.
.
.
Exhibit 99.1
MERCK / Schering-Plough Pharmaceuticals News Release
- --------------------------------------------------------------------------------
FOR IMMEDIATE RELEASE
Media Contacts: Chris Loder Investor Contacts: Mark Stejbach
Merck & Co., Inc. Merck & Co., Inc.
(908) 423-3786 (908) 423-5185
Skip Irvine Alex Kelly
Merck & Co., Inc. Lisa DeBerardine
(267) 305-5397 Janet Barth
Schering-Plough Corp.
Denise Foy (908) 298-7436
Schering-Plough Corp.
(908) 298-7616
Mary Fran Faraji
Schering-Plough Corp.
(908) 298-7109
FDA APPROVES VYTORIN(TM) (EZETIMIBE/SIMVASTATIN), THE FIRST AND ONLY PRODUCT
TO DELIVER POWERFUL LDL CHOLESTEROL REDUCTION THROUGH DUAL INHIBITION OF THE
TWO SOURCES OF CHOLESTEROL IN ONE TABLET
VYTORIN LOWERED LDL CHOLESTEROL BY 52 PERCENT AT THE RECOMMENDED
STARTING DOSE (10/20 MG) AND 60 PERCENT AT THE MAXIMUM DOSE (10/80 MG)
WHITEHOUSE STATION and KENILWORTH, N.J., July 23, 2004 -- Merck/Schering-Plough
Pharmaceuticals announced today that the U.S. Food and Drug Administration has
approved VYTORIN(TM) (ezetimibe/simvastatin) for the treatment of high LDL
cholesterol (LDL-C) in patients with primary hypercholesterolemia or mixed
hyperlipidemia as adjunctive therapy to diet when diet alone is not enough.
VYTORIN is the first and only product approved to treat the two sources of
cholesterol by inhibiting the production of cholesterol in the liver and
blocking the absorption of cholesterol in the intestine, including cholesterol
from food. The active ingredients in VYTORIN are ezetimibe and simvastatin. The
recommended starting dose of VYTORIN is 10/20 mg (10 mg ezetimibe/20 mg
simvastatin).
"Many patients who continue to have high cholesterol despite diet and
other lifestyle modifications may require powerful LDL cholesterol-lowering
agents and to do this we frequently look to highly efficacious medicines to
provide the reduction they need," said Christie
VYTORIN IS A TRADEMARK OF MSP SINGAPORE COMPANY, LLC. ZETIA IS A REGISTERED
TRADEMARK OF MSP MARKETING SERVICES (C) LLC. ALL OTHER BRANDS ARE TRADEMARKS OF
THEIR RESPECTIVE OWNERS AND ARE NOT TRADEMARKS OF MSP SINGAPORE COMPANY, LLC OR
MSP MARKETING SERVICES (C) LLC.
(LOGO)
-2-
Ballantyne, M.D., director of the Center for Cardiovascular Disease Prevention,
Methodist DeBakey Heart Center, Houston, TX.
- more -
VYTORIN LOWERED LDL CHOLESTEROL BY 52 PERCENT AT THE RECOMMENDED STARTING DOSE
(10/20 MG) AND 60 PERCENT AT THE MAXIMUM DOSE (10/80 MG)
In a 12-week, multi-center, double-blind, placebo-controlled clinical
study of 1,528 patients with LDL cholesterol levels of 145 mg/dL to 250 mg/dL,
VYTORIN provided LDL cholesterol reductions of 52 percent at the recommended
starting dose (10/20 mg), 55 percent at the 10/40 mg dose and 60 percent at the
maximum dose (10/80 mg). VYTORIN is administered as a once-daily tablet and
should be taken in the evening with or without food.
"VYTORIN is the first single cholesterol treatment to provide LDL
cholesterol lowering through dual inhibition of cholesterol production and
absorption. VYTORIN represents an important new treatment alternative for the
millions of patients with elevated cholesterol for whom diet alone is not
enough," said Raymond V. Gilmartin, chairman, president and chief executive
officer of Merck & Co., Inc.
"With the approval of VYTORIN, physicians have a powerful new option
that treats the two sources of cholesterol in one tablet," said Fred Hassan,
chairman and chief executive officer of Schering-Plough. "VYTORIN represents an
important new therapy that can provide patients with significant LDL cholesterol
reductions."
IN HEAD-TO-HEAD TRIALS, VYTORIN PROVIDED GREATER REDUCTIONS IN LDL CHOLESTEROL
THAN ATORVASTATIN (LIPITOR) AND SIMVASTATIN (ZOCOR) ACROSS THE DOSING RANGE
In a 24-week, multi-center, randomized, double-blind, active-controlled,
forced titration study of 788 patients, VYTORIN (doses ranging from 10/10 mg to
10/80 mg) was compared to atorvastatin monotherapy (doses ranging from 10 mg to
80 mg). The average LDL cholesterol levels at baseline across treatment groups
ranged from 179 mg/dL to 181 mg/dL. At each pre-specified dose comparison,
VYTORIN lowered LDL cholesterol to a significantly greater degree than
atorvastatin. At the recommended usual starting doses, VYTORIN 10/20 mg lowered
LDL cholesterol by 50 percent vs. 37 percent for atorvastatin 10 mg and 44
percent for atorvastatin 20 mg. The impact on clinical outcomes of these
differences in lipid altering effects is unknown.
(LOGO)
-3-
In the 12-week study of 1,528 patients with LDL cholesterol levels of
145 mg/dL to 250 mg/dL, those taking VYTORIN experienced significantly greater
LDL cholesterol reductions compared to simvastatin. VYTORIN 10/20 mg achieved a
52 percent LDL cholesterol reduction compared to reductions of 34 percent and 41
percent, respectively, for simvastatin 20 mg and 40 mg (typical starting doses
for simvastatin). No incremental benefit of VYTORIN on cardiovascular morbidity
and mortality over and above that demonstrated for simvastatin has been
established.
- more -
"The dual inhibition of cholesterol provided by VYTORIN delivers
impressive LDL cholesterol reductions across the dosing range and offers
physicians a unique and powerful new option in the evolving treatment of
hyperlipidemia, especially in people who need more aggressive treatment to reach
goal," said Margo Denke, M.D., clinical professor, University of Texas Health
Science Center, San Antonio, TX.
IN A CLINICAL TRIAL, GREATER LDL CHOLESTEROL REDUCTION WITH VYTORIN COMPARED TO
SIMVASTATIN (ZOCOR) RESULTED IN GREATER GOAL ATTAINMENT
Results from a phase III, multi-center, randomized, double-blind
controlled study of 710 patients showed that, after five weeks of treatment,
VYTORIN 10/20 mg lowered LDL cholesterol by 53 percent compared to a 38 percent
reduction with simvastatin 20 mg. This greater LDL cholesterol reduction
resulted in 83 percent of patients treated with VYTORIN 10/20 mg achieving the
study LDL cholesterol goal of less than 100 mg/dL as compared to 46 percent of
patients taking simvastatin 20 mg.
Patients in this study were randomized to one of four treatment groups
for 23 weeks: VYTORIN (10/10 mg, 10/20 mg or 10/40 mg) or simvastatin 20 mg. All
710 patients enrolled in the study had LDL cholesterol levels of 130 mg/dL or
more (mean 165 mg/dL to 174 mg/dL across treatment arms) and coronary heart
disease (CHD) or CHD risk equivalents as defined by the National Cholesterol
Education Program/Adult Treatment Panel (NCEP/ATP) III.
"A medicine like VYTORIN, which provides dramatic LDL
cholesterol-lowering efficacy and impressive goal attainment, is a welcome
option for physicians and patients," said Dr. Ballantyne.
VYTORIN LOWERS CHOLESTEROL THROUGH DUAL INHIBITION OF CHOLESTEROL PRODUCTION BY
THE BODY AND ABSORPTION IN THE SMALL INTESTINE
Cholesterol in the blood is derived from two sources - production by the
body and absorption from the small intestine. The most widely prescribed
cholesterol-lowering medications, called statins, work in the liver to reduce
cholesterol production and increase clearance of cholesterol from the
bloodstream. VYTORIN inhibits absorption of cholesterol in
(LOGO)
-4-
the small intestine, while also reducing cholesterol synthesis in the liver
leading to clearance of cholesterol from the bloodstream.
INDICATIONS AND CONTRAINDICATIONS FOR VYTORIN
VYTORIN is indicated as adjunctive therapy to diet for the reduction of
elevated total cholesterol, LDL cholesterol, Apo B, triglycerides and non-HDL
cholesterol and to increase HDL cholesterol in patients with primary
(heterozygous familial and non-familial) hypercholesterolemia or mixed
hyperlipidemia. VYTORIN also is indicated for the reduction of elevated total
cholesterol and LDL cholesterol in patients with homozygous familial
- more -
hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL
apheresis) or if such treatments are unavailable.
VYTORIN is a prescription medicine and should not be taken by people who
are hypersensitive to any of its components. VYTORIN should not be taken by
anyone with active liver disease or unexplained persistent elevations of serum
transaminases. Women who are of childbearing age (unless highly unlikely to
conceive), are nursing or who are pregnant should not take VYTORIN.
SELECTED CAUTIONARY INFORMATION FOR VYTORIN
Muscle pain, tenderness or weakness in people taking VYTORIN should be
reported to a doctor promptly because these could be signs of a serious side
effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To
help avoid serious side effects, patients should talk to their doctor about
medicine or food they should avoid while taking VYTORIN. In three
placebo-controlled, 12-week trials, the incidence of consecutive elevations
((greater than or equal to) 3 X ULN) in serum transaminases was 1.7 percent
overall for patients treated with VYTORIN and 2.6 percent for patients treated
with VYTORIN 10/80 mg. In controlled long-term (48 week) extensions, which
included both newly-treated and previously-treated patients, the incidence of
consecutive elevations ((greater than or equal to) 3 X ULN) in serum
transaminases was 1.8 percent overall and 3.6 percent for patients treated with
VYTORIN 10/80 mg. These elevations in transaminases were generally
asymptomatic, not associated with cholestasis and returned to baseline after
discontinuation of therapy or with continued treatment. Doctors should perform
blood tests before, and periodically during treatment with VYTORIN when
clinically indicated to check for liver problems. People taking VYTORIN 10/80
mg should receive an additional liver function test prior to and three months
after titration and periodically during the first year.
Due to the unknown effects of increased exposure to ezetimibe (an
ingredient in VYTORIN) in patients with moderate or severe hepatic
insufficiency, VYTORIN is not recommended in these patients. The safety and
effectiveness of VYTORIN with fibrates have
(Business Confidential use only LOGO)
-5-
not been established; therefore, co-administration with fibrates is not
recommended. Caution should be exercised when initiating VYTORIN in patients
treated with cyclosporine and in patients with severe renal insufficiency.
VYTORIN TO BE AVAILABLE IN VARIOUS DOSES
VYTORIN has been approved for use in patients at the following doses:
10/10 mg, 10/20 mg, 10/40 mg and 10/80 mg. Across the dosing range, the
ezetimibe component of VYTORIN is held constant at 10 mg, while the simvastatin
component ranges from 10 mg to 80 mg. The recommended starting dose for VYTORIN
is 10/20 mg. Patients requiring LDL cholesterol reductions greater than 55
percent can be started on 10/40 mg. Patients
- more -
requiring less aggressive LDL cholesterol reductions may be started at 10/10 mg.
The dose of VYTORIN should be limited to 10/10 mg daily in patients on
cyclosporine and 10/20 mg daily in patients on amiodarone or verapamil.
VYTORIN WAS WELL TOLERATED WITH A LOW INCIDENCE OF ADVERSE EVENTS
VYTORIN has been evaluated for safety in more than 3,800 patients in
clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20
mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side
effects, regardless of cause, included headache (6.8 percent), upper respiratory
tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent),
and extremity pain (2.3 percent).
PRICING AND AVAILABILITY FOR VYTORIN
The price of VYTORIN will be $2.34 at all doses. This means that the
significant LDL cholesterol reductions of VYTORIN are available to patients,
physicians and payors at a price that is very competitive with other first-line
agents in the marketplace. VYTORIN will be broadly available in pharmacies in
the near future.
ABOUT MERCK/SCHERING-PLOUGH PHARMACEUTICALS
Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck &
Co., Inc. and Schering-Plough Corporation formed to develop and market in the
United States new prescription medicines in cholesterol management. The
collaboration was expanded 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 may include statements regarding product development,
product potential or financial performance. No forward-looking
(Business Confidential use only LOGO)
-6-
statement can be guaranteed, and actual results may differ materially from those
projected. Merck undertakes 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 Merck's business, particularly those
mentioned in the cautionary statements in Item 1 of our Form 10-K for the year
ended Dec. 31, 2003, and in our periodic reports on Form 10-Q and Form 8-K (if
any), which the company incorporates by reference.
SCHERING-PLOUGH DISCLOSURE NOTICE: This press release contains "forward-looking
statements" within the meaning of the Private Securities Litigation Reform Act
of 1995, including the market for VYTORIN. Forward-looking statements relate to
expectations or forecasts of future events and not to historical information.
Schering-Plough does not assume the obligation
- more -
to update any forward-looking statement. There are no guarantees about the
market performance of VYTORIN, Schering-Plough stock or Schering-Plough's
business. Actual results may vary materially from forward-looking statements
made here or in other Schering-Plough written or spoken communications due to
many factors and uncertainties, which include the market acceptance of VYTORIN,
trade buying patterns, the introduction and performance of competitive products
in the market, legislation that may impact the pricing/availability of VYTORIN
and other items discussed in Schering-Plough's Securities and Exchange
Commission filings, including the 2004 first quarter 10-Q, the 8-K filed July
21, 2004, and future SEC filings.
# # #
FULL PRESCRIBING INFORMATION AND PATIENT PRODUCT INFORMATION FOR VYTORIN(TM) IS
AVAILABLE BY CALLING 1-800-391-5686.
(Business Confidential use only LOGO)
9619600
VYTORIN (TM) 10/10
(EZETIMIBE 10 MG/SIMVASTATIN 10 MG TABLETS)
VYTORIN (TM) 10/20
(EZETIMIBE 10 MG/SIMVASTATIN 20 MG TABLETS)
VYTORIN (TM) 10/40
(EZETIMIBE 10 MG/SIMVASTATIN 40 MG TABLETS)
VYTORIN (TM) 10/80
(EZETIMIBE 10 MG/SIMVASTATIN 80 MG TABLETS)
DESCRIPTION
VYTORIN contains ezetimibe, a selective inhibitor of intestinal cholesterol
and related phytosterol absorption, and simvastatin, a
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
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)
and its molecular weight is 409.4.
Ezetimibe is a white, crystalline powder that is freely to very soluble in
ethanol, methanol, and acetone and practically insoluble in water. Its
structural formula is:
(STRUCTURAL FORMULA)
Simvastatin, an inactive lactone, is hydrolyzed to the corresponding (beta)-
hydroxyacid form, which is an inhibitor of HMG-CoA reductase. Simvastatin is
butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-
(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester,
[1S-[1(alpha),3(alpha),7(beta),8(beta)(2S*,4S*),-8a(beta)]]. The empirical
formula of simvastatin is C(25)H(38)O(5) and its molecular weight is 418.57.
Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that
is practically insoluble in water, and freely soluble in chloroform, methanol
and ethanol. Its structural formula is:
(STRUCTURAL FORMULA)
VYTORIN is available for oral use as tablets containing 10 mg of ezetimibe,
and 10 mg of simvastatin (VYTORIN 10/10), 20 mg of simvastatin (VYTORIN 10/20),
40 mg of simvastatin (VYTORIN 10/40), or 80 mg of simvastatin (VYTORIN 10/80).
Each tablet contains the following inactive ingredients: butylated
hydroxyanisole NF, citric acid monohydrate USP, croscarmellose sodium NF,
hydroxypropyl methylcellulose USP, lactose monohydrate NF, magnesium stearate
NF, microcrystalline cellulose NF, and propyl gallate NF.
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
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.
MODE OF ACTION
VYTORIN
Plasma cholesterol is derived from intestinal absorption and endogenous
synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering
compounds with complementary mechanisms of action. VYTORIN reduces elevated
total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual
inhibition of cholesterol absorption and synthesis.
Ezetimibe
Ezetimibe reduces blood cholesterol by inhibiting the absorption of
cholesterol by the small intestine. In a 2-week clinical study in 18
hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol
absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful
effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and
did not impair adrenocortical steroid hormone production.
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).
Simvastatin
Simvastatin reduces cholesterol by inhibiting the conversion of HMG-CoA to
mevalonate, an early step in the biosynthetic pathway for cholesterol. In
addition, simvastatin reduces VLDL and TG and increases HDL-C.
PHARMACOKINETICS
ABSORPTION
VYTORIN
VYTORIN is bioequivalent to coadministered ezetimibe and simvastatin.
Ezetimibe
After oral administration, ezetimibe is absorbed and extensively conjugated
to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
EFFECT OF FOOD ON ORAL ABSORPTION
Ezetimibe
Concomitant food administration (high-fat or non-fat meals) had no effect on
the extent of absorption of ezetimibe when administered as 10-mg tablets. The
Cmax value of ezetimibe was increased by 38% with consumption of high-fat meals.
Simvastatin
Relative to the fasting state, the plasma profiles of both active and total
inhibitors of HMG-CoA reductase were not affected when simvastatin was
administered immediately before an American Heart Association recommended
low-fat meal.
2
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
DISTRIBUTION
Ezetimibe
Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma
proteins.
Simvastatin
Both simvastatin and its (beta)-hydroxyacid metabolite are highly bound
(approximately 95%) to human plasma proteins. When radiolabeled simvastatin was
administered to rats, simvastatin-derived radioactivity crossed the blood-brain
barrier.
METABOLISM AND EXCRETION
Ezetimibe
Ezetimibe is primarily metabolized in the small intestine and liver via
glucuronide conjugation with subsequent biliary and renal excretion. Minimal
oxidative metabolism 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.
Simvastatin
Simvastatin is a lactone that is readily hydrolyzed in vivo to the
corresponding (beta)-hydroxyacid, a potent inhibitor of HMG-CoA reductase.
Inhibition of HMG-CoA reductase is a basis for an assay in pharmacokinetic
studies of the (beta)-hydroxyacid metabolites (active inhibitors) and, following
base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma
following administration of simvastatin. The major active metabolites of
simvastatin present in human plasma are the (beta)-hydroxyacid of simvastatin
and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives.
Plasma concentrations of total radioactivity (simvastatin plus
(14)C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak
by 12 hours postdose. Simvastatin undergoes extensive first-pass extraction in
the liver, its primary site of action, with subsequent excretion of drug
equivalents in the bile. As a consequence of extensive hepatic extraction of
simvastatin (estimated to be >60% in man), the availability of drug to the
general circulation is low.
Following an oral dose of (14)C-labeled simvastatin in man, 13% of the dose
was excreted in urine and 60% in feces. The latter represents absorbed drug
equivalents excreted in bile, as well as any unabsorbed drug.
In a single-dose study in nine healthy subjects, it was estimated that less
than 5% of an oral dose of simvastatin reaches the general circulation as active
inhibitors.
SPECIAL POPULATIONS
GERIATRIC PATIENTS
Ezetimibe
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 or equal to) 65 years) healthy subjects compared to younger
subjects.
3
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
Simvastatin
In a study including 16 elderly patients between 70 and 78 years of age who
received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase
inhibitory activity was increased approximately 45% compared with 18 patients
between 18-30 years of age.
PEDIATRIC PATIENTS
Ezetimibe
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
Ezetimibe
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
Ezetimibe
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
Ezetimibe
After a single 10-mg dose of ezetimibe, the mean exposure (based on area
under the curve [AUC]) to 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
increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients
with moderate (Child-Pugh score 7 to 9) or severe hepatic impairment (Child-Pugh
score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with
moderate hepatic insufficiency, the mean AUC for total ezetimibe and ezetimibe
increased approximately 4-fold compared to healthy subjects.
RENAL INSUFFICIENCY
Ezetimibe
After a single 10-mg dose of ezetimibe in patients with severe renal disease
(n=8; mean CrCl less than or equal to 30 mL/min/1.73 m(2)), the mean AUC for
total ezetimibe and ezetimibe increased approximately 1.5-fold, compared to
healthy subjects (n=9).
Simvastatin
Pharmacokinetic studies with another statin having a similar principal route
of elimination to that of simvastatin have suggested that for a given dose level
higher systemic exposure may be achieved in patients with severe renal
insufficiency (as measured by creatinine clearance).
DRUG INTERACTIONS (SEE ALSO PRECAUTIONS, DRUG INTERACTIONS)
No clinically significant pharmacokinetic interaction was seen when ezetimibe
was coadministered with simvastatin. Specific pharmacokinetic drug interaction
studies with VYTORIN have not been performed.
CYTOCHROME P450: Ezetimibe had no significant effect on a series of probe
drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be
metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a "cocktail" study
of twelve healthy adult males. This indicates that ezetimibe is neither an
inhibitor nor an inducer of these cytochrome P450 isozymes, and it is unlikely
that ezetimibe will affect the metabolism of drugs that are metabolized by these
enzymes.
In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no
effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4)
substrates midazolam and erythromycin. This indicates that simvastatin is not an
inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels
of other drugs metabolized by CYP3A4.
Simvastatin is a substrate for CYP3A4. Potent inhibitors of CYP3A4 can raise
the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk
of myopathy. (See WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug
Interactions.)
4
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
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%.
CHOLESTYRAMINE: In a study of forty healthy hypercholesterolemic (LDL-C
greater than or equal to 130 mg/dL) adult subjects, concomitant cholestyramine
(4 g twice daily) administration decreased the mean AUC of total ezetimibe and
ezetimibe approximately 55% and 80%, respectively.
CYCLOSPORINE: In a study of eight post-renal transplant patients with mildly
impaired or normal renal function (creatinine clearance of >50 mL/min), stable
doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax
values of total ezetimibe 3.4-fold (range 2.3- to 7.9-fold) and 3.9-fold (range
3.0- to 4.4-fold), respectively, compared to a historical healthy control
population (n=17). In a different study, a renal transplant patient with severe
renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m(2)) who was
receiving multiple medications, including cyclosporine, demonstrated a 12-fold
greater exposure to total ezetimibe compared to healthy subjects.
FENOFIBRATE: In a study of thirty-two healthy hypercholesterolemic (LDL-C
greater than or 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).
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.
GRAPEFRUIT JUICE: Grapefruit juice contains one or more components that
inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized
by CYP3A4. In one study(1), 10 subjects consumed 200 mL of double-strength
grapefruit juice (one can of frozen concentrate diluted with one rather than 3
cans of water) three times daily for 2 days and an additional 200 mL
double-strength grapefruit juice together with, and 30 and 90 minutes following,
a single dose of 60 mg simvastatin on the third day. This regimen of grapefruit
juice resulted in mean increases in the concentration (as measured by the area
under the concentration-time curve) of active and total HMG-CoA reductase
inhibitory activity [measured using a radioenzyme inhibition assay both before
(for active inhibitors) and after (for total inhibitors) base hydrolysis] of
2.4-fold and 3.6-fold, respectively, and of simvastatin and its
(beta)-hydroxyacid metabolite [measured using a chemical assay -- liquid
chromatography/tandem mass spectrometry] of 16-fold and 7-fold, respectively. In
a second study, 16 subjects consumed one 8 oz glass of single-strength
grapefruit juice (one can of frozen concentrate diluted with 3 cans of water)
with breakfast for 3 consecutive days and a single dose of 20 mg simvastatin in
the evening of the third day. This regimen of grapefruit juice resulted in a
mean increase in the plasma concentration (as measured by the area under the
concentration-time curve) of active and total HMG-CoA reductase inhibitory
activity [using a validated enzyme inhibition assay different from that used in
the first (1) study, both before (for active inhibitors) and after (for total
inhibitors) base hydrolysis] of 1.13-fold and 1.18-fold, respectively, and of
simvastatin and its (BETA)-hydroxyacid metabolite [measured using a chemical
assay -- liquid chromatography/tandem mass spectrometry] of 1.88-fold and
1.31-fold, respectively. The effect of amounts of grapefruit juice between those
used in these two studies on simvastatin pharmacokinetics has not been studied.
ANIMAL PHARMACOLOGY
Ezetimibe
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 ezetimibe being a potent cholesterol absorption
inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe
(ezetimibe-glucuronide) was administered intraduodenally, the metabolite was as
potent as ezetimibe in inhibiting the absorption of cholesterol, suggesting that
the glucuronide metabolite had activity similar to the parent drug.
- --------
1 Lilja JJ, Kivisto KT, Neuvonen PJ. Clin Pharmacol Ther 1998;64(5):477-83.
5
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
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 ezetimibe for inhibiting cholesterol absorption. Ezetimibe
inhibited the absorption of (14)C-cholesterol with no effect on the absorption
of triglycerides, fatty acids, bile acids, progesterone, 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
VYTORIN
VYTORIN reduces total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C
in patients with hypercholesterolemia. Maximal to near maximal response is
generally achieved within 2 weeks and maintained during chronic therapy.
VYTORIN is effective in men and women with hypercholesterolemia. Experience
in non-Caucasians is limited and does not permit a precise estimate of the
magnitude of the effects of VYTORIN.
In a multicenter, double-blind, placebo-controlled, 12-week trial, 1528
hypercholesterolemic patients were randomized to one of ten treatment groups:
placebo, ezetimibe (10 mg), simvastatin (10 mg, 20 mg, 40 mg, or 80 mg), or
VYTORIN (10/10, 10/20, 10/40, or 10/80).
When patients receiving VYTORIN were compared to those receiving all doses of
simvastatin, VYTORIN significantly lowered total-C, LDL-C, Apo B, TG, and
non-HDL-C. The effects of VYTORIN on HDL-C were similar to the effects seen with
simvastatin. Further analysis showed VYTORIN significantly increased HDL-C
compared with placebo. (See Table 1.) The lipid response to VYTORIN was similar
in patients with TG levels greater than or less than 200 mg/dL.
TABLE 1
RESPONSE TO VYTORIN IN PATIENTS WITH PRIMARY HYPERCHOLESTEROLEMIA
(MEAN(a) % CHANGE FROM UNTREATED BASELINE(b))
Treatment
(Daily Dose) N Total-C LDL-C Apo B HDL-C TG(a) Non-HDL-C
------------ - ------- ----- ----- ----- ----- ---------
Pooled data (All VYTORIN doses)(c) 609 -38 -53 -42 +7 -24 -49
Pooled data (All simvastatin doses)(c) 622 -28 -39 -32 +7 -21 -36
Ezetimibe 10 mg 149 -13 -19 -15 +5 -11 -18
Placebo 148 -1 -2 0 0 -2 -2
VYTORIN by dose
10/10 152 -31 -45 -35 +8 -23 -41
10/20 156 -36 -52 -41 +10 -24 -47
10/40 147 -39 -55 -44 +6 -23 -51
10/80 154 -43 -60 -49 +6 -31 -56
Simvastatin by dose
10 mg 158 -23 -33 -26 +5 -17 -30
20 mg 150 -24 -34 -28 +7 -18 -32
40 mg 156 -29 -41 -33 +8 -21 -38
80 mg 158 -35 -49 -39 +7 -27 -45
(a) For triglycerides, median % change from baseline
6
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
(b) Baseline - on no lipid-lowering drug
(c) VYTORIN doses pooled (10/10-10/80) significantly reduced total-C, LDL-C,
Apo B, TG, and non-HDL-C compared to simvastatin, and significantly
increased HDL-C compared to placebo.
In a multicenter, double-blind, controlled, 23-week study, 710 patients with
known CHD or CHD risk equivalents, as defined by the NCEP ATP III guidelines,
and an LDL-C (greater than or equal to)130 mg/dL were randomized to one of four
treatment groups: coadministered ezetimibe and simvastatin equivalent to
VYTORIN (10/10, 10/20, and 10/40), or simvastatin 20 mg. Patients not reaching
an LDL-C <100 mg/dL had their simvastatin dose titrated at 6-week intervals to
a maximal dose of 80 mg.
At Week 5, the LDL-C reductions with VYTORIN 10/10, 10/20, or 10/40 were
significantly larger than with simvastatin 20 mg (see Table 2).
TABLE 2
RESPONSE TO VYTORIN AFTER 5 WEEKS IN PATIENTS WITH CHD
OR CHD RISK EQUIVALENTS AND AN LDL-C (GREATER THAN OR EQUAL TO)130 MG/DL
Simvastatin VYTORIN VYTORIN VYTORIN
20 mg 10/10 10/20 10/40
----- ----- ----- -----
N 253 251 109 97
Mean baseline LDL-C 174 165 167 171
Percent change LDL-C -38 -47 -53 -59
In a multicenter, double-blind, 24-week, forced titration study, 788 patients
with primary hypercholesterolemia, who had not met their NCEP ATP III target
LDL-C goal, were randomized to receive coadministered ezetimibe and simvastatin
equivalent to VYTORIN (10/10 and 10/20) or atorvastatin 10 mg. For all three
treatment groups, the dose of the statin was titrated at 6-week intervals to 80
mg. At each pre-specified dose comparison, VYTORIN lowered LDL-C to a greater
degree than atorvastatin (see Table 3).
TABLE 3
RESPONSE TO VYTORIN AND ATORVASTATIN IN PATIENTS WITH PRIMARY
HYPERCHOLESTEROLEMIA
(MEAN(a) % CHANGE FROM UNTREATED BASELINE(b))
Treatment N Total-C LDL-C Apo B HDL-C TG(a) Non-HDL-C
--------- - ------- ----- ----- ----- ----- ---------
Week 6
Atorvastatin 10 mg(c) 262 -28 -37 -32 +5 -23 -35
VYTORIN 10/10(d) 263 -34f -46f -38f +8f -26 -43f
VYTORIN 10/20(e) 263 -36f -50f -41f +10f -25 -46f
Week 12
Atorvastatin 20 mg 246 -33 -44 -38 +7 -28 -42
VYTORIN 10/20 250 -37f -50f -41f +9 -28 -46f
VYTORIN 10/40 252 -39f -54f -45f +12f -31 -50f
Week 18
Atorvastatin 40 mg 237 -37 -49 -42 +8 -31 -47
VYTORIN 10/40(g) 482 -40f -56f -45f +11f -32 -52f
Week 24
Atorvastatin 80 mg 228 -40 -53 -45 +6 -35 -50
VYTORIN 10/80(g) 459 -43f -59f -49f +12f -35 -55f
7
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
(a) For triglycerides, median % change from baseline
(b) Baseline - on no lipid-lowering drug
(c) Atorvastatin: 10 mg start dose titrated to 20 mg, 40 mg, and 80 mg through
Weeks 6, 12, 18, and 24
(d) VYTORIN: 10/10 start dose titrated to 10/20, 10/40, and 10/80 through Weeks
6, 12, 18, and 24
(e) VYTORIN: 10/20 start dose titrated to 10/40, 10/40, and 10/80 through Weeks
6, 12, 18, and 24
(f) p (less than or equal to) 0.05 for difference with atorvastatin in the
specified week
(g) Data pooled for common doses of VYTORIN at Weeks 18 and 24.
In a multicenter, double-blind, 24-week trial, 214 patients with type 2
diabetes mellitus treated with thiazolidinediones (rosiglitazone or
pioglitazone) for a minimum of 3 months and simvastatin 20 mg for a minimum of 6
weeks, were randomized to receive either simvastatin 40 mg or the coadministered
active ingredients equivalent to VYTORIN 10/20. The median LDL-C and HbA1c
levels at baseline were 89 mg/dL and 7.1%, respectively.
VYTORIN 10/20 was significantly more effective than doubling the dose of
simvastatin to 40 mg. The median percent changes from baseline for VYTORIN vs
simvastatin were: LDL-C -25% and -5%; total-C -16% and -5%; Apo B -19% and -5%;
and non-HDL-C -23% and -5%. Results for HDL-C and TG between the two treatment
groups were not significantly different.
Ezetimibe
In two multicenter, double-blind, placebo-controlled, 12-week studies in
1719 patients with primary hypercholesterolemia, ezetimibe significantly lowered
total-C (-13%), LDL-C (-19%), Apo B (-14%), and TG (-8%), and increased HDL-C
(+3%) compared to placebo. Reduction in LDL-C was consistent across age, sex,
and baseline LDL-C.
Simvastatin
In two large, placebo-controlled clinical trials, the Scandinavian
Simvastatin Survival Study (N=4,444 patients) and the Heart Protection Study
(N=20,536 patients), the effects of treatment with simvastatin were assessed in
patients at high risk of coronary events because of existing coronary heart
disease, diabetes, peripheral vessel disease, history of stroke or other
cerebrovascular disease. Simvastatin was proven to reduce: the risk of total
mortality by reducing CHD deaths; the risk of non-fatal myocardial infarction
and stroke; and the need for coronary and non-coronary revascularization
procedures.
No incremental benefit of VYTORIN on cardiovascular morbidity and mortality
over and above that demonstrated for simvastatin has been established.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH)
A double-blind, randomized, 12-week study was performed in patients with a
clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup
of patients (n=14) receiving simvastatin 40 mg at baseline. Increasing the dose
of simvastatin from 40 to 80 mg (n=5) produced a reduction of LDL-C of 13% from
baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin
equivalent to VYTORIN (10/40 and 10/80 pooled, n=9), produced a reduction of
LDL-C of 23% from baseline on simvastatin 40 mg. In those patients
coadministered ezetimibe and simvastatin equivalent to VYTORIN (10/80, n=5), a
reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.
INDICATIONS AND USAGE
PRIMARY HYPERCHOLESTEROLEMIA
VYTORIN is indicated as adjunctive therapy to diet for the reduction of
elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and to increase HDL-C in
patients with primary (heterozygous familial and non-familial)
hypercholesterolemia or mixed hyperlipidemia.
HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (HOFH)
VYTORIN is indicated for the reduction of elevated total-C and LDL-C in
patients with homozygous familial hypercholesterolemia, as an adjunct to other
lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are
unavailable.
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
8
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
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 4.)
TABLE 4
SUMMARY OF NCEP ATP III GUIDELINES
LDL LEVEL AT WHICH TO INITIATE LDL LEVEL AT WHICH TO
RISK CATEGORY LDL GOAL THERAPEUTIC LIFESTYLE CHANGES(a) CONSIDER DRUG THERAPY
(MG/DL) (MG/DL) (MG/DL)
------- ------- -------
CHD or CHD risk equivalents(b) <100 (GREATER THAN OR EQUAL TO)100 (GREATER THAN OR EQUAL TO)130
(10-year risk >20%)(c) (100-129: drug optional)(d)
2+ Risk factors(e) <130 (GREATER THAN OR EQUAL TO)130 10-year risk 10-20%:(GREATER THAN OR EQUAL TO)130(c)
(10-year risk (less than 10-year risk <10%: (GREATER THAN OR EQUAL TO)160(c)
or equal to) 20%)(c)
(GREATER THAN OR EQUAL TO)190
0-1 Risk factor(f) (160-189: LDL-lowering drug
<160 (GREATER THAN OR EQUAL TO)160 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 (GREATER THAN OR EQUAL
TO)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 (GREATER THAN OR EQUAL TO)45 years; women (GREATER THAN OR EQUAL TO)55
years). HDL cholesterol (GREATER THAN OR 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 <10%; thus,
10-year risk assessment in people with 0-1 risk factor is not necessary.
Prior to initiating therapy with VYTORIN, 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.
Active liver disease or unexplained persistent elevations in serum
transaminases (see WARNINGS, Liver Enzymes).
Pregnancy and lactation. Atherosclerosis is a chronic process and the
discontinuation of lipid-lowering drugs during pregnancy should have little
impact on the outcome of long-term therapy of primary hypercholesterolemia.
Moreover, cholesterol and other products of the cholesterol biosynthesis pathway
are essential components for fetal development, including synthesis of steroids
and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase
such as simvastatin to decrease the synthesis of cholesterol and possibly other
products of the cholesterol biosynthesis pathway, VYTORIN is contraindicated
during pregnancy and in nursing mothers. VYTORIN SHOULD BE ADMINISTERED TO WOMEN
OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE. If
the patient becomes
9
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
pregnant while taking this drug, VYTORIN should be discontinued immediately and
the patient should be apprised of the potential hazard to the fetus (see
PRECAUTIONS, Pregnancy).
WARNINGS
MYOPATHY/RHABDOMYOLYSIS
In clinical trials, there was no excess of myopathy or rhabdomyolysis
associated with ezetimibe 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 CK >10 X the upper limit of normal
[ULN] was 0.2% for VYTORIN.
Simvastatin, like other inhibitors of HMG-CoA reductase, occasionally
causes myopathy manifested as muscle pain, tenderness or weakness with creatine
kinase above 10 X ULN. Myopathy sometimes takes the form of rhabdomyolysis with
or without acute renal failure secondary to myoglobinuria, and rare fatalities
have occurred. The risk of myopathy is increased by high levels of HMG-CoA
reductase inhibitory activity in plasma.
- - BECAUSE VYTORIN CONTAINS SIMVASTATIN, THE RISK OF MYOPATHY/RHABDOMYOLYSIS IS
INCREASED BY CONCOMITANT USE OF VYTORIN WITH THE FOLLOWING:
POTENT INHIBITORS OF CYP3A4: CYCLOSPORINE, ITRACONAZOLE, KETOCONAZOLE,
ERYTHROMYCIN, CLARITHROMYCIN, HIV PROTEASE INHIBITORS, NEFAZODONE, OR LARGE
QUANTITIES OF GRAPEFRUIT JUICE (>1 QUART DAILY), PARTICULARLY WITH HIGHER
DOSES OF VYTORIN (see CLINICAL PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS,
Drug Interactions, CYP3A4 Interactions).
OTHER DRUGS:
GEMFIBROZIL, PARTICULARLY WITH HIGHER DOSES OF VYTORIN (see CLINICAL
PHARMACOLOGY, Pharmacokinetics; PRECAUTIONS, Drug Interactions, Interactions
with lipid-lowering drugs that can cause myopathy when given alone).
OTHER LIPID-LOWERING DRUGS (OTHER FIBRATES OR (GREATER THAN OR EQUAL TO)1
G/DAY OF NIACIN) THAT CAN CAUSE MYOPATHY WHEN GIVEN ALONE (see PRECAUTIONS,
Drug Interactions, Interactions with lipid-lowering drugs that can cause
myopathy when given alone).
AMIODARONE OR VERAPAMIL WITH HIGHER DOSES OF VYTORIN (see PRECAUTIONS, Drug
Interactions, Other drug interactions). In an ongoing clinical trial,
myopathy has been reported in 6% of patients receiving simvastatin 80 mg and
amiodarone. In an analysis of clinical trials involving 25,248 patients
treated with simvastatin 20 to 80 mg, the incidence of myopathy was higher
in patients receiving verapamil and simvastatin (4/635; 0.63%) than in
patients taking simvastatin without a calcium channel blocker (13/21,224;
0.061%).
- - THE RISK OF MYOPATHY/RHABDOMYOLYSIS IS DOSE RELATED FOR SIMVASTATIN. The
incidence in clinical trials, in which patients were carefully monitored and
some interacting drugs were excluded, has been approximately 0.02% at 20 mg,
0.07% at 40 mg and 0.3% at 80 mg.
CONSEQUENTLY:
1. USE OF VYTORIN CONCOMITANTLY WITH ITRACONAZOLE, KETOCONAZOLE, ERYTHROMYCIN,
CLARITHROMYCIN, HIV PROTEASE INHIBITORS, NEFAZODONE, OR LARGE QUANTITIES OF
GRAPEFRUIT JUICE (>1 QUART DAILY) SHOULD BE AVOIDED. If treatment with
itraconazole, ketoconazole, erythromycin, or clarithromycin is unavoidable,
therapy with VYTORIN should be suspended during the course of treatment.
Concomitant use with other medicines labeled as having a potent inhibitory
effect on CYP3A4 at therapeutic doses should be avoided unless the benefits of
combined therapy outweigh the increased risk.
2. There is an increased risk of myopathy when simvastatin is used concomitantly
with gemfibrozil or other fibrates; the safety and effectiveness of ezetimibe
administered with fibrates have not been
10
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
established. THEREFORE, THE CONCOMITANT USE OF VYTORIN AND FIBRATES SHOULD BE
AVOIDED. (See PRECAUTIONS, Drug Interactions, Other Drug Interactions,
Fibrates.)
3. Caution should be used when prescribing lipid-lowering doses ((GREATER THAN
OR EQUAL TO)1 g/day) of niacin with VYTORIN, as niacin can cause myopathy when
given alone. THE BENEFIT OF FURTHER ALTERATIONS IN LIPID LEVELS BY THE COMBINED
USE OF VYTORIN WITH NIACIN SHOULD BE CAREFULLY WEIGHED AGAINST THE POTENTIAL
RISKS OF THIS DRUG COMBINATION.
4. THE DOSE OF VYTORIN SHOULD NOT EXCEED 10/10 MG DAILY IN PATIENTS RECEIVING
CONCOMITANT MEDICATION WITH CYCLOSPORINE. The benefits of the use of VYTORIN in
patients receiving cyclosporine should be carefully weighed against the risks of
this combination. (SEE PRECAUTIONS, DRUG INTERACTIONS, OTHER DRUG INTERACTIONS,
CYCLOSPORINE.)
5. THE DOSE OF VYTORIN SHOULD NOT EXCEED 10/20 MG DAILY IN PATIENTS RECEIVING
CONCOMITANT MEDICATION WITH AMIODARONE OR VERAPAMIL. THE COMBINED USE OF VYTORIN
AT DOSES HIGHER THAN 10/20 MG DAILY WITH AMIODARONE OR VERAPAMIL SHOULD BE
AVOIDED UNLESS THE CLINICAL BENEFIT IS LIKELY TO OUTWEIGH THE INCREASED RISK OF
MYOPATHY.
6. ALL PATIENTS STARTING THERAPY WITH VYTORIN, OR WHOSE DOSE OF VYTORIN IS BEING
INCREASED, SHOULD BE ADVISED OF THE RISK OF MYOPATHY AND TOLD TO REPORT PROMPTLY
ANY UNEXPLAINED MUSCLE PAIN, TENDERNESS OR WEAKNESS. VYTORIN THERAPY SHOULD BE
DISCONTINUED IMMEDIATELY IF MYOPATHY IS DIAGNOSED OR SUSPECTED. The presence of
these symptoms, and/or a CK level >10 times the ULN indicates myopathy. In most
cases, when patients were promptly discontinued from simvastatin treatment,
muscle symptoms and CK increases resolved. Periodic CK determinations may be
considered in patients starting therapy with VYTORIN or whose dose is being
increased, but there is no assurance that such monitoring will prevent myopathy.
7. Many of the patients who have developed rhabdomyolysis on therapy with
simvastatin have had complicated medical histories, including renal
insufficiency usually as a consequence of long-standing diabetes mellitus. Such
patients taking VYTORIN merit closer monitoring. Therapy with VYTORIN should be
temporarily stopped a few days prior to elective major surgery and when any
major medical or surgical condition supervenes.
LIVER ENZYMES
In three placebo-controlled, 12-week trials, the incidence of consecutive
elevations (greater than or equal to 3 X ULN) in serum transaminases was 1.7%
overall for patients treated with VYTORIN and appeared to be dose-related with
an incidence of 2.6% for patients treated with VYTORIN 10/80. In controlled
long-term (48-week) extensions, which included both newly-treated and
previously-treated patients, the incidence of consecutive elevations (greater
than or equal to 3 X ULN) in serum transaminases was 1.8% overall and 3.6% for
patients treated with VYTORIN 10/80. These elevations in transaminases were
generally asymptomatic, not associated with cholestasis, and returned to
baseline after discontinuation of therapy or with continued treatment.
It is recommended that liver function tests be performed before the
initiation of treatment with VYTORIN, and thereafter when clinically indicated.
Patients titrated to the 10/80-mg dose should receive an additional test prior
to titration, 3 months after titration to the 10/80-mg dose, and periodically
thereafter (e.g., semiannually) for the first year of treatment. Patients who
develop increased transaminase levels should be monitored with a second liver
function evaluation to confirm the finding and be followed thereafter with
frequent liver function tests until the abnormality(ies) return to normal.
Should an increase in AST or ALT of 3 X ULN or greater persist, withdrawal of
therapy with VYTORIN is recommended.
VYTORIN should be used with caution in patients who consume substantial
quantities of alcohol and/or have a past history of liver disease. Active liver
diseases or unexplained persistent transaminase elevations are contraindications
to the use of VYTORIN.
11
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
PRECAUTIONS
INFORMATION FOR PATIENTS
PATIENTS SHOULD BE ADVISED ABOUT SUBSTANCES THEY SHOULD NOT TAKE
CONCOMITANTLY WITH VYTORIN AND BE ADVISED TO REPORT PROMPTLY UNEXPLAINED MUSCLE
PAIN, TENDERNESS, OR WEAKNESS (SEE LIST BELOW AND WARNINGS,
MYOPATHY/RHABDOMYOLYSIS). PATIENTS SHOULD ALSO BE ADVISED TO INFORM OTHER
PHYSICIANS PRESCRIBING A NEW MEDICATION THAT THEY ARE TAKING VYTORIN.
HEPATIC INSUFFICIENCY
Due to the unknown effects of the increased exposure to ezetimibe in
patients with moderate or severe hepatic insufficiency, VYTORIN is not
recommended in these patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics,
Special Populations.)
DRUG INTERACTIONS (SEE ALSO CLINICAL PHARMACOLOGY, DRUG INTERACTIONS)
VYTORIN
CYP3A4 INTERACTIONS
Potent inhibitors of CYP3A4 (below) increase the risk of myopathy by
reducing the elimination of the simvastatin component of VYTORIN.
SEE WARNINGS, MYOPATHY/RHABDOMYOLYSIS, AND CLINICAL PHARMACOLOGY,
PHARMACOKINETICS, DRUG INTERACTIONS.
ITRACONAZOLE
KETOCONAZOLE
ERYTHROMYCIN
CLARITHROMYCIN
HIV PROTEASE INHIBITORS
NEFAZODONE
CYCLOSPORINE
LARGE QUANTITIES OF GRAPEFRUIT JUICE (>1 QUART DAILY)
INTERACTIONS WITH LIPID-LOWERING DRUGS THAT CAN CAUSE MYOPATHY WHEN GIVEN ALONE
SEE WARNINGS, MYOPATHY/RHABDOMYOLYSIS.
The risk of myopathy is increased by gemfibrozil and to a lesser extent by
other fibrates and niacin (nicotinic acid) ((GREATER THAN OR EQUAL TO)1 g/day).
OTHER DRUG INTERACTIONS
Amiodarone or Verapamil: The risk of myopathy/rhabdomyolysis is increased
by concomitant administration of amiodarone or verapamil (see WARNINGS,
Myopathy/Rhabdomyolysis).
Cholestyramine: Concomitant cholestyramine administration decreased the
mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction
due to adding VYTORIN to cholestyramine may be reduced by this interaction.
Cyclosporine: Caution should be exercised when initiating VYTORIN in
patients treated with cyclosporine due to increased exposure to ezetimibe. This
exposure may be greater in patients with severe renal insufficiency. In patients
treated with cyclosporine, the potential effects of the increased exposure to
ezetimibe from concomitant use should be carefully weighed against the benefits
of alterations in lipid levels provided by ezetimibe. In a pharmacokinetic study
in post-renal transplant patients with mildly impaired or normal renal function
(creatinine clearance of >50 mL/min), concomitant cyclosporine administration
increased the mean AUC and Cmax of total ezetimibe 3.4-fold (range 2.3- to
7.9-fold) and 3.9-fold (range 3.0- to 4.4-fold), respectively. In a separate
study, the total ezetimibe exposure increased 12-fold in one renal transplant
patient with severe renal insufficiency receiving multiple medications,
including cyclosporine. (See CLINICAL PHARMACOLOGY, Drug Interactions and
WARNINGS, Myopathy/Rhabdomyolysis.)
Digoxin: Concomitant administration of a single dose of digoxin in healthy
male volunteers receiving simvastatin resulted in a slight elevation (less than
0.3 ng/mL) in plasma digoxin concentrations compared
12
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
to concomitant administration of placebo and digoxin. Patients taking digoxin
should be monitored appropriately when VYTORIN is initiated.
Fibrates: The safety and effectiveness of VYTORIN 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). Coadministration of VYTORIN
with fibrates is not recommended until use in patients is studied. (See
WARNINGS, Myopathy/Rhabdomyolysis.)
Warfarin: Simvastatin 20-40 mg/day modestly potentiated the effect of
coumarin anticoagulants: the prothrombin time, reported as International
Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to
3.4 in a normal volunteer study and in a hypercholesterolemic patient study,
respectively. With other statins, clinically evident bleeding and/or increased
prothrombin time has been reported in a few patients taking coumarin
anticoagulants concomitantly. In such patients, prothrombin time should be
determined before starting VYTORIN and frequently enough during early therapy to
insure that no significant alteration of prothrombin time occurs. Once a stable
prothrombin time has been documented, prothrombin times can be monitored at the
intervals usually recommended for patients on coumarin anticoagulants. If the
dose of VYTORIN is changed or discontinued, the same procedure should be
repeated. Simvastatin therapy has not been associated with bleeding or with
changes in prothrombin time in patients not taking anticoagulants.
Ezetimibe
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.
Simvastatin
Propranolol: In healthy male volunteers there was a significant decrease in
mean Cmax, but no change in AUC, for simvastatin total and active inhibitors
with concomitant administration of single doses of simvastatin and propranolol.
The clinical relevance of this finding is unclear. The pharmacokinetics of the
enantiomers of propranolol were not affected.
CNS TOXICITY
Optic nerve degeneration was seen in clinically normal dogs treated with
simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug
levels about 12 times higher than the mean plasma drug level in humans taking 80
mg/day.
A chemically similar drug in this class also produced optic nerve
degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically
normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that
produced mean plasma drug levels about 30 times higher than the mean plasma drug
level in humans taking the highest recommended dose (as measured by total enzyme
inhibitory activity). This same drug also produced vestibulocochlear
Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs
treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma
drug level similar to that seen with the 60 mg/kg/day dose.
CNS vascular lesions, characterized by perivascular hemorrhage and edema,
mononuclear cell infiltration of perivascular spaces, perivascular fibrin
deposits and necrosis of small vessels were seen in dogs treated with
simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug
levels that were about 14 times higher than the mean plasma drug levels in
humans taking 80 mg/day. Similar CNS vascular lesions have been observed with
several other drugs of this class.
There were cataracts in female rats after two years of treatment with 50
and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and
in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50
mg/kg/day (5 times).
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
VYTORIN
No animal carcinogenicity or fertility studies have been conducted with the
combination of ezetimibe and simvastatin. The combination of ezetimibe with
simvastatin did not show evidence of mutagenicity in
13
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
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 ezetimibe and simvastatin with or without
metabolic activation. There was no evidence of genotoxicity at doses up to 600
mg/kg with the combination of ezetimibe and simvastatin (1:1) in the in vivo
mouse micronucleus test.
Ezetimibe
A 104-week dietary carcinogenicity study with ezetimibe was conducted in
rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day (females) (~20
times the human exposure at 10 mg daily based on AUC(0-24hr) for total
ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also
conducted in mice at doses up to 500 mg/kg/day (>150 times the human exposure
at 10 mg daily based on AUC(0-24hr) for total ezetimibe). There were no
statistically significant increases in tumor incidences in drug-treated rats or
mice.
No evidence of mutagenicity was observed in vitro in a microbial
mutagenicity (Ames) test with Salmonella typhimurium and Escherichia coli with
or without metabolic activation. No evidence of clastogenicity was observed in
vitro in a chromosomal aberration assay in human peripheral blood lymphocytes
with or without metabolic activation. In addition, there was no evidence of
genotoxicity in the in vivo mouse micronucleus test.
In oral (gavage) fertility studies of ezetimibe conducted in rats, there
was no evidence of reproductive toxicity at doses up to 1000 mg/kg/day in male
or female rats (~7 times the human exposure at 10 mg daily based on AUC(0-24hr)
for total ezetimibe).
Simvastatin
In a 72-week carcinogenicity study, mice were administered daily doses of
simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma
drug levels approximately 1, 4, and 8 times higher than the mean human plasma
drug level, respectively (as total inhibitory activity based on AUC) after an
80-mg oral dose. Liver carcinomas were significantly increased in high-dose
females and mid- and high-dose males with a maximum incidence of 90% in males.
The incidence of adenomas of the liver was significantly increased in mid- and
high-dose females. Drug treatment also significantly increased the incidence of
lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian
gland (a gland of the eye of rodents) were significantly higher in high-dose
mice than in controls. No evidence of a tumorigenic effect was observed at 25
mg/kg/day.
In a separate 92-week carcinogenicity study in mice at doses up to 25
mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug
levels were 1 times higher than humans given 80 mg simvastatin as measured by
AUC).
In a two-year study in rats at 25 mg/kg/day, there was a statistically
significant increase in the incidence of thyroid follicular adenomas in female
rats exposed to approximately 11 times higher levels of simvastatin than in
humans given 80 mg simvastatin (as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and 100
mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at
both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were
increased in males and females at both doses; thyroid follicular cell carcinomas
were increased in females at 100 mg/kg/day. The increased incidence of thyroid
neoplasms appears to be consistent with findings from other HMG-CoA reductase
inhibitors. These treatment levels represented plasma drug levels (AUC) of
approximately 7 and 15 times (males) and 22 and 25 times (females) the mean
human plasma drug exposure after an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbial mutagenicity (Ames)
test with or without rat or mouse liver metabolic activation. In addition, no
evidence of damage to genetic material was noted in an in vitro alkaline elution
assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in
vitro chromosome aberration study in CHO cells, or an in vivo chromosomal
aberration assay in mouse bone marrow.
There was decreased fertility in male rats treated with simvastatin for 34
weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based
on AUC, in patients receiving 80 mg/day); however, this effect was not observed
during a subsequent fertility study in which simvastatin was administered at
this same dose level to male rats for 11 weeks (the entire cycle of
spermatogenesis
14
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
including epididymal maturation). No microscopic changes were observed in the
testes of rats from either study. At 180 mg/kg/day, (which produces exposure
levels 22 times higher than those in humans taking 80 mg/day based on surface
area, mg/m(2)), seminiferous tubule degeneration (necrosis and loss of
spermatogenic epithelium) was observed. In dogs, there was drug-related
testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and
giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure,
based on AUC, at 80 mg/day). The clinical significance of these findings is
unclear.
PREGNANCY
Pregnancy Category: X
See CONTRAINDICATIONS.
VYTORIN
As safety in pregnant women has not been established, treatment should be
immediately discontinued as soon as pregnancy is recognized. VYTORIN should be
administered to women of child-bearing potential only when such patients are
highly unlikely to conceive and have been informed of the potential hazards.
Ezetimibe
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in
rats and rabbits during organogenesis, there was no evidence of embryolethal
effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased
incidences of common fetal skeletal findings (extra pair of thoracic ribs,
unossified cervical vertebral centra, shortened ribs) were observed at 1000
mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC(0-24hr) for
total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of
extra thoracic ribs was observed at 1000 mg/kg/day (150 times the human exposure
at 10 mg daily based on AUC(0-24hr) for total ezetimibe). Ezetimibe crossed the
placenta when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe coadministered 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
coadministration therapy compared to monotherapy.
Simvastatin
Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in
rabbits at doses up to 10 mg/kg daily. These doses resulted in 3 times (rat) or
3 times (rabbit) the human exposure based on mg/m(2) surface area. However, in
studies with another structurally-related HMG-CoA reductase inhibitor, skeletal
malformations were observed in rats and mice.
Rare reports of congenital anomalies have been received following
intrauterine exposure to HMG-CoA reductase inhibitors. In a review (2) of
approximately 100 prospectively followed pregnancies in women exposed to
simvastatin or another structurally related HMG-CoA reductase inhibitor, the
incidences of congenital anomalies, spontaneous abortions and fetal
deaths/stillbirths did not exceed what would be expected in the general
population. The number of cases is adequate only to exclude a 3- to 4-fold
increase in congenital anomalies over the background incidence. In 89% of the
prospectively followed pregnancies, drug treatment was initiated prior to
pregnancy and was discontinued at some point in the first trimester when
pregnancy was identified.
LABOR AND DELIVERY
The effects of VYTORIN on labor and delivery in pregnant women are unknown.
NURSING MOTHERS
In rat studies, exposure to ezetimibe in nursing pups was up to half of
that observed in maternal plasma. It is not known whether ezetimibe or
simvastatin are excreted into human breast milk. Because a small amount of
another drug in the same class as simvastatin is excreted in human milk and
because of the potential for serious adverse reactions in nursing infants, women
who are nursing should not take VYTORIN (see CONTRAINDICATIONS).
- --------
2 Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P.,
Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During
Pregnancy, Reproductive Toxicology, 10(6):439-446, 1996.
15
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
PEDIATRIC USE
VYTORIN
There are insufficient data for the safe and effective use of VYTORIN in
pediatric patients. (See Ezetimibe and Simvastatin below.)
Ezetimibe
The pharmacokinetics of ezetimibe in adolescents (10 to 18 years) have been
shown to be similar to that in adults. Treatment experience with ezetimibe in
the pediatric population is limited to 4 patients (9 to 17 years) with
homozygous sitosterolemia and 5 patients (11 to 17 years) with HoFH. Treatment
with ezetimibe in children (<10 years) is not recommended.
Simvastatin
Safety and effectiveness of simvastatin in patients 10-17 years of age with
heterozygous familial hypercholesterolemia have been evaluated in a controlled
clinical trial in adolescent boys and in girls who were at least 1 year
post-menarche. Patients treated with simvastatin had an adverse experience
profile generally similar to that of patients treated with placebo. DOSES
GREATER THAN 40 MG HAVE NOT BEEN STUDIED IN THIS POPULATION. In this limited
controlled study, there was no detectable effect on growth or sexual maturation
in the adolescent boys or girls, or any effect on menstrual cycle length in
girls. Adolescent females should be counseled on appropriate contraceptive
methods while on therapy with simvastatin (see CONTRAINDICATIONS and
PRECAUTIONS, Pregnancy). Simvastatin has not been studied in patients younger
than 10 years of age, nor in pre-menarchal girls.
GERIATRIC USE
Of the patients who received VYTORIN in clinical studies, 792 were 65 and
older (this included 176 who were 75 and older). The safety of VYTORIN was
similar between these patients and younger patients. Greater sensitivity of some
older individuals cannot be ruled out. (See CLINICAL PHARMACOLOGY, Special
Populations and ADVERSE REACTIONS.)
ADVERSE REACTIONS
VYTORIN has been evaluated for safety in more than 3800 patients in
clinical trials. VYTORIN was generally well tolerated.
Table 5 summarizes the frequency of clinical adverse experiences reported
in greater than or equal to 2% of patients treated with VYTORIN (n=1236) and at
an incidence greater than placebo regardless of causality assessment from three
similarly designed, placebo-controlled trials.
TABLE 5*
CLINICAL ADVERSE EVENTS OCCURRING IN (GREATER THAN OR EQUAL TO)2% OF PATIENTS
TREATED WITH VYTORIN AND AT AN INCIDENCE GREATER THAN PLACEBO,
REGARDLESS OF CAUSALITY
Ezetimibe
Body System/Organ Class Placebo 10 mg Simvastatin** VYTORIN**
Adverse Event (%) (%) (%) (%)
n=311 n=302 n=1234 n=1236
----- ----- ------ ------
Body as a whole - general disorders
Headache 6.4 6.0 5.9 6.8
Infection and infestations
Influenza 1.0 1.0 1.9 2.6
Upper respiratory tract infection 2.6 5.0 5.0 3.9
Musculoskeletal and connective tissue disorders
Myalgia 2.9 2.3 2.6 3.5
Pain in extremity 1.3 3.0 2.0 2.3
* Includes two placebo-controlled combination studies in which the active
ingredients equivalent to VYTORIN were coadministered and one
placebo-controlled study in which VYTORIN was administered.
** All doses.
Ezetimibe
Other adverse experiences reported with ezetimibe in placebo-controlled
studies, regardless of causality assessment: Body as a whole - general
disorders: fatigue; Gastrointestinal system disorders: abdominal pain, diarrhea;
Infection and infestations: infection viral, pharyngitis, sinusitis;
Musculoskeletal system disorders: arthralgia, back pain; Respiratory system
disorders: coughing.
16
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
Post-marketing Experience
The following adverse reactions have been reported in post-marketing
experience, regardless of causality assessment:
Hypersensitivity reactions, including angioedema and rash; pancreatitis;
nausea; cholelithiasis; cholecystitis.
Simvastatin
Other adverse experiences reported with simvastatin in placebo-controlled
clinical studies, regardless of causality assessment: Body as a whole - general
disorders: asthenia; Eye disorders: cataract; Gastrointestinal system disorders:
abdominal pain, constipation, diarrhea, dyspepsia, flatulence, nausea; Skin and
subcutaneous tissue disorders: eczema, pruritus, rash.
The following effects have been reported with other HMG-CoA reductase
inhibitors. Not all the effects listed below have necessarily been associated
with simvastatin therapy.
Musculoskeletal system disorders: muscle cramps, myalgia, myopathy,
rhabdomyolysis, arthralgias.
Nervous system disorders: dysfunction of certain cranial nerves (including
alteration of taste, impairment of extra-ocular movement, facial paresis),
tremor, dizziness, memory loss, paresthesia, peripheral neuropathy, peripheral
nerve palsy, psychic disturbances.
Ear and labyrinth disorders: vertigo.
Psychiatric disorders: anxiety, insomnia, depression, loss of libido.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been
reported rarely which has included one or more of the following features:
anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia
rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia,
hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis,
arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing,
malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including
Stevens-Johnson syndrome.
Gastrointestinal system disorders: pancreatitis, vomiting.
Hepatobiliary disorders: hepatitis, including chronic active hepatitis,
cholestatic jaundice, fatty change in liver, and, rarely, cirrhosis, fulminant
hepatic necrosis, and hepatoma.
Metabolism and nutrition disorders: anorexia.
Skin and subcutaneous tissue disorders: alopecia, pruritus. A variety of
skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes,
changes to hair/nails) have been reported.
Reproductive system and breast disorders: gynecomastia, erectile
dysfunction.
Eye disorders: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase,
(gamma) -glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
LABORATORY TESTS
Marked persistent increases of serum transaminases have been noted (see
WARNINGS, Liver Enzymes). About 5% of patients taking simvastatin had elevations
of CK levels of 3 or more times the normal value on one or more occasions. This
was attributable to the noncardiac fraction of CK. Muscle pain or dysfunction
usually was not reported (see WARNINGS, Myopathy/Rhabdomyolysis).
CONCOMITANT LIPID-LOWERING THERAPY
In controlled clinical studies in which simvastatin was administered
concomitantly with cholestyramine, no adverse reactions peculiar to this
concomitant treatment were observed. The adverse reactions that occurred were
limited to those reported previously with simvastatin or cholestyramine.
ADOLESCENT PATIENTS (AGES 10-17 YEARS)
In a 48-week controlled study in adolescent boys and girls who were at
least 1 year post-menarche, 10-17 years of age with heterozygous familial
hypercholesterolemia (n=175), the safety and tolerability profile of the group
treated with simvastatin (10-40 mg daily) was generally similar to that of the
group treated with placebo, with the most common adverse experiences observed in
both groups being upper respiratory infection, headache, abdominal pain, and
nausea (see CLINICAL PHARMACOLOGY, Special Populations and PRECAUTIONS,
Pediatric Use).
17
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
OVERDOSAGE
VYTORIN
No specific treatment of overdosage with VYTORIN can be recommended. In the
event of an overdose, symptomatic and supportive measures should be employed.
Ezetimibe
In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy
subjects for up to 14 days, or 40 mg/day to 18 patients with primary
hypercholesterolemia for up to 56 days, was generally well tolerated.
A few cases of overdosage have been reported; most have not been associated
with adverse experiences. Reported adverse experiences have not been serious.
Simvastatin
A few cases of overdosage with simvastatin have been reported; the maximum
dose taken was 3.6 g. All patients recovered without sequelae.
The dialyzability of simvastatin and its metabolites in man is not known at
present.
DOSAGE AND ADMINISTRATION
The patient should be placed on a standard cholesterol-lowering diet before
receiving VYTORIN and should continue on this diet during treatment with
VYTORIN. The dosage should be individualized according to the baseline LDL-C
level, the recommended goal of therapy, and the patient's response. (See NCEP
Adult Treatment Panel (ATP) III Guidelines, summarized in Table 4.) VYTORIN
should be taken as a single daily dose in the evening, with or without food.
The dosage range is 10/10 mg/day through 10/80 mg/day. The recommended
usual starting dose is 10/20 mg/day. Initiation of therapy with 10/10 mg/day may
be considered for patients requiring less aggressive LDL-C reductions. Patients
who require a larger reduction in LDL-C (greater than 55%) may be started at
10/40 mg/day. After initiation or titration of VYTORIN, lipid levels may be
analyzed after 2 or more weeks and dosage adjusted, if needed. See below for
dosage recommendations for patients receiving certain concomitant therapies and
for those with renal insufficiency.
PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
The recommended dosage for patients with homozygous familial
hypercholesterolemia is VYTORIN 10/40 mg/day or 10/80 mg/day in the evening.
VYTORIN should be used as an adjunct to other lipid-lowering treatments (e.g.,
LDL apheresis) in these patients or if such treatments are unavailable.
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 mild or moderate renal
insufficiency. However, for patients with severe renal insufficiency, VYTORIN
should not be started unless the patient has already tolerated treatment with
simvastatin at a dose of 5 mg or higher. Caution should be exercised when
VYTORIN is administered to these patients and they should be closely monitored
(see CLINICAL PHARMACOLOGY, Pharmacokinetics and WARNINGS,
Myopathy/Rhabdomyolysis).
GERIATRIC PATIENTS
No dosage adjustment is necessary in geriatric patients (see CLINICAL
PHARMACOLOGY, Special Populations).
COADMINISTRATION WITH BILE ACID SEQUESTRANTS
Dosing of VYTORIN should occur either(greater than or equal to)2 hours
before or(greater than or equal to)4 hours after
administration of a bile acid sequestrant (see PRECAUTIONS, Drug Interactions).
PATIENTS TAKING CYCLOSPORINE
Caution should be exercised when initiating VYTORIN in the setting of
cyclosporine. In patients taking cyclosporine, VYTORIN should not be started
unless the patient has already tolerated treatment with simvastatin at a dose of
5 mg or higher. The dose of VYTORIN should not exceed 10/10 mg/day.
PATIENTS TAKING AMIODARONE OR VERAPAMIL
18
VYTORIN(TM) (ezetimibe/simvastatin) 9619600
In patients taking amiodarone or verapamil concomitantly with VYTORIN, the
dose should not exceed 10/20 mg/day (see WARNINGS, Myopathy/Rhabdomyolysis and
PRECAUTIONS, Drug Interactions, Other drug interactions).
HOW SUPPLIED
No. 3873 -- Tablets VYTORIN 10/10 are white to off-white capsule-shaped
tablets with code "311" on one side.
They are supplied as follows:
NDC 66582-311-31 bottles of 30
NDC 66582-311-54 bottles of 90
NDC 66582-311-82 bottles of 1000 (If repackaged in blisters, then opaque or
light-resistant blisters should be used.)
NDC 66582-311-28 unit dose packages of 100.
No. 3874 -- Tablets VYTORIN 10/20 are white to off-white capsule-shaped
tablets with code "312" on one side.
They are supplied as follows:
NDC 66582-312-31 bottles of 30
NDC 66582-312-54 bottles of 90
NDC 66582-312-82 bottles of 1000 (If repackaged in blisters, then opaque or
light-resistant blisters should be used.)
NDC 66582-312-28 unit dose packages of 100.
No. 3875 -- Tablets VYTORIN 10/40 are white to off-white capsule-shaped
tablets with code "313" on one side.
They are supplied as follows:
NDC 66582-313-31 bottles of 30
NDC 66582-313-54 bottles of 90
NDC 66582-313-74 bottles of 500 (If repackaged in blisters, then opaque or
light-resistant blisters should be used.)
NDC 66582-313-52 unit dose packages of 50.
No. 3876 -- Tablets VYTORIN 10/80 are white to off-white capsule-shaped
tablets with code "315" on one side.
They are supplied as follows:
NDC 66582-315-31 bottles of 30
NDC 66582-315-54 bottles of 90
NDC 66582-315-74 bottles of 500 (If repackaged in blisters, then opaque or
light-resistant blisters should be used.)
NDC 66582-315-52 unit dose packages of 50.
Storage
Store at 20-25(DEGREE)C (68-77(DEGREE)F). [See USP Controlled Room
Temperature.] Keep container tightly closed.
Issued July 2004
Printed in USA
(LOGO) Manufactured for:
MERCK/Schering-Plough Pharmaceuticals
North Wales, PA 19454, USA
By:
MSD Technology Singapore Pte. Ltd.
Singapore 637766
19