Title: PharmaNote
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Permanent Link: http://ufdc.ufl.edu/UF00087345/00028
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Title: PharmaNote
Series Title: PharmaNote
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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: March 2005
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Benjamin Spitz, Pharm.D. Candidate

In July 2004, the National Cholesterol Educa-
tion Panel (NCEP) published an update of the
Adult Treatment Panel III (ATP III) cholesterol
guidelines that were previously released in 2001.
The update, entitled "Implications of Recent Clini-
cal Trials for the National Cholesterol Education
Program Adult Treatment Panel III Guidelines",
endorses more aggressive cholesterol-lowering
treatment for people at high and moderately high
risk for heart disease. The publication presents data
from recent clinical trials, which showed that ag-
gressive lowering of low-density lipoprotein cho-
lesterol (LDL-C) was associated with a reduced
risk of suffering from a cardiovascular event. Al-
though it is unclear whether clinical benefit was
due to the low level of LDL-C or to non-lipid low-
ering effects of stations, these results have led to a
lowering of the target LDL-C goals to 70 mg/dl or
less in "very high risk" patients.1 The higher the
risk, the more aggressively LDL should be treated.
Current statistics show nearly 105 million
American adults have total cholesterol (TC) levels
greater than 200 mg/dL.2 This astonishing statistic
implies that there are many people in America at
increased risk for coronary heart disease (CHD).
Reduction in LDL-C is a crucial means for lower-

ing the risk of CHD and subsequent outcomes.
There are two main ways to lower cholesterol.
First, there is therapeutic lifestyle changes (TLC)
which includes a cholesterol-lowering diet, physi-
cal activity, and weight management. The second
option is through drug treatment. If cholesterol-
lowering drugs are needed, they are used together
with TLC to help lower LDL. Over the past decade
many new cholesterol lowering options have been
approved. These include fibric acid derivatives (i.
e., fibrates), niacin, bile acid sequestrants (e.g.,
cholestyramine), hydroxymethylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors (i.e., stations ,
and more recently, cholesterol absorption inhibitors
(e.g., ezetimibe).
In July 2004, Merck/Schering-Plough Pharma-
ceuticals announced that the FDA approved their
new combination product, VytorinTM. The new
product is a combination of previously approved
simvastatin and ezetimibe. VytorinTM was approved
for the treatment of high LDL-C in patients with
primary hypercholesterolemia or mixed hyperlipi-
demia as adjunctive therapy to TLC when TLC
alone is not enough. Ezetimibe (Zetia), the first
and only cholesterol absorption inhibitor, was ap-
proved by the FDA in October 2003 for the treat-
ment of hypercholesterolemia. The other compo-



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Table 1. LDL cholesterol goal attainment after the first treatment period and at the end of treatment*.6
Treatment S(20) E(10) + S(10) E(10) + S(20) E(10) + S(40)
After First Treatment Period (week 5) (n=246) (n=242) (n= 108) (n=96)
No. (%) of patients attaining LDL 181(75 90(83 84 (87
112 (46%) 181 (75%)1 90 (83%)1 84 (87%)t
cholesterol goal (<100 mg/dl)
End of the Study
No. (%) of patients attaining LDL 190(78 90(83 83 (86
147 (59%) 190 (78%)7 90 (83%)7 83 (86%)
cholesterol goal (<100 mg/dl)*
Percentage of patients requiring 68 331 221 121
simvastatin up-titration
E = ezetimibe (milligrams); S = simvastatin (milligrams). *Modified intention-to-treat population that included patients with baseline and > 1 post-baseline meas-
urement during treatment period. p<0.001 versus S20. 1Based on entire study cohort regardless of whether patients were at goal at the end of the study.

nent, simvastatin, was approved by the FDA in De-
cember 1991 under the brand name Zocor for the
treatment of hypercholesterolemia. This article will
review the pharmacology, clinical trials, and perti-
nent prescribing information for VytorinTM.

Pharmacology and Pharmacokinetics
VytorinTM contains ezetimibe and simvastatin,
two lipid-lowering compounds with complemen-
tary mechanisms of action." VytorinTM reduces ele-
vated TC, LDL-C, apolipoprotein B (Apo B),
triglycerides (TG), and non-high density lipopro-
tein cholesterol (non-HDL-C), and increases HDL-
C through dual inhibition of cholesterol absorption
and synthesis.
Ezetimibe has a mechanism unlike any other
cholesterol lowering compound. Ezetimibe de-
creases LDL-C by inhibiting the absorption of cho-
lesterol by the small intestine. It does not inhibit
cholesterol synthesis in the liver like stations, nor
does it increase bile acid secretion like bile acid se-
questrants. Ezetimibe localizes and acts on the
brush border of the small intestine inhibiting cho-
lesterol absorption. This leads to a decrease in de-
livery of intestinal cholesterol to the liver. The de-
crease in cholesterol delivery to the liver causes a
reduction of hepatic cholesterol stores and an in-
crease in clearance of cholesterol from the blood.
Ezetimibe has no clinically meaningful effect on
the plasma concentrations of the fat-soluble vita-
mins A, D, and E and does not impair adrenocorti-
cal steroid hormone production. This unique
mechanism of action is complementary to that of
Simvastatin is a specific inhibitor of HMG-CoA

reductase, the enzyme that catalyzes the conversion
of HMG-CoA to mevalonate. The conversion of
HMG-CoA to mevalonate is an early step in the
biosynthetic pathway for cholesterol. Simvastatin
reduces both normal and elevated LDL-C concen-
trations. In addition, simvastatin reduces very low
density lipoproteins (VLDL) and TG, and mini-
mally increases HDL-C.
Specific pharmacokinetic drug interaction stud-
ies with VytorinTM have not been performed. No
clinically significant pharmacokinetic interactions
were seen when ezetimibe was co-administered
with simvastatin. Ezetimibe administered alone had
no significant effect on the cytochrome P450 en-
zyme system. Tests indicate that ezetimibe is nei-
ther an inhibitor nor an inducer of the CYP450
isozymes, and is unlikely to affect the metabolism
of drugs that are metabolized by these enzymes.
Simvastatin is a substrate of the CYP450 iso-
form 3A4. It does not inhibit CYP3A4; therefore, it
is not expected to affect the plasma levels of other
drugs metabolized by these enzymes. Potent inhibi-
tors of CYP3A4 can raise plasma levels of some
station drugs (e.g., simvastatin, atorvastatin, lovas-
tatin), thereby increasing the risk of myopathy. Pa-
tients using drugs that inhibit CYP3A4 should be
monitored more closely for statin-related adverse
effects. This includes grapefruit juice, which inhib-
its CYP3A4 in the gut wall, thus, increasing station
Following oral administration of a 10 mg dose
of ezetimibe, a Cmax of 3.4 5.5 ng/ml was reached
within 4 to 12 hours. The Cmax value of ezetimibe
was increased by 38% with consumption of high
fats meals. However, concomitant food administra-

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Table 2. Percentage change in lipid parameters after the first treatment period.6
Least Square Mean (SE) % Change From Baseline After First Treatment Period (5 weeks)
Treatment S(20) E(10) + S(10) E(10) + S(20) E(10) + S(40)
(n=248) (n=245) (n=109) (n=97)
LDL cholesterol -38 (0.8) -47 (0.8) -53 (1.2) -59 (1.3)
Total Cholesterol -27 (0.7) -33 (0.6) -38 (0.9) -42 (1.0)
Non-HDL-C -34 (0.8) -42 (0.8) -48 (1.1) -53 (1.2)
Triglyceride -19(1.9) -19(1.5) -25 (2.7) -30 (2.6)
HDL cholesterol 5.1(0.7) 6.2(0.7) 8.0 (1.0)* 7.4(1.1)
LDL-C: HDL-C -41 (0.8) -50 (0.8) -56 (1.2) -61 (1.3)

SE denotes standard error. E = ezetimibe (milligrams); S = simvastatin (milligrams). p<0.001 versus S20.

tion (high-fat or non-fat meals) had no effect on the
extent of absorption of ezetimibe. Ezetimibe is pri-
marily metabolized in the small intestine and liver
via glucuronide conjugation with subsequent biliary
and renal excretion. Both the parent compound and
its active metabolite are slowly eliminated from the
plasma with a half-life of approximately 22 hours.
Absorption of simvastatin is 85%, but bioavail-
ability is less than 5% due to a significant first pass
effect. Food had no effect on the rate and extent of
absorption. Simvastatin is administered as an inac-
tive prodrug and must be activated in the liver.
Sixty percent of an oral dose is excreted in the fe-
ces and 13% in the urine. The half-life of simvas-
tatin is 1.9 hours. Simvastatin circulates in plasma
highly bound to plasma proteins (>95%), predomi-
nantly albumin.

Dosage and Administration
VytorinTM is available as tablets containing 10
mg of ezetimibe combined with 10, 20, 40 or 80
mg of simvastatin. The dosage should be individu-
alized according to the baseline LDL-C level, the
recommended goal of therapy (NCEP ATP III
Guidelines), and patient response. The recom-
mended starting dose is 10/20 mg/day.3 Initiation of
therapy with 10/10 mg/day may be considered for
patients requiring less aggressive LDL-C reduction.
Patients who require a larger reduction in LDL-C
(greater than 55%) may be started at 10/40 mg/day."
No dosage adjustment is needed for mild hepatic
impairment. Active liver disease is a contraindica-
tion for simvastatin use. Avoid VytorinTM in patients

with moderate to severe hepatic impairment or any
persistent and unexplained increases in LFTs." No
dosage adjustment is necessary in patients with
mild or moderate renal impairment. In patients with
a CrCl < 30 ml/min, do not start VytorinTM unless
the patient has already tolerated monotherapy with
simvastatin > 5 mg/day.1 VytorinTM should be taken
as a single dose in the evening, with or without

Clinical Trials
In a 23 week, multi-center, parallel group study,
710 patients with LDL-C >130 mg/dl with CHD or
an equivalent were randomized to 1 of 4 treatment
groups.6 Patients received simvastatin 20 mg,
ezetimibe 10 mg plus simvastatin 10 mg, ezetimibe
10 mg plus simvastatin 20 mg, or ezetimibe 10 mg
plus simvastatin 40 mg. Simvastatin was titrated up
every 6 weeks to a maximal dose of 80 mg in pa-
tients who did not achieve target LDL-C goal. The
primary objective was to evaluate the efficacy of
ezetimibe 10 mg plus simvastatin 10 mg versus
simvastatin 20 mg monotherapy in attaining the tar-
get LDL-C goal of <100 mg/dl after 5 weeks. Sec-
ondary endpoints included the percentage of pa-
tients achieving goal at study close, the number of
simvastatin dose titrations, and the median simvas-
tatin dose used throughout the study.
The percentage of patients achieving the LDL-C
goal of <100 mg/dl after the first treatment period
(week 5) in the ezetimibe plus simvastatin 10, 20,
and 40 mg groups (75%, 83%, and 87% respec-
tively) was significantly greater than in the simvas-

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Table 3. Response to VytorinT and atorvastatin in patients with primary hypercholesterolemia.7
Mean % Change from Untreated Baselinea
Treatment N Total-C LDL-C HDL-C Tgb Non-HDL-C
Week 6
Atorvastatin 10 mg' 262 -28 -37 +5 -23 -35
VytorinTM 10/10d 263 -34' -46' +8f -26 -43f
VytorinTm 10/20e 263 -36f -50f +10f -25 -46f
Week 12
Atorvastatin 20 mg 246 -33 -44 +7 -28 -42
VytorinTm 10/20 250 -37f -50f +9 -28 -46f
VytorinTm 10/40 252 -39f -54f +12f -31 -50f
Week 18
Atorvastatin 40 mg 237 -37 -49 +8 -31 -47
VytorinM 1) 40- 482 -40f -56f +11f -32 -52f
Week 24
Atorvastatin 80 mg 228 -40 -53 +6 -35 -50
VytorinM 10/80g 459 -43f -59f +12f -35 -55f
A Baseline -on no lipid-lowering drug. B For triglycerides, median % change from baseline. c Atorvastatin: 10 mg start dose titrated to 20, 40, and 80 mg
through weeks 6, 12, 18, and 24. dVytorinTM:start 10/10 start dose titrated to 10/20, 10/40, and 10/80 through weeks 6, 12, 18, and 24. eVytorinTM:start 10/20 start
dose titrated to 10/40, 10/40, and 10/80 through weeks 6, 12, 18, and 24. Fp<0.05 for difference with atorvastatin in the specified week. Data pooled for common
doses of VytorinTm at weeks 18 and 24.

tatin 20 mg group (46%; p<0.001 for all 3 compari-
sons; Table 1). Patients treated with ezetimibe 10
mg plus simvastatin 10 mg had a 3.6 fold greater
risk of reaching goal after 5 weeks than patients
treated with simvastatin 20 mg (odds ratio [OR],
3.6; 95% CI, 2.4 to 5.2). The data in Table 2 show
that mean plasma levels of LDL-C were reduced
significantly more by all doses of ezetimibe plus
simvastatin than by simvastatin 20 mg after the
first treatment period. Relative to simvastatin 20
mg, ezetimibe plus simvastatin 10 mg also pro-
duced significantly larger reductions in TC, non-
HDL, and the ratio of LDL-C to HDL-C. Triglyc-
erides were significantly reduced by ezetimibe plus
simvastatin 20 and 40 mg compared with simvas-
tatin 20 mg. Although HDL-C was numerically
greater in all 3 co-administration groups than in the
simvastatin 20 mg group, the increase was only sig-
nificant in the ezetimibe plus simvastatin 20 mg
In a 28-week (4 week placebo/diet run in and 24
week active treatment period) multi-center, active-
controlled, double blind study, 788 patients with an
LDL-C level at or above drug treatment threshold

established by NCEP ATP III guidelines were ran-
domized to receive co-administered ezetimibe and
simvastatin (equivalent to VytorinTM 10/10 and
10/20) or atorvastatin 10 mg.' For all three treat-
ment groups, the dose of the station was titrated at 6
week intervals to 80 mg. The primary efficacy
measure was mean percentage change in LDL-C
from baseline to the end of the initial 6-week treat-
ment period. Key secondary efficacy measures in-
cluded percent change from baseline to the end of
the second and fourth (final) 6-week treatment peri-
ods and percentage change in HDL-C from baseline
to the end of the final 6-week treatment period. Ta-
ble 3 depicts the mean percentage change from
baseline measured at each 6 week interval. At each
pre-specified dose comparison, co-administered
ezetimibe and simvastatin significantly lowered to-
tal cholesterol and LDL-C to a greater degree than
atorvastatin. At 24 weeks, mean change in HDL-C
levels for patients taking 10 mg ezetimibe plus 80
mg of simvastatin were also significantly greater
than for patients treated with atorvastatin 80 mg.
(Table 3)

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Table 4. Clinical Adverse Events* Occurring in >2% of Patients Treated with VytorinTM.3
Placebo Ezetimibe 10 mg Simvastatin** VytorinTM
Body System/Organ Class (n = 311) (n = 302) (n = 1234) (n = 1236)
Body as a whole general disorders
Headache (%) 6.4 6.0 5.9 6.8
Infections 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
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 T were co-administered and one placebo-controlled
study in which Vytorin T was administered. Adverse events are reported regardless of causality. **All doses.

Precautions and Warnings/Contraindications
In clinical trials, there was no excess of myopa-
thy or rhabdomyolysis associated with ezetimibe
compared with the relevant control arm (placebo or
station alone)." However, myopathy and rhabdo-
myolysis are known to occur in patients treated
with stations and other lipid lowering agents and,
thus, may occur with VytorinTM. In clinical trials,
the incidence of creatinine kinase (CK) >10 times
the upper limit of normal was 0.2% for VytorinTM.
Increases in serum transaminases (3 times above
normal) occurs slightly more often with the combi-
nation of ezetimibe and a station than with a station
alone (1.3% vs. 0.4%).
VytorinTM is pregnancy category X and should
not be used in pregnant women and administered to
women of childbearing age only when such pa-
tients are highly unlikely to conceive. Cholesterol
and other products of the cholesterol biosynthesis
pathway are essential components for fetal devel-
opment, including synthesis of steroids and cell
membranes. HMG-CoA reductase inhibitors, such
as simvastatin, block the cholesterol biosynthesis
pathway increasing the potential risks to the fetus.
If the patient becomes pregnant while taking this
drug, it should be discontinued immediately. Pa-
tients that have active liver disease or unexplained
persistent elevations in serum transaminases or
have hypersensitivity to any component of this
medication should not use VytorinTM.

Adverse Reactions
VytorinTM has been evaluated for safety in

more than 3800 patients in clinical trials." Vy-
torinTM was generally well tolerated. Table 4 sum-
marizes adverse events reported in >2% of pa-
tients treated with VytorinTM (n=1236) and at inci-
dence greater than placebo regardless of causality
from three similarly designed, placebo-controlled
trials. Other adverse reactions that have been re-
ported include abdominal pain, nausea, diarrhea;
hypersensitivity reactions, including angioedema
and rash; pancreatitis; cholelithiasis; cholecystitis.

Drug Interactions
VytorinTM should be used cautiously with known
inhibitors of the CYP3A4 enzymes."5 Concomitant
use of CP3A4 inhibitors increases the risk for
myopathy/rhabdomyolysis by reducing the elimina-
tion of the simvastatin component. When adminis-
tering VytorinTM with amiodarone or verapamil, the
dose should not exceed 10/20 mg daily. Caution
should also be exercised when initiating VytorinTM
in patients treated with cyclosporine due to in-
creased exposure to ezetimibe. The dose should not
exceed 10/10 mg daily in patients receiving cyc-
VytorinTM should not be administered with other
stations. Since compounds in red yeast rice are
chemically similar to lovastatin, red yeast rice
should not be used in combination with stations.
Concomitant use can increase the risk of drug-
related toxicity, such as myopathy, rhabdomyoly-
sis, and/or transaminitis.
Co-administration of VytorinTM with fibrates is
not recommended until clinical trials have been

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Table 5. Average cost* of Vytorin TM and its components

Drug Tablet Size Cost*
VytorinTm 10/10 mg $84.24
10/20 mg $84.24
10/40 mg $84.24
10/80 mg $84.24
Ezetimibe (Zetia) 10 mg $77.77
Simvastatin (Zocor") 10 mg $79.02
20 mg $137.87
40 mg $137.87
80 mg $137.87
*Cost information derived from reference 1.

conducted to establish safety and efficacy. In a
pharmacokinetic study, concomitant fenofibrate or
gemfibrozil administration increased total
ezetimibe concentrations by approximately 1.5 or
1.7-fold, respectively. The combined use of
ezetimibe with fibrates has not been thoroughly
studied and should be used with caution if at all.
VytorinTM is expected to interact with the bile
acid sequestrants. The oral absorption of ezetimibe
is decreased by the concomitant administration of
cholestyramine, resulting in reduced efficacy of
ezetimibe. A similar effect might be expected to oc-
cur with co-administration of colestipol. No data
are available for colesevelam, a bile acid seques-
trant that exhibits few absorptive interactions. To
limit interactions, dosing of VytorinTM should occur
either > 2 hours before or > 4 hours after admini-
stration of a bile acid sequestrant.

The cost of a 30-day supply of VytorinTM and its
separate components are depicted in Table 5.1

VytorinTM is the newest addition to the cholesterol
lowering drug market. It offers substantial choles-
terol lowering power through a combination of two
separate medications, simvastatin and ezetimibe,
with two distinct mechanisms. The fixed dose com-
bination of ezetimibe and simvastatin is more con-
venient and less expensive than taking the 2 drugs
separately. Since clinical outcomes data is still un-
available VytorinTM should not be considered as a
first line lipid-lowering agent. VytorinM should be

considered as a viable option for patients in which
high dose stations are contraindicated or intolerable
and intense lipid lowering therapy is needed. The
combination of ezetimibe and simvastatin offers
high-risk patients the opportunity to reach LDL-C
goals in accordance with the newly updated ATP
III guidelines when a station alone has been insuffi-
cient or higher doses can not be tolerated. VytorinT
offers a well-tolerated, efficacious treatment strat-
egy for patients with hypercholesterolemia.

1. VytorinTM: A Combination of Ezetimibe and Simvastatin. Med
Lett Drugs Ther. 2004 Sep; 46(1191):73-74. Accessed online at

2. Cholesterol Statistics. American Heart Association. Accessed
online at www.americanheart.org. Dec 12, 2004
3. Merck/Schering-Plough Pharmaceuticals. VytorinTM (ezetimibe/
simvastatin) [package insert]. North Wales, PA: (11/2004) re-
viewed 12/2005.
4. Merck & Co. Zocor (simvastatin) [package insert]. Cramling-
ton, Northumberland, UK: (2/2004)
5. VytorinTM Drug Monograph. Clinical Pharmacology Online
2004 December. Gold Standard Media. Available from: URL:
6. Feldman T, Koren M et al. Treatment of High-Risk Patients
With Ezetimibe Plus Simvastatin Co-Administration Versus
Simvastatin Alone to Attain National Cholesterol Education
Program Adult Treatment Panel III Low-Density Lipoprotein
Cholesterol Goal. Am J Cardiol 2004;93:1481-1486.
7. Ballantyne CM, Blanzig MA et al. Efficacy and Safety of
Ezetimibe Co-Administered With Simvastatin Compared With
Atorvastatin in Adults With Hypercholesterolemia. Am J Car-
diol 2004:93;1487-1493.

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida

John G. Gums Editor

R. Whit Curry, M.D. Associate Editor

Benjamin J. Epstein Assistant Editor

PharmaNote Volume 20, Issue 6, March 2005


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