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NEW ORLEANS--(BUSINESS WIRE)--March 8, 2004--
Ezetimibe with Simvastatin Provided LDL-C
Reductions Ranging from 46 to 61 Percent
Results from Phase III clinical trials showed that patients taking ezetimibe with simvastatin experienced significantly greater reductions in LDL ("bad") cholesterol across the dosing ranges studied compared to reductions seen in patients taking Lipitor(R) (atorvastatin) or Zocor(R) (simvastatin), alone. Results from the studies, conducted in support of VYTORIN(TM) (ezetimibe/simvastatin), an investigational medicine, were presented here today at the 53rd Annual Scientific Meeting of the American College of Cardiology (ACC). Ezetimibe and simvastatin, the active ingredients in VYTORIN, achieve dual inhibition of two sources of cholesterol by inhibiting both cholesterol production in the liver and cholesterol absorption in the intestine.
"Results from these studies showed that ezetimibe with simvastatin provided significantly greater reductions in LDL cholesterol compared to atorvastatin or simvastatin alone. These results suggest that, if approved, this investigational medicine would offer physicians a different treatment option which targets two sources of cholesterol through dual inhibition of both cholesterol production and absorption," said Christie Ballantyne, M.D., FACC, FACP, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Baylor College of Medicine/The Methodist DeBakey Heart Center in Houston.
Study Results
Ezetimibe with simvastatin provided greater LDL-C reductions compared to Lipitor
Results from a 24-week, 788-patient study of ezetimibe 10 mg taken with simvastatin (doses ranging from 10 mg to 80 mg) compared to atorvastatin monotherapy (doses ranging from 10 mg to 80 mg) showed significantly greater LDL-C reductions in patients taking ezetimibe with simvastatin compared to patients taking atorvastatin alone across the dosing ranges. The average LDL-C levels at baseline across treatment groups ranged from 179 mg/dL to 181 mg/dL.
The primary endpoint of this study was the efficacy comparison after the first six-week treatment period. After six weeks of therapy, patients taking ezetimibe 10 mg with simvastatin 10 mg and patients taking ezetimibe 10 mg with simvastatin 20 mg experienced greater LDL-C reductions (46 percent and 50 percent, respectively) compared to atorvastatin 10 mg, which produced a 37 percent reduction (p<0.01 for each versus atorvastatin). In addition, as each treatment group was titrated through the dosing ranges (by doubling the respective statin dose up to a maximum of 80 mg), ezetimibe with simvastatin consistently provided greater LDL-C reductions than atorvastatin at all points in the treatment period.
Study patients underwent a four-week diet/placebo run-in period and were then randomized to three treatment groups, each of which underwent four sequential, six-week treatment periods: (1) atorvastatin 10 mg in Period One, titrated to A20 mg, A40 mg, and A80 mg in Periods Two through Four (n=262); (2) ezetimibe with simvastatin 10 mg (10/10) in Period One, titrated to EZE/S20 mg (10/20), EZE/S40 mg (10/40), and EZE/S80 mg (10/80) in Periods Two through Four (n=263); and (3) ezetimibe with simvastatin 20 mg (10/20) in Period One, titrated to EZE/S40 (10/40) mg for Periods Two and Three, then EZE/S80 mg (10/80) in Period Four (n=263).
Results from this study also showed greater mean HDL-C increases across the treatment periods in patients taking ezetimibe with simvastatin (mean of 10 percent, range 8 to 12 percent) compared to patients taking atorvastatin alone (mean of 6 percent, range 5 to 8 percent).
Ezetimibe with simvastatin was well tolerated and had an overall safety profile similar to atorvastatin monotherapy in the study; there were no clinically or statistically significant differences in the incidence of muscle enzyme elevations (5 to10 times or more than 10 times the upper limit of normal) or consecutive liver enzyme elevations (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3 times the upper limit of normal).
Ezetimibe with simvastatin provided greater LDL-C reductions compared to Zocor
In another study, patients taking ezetimibe with simvastatin experienced significantly greater LDL-C reductions across the doses tested compared to Zocor (simvastatin) alone.
Ezetimibe 10 mg with simvastatin 20 mg achieved a 51 percent LDL-C reduction compared to reductions of 35 percent and 42 percent, respectively, for simvastatin 20 mg and 40 mg (typical starting doses for simvastatin) alone. In pooled results across the dosing ranges, patients taking ezetimibe with simvastatin experienced significantly greater LDL cholesterol reductions ranging from 46 to 61 percent compared to 31 to 46 percent reductions seen with simvastatin alone across the dosing ranges.
This multi-center, double-blind, randomized, placebo-controlled trial was conducted over 12 weeks. After a four-week placebo/diet run-in, 887 patients with LDL-C 145 mg/dL to 250 mg/dL and triglyceride levels at or below 350 mg/dL were randomized to one of 10 daily treatments: placebo (n=93); ezetimibe 10 mg (n=92); simvastatin 10, 20, 40, or 80 mg (n=349); ezetimibe 10 mg with simvastatin 10, 20, 40, or 80 mg (n=353).
Co-administration of ezetimibe with simvastatin was well tolerated and had an overall safety profile similar to that of simvastatin monotherapy in the study. There were more (6 vs. 0) cases of asymptomatic, consecutive elevations (more than 3 times the upper limit of normal) of aminotransferases with ezetimibe with simvastatin compared to simvastatin alone. In patients for whom follow-up testing could be obtained (five out of six), transaminase elevations remained asymptomatic and returned to baseline after treatment was discontinued as called for by study design.
VYTORIN (ezetimibe/simvastatin) provided greater reductions in remnant lipoproteins compared to Zocor
A similar, 12-week study compared the effects of the single tablet VYTORIN (ezetimibe/simvastatin) versus Zocor (simvastatin) pooled across the dosing ranges. After a four-week diet/placebo run-in period, 1,528 patients with LDL-C 145 mg/dL to 250 mg/dL and triglyceride levels at or below 350 mg/dL were randomized to one of ten treatment groups: placebo (n=141), ezetimibe 10 mg (n=144), simvastatin 10, 20, 40, or 80 mg (n=597), and VYTORIN (ezetimibe/simvastatin) 10/10, 10/20, 10/40, and 10/80 mg (n=570). The objective of this analysis was to examine the effects of VYTORIN (ezetimibe/simvastatin) on remnant-like-particle cholesterol (RLP-C). The study's primary endpoint was percentage change from baseline LDL-C.
"Preliminary evidence suggests that the level of cholesterol-rich remnant lipoproteins or 'RLP-C' may be an independent factor in assessing coronary risk," said Harold E. Bays, M.D., FACP, medical director/president of the Louisville Metabolic and Atherosclerosis Research Center Inc. "While the clinical significance of reducing RLP-C is unknown, this analysis showed that VYTORIN reduced RLP-C by 41 percent compared to 29 percent for simvastatin (p<0.001). In addition, VYTORIN provided significantly greater LDL-C reductions of 53 percent compared to 39 percent for simvastatin alone (p<0.001), similar to LDL-C reductions seen in patients taking ezetimibe with simvastatin in other studies presented here at ACC."
VYTORIN (ezetimibe/simvastatin) was well tolerated and had an overall safety profile similar to simvastatin in the study; there were no clinically or statistically significant differences in the incidence of muscle enzyme elevations (five to10 times or more than 10 times the upper limit of normal) or consecutive liver enzyme elevations (ALT or AST more than three times the upper limit of normal).
Important information about ZETIA (ezetimibe)
The effects of ZETIA, either alone or in addition to a statin, on the risk of cardiovascular morbidity and mortality have not been established. ZETIA is a prescription medicine and should not be taken by people who are allergic to any of its ingredients. 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 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.
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 with the 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. 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.
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).
ZETIA, marketed by Merck/Schering-Plough Pharmaceuticals, is the first in a class of cholesterol-lowering agents that inhibits the intestinal absorption of cholesterol through a unique mechanism of action. ZETIA is complementary to the class of cholesterol-lowering agents known as statins, which work in the liver to reduce the production of cholesterol. ZETIA, along with diet, is indicated for use either by itself or together with statins in patients with high cholesterol to reduce LDL "bad" cholesterol and total cholesterol when the response to diet and exercise has been inadequate. ZETIA has been proven to significantly improve LDL cholesterol levels.
Important information about simvastatin
Simvastatin should not be used by anyone allergic to any of its components, with liver disease, or by women who are pregnant, breast-feeding or likely to become pregnant. Muscle pain or weakness in people taking simvastatin should be reported to a doctor because these could be signs of a serious side effect. Doctors may perform blood tests before and periodically during treatment with simvastatin to check for liver problems. People taking 80 mg of simvastatin should receive an additional liver function test at three months. To help avoid serious side effects, discuss with your doctor medicine or food you should avoid while taking simvastatin. In clinical trials, adverse reactions usually have been mild and transient. Most common side effects included headache (3.5 percent), abdominal pain (3.2 percent) and constipation (2.3 percent).
Simvastatin is marketed by Merck & Co., Inc. under the trade name Zocor and is in the class of cholesterol lowering agents known as statins. Zocor is used along with diet to improve cholesterol levels in people with high-cholesterol, when diet alone is not enough. Zocor has been proven to significantly improve LDL and HDL cholesterol levels, as well as triglyceride levels.
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).
ZETIA, discovered by Schering-Plough scientists, is marketed by Merck/Schering-Plough Pharmaceuticals. Since its introduction in November 2002, more than six million prescriptions have been written for ZETIA in the U.S. and it is one of the fastest growing products in the lipid lowering market.(1) The once-daily tablet of ZETIA 10 mg was approved in the United States in October 2002. Ezetimibe is also approved in several countries throughout the world. Following the successful completion of the European Union Mutual Recognition Procedure, EZETROL (the brand name for ZETIA outside of the United States) has now been launched in five European countries -- Germany, the United Kingdom, Switzerland, Sweden and Holland.
On Sept. 24, 2003, Merck/Schering-Plough Pharmaceuticals submitted to the U.S. Food and Drug Administration (FDA) for standard review a New Drug Application for VYTORIN, ezetimibe/simvastatin tablet, an investigational cholesterol-lowering medicine, as adjunctive to diet, for the reduction of elevated cholesterol levels (hypercholesterolemia). The application for filing was accepted for review on Nov. 23, 2003.
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. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. We undertake no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward- looking statements in this press release should be evaluated together with the many uncertainties that affect our businesses, particularly those mentioned in the cautionary statements in Item 1 of our Form 10-K for the year ended Dec. 31, 2002, and in our periodic reports on Form 10-Q and Form 8-K (if any) which we incorporate by reference.
SCHERING-PLOUGH FORWARD-LOOKING STATEMENT: The information in this press release includes certain "forward-looking" information including the market potential for VYTORIN and ZETIA. The reader of this release should understand that the extent that VYTORIN and ZETIA will be prescribed will be determined by market forces and the market viability of VYTORIN and ZETIA is subject to substantial risks and uncertainties. In addition, the forward-looking statements may also be adversely affected by general market and economic 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 10-K filed Feb. 26, 2004.
Full prescribing information and patient product information for ZETIA(TM) is attached.
(1) IMS Health, NPA Plus (TM) and NPA Plus 7 (TM), TRXs Nov 02 - Jan 04, and weeks ending 2/6/04 and 2/13/04.
ZETIA(TM) and VYTORIN(TM) are trademarks 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.
VERSION 25751817
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 C(24)H(21)F(2)NO(3). Its molecular weight is 409.4 and its structural formula is:
(OBJECT 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 AUC values.
Effect of Food on Oral Absorption
Concomitant food administration (high fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as ZETIA 10-mg tablets. The Cmax value of ezetimibe was increased by 38% with consumption of high fat meals. ZETIA can be administered with or without food.
Distribution
Ezetimibe and ezetimibe-glucuronide are highly bound (greater than90%) 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 ((greater than,equal to)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 less than10 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 (less than20%) 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 less than,equal to30 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.
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 (greater than,equal to)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 (greater than,equal to)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 (greater than,equal to)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 ED(50) value of 0.5 (mu)g/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 (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.
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.
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
--------------------------------------------------------------------
Placebo 205 +1 +1 -1 -1 -1
Study 1(c) -------------------------------------------------------
Ezetimibe 622 -12 -18 -15 -7 +1
--------------------------------------------------------------------
Placebo 226 +1 +1 -1 +2 -2
Study 2(c) -------------------------------------------------------
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 reductase inhibitor +Placebo(d) 390 -2 -4 -3 -3 +1 ------------------------------------------------------------------ On-going HMG-CoA reductase inhibitor +ZETIA(d) 379 -17 -25 -19 -14 +3 ------------------------------------------------------------------
(a) Patients receiving each HMG-CoA reductase inhibitor: 40% atorvastatin, 31% simvastatin, 29% others (pravastatin, fluvastatin, cerivastatin, lovastatin)
(b) For triglycerides, median % change from baseline
(c) Baseline - on an HMG-CoA reductase inhibitor alone.
(d) ZETIA + HMG-CoA reductase inhibitor significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to HMG-CoA reductase inhibitor alone.
ZETIA Initiated Concurrently with an HMG-CoA Reductase Inhibitor
In four, multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hypercholesterolemic patients, ZETIA or placebo was administered alone or with various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
| Mentioned | Last | Change |
|---|---|---|
| INDU | 9944.81 |
 21.93dollars or (0.22%) |
| MRK | 45.87 |
0.72dollars or (1.54%) |
| SGP | 16.17 |
0.23dollars or (1.40%) |
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 +
Atorvastatin 10 mg 65 -38 -53 -43 -31 +9
-----------------------------------------------------------------
Atorvastatin 20 mg 60 -30 -42 -34 -23 +4
-----------------------------------------------------------------
ZETIA +
Atorvastatin 20 mg 62 -39 -54 -44 -30 +9
-----------------------------------------------------------------
Atorvastatin 40 mg 66 -32 -45 -37 -24 +4
-----------------------------------------------------------------
ZETIA +
Atorvastatin 40 mg 65 -42 -56 -45 -34 +5
-----------------------------------------------------------------
Atorvastatin 80 mg 62 -40 -54 -46 -31 +3
-----------------------------------------------------------------
ZETIA +
Atorvastatin 80 mg 63 -46 -61 -50 -40 +7
-----------------------------------------------------------------
Pooled data (All
Atorvastatin
Doses)(c) 248 -32 -44 -36 -24 +4
-----------------------------------------------------------------
Pooled data (All
ZETIA +
Atorvastatin
Doses)(c) 255 -41 -56 -45 -33 +7
-----------------------------------------------------------------
(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 +
Simvastatin 10 mg 67 -32 -46 -35 -26 +9
-----------------------------------------------------------------
Simvastatin 20 mg 61 -26 -36 -29 -18 +6
-----------------------------------------------------------------
ZETIA +
Simvastatin 20 mg 69 -33 -46 -36 -25 +9
-----------------------------------------------------------------
Simvastatin 40 mg 65 -27 -38 -32 -24 +6
-----------------------------------------------------------------
ZETIA +
Simvastatin 40 mg 73 -40 -56 -45 -32 +11
-----------------------------------------------------------------
Simvastatin 80 mg 67 -32 -45 -37 -23 +8
-----------------------------------------------------------------
ZETIA +
Simvastatin 80 mg 65 -41 -58 -47 -31 +8
-----------------------------------------------------------------
Pooled data (All
Simvastatin
Doses)(c) 263 -26 -36 -30 -20 +7
-----------------------------------------------------------------
Pooled data (All
ZETIA +
Simvastatin
Doses)(c) 274 -37 -51 -41 -29 +9
-----------------------------------------------------------------
(a) For triglycerides, median % change from baseline
(b) Baseline - on no lipid-lowering drug
(c) ZETIA + all doses of simvastatin pooled (10-80 mg) significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of simvastatin pooled (10-80 mg).
Table 5
Response to ZETIA and Pravastatin Initiated Concurrently
in Patients with Primary Hypercholesterolemia
(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 +
Pravastatin 10 mg 71 -24 -34 -27 -23 +8
-----------------------------------------------------------------
Pravastatin 20 mg 69 -15 -23 -18 -8 +8
-----------------------------------------------------------------
ZETIA +
Pravastatin 20 mg 66 -27 -40 -31 -21 +8
-----------------------------------------------------------------
Pravastatin 40 mg 70 -22 -31 -26 -19 +6
-----------------------------------------------------------------
ZETIA +
Pravastatin 40 mg 67 -30 -42 -32 -21 +8
-----------------------------------------------------------------
Pooled data (All
Pravastatin
Doses)(c) 205 -17 -25 -20 -14 +7
-----------------------------------------------------------------
Pooled data (All
ZETIA +
Pravastatin
Doses)(c) 204 -27 -39 -30 -21 +8
-----------------------------------------------------------------
(a) For triglycerides, median % change from baseline
(b) Baseline - on no lipid-lowering drug
(c) ZETIA + all doses of pravastatin pooled (10-40 mg) significantly reduced total-C, LDL-C, Apo B, and TG compared to all doses of pravastatin pooled (10-40 mg).
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 +
Lovastatin 10 mg 65 -24 -34 -27 -19 +8
-----------------------------------------------------------------
Lovastatin 20 mg 74 -19 -26 -21 -12 +3
-----------------------------------------------------------------
ZETIA +
Lovastatin 20 mg 62 -29 -41 -34 -27 +9
-----------------------------------------------------------------
Lovastatin 40 mg 73 -21 -30 -25 -15 +5
-----------------------------------------------------------------
ZETIA +
Lovastatin 40 mg 65 -33 -46 -38 -27 +9
-----------------------------------------------------------------
Pooled data (All
Lovastatin
Doses)(c) 220 -18 -25 -21 -12 +4
-----------------------------------------------------------------
Pooled data (All
ZETIA +
Lovastatin
Doses)(c) 192 -29 -40 -33 -25 +9
-----------------------------------------------------------------
(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 (greater than 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 LDL level
Which to at Which
LDL Goal Initiate to
Risk Category (mg/dL) Therapeutic Consider
Lifestyle Drug
Changes(a) Therapy
(mg/dL) (mg/dL)
----------------------------------------------------------------------
(greater
CHD or CHD risk equivalents(b) (greater than=)130
(10-year risk greater than20%)(c) less than100 than=)100 (100-129:
drug
optional)(d)
----------------------------------------------------------------------
10-year
risk 10-
20%:
(greater
2+ Risk factors(e) less than130 (greater than=)130(c)
(10-year risk (less than=)20%)(c) than=)130 10-year
risk less
than10%:
(greater
than=)160(c)
----------------------------------------------------------------------
(greater
than=)190
(greater (160-189:
0-1 Risk factor(f) less than160 than=)160 LDL-
lowering
drug
optional)
----------------------------------------------------------------------
(a) Therapeutic lifestyle changes include: 1) dietary changes: reduced intake of saturated fats (less than7% of total calories) and cholesterol (less than200 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 greater than20%, 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 less than100 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 (greater than,equal to)140/90 mm Hg or on anti-hypertensive medication), low HDL cholesterol (less than40 mg/dL), family history of premature CHD (CHD in male first-degree relative less than55 years; CHD in female first-degree relative less than65 years), age (men (greater than,equal to)45 years; women (greater than,equal to)55 years). HDL cholesterol (greater than,equal to)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 less than10%; 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 greater than400 mg/dL (greater than4.5 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 ((greater than,equal to)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 ((greater than,equal to)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 greater than10 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 (greater than150 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 AUC0-24hr 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 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 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 (less than10 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 (greater than,equal to)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 (greater than,equal to)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 (greater than,equal to)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 (greater than=)2% of Patients and
at an Incidence Greater than Placebo, Regardless of Causality, in
ZETIA/Statin Combination Studies
----------------------------------------------------------------------
ZETIA ZETIA +
Body System/Organ Class Placebo 10 mg All All
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.
Post-marketing Experience
The following adverse reactions have been reported in post-marketing experience:
Hypersensitivity reactions, including angioedema and rash.
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 (greater than,equal to)2 hours before or (greater than,equal to)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.
Issued March 2003
Printed in USA.
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.
25751710T
ZETIA(TM) (ezetimibe) Tablets
Patient Information about ZETIA (zt'-e-a)
Generic name: ezetimibe (-zt'--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.
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, and rash.
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.
Issued March 2003
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.
Printed in USA.
CONTACT: Media:
Merck & Co., Inc.
Chris Loder, 908-423-3786
cell: 908-347-4949
Skip Irvine, 267-305-5397
cell: 215-806-6757
or
Schering-Plough Corp.
Denise Foy, 908-298-7616
cell: 908-670-0495
or
Investor:
Merck & Co., Inc.
Mark Stejbach, 908-423-5185
or
Schering-Plough Corp.
Lisa DeBerardine, 908-298-7436
Janet Barth, 908-298-7436
SOURCE: Merck/Schering-Plough Pharmaceuticals
