Package/Label Display Panel – Blister – 10 mg

Ezetimibe
Tablet, USP

10 mg

7 DRUG INTERACTIONS

[See Clinical Pharmacology (12.3).]

7.1 Cyclosporine

Caution should be exercised when using Ezetimibe Tablets and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe Tablets and cyclosporine.

The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe.

7.2 Fibrates

The efficacy and safety of co-administration of ezetimibe with fibrates other than fenofibrate have not been studied.

Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [see Nonclinical Toxicology (13.2)]. Co- administration of Ezetimibe Tablets with fibrates other than fenofibrate is not recommended until use in patients is adequately studied.

7.3 Fenofibrate

If cholelithiasis is suspected in a patient receiving Ezetimibe Tablets and fenofibrate, gallbladder studies are indicated and alternative lipid-lowering therapy should be considered [see Adverse Reactions (6.1) and the product labeling for fenofibrate].

7.4 Cholestyramine

Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.

7.5 Coumarin Anticoagulants

If ezetimibe is added to warfarin, a coumarin anticoagulant, the International Normalized Ratio (INR) should be appropriately monitored.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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, Ezetimibe Tablets inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe Tablets 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 (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.

Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes 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 statins and of fenofibrate [see Clinical Studies (14.1)].

12.2 Pharmacodynamics

Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human atherosclerosis. In addition, decreased levels of 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 TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Ezetimibe Tablets reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of Ezetimibe Tablets with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe Tablets with fenofibrate is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a statin or fenofibrate on cardiovascular morbidity and mortality have not been established.

12.3 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 Ezetimibe Tablets to fasted adults, mean ezetimibe peak plasma concentrations (C max) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (T max). Ezetimibe-glucuronide mean C max values of 45 to 71 ng/mL were achieved between 1 and 2 hours (T max). 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.

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 Ezetimibe tablets 10-mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe Tablets 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 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 radio activity 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.

Specific 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:[See Use in Specific Populations (8.4)]

**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 Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.

**Hepatic Impairment:**After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 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 impairment, 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 impairment, Ezetimibe Tablet is not recommended in these patients [see Warnings and Precautions (5.4)].

**Renal Impairment:**After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl ≤30mL/min/1.73 m 2), 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 Drug Interactions (7)]
Ezetimibe Tablets 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.

TABLE 4: Effect of Co-Administered Drugs on Total Ezetimibe

Based on 10 mg dose of ezetimibe † Post-renal transplant patients with mild impaired or normal renal function. In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. ‡ See Drug Interactions (7). § Supralox, 20 mL.
Co-Administered Drug and Dosing Regimen	Total Ezetimibe*
Change in AUC	Change in C****max
Cyclosporine-stable dose required (75 to 150 mg BID) †, ‡	↑240%	↑290%
Fenofibrate, 200 mg QD, 14 days ‡	↑48%	↑64%
Gemfibrozil, 600 mg BID, 7 days ‡	↑64%	↑91%
Cholestyramine, 4 g BID, 14 days ‡	↓55%	↓4%
Aluminum & magnesium hydroxide combination antacid, single dose §	↓4%	↓30%
Cimetidine, 400 mg BID, 7 days	↑6%	↑22%
Glipizide, 10 mg, single dose	↑4%	↓8%
Statins
Lovastatin 20 mg QD, 7 days	↑9%	↑3%
Pravastatin 20 mg QD, 14 days	↑7%	↑23%
Atorvastatin 10 mg QD, 14 days	↓2%	↑12%
Rosuvastatin 10 mg QD, 14 days	↑13%	↑18%
Fluvastatin 20 mg QD, 14 days	↓19%	↑7%

TABLE 5: Effect of Ezetimibe Co-Administration on Systemic Exposure to Other Drugs

