FDA Approves ZETIA, ezetimibe, for Cholesterol Reduction.

Business Editors/Health & Pharmaceutical Writers

WHITEHOUSE STATION & KENILWORTH, N.J.--(BUSINESS WIRE)--Oct. 28, 2002

First New Class To Treat Cholesterol Since Statins Introduced 15

Years Ago; Studies Show Significant Reductions in LDL

Cholesterol When Added to All Statins Tested

Following a 10-month review, the FDA has approved ZETIA(TM) (ezetimibe), the first in a new class of cholesterol-lowering agents that inhibits the intestinal absorption of cholesterol, Merck/Schering-Plough Pharmaceuticals announced today. The once-daily tablet of ZETIA 10 mg was approved for use either by itself or together with statins in patients with high cholesterol to reduce LDL "bad" cholesterol and total cholesterol. Cholesterol-lowering medicines should be used in addition to an appropriate diet when the response to diet and exercise has been inadequate.

In clinical trials, ZETIA was generally well tolerated with an overall side effect profile similar to placebo.

"Sixty percent of the estimated 13 million patients taking statins continue to have LDL cholesterol higher than recommended levels," said H. Bryan Brewer, M.D., chief of the molecular disease branch, National Heart, Lung and Blood Institute, National Institutes of Health (NIH). "As the first breakthrough to treat cholesterol since statins were introduced 15 years ago, ZETIA provides physicians with a new option to get more of these patients to goal. This is particularly important in view of last year's changes to the NIH's cholesterol guidelines, which substantially expand the number of Americans eligible for drug therapy and call for lower cholesterol goals for many patients," he said.

"Discovered by Schering-Plough scientists and developed in partnership with Merck, ZETIA offers patients an important therapeutic advance in the treatment of high cholesterol," said Richard Jay Kogan, chairman and chief executive officer of Schering-Plough. "ZETIA is expected to be a major growth driver for Schering-Plough and an important new entry in the global cholesterol management market, now valued at $19 billion," he added.

ZETIA has a unique, complementary mechanism of action

Cholesterol in the blood is controlled primarily by two organs: the liver, which produces cholesterol and bile acids (which are used in digestion), and the intestine, which absorbs cholesterol both from food and from the bile (made by the liver). ZETIA lowers cholesterol through a unique mechanism of action by inhibiting cholesterol absorption in the intestine. This mechanism of action makes ZETIA complementary to statins, which work in the liver. Therefore, patients who take ZETIA with a statin can achieve additional reductions in LDL and total cholesterol. The mechanism of ZETIA is also quite different from a currently available class of drugs known as "bile acid sequestrants," which lower cholesterol by physically binding to bile acids in the small intestine.

ZETIA is administered as a once-daily tablet in a single 10 mg strength. It can be taken with or without food.

ZETIA is a prescription medicine and should not be taken by people who are allergic to any of its ingredients. When ZETIA is prescribed with a statin, it should not be taken by anyone with active liver disease or unexplained persistent liver enzyme elevations. All statins are contraindicated in such patients and in pregnant and nursing women. When ZETIA is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin.

ZETIA added to ongoing statin treatment provided 25 percent (36 mg/dL) additional LDL cholesterol reduction vs. 4 percent (6 mg/dL) with addition of placebo

In a pivotal, multi-center study known as the "Add-On" study, patients who had not reached their LDL cholesterol goal on a stable dose of a statin alone had ZETIA or placebo added to their statin regimen. The statin dose remained constant. The study showed that adding ZETIA to ongoing statin treatment provided a 25 percent (36 mg/dL) additional reduction in LDL cholesterol versus 4 percent (6 mg/dL) with the addition of placebo. Mean LDL cholesterol levels of patients on statin therapy dropped from 138 mg/dL to 102 mg/dL when ZETIA was added versus a drop from 139 mg/dL to 133 mg/dL when placebo was added. Most of the response in LDL cholesterol reduction was seen within two weeks of adding ZETIA and the additive reduction provided by ZETIA was generally consistent across all statins tested.

"The approval of ZETIA represents a major success of the U.S. joint venture between Merck and Schering-Plough and demonstrates the value of external collaboration and key strategic partnerships," said Raymond V. Gilmartin, chairman, president and chief executive officer, Merck & Co., Inc. "There is tremendous potential for ZETIA to positively impact the treatment of millions of statin-treated patients who need additional cholesterol reduction."

Seventy-two percent of statin-treated patients not at goal reached NCEP II goal when ZETIA was added to ongoing statin treatment vs. 19 percent with addition of placebo

Another important endpoint of the "Add-On" study was the percentage of patients who reached the National Cholesterol Education Program (NCEP) II target LDL cholesterol goal when either ZETIA or placebo was added to their ongoing statin therapy. The study showed that 72 percent of the patients who were not at goal on their statin dose at baseline reached goal when ZETIA was added, compared to 19 percent of patients with the addition of placebo.

Patients enrolled in the study had been taking any dose of a marketed statin for a minimum of six weeks and had not reached their LDL cholesterol goal. At the beginning of the study, mean baseline LDL cholesterol concentrations were 139 mg/dL for the statin plus placebo group versus 138 mg/dL for the group on statin plus ZETIA. Sixty-eight percent of these patients had LDL cholesterol goal <=100 mg/dL, 23 percent had a goal of <130 mg/dL and 10 percent had a goal of <160 mg/dL.

ZETIA delivered significant reductions in LDL cholesterol when co-administered with all statins tested, including Lipitor and Zocor

The U.S. approval of ZETIA was also based on four placebo-controlled co-administration studies, in which ZETIA and either Lipitor (atorvastatin), Zocor (simvastatin), Pravachol (pravastatin) or Mevacor (lovastatin) were started together in previously untreated patients with high cholesterol levels.

"These studies showed that ZETIA, given with statins, provided impressive reductions in LDL cholesterol compared to statins alone and at all doses tested," said Michael Davidson, M.D., director of preventive cardiology, Rush-Presbyterian-St. Luke's Medical School, Chicago. "This includes the two most commonly used statins, Lipitor and Zocor, demonstrating consistent efficacy while also being generally well tolerated."

When ZETIA was initiated with Lipitor 10 mg, the most frequently prescribed starting dose, there was a 53 percent reduction in LDL cholesterol from the original untreated baseline. This was significantly more effective than the LDL cholesterol-lowering achieved by Lipitor 10 mg (37 percent), Lipitor 20 mg (42 percent), or 40 mg (45 percent) alone. ZETIA provided significant reductions across all doses of Lipitor.

A similar study with Zocor showed that administering ZETIA with Zocor 20 mg, the most frequently prescribed starting dose, resulted in a 46 percent reduction in LDL cholesterol. This was significantly more effective than reductions achieved with 20 mg (36 percent) or 40 mg (38 percent) of Zocor alone, and was similar to the LDL cholesterol reduction seen with Zocor 80 mg (45 percent) by itself. ZETIA provided significant reductions across all doses of Zocor.

Both of these studies were 12-week, double-blind studies in patients with high cholesterol (n=628 for the co-administration study with Lipitor; n=668 for the co-administration study with Zocor), evaluating the efficacy and safety of ZETIA on LDL cholesterol when given with either Lipitor or Zocor, compared to these statins taken alone. Mean baseline LDL cholesterol in these studies ranged from 176 mg/dL to 180 mg/dL across treatment groups.

ZETIA co-administered with Lipitor and Zocor further improved triglycerides and HDL "good" cholesterol

In patients with elevated LDL cholesterol, ZETIA, when used with statins, was also shown in the co-administration studies with Lipitor and Zocor to reduce triglycerides and increase HDL "good" cholesterol more than the statins alone.

In the co-administration study with Lipitor:

-- 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.

The results from the co-administration study with Zocor showed:

- Triglycerides were reduced by 29 percent with ZETIA plus Zocor

compared to 20 percent for Zocor alone.

- HDL cholesterol was improved by 9 percent with ZETIA plus

Zocor versus 7 percent for Zocor alone.

These results were statistically significant and reflect average changes across all statin doses. The effect of ZETIA alone or in addition to a statin on the risk of cardiovascular morbidity and mortality has not been established.

ZETIA demonstrated an excellent safety and tolerability profile

ZETIA has been evaluated for safety in more than 4,700 patients in clinical trials. Clinical studies of ZETIA (administered alone or with a statin) 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.

For monotherapy, the most frequent adverse events reported with greater incidence than placebo, regardless of causality, were back pain (4.1 percent vs. 3.9 percent) and arthralgia (3.8 percent vs. 3.4 percent). In co-administration with a statin, the most frequent adverse events reported with greater incidence for ZETIA plus statin versus statin or placebo alone, regardless of causality, were back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent, respectively) and abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent, respectively).

When ZETIA was co-administered with a statin, consecutive elevations in liver enzymes more than three times the upper limit of normal were slightly higher than those of statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. ZETIA had no significant effect on drugs known to be metabolized by the cytochrome P450 system. Co-administration with cholestyramine has been shown to decrease the bioavailability of ZETIA while co-administration with gemfibrozil has been shown to increase the bioavailability. Because of significantly increased blood levels of ZETIA in one patient on multiple medications including cyclosporine, patients who take both ZETIA and cyclosporine should be carefully monitored.

Important information about ZETIA

When ZETIA is used with a statin, liver function tests should be performed at the start of therapy and after that in accordance with the label for that statin. Liver function tests are not required when ZETIA is used alone. Due to the unknown effects of the increased exposure to ZETIA in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients. In clinical trials, there was no increased incidence of myopathy or rhabdomyolysis associated with ZETIA. However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. There are no adequate and well-controlled studies of ZETIA in pregnant women. ZETIA should not be used in pregnant or nursing women unless the benefit outweighs the potential risks. The safety and effectiveness of ZETIA with fibrates have not been established; therefore, co-administration with fibrates is not recommended.

Other indications

The FDA also approved ZETIA for use in two rare genetic disorders: homozygous familial hypercholesterolemia and homozygous sitosterolemia. In homozygous familial hypercholesterolemia, ZETIA, administered with Lipitor or Zocor, is indicated for the reduction of elevated total cholesterol and LDL cholesterol as an adjunct to other lipid-lowering treatments.

In sitosterolemia, ZETIA is indicated as adjunctive therapy for the reduction of elevated sitosterol and campesterol levels in addition to diet. ZETIA is the only medicine approved for this serious condition.

Price and availability

The catalog price to all direct purchasers for ZETIA 10 mg is $57.90 for a 30-day supply. Prices at the retail level are independently established by pharmacies, not by Merck/Schering-Plough Pharmaceuticals. The 10 mg tablets of ZETIA should be widely available in pharmacies within two to three weeks.

About Merck/Schering-Plough Pharmaceuticals

Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed in May 2000 to develop and market in the United States new prescription medicines in cholesterol management. The collaboration was expanded in December 2001 to include worldwide markets (excluding Japan).

MERCK FORWARD-LOOKING STATEMENT: This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties which may cause results to differ materially from those set forth in the statements. The forward-looking statements include statements regarding product development and product potential. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Additional detailed information concerning a number of factors that could cause actual results to differ materially is available in Item 1 of Merck's Annual Report on Form 10-K for the year ended Dec. 31, 2001, in its periodic reports on Form 10-Q and in its reports on Form 8-K (if any). Copies of these forms are available on request to Merck's Office of Stockholder Services.

SCHERING-PLOUGH FORWARD-LOOKING STATEMENT: The information in this press release includes certain "forward-looking" information including the size of the cholesterol treatment market, the market potential for ZETIA and its projected availability in the marketplace. The reader of this release should understand that the extent that ZETIA will be prescribed will be determined by market forces and the market viability of ZETIA is subject to substantial risks and uncertainties. In addition, the forward-looking statements may also be adversely affected by general market factors, competitive product development, product availability, the extent of market acceptance of new products, current and future branded, generic or over-the-counter competition, federal and state regulations and legislation, the regulatory process for new products and indications, manufacturing issues, trade buying patterns, patent positions, litigation and investigations. For further details and a discussion of these and other risks and uncertainties, see the company's Securities and Exchange Commission filings, including the company's 2001 annual report on Form 10-K and subsequent quarterly reports on Form 10-Q and current reports on Form 8-K.

Full prescribing information and patient product information for ZETIA(TM) is attached.

ZETIA(TM)is a trademark of MSP Marketing Services(c)LLC. All other brands are trademarks of their respective owners and are not trademarks of MSP Marketing Services(c)LLC.

ZETIA(TM)

(EZETIMIBE)

TABLETS

DESCRIPTION

ZETIA (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl)-3(S)-hydroxypropyl)-4(S)- (4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is:

(GRAPHIC OMITTED)

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(degree)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 (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection. Ezetimibe has variable bioavailability; the coefficient of variation, based on inter-subject variability, was 35 to 60% for values.

Effect of Food on Oral Absorption

Concomitant food administration (high fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ZETIA 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high fat meals. ZETIA can be administered with or without food.

Distribution

Ezetimibe and ezetimibe-glucuronide are highly bound (> 90%) to human plasma proteins.

Metabolism and Excretion

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.

In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are slowly eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

Special Populations

Geriatric Patients

In a multiple dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (=> 65 years) healthy subjects compared to younger subjects.

Pediatric Patients

In a multiple dose study with ezetimibe given 10 mg once daily for 7 days, the absorption and metabolism of ezetimibe were similar in adolescents (10 to 18 years) and adults. Based on total ezetimibe, there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population < 10 years of age are not available.

Gender

In a multiple dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (< 20%) in women than in men.

Race

Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Blacks and Caucasians. There were too few patients in other racial or ethnic groups to permit further pharmacokinetic comparisons.

Hepatic Insufficiency

After a single 10-mg dose of ezetimibe, the mean area under the curve (AUC) for total ezetimibe was increased approximately 1.7-fold in patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3-4 fold and 5-6 fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate hepatic insufficiency, the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients (see CONTRAINDICATIONS and PRECAUTIONS, Hepatic Insufficiency).

Renal Insufficiency

After a single 10-mg dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl < 30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9). Drug Interactions (See also PRECAUTIONS, Drug Interactions)

ZETIA had no significant effect on a series of probe drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study of twelve healthy adult males. This indicates that ezetimibe is neither an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely that ezetimibe will affect the metabolism of drugs that are metabolized by these enzymes.

Warfarin: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males.

Digoxin: Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of digoxin and the ECG parameters (HR, PR, QT, and QTc intervals) in a study of twelve healthy adult males.

Gemfibrozil: In a study of twelve healthy adult males, concomitant administration of gemfibrozil (600 mg twice daily) significantly increased the oral bioavailability of total ezetimibe by a factor of 1.7. Ezetimibe (10 mg once daily) did not significantly affect the bioavailability of gemfibrozil.

Oral Contraceptives: Co-administration of ezetimibe (10 mg once daily) with oral contraceptives had no significant effect on the bioavailability of ethinyl estradiol or levonorgestrel in a study of eighteen healthy adult females.

Cimetidine: Multiple doses of cimetidine (400 mg twice daily) had no significant effect on the oral bioavailability of ezetimibe and total ezetimibe in a study of twelve healthy adults.

Antacids: In a study of twelve healthy adults, a single dose of antacid (Supralox(TM) 20 mL) administration had no significant effect on the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or ezetimibe based on AUC values. The Cmax value of total ezetimibe was decreased by 30%.

Glipizide: In a study of twelve healthy adult males, steady-state levels of ezetimibe (10 mg once daily) had no significant effect on the pharmacokinetics and pharmacodynamics of glipizide. A single dose of glipizide (10 mg) had no significant effect on the exposure to total ezetimibe or ezetimibe.

HMG-CoA reductase inhibitors: In studies of healthy hypercholesterolemic (LDL-C => 130 mg/dl) adult subjects, concomitant administration of ezetimibe (10 mg once daily) had no significant effect on the bioavailability of either lovastatin, simvastatin, pravastatin, atorvastatin, or fluvastatin. No significant effect on the bioavailability of total ezetimibe and ezetimibe was demonstrated by either lovastatin (20 mg once daily), pravastatin (20 mg once daily), atorvastatin (10 mg once daily), or fluvastatin (20 mg once daily).

Fenofibrate: In a study of thirty-two healthy hypercholesterolemic (LDL-C => 130 mg/dl) adult subjects, concomitant fenofibrate (200 mg once daily) administration increased the mean Cmax and AUC values of total ezetimibe approximately 64% and 48%, respectively. Pharmacokinetics of fenofibrate were not significantly affected by ezetimibe (10 mg once daily).

Cholestyramine: In a study of forty healthy hypercholesterolemic (LDL-C => 130 mg/dl) adult subjects, concomitant cholestyramine (4 g twice daily) administration decreased the mean AUC values of total ezetimibe and ezetimibe approximately 55% and 80%, respectively.

ANIMAL PHARMACOLOGY

The hypocholesterolemic effect of ezetimibe was evaluated in cholesterol-fed Rhesus monkeys, dogs, rats, and mouse models of human cholesterol metabolism. Ezetimibe was found to have an ED50 value of 0.5 (mu)g/kg/day for inhibiting the rise in plasma cholesterol levels in monkeys. The ED50 values in dogs, rats, and mice were 7, 30, and 700 (mu)g/kg/day, respectively. These results are consistent with ZETIA being a potent cholesterol absorption inhibitor.

In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was administered intraduodenally, the metabolite was as potent as the parent compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting that the glucuronide metabolite had activity similar to the parent drug.

In 1-month studies in dogs given ezetimibe (0.03-300 mg/kg/day), the concentration of cholesterol in gallbladder bile increased 2- to 4-fold. However, a dose of 300 mg/kg/day administered to dogs for one year did not result in gallstone formation or any other adverse hepatobiliary effects. In a 14-day study in mice given ezetimibe (0.3-5 mg/kg/day) and fed a low-fat or cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was either unaffected or reduced to normal levels, respectively.

Editor's Note: There is a tilde sign before the number 2 in xxx bile increased 2- to 4-fold xxx

A series of acute preclinical studies was performed to determine the selectivity of ZETIA for inhibiting cholesterol absorption. Ezetimibe inhibited the absorption of C14 cholesterol with no effect on the absorption of triglycerides, fatty acids, bile acids, progesterone, ethyl estradiol, or the fat-soluble vitamins A and D.

In 4- to 12-week toxicity studies in mice, ezetimibe did not induce cytochrome P450 drug metabolizing enzymes. In toxicity studies, a pharmacokinetic interaction of ezetimibe with HMG-CoA reductase inhibitors (parents or their active hydroxy acid metabolites) was seen in rats, dogs, and rabbits.

CLINICAL STUDIES

Primary Hypercholesterolemia

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

ZETIA is effective in patients with hypercholesterolemia, in men and women, in younger and older patients, alone or administered with an HMG-CoA reductase inhibitor. Experience in pediatric and adolescent patients (ages 9 to 17) has been limited to patients with homozygous familial hypercholesterolemia (HoFH) or sitosterolemia.

Experience in non-Caucasians is limited and does not permit a precise estimate of the magnitude of the effects of ZETIA.

Monotherapy

In two, multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary hypercholesterolemia, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to placebo (see Table 1). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.

                                Table 1
    Response to ZETIA in Patients with Primary Hypercholesterolemia
               (Mean a % Change from Untreated Baseline b)

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

Combination with HMG-CoA Reductase Inhibitors

ZETIA Added to On-going HMG-CoA Reductase Inhibitor Therapy

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary hypercholesterolemia, known coronary heart disease or multiple cardiovascular risk factors who were already receiving HMG-CoA reductase inhibitor monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either ZETIA or placebo in addition to their on-going HMG-CoA reductase inhibitor therapy.

ZETIA, added to on-going HMG-CoA reductase inhibitor therapy, significantly lowered total-C, LDL-C, Apo B, and TG, and increased HDL-C compared with an HMG-CoA reductase inhibitor administered alone (see Table 2). LDL-C reductions induced by ZETIA were generally consistent across all HMG-CoA reductase inhibitors.

                                Table 2
 Response to Addition of ZETIA to On-going HMG-CoA Reductase Inhibitor
            Therapy a in Patients with Hypercholesterolemia
                (Mean b % Change from Treated Baseline c)

      Treatment      N  Total-C   LDL-C     Apo B     TG b      HDL-C
    (Daily Dose)
------------------- ---- ------- ----------- -------- --------- ------
On-going HMG-CoA    390    -2       -4       -3        -3        +1
reductase inhibitor
+Placebo d
------------------- ---- ------- ----------- -------- --------- ------
On-going HMG-CoA    379   -17      -25       -19      -14        +3
reductase inhibitor
+ZETIA d
------------------- ---- ------- ----------- -------- --------- ------
a   Patients receiving each HMG-CoA reductase inhibitor: 40%
    atorvastatin, 31% simvastatin, 29% others (pravastatin,
    fluvastatin, cerivastatin, lovastatin)
b   For triglycerides, median % change from baseline
c   Baseline - on an HMG-CoA reductase inhibitor alone.
d   ZETIA + HMG-CoA reductase inhibitor significantly reduced total-C,
    LDL-C, Apo B, and TG, and increased HDL-C compared to HMG-CoA
    reductase inhibitor alone.

ZETIA Initiated Concurrently with an HMG-CoA Reductase Inhibitor

In four, multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hypercholesterolemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.

When all patients receiving ZETIA with an HMG-CoA reductase inhibitor were compared to all those receiving the corresponding HMG-CoA reductase inhibitor alone, ZETIA significantly lowered total-C, LDL-C, Apo B, and TG, and, with the exception of pravastatin, increased HDL-C compared to the HMG-CoA reductase inhibitor administered alone. LDL-C reductions induced by ZETIA were generally consistent across all HMG-CoA reductase inhibitors. (See footnote c, Tables 3 to 6.)

                                Table 3
       Response to ZETIA and Atorvastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
               (Mean a % Change from Untreated Baseline b)

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

                                Table 4
       Response to ZETIA and Simvastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
               (Mean a % Change from Untreated Baseline b)

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

                                Table 5
       Response to ZETIA and Pravastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
               (Mean a % Change from Untreated Baseline b)

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

                                Table 6
        Response to ZETIA and Lovastatin Initiated Concurrently
             in Patients with Primary Hypercholesterolemia
               (Mean a % Change from Untreated Baseline b)

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

Homozygous Familial Hypercholesterolemia (HoFH)

A study was conducted to assess the efficacy of ZETIA in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), ZETIA administered with atorvastatin or simvastatin (40 mg), or ZETIA administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine (see PRECAUTIONS), ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to ZETIA plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. ZETIA, administered with atorvastatin or simvastatin (40 and 80 mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with ZETIA plus 80 mg atorvastatin or with ZETIA plus 80 mg simvastatin, LDL-C was reduced by 27%.

Homozygous Sitosterolemia (Phytosterolemia)

A study was conducted to assess the efficacy of ZETIA in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia with elevated plasma sitosterol levels (>5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, HMG-CoA reductase inhibitors, ileal bypass surgery and/or LDL apheresis), were randomized to receive ZETIA (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine (see PRECAUTIONS), ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL-apheresis, ZETIA significantly lowered plasma sitosterol and campesterol, by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in sitosterol and campesterol of 4% and 3% from baseline, respectively. For patients treated with ZETIA, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma sitosterol and campesterol on reducing the risks of cardiovascular morbidity and mortality have not been established.

Reductions in sitosterol and campesterol were consistent between patients taking ZETIA concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

INDICATIONS AND USAGE

Primary Hypercholesterolemia

Monotherapy

ZETIA, administered alone is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.

Combination therapy with HMG-CoA reductase inhibitors

ZETIA, administered in combination with an HMG-CoA reductase inhibitor, is indicated as adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with primary (heterozygous familial and non-familial) hypercholesterolemia.

Homozygous Familial Hypercholesterolemia (HoFH)

The combination of ZETIA and atorvastatin or simvastatin, is indicated for the reduction of elevated total-C and LDL-C levels in patients with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable.

Homozygous Sitosterolemia

ZETIA is indicated as adjunctive therapy to diet for the reduction of elevated sitosterol and campesterol levels in patients with homozygous familial sitosterolemia.

Therapy with lipid-altering agents should be a component of multiple risk-factor intervention in individuals at increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to an appropriate diet (including restriction of saturated fat and cholesterol) and when the response to diet and other non-pharmacological measures has been inadequate. (See NCEP Adult Treatment Panel (ATP) III Guidelines, summarized in Table 7.)

                                Table 7
                  Summary of NCEP ATP III Guidelines

                               LDL level at
                                Which to
                                Initiate
                               Therapeutic
                                Lifestyle        Level at Which to
   Risk Category      LDL Goal  Changes a     Consider Drug Therapy
                      (mg/dL)    (mg/dL)             (mg/dL)
---------------------- -------- --------------------------------------
CHD or CHD risk        < 100      => 100     => 130
equivalents b                               (100-129: drug optional) d
(10-year risk
> 20%) c
---------------------- -------- --------------------------------------
                                           10-year risk 10-20%:
2+ Risk factors e      < 130     => 130    => 130 c
(10-year risk                              10-year risk < 10%:
<=20%) c                                   => 160 c
---------------------- -------- --------------------------------------
                                           => 190
 0-1 Risk factor f     < 160     => 160    (160-189: LDL-lowering
                                           drug optional)
---------------------- -------- --------------------------------------
a   Therapeutic lifestyle changes include: 1) dietary changes: reduced
    intake of saturated fats (< 7% of total calories) and cholesterol
    (< 200 mg per day), and enhancing LDL lowering with plant
    stanols/sterols (2 g/d) and increased viscous (soluble) fiber
    (10-25 g/d), 2) weight reduction, and 3) increased physical
    activity.
b   CHD risk equivalents comprise: diabetes, multiple risk factors
    that confer a 10-year risk for CHD > 20%, and other clinical forms
    of atherosclerotic disease (peripheral arterial disease, abdominal
    aortic aneurysm and symptomatic carotid artery disease).
c   Risk assessment for determining the 10-year risk for developing
    CHD is carried out using the Framingham risk scoring. Refer to
    JAMA, May 16, 2001; 285 (19): 2486-2497, or the NCEP website
    (http://www.nhlbi.nih.gov) for more details.
d   Some authorities recommend use of LDL-lowering drugs in this
    category if an LDL cholesterol < 100 mg/dL cannot be achieved by
    therapeutic lifestyle changes. Others prefer use of drugs that
    primarily modify triglycerides and HDL, e.g., nicotinic acid or
    fibrate. Clinical judgment also may call for deferring drug
    therapy in this subcategory.
e   Major risk factors (exclusive of LDL cholesterol) that modify LDL
    goals include cigarette smoking, hypertension (BP => 140/90 mm Hg
    or on anti-hypertensive medication), low HDL cholesterol (< 40
    mg/dL), family history of premature CHD (CHD in male first-degree
    relative < 55 years; CHD in female first-degree relative < 65
    years), age (men => 45 years; women => 55 years). HDL cholesterol
    => 60 mg/dL counts as a "negative" risk factor; its presence
    removes one risk factor from the total count.
f   Almost all people with 0-1 risk factor have a 10-year risk < 10%;
    thus, 10-year risk assessment in people with 0-1 risk factor is
    not necessary.

Prior to initiating therapy with ZETIA, secondary causes for dyslipidemia (i.e., diabetes, hypothyroidism, obstructive liver disease, chronic renal failure, and drugs that increase LDL-C and decrease HDL-C (progestins, anabolic steroids, and corticosteroids)), should be excluded or, if appropriate, treated. A lipid profile should be performed to measure total-C, LDL-C, HDL-C and TG. For TG levels > 400 mg/dL (> 4.5 mmol/L), LDL-C concentrations should be determined by ultracentrifugation.

At the time of hospitalization for an acute coronary event, lipid measures should be taken on admission or within 24 hours. These values can guide the physician on initiation of LDL-lowering therapy before or at discharge.

CONTRAINDICATIONS

Hypersensitivity to any component of this medication.

The combination of ZETIA with an HMG-CoA reductase inhibitor is contraindicated in patients with active liver disease or unexplained persistent elevations in serum transaminases.

All HMG-CoA reductase inhibitors are contraindicated in pregnant and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor in a woman of childbearing potential, refer to the pregnancy category and product labeling for the HMG-CoA reductase inhibitor. (See PRECAUTIONS, Pregnancy.)

PRECAUTIONS

Concurrent administration of ZETIA with a specific HMG-CoA reductase inhibitor should be in accordance with the product labeling for that HMG-CoA reductase inhibitor.

Liver Enzymes

In controlled clinical monotherapy studies, the incidence of consecutive elevations (=> 3 X the upper limit of normal (ULN) in serum transaminases was similar between ZETIA (0.5%) and placebo (0.3%).

In controlled clinical combination studies of ZETIA initiated concurrently with an HMG-CoA reductase inhibitor, the incidence of consecutive elevations (=> 3 X ULN) in serum transaminases was 1.3% for patients treated with ZETIA administered with HMG-CoA reductase inhibitors and 0.4% for patients treated with HMG-CoA reductase inhibitors alone. These elevations in transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA is co-administered with an HMG-CoA reductase inhibitor, liver function tests should be performed at initiation of therapy and according to the recommendations of the HMG-CoA reductase inhibitor.

Skeletal Muscle

In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ZETIA compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. In clinical trials, the 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.

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, or fluvastatin.

Cyclosporine: The total ezetimibe level increased 12-fold in one renal transplant patient receiving multiple medications, including cyclosporine. Patients who take both ezetimibe and cyclosporine should be carefully 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 AUC0-24hr 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 AUC0-24hr for total ezetimibe). There were no statistically significant increases in tumor incidences in drug-treated rats or mice.

Editor's Note: There is a tilde sign before the number 20 in xxx 20 times the human exposure xxx

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 AUC0-24hr for total ezetimibe).

Editor's Note: There is a tilde sign before the number 7 in xxx 7 times the human exposure xxx

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 AUC0-24hr for total ezetimibe).

Editor's Note: There is a tilde sign before the number 10 in xxx 10 times the human exposure xxx

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 AUC0-24hr 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 package 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.

                              Table 8 (a)
        Clinical Adverse Events Occurring in => 2% of Patients
     Treated with ZETIA and at an Incidence Greater than Placebo,
                       Regardless of Causality
----------------------------------- ---------------- -----------------
 Body System/Organ Class                Placebo          ZETIA 10 mg
     Adverse Event                        (%)                (%)
                                        n = 795           n = 1691
----------------------------------- ---------------- -----------------
Body as a whole - general disorders
     Fatigue                              1.8                 2.2
Gastro-intestinal system disorders
     Abdominal pain                       2.8                 3.0
     Diarrhea                             3.0                 3.7
Infection and infestations
     Infection viral                      1.8                 2.2
     Pharyngitis                          2.1                 2.3
     Sinusitis                            2.8                 3.6
Musculo-skeletal system disorders
     Arthralgia                           3.4                 3.8
     Back pain                            3.9                 4.1
Respiratory system disorders
     Coughing                             2.1                 2.3
----------------------------------- ---------------- -----------------
(a) Includes patients who received placebo or ZETIA alone reported in
    Table 9.

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.

                              Table 9(a)
  Clinical Adverse Events occurring in => 2% of Patients
        and at an Incidence Greater than Placebo, Regardless of
            Causality, in ZETIA/Statin Combination Studies
----------------------------------------------------------------------
                                                             ZETIA +
                                           ZETIA   All        All
Body System/Organ Class            Placebo 10 mg Statins(b) Statins(b)
Adverse Event                        (%)    (%)     (%)        (%)
                                    n=259  n=262   n=936      n=925
----------------------------------------------------------------------
Body as a whole - general disorders
     Chest pain                         1.2    3.4     2.0      1.8
     Dizziness                          1.2    2.7     1.4      1.8
     Fatigue                            1.9    1.9     1.4      2.8
     Headache                           5.4    8.0     7.3      6.3
Gastro-intestinal system disorders
     Abdominal pain                     2.3    2.7     3.1      3.5
     Diarrhea                           1.5    3.4     2.9      2.8
Infection and infestations
     Pharyngitis                        1.9    3.1     2.5      2.3
     Sinusitis                          1.9    4.6     3.6      3.5
     Upper respiratory tract infection 10.8   13.0    13.6      11.8
Musculo-skeletal system disorders
     Arthralgia                         2.3    3.8     4.3      3.4
     Back pain                          3.5    3.4     3.7      4.3
     Myalgia                            4.6    5.0     4.1      4.5
----------------------------------------------------------------------
(a) Includes four placebo-controlled combination studies in which
    ZETIA was initiated concurrently with an HMG-CoA reductase
    inhibitor.
(b) All Statins = all doses of all HMG-CoA reductase inhibitors.

OVERDOSAGE

No cases of overdosage with ZETIA have been reported. Administration of ezetimibe, 50 mg/day, to 15 subjects for up to 14 days was generally well tolerated. 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(Degree)C (77(Degree)F); excursions permitted to 15-30(Degree)C (59-86(Degree)F). (See USP Controlled Room Temperature.) Protect from moisture.

ZETIA(TM) (ezetimibe) Tablets

Patient Information about ZETIA (z t'-e-a)

Generic name: ezetimibe (-z t'- -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?

Patients reported few side effects while taking ZETIA. Tell your doctor if you are having stomach pain, are feeling tired, or have 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.

Issued October 2002

Manufactured for:

Merck/Schering-Plough Pharmaceuticals North

Wales, PA 19454, USA By:

Schering Corporation

Kenilworth, NJ 07033, USA

COPYRIGHT (c) Merck/Schering-Plough Pharmaceuticals, 2001, 2002.

All rights reserved.