Zetia Tablets (Merck/Schering Plough)

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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 C ₂₄ H ₂₁ F ₂ NO ₃ . Its molecular weight is 409.4 and its structural formula is:

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).

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 (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. 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 C _max 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 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.

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- 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 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 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 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. There have been post-marketing reports of increased International Normalized Ratio (INR) in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications (See PRECAUTIONS , Drug Interactions ).

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 (Supralox™ 20 mL) administration had no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on AUC values. The C _max 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, fluvastatin, or rosuvastatin. 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), fluvastatin (20 mg once daily), or rosuvastatin (10 mg once daily). (See PRECAUTIONS , Skeletal Muscle ).

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 C _max 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.

Cyclosporine:    In a study of eight post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and C _max values of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively, compared to a historical healthy control population (n=17). 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. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days with a single 100-mg dose of cyclosporine on Day 7 resulted in a mean 15% increase in cyclosporine AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of cyclosporine alone (see PRECAUTIONS , Drug Interactions ).

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 ED ₅₀ value of 0.5 µg/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 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 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 (0.3-5 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 ¹⁴ C-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.

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.

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.)

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 aphere-sis), 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.)

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 × 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 × 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 incidence of CPK >10 X ULN was 0.2% for ZETIA vs 0.1% for placebo, and 0.1% for ZETIA co-administered with an HMG-CoA reductase inhibitor vs 0.4% for HMG-CoA reductase inhibitors alone.

In post-marketing experience with ZETIA, cases of myopathy and rhabdomyolysis have been reported regardless of causality. Most patients who developed rhabdomyolysis were taking an HMG-CoA reductase inhibitor prior to initiating ZETIA. However, rhabdomyolysis has been reported very rarely with ZETIA monotherapy and very rarely with the addition of ZETIA to agents known to be associated with increased risk of rhabdomyolysis, such as fibrates. 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. ZETIA and any HMG-CoA reductase inhibitor or fibrate that the patient is taking concomitantly should be immediately discontinued if myopathy is diagnosed or suspected. The presence of these symptoms and a creatine phosphokinase (CPK) level >10 times the ULN indicates myopathy.

Hepatic Insufficiency

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 CLINICAL PHARMACOLOGY , Special Populations .)

Drug Interactions   (See also CLINICAL PHARMACOLOGY , Drug Interactions )

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

Fibrates:    The safety and effectiveness of ezetimibe administered with fibrates have not been established.

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 ANIMAL PHARMACOLOGY ). Co-administration of ZETIA with fibrates is not recommended until use in patients is studied.

Fenofibrate:    In a pharmacokinetic study, concomitant fenofibrate administration increased total ezetimibe concentrations approximately 1.5-fold.

Gemfibrozil:    In a pharmacokinetic study, concomitant gemfibrozil administration increased total ezetimibe concentrations approximately 1.7-fold.

HMG-CoA Reductase Inhibitors:    No clinically significant pharmacokinetic interactions were seen when ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.

Cyclosporine:    Caution should be exercised when using ZETIA and cyclosporine concomitantly due to increased exposure to both ezetimibe and cyclosporine. Cyclosporine concentrations should be monitored in patients receiving ZETIA 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. In a pharmacokinetic study in post-renal transplant patients with mildly impaired or normal renal function (creatinine clearance of >50 mL/min), concomitant cyclosporine administration increased the mean AUC and C _max of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively. In a separate study, the total ezetimibe exposure increased 12-fold in one renal transplant patient with severe renal insufficiency receiving multiple medications, including cyclosporine (see CLINICAL PHARMACOLOGY , Drug Interactions ).

Warfarin:    If ezetimibe is added to warfarin, the International Normalized Ratio should be appropriately monitored.

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 times 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 times 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 times the human exposure at 10 mg daily based on AUC _0-24hr for total ezetimibe).

Pregnancy

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 times 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 times 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 HMG-CoA reductase inhibitors (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 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 CONTRAINDICATIONS .)

Labor and Delivery

The effects of ZETIA on labor and delivery in pregnant women are unknown.

Nursing Mothers

In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. It is not known whether ezetimibe is excreted into human breast milk; therefore, ZETIA should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.

Pediatric Use

The pharmacokinetics of ZETIA in adolescents (10 to 18 years) have been shown to be similar to that in adults. Treatment experience with ZETIA in the pediatric population is limited to 4 patients (9 to 17 years) in the sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment with ZETIA in children (<10 years) is not recommended. (See CLINICAL PHARMACOLOGY , Special Populations .)

Geriatric Use

Of the patients who received ZETIA in clinical studies, 948 were 65 and older (this included 206 who were 75 and older). The effectiveness and safety of ZETIA were similar between these patients and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. (See CLINICAL PHARMACOLOGY , Special Populations , and ADVERSE REACTIONS .)

ADVERSE REACTIONS

ZETIA has been evaluated for safety in more than 4700 patients in clinical trials. Clinical studies of ZETIA (administered alone or with an HMG-CoA reductase inhibitor) demonstrated that ZETIA was generally well tolerated. The overall incidence of adverse events reported with ZETIA was similar to that reported with placebo, and the discontinuation rate due to adverse events was also similar for ZETIA and placebo.

Monotherapy

Adverse experiences reported in >/=2% of patients treated with ZETIA and at an incidence greater than placebo in placebo-controlled studies of ZETIA, regardless of causality assessment, are shown in Table 8.

The frequency of less common adverse events was comparable between ZETIA and placebo.

Combination with an HMG-CoA Reductase Inhibitor

ZETIA has been evaluated for safety in combination studies in more than 2000 patients.

In general, adverse experiences were similar between ZETIA administered with HMG-CoA reductase inhibitors and HMG-CoA reductase inhibitors alone. However, the frequency of increased transaminases was slightly higher in patients receiving ZETIA administered with HMG-CoA reductase inhibitors than in patients treated with HMG-CoA reductase inhibitors alone. (See PRECAUTIONS , Liver Enzymes .)

Clinical adverse experiences reported in >/=2% of patients and at an incidence greater than placebo in four placebo-controlled trials where ZETIA was administered alone or initiated concurrently with various HMG-CoA reductase inhibitors, regardless of causality assessment, are shown in Table 9.

Post-marketing Experience

The following adverse reactions have been reported in post-marketing experience, regardless of causality assessment:

Hypersensitivity reactions, including angioedema, rash, and urticaria; arthralgia; myalgia; elevated creatine phosphokinase; myopathy/rhabdomyolysis (very rarely; see PRECAUTIONS , Skeletal Muscle ); elevations in liver transaminases; hepatitis; thrombocytopenia; pancreatitis; nausea; cholelithiasis; cholecystitis.

OVERDOSAGE

In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, or 40 mg/day to 18 patients with primary hypercholesterolemia for up to 56 days, was generally well tolerated.

A few cases of overdosage with ZETIA have been reported; most have not been associated with adverse experiences. Reported adverse experiences have not been serious. In the event of an overdose, symptomatic and supportive measures should be employed.

DOSAGE AND ADMINISTRATION

The patient should be placed on a standard cholesterol-lowering diet before receiving ZETIA and should continue on this diet during treatment with ZETIA.

The recommended dose of ZETIA is 10 mg once daily. ZETIA can be administered with or without food.

ZETIA may be administered with an HMG-CoA reductase inhibitor for incremental effect. For convenience, the daily dose of ZETIA may be taken at the same time as the HMG-CoA reductase inhibitor, according to the dosing recommendations for the HMG-CoA reductase inhibitor.

Patients with Hepatic Insufficiency

No dosage adjustment is necessary in patients with mild hepatic insufficiency (see PRECAUTIONS , Hepatic Insufficiency ).

Patients with Renal Insufficiency

No dosage adjustment is necessary in patients with renal insufficiency (see CLINICAL PHARMACOLOGY , Special Populations ).

Geriatric Patients

No dosage adjustment is necessary in geriatric patients (see CLINICAL PHARMACOLOGY , Special Populations ).

Co-administration with Bile Acid Sequestrants

Dosing of ZETIA should occur either >/=2 hours before or >/=4 hours after administration of a bile acid sequestrant (see PRECAUTIONS , Drug Interactions ).

HOW SUPPLIED

No. 3861 - Tablets ZETIA, 10 mg, are white to off-white, capsule-shaped tablets debossed with "414" on one side. They are supplied as follows:

NDC 66582-414-31 bottles of 30

NDC 66582-414-54 bottles of 90

NDC 66582-414-74 bottles of 500

NDC 66582-414-28 unit dose packages of 100.

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.] Protect from moisture.

29480907T

REV 08

Issued July 2005

Printed in USA.

Manufactured for:

Merck/Schering-Plough Pharmaceuticals

North Wales, PA 19454, USA

By:

Schering Corporation

Kenilworth, NJ 07033, USA

or

Merck & Co., Inc.

Whitehouse Station, NJ 08889, USA

COPYRIGHT © Merck/Schering-Plough Pharmaceuticals, 2001, 2002, All rights reserved.

ZETIA® (ezetimibe) Tablets

Patient Information about ZETIA (z[ebreve]t'-e-[abreve])

Generic name: ezetimibe ([ebreve]-z[ebreve]t'-[ebreve]-mib)

Read this information carefully before you start taking ZETIA and each time you get more ZETIA. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ZETIA, ask your doctor. Only your doctor can determine if ZETIA is right for you.

What is ZETIA?

ZETIA is a medicine used to lower levels of total cholesterol and LDL (bad) cholesterol in the blood. It is used for patients who cannot control their cholesterol levels by diet alone. It can be used by itself or with other medicines to treat high cholesterol. You should stay on a cholesterol-lowering diet while taking this medicine.

ZETIA works to reduce the amount of cholesterol your body absorbs. ZETIA does not help you lose weight.

For more information about cholesterol, see the "What should I know about high cholesterol?" section that follows.

Who should not take ZETIA?

• Do not take ZETIA if you are allergic to ezetimibe, the active ingredient in ZETIA, or to the inactive ingredients. For a list of inactive ingredients, see the "Inactive ingredients" section that follows.
• If you have active liver disease, do not take ZETIA while taking cholesterol-lowering medicines called statins.
• If you are pregnant or breast-feeding, do not take ZETIA while taking a statin.

What should I tell my doctor before and while taking ZETIA?

Tell your doctor about any prescription and non-prescription medicines you are taking or plan to take, including natural or herbal remedies.

Tell your doctor about all your medical conditions including allergies.

Tell your doctor if you:

• ever had liver problems. ZETIA may not be right for you.
• are pregnant or plan to become pregnant. Your doctor will decide if ZETIA is right for you.
• are breast-feeding. We do not know if ZETIA can pass to your baby through your milk. Your doctor will decide if ZETIA is right for you.
• experience unexplained muscle pain, tenderness, or weakness.

How should I take ZETIA?

• Take ZETIA once a day, with or without food. It may be easier to remember to take your dose if you do it at the same time every day, such as with breakfast, dinner, or at bedtime. If you also take another medicine to reduce your cholesterol, ask your doctor if you can take them at the same time.
• If you forget to take ZETIA, take it as soon as you remember. However, do not take more than one dose of ZETIA a day.
• Continue to follow a cholesterol-lowering diet while taking ZETIA. Ask your doctor if you need diet information.
• Keep taking ZETIA unless your doctor tells you to stop. It is important that you keep taking ZETIA even if you do not feel sick.

See your doctor regularly to check your cholesterol level and to check for side effects. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment.

What are the possible side effects of ZETIA?

In clinical studies patients reported few side effects while taking ZETIA. These included stomach pain and feeling tired.

Very rarely, patients have experienced severe muscle problems while taking ZETIA, usually when ZETIA was added to a statin drug. If you experience unexplained muscle pain, tenderness, or weakness while taking ZETIA, contact your doctor immediately. You need to do this promptly, because on rare occasions, these mucle problems can be serious, with muscle breakdown resulting in kidney damage.

Additionally, the following side effects have been reported in general use: allergic reactions (which may require treatment right away) including swelling of the face, lips, tongue, and/or throat that may cause difficulty in breathing or swallowing, rash, and hives; joint pain; muscle aches; alterations in some laboratory blood tests; liver problems; inflammation of the pancreas; nausea; gallstones; inflammation of the gallbladder.

Tell your doctor if you are having these or any other medical problems while on ZETIA. For a complete list of side effects, ask your doctor or pharmacist.

What should I know about high cholesterol?

Cholesterol is a type of fat found in your blood. Your total cholesterol is made up of LDL and HDL cholesterol.

LDL cholesterol is called "bad" cholesterol because it can build up in the wall of your arteries and form plaque. Over time, plaque build-up can cause a narrowing of the arteries. This narrowing can slow or block blood flow to your heart, brain, and other organs. High LDL cholesterol is a major cause of heart disease and stroke.

HDL cholesterol is called "good" cholesterol because it keeps the bad cholesterol from building up in the arteries.

Triglycerides also are fats found in your blood.

General Information about ZETIA

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ZETIA for a condition for which it was not prescribed. Do not give ZETIA to other people, even if they have the same condition you have. It may harm them.

This summarizes the most important information about ZETIA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about ZETIA that is written for health professionals.

Inactive ingredients:

Croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.

29480800T

Rev 08

Issued July 2005

Manufactured for:

Merck/Schering-Plough Pharmaceuticals

North Wales, PA 19454, USA

By:

Schering Corporation

Kenilworth, NJ 07033, USA

or

Merck & Co., Inc.

Whitehouse Station, NJ 08889, USA

All right reserved.

Printed in USA.

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