See Drug Interactions (7).
Co-Administered Drug and its Dosage Regimen	Ezetimibe Dosage Regimen	Change in AUC of Co-Administered Drug	Change in Cmax of Co-Administered Drug
Warfarin, 25 mg single dose on day 7	10 mg QD, 11 days	↓2% (R-warfarin) ↓4% (S-warfarin)	↑3% (R-warfarin) ↑1% (S-warfarin)
Digoxin, 0.5 mg single dose	10 mg QD, 8 days	↑2%	↓7%
Gemfibrozil, 600 mg BID, 7 days *	10 mg QD, 7 days	↓1%	↓11%
Ethinyl estradiol & Levonorgestrel, QD, 21 days	10 mg QD, days 8 to14 of 21d oral contraceptive cycle	Ethinyl estradiol 0% Levonorgestrel 0%	Ethinyl estradiol ↓9% Levonorgestrel ↓5%
Glipizide, 10 mg on days 1 and 9	10 mg QD, days 2 to 9	↓3%	↓5%
Fenofibrate, 200 mg QD, 14 days *	10 mg QD, 14 days	↑11%	↑7%
Cyclosporine, 100 mg single dose day 7 *	20 mg QD, 8 days	↑15%	↑10%
Statins
Lovastatin 20 mg QD, 7 days	10 mg QD, 7 days	↑19%	↑3%
Pravastatin 20 mg QD, 14 days	10 mg QD, 14 days	↓20%	↓24%
Atorvastatin 10 mg QD, 14 days	10 mg QD, 14 days	↓4%	↑7%
Rosuvastatin 10 mg QD, 14 days	10 mg QD, 14 days	↑19%	↑17%
Fluvastatin 20 mg QD, 14 days	10 mg QD, 14 days	↓39%	↓27%

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week dietary carcinogenicity study with ezetimibe was conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20 x the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted in mice at doses up to 500 mg/kg/day (>150 x the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

No evidence of mutagenicity was observed in vitro in a microbial mutagenicity (Ames) test with Salmonella typhimuriumand Escherichia coliwith or without metabolic activation. No evidence of clastogenicity was observed in vitro in a chromosomal aberration assay in human peripheral blood lymphocytes with or without metabolic activation. In addition, there was no evidence of genotoxicity in the in vivo mouse micronucleus test.

In oral (gavage) fertility studies of ezetimibe conducted in rats, there was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male or female rats (~7 x the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe).

13.2 Animal Pharmacology and/or Toxicology

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 ED 50value of 0.5 mcg/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED 50 values in dogs, rats, and mice were 7, 30, and 700 mcg/kg/day, respectively. These results are consistent with Ezetimibe Tablets 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 to 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 to 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 Ezetimibe Tablets for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14C-cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl 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 statins (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

14 CLINICAL STUDIES

14.1 Primary Hyperlipidemia

Ezetimibe Tablets reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

Monotherapy
In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hyperlipidemia, Ezetimibe Tablets significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (seeTable 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

TABLE 6: Response to Ezetimibe Tablets in Patients with Primary Hyperlipidemia (Mean *% Change from Untreated Baseline †)

For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug ‡ Ezetimibe Tablets significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo.
	Treatment Group	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG†	HDL-C
Study 1‡	Placebo	205	+1	+1	-1	+1	-1	-1
Ezetimibe	622	-12	-18	-15	-16	-7	+1
Study 2‡	Placebo	226	+1	+1	-1	+2	+2	-2
Ezetimibe	666	-12	-18	-16	-16	-9	+1
Pooled Data‡ (Studies 1 & 2)	Placebo	431	0	+1	-2	+1	0	-2
Ezetimibe	1288	-13	-18	-16	-16	-8	+1

Combination with Statins
Ezetimibe Tablets Added to On-going Statin Therapy
In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hyperlipidemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe Tablets or placebo in addition to their on-going statin.

Ezetimibe Tablets, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (seeTable 7). LDL-C reductions induced by Ezetimibe Tablets were generally consistent across all statins.

TABLE 7: Response to Addition of Ezetimibe Tablets to On-Going Statin Therapy *in Patients with Hyperlipidemia (Mean †% Change from Treated Baseline ‡)

Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin) † For triglycerides, median % change from baseline ‡ Baseline - on a statin alone. § Ezetimibe Tablets + statin significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to statin alone.
Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG†	HDL-C
On-going Statin + Placebo §	390	-2	-4	-3	-3	-3	+1
On-going Statin + Ezetimibe Tablets §	379	-17	-25	-19	-23	-14	+3

Ezetimibe Tablets Initiated Concurrently with a Statin
In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe Tablets or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving Ezetimibe Tablets with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe Tablets significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the statin administered alone. LDL-C reductions induced by Ezetimibe Tablets were generally consistent across all statins. (See footnote ‡,Tables 8to11.)

TABLE 8: Response to Ezetimibe Tablets and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean *% Change from Untreated Baseline †)

For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug ‡ Ezetimibe Tablets + all doses of atorvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of atorvastatin pooled (10 to 80 mg).
Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG†	HDL-C
Placebo	60	+4	+4	+3	+4	-6	+4
Ezetimibe Tablets	65	-14	-20	-15	-18	-5	+4
Atorvastatin 10 mg	60	-26	-37	-28	-34	-21	+6
Ezetimibe Tablets + Atorvastatin 10 mg	65	-38	-53	-43	-49	-31	+9
Atorvastatin 20 mg	60	-30	-42	-34	-39	-23	+4
Ezetimibe Tablets + Atorvastatin 20 mg	62	-39	-54	-44	-50	-30	+9
Atorvastatin 40 mg	66	-32	-45	-37	-41	-24	+4
Ezetimibe Tablets + Atorvastatin 40 mg	65	-42	-56	-45	-52	-34	+5
Atorvastatin 80 mg	62	-40	-54	-46	-51	-31	+3
Ezetimibe Tablets + Atorvastatin 80 mg	63	-46	-61	-50	-58	-40	+7
Pooled data (All Atorvastatin Doses) ‡	248	-32	-44	-36	-41	-24	+4
Pooled data (All Ezetimibe Tablets + Atorvastatin Doses) ‡	255	-41	-56	-45	-52	-33	+7

TABLE 9: Response to Ezetimibe Tablets and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean *% Change from Untreated Baseline †)

For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug ‡ For triglycerides, median % change from baseline § Ezetimibe Tablets + all doses of simvastatin pooled (10 to 80 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10 to 80 mg).
Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG‡	HDL-C
Placebo	70	-1	-1	0	-1	+2	+1
Ezetimibe Tablets	61	-13	-19	-14	-17	-11	+5
Simvastatin 10 mg	70	-18	-27	-21	-25	-14	+8
Ezetimibe Tablets + Simvastatin 10 mg	67	-32	-46	-35	-42	-26	+9
Simvastatin 20 mg	61	-26	-36	-29	-33	-18	+6
Ezetimibe Tablets + Simvastatin 20 mg	69	-33	-46	-36	-42	-25	+9
Simvastatin 40 mg	65	-27	-38	-32	-35	-24	+6
Ezetimibe Tablets + Simvastatin 40 mg	73	-40	-56	-45	-51	-32	+11
Simvastatin 80 mg	67	-32	-45	-37	-41	-23	+8
Ezetimibe Tablets + Simvastatin 80 mg	65	-41	-58	-47	-53	-31	+8
Pooled data (All Simvastatin Doses) §	263	-26	-36	-30	-34	-20	+7
Pooled data (All Ezetimibe Tablets + Simvastatin Doses) §	274	-37	-51	-41	-47	-29	+9

TABLE 10: Response to Ezetimibe Tablets and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean *% Change from Untreated Baseline †)

For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug ‡ Ezetimibe Tablets + all doses of pravastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG compared to all doses of pravastatin pooled (10 to 40 mg).
Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG*	HDL-C
Placebo	65	0	-1	-2	0	-1	+2
Ezetimibe Tablets	64	-13	-20	-15	-17	-5	+4
Pravastatin 10 mg	66	-15	-21	-16	-20	-14	+6
Ezetimibe Tablets + Pravastatin 10 mg	71	-24	-34	-27	-32	-23	+8
Pravastatin 20 mg	69	-15	-23	-18	-20	-8	+8
Ezetimibe Tablets + Pravastatin 20 mg	66	-27	-40	-31	-36	-21	+8
Pravastatin 40 mg	70	-22	-31	-26	-28	-19	+6
Ezetimibe Tablets + Pravastatin 40 mg	67	-30	-42	-32	-39	-21	+8
Pooled data (All Pravastatin Doses) ‡	205	-17	-25	-20	-23	-14	+7
Pooled data (All Ezetimibe Tablets + Pravastatin Doses) ‡	204	-27	-39	-30	-36	-21	+8

TABLE 11: Response to Ezetimibe Tablets and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean *% Change from Untreated Baseline †)

For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug ‡ Ezetimibe Tablets + all doses of lovastatin pooled (10 to 40 mg) significantly reduced total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to all doses of lovastatin pooled (10 to 40 mg).
Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	Non-HDL-C	TG*	HDL-C
Placebo	64	+1	0	+1	+1	+6	0
Ezetimibe Tablets	72	-13	-19	-14	-16	-5	+3
Lovastatin 10 mg	73	-15	-20	-17	-19	-11	+5
Ezetimibe Tablets + Lovastatin 10 mg	65	-24	-34	-27	-31	-19	+8
Lovastatin 20 mg	74	-19	-26	-21	-24	-12	+3
Ezetimibe Tablets + Lovastatin 20 mg	62	-29	-41	-34	-39	-27	+9
Lovastatin 40 mg	73	-21	-30	-25	-27	-15	+5
Ezetimibe Tablets + Lovastatin 40 mg	65	-33	-46	-38	-43	-27	+9
Pooled data (All Lovastatin Doses) ‡	220	-18	-25	-21	-23	-12	+4
Pooled data (All Ezetimibe Tablets + Lovastatin Doses) ‡	192	-29	-40	-33	-38	-25	+9

Combination with Fenofibrate
In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe Tablets alone, 160 mg fenofibrate alone, or Ezetimibe Tablets and 160 mg fenofibrate in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe Tablets co- administered with fenofibrate or fenofibrate monotherapy for an additional 48 weeks.

Ezetimibe Tablets co-administered with fenofibrate significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe Tablets co-administered with fenofibrate were comparable to those for fenofibrate administered alone (see Table 12).

TABLE 12: Response to Ezetimibe Tablets and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean *% Change from Untreated Baseline †at 12 weeks)

For triglycerides, median % change from baseline † Baseline - on no lipid-lowering drug
Treatment (Daily Dose)	N	Total-C	LDL-C	Apo B	TG†	HDL-C	Non-HDL-C
Placebo	63	0	0	-1	-9	+3	0
Ezetimibe Tablets	185	-12	-13	-11	-11	+4	-15
Fenofibrate 160 mg	188	-11	-6	-15	-43	+19	-16
Ezetimibe Tablets + Fenofibrate 160 mg	183	-22	-20	-26	-44	+19	-30

The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe Tablets co-administered with fenofibrate or with fenofibrate alone were consistent with the 12-week data displayed above.

14.2 Homozygous Familial Hypercholesterolemia (HoFH)

A study was conducted to assess the efficacy of Ezetimibe Tablets 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), Ezetimibe Tablets administered with atorvastatin or simvastatin (40 mg), or Ezetimibe Tablets administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], 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 Ezetimibe Tablets plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe Tablets, 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 Ezetimibe Tablets plus 80 mg atorvastatin or with Ezetimibe Tablets plus 80 mg simvastatin, LDL-C was reduced by 27%.

14.3 Homozygous Sitosterolemia (Phytosterolemia)

A study was conducted to assess the efficacy of Ezetimibe Tablets 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, statins, ileal bypass surgery and/or LDL apheresis), were randomized to receive Ezetimibe Tablets (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine [see Drug Interactions (7.4)], ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe Tablets 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 Ezetimibe Tablets, 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 Ezetimibe Tablets concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

Limitations of Use
The effect of Ezetimibe Tablets on cardiovascular morbidity and mortality has not been determined.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling ( Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

17.1 Muscle Pain

All patients starting therapy with ezetimibe should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician.

17.2 Liver Enzymes

Liver tests should be performed when Ezetimibe Tablet is added to statin therapy and according to statin recommendations.

17.3 Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Ezetimibe Tablets added to statin therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination Ezetimibe Tablets and statin therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination Ezetimibe Tablets and statin therapy and call their healthcare professional.

17.4 Breastfeeding

Women who are breastfeeding should be advised to not use Ezetimibe Tablets added to statin therapy. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals.