Generic: ezetimibe
is used for the treatment of
HypercholesterolemiaHyperlipoproteinemia Type IIHyperlipidemia, Familial CombinedPregnancy
Pregnancy Risk
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.
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. 1.1 Primary Hyperlipidemia Monotherapy
ZETIA, 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. Combination Therapy with Fenofibrate
ZETIA, 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. 1.2 Homozygous Familial Hypercholesterolemia
(HoFH) The combination of ZETIA 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. 1.3 Homozygous Sitosterolemia ZETIA is indicated as adjunctive therapy to diet for the
reduction of elevated sitosterol and campesterol levels in patients with
homozygous familial sitosterolemia. 1.4 Limitations of Use The effect of ZETIA on cardiovascular morbidity and mortality has
not been determined.
ZETIA has not been studied in Fredrickson Type I, III, IV, and V
dyslipidemias.
ZETIA® is an inhibitor of intestinal
cholesterol (and related phytosterol) absorption indicated as an adjunct to diet
to:
Reduce elevated total-C, LDL-C, and Apo B in patients with primary
hyperlipidemia, alone or in combination with an HMG-CoA reductase inhibitor
(statin) (1.1)
Reduce elevated total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed
hyperlipidemia in combination with fenofibrate (1.1)
Reduce elevated total-C and LDL-C in patients with homozygous familial
hypercholesterolemia (HoFH), in combination with atorvastatin or simvastatin (1.2)
Reduce elevated sitosterol and campesterol in patients with homozygous
sitosterolemia (phytosterolemia) (1.3)
Limitations of Use (1.4)
The effect of ZETIA on cardiovascular morbidity and mortality has not been
determined.
ZETIA has not been studied in Fredrickson Type I, III, IV, and V
dyslipidemias.
2 Dosage And Administration
One 10-mg tablet once daily, with or without food (2.1)
Dosing of ZETIA should occur either ≥2 hours before or ≥4 hours after
administration of a bile acid sequestrant. (2.3, 7.4)
3 Dosage Forms And Strengths
10-mg tablets are white to off-white, capsule-shaped tablets debossed with "414"
on one side.
Tablets: 10 mg (3)
4 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. [See Use in Specific Populations
(8.1).]
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 [see Use in Specific Populations (8.3)].
Patients with a known hypersensitivity to any component of this product.
Hypersensitivity reactions including anaphylaxis, angioedema, rash and urticaria
have been reported with ZETIA [see Adverse
Reactions (6.2)].
Statin contraindications apply when ZETIA is used with a statin:
Active liver disease, which may include unexplained persistent elevations in
hepatic transaminase levels (4, 5.2)
Women who are pregnant or may become pregnant (4, 8.1)
Nursing mothers (4, 8.3)
Known hypersensitivity to product components (4, 6.2)
5 Warnings And Precautions
5.1 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. 5.2 Liver Enzymes 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 (0.5%) and placebo (0.3%).
In controlled clinical combination studies of ZETIA initiated concurrently
with a statin, the incidence of consecutive elevations (≥3 × 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 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 and/or the statin. 5.3 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 × ULN was 0.2% for ZETIA vs
0.1% for placebo, and 0.1% for ZETIA 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, 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 × the ULN indicates myopathy. 5.4 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. [See Clinical
Pharmacology (12.3).]
ZETIA is not recommended in patients with moderate or severe hepatic
impairment. (5.4, 8.6, 12.3)
Liver enzyme abnormalities and monitoring: Persistent elevations in hepatic
transaminase can occur when ZETIA is added to a statin. Therefore, when ZETIA is
added to statin therapy, monitor hepatic transaminase levels before and during
treatment according to the recommendations for the individual statin used. (5.2)
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis):
Cases of myopathy and rhabdomyolysis have been reported in patients treated
with ZETIA co-administered with a statin and with ZETIA administered 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. (5.3, 6.2)
6 Adverse Reactions
The following serious adverse reactions are discussed in greater
detail in other sections of the label:
Liver enzyme abnormalities [see Warnings
and Precautions (5.2)]
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 Co-Administration 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%). 6.1 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%). [See Warnings and Precautions (5.2).]
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 Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Co-Administered 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
*Â Â Â Â All Statins = all dose 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 co-administration 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 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 co-administered with fenofibrate, respectively
[see Drug Interactions (7.3)].
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. 6.2 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 [see Warnings and Precautions (5.3)]; elevations in liver
transaminases; hepatitis; abdominal pain; thrombocytopenia; pancreatitis;
nausea; dizziness; paresthesia; depression; headache; cholelithiasis;
cholecystitis.
Common adverse reactions in clinical trials:
ZETIA co-administered with a statin (incidence ≥2% and greater than statin
alone):
nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, and
diarrhea (6)
ZETIA administered alone (incidence ≥2% and greater than placebo):
upper respiratory tract infection, diarrhea, arthralgia, sinusitis, and pain
in extremity (6)
To report SUSPECTED ADVERSE REACTIONS, contact
Merck/Schering-Plough Pharmaceuticals at 1-866-637-2501 or FDA at 1-800-FDA-1088
or www.fda.gov/medwatch.
7 Drug Interactions
[See Clinical Pharmacology
(12.3).] 7.1 Cyclosporine Caution should be exercised when using ZETIA and cyclosporine
concomitantly due to increased exposure to both ezetimibe and cyclosporine.
Cyclosporine concentrations should be monitored in patients receiving ZETIA 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. 7.2 Fibrates 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 [see Nonclinical
Toxicology (13.2)]. Co-administration of ZETIA with fibrates other
than fenofibrate is not recommended until use in patients is adequately
studied. 7.3 Fenofibrate If cholelithiasis is suspected in a patient receiving ZETIA and
fenofibrate, gallbladder studies are indicated and alternative lipid-lowering
therapy should be considered [see Adverse
Reactions (6.1) and the product labeling for fenofibrate]. 7.4 Cholestyramine 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. 7.5 Coumarin Anticoagulants If ezetimibe is added to warfarin, a coumarin anticoagulant, the
International Normalized Ratio (INR) should be appropriately monitored.
Cyclosporine: Combination increases exposure of ZETIA and cyclosporine.
Cyclosporine concentrations should be monitored in patients taking ZETIA
concomitantly. (7.1, 12.3)
Fenofibrate: Combination increases exposure of ZETIA. If cholelithiasis is
suspected in a patient receiving ZETIA and fenofibrate, gallbladder studies are
indicated and alternative lipid-lowering therapy should be considered. (6.1, 7.3)
Fibrates: Co-administration of ZETIA with fibrates other than fenofibrate is
not recommended until use in patients is adequately studied. (7.2)
Cholestyramine: Combination decreases exposure of ZETIA. (2.3, 7.4, 12.3)
8 Use In Specific Populations
8.1 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 × 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 × 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.
[See Contraindications (4).] 8.3 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. 8.4 Pediatric Use The effects of ZETIA 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 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 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 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 and 40 mg simvastatin or 40 mg simvastatin monotherapy for
the next 27 weeks, and open-label co-administered 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
Co-Administered 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%)
*Â Â Â Â 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 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 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 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 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 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. 8.5 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 Co-Administration 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
[see Clinical Pharmacology
(12.3)]. 8.6 Hepatic Impairment ZETIA is not recommended in patients with moderate to severe
hepatic impairment [see Warnings and
Precautions (5.4)
and Clinical
Pharmacology (12.3)].
ZETIA given concomitantly with a statin is contraindicated in patients with
active liver disease or unexplained persistent elevations of hepatic
transaminase levels [see Contraindications
(4)
; Warnings and Precautions
(5.2), and Clinical Pharmacology (12.3)].
10 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 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.
11 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 C24H21F2NO3. 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 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.
12 Clinical Pharmacology
12.1 Mechanism of Action 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 inhibited intestinal cholesterol absorption
by 54%, compared with placebo. ZETIA 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 [see Clinical
Studies (14.1)]. 12.2 Pharmacodynamics 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, 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, 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. 12.3 Pharmacokinetics 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. 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 Cmax 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 (greater than 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 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 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. Specific Populations
Geriatric Patients: In a multiple-dose
study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations
for total ezetimibe were about 2-fold higher in older (greater than or equal to 65 years) healthy
subjects compared to younger subjects. Pediatric Patients:
[See Use in Specific Populations (8.4).]
Gender: In a multiple-dose study with
ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total
ezetimibe were slightly higher (less than 20%) in women than in men. Race: Based on a meta-analysis of
multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences
between Black and Caucasian subjects. Studies in Asian subjects indicated that
the pharmacokinetics of ezetimibe were similar to those seen in Caucasian
subjects. Hepatic Impairment: After a single 10-mg
dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately
1.7-fold in patients with mild hepatic impairment (Child-Pugh score 5 to 6),
compared to healthy subjects. The mean AUC values for total ezetimibe and
ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold,
respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe
hepatic impairment (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study
(10 mg daily) in patients with moderate hepatic impairment, the mean AUC values
for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1
and Day 14 compared to healthy subjects. Due to the unknown effects of the
increased exposure to ezetimibe in patients with moderate or severe hepatic
impairment, ZETIA is not recommended in these patients [see
Warnings and Precautions (5.4)]. Renal Impairment: After a single 10-mg
dose of ezetimibe in patients with severe renal disease (n=8; mean CrCl less than or equal to 30
mL/min/1.73 m2), the mean AUC values for total ezetimibe,
ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold,
compared to healthy subjects (n=9). Drug Interactions [See also Drug Interactions (7)]
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 Co-Administered Drugs on Total Ezetimibe
Aluminum & magnesium hydroxide combination antacid, single dose§
↓4%
↓30%
Cimetidine, 400 mg BID, 7 days
↑6%
↑22%
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%
*Â Â Based on 10 mg dose of ezetimibe
†  See Drug Interactions (7)‡  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.
§  Supralox, 20 mL
TABLE 5: Effect of Ezetimibe Co-Administration on Systemic Exposure to Other Drugs
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 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 × 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 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). 13.2 Animal Toxicology and/or Pharmacology 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 ED50 value of 0.5 µg/kg/day for inhibiting the rise in plasma
cholesterol levels in monkeys. The ED50 values in dogs,
rats, and mice were 7, 30, and 700 µg/kg/day, respectively. These results are
consistent with ZETIA 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 for inhibiting cholesterol absorption. Ezetimibe inhibited
the absorption of 14C-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.
14 Clinical Studies
14.1 Primary Hyperlipidemia ZETIA 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. Monotherapy
In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719
patients with primary hyperlipidemia, ZETIA significantly lowered total-C,
LDL-C, Apo B, and TG, and increased HDL-C compared to placebo (see Table 6). Reduction in LDL-C was
consistent across age, sex, and baseline LDL-C.
TABLE 6: Response to ZETIA in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
*Â Â For triglycerides, median % change from baseline
†  Baseline - on no lipid-lowering drug
‡  ZETIA significantly reduced total-C, LDL-C, Apo B, and TG, and increased HDL-C
compared to placebo.
Combination with Statins
ZETIA Added to On-going Statin Therapy
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 or placebo in addition to their on-going statin.
ZETIA, 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 Table 7). LDL-C
reductions induced by ZETIA were generally consistent across all statins.
TABLE 7: Response to Addition of ZETIA to On-Going Statin Therapy* in Patients with Hyperlipidemia (Mean†% Change from Treated Baseline‡)
*Â Â Patients receiving each statin: 40% atorvastatin, 31% simvastatin, 29% others
(pravastatin, fluvastatin, cerivastatin, lovastatin)
†  For triglycerides, median % change from baseline
‡  Baseline - on a statin alone.
§  ZETIA + statin significantly reduced total-C, LDL-C, Apo B, and TG, and
increased HDL-C compared to statin alone.
ZETIA Initiated Concurrently with a
Statin
In four multicenter, double-blind, placebo-controlled, 12-week trials, in
2382 hyperlipidemic patients, ZETIA or placebo was administered alone or with
various doses of atorvastatin, simvastatin, pravastatin, or lovastatin.
When all patients receiving ZETIA with a statin were compared to all those
receiving the corresponding statin alone, ZETIA 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
were generally consistent across all statins. (See footnote ‡, Tables 8 to
11.)
TABLE 8: Response to ZETIA and Atorvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
*Â Â For triglycerides, median % change from baseline
†  Baseline - on no lipid-lowering drug
‡  ZETIA + all doses of atorvastatin pooled (10–80 mg) significantly reduced
total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of
atorvastatin pooled (10–80 mg).
TABLE 9: Response to ZETIA and Simvastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
* Â For triglycerides, median % change from baseline
†  Baseline - on no lipid-lowering drug
‡  ZETIA + all doses of simvastatin pooled (10–80 mg) significantly reduced
total-C, LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of
simvastatin pooled (10–80 mg).
TABLE 10: Response to ZETIA and Pravastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
*Â Â For triglycerides, median % change from baseline
†  Baseline - on no lipid-lowering drug
‡  ZETIA + all doses of pravastatin pooled (10–40 mg) significantly reduced total-C,
LDL-C, Apo B, and TG compared to all doses of pravastatin pooled (10–40 mg).
TABLE 11: Response to ZETIA and Lovastatin Initiated Concurrently in Patients with Primary Hyperlipidemia (Mean* % Change from Untreated Baseline†)
*Â Â For triglycerides, median % change from baseline
†  Baseline - on no lipid-lowering drug
‡  ZETIA + all doses of lovastatin pooled (10–40 mg) significantly reduced total-C,
LDL-C, Apo B, and TG, and increased HDL-C compared to all doses of lovastatin
pooled (10–40 mg).
Combination with Fenofibrate
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 alone, 160 mg fenofibrate alone, or ZETIA and 160 mg fenofibrate
in the 12-week study. After completing the 12-week study, eligible patients were
assigned to ZETIA co-administered with fenofibrate or fenofibrate monotherapy
for an additional 48 weeks.
ZETIA 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 co-administered with
fenofibrate were comparable to those for fenofibrate administered alone (see
Table 12).
TABLE 12: Response to ZETIA and Fenofibrate Initiated Concurrently in Patients with Mixed Hyperlipidemia (Mean* % Change from Untreated Baseline†at 12 weeks)
*Â Â For triglycerides, median % change from baseline
†  Baseline - on no lipid-lowering drug
The changes in lipid endpoints after an additional 48 weeks of treatment with
ZETIA co-administered with fenofibrate or with fenofibrate alone were consistent
with the 12-week data displayed above.
14.2 Homozygous Familial Hypercholesterolemia
(HoFH) A study was conducted to assess the efficacy of ZETIA 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 administered with atorvastatin or simvastatin (40
mg), or ZETIA administered with atorvastatin or simvastatin (80 mg). Due to
decreased bioavailability of ezetimibe in patients concomitantly receiving
cholestyramine [see Drug Interactions
(7.1)], 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 plus atorvastatin 40 or 80 mg or simvastatin 40 or 80
mg. ZETIA, 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 plus 80 mg atorvastatin or with ZETIA plus 80 mg simvastatin,
LDL-C was reduced by 27%. 14.3 Homozygous Sitosterolemia (Phytosterolemia) A study was conducted to assess the efficacy of ZETIA 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 (n=30) or
placebo (n=7). Due to decreased bioavailability of ezetimibe in patients
concomitantly receiving cholestyramine [see Drug Interactions (7.1)], ezetimibe was dosed at least 2
hours before or 4 hours after resins were administered. Excluding the one
subject receiving LDL apheresis, ZETIA 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, 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 concomitantly with bile acid sequestrants (n=8) and patients not on
concomitant bile acid sequestrant therapy (n=21). Limitations of Use
The effect of ZETIA on cardiovascular morbidity and mortality has not been
determined.
16 How Supplied/storage And Handling
No. 3861 — Tablets ZETIA, 10 mg, are white to off-white,
capsule-shaped tablets debossed with "414" on one side. They are supplied as
follows:
NDC 54868-4719-1 bottles of 30
NDC 54868-4719-0 bottles of 90.
Storage
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [See USP
Controlled Room Temperature.] Protect from moisture.
17 Patient Counseling Information
[See FDA-approved Patient
Labeling (17.5).]
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.
17.1 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.
17.2 Liver Enzymes
Liver tests should be performed when ZETIA is added to statin therapy and
according to statin recommendations.
17.3 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.
17.4 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.
17.5 FDA-approved Patient Labeling
Enter section text here
32147054TREV 21
Issued July 2009U.S. Patent Nos. 5,846,966; 7,030,106 and RE37,721.
Manufactured for:Merck/Schering-Plough PharmaceuticalsNorth Wales, PA
19454, USABy:Schering CorporationKenilworth, NJ 07033,
USAorMerck & Co., Inc.Whitