ZETIATM
`(EZETIMIBE)
`TABLETS
`
`DESCRIPTION
`ZETIA∗ (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption
`of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-
`fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3.
`Its molecular weight is 409.4 and its structural formula is:
`
`O H
`
`S
`
`SR
`
`N
`
`O
`
`F
`
`O H
`
`F
`
`Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and
`practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient
`temperature. ZETIA is available as a tablet for oral administration containing 10 mg of ezetimibe and the
`following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF,
`microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
`
`CLINICAL PHARMACOLOGY
`Background
`Clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein
`cholesterol (LDL-C) and apolipoprotein B (Apo B), the major protein constituent of LDL, promote human
`atherosclerosis. In addition, decreased levels of high density lipoprotein cholesterol (HDL-C) are associated with
`the development of atherosclerosis. Epidemiologic studies have established that cardiovascular morbidity and
`mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL,
`cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-
`density lipoproteins (IDL), and remnants, can also promote atherosclerosis. The independent effect of raising
`HDL-C or lowering triglycerides (TG) on the risk of coronary and cardiovascular morbidity and mortality has not
`been determined.
`ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with hypercholesterolemia.
`Administration of ZETIA with an HMG-CoA reductase inhibitor is effective in improving serum total-C, LDL-C,
`Apo B, TG, and HDL-C beyond either treatment alone. The effects of ezetimibe given either alone or in addition
`to an HMG-CoA reductase inhibitor on cardiovascular morbidity and mortality have not been established.
`Mode of Action
`Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a
`2-week clinical study in 18 hypercholesterolemic patients, ZETIA inhibited intestinal cholesterol absorption by
`54%, compared with placebo. ZETIA had no clinically meaningful effect on the plasma concentrations of the fat-
`soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone
`production (in a study of 118 patients).
`The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize
`cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by
`the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from
`dietary cholesterol.
`Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing
`compounds (HMG-CoA reductase inhibitors, bile acid sequestrants [resins], fibric acid derivatives, and plant
`stanols).
`
`* COPYRIGHT © Merck/Schering-Plough Pharmaceuticals, 2001, 2002
`
`All rights reserved
`
`CFAD Exhibit 1051
`
`

`
`
`
`
`
`Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead,
`ezetimibe localizes and appears to act at the brush border of the small intestine and inhibits the absorption of
`cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of
`hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is
`complementary to that of HMG-CoA reductase inhibitors (see CLINICAL STUDIES).
`Pharmacokinetics
`Absorption
`After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active
`phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted adults, mean
`ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax).
`Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There
`was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of
`ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.
`Ezetimibe has variable bioavailability; the coefficient of variation, based on inter-subject variability, was 35 to
`60% for AUC values.
`Effect of Food on Oral Absorption
`Concomitant food administration (high fat or non-fat meals) had no effect on the extent of absorption of
`ezetimibe when administered as ZETIA 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with
`consumption of high fat meals. ZETIA can be administered with or without food.
`Distribution
`Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.
`Metabolism and Excretion
`Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II
`reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has
`been observed in all species evaluated.
`In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide
`are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90%
`of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from
`plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma
`concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
`Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe +
`ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours,
`there were no detectable levels of radioactivity in the plasma.
`Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine,
`respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for
`69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted
`for 9% of the administered dose.
`Special Populations
`Geriatric Patients
`In a multiple dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total
`ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.
`Pediatric Patients
`In a multiple dose study with ezetimibe given 10 mg once daily for 7 days, the absorption and metabolism of
`ezetimibe were similar in adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no
`pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population
`<10 years of age are not available.
`Gender
`In a multiple dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total
`ezetimibe were slightly higher (<20%) in women than in men.
`Race
`Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic
`differences between Blacks and Caucasians. There were too few patients in other racial or ethnic groups to
`permit further pharmacokinetic comparisons.
`
`

`
`
`Hepatic Insufficiency
`After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was
`increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), compared
`to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3-4
`fold and 5-6 fold, respectively, in patients with moderate (Child Pugh score 7 to 9) or severe hepatic impairment
`(Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic
`insufficiency, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on
`Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to
`ezetimibe in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients
`(see CONTRAINDICATIONS and PRECAUTIONS, Hepatic Insufficiency).
`Renal Insufficiency
`After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl
`<30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were
`increased approximately 1.5-fold, compared to healthy subjects (n=9).
`Drug Interactions (See also PRECAUTIONS, Drug Interactions)
`ZETIA had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV
`midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “cocktail” study of
`twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these
`cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are
`metabolized by these enzymes.
`Warfarin: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on
`bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males.
`Digoxin: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the
`bioavailability of digoxin and the ECG parameters (HR, PR, QT, and QTc intervals) in a study of twelve healthy
`adult males.
`Gemfibrozil: In a study of twelve healthy adult males, concomitant administration of gemfibrozil (600 mg
`twice daily) significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7. Ezetimibe (10 mg
`once daily) did not significantly affect the bioavailability of gemfibrozil.
`Oral Contraceptives: Co-administration of ezetimibe (10 mg once daily) with oral contraceptives had no
`significant effect on the bioavailability of ethinyl estradiol or levonorgestrel in a study of eighteen healthy adult
`females.
`Cimetidine: Multiple doses of cimetidine (400 mg twice daily) had no significant effect on the oral
`bioavailability of ezetimibe and total ezetimibe in a study of twelve healthy adults.
`Antacids: In a study of twelve healthy adults, a single dose of antacid (SupraloxTM 20 mL) administration had
`no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on
`AUC values. The Cmax value of total ezetimibe was decreased by 30%.
`Glipizide: In a study of twelve healthy adult males, steady-state levels of ezetimibe (10 mg once daily) had
`no significant effect on the pharmacokinetics and pharmacodynamics of glipizide. A single dose of glipizide
`(10 mg) had no significant effect on the exposure to total ezetimibe or ezetimibe.
`HMG-CoA reductase inhibitors: In studies of healthy hypercholesterolemic (LDL-C ≥130 mg/dl) adult
`subjects, concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the
`bioavailability of either lovastatin, simvastatin, pravastatin, atorvastatin, or fluvastatin. No significant effect on
`the bioavailability of total ezetimibe and ezetimibe was demonstrated by either lovastatin (20 mg once daily),
`pravastatin (20 mg once daily), atorvastatin (10 mg once daily), or fluvastatin (20 mg once daily).
`Fenofibrate: In a study of thirty-two healthy hypercholesterolemic (LDL-C ≥130 mg/dl) adult subjects,
`concomitant fenofibrate (200 mg once daily) administration increased the mean Cmax and AUC values of total
`ezetimibe approximately 64% and 48%, respectively. Pharmacokinetics of fenofibrate were not significantly
`affected by ezetimibe (10 mg once daily).
`Cholestyramine: In a study of forty healthy hypercholesterolemic (LDL-C ≥130 mg/dl) adult subjects,
`concomitant cholestyramine (4 g twice daily) administration decreased the mean AUC values of total ezetimibe
`and ezetimibe approximately 55% and 80%, respectively.
`
`
`
`

`
`
`
`ANIMAL PHARMACOLOGY
`The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats,
`and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5
`µg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice
`were 7, 30, and 700 µg/kg/day, respectively. These results are consistent with ZETIA being a potent cholesterol
`absorption inhibitor.
`In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered
`intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption
`of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.
`In 1-month studies in dogs given ezetimibe (0.03-300 mg/kg/day), the concentration of cholesterol in
`gallbladder bile increased ~2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year
`did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given
`ezetimibe (0.3-5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in
`gallbladder bile was either unaffected or reduced to normal levels, respectively.
`A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting
`cholesterol absorption. Ezetimibe inhibited the absorption of C14 cholesterol with no effect on the absorption of
`triglycerides, fatty acids, bile acids, progesterone, ethyl estradiol, or the fat soluble vitamins A and D.
`In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing
`enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase inhibitors
`(parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
`
`CLINICAL STUDIES
`Primary Hypercholesterolemia
`ZETIA reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with hypercholesterolemia.
`Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.
`ZETIA is effective in patients with hypercholesterolemia, in men and women, in younger and older patients,
`alone or administered with an HMG-CoA reductase inhibitor. Experience in pediatric and adolescent patients
`(ages 9 to 17) has been limited to patients with homozygous familial hypercholesterolemia (HoFH) or
`sitosterolemia.
`Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the
`effects of ZETIA.
`Monotherapy
`In two, multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary
`hypercholesterolemia, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C
`compared to placebo (see Table 1). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
`
`Table 1
`Response to ZETIA in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`
`
`
`
`
`Study 1c
`
`Study 2c
`
`Pooled Datac
`(Studies 1 & 2)
`
`Treatment
`group
`Placebo
`Ezetimibe
`Placebo
`Ezetimibe
`
`Placebo
`Ezetimibe
`
`N
`
`205
`622
`226
`666
`431
`1288
`
`Total-C
`
`LDL-C
`
`Apo B
`
`TGa
`
`HDL-C
`
`+1
`-12
`+1
`-12
`
`0
`-13
`
`+1
`-18
`+1
`-18
`
`+1
`-18
`
`-1
`-15
`-1
`-16
`
`-2
`-16
`
`-1
`-7
`+2
`-9
`
`0
`-8
`
`-1
`+1
`-2
`+1
`
`-2
`+1
`
` a
`
`
`
` For triglycerides, median % change from baseline
`b Baseline - on no lipid-lowering drug
`c ZETIA significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to placebo.
`
`

`
`
`Combination with HMG-CoA Reductase Inhibitors
`ZETIA Added to On-going HMG-CoA Reductase Inhibitor Therapy
`In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary
`hypercholesterolemia, known coronary heart disease or multiple cardiovascular risk factors who were already
`receiving HMG-CoA reductase inhibitor monotherapy, but who had not met their NCEP ATP II target LDL-C goal
`were randomized to receive either ZETIA or placebo in addition to their on-going HMG-CoA reductase inhibitor
`therapy.
`ZETIA, added to on-going HMG-CoA reductase inhibitor therapy, significantly lowered total-C, LDL-C, Apo B,
`and TG, and increased HDL-C compared with an HMG-CoA reductase inhibitor administered alone (see Table
`2). LDL-C reductions induced by ZETIA were generally consistent across all HMG-CoA reductase inhibitors.
`
`Table 2
`Response to Addition of ZETIA to On-going HMG-CoA Reductase Inhibitor Therapya in Patients with
`Hypercholesterolemia
`(Meanb % Change from Treated Baselinec)
`
`Treatment
`(Daily Dose)
`On-going HMG-CoA
`reductase inhibitor
`+Placebod
`On-going HMG-CoA
`reductase inhibitor
`+ZETIAd
`
`N
`
`Total-C
`
`LDL-C
`
`Apo B
`
`TGb
`
`HDL-C
`
`390
`
`-2
`
`379
`
`-17
`
`-4
`
`-25
`
`-3
`
`-3
`
`-19
`
`-14
`
`+1
`
`+3
`
`
`
`
`
`a Patients receiving each HMG-CoA reductase inhibitor: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin,
`fluvastatin, cerivastatin, lovastatin)
`b For triglycerides, median % change from baseline
`c Baseline - on an HMG-CoA reductase inhibitor alone.
`d ZETIA + HMG-CoA reductase inhibitor significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to HMG-CoA reductase
`inhibitor alone.
`
`ZETIA Initiated Concurrently with an HMG-CoA Reductase Inhibitor
`In four, multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hypercholesterolemic patients,
`ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or
`lovastatin.
`
`When all patients receiving ZETIA with an HMG-CoA reductase inhibitor were compared to all those
`receiving the corresponding HMG-CoA reductase inhibitor alone, ZETIA significantly lowered total-C, LDL-C,
`Apo B, and TG, and, with the exception of pravastatin, increased HDL-C compared to the HMG-CoA reductase
`inhibitor administered alone. LDL-C reductions induced by ZETIA were generally consistent across all HMG-
`CoA reductase inhibitors. (See footnote c, Tables 3 to 6.)
`
`

`
`
`
`
`
` a
`
`Table 3
`Response to ZETIA and Atorvastatin Initiated Concurrently
`in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`
`Treatment
`(Daily Dose)
`Placebo
`ZETIA
`Atorvastatin 10 mg
`ZETIA +
`Atorvastatin 10 mg
`Atorvastatin 20 mg
`ZETIA +
`Atorvastatin 20 mg
`Atorvastatin 40 mg
`ZETIA +
`Atorvastatin 40 mg
`Atorvastatin 80 mg
`ZETIA +
`Atorvastatin 80 mg
`Pooled data (All
`Atorvastatin Doses)c
`Pooled data (All ZETIA +
`Atorvastatin Doses)c
`
`N
`
`60
`65
`60
`
`65
`
`60
`
`62
`
`66
`
`65
`
`62
`
`63
`
`248
`
`255
`
`Total-C
`
`LDL-C
`
`Apo B
`
`TGa
`
`HDL-C
`
`+4
`-14
`-26
`
`-38
`
`-30
`
`-39
`
`-32
`
`-42
`
`-40
`
`-46
`
`-32
`
`-41
`
`+4
`-20
`-37
`
`-53
`
`-42
`
`-54
`
`-45
`
`-56
`
`-54
`
`-61
`
`-44
`
`-56
`
`+3
`-15
`-28
`
`-43
`
`-34
`
`-44
`
`-37
`
`-45
`
`-46
`
`-50
`
`-36
`
`-45
`
`-6
`-5
`-21
`
`-31
`
`-23
`
`-30
`
`-24
`
`-34
`
`-31
`
`-40
`
`-24
`
`-33
`
`+4
`+4
`+6
`
`+9
`
`+4
`
`+9
`
`+4
`
`+5
`
`+3
`
`+7
`
`+4
`
`+7
`
` For triglycerides, median % change from baseline
`b Baseline - on no lipid-lowering drug
`c ZETIA + all doses of atorvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of
`atorvastatin pooled (10-80 mg).
`
`

`
`Table 4
`Response to ZETIA and Simvastatin Initiated Concurrently
`in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`
`Treatment
`(Daily Dose)
`Placebo
`ZETIA
`Simvastatin 10 mg
`ZETIA +
`Simvastatin 10 mg
`Simvastatin 20 mg
`ZETIA +
`Simvastatin 20 mg
`Simvastatin 40 mg
`ZETIA +
`Simvastatin 40 mg
`Simvastatin 80 mg
`ZETIA +
`Simvastatin 80 mg
`Pooled data (All
`Simvastatin Doses)c
`Pooled data (All ZETIA +
`Simvastatin Doses)c
`
`N
`
`70
`61
`70
`67
`
`61
`69
`
`65
`73
`
`67
`65
`
`263
`
`274
`
`Total-C
`
`LDL-C
`
`Apo B
`
`TGa
`
`HDL-C
`
`-1
`-13
`-18
`-32
`
`-26
`-33
`
`-27
`-40
`
`-32
`-41
`
`-26
`
`-37
`
`-1
`-19
`-27
`-46
`
`-36
`-46
`
`-38
`-56
`
`-45
`-58
`
`-36
`
`-51
`
`0
`-14
`-21
`-35
`
`-29
`-36
`
`-32
`-45
`
`-37
`-47
`
`-30
`
`-41
`
`+2
`-11
`-14
`-26
`
`-18
`-25
`
`-24
`-32
`
`-23
`-31
`
`-20
`
`-29
`
`+1
`+5
`+8
`+9
`
`+6
`+9
`
`+6
`+11
`
`+8
`+8
`
`+7
`
`+9
`
` a
`
` For triglycerides, median % change from baseline
`
`b Baseline - on no lipid-lowering drug
`c ZETIA + all doses of simvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of
`simvastatin pooled (10-80 mg).
`
`
`
`
`
`
`
`

`
`Table 5
`Response to ZETIA and Pravastatin Initiated Concurrently
`in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`
`Treatment
`(Daily Dose)
`Placebo
`ZETIA
`Pravastatin 10 mg
`ZETIA +
`Pravastatin 10 mg
`Pravastatin 20 mg
`ZETIA +
`Pravastatin 20 mg
`Pravastatin 40 mg
`ZETIA +
`Pravastatin 40 mg
`Pooled data (All
`Pravastatin Doses)c
`Pooled data (All ZETIA +
`Pravastatin Doses)c
`
`N
`
`65
`64
`66
`71
`
`69
`66
`
`70
`67
`
`205
`
`204
`
`Total-C
`
`LDL-C
`
`Apo B
`
`TGa
`
`HDL-C
`
`0
`-13
`-15
`-24
`
`-15
`-27
`
`-22
`-30
`
`-17
`
`-27
`
`-1
`-20
`-21
`-34
`
`-23
`-40
`
`-31
`-42
`
`-25
`
`-39
`
`-2
`-15
`-16
`-27
`
`-18
`-31
`
`-26
`-32
`
`-20
`
`-30
`
`-1
`-5
`-14
`-23
`
`-8
`-21
`
`-19
`-21
`
`-14
`
`-21
`
`+2
`+4
`+6
`+8
`
`+8
`+8
`
`+6
`+8
`
`+7
`
`+8
`
`a For triglycerides, median % change from baseline
`
`b Baseline - on no lipid-lowering drug
`c
`ZETIA + all doses of pravastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and TG compared to all doses of pravastatin pooled (10-
`40 mg).
`
`
`
`
`
`
`
`

`
`N
`
`64
`72
`73
`65
`
`74
`62
`
`73
`65
`
`220
`
`192
`
`
`
`
`
`
`
`Table 6
`Response to ZETIA and Lovastatin Initiated Concurrently
`in Patients with Primary Hypercholesterolemia
`(Meana % Change from Untreated Baselineb)
`
`Total-C
`
`LDL-C
`
`Apo B
`
`TGa
`
`Treatment
`(Daily Dose)
`Placebo
`ZETIA
`Lovastatin 10 mg
`ZETIA +
`Lovastatin 10 mg
`Lovastatin 20 mg
`ZETIA +
`Lovastatin 20 mg
`Lovastatin 40 mg
`ZETIA +
`Lovastatin 40 mg
`Pooled data (All
`Lovastatin Doses)c
`Pooled data (All ZETIA +
`Lovastatin Doses)c
`
`a For triglycerides, median % change from baseline
`
`b Baseline - on no lipid-lowering drug
`c ZETIA + all doses of lovastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of
`lovastatin pooled (10-40 mg).
`
`+1
`-13
`-15
`-24
`
`-19
`-29
`
`-21
`-33
`
`-18
`
`-29
`
`0
`-19
`-20
`-34
`
`-26
`-41
`
`-30
`-46
`
`-25
`
`-40
`
`+1
`-14
`-17
`-27
`
`-21
`-34
`
`-25
`-38
`
`-21
`
`-33
`
`+6
`-5
`-11
`-19
`
`-12
`-27
`
`-15
`-27
`
`-12
`
`-25
`
`HDL-C
`
`0
`+3
`+5
`+8
`
`+3
`+9
`
`+5
`+9
`
`+4
`
`+9
`
`

`
`
`
`Homozygous Familial Hypercholesterolemia (HoFH)
`A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH. This double-blind,
`randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or
`without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were
`randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA administered with
`atorvastatin or simvastatin (40 mg), or ZETIA administered with atorvastatin or simvastatin (80 mg). Due to
`decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine (see PRECAUTIONS),
`ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341
`mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the
`group randomized to ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. ZETIA, administered with
`atorvastatin or simvastatin (40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared
`with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with
`ZETIA plus 80 mg atorvastatin or with ZETIA plus 80 mg simvastatin, LDL-C was reduced by 27%.
`Homozygous Sitosterolemia (Phytosterolemia)
`A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia. In
`this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with
`elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins,
`HMG-CoA reductase inhibitors, ileal bypass surgery and/or LDL apheresis), were randomized to receive ZETIA
`(n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving
`cholestyramine (see PRECAUTIONS), ezetimibe was dosed at least 2 hours before or 4 hours after resins were
`administered. Excluding the one subject receiving LDL-apheresis, ZETIA significantly lowered plasma sitosterol
`and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had
`increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with
`ZETIA, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects
`of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality
`have not been established.
`Reductions in sitosterol and campesterol were consistent between patients taking ZETIA concomitantly with
`bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).
`
`INDICATIONS AND USAGE
`Primary Hypercholesterolemia
`Monotherapy
`ZETIA, administered alone, is indicated as adjunctive therapy to diet for the reduction of elevated total-C,
`LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.
`Combination therapy with HMG-CoA reductase inhibitors
`ZETIA, administered in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy
`to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial
`and non-familial) hypercholesterolemia.
`Homozygous Familial Hypercholesterolemia (HoFH)
`The combination of ZETIA and atorvastatin or simvastatin, is indicated for the reduction of elevated total-C
`and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or
`if such treatments are unavailable.
`Homozygous Sitosterolemia
`ZETIA is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol
`levels in patients with homozygous familial sitosterolemia.
`Therapy with lipid-altering agents should be a component of multiple risk-factor intervention in individuals at
`increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be
`used in addition to an appropriate diet (including restriction of saturated fat and cholesterol) and when the
`response to diet and other non-pharmacological measures has been inadequate. (See NCEP Adult Treatment
`Panel (ATP) III Guidelines, summarized in Table 7.)
`
`
`

`
`Table 7
`Summary of NCEP ATP III Guidelines
`
`LDL Level at Which to Initiate
`Therapeutic Lifestyle Changesa
`(mg/dL)
`
`LDL Goal
`(mg/dL)
`
`<100
`
`<130
`
`<160
`
`≥100
`
`≥130
`
`≥160
`
`LDL level at Which to
`Consider Drug Therapy
`(mg/dL)
`
`≥130
`(100-129: drug optional)d
`10-year risk 10-20%: ≥130c
`10-year risk <10%: ≥160c
`≥190
`(160-189: LDL-lowering
`drug optional)
`
`
`
`Risk Category
`
`CHD or CHD risk
`equivalentsb
`(10-year risk >20%)c
`2+ Risk factorse
`(10-year risk ≤20%)c
`
`0-1 Risk factorf
`
` a
`
` Therapeutic lifestyle changes include: 1) dietary changes: reduced intake of saturated fats (<7% of total calories) and cholesterol (<200 mg
`per day), and enhancing LDL lowering with plant stanols/sterols (2 g/d) and increased viscous (soluble) fiber (10-25 g/d), 2) weight reduction,
`and 3) increased physical activity.
`b CHD risk equivalents comprise: diabetes, multiple risk factors that confer a 10-year risk for CHD >20%, and other clinical forms of
`atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm and symptomatic carotid artery disease).
`c Risk assessment for determining the 10-year risk for developing CHD is carried out using the Framingham risk scoring. Refer to JAMA, May
`16, 2001; 285 (19): 2486-2497, or the NCEP website (http://www.nhlbi.nih.gov) for more details.
`d Some authorities recommend use of LDL-lowering drugs in this category if an LDL cholesterol <100 mg/dL cannot be achieved by therapeutic
`lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL, e.g., nicotinic acid or fibrate. Clinical judgment also
`may call for deferring drug therapy in this subcategory.
`e Major risk factors (exclusive of LDL cholesterol) that modify LDL goals include cigarette smoking, hypertension (BP ≥140/90 mm Hg or on
`anti-hypertensive medication), low HDL cholesterol (<40 mg/dL), family history of premature CHD (CHD in male first-degree relative <55
`years; CHD in female first-degree relative <65 years), age (men ≥45 years; women ≥55 years). HDL cholesterol ≥60 mg/dL counts as a
`“negative” risk factor; its presence removes one risk factor from the total count.
`f Almost all people with 0-1 risk factor have a 10-year risk <10%; thus, 10-year risk assessment in people with 0-1 risk factor is not necessary.
`
`Prior to initiating therapy with ZETIA, secondary causes for dyslipidemia (i.e., diabetes, hypothyroidism,
`obstructive liver disease, chronic renal failure, and drugs that increase LDL-C and decrease HDL-C [progestins,
`anabolic steroids, and corticosteroids]), should be excluded or, if appropriate, treated. A lipid profile should be
`performed to measure total-C, LDL-C, HDL-C and TG. For TG levels >400 mg/dL (>4.5 mmol/L), LDL-C
`concentrations should be determined by ultracentrifugation.
`At the time of hospitalization for an acute coronary event, lipid measures should be taken on admission or
`within 24 hours. These values can guide the physician on initiation of LDL-lowering therapy before or at
`discharge.
`
`CONTRAINDICATIONS
`Hypersensitivity to any component of this medication.
`
`The combination of ZETIA with an HMG-CoA reductase inhibitor is contraindicated in patients with active
`liver disease or unexplained persistent elevations in serum transaminases.
`All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA
`is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the
`pregnancy category and product labeling for the HMG-CoA reductase inhibitor. (See PRECAUTIONS,
`Pregnancy.)
`
`PRECAUTIONS
`Concurrent administration of ZETIA with a specific HMG-CoA reductase inhibitor should be in accordance
`with the product labeling for that HMG-CoA reductase inhibitor.
`
`

`
`
`
`Liver Enzymes
`In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 X the upper
`limit of normal [ULN]) in serum transaminases was similar between ZETIA (0.5%) and placebo
`(0.3%).
`In controlled clinical combination studies of ZETIA initiated concurrently with an HMG-CoA
`reductase inhibitor, the incidence of consecutive elevations (≥3 X ULN) in serum transaminases was
`1.3% for patients treated with ZETIA administered with HMG-CoA reductase inhibitors and 0.4% for
`patients treated with HMG-CoA reductase inhibitors alone. These elevations in transaminases were
`generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation
`of therapy or with continued treatment. When ZETIA is co-administered with an HMG-CoA reductase
`inhibitor, liver function tests should be performed at initiation of therapy and according to the
`recommendations of the HMG-CoA reductase inhibitor.
`Skeletal Muscle
`In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ZETIA compared with
`the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and
`rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs.
`In clinical trials, the in