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Formulary Review
March 2003
Generic Name: Ezetimibe
Brand Name: Zetia® (Merck/Schering-Plough)
Similar Drugs on Formulary: Lipitor® (atorvastatin), Pravachol® (pravastatin)
Indications:
Ezetimibe is indicated in primary hypercholesterolemia as monotherapy or in
combination with HMG-CoA reductase inhibitors (statins), in homozygous familial
hypercholesterolemia (HoFH), and in homozygous sitosterolemia.1
Pharmacology:
Ezetimibe has a different mechanism of action than the statins, which is also
complementary. It appears to act on the brush border cells of the intestine to inhibit
cholesterol absorption, which leads to a decrease in the stores of cholesterol in the liver
and an increase in clearance from the blood.1
Pharmacokinetics:
Absorption
Oral bioavailability is 35%-60%. Absolute bioavailability could not be determined
because ezetimibe is too insoluble in water for IV dosing. The absorption halflife is 0.5
to 0.8 hours, and Cmax is estimated to occur at 1.3 hours, reaching a single-dose
concentration of 74 ng/mL, and 131 ng/ml for multiple-dose administration.1
Peaks in ezetimibe concentration-time profiles corresponded to the times at which the
patients ate meals; therefore, it is suggested that ezetimibe and/or its metabolite is
secreted along with bile into the gastrointestinal tract, when the gallbladder empties in the
presence of food, and then undergoes enterohepatic recycling. The active site for
ezetimibe is the intestinal wall; therefore, this process may help increase the effectiveness
of ezetimibe.6
Distribution
Ezetimibe and its metabolite ezetimibe-glucuronide are highly bound (>90%) to plasma
proteins.1 Approximately 17-20% of the total amount of ezetimibe absorbed is recycled
into the central compartment regardless of volume of distribution. Relative volume of
distribution varies widely between individuals.11
Metabolism
Ezetimibe is metabolized in the liver to an active glucuronide conjugate through a Phase
II reaction. Oxidative metabolism by the CYP isoenzyme family is minimal.1 Ezetimibe
is glucuronidated at its site of action, the intestine. Its metabolite is then excreted into
bile. The parent and its glucuronide are recycled enterohepatically back to the intestine
after reabsorption. Enterohepatic recirculation (EHC) continues on an approximate 4-
hour cycle for 24 hours after a dose of ezetimibe. EHC results in longer time at the site of
action (larger AUC) and multiple peaks in the concentration-time profile. EHC appears to
be more extensive in patients with lower exposure to ezetimibe.11
Elimination
The estimated terminal half-life of ezetimibe is approximately 22 hours. It is eliminated
in the feces (78%, 69% as ezetimibe) and in the urine (11%, 9% as glucuronide.)1,6
Elimination is from the central compartment of the 2-compartment model. Terminal
elimination half-life is 30 hours. Ezetimibe-glucuronide is not detected in the feces.11
Special Populations
In the elderly (>65 years), plasma concentrations for total ezetimibe (ezetimibe plus
ezetimibe-glucuronide) were about twice as high as in younger subjects. Plasma
concentrations were slightly higher (<20%) in women than in men. Use is not
recommended in children under the age of 10.
In patients with hepatic function impairment, the mean AUC values were increased four
times compared with healthy subjects. Because the effects of increased exposure are
unknown, ezetimibe should not be used in patients with moderate or severe hepatic
insufficiency.
In patients with renal function impairment, the mean AUC values were increased
approximately 1.5 times compared with healthy subjects. Ezetimibe may be safely used
in these patients.1
Clinical Efficacy
The first evaluation of ezetimibe in man was performed by Sudhop et al. The study was a
double-blind, placebo-controlled, 2-period crossover trial in which subjects were
randomized to either ezetimibe 10 mg QD in period one then placebo in period 2, or
placebo in period 1 then ezetimibe 10 mg QD in period 2, with a 2 week placebo run-in
period and a 2 week washout period between treatment periods. Treatment periods lasted
2 weeks each. The 18 patients were enrolled based partly on LDL 130-180 mg/dl,
dietary cholesterol intake of 200-500 mg/day, and having not received lipid-lowering
drugs within 6 weeks prior to the study. All patients completed the study. The primary
objective, intestinal absorption of cholesterol, was measured during the second week of
each treatment period with the continuous feeding dual-isotope method using tracer
capsules of radio-labeled cholesterol and sitostanol. Parameters were measured by gas
chromatography, mass spectrometry and liquid chromatography of subsequent stool
samples and analyzed using ANOVA. Though cholesterol production increased 89% with
ezetimibe relative to placebo (p<0.001), fractional cholesterol absorption was 22.7% on
ezetimibe compared to 49.8% with placebo, a 54% reduction (p<0.001) and fecal
excretion of neutral sterols increased 72% with ezetimibe use compared to placebo
(p<0.001). Baseline lipid panels were taken after the placebo run-in period, after 2 weeks
of treatment and again at completion of the study. Total treatment difference of 13.2%
lower LDL cholesterol was observed for ezetimibe compared with placebo (p<0.001). A
significant decrease in plasma noncholesterol sterols camptosterol and sitosterol was also
observed (p<0.001). Ezetimibe was tolerated with no serious clinical adverse events or
laboratory changes.12
The efficacy and tolerability of ezetimibe were assessed by Bays et al. in two 12-week,
multicenter, placebo-controlled, double-blind, randomized, parallel group trials in
patients with primary hypercholesterolemia. Study A, which involved 243 patients, was
a dose-response trial; study B, which involved 189 patients, was a dose-regimen trial.
Both studies were comprised of three phases: a screening phase (including a washout
period), a prerandomization phase (including a six-week-long placebo lead-in), and an
active-treatment phase. Efficacy was assessed via the percentage change from baseline to
end point in plasma LDL-cholesterol levels (measured directly and by calculation). In
study A, patients were randomized to receive either 0.25, 1, 5, or 10 mg oral ezetimibe or
placebo to be taken before breakfast. The mean reduction of plasma LDL-C levels was
9.9% and 18.7% with 0.25 mg and 10 mg of ezetimibe (vs. placebo), respectively, after
12 weeks. In study B, patients were randomized to receive either 5 or 10 mg oral
ezetimibe or placebo to be taken either before breakfast or at bedtime. All regimens
produced a decrease in plasma LDL-C levels of 13.8% to 18.2% after 12 weeks (with no
apparent difference between morning and evening regimens). Adverse events in both
studies were determined to be mild to moderate in severity with no clinically significant
differences between any of the ezetimibe and placebo groups. Limitations of the study
include the relatively short trial period (12 weeks), lack of cardiovascular or mortalityrelated endpoints, fairly strict exclusion criteria, and a homogeneous population (mostly
Caucasian). However, this study did demonstrate that ezetimibe was effective at
lowering LDL-C levels, that there was little difference in efficacy due to administration
in the morning or evening, or with or without food, and also that this drug was well
tolerated.4
Dujovne et al. describe another multi-center, randomized, double-blind, placebocontrolled study that was conducted at 53 centers in the US. 892 patients with primary
hypercholesterolemia (mean baseline LDL = 168 mg/dl) were enrolled in the study and
underwent a 6 to 12 week washout of other lipid-lowering drugs during which time they
received dietary counseling and were instructed to follow a NCEP Step I or stricter diet.
Patients were randomly assigned by computer in a 3:1 ratio to either ezetimibe 10 mg QD
or placebo QD for 12 weeks. The primary variable, percent change in plasma LDL from
baseline, was measured as part of a standard lipid panel. Safety was evaluated through
patient reports, investigator observation, and specific test results. Efficacy was
determined using a 2-way ANOVA in an intent-to-treat manner. The study was
completed by 91% of patients with a similar rate for treatment and placebo groups. 46%
of dropouts were due to adverse events. Ezetimibe treatment resulted in a 17% lowering
of LDL cholesterol with 60% of patients experiencing > 15% reduction, compared to
placebo resulting in a mean 0.4% increase in LDL cholesterol and 10% of patients
achieving > 15% reduction (p<0.01). Reduction of LDL cholesterol occurred within 2
weeks of initiating ezetimibe, was maintained throughout the study, and was apparent to
researchers. In this trial, ezetimibe also resulted in decreased apolipoprotein B, total
cholesterol, and triglycerides, and an increase in HDL cholesterol (p<0.01). However, it
must be taken into account that the subjects were instructed to maintain a strict diet and
submitted diaries for analysis. Adverse events were reported at a similar rate for
ezetimibe (63%) and placebo (66%), with only URI and headache accounting for >5%
each. The investigators concluded that ezetimibe 10 mg QD was proven to be an
effective LDL-lowering agent with acceptable safety and tolerability.13
Efficacy when used in concomitant statin therapy
Clinical efficacy and safety of adding ezetimibe to concurrent statin therapy was
evaluated in a multi-center, double-blind, randomized, placebo-controlled study
involving 769 patients with primary hypercholesterolemia who had failed to reach NCEP
ATP II goals. Enrolled patients added to their ongoing statin therapy either 10 mg
ezetimibe QD or placebo for 8 weeks. The distribution was approximately one third on
each of simvastatin or atorvastatin, and one third on all other statins combined. Mean
percentage change in LDL-C, the primary efficacy parameter, was measured as part of a
lipid panel at baseline and on visits 1, 2, 3, and 6. Maximum reduction of LDL-C (up to
an additional 26.8%) occurred within two weeks of initiation and was maintained for the
duration of the study. Percent of patients achieving NCEP ATP II goals after 8 weeks of
therapy, the secondary efficacy parameter, was calculated using an intent-to-treat
approach. 75.5% of the statin plus ezetimibe group achieved NCEP ATP II goals,
compared to 27.3% of statin plus placebo patients, a statistically significant result (p <
0.001). Safety and tolerability were evaluated via patient reports, investigator
observation, and specific test results. Approximately 95% of patients completed the
study in both arms, with the primary reason for dropping out being adverse events of a GI
nature (14 patients in each arm). The authors concluded that meaningful reduction in
LDL -C occurs when ezetimibe is added to ongoing statin therapy.7
Use in Homozygous Familial Hypercholesterolemia (HoFH)
Efficacy in HoFH was evaluated in a randomized, double-blind, parallel-group study.
The two treatment phases were an open-label lead-in phase, with either 40 mg of
atorvastatin or simvastatin daily, and a twelve-week study phase, during which patients
were randomized to either 80 mg statin, 40 mg statin plus 10 mg ezetimibe, or 80 mg
statin plus 10 mg ezetimibe per day. Patients continued on the same statin as in the leadin phase, but the dose was blinded and randomized. Efficacy was evaluated based on
percentage change from baseline, and patients had visits at two to four week intervals.
Patients receiving ezetimibe plus 40 or 80 mg of statin had a greater reduction of LDL-C
than patients receiving only 80 mg of statin (20.7% versus 6.7%) Seventy-six percent of
patients receiving ezetimibe plus 80 mg statin had a reduction in LDL-C greater than
15% compared to 18% of patients in the 80 mg statin group. In HoFH, statins alone only
reduce LDL-C by about 7%. The authors concluded that ezetimibe should be used as an
adjunctive, complementary therapy to statins in this population.9
Meta-analysis
Sudhop and von Bergmann3 summarized and analyzed many trials on ezetimibe, used
either as monotherapy or in combination with statins. Adding ezetimibe to any statin
produces a greater LDL-C lowering effect than doubling the dose of statin. In one
randomized, double-blind, parallel-group study10, patients were given atorvastatin 10, 20,
40, or 80 mg either alone or in combination with ezetimibe. Patients receiving
atorvastatin alone experienced 36%, 42%, 45%, and 54% reductions in LDL-C, in order
of increasing dose. Patients who received both a statin and ezetimibe experienced 53%,
54%, 56%, and 61% reductions in LDL-C, respectively. A similar trend was shown with
the other statins.3
Adverse Effects
Ezetimibe has very few adverse effects, which occur at a similar rate to placebo. The
most common side effects noted are gastrointestinal in nature and include abdominal pain
and diarrhea. Fatigue was also noted, but no adverse effect occurred in greater than five
percent of patients.1
When used in conjunction with a statin, the adverse effect profile was not markedly
different from that of the statin itself. One adverse effect of note that ezetimibe does not
have is rhabdomyolysis,1 which is seen with statins. If a patient has been on a statin and
experienced rhabdomyolysis or myalgias, the patient may safely take ezetimibe.
Drug Interactions
Ezetimibe is not metabolized through the CYP450 system and therefore does not inhibit
or induce any specific P-450 isoenzymes. As a result, there are no metabolic interactions
with ezetimibe. Concomitant administration of cimetidine, warfarin, digoxin, glipizide, or
oral contraceptives is not expected to affect ezetimibe.1
Antacids containing aluminum and magnesium decrease the peak plasma concentration
of ezetimibe by 30% but have no significant effect on the AUC. To avoid this, ezetimibe
should be administered two hours before or four hours after antacid administration.1
Cholestyramine decreases the mean AUC of ezetimibe by 55% and may decrease any
synergistic effects. Although concomitant administration of other bile acid sequestrants
has not been studied, it is expected that similar effects are likely to occur. Ezetimibe
should be administered two hours before or four hours after a bile acid sequestrant has
been administered.1
Fibric acid derivatives, such as fenofibrate or gemfibrozil, increase the total ezetimibe
concentration approximately 1.5-fold. This may lead to cholelithiasis due to increased
cholesterol excretion into bile, and concomitant administration is not recommended.2
Cyclosporine is suspected to increase the total ezetimibe level. A renal transplant patient
experienced a 12-fold increase in ezetimibe concentration. Although this patient was
taking multiple medications including cyclosporine, it is recommended that all patients
undergoing concomitant therapy with cyclosporine be closely monitored for adverse
effects due to ezetimibe, until further studies are conducted.1
Dose
Ezetimibe is available in 10 mg tablets, and the recommended dose is 10 mg once daily,
with or without food. No increase in effectiveness was seen with increased dose.3
If ezetimibe is used in combination with a statin, it may be taken at the same time as the
dose of statin. If ezetimibe is used in combination with a bile acid sequestrant, ezetimibe
should be taken two hours before or four hours after administration of the sequestrant.1
Cost
Ezetimibe8
Dose
Per Day
10 mg
$1.93
30 tablets = $57.90
Pravastatina
Dose
10 mg
20 mg
Per Day
$1.45
$1.52
Atorvastatina
Dose
10 mg
20 mg
40 mg
Per Day
$1.59
2.45
2.86
a: based on cost to Duke University Hospitals
Summary
Ezetimibe is a new antihyperlipidemic with a novel mechanism of action. It is believed
to inhibit the absorption of cholesterol at the brush border of the intestine and may act
synergistically with other cholesterol-lowering drugs. It is well absorbed, highly proteinbound, and appears to exhibit enterohepatic recycling through biliary excretion. The drug
is primarily eliminated (70%) in the feces, and its glucuronide conjugate is eliminated in
the urine. Ezetimibe should not be used in patients with moderate or severe hepatic
insufficiency.
There are no major adverse events associated with ezetimibe. Minor adverse events
occur in a small percentage of patients, at a rate similar to placebo. These include
fatigue, nausea, and diarrhea.
Ezetimibe is not metabolized by the CYP450 system and therefore does not exhibit
metabolic interactions. There are pharmacodynamic interactions with antacids and bile
acid sequestrants, and fibric acid derivatives may increase the risk of cholelithiasis due to
biliary recirculation.
Ezetimibe should be dosed once daily, with or without food, at whatever time is
convenient for the patient. Due to the decrease in distribution when taken with antacids
and bile acid sequestrants, ezetimibe should be taken two hours before or four hours after
those agents. An increase in dose above 10 mg was not shown to be more effective.
Several studies show that ezetimibe has a significant effect on cholesterol when used as
monotherapy or in combination with a statin. Adding ezetimibe to a low-dose statin
regimen was shown to be more effective than doubling to dose of the statin. Ezetimibe
may also be used in patients who cannot tolerate statin therapy due to myalgias. It is
recommended that ezetimibe be added to the formulary.
Prepared by Cameron Chandler, Conni Covington, Marissa DiCola, Sarah Reibold, and
Erin Shiver
To do
1.study vs atorvastatin (5)
2.references below horizontal line: use? Discard? Should probably include more
references: example paper had 17.
3.Adverse events
interactions: seem too close to wording in drug info sourcesReferences
1.Zetia® (Ezetimibe) [product information]. North Wales, PA: Merck/Schering-Plough
Pharmaceuticals, Oct 2002.
2.Drug Facts and Comparisons. Online edition. http://www.factsandcomparisons.com
3.Sudhop T. and von Bergmann, K. Cholesterol absorption inhibitors for the treatment of
hypercholesterolaemia. Drugs 2002; 62 (16):2333-2347.
4.Bays HE, Moore PB, Drehobl MS, et al. Effectiveness and tolerability of ezetimibe in
patients with primary hypercholesterolemia: pooled analysis of two phase II studies.
Clin Ther 2001; 23 (8): 1209-1230.
5.Kosoglou T, Seiberling M, Statkevich P, et al. Pharmacodynamic interaction between
the new selective cholesterol absorption inhibitor ezetimibe and atorvastatin. J Am
Coll Cardiol 2001; 37 Suppl.: 229A.
6.Patrick JE, Kosoglou T, Stauber KL, et al. Disposition of the Selective Cholesterol
Absorption Inhibitor Ezetimibe in Healthy Male Subjects. Drug Metabolism and
Disposition 2002; 30 (4):430-437.
7.Gagné C, et al. for the Ezetimibe Study Group. Efficacy and safety of ezetimibe added
to ongoing statin therapy for treatment of patients with primary hypercholesterolemia.
Am J Cardiol 2002; 90:1084-1091.
8.Erickson, A. New options for getting lipids to goal. Pharmacy Today, December 2002.
9.Gagné C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with
atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.
Circulation 2002; 105: 2469-2475.
10.Ballantyne C, Houri J, Notarbartolo A, et al. Ezetimibe co-administered with
atorvastatin in 628 patients with primary hypercholesterolemia. J Am Coll Cardiol
2002; 39 Suppl.: 227A.
11.Ezzet F, Krishna G, Wexler DB, et al. A population pharmacokinetic model that
describes multiple peaks due to enterohepatic recirculation of ezetimibe. Clinical
Therapeutics 2001; 23: 1209-1230.
12.Sudhop T, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in
humans. Circulation 2002; 106: 1943-1948.
13.Dujovne C, et al. Efficacy and safety of a potent new selective cholesterol absorption
inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol
2002; 1092-1097.
14.Jones P, Kafonek S, Laurora I, et al. Comparative dose efficacy study of atorvastatin
versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with
hypercholesterolemia (the CURVES study). Am J Cardiol 1998; 81 (5): 582-587.
15.Knopp RH, Gitter H, Truitt T, et al. Ezetimibe reduces low-density lipoprotein
cholesterol: results of a Phase III, randomized, double-blind, placebo-controlled trial.
Atherosclerosis 2001; 2 Suppl.: 38.
16.Bays H, Weiss S, Gagné C, et al. Ezetimibe added on ongoing statin therapy for
treatment of primary hypercholesterolemia. J Am Coll Cardiol 2002; 39 Suppl.:
245A.