when the drug is combined with dietary measures in the treatment of primary As combination therapy with 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for the treatment of homozygous familial (HoFH) Reduction of elevated sitosterol and campesterol levels in the treatment of homozygous familial sitosterolemia Ezetimibe inhibits the intestinal absorption of dietary and biliary cholesterol, decreasing the delivery of intestinal cholesterol to the liver, although its precise mechanism of action remains unclear. 1,2 It has no effect on absorption of lipidsoluble vitamins, bile acids, triglycerides, or fatty acids. 3 In addition, unlike bile acid sequestering resins, which also act by altering enterohepatic cycling and which can lead to elevated triglyceride levels, ezetimibe decreases triglyceride levels to a mild degree HoFH affects only one in one million people, but it is associated with a poor overall prognosis for the children and adults with the condition. 10 This rare disorder is caused by an absence of functioning LDL receptors, resulting in plasma cholesterol levels above 500 mg/dl. These high levels are very difficult to reduce despite aggressive treatment with statins. 10 The mean LDL-C reduction with statins alone in this population is only approximately 20 mg/dl, which translates to a cholesterol reduction of less than 10%. 10 As a result, combination therapy with fibrates, bile acid sequestrants, and statins is often necessary. However, the use of such multidrug combinations is Dr. Domagala is a Pharmacist at the University of Michigan Health System in Ann Arbor, Michigan. Dr. Leady is a Clinical Instructor in the University of Michigan s College of Pharmacy and a Clinical Pharmacist in the Department of Pharmacy Services at the University of Michigan Health System in Ann Arbor. Dr. Streetman is a Clinical Pharmacist in the Department of Pharmacy Services in the University of Michigan Health System and a Clinical Assistant Professor in the Department of Clinical Sciences at the University of Michigan s College of Pharmacy in Ann Arbor. often undesirable because of a potential increased risk of adverse effects, such as rhabdomyolysis, myopathy, and gastrointestinal discomfort. Thus, the availability of new adjunct medications with unique mechanisms of action would be particularly advantageous in this patient population. Homozygous familial sitosterolemia is a rare autosomal recessive lipoprotein condition that is caused by an increased absorption of plant sterols, such as sitosterol and campesterol, from fruits and vegetables. 11 Like HoFH, the onset of sitosterolemia tends to occur in childhood and is implicated with a poor long-term prognosis for atherosclerosis. 12 Ezetimibe is the first cholesterol-lowering agent to be approved for this indication. 1 Unlike the patients with the former disorders, the numbers of patients treated annually for primary are extensive. Approximately 13 million people are currently taking statins in the U.S. Despite this number, approximately 60% will not achieve their cholesterol goals. 13 Although many factors contribute to this overall inability to achieve treatment goals, one particular problem has been a failure on the part of providers to titrate the statin dosages of these patients appropriately. Although atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck) can bring about reductions of LDL-C concentrations by roughly 30% to 40% at initial doses, subsequent doubling of doses reduces LDL-C by only an additional 5% to 7%. 7,8 Further, adverse effects, many of which are dose-dependent, may also limit a provider s ability to titrate the statin dosages effectively. From 0.1% to 0.5% and from 0.04 to 0.2% of patients taking statin therapy experience side effects such as myopathy and rhabdomyolysis, respectively. 14 MECHANISM OF ACTION AND ANIMAL PHARMACOLOGY Ezetimibe is a potent inhibitor of cholesterol absorption, acting at the brush border of the small intestine to inhibit intestinal absorption of dietary and biliary cholesterol across the intestinal wall and decreasing the delivery of intestinal cholesterol to the liver. 1,2 Several animal and cell-based experiments have attempted to further identify a particular target or mechanism by which ezetimibe exerts its effects. These studies suggest that ezetimibe might bind to and inhibit intestinal scavenger receptor class B, type I (SR-BI), a protein that is believed to be involved in cholesterol absorption. 15 Studies demonstrating the effectiveness of ezetimibe in SR-BI knockout mice indicate that SR-BI is not the primary site of ezetimibe action. 15 Other studies have shown that ezetimibe does not alter the expression of messenger ribonucleic acid (mrna) for ABCA1, ABCG5, and ABCG8, and the various Vol. 28 No. 3 March 2003 P&T 191

2 intestinal adenosine triphosphate (ATP) binding cassette (ABC) transporters involved in cholesterol efflux from intestinal enterocytes. 16 Studies have shown that ezetimibe inhibits up to 96% of cholesterol absorption in animal models and roughly 50% to 55% of cholesterol absorption in patients with mild to moderate. 2,17 As a result of this reduced cholesterol absorption, hepatic cholesterol stores decrease and clearance of cholesterol from the blood increases, leading to a reduction in circulating cholesterol concentrations. 1 Following initiation of ezetimibe therapy, peak LDL-C reductions are observed within approximately two weeks, after which time a plateau is reached Ezetimibe has no effect on absorption of lipid-soluble vitamins, bile acids, triglycerides, or fatty acids. 3 PHARMACOKINETICS Following oral administration, ezetimibe is rapidly absorbed, with the time to maximum concentration (t max ) being approximately one hour. 18 Once absorbed, ezetimibe undergoes extensive phase II metabolism in the intestine and liver to form an active glucuronide metabolite. 19 Both ezetimibe and ezetimibe glucuronide are highly bound (greater than 90%) to plasma proteins and have relatively long terminal half-lives of 13 to 22 hours. 1,20 Ezetimibe and its glucuronide are eliminated primarily in the feces, with approximately only 11% recovered in the urine (principally as the glucuronide). The ezetimibe concentration-time profiles contain several peaks, suggesting enterohepatic recirculation. Studies in elderly patients suggest a slightly higher peak concentration and area under the plasma concentration-time curve as well as a somewhat longer half-life. Despite these small pharmacokinetic differences, the manufacturer does not recommend special dosing or monitoring for older patients. 1,20 Studies in patients with hepatic or renal dysfunction have also demonstrated pharmacokinetic changes; consequently, ezetimibe is not recommended for patients with moderate to severe hepatic disease. 1 CLINICAL EFFICACY Eight randomized, multicenter studies in which ezetimibe was administered either as monotherapy or in combination with statins are presented in Table 1. As monotherapy in patients with primary, 10 mg daily of ezetimibe significantly reduces LDL-C concentrations by approximately 17%, TC by approximately 12%, triglycerides (TGs) by about 6%, apob by approximately 16%, sitosterol by approximately 21%, and campesterol levels by about 24%, with an increase in high-density lipoprotein cholsterol (HDL- C) of approximately 1.3%, relative to placebo. 4,5,11 Studies indicate that these effects on LDL-C plateaued after two weeks of therapy Differing mechanisms for ezetimibe and statins suggest that the two classes of agents have complementary effects on lowering plasma cholesterol levels. This relationship has been demonstrated in studies in which ezetimibe was added to either simvastatin or atorvastatin in patients with primary, to yield an additional 15% reduction in LDL-C. 7,8 These supplementary reductions were typically seen two weeks after initiation of drug therapy. 7,8 A similar study, in which ezetimibe was added to any current statin regimen of patients with primary and a mean baseline LDL-C of 139 mg/dl, demonstrated similar lipid effects (e.g., an additional 21% reduction in LDL-C), suggesting equivalent effects regardless of the particular statin used in combination. 9 It is notable that nearly 72% of patients receiving the ezetimibe statin combination reached the National Cholesterol Education Program s (NCEP) LDL goal, in contrast to only 18.9% of patients receiving placebo plus a statin (P <.001). In addition to the studies of patients with primary, one trial did investigate the efficacy of ezetimibe statin combination therapy in patients with HoFH. After 12 weeks of therapy, 80 mg of statin alone resulted in a reduction in LDL-C of approximately 7%, whereas the addition of ezetimibe resulted in a decrease in LDL-C of approximately 28%, or a four-fold decrease (P =.0001). 10 ADVERSE EFFECTS The side-effect profile of ezetimibe is similar to that of placebo. 1,4 6,9,10 Headaches have been reported in 6% of patients, and upper respiratory infections have been noted in 11.8%. 1 Other common adverse events reported during ezetimibe monotherapy studies included arthralgia, upper respiratory infection, and gastrointestinal discomfort, each of which occurred in fewer than 5% of patients. 1 When ezetimibe was combined with any statin, the drug s adverse-event profile was similar to that of the statin As monotherapy, ezetimibe is considered to fall within pregnancy category C (Table 2). The drug should be administered to pregnant or lactating women only when the potential benefit to the mother justifies the potential risk to the infant. Statins are contraindicated in pregnancy (category X) because of the risk of severe malformations. 21,22 Therefore, ezetimibe is contraindicated in pregnant women when it is used as adjunctive therapy with statins. 1 No significant changes or trends were detected in laboratory tests for muscle and liver function. 1,6 9 Elevations in serum transaminase levels three times the upper limit of normal were elevated only slightly in patients receiving ezetimibe in combination with statins compared with those receiving statins alone (1.3% vs. 0.4%). These patients were asymptomatic, and their transaminase levels returned to baseline values upon discontinuation of the drug. 1 Patients with overt liver dysfunction, however, whose liver-function test findings were greater than two times the upper limit of normal, were excluded from most trials. 7 No cases of rhabdomyolysis were reported. 6 9 Because of its lack of significant additive effect on muscle pain or liverfunction tests, ezetimibe now offers a safe alternative for bringing patients to targeted cholesterol levels. DRUG INTERACTIONS No significant food or cytochrome P-450 (CYP) interactions have been reported in trials with ezetimibe. 1,7,8,10,11 In addition, ezetimibe does not alter biliary micelle formation and therefore does not interfere with absorption of lipid-soluble nutrients. 3 Because bile acid sequestrants can decrease the plasma level of ezetimibe by 55% to 80%, 1 it is recommended that ezetimibe 192 P&T March 2003 Vol. 28 No. 3

3 Table 1 Clinical Efficacy of Ezetimibe Design Treatment No. Study Parameters Trial Results Tolerability Outcomes Author, MC 606 Dujovne et al. 4 Population: Patients with mild to moderate primary q morn. P Secondary: changes from baseline in LDL-C calculated, TC, TG, HDL-C, HDL 3, apob E P P LDL-C 16.9% 0.4% <.01 TG 5.7% 5.7% <.01 HDL-C 1.3% 1.6% <.01 E calculated LDL-C, apob, _TC, and HDL 3 compared with placebo (P <.01) Summary: Ezetimibe LDL-C by ~17% and has favorable effects on other lipid variables (E = 29 (4%) patients D/C treatment vs. P = six patients (3%) D/C treatment) Most common ADRs: URTI (E = 9%, P = 11%) Headache (E = 8%, P = 8%) Laboratory tests similar in treatment groups: ALT or AST > 3x ULN (E = < 1%, P = < 1%) Population: Patients with primary q morn. 606 P 203 E P P LDL-C 17.7% 0.8% <.01 TC 12.4% 0.6% <.01 HDL-C 1% 1.3% <.01 TG 1.7% 2.4% P =.09 Ezetimibe well tolerated; safety profile similar to that of placebo Knopp et al. 5, parallel group Population: patients with primary LDL-C > 130 to 250 mg/dl TG < 300 mg/dl Pooled data from 12-week studies Population: patients with primary LDL-C > 145 to 250 mg/dl TG < 350 mg/dl E 0.25, 1, 5, or 10 mg or P (dose response trial) E 5 or 10 mg or P (dose regimen trial) qd 61 S 10, 20, 40, or 80 mg qd + S 10, 20, 40 or 80 mg qd P Secondary: changes in HDL-C and TG from Secondary: changes in HDL-C and TG from Summary: Ezetimibe LDL-C by ~18% and has favorable effects on other lipid variables (Pooled efficacy results) E 5 E 10 P LDL-C 15.7% 8.5% <.01 HDL-C 2.9% 3.5% <.05 Summary: Ezetimibe LDL-C by ~18.5% and has favorable effects on other lipid variables in LDL-C was greater with ezetimibe 10 mg than 5 mg (P <.05) E S E + S LDL-C 18% 36.1% 49.9% TG 8% 16.6% 6.9% HDL-C 5% 24.1% 9.3% E + S significantly better than S for all variables Summary: Addition of ezetimibe to S provided additional LDL-C 13.8%, TG 7.5%, HDL-C 2.4% compared with S alone E (10 mg) + S (10 mg) = S (80 mg) = 44% reduction in LDL-C Ezetimibe well tolerated; safety profile similar to that with placebo 2% E + S had AST/ALT 3x ULN vs. <1% S Bays et al. 6 Davidson et al P&T March 2003 Vol. 28 No. 3

4 Population: patients with primary LDL-C > 145 to 250 mg/dl TG < 350 mg/dl qd A 10, 20, 40 or 80 mg qd + A 10, 20, 40 or 80 mg qd P , MC Population: patients with primary who had not achieved NCEP adult treatment panel II goals with diet and statin monotherapy 70% of patients had history of CAD or diabetes LDL-C at or above target for individual TG < 350 mg/dl Statin* 6 weeks plus E 10 mg/day Statin* > 6 weeks plus P Secondary: changes in HDL-C and TG from LDL-C from baseline with statin monotherapy to endpoint Secondary: change in baseline in HDL-C, TG, percentage of patients who achieved NCEP LDL-C goals after addition of ezetimibe E A E + A LDL-C 18.4% 42.2% 54.5% TG 3.5% 21.5% 29.5% HDL-C 4.2% 4.3% 7.3% E + A P <.01 vs. A Summary: Addition of ezetimibe to atorvastatin provided additional LDL-C 12.1%, TG 8%, HDL-C 3% compared with atorvastatin alone E + S P + S P LDL-C 25.1% 3.7% <.001 TG 14% 2.9% <.001 HDL-C 2.7% 1% <.05 Of patients not at LDL-C goal at baseline: 71.5% E + statin reached goal at endpoint vs. 18.9% P + statin (P <.001) Summary: Patients receiving current statin therapy can achieve greater LDL-C with addition of ezetimibe to help them reach NCEP goal 2% E + A had AST/ALT 3x ULN vs. <1% A Most common ADR: gastrointestinal disorders (~10% incidence, both groups) Four patients in treatment group and one in placebo group had ALT/AST No cases of rhabdomyolysis 28 patients discontinued therapy owing to ADRs, 14 (E + S) and 14 (S + P) Ballantyne et al. 8 Gagné et al. 9 Eight-week study Population: patients with HoFH receiving A or S Children >12 years old or weighing > 40 kg could enroll LDL-C > 220 mg/dl; addition of fibrinic acid allowed, MC Population: patients with sitosterolemia Eight-week study S/A 80 mg + S/A 40 mg + S/A 80 mg qd P Primary efficacy was percentage change from baseline (open-label statin at 40 mg/day) to study endpoint in LDL-C Secondary endpoints were percentage change in calculated LDL-C, HDL-C, TC, TG, apolipoprotein, and LDL-C/ HDL-C ratio Primary endpoints were reduction in sitosterol and campesterol levels E + S/A (40/80) S/A 80 P LDL-C 20.7% 6.7% P =.007 TC 18.7% 5.3% P <.01 No significant differences in HDL-C, TG, or apolipoproteins E + S/A (80) S/A-80 P LDL-C 27.5% 7% P =.0001 Summary: E + S/A can achieve greater LDL-C in HoFH than S/A alone E P P <.001 Sitosterol 21% 4% Campesterol 24.3% 3.2% Most common ADRs: Headache (E + S/A: 40/80 = 12%, S/A-80 = 18%) Two patients in E + S/A: 40/80 group had ALT/AST 3x ULN (one at baseline) No cases of rhabdomyolysis or myopathy Gagné et al. 10 Well tolerated Von Bergmann et al. 11 A = atorvastatin; ADR = adverse drug reaction; ALT = alanine transaminase; apob = apolipoprotein B; AST = aspartate transaminase; CAD = coronary artery disease; DB = double-blind; E = ezetimibe; LDL-C = low-density lipoprotein-cholesterol; HDL-C = high-density lipoprotein-cholesterol; HoFH = homozygous familial ; MC = multicenter; morn. = morning; NCEP = National Cholesterol Education Program; P = placebo; P = statistical significance; PC = placebo-controlled; R = randomized; S = simvastatin; S/A = simvastatin or atorvastatin; TC = total cholesterol;tg = triglycerides; ULN = upper limit of normal; URTI = upper respiratory tract infection. *Statin = one-third atorvastatin, one-third simvastatin, and one-third all other statins. Vol. 28 No. 3 March 2003 P&T 195

5 Table 2 Pregnancy Categories for Antihyperlipidemic Agents Drug or Drug Class Statins (HMG CoA reductase inhibitors) and statin combinations (niacin/lovastatin) Bile acid sequestrants (cholestyramine, colestipol, colesevelam) Cholesterol absorption inhibitors (ezetimibe) Fibric acid derivatives (gemfibrozil, fenofibrate, clofibrate, niacin) Pregnancy Category HMG-CoA = 3-hydroxyl-3-methylglutaryl coenzyme A. Data from Briggs GG, et al. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002; and Cohen HE, ed. Red Book. Montvale, NJ: Thomson Medical Economics; X B C C be given two hours before or four hours after administration of the bile acid sequestrant. Cyclosporine and fibrates have been observed to increase plasma ezetimibe levels. One renal transplant recipient who was given cyclosporine and ezetimibe experienced a 12-fold increase in ezetimibe concentrations; 32 patients who received fenofibrate and ezetimibe experienced a 1.5-fold increase in ezetimibe levels; and 12 patients who were given gemfibrozil with ezetimibe experienced a 1.7-fold increase in ezetimibe levels. 1 At this time, the manufacturer of ezetimibe recommends not prescribing this drug concomitantly with fibrates until more data are available; cyclosporine, however, may be used with caution and monitoring. Significant drug interactions are presented in Table 3. 1 DOSING, ADMINISTRATION, AND COST Ezetimibe administered as monotherapy is currently labeled as adjunctive therapy in patients who have not attained LDL-C goals despite an adequate trial of a standard low-fat/lowcholesterol diet. Patients should continue on their diet while taking ezetimibe. The recommended dose of ezetimibe is 10 mg once daily, taken without regard to meals, time of day, or time of statin administration. It is recommended that most statins be taken in the evening to coincide with peak cholesterol production. Because the time of day does not enhance the cholesterollowering action of ezetimibe, it can be taken anytime. 1 No dose adjustment is necessary in patients with mild hepatic or renal insufficiency or in geriatric patients. In a clinical trial of patients with creatinine clearance below 30 ml/minute, however, eight patients experienced mean plasma level increases of ezetimibe at a rate of 1.5 times that of healthy volunteers. In a study of healthy geriatric patients, a two-fold Table 3 Drug Interactions with Ezetimibe Concomitant Drug or Food Gemfibrozil (Lopid, Parke-Davis) Fenofibrate (Tricor, Abbott) Fibrates Bile acid sequestrants (cholestyramine) Cyclosporine Antacids High-fat meal Identified Risk A risk of cholelithiasis exists from ezetimibe increase in gallbladder bile. Twelve patients treated with gemfibrozil experienced 1.7-fold increases in ezetimibe concentrations. A risk of cholelithiasis exists from elevations of ezetimibe in gallbladder bile. Thirty-two patients given fenofibrate experienced 1.5-fold increases in ezetimibe concentrations. A risk of cholelithiasis exists from increased ezetimibe levels in gallbladder bile. Forty patients treated with cholestyramine experienced decreases in plasma levels of ezetimibe by 80%. One renal transplant patient who received multiple medications, including cyclosporine and ezetimibe, experienced a 12-fold increase in ezetimibe levels. The C max of ezetimibe was decreased by 30%, but the AUC was unchanged. The C max of ezetimibe was increased by 38%, but no effect on the extent of absorption was noted. AUC = area under the curve; C max = maximum concentration. Data from Zetia TM (ezetimibe) package insert. Kenilworth, NJ: Merck/Schering-Plough. Management Do not prescribe ezetimibe concomitantly with fibrates until more data are available. Do not prescribe ezetimibe concomitantly with fibrates until more data are available. Do not prescribe ezetimibe concomitantly with fibrates until more data are available. Give ezetimibe two hours before or four hours after bile acid sequestrant is given. Prescribe cyclosporine with caution, and perform monitoring. May prescribe without regard to antacid administration. May prescribe without regard to food. 196 P&T March 2003 Vol. 28 No. 3

6 Ezetimibe: The First Cholesterol Absorption Inhibitor continued from page 196 increase in the plasma concentration was found. Patients with moderate to severe hepatic insufficiency should not take ezetimibe because the hepatic effects are still unknown. 1 Treatment with ezetimibe in patients younger than 10 years of age is not recommended currently because of a lack of information. Five patients aged 11 to 17 years in the HoFH study and four patients ages nine to 17 years in the sitosterolemia study received ezetimibe. 1 The drug was found to be as safe and effective in this population as in adults. Another study by Kosoglou et al. 23 evaluated the safety and pharmacokinetics of ezetimibe in adolescents. Nine males (ages 10 to 18) received 10 mg of the drug once daily for one week. The drug s pharmacokinetic activity in the studied population was similar to that in young adults. 23 Ezetimibe is supplied as 10-mg unscored tablets. The tablet size is relatively small and can thus be administered relatively easily to a pediatric population. Although ezetimibe is nearly insoluble in water and the bioavailability of crushing and mixing the drug with food or other Table 4 Comparative Cost of Ezetimibe with HMG-CoA Reductase Inhibitors AWP ($) AWP ($) AWP ($) Ezetimibe + Drug Dose per Tablet per Month Statin per Month Ezetimibe 10 mg PO qd (Zetia, Merck/ Schering-Plough) Simvastatin 5 mg PO qd (Zocor, Merck) 10 mg PO qd mg PO qd mg PO qd mg PO qd Atorvastatin 10 mg PO qd (Lipitor, Pfizer) 20 mg PO qd mg PO qd mg PO qd Pravastatin 10 mg PO qd (Pravachol, Bristol-Myers Squibb) 20 mg PO dq mg PO qd mg PO qd Fluvastatin 20 mg PO qd (Lescol, Novartis) 40 mg PO qd mg PO qd Lovastatin 10 mg PO qd (Mevacor, Merck) 20 mg PO qd mg PO qd AWP = average wholesale price; HMG-CoA = 3-hydroxyl-3-methylglutaryl coenzyme A. Data from Cohen HE, ed. Red Book. Montvale, NJ: Thomson Medical Economics, Vol. 28 No. 3 March 2003 P&T 205

7 liquids has not been studied, the manufacturer has identified no reason why this method could not be used to improve palatability. 1,24 The average wholesale price for a one-month, 30-day supply of ezetimibe 10 mg is $57.90 (Table 4). 22 This price is lower than that of simvastatin and atorvastatin at higher doses. Table 4 summarizes comparative costs between ezetimibe and the statins currently available. THE ROLE OF EZETIMIBE IN THERAPY Ezetimibe has been shown to be safe and effective in the treatment of primary, HoFH, and homozygous familial sitosterolemia. The drug is effective as both monotherapy and as combination therapy for patients with. As monotherapy, ezetimibe seems to be able to reduce overall LDL-C by 17%; as combination therapy, with either simvastatin or atorvastatin, it lowers LDL-C by an additional 12% to 20%. 4 9 Considering that doubling of statin doses yields only an additional 5% to 7% LDL-C reduction on average, this additional LDL-C potency with combination therapy appears to be the major potential clinical niche for ezetimibe. However, statins clearly remain preferred as first-line therapy for primary because of their demonstrated benefits vis-à-vis morbidity and mortality rates and because of their superiority in reducing LDL-C levels. Therefore, most patients with primary should be initiated on ezetimibe only when they must achieve additional decreases in LDL-C levels, when they have experienced adverse effects with higher statin doses, or, perhaps, as an alternative for monotherapy or in combination when they are intolerant of statins but need to achieve lower LDL-C levels. REFERENCES 1. Zetia TM (ezetimibe) package insert. Kenilworth, NJ: Merck/Schering-Plough, October Sudhop T, Lujohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002; 106: Knopp RH, Bays H, Manion CV, et al. Effect of ezetimibe on serum concentrations of lipid-soluble vitamins (Abstract). Atherosclerosis 2001;2(Suppl): Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary. Am J Cardiol 2002; 90: Knopp RH, Gitter H, Truitt, T, et al. Ezetimibe reduces lowdensity lipoprotein cholesterol: Results of a phase III, randomized, double-blind, placebo-controlled trial (Abstract). Atherosclerosis 2001;2(Suppl): Bays HE, Moore PB, Drehobl MA, et al. Effectiveness and tolerability of ezetimibe in patients with primary : Pooled analysis of two phase II studies. Clin Ther 2001;23: Davidson M, McGarry T, Bettis R, et al. Ezetimibe coadministered with simvastatin in patients with primary. J Am Coll Cardiol 2002;40(12): Ballantyne C, Houri C, Notarbartolo A, et al. Ezetimibe coadministered with atorvastatin in 628 patients with primary (Abstract). J Am Coll Cardiol 2002;39(Suppl A):227A. 9. Gagné C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary. Am J Cardiol 2002;90: Gagné C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin with homozygous familial. Circulation 2002;105: Von Bergmann K, Salen G, Lutjohann D, et al. Ezetimibe effectively reduces serum plant sterols in patients with sitosterolemia (Abstract). Atherosclerosis 2002;3(2): Lee M, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol 2001;12: Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160: Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35: Altman SW, Davis HR Jr, Yao X, et al. The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorption. Biochem Biophys Acta 2002;1580: Repa JJ, Dietschy JM, Turley SD. Inhibition of cholesterol absorption by SCH in the mouse is not mediated via changes in either the intestinal bile acid pool or the expression of mrna for ABCA1, ABCG5, or ABCG8 in the enterocyte. J Lipid Res 2002;43: van Heek M, Farley C, Compton DS, et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Clin Pharmacol 2001;134: Ezzet F, Krishna G, Wexler DB, et al. A population pharmacokinetic model that describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clin Ther 2001;23: van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH58235, and its glucuronide, SCH Br J Clin Pharmacol 2000;129: Zhu Y, Statkevich P, Kosoglou T, et al. Effect of age on the pharmacokinetics of ezetimibe. American Association of Pharmaceutical Scientists (AAPS) PharmSci Suppl 2000;2: Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 6 th ed. Philadelphia: Lippincott Williams & Wilkins; Cohen HE, ed. Red Book. Montvale, NJ: Thomson Medical Economics; Kosoglou T, Kakkar T, Statkevich P, et al. Multiple-dose safety and pharmacokinetics of eztemibe in adolescent children (Abstract). Clin Pharmacol Ther 2001;69(2):P Calder RA. Ezetimibe (Zetia TM ) data on file (letter). North Wales, PA: Merck/Schering-Plough, January 10, P&T March 2003 Vol. 28 No. 3