Package Label.principal Display Panel

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

One 10 mg tablet once daily, with or without food ( 2.1 ) Dosing of ezetimibe tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ( 2.3 , 7.4 )

Ezetimibe Tablets USP, 10 mg white to off-white, capsule shaped beveled edge tablets debossed with "K 31" on one side and plain on other side. They are supplied as follows:              Blistercards of 30                   NDC 0615-8300-39             Blistercards of 15                   NDC 0615-8300-05              Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Ezetimibe tablets are contraindicated in the following conditions: The combination of ezetimibe tablets with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe tablets in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. [See Use in Specific Populations (8.1) .] Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ezetimibe tablets treatment in combination with a statin should be advised not to nurse their infants [see Use in Specific Populations (8.3) ]. Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe tablets [see Adverse Reactions (6.2) ] .

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 molecular formula is C 24 H 21 F 2 NO 3 . Its molecular weight is 409.4 and its structural formula is: Ezetimibe USP is a white crystalline powder that is freely to very soluble in ethanol, methanol, acetonitrile and acetone and practically insoluble in water. It is also insoluble in non-polar solvents such as hexane. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe tablets USP is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. USP dissolution test is pending.

 [See Clinical Pharmacology (12.3) .]

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.

It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

The effects of ezetimibe co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent  boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either ezetimibe co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the ezetimibe co-administered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week 6 are summarized in Table 3 . Results at Week 33 were consistent with those at Week 6. TABLE 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia   Total-C LDL-C Apo B Non-HDL-C TG* HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) (-9%, +4%) (-3%, +3%) * For triglycerides, median % change from baseline From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group. During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 X ULN) occurred in four (3%) individuals in the ezetimibe co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two (2%) individuals in the ezetimibe co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Co-administration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, ezetimibe has not been studied in patients younger than 10 years of age or in pre­menarchal girls. Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population < 10 years of age are not available.

Monotherapy Studies Of the 2396 patients who received ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. Statin Co-Administration Studies Of the 11,308 patients who received ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] .

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 typhimurium and Escherichia coli with 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).

The following serious adverse reactions are discussed in greater detail in other sections of the label: Liver enzyme abnormalities [see Warnings and Precautions (5.2) ] Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3) ] Monotherapy Studies: In the ezetimibe controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on ezetimibe and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were: Arthralgia (0.3%) Dizziness (0.2%) Gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the ezetimibe monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Co-Administration Studies: In the ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on ezetimibe + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ezetimibe + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: Alanine aminotransferase increased (0.6%) Myalgia (0.5%) Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the ezetimibe + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In the event of an overdose, symptomatic and supportive measures should be employed.

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 50 value 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 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 for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14 C-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.

Pregnancy Category C: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All statins are contraindicated in pregnant and nursing women. When ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4) .]

Monotherapy Ezetimibe tablets, administered alone, is indicated as adjunctive therapy  to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non­-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with HMG-CoA Reductase Inhibitors (Statins) Ezetimibe tablets, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy  to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with Fenofibrate Ezetimibe tablets, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.

Ezetimibe tablets USP, 10 mg are white to off-white, capsule shaped beveled edge tablets debossed with "K 31" on one side and plain on other side.

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 inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe 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) ] .

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 reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of ezetimibe 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 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.

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 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 10 mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe 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 14 C-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. 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 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 ≤30 mL/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 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 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% * 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 m 2 ) 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 TABLE 5: Effect of Ezetimibe Co-Administration on Systemic Exposure to Other Drugs Co-Administered Drug and its Dosage Regimen Ezetimibe Dosage Regimen Change in AUC of Co-Administered Drug Change in C max 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% * See Drug Interactions (7) .

Indications and Usage Addition of non-HDL lipid parameter to Monotherapy and Combination therapy ( 1.1 )                          07/2011 Dosage and Administration Patients with Renal Impairment ( 2.5 )                                         01/2012

Ezetimibe is not recommended in patients with moderate or severe hepatic impairment. ( 5.4 , 8.7 , 12.3 ) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when ezetimibe is added to a statin. Therefore, when ezetimibe is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used. ( 5.2 ) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Cases of myopathy and rhabdomyolysis have been reported in patients treated with ezetimibe co-administered with a statin and with ezetimibe administered alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age ( > 65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. ( 5.3 , 6.2)

PRINCIPAL DISPLAY PANEL

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.

One 10 mg tablet once daily, with or without food ( 2.1 ) Dosing of ezetimibe tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. ( 2.3 , 7.4 )

Ezetimibe Tablets USP, 10 mg white to off-white, capsule shaped beveled edge tablets debossed with "K 31" on one side and plain on other side. They are supplied as follows:              Blistercards of 30                   NDC 0615-8300-39             Blistercards of 15                   NDC 0615-8300-05              Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.

Ezetimibe tablets are contraindicated in the following conditions: The combination of ezetimibe tablets with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic transaminase levels. Women who are pregnant or may become pregnant. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, ezetimibe tablets in combination with a statin may cause fetal harm when administered to pregnant women. Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy. [See Use in Specific Populations (8.1) .] Nursing mothers. Because statins may pass into breast milk, and because statins have the potential to cause serious adverse reactions in nursing infants, women who require ezetimibe tablets treatment in combination with a statin should be advised not to nurse their infants [see Use in Specific Populations (8.3) ]. Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria have been reported with ezetimibe tablets [see Adverse Reactions (6.2) ] .

 [See Clinical Pharmacology (12.3) .]

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.

It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

The effects of ezetimibe co-administered with simvastatin (n=126) compared to simvastatin monotherapy (n=122) have been evaluated in adolescent  boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either ezetimibe co-administered with simvastatin or simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161 to 351 mg/dL) in the ezetimibe co-administered with simvastatin group compared to 219 mg/dL (range: 149 to 336 mg/dL) in the simvastatin monotherapy group. The patients received co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, co-administered ezetimibe and 40 mg simvastatin or 40 mg simvastatin monotherapy for the next 27 weeks, and open-label co-administered ezetimibe and simvastatin (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter. The results of the study at Week 6 are summarized in Table 3 . Results at Week 33 were consistent with those at Week 6. TABLE 3: Mean Percent Difference at Week 6 Between the Pooled Ezetimibe Co-Administered with Simvastatin Group and the Pooled Simvastatin Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia   Total-C LDL-C Apo B Non-HDL-C TG* HDL-C Mean percent difference between treatment groups -12% -15% -12% -14% -2% +0.1% 95% Confidence Interval (-15%, -9%) (-18%, -12%) (-15%, -9%) (-17%, -11%) (-9%, +4%) (-3%, +3%) * For triglycerides, median % change from baseline From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the ezetimibe co-administered with simvastatin group and in 2 (2%) patients in the simvastatin monotherapy group. During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 X ULN) occurred in four (3%) individuals in the ezetimibe co-administered with simvastatin group and in two (2%) individuals in the simvastatin monotherapy group. Elevations of CPK (≥10 X ULN) occurred in two (2%) individuals in the ezetimibe co-administered with simvastatin group and in zero individuals in the simvastatin monotherapy group. In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls. Co-administration of ezetimibe with simvastatin at doses greater than 40 mg/day has not been studied in adolescents. Also, ezetimibe has not been studied in patients younger than 10 years of age or in pre­menarchal girls. Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population < 10 years of age are not available.

Monotherapy Studies Of the 2396 patients who received ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older. Statin Co-Administration Studies Of the 11,308 patients who received ezetimibe + statin in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older. No overall differences in safety and effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] .

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 typhimurium and Escherichia coli with 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).

The following serious adverse reactions are discussed in greater detail in other sections of the label: Liver enzyme abnormalities [see Warnings and Precautions (5.2) ] Rhabdomyolysis and myopathy [see Warnings and Precautions (5.3) ] Monotherapy Studies: In the ezetimibe controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on ezetimibe and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were: Arthralgia (0.3%) Dizziness (0.2%) Gamma-glutamyltransferase increased (0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the ezetimibe monotherapy controlled clinical trial database of 2396 patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%), arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%). Statin Co-Administration Studies: In the ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on ezetimibe + statin and 3.3% of patients on statin alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with ezetimibe + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were: Alanine aminotransferase increased (0.6%) Myalgia (0.5%) Fatigue, aspartate aminotransferase increased, headache, and pain in extremity (each at 0.2%) The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the ezetimibe + statin controlled clinical trial database of 11,308 patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with homozygous sitosterolemia took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events. In the event of an overdose, symptomatic and supportive measures should be employed.

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 molecular formula is C 24 H 21 F 2 NO 3 . Its molecular weight is 409.4 and its structural formula is: Ezetimibe USP is a white crystalline powder that is freely to very soluble in ethanol, methanol, acetonitrile and acetone and practically insoluble in water. It is also insoluble in non-polar solvents such as hexane. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe tablets USP is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. USP dissolution test is pending.

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 50 value 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 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 for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of 14 C-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.

Pregnancy Category C: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus. In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 X the human exposure at 10 mg daily based on AUC 0-24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses. Multiple-dose studies of ezetimibe given in combination with statins in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy. All statins are contraindicated in pregnant and nursing women. When ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. [See Contraindications (4) .]

Monotherapy Ezetimibe tablets, administered alone, is indicated as adjunctive therapy  to diet for the reduction of elevated total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), and non­-high-density lipoprotein cholesterol (non-HDL-C) in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with HMG-CoA Reductase Inhibitors (Statins) Ezetimibe tablets, administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy  to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with primary (heterozygous familial and non-familial) hyperlipidemia. Combination Therapy with Fenofibrate Ezetimibe tablets, administered in combination with fenofibrate, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B, and non-HDL-C in adult patients with mixed hyperlipidemia.

Ezetimibe tablets USP, 10 mg are white to off-white, capsule shaped beveled edge tablets debossed with "K 31" on one side and plain on other side.

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 inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe 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) ] .

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 reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with hyperlipidemia. Administration of ezetimibe 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 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.

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 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 10 mg tablets. The C max value of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe 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 14 C-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. 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 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 ≤30 mL/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 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 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% * 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 m 2 ) 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 TABLE 5: Effect of Ezetimibe Co-Administration on Systemic Exposure to Other Drugs Co-Administered Drug and its Dosage Regimen Ezetimibe Dosage Regimen Change in AUC of Co-Administered Drug Change in C max 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% * See Drug Interactions (7) .

Indications and Usage Addition of non-HDL lipid parameter to Monotherapy and Combination therapy ( 1.1 )                          07/2011 Dosage and Administration Patients with Renal Impairment ( 2.5 )                                         01/2012

Ezetimibe is not recommended in patients with moderate or severe hepatic impairment. ( 5.4 , 8.7 , 12.3 ) Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic transaminase can occur when ezetimibe is added to a statin. Therefore, when ezetimibe is added to statin therapy, monitor hepatic transaminase levels before and during treatment according to the recommendations for the individual statin used. ( 5.2 ) Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Cases of myopathy and rhabdomyolysis have been reported in patients treated with ezetimibe co-administered with a statin and with ezetimibe administered alone. Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age ( > 65), hypothyroidism, renal impairment, and depending on the statin used, concomitant use of other drugs. ( 5.3 , 6.2)

PRINCIPAL DISPLAY PANEL