Zetia Information
Zetia (Ezetimibe) Indications And Usage
Therapy with lipid-altering agents should be only one component
of multiple risk factor intervention in individuals at significantly increased
risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug
therapy is indicated as an adjunct to diet when the response to a diet
restricted in saturated fat and cholesterol and other nonpharmacologic measures
alone has been inadequate.
Zetia (Ezetimibe) ,
administered alone, is indicated as adjunctive therapy to diet for the reduction
of elevated total cholesterol (total-C), low-density lipoprotein cholesterol
(LDL-C), and apolipoprotein B (Apo B) in patients with primary (heterozygous
familial and non-familial) hyperlipidemia.
Zetia (Ezetimibe) , administered in combination with a 3-hydroxy-3-methylglutaryl-coenzyme
A (HMG-CoA) reductase inhibitor (statin), is indicated as adjunctive therapy to
diet for the reduction of elevated total-C, LDL-C, and Apo B in patients with
primary (heterozygous familial and non-familial) hyperlipidemia.
Zetia (Ezetimibe) , administered in combination with fenofibrate, is indicated as
adjunctive therapy to diet for the reduction of elevated total-C, LDL-C, Apo B,
and non-high-density lipoprotein cholesterol (non-HDL-C) in adult patients with
mixed hyperlipidemia.
The combination of Zetia (Ezetimibe) and atorvastatin or simvastatin is
indicated for the reduction of elevated total-C and LDL-C levels in patients
with HoFH, as an adjunct to other lipid-lowering treatments (e.g., LDL
apheresis) or if such treatments are unavailable.
Zetia (Ezetimibe) is indicated as adjunctive therapy to diet for the
reduction of elevated sitosterol and campesterol levels in patients with
homozygous familial sitosterolemia.
The effect of Zetia (Ezetimibe) on cardiovascular morbidity and mortality has
not been determined.
Zetia (Ezetimibe) has not been studied in Fredrickson Type I, III, IV, and V
dyslipidemias.
Zetia (Ezetimibe) Dosage And Administration
The recommended dose of Zetia (Ezetimibe) is 10 mg once daily.
Zetia (Ezetimibe) can be administered with or without food.
Zetia (Ezetimibe) may be administered with a statin (in patients with primary
hyperlipidemia) or with fenofibrate (in patients with mixed hyperlipidemia) for
incremental effect. For convenience, the daily dose of Zetia (Ezetimibe) may be taken at the
same time as the statin or fenofibrate, according to the dosing recommendations
for the respective medications.
Dosing of Zetia (Ezetimibe) should occur either ≥2 hours before or ≥4 hours
after administration of a bile acid sequestrant .
No dosage adjustment is necessary in patients with mild hepatic
impairment .
No dosage adjustment is necessary in patients with renal
impairment
No dosage adjustment is necessary in geriatric patients .
Zetia (Ezetimibe) Dosage Forms And Strengths
10-mg tablets are white to off-white, capsule-shaped tablets debossed with "414"
on one side.
Zetia (Ezetimibe) Contraindications
Zetia (Ezetimibe) is contraindicated in the following conditions:
Zetia (Ezetimibe) Warnings And Precautions
Concurrent administration of Zetia (Ezetimibe) with a specific statin or
fenofibrate should be in accordance with the product labeling for that
medication.
In controlled clinical monotherapy studies, the incidence of
consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic
transaminase levels was similar between Zetia (Ezetimibe) (0.5%) and placebo (0.3%).
In controlled clinical combination studies of Zetia (Ezetimibe) initiated concurrently
with a statin, the incidence of consecutive elevations (≥3 × ULN) in hepatic
transaminase levels was 1.3% for patients treated with Zetia (Ezetimibe) administered with
statins and 0.4% for patients treated with statins alone. These elevations in
transaminases were generally asymptomatic, not associated with cholestasis, and
returned to baseline after discontinuation of therapy or with continued
treatment. When Zetia (Ezetimibe) is co-administered with a statin, liver tests should be
performed at initiation of therapy and according to the recommendations of the
statin. Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal
of Zetia (Ezetimibe) and/or the statin.
In clinical trials, there was no excess of myopathy or
rhabdomyolysis associated with Zetia (Ezetimibe) compared with the relevant control arm
(placebo or statin alone). However, myopathy and rhabdomyolysis are known
adverse reactions to statins and other lipid-lowering drugs. In clinical trials,
the incidence of creatine phosphokinase (CPK) >10 × ULN was 0.2% for Zetia (Ezetimibe) vs
0.1% for placebo, and 0.1% for Zetia (Ezetimibe) co-administered with a statin vs 0.4% for
statins alone. Risk for skeletal muscle toxicity increases with higher doses of
statin, advanced age (>65), hypothyroidism, renal impairment, and depending
on the statin used, concomitant use of other drugs.
In post-marketing experience with Zetia (Ezetimibe) , cases of myopathy and rhabdomyolysis
have been reported. Most patients who developed rhabdomyolysis were taking a
statin prior to initiating Zetia (Ezetimibe) . However, rhabdomyolysis has been reported with
Zetia (Ezetimibe) monotherapy and with the addition of Zetia (Ezetimibe) to agents known to be
associated with increased risk of rhabdomyolysis, such as fibrates. Zetia (Ezetimibe) and
any statin or fibrate that the patient is taking concomitantly should be
immediately discontinued if myopathy is diagnosed or suspected. The presence of
muscle symptoms and a CPK level >10 × the ULN indicates myopathy.
Due to the unknown effects of the increased exposure to ezetimibe
in patients with moderate to severe hepatic impairment, Zetia (Ezetimibe) is not recommended
in these patients.
Zetia (Ezetimibe) Adverse Reactions
The following serious adverse reactions are discussed in greater
detail in other sections of the label:
The most commonly reported adverse reactions (incidence ≥2% and greater than
placebo) in the Zetia (Ezetimibe) monotherapy controlled clinical trial database of 2396
patients were: upper respiratory tract infection (4.3%), diarrhea (4.1%),
arthralgia (3.0%), sinusitis (2.8%), and pain in extremity (2.7%).
The most commonly reported adverse reactions (incidence ≥2% and greater than
statin alone) in the Zetia (Ezetimibe) + statin controlled clinical trial database of 11,308
patients were: nasopharyngitis (3.7%), myalgia (3.2%), upper respiratory tract
infection (2.9%), arthralgia (2.6%) and diarrhea (2.5%).
Because clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical studies of a drug
cannot be directly compared to rates in the clinical studies of another drug and
may not reflect the rates observed in clinical practice.
In 10 double-blind, placebo-controlled clinical trials, 2396 patients with
primary hyperlipidemia (age range 9–86 years, 50% women, 90% Caucasians, 5%
Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Zetia (Ezetimibe) 10
mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).
Adverse reactions reported in ≥2% of patients treated with Zetia (Ezetimibe) and at an
incidence greater than placebo in placebo-contr
The frequency of less common adverse reactions was comparable between Zetia (Ezetimibe)
and placebo.
In 28 double-blind, controlled (placebo- or active-controlled) clinical
trials, 11,308 patients with primary hyperlipidemia (age range 10–93 years, 48%
women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C
were treated with Zetia (Ezetimibe) 10 mg/day concurrently with or added to on-going statin
therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).
The incidence of consecutive increased transaminases (≥3 × ULN) was higher in
patients receiving Zetia (Ezetimibe) administered with statins (1.3%) than in patients
treated with statins alone (0.4%).
Clinical adverse reactions reported in ≥2% of patients treated with Zetia (Ezetimibe) +
statin and at an incidence greater than statin, regardless of causality
assessment, are shown in .
This clinical study involving 625 patients with mixed dyslipidemia (age range
20–76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians)
treated for up to 12 weeks and 576 patients treated for up to an additional 48
weeks evaluated co-administration of Zetia (Ezetimibe) and fenofibrate. This study was not
designed to compare treatment groups for infrequent events. Incidence rates (95%
CI) for clinically important elevations (≥3 × ULN, consecutive) in hepatic
transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for fenofibrate
monotherapy (n=188) and Zetia (Ezetimibe) co-administered with fenofibrate (n=183),
respectively, adjusted for treatment exposure. Corresponding incidence rates for
cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for
fenofibrate monotherapy and Zetia (Ezetimibe) co-administered with fenofibrate, respectively
.
The numbers of patients exposed to co-administration therapy as well as
fenofibrate and ezetimibe monotherapy were inadequate to assess gallbladder
disease risk. There were no CPK elevations >10 × ULN in any of the treatment
groups.
Because the reactions below are reported voluntarily from a
population of uncertain size, it is generally not possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
The following additional adverse reactions have been identified during
post-approval use of Zetia (Ezetimibe) :
Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and
urticaria; erythema multiforme; arthralgia; myalgia; elevated creatine
phosphokinase; myopathy/rhabdomyolysis ; elevations in liver
transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis;
nausea; dizziness; paresthesia; depression; headache; cholelithiasis;
cholecystitis.
Zetia (Ezetimibe) Drug Interactions
Caution should be exercised when using Zetia (Ezetimibe) and cyclosporine
concomitantly due to increased exposure to both ezetimibe and cyclosporine.
Cyclosporine concentrations should be monitored in patients receiving Zetia (Ezetimibe) and
cyclosporine.
The degree of increase in ezetimibe 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.
The efficacy and safety of co-administration of ezetimibe with
fibrates other than fenofibrate have not been studied.
Fibrates may increase cholesterol excretion into the bile, leading to
cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol
in the gallbladder bile . Co-administration of Zetia (Ezetimibe) with fibrates other
than fenofibrate is not recommended until use in patients is adequately
studied.
If cholelithiasis is suspected in a patient receiving Zetia (Ezetimibe) and
fenofibrate, gallbladder studies are indicated and alternative lipid-lowering
therapy should be considered .
Concomitant cholestyramine administration decreased the mean area
under the curve (AUC) of total ezetimibe approximately 55%. The incremental
LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this
interaction.
If ezetimibe is added to warfarin, a coumarin anticoagulant, the
International Normalized Ratio (INR) should be appropriately monitored.
Zetia (Ezetimibe) Use In Specific Populations
8.1 Pregnancy
There are no adequate and well-controlled studies of ezetimibe in pregnant
women. Ezetimibe should be used during pregnancy only if the potential benefit
justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in
rats and rabbits during organogenesis, there was no evidence of embryolethal
effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased
incidences of common fetal skeletal findings (extra pair of thoracic ribs,
unossified cervical vertebral centra, shortened ribs) were observed at 1000
mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC for total ezetimibe). In rabbits treated with ezetimibe,
an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day
(150 × the human exposure at 10 mg daily based on AUC for total ezetimibe). Ezetimibe crossed the placenta
when pregnant rats and rabbits were given multiple oral doses.
Multiple-dose studies of ezetimibe given in combination with statins in rats
and rabbits during organogenesis result in higher ezetimibe and statin
exposures. Reproductive findings occur at lower doses in combination therapy
compared to monotherapy.
It is not known whether ezetimibe is excreted into human breast
milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half
of that observed in maternal plasma. Because many drugs are excreted in human
milk, caution should be exercised when Zetia (Ezetimibe) is administered to a nursing woman.
Zetia (Ezetimibe) should not be used in nursing mothers unless the potential benefit
justifies the potential risk to the infant.
The effects of Zetia (Ezetimibe) co-administered with simvastatin (n=126)
compared to simvastatin monotherapy (n=122) have been evaluated in adolescent
boys and girls with heterozygous familial hypercholesterolemia (HeFH). In a
multicenter, double-blind, controlled study followed by an open-label phase, 142
boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years,
43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH
were randomized to receive either Zetia (Ezetimibe) co-administered with simvastatin or
simvastatin monotherapy. Inclusion in the study required 1) a baseline LDL-C
level between 160 and 400 mg/dL and 2) a medical history and clinical
presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL
(range: 161–351 mg/dL) in the Zetia (Ezetimibe) co-administered with simvastatin group
compared to 219 mg/dL (range: 149–336 mg/dL) in the simvastatin monotherapy
group. The patients received co-administered Zetia (Ezetimibe) and simvastatin (10 mg, 20
mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks,
co-administered Zetia (Ezetimibe) and 40 mg simvastatin or 40 mg simvastatin monotherapy for
the next 27 weeks, and open-label co-administered Zetia (Ezetimibe) and simvastatin (10 mg,
20 mg, or 40 mg) for 20 weeks thereafter.
The results of the study at Week 6 are summarized in . Results at Week 33 were consistent with those at Week 6.
From the start of the trial to the end of Week 33, discontinuations due to an
adverse reaction occurred in 7 (6%) patients in the Zetia (Ezetimibe) co-administered with
simvastatin group and in 2 (2%) patients in the simvastatin monotherapy
group.
During the trial, hepatic transaminase elevations (two consecutive
measurements for ALT and/or AST greater than or equal to 3 × ULN) occurred in four (3%) individuals in
the Zetia (Ezetimibe) co-administered with simvastatin group and in two (2%) individuals in
the simvastatin monotherapy group. Elevations of CPK (greater than or equal to 10 × ULN) occurred in two
(2%) individuals in the Zetia (Ezetimibe) co-administered with simvastatin group and in zero
individuals in the simvastatin monotherapy group.
In this limited controlled study, there was no significant effect on growth
or sexual maturation in the adolescent boys or girls, or on menstrual cycle
length in girls.
Co-administration of Zetia (Ezetimibe) with simvastatin at doses greater than 40 mg/day
has not been studied in adolescents. Also, Zetia (Ezetimibe) has not been studied in
patients younger than 10 years of age or in pre-menarchal girls.
Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no
pharmacokinetic differences between adolescents and adults. Pharmacokinetic data
in the pediatric population less than 10 years of age are not available.
Of the 2396 patients who received Zetia (Ezetimibe) in clinical studies, 669 (28%) were
65 and older, and 111 (5%) were 75 and older.
Of the 11,308 patients who received Zetia (Ezetimibe) + statin in clinical studies, 3587
(32%) were 65 and older, and 924 (8%) were 75 and older.
No overall differences in safety and effectiveness were observed between
these patients and younger patients, and other reported clinical experience has
not identified differences in responses between the elderly and younger
patients, but greater sensitivity of some older individuals cannot be ruled out
.
Zetia (Ezetimibe) is not recommended in patients with moderate to severe
hepatic impairment and .
Zetia (Ezetimibe) given concomitantly with a statin is contraindicated in patients with
active liver disease or unexplained persistent elevations of hepatic
transaminase levels; .
Zetia (Ezetimibe) Overdosage
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
hyperlipidemia for up to 56 days, was generally well tolerated.
A few cases of overdosage with Zetia (Ezetimibe) have been reported; most have not been
associated with adverse experiences. Reported adverse experiences have not been
serious. In the event of an overdose, symptomatic and supportive measures should
be employed.
Zetia (Ezetimibe) Description
Zetia (Ezetimibe) is in a class of lipid-lowering compounds that
selectively inhibits the intestinal absorption of cholesterol and related
phytosterols. The chemical name of ezetimibe is
1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone.
The empirical formula is CHFNO. Its
molecular weight is 409.4 and its structural formula is:
Ezetimibe is a white, crystalline powder that is freely to very soluble in
ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has
a melting point of about 163°C and is stable at ambient temperature. Zetia (Ezetimibe) is
available as a tablet for oral administration containing 10 mg of ezetimibe and
the following inactive ingredients: croscarmellose sodium NF, lactose
monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone
USP, and sodium lauryl sulfate NF.
Zetia (Ezetimibe) Clinical Pharmacology
Ezetimibe reduces blood cholesterol by inhibiting the absorption
of cholesterol by the small intestine. In a 2-week clinical study in 18
hypercholesterolemic patients, Zetia (Ezetimibe) inhibited intestinal cholesterol absorption
by 54%, compared with placebo. Zetia (Ezetimibe) had no clinically meaningful effect on the
plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113
patients), and did not impair adrenocortical steroid hormone production (in a
study of 118 patients).
The cholesterol content of the liver is derived predominantly from three
sources. The liver can synthesize cholesterol, take up cholesterol from the
blood from circulating lipoproteins, or take up cholesterol absorbed by the
small intestine. Intestinal cholesterol is derived primarily from cholesterol
secreted in the bile and from dietary cholesterol.
Ezetimibe has a mechanism of action that differs from those of other classes
of cholesterol-reducing compounds (statins, bile acid sequestrants [resins],
fibric acid derivatives, and plant stanols). The molecular target of ezetimibe
has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1),
which is involved in the intestinal uptake of cholesterol and phytosterols.
Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase
bile acid excretion. Instead, ezetimibe localizes 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
statins and of fenofibrate .
Clinical studies have demonstrated that elevated levels of
total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human
atherosclerosis. In addition, decreased levels of 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 TG on the
risk of coronary and cardiovascular morbidity and mortality has not been
determined.
Zetia (Ezetimibe) reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients
with hyperlipidemia. Administration of Zetia (Ezetimibe) with a statin is effective in
improving serum total-C, LDL-C, Apo B, TG, and HDL-C beyond either treatment
alone. Administration of Zetia (Ezetimibe) with fenofibrate is effective in improving serum
total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed hyperlipidemia as
compared to either treatment alone. The effects of ezetimibe given either alone
or in addition to a statin or fenofibrate on cardiovascular morbidity and
mortality have not been established.
After oral administration, ezetimibe is absorbed and extensively conjugated
to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide).
After a single 10-mg dose of Zetia (Ezetimibe) to fasted adults, mean ezetimibe peak plasma
concentrations (C) of 3.4 to 5.5 ng/mL were attained
within 4 to 12 hours (T). Ezetimibe-glucuronide mean
C values of 45 to 71 ng/mL were achieved between 1 and
2 hours (T). There was no substantial deviation from
dose proportionality between 5 and 20 mg. The absolute bioavailability of
ezetimibe cannot be determined, as the compound is virtually insoluble in
aqueous media suitable for injection.
Concomitant food administration (high-fat or non-fat meals) had no effect on
the extent of absorption of ezetimibe when administered as Zetia (Ezetimibe) 10-mg tablets.
The C value of ezetimibe was increased by 38% with
consumption of high-fat meals. Zetia (Ezetimibe) can be administered with or without
food.
Ezetimibe and ezetimibe-glucuronide are highly bound (greater than 90%) to human
plasma proteins.
Ezetimibe is primarily metabolized in the small intestine and liver via
glucuronide conjugation (a phase II reaction) with subsequent biliary and renal
excretion. Minimal oxidative metabolism (a phase I reaction) has been observed
in all species evaluated.
In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide.
Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds
detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the
total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are
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 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.
Zetia (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.
Zetia (Ezetimibe) Non Clinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
A 104-week dietary carcinogenicity study with ezetimibe was
conducted in rats at doses up to 1500 mg/kg/day (males) and 500 mg/kg/day
(females) (~20 × the human exposure at 10 mg daily based on AUC 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 × the human exposure at 10 mg daily based on AUC 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 a microbial mutagenicity (Ames) test with and with or without metabolic activation. No evidence of clastogenicity
was observed 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 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 × the human exposure at 10 mg daily based on AUC for total 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 value of 0.5 µg/kg/day for inhibiting the rise in plasma
cholesterol levels in monkeys. The ED values in dogs,
rats, and mice were 7, 30, and 700 µg/kg/day, respectively. These results are
consistent with Zetia (Ezetimibe) being a potent cholesterol absorption inhibitor.
In a rat model, where the glucuronide metabolite of ezetimibe (SCH 60663) was
administered intraduodenally, the metabolite was as potent as the parent
compound (SCH 58235) in inhibiting the absorption of cholesterol, suggesting
that the glucuronide metabolite had activity similar to the parent drug.
In 1-month studies in dogs given ezetimibe (0.03 to 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 to 5 mg/kg/day) and fed a low-fat or
cholesterol-rich diet, the concentration of cholesterol in gallbladder bile was
either unaffected or reduced to normal levels, respectively.
A series of acute preclinical studies was performed to determine the
selectivity of Zetia (Ezetimibe) for inhibiting cholesterol absorption. Ezetimibe inhibited
the absorption of C-cholesterol with no effect on the
absorption of triglycerides, fatty acids, bile acids, progesterone, ethinyl
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 statins (parents or their active
hydroxy acid metabolites) was seen in rats, dogs, and rabbits.
Zetia (Ezetimibe) Clinical Studies
Zetia (Ezetimibe) reduces total-C, LDL-C, Apo B, and TG, and increases HDL-C
in patients with hyperlipidemia. Maximal to near maximal response is generally
achieved within 2 weeks and maintained during chronic therapy.
In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719
patients with primary hyperlipidemia, Zetia (Ezetimibe) significantly lowered total-C,
LDL-C, Apo B, and TG, and increased HDL-C compared to placebo (see ). Reduction in LDL-C was
consistent across age, sex, and baseline LDL-C.
In a multicenter, double-blind, placebo-controlled, 8-week study, 769
patients with primary hyperlipidemia, known coronary heart disease or multiple
cardiovascular risk factors who were already receiving statin monotherapy, but
who had not met their NCEP ATP II target LDL-C goal were randomized to receive
either Zetia (Ezetimibe) or placebo in addition to their on-going statin.
Zetia (Ezetimibe) , added to on-going statin therapy, significantly lowered total-C,
LDL-C, Apo B, and TG, and increased HDL-C compared with a statin administered
alone (see ). LDL-C
reductions induced by Zetia (Ezetimibe) were generally consistent across all statins.
In four multicenter, double-blind, placebo-controlled, 12-week trials, in
2382 hyperlipidemic patients, Zetia (Ezetimibe) or placebo was administered alone or with
various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
When all patients receiving Zetia (Ezetimibe) with a statin were compared to all those
receiving the corresponding statin alone, Zetia (Ezetimibe) significantly lowered total-C,
LDL-C, Apo B, and TG, and, with the exception of pravastatin, increased HDL-C
compared to the statin administered alone. LDL-C reductions induced by Zetia (Ezetimibe)
were generally consistent across all statins. (See footnote , to.)
In a multicenter, double-blind, placebo-controlled, clinical study in
patients with mixed hyperlipidemia, 625 patients were treated for up to 12 weeks
and 576 for up to an additional 48 weeks. Patients were randomized to receive
placebo, Zetia (Ezetimibe) alone, 160 mg fenofibrate alone, or Zetia (Ezetimibe) and 160 mg fenofibrate
in the 12-week study. After completing the 12-week study, eligible patients were
assigned to Zetia (Ezetimibe) co-administered with fenofibrate or fenofibrate monotherapy
for an additional 48 weeks.
Zetia (Ezetimibe) co-administered with fenofibrate significantly lowered total-C, LDL-C,
Apo B, and non-HDL-C compared to fenofibrate administered alone. The percent
decrease in TG and percent increase in HDL-C for Zetia (Ezetimibe) co-administered with
fenofibrate were comparable to those for fenofibrate administered alone (see
).
A study was conducted to assess the efficacy of Zetia (Ezetimibe) in the
treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50
patients with a clinical and/or genotypic diagnosis of HoFH, with or without
concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40
mg). Patients were randomized to one of three treatment groups, atorvastatin or
simvastatin (80 mg), Zetia (Ezetimibe) administered with atorvastatin or simvastatin (40
mg), or Zetia (Ezetimibe) administered with atorvastatin or simvastatin (80 mg). Due to
decreased bioavailability of ezetimibe in patients concomitantly receiving
cholestyramine , ezetimibe was dosed at least 4 hours before or after
administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients
randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the
group randomized to Zetia (Ezetimibe) plus atorvastatin 40 or 80 mg or simvastatin 40 or 80
mg. Zetia (Ezetimibe) , administered with atorvastatin or simvastatin (40 and 80 mg statin
groups, pooled), significantly reduced LDL-C (21%) compared with increasing the
dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those
treated with Zetia (Ezetimibe) plus 80 mg atorvastatin or with Zetia (Ezetimibe) plus 80 mg simvastatin,
LDL-C was reduced by 27%.
A study was conducted to assess the efficacy of Zetia (Ezetimibe) in the
treatment of homozygous sitosterolemia. In this multicenter, double-blind,
placebo-controlled, 8-week trial, 37 patients with homozygous sitosterolemia
with elevated plasma sitosterol levels (greater than 5 mg/dL) on their current
therapeutic regimen (diet, bile-acid-binding resins, statins, ileal bypass
surgery and/or LDL apheresis), were randomized to receive Zetia (Ezetimibe) (n=30) or
placebo (n=7). Due to decreased bioavailability of ezetimibe in patients
concomitantly receiving cholestyramine , ezetimibe was dosed at least 2
hours before or 4 hours after resins were administered. Excluding the one
subject receiving LDL apheresis, Zetia (Ezetimibe) significantly lowered plasma sitosterol
and campesterol, by 21% and 24% from baseline, respectively. In contrast,
patients who received placebo had increases in sitosterol and campesterol of 4%
and 3% from baseline, respectively. For patients treated with Zetia (Ezetimibe) , mean plasma
levels of plant sterols were reduced progressively over the course of the study.
The effects of reducing plasma sitosterol and campesterol on reducing the risks
of cardiovascular morbidity and mortality have not been established.
Reductions in sitosterol and campesterol were consistent between patients
taking Zetia (Ezetimibe) concomitantly with bile acid sequestrants (n=8) and patients not on
concomitant bile acid sequestrant therapy (n=21).
The effect of Zetia (Ezetimibe) on cardiovascular morbidity and mortality has not been
determined.
Zetia (Ezetimibe) How Supplied/storage And Handling
No. 3861 — Tablets Zetia (Ezetimibe) , 10 mg, are white to off-white,
capsule-shaped tablets debossed with "414" on one side. They are supplied as
follows:
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [See USP
Controlled Room Temperature.] Protect from moisture.
Zetia (Ezetimibe) Patient Counseling Information
Patients should be advised to adhere to their National Cholesterol Education
Program (NCEP)-recommended diet, a regular exercise program, and periodic
testing of a fasting lipid panel.
Zetia (Ezetimibe)
Zetia (Ezetimibe) Principal Display Panel
