Overdose
In clinical studies, administration of ezetimibe, 50
mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with
primary hyperlipidemia for up to 56 days, and 40 mg/day to 27 patients with homozygous
sitosterolemia for 26 weeks was generally well tolerated. One female patient
with homozygous sitosterolemia took an accidental overdose of ezetimibe 120
mg/day for 28 days with no reported clinical or laboratory adverse events.
In the event of an overdose, symptomatic and supportive
measures should be employed.
Contraindications
ZETIA is contraindicated in the following conditions:
- The combination of ZETIA with a statin is contraindicated
in patients with active liver disease or unexplained persistent elevations in
hepatic transaminase levels.
- Women who are pregnant or may become pregnant. Because
statins decrease cholesterol synthesis and possibly the synthesis of other
biologically active substances derived from cholesterol, ZETIA in combination
with a statin may cause fetal harm when administered to pregnant women. Additionally,
there is no apparent benefit to therapy during pregnancy, and safety in
pregnant women has not been established. If the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the
fetus and the lack of known clinical benefit with continued use during
pregnancy.
- Nursing mothers. Because statins may pass into breast
milk, and because statins have the potential to cause serious adverse reactions
in nursing infants, women who require ZETIA treatment in combination with a
statin should be advised not to nurse their infants.
- Patients with a known hypersensitivity to any component
of this product. Hypersensitivity reactions including anaphylaxis, angioedema,
rash and urticaria have been reported with ZETIA.
Undesirable effects
The following serious adverse reactions are discussed in
greater detail in other sections of the label:
- Liver enzyme abnormalities
- Rhabdomyolysis and myopathy
Monotherapy Studies
In the ZETIA controlled clinical trials database
(placebo-controlled) of 2396 patients with a median treatment duration of 12
weeks (range 0 to 39 weeks), 3.3% of patients on ZETIA and 2.9% of patients on
placebo discontinued due to adverse reactions. The most common adverse reactions
in the group of patients treated with ZETIA that led to treatment
discontinuation and occurred at a rate greater than placebo were:
- Arthralgia (0.3%)
- Dizziness (0.2%)
- Gamma-glutamyltransferase increased (0.2%)
The most commonly reported adverse reactions (incidence
≥2% and greater than placebo) in the ZETIA 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%).
Statin Coadministration Studies
In the ZETIA + statin controlled clinical trials database
of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112
weeks), 4.0% of patients on ZETIA + statin and 3.3% of patients on statin alone
discontinued due to adverse reactions. The most common adverse reactions in the
group of patients treated with ZETIA + statin that led to treatment discontinuation
and occurred at a rate greater than statin alone were:
- Alanine aminotransferase increased (0.6%)
- Myalgia (0.5%)
- Fatigue, aspartate aminotransferase increased, headache,
and pain in extremity (each at 0.2%)
The most commonly reported adverse reactions (incidence
≥2% and greater than statin alone) in the ZETIA + 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%).
Clinical Trials Experience
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.
Monotherapy
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 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 and at an incidence greater than placebo in
placebo-controlled studies of ZETIA, regardless of causality assessment, are
shown in Table 1.
TABLE 1: Clinical Adverse Reactions Occurring in
≥2% of Patients Treated with ZETIA and at an Incidence Greater than
Placebo, Regardless of Causality
Body System/Organ Class
Adverse Reaction |
ZETIA 10 mg (%)
n = 2396 |
Placebo (%)
n = 1159 |
| Gastrointestinal disorders |
| Diarrhea |
4.1 |
3.7 |
| General disorders and administration site conditions |
| Fatigue |
2.4 |
1.5 |
| Infections and infestations |
| Influenza |
2.0 |
1.5 |
| Sinusitis |
2.8 |
2.2 |
| Upper respiratory tract infection |
4.3 |
2.5 |
| Musculoskeletal and connective tissue disorders |
| Arthralgia |
3.0 |
2.2 |
| Pain in extremity |
2.7 |
2.5 |
The frequency of less common adverse reactions was
comparable between ZETIA and placebo.
Combination with a Statin
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 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 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 + statin and at an incidence greater than statin,
regardless of causality assessment, are shown in Table 2.
TABLE 2: Clinical Adverse Reactions Occurring in
≥2% of Patients Treated with ZETIA Coadministered with a Statin and at an
Incidence Greater than Statin, Regardless of Causality
| Body System/Organ Class Adverse Reaction |
All Statins* (%)
n=9361 |
ZETIA + All Statins* (%)
n = 11,308 |
| Gastrointestinal disorders |
| Diarrhea |
2.2 |
2.5 |
| General disorders and administration site conditions |
| Fatigue |
1.6 |
2.0 |
| Infections and infestations |
| Influenza |
2.1 |
2.2 |
| Nasopharyngitis |
3.3 |
3.7 |
| Upper respiratory tract infection |
2.8 |
2.9 |
| Musculoskeletal and connective tissue disorders |
| Arthralgia |
2.4 |
2.6 |
| Back pain |
2.3 |
2.4 |
| Myalgia |
2.7 |
3.2 |
| Pain in extremity |
1.9 |
2.1 |
| * All Statins = all doses of all statins |
Combination with Fenofibrate
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 coadministration of ZETIA 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
coadministered 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
coadministered with fenofibrate, respectively.
The numbers of patients exposed to coadministration 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.
Post-Marketing Experience
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:
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.
Pharmacodynamic properties
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 reduces total-C, LDL-C, Apo B, non-HDL-C, and TG,
and increases HDL-C in patients with hyperlipidemia. Administration of ZETIA
with a statin is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C,
TG, and HDL-C beyond either treatment alone. Administration of ZETIA 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.
Pharmacokinetic properties
Absorption
After oral administration, ezetimibe is absorbed and
extensively conjugated to a pharmacologically active phenolic glucuronide
(ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted adults,
mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were
attained within 4 to 12 hours (Tmax ). Ezetimibe-glucuronide mean Cmax values
of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no
substantial deviation from dose proportionality between 5 and 20 mg. Â The
absolute bioavailability of ezetimibe cannot be determined, as the compound is
virtually insoluble in aqueous media suitable for injection.
Effect Of Food On Oral Absorption
Concomitant food administration (high-fat or non-fat
meals) had no effect on the extent of absorption of ezetimibe when administered
as ZETIA 10-mg tablets. The C value of ezetimibe was increased by 38% with
consumption of high-fat meals. ZETIA can be administered with or without food.
Distribution
Ezetimibe and ezetimibe-glucuronide are highly bound
( > 90%) to human plasma proteins.
Metabolism And Excretion
Ezetimibe is primarily metabolized in the small intestine
and liver via glucuronide conjugation (a phase II reaction) with subsequent
biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction)
has been observed in all species evaluated.
In humans, ezetimibe is rapidly metabolized to
ezetimibe-glucuronide. Ezetimibe and ezetimibeglucuronide 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 ezetimibeglucuronide. Plasma
concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.
Following oral administration of 14C-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.
Date of revision of the text
Aug 2013
Fertility, pregnancy and lactation
Pregnancy Category C
There are no adequate and well-controlled studies of
ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if
the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of
ezetimibe conducted in rats and rabbits during organogenesis, there was no
evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day).
In rats, increased incidences of common fetal skeletal findings (extra pair of
thoracic ribs, unossified cervical vertebral centra, shortened ribs) were
observed at 1000 mg/kg/day (~10 x the human exposure at 10 mg daily based on
AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased
incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 x the human
exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe
crossed the placenta when pregnant rats and rabbits were given multiple oral
doses.
Multiple-dose studies of ezetimibe given in combination
with statins in rats and rabbits during organogenesis result in higher
ezetimibe and statin exposures. Reproductive findings occur at lower doses in
combination therapy compared to monotherapy.
All statins are contraindicated in pregnant and
nursing women. When ZETIA is administered with a statin in a woman of
childbearing potential, refer to the pregnancy category and product labeling
for the statin.
Special warnings and precautions for use
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Use With Statins Or Fenofibrate
Concurrent administration of ZETIA with a specific statin
or fenofibrate should be in accordance with the product labeling for that
medication.
Liver Enzymes
In controlled clinical monotherapy studies, the incidence
of consecutive elevations (≥3 x the upper limit of normal [ULN]) in
hepatic transaminase levels was similar between ZETIA (0.5%) and placebo (0.3%).
In controlled clinical combination studies of ZETIA
initiated concurrently with a statin, the incidence of consecutive elevations
(≥3 x ULN) in hepatic transaminase levels was 1.3% for patients treated
with ZETIA 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 is coadministered 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 x ULN
persist, consider withdrawal of ZETIA and/or the statin.
Myopathy/Rhabdomyolysis
In clinical trials, there was no excess of myopathy or
rhabdomyolysis associated with ZETIA 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 x ULN was 0.2% for
ZETIA vs. 0.1% for placebo, and 0.1% for ZETIA coadministered 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, cases of
myopathy and rhabdomyolysis have been reported. Most patients who developed
rhabdomyolysis were taking a statin prior to initiating ZETIA. However, rhabdomyolysis
has been reported with ZETIA monotherapy and with the addition of ZETIA to
agents known to be associated with increased risk of rhabdomyolysis, such as
fibrates. ZETIA 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 x the ULN
indicates myopathy.
Hepatic Impairment
Due to the unknown effects of the increased exposure to
ezetimibe in patients with moderate to severe hepatic impairment, ZETIA is not
recommended in these patients.
Patient Counseling Information
See FDA-Approved Patient Labeling (PATIENT 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.
Muscle Pain
All patients starting therapy with ezetimibe should be
advised of the risk of myopathy and told to report promptly any unexplained
muscle pain, tenderness or weakness. The risk of this occurring is increased when
taking certain types of medication. Patients should discuss all medication,
both prescription and over-the-counter, with their physician.
Liver Enzymes
Liver tests should be performed when ZETIA is added to
statin therapy and according to statin recommendations.
Pregnancy
Women of childbearing age should be advised to use an
effective method of birth control to prevent pregnancy while using ZETIA added
to statin therapy. Discuss future pregnancy plans with your patients, and
discuss when to stop combination ZETIA and statin therapy if they are trying to
conceive. Patients should be advised that if they become pregnant they should
stop taking combination ZETIA and statin therapy and call their healthcare
professional.
Breastfeeding
Women who are breastfeeding should be advised to not use
ZETIA added to statin therapy. Patients who have a lipid disorder and are
breastfeeding should be advised to discuss the options with their healthcare
professionals.
Nonclinical Toxicology
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 x the human exposure at 10 mg daily based on AUC0-24hr for total
ezetimibe). A 104-week dietary carcinogenicity study with ezetimibe was also conducted
in mice at doses up to 500 mg/kg/day ( > 150 x the human exposure at 10 mg
daily based on AUC0-24hr 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 x the human exposure at 10 mg daily based
on AUC0-24hr for total ezetimibe).
Use In Specific Populations
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of
ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if
the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of
ezetimibe conducted in rats and rabbits during organogenesis, there was no
evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day).
In rats, increased incidences of common fetal skeletal findings (extra pair of
thoracic ribs, unossified cervical vertebral centra, shortened ribs) were
observed at 1000 mg/kg/day (~10 x the human exposure at 10 mg daily based on
AUC0-24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased
incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 x the human
exposure at 10 mg daily based on AUC0-24hr for total ezetimibe). Ezetimibe
crossed the placenta when pregnant rats and rabbits were given multiple oral
doses.
Multiple-dose studies of ezetimibe given in combination
with statins in rats and rabbits during organogenesis result in higher
ezetimibe and statin exposures. Reproductive findings occur at lower doses in
combination therapy compared to monotherapy.
All statins are contraindicated in pregnant and
nursing women. When ZETIA is administered with a statin in a woman of
childbearing potential, refer to the pregnancy category and product labeling
for the statin.
Nursing Mothers
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 is administered to a nursing
woman. ZETIA should not be used in nursing mothers unless the potential benefit
justifies the potential risk to the infant.
Pediatric Use
The effects of ZETIA coadministered 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
openlabel 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 coadministered
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 coadministered with simvastatin
group compared to 219 mg/dL (range: 149-336 mg/dL) in the simvastatin
monotherapy group. The patients received coadministered ZETIA and simvastatin
(10 mg, 20 mg, or 40 mg) or simvastatin monotherapy (10 mg, 20 mg, or 40 mg)
for 6 weeks, coadministered ZETIA and 40-mg simvastatin or 40-mg simvastatin
monotherapy for the next 27 weeks, and open-label coadministered ZETIA and simvastatin
(10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.
The results of the study at Week 6 are summarized in
Table 3. Results at Week 33 were consistent with those at Week 6.
TABLE 3: Mean Percent Difference at Week 6 Between the
Pooled ZETIA Coadministered with Simvastatin Group and the Pooled Simvastatin
Monotherapy Group in Adolescent Patients with Heterozygous Familial Hypercholesterolemia
| |
Total-C |
LDL-C |
Apo B |
Non-HDL- C |
TG* |
HDL-C |
| Mean percent difference between treatment groups |
-12% |
-15% |
-12% |
-14% |
-2% |
+0.1% |
| 95% Confidence Interval |
(-15%, -9%) |
(-18%, - 12%) |
(-15%, -9%) |
(-17%, -11%) |
(-9%, +4%) |
(-3%, +3%) |
| * For triglycerides, median % change from baseline. |
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
coadministered 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 ≥3 x ULN) occurred in four
(3%) individuals in the ZETIA coadministered with simvastatin group and in two
(2%) individuals in the simvastatin monotherapy group. Elevations of CPK
(≥10 x ULN) occurred in two (2%) individuals in the ZETIA coadministered
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.
Coadministration of ZETIA with simvastatin at doses
greater than 40 mg/day has not been studied in adolescents. Also, ZETIA has not
been studied in patients younger than 10 years of age or in premenarchal girls.
Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide),
there are no pharmacokinetic differences between adolescents and adults.
Pharmacokinetic data in the pediatric population < 10 years of age are not
available.
Geriatric Use
Monotherapy Studies
Of the 2396 patients who received ZETIA in clinical studies,
669 (28%) were 65 and older, and 111 (5%) were 75 and older.
Statin Coadministration Studies
Of the 11,308 patients who received ZETIA + 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.
Renal Impairment
When used as monotherapy, no dosage adjustment of ZETIA
is necessary.
In the Study of Heart and Renal Protection (SHARP) trial
of 9270 patients with moderate to severe renal impairment (6247 non-dialysis
patients with median serum creatinine 2.5 mg/dL and median estimated glomerular
filtration rate 25.6 mL/min/1.73 m², and 3023 dialysis patients), the incidence
of serious adverse events, adverse events leading to discontinuation of study
treatment, or adverse events of special interest (musculoskeletal adverse
events, liver enzyme abnormalities, incident cancer) was similar between
patients ever assigned to ezetimibe 10 mg plus simvastatin 20 mg (n=4650) or
placebo (n=4620) during a median follow-up of 4.9 years. However, because renal
impairment is a risk factor for statin-associated myopathy, doses of
simvastatin exceeding 20 mg should be used with caution and close monitoring
when administered concomitantly with ZETIA in patients with moderate to severe
renal impairment.
Hepatic Impairment
ZETIA is not recommended in patients with moderate to
severe hepatic impairment.
ZETIA given concomitantly with a statin is
contraindicated in patients with active liver disease or unexplained persistent
elevations of hepatic transaminase levels.
Dosage (Posology) and method of administration
General Dosing Information
The recommended dose of ZETIA is 10 mg once daily.
ZETIA can be administered with or without food.
Concomitant Lipid-Lowering Therapy
ZETIA 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 may be taken at the same time as the statin or fenofibrate, according to
the dosing recommendations for the respective medications.
Coadminis With Bile Acid Sequestrants
Dosing of ZETIA should occur either ≥2 hours before
or ≥4 hours after administration of a bile acid sequestrant.
Patients With Hepatic Impairment
No dosage adjustment is necessary in patients with mild
hepatic impairment.
Patients with Renal Impairment
No dosage adjustment is necessary in patients with renal
impairment. When given with simvastatin in
patients with moderate to severe renal impairment (estimated glomerular filtration
rate < 60 mL/min/1.73 m²), doses of simvastatin exceeding 20 mg should be
used with caution and close monitoring.
Geriatric Patients
No dosage adjustment is necessary in geriatric patients.
Interaction with other medicinal products and other forms of interaction
ZETIA had no significant effect on a series of probe
drugs (caffeine, dextromethorphan, tolbutamide, and IV midazolam) known to be
metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a “cocktail”
study of twelve healthy adult males. This indicates that ezetimibe is neither
an inhibitor nor an inducer of these cytochrome P450 isozymes, and it is
unlikely that ezetimibe will affect the metabolism of drugs that are
metabolized by these enzymes.
TABLE 4: Effect of Coadministered Drugs on Total
Ezetimibe
| Coadministered Drug and Dosing Regimen |
Total Ezetimibe * |
| Change in AUC |
Change in Cmax |
| Cyclosporine-stable dose required (75-150 mg BID)†,‡ |
↑240% |
↑290% |
| Fenofibrate, 200 mg QD, 14 days‡ |
↑48% |
↑64% |
| Gemfibrozil, 600 mg BID, 7 days‡ |
↑64% |
↑91% |
| Cholestyramine, 4 g BID, 14 days‡ |
↓55% |
↓4% |
| Aluminum & magnesium hydroxide combination antacid, single dose§ |
↓4% |
↓30% |
| Cimetidine, 400 mg BID, 7 days |
↑6% |
↓30% |
| Glipizide, 10 mg, single dose |
↑4% |
↓8% |
| Statins |
| Lovastatin 20 mg QD, 7 days |
↑9% |
↑3% |
| Pravastatin 20 mg QD, 14 days |
↑7% |
↑23% |
| Atorvastatin 10 mg QD, 14 days |
↓2% |
↑12% |
| Rosuvastatin 10 mg QD, 14 days |
↑13% |
↑18% |
| Fluvastatin 20 mg QD, 14 days |
↓19% |
↑7% |
*Based on 10-mg dose of ezetimibe.
† Post-renal transplant patients with mild impaired or normal renal function.
In a different study, a renal transplant patient with severe renal
insufficiency (creatinine clearance of 13.2 mL/min/1.73 m²) who was receiving
multiple medications, including cyclosporine, demonstrated a 12-fold greater
exposure to total ezetimibe compared to healthy subjects.
‡ See DRUG INTERACTIONS.
§ Supralox, 20 mL. |
TABLE 5: Effect of Ezetimibe Coadministration on Systemic
Exposure to Other Drugs
| Coadministered Drug and its Dosage Regimen |
Ezetimibe Dosage Regimen |
Change in AUC of Coadministered Drug |
Change in Cmax of Coadministered Drug |
| Warfarin. 25-mg single dose on Day 7 |
10 mg QD, 11 days |
↓2% (R-warfarin) |
↑3% (R-warfarin) |
| ↓4% (S-warfarin) |
↑1% (S-warfarin) |
| Digoxin. 0.5-mg single dose |
10 mg QD, 8 days |
↑2% |
↓7% |
| Gemfibrozil, 600 mg BID, 7 days* |
10 mg QD, 7 days |
↓1% |
↓11% |
| Ethinyl estradiol & Levonorgestrel, QD, 21 days |
10 mg QD, days 8-14 of 21d oral contraceptive cycle |
Ethinyl estradiol 0% |
Ethinyl estradiol ↓9% |
|
|
| Levonorgesnel 0% |
Levonorgesirel ↓5% |
| Glipizide, 10 mg on Days 1 and 9 |
10 mg QD, days 2-9 |
↓3% |
↓5% |
| Fenofibrate, 200 mg QD, 14 days* |
10 mg QD, 14 days |
↑11% |
↑7% |
| Cyclosporine, 100-mg single dose Day 7* |
20 mg QD, 8 days |
↑15% |
↑10% |
| Statins |
| Lovastatin 20 mg QD, 7 days |
10 mg QD, 7 days |
↑19% |
↑3% |
| Pravastatin 20 mg QD, 14 days |
10 mg QD, 14 days |
↓20% |
↓24% |
| Atorvastatin 10 mg QD, 14 days |
10 mg QD, 14 days |
↓4% |
↑7% |
| Rosuvastatin 10 mg QD, 14 days |
10 mg QD, 14 days |
↑19% |
↑17% |
| Fluvastatin 20 mg QD, 14 days |
10 mg QD, 14 days |
↓39% |
↓27% |
| * See DRUG INTERACTIONS |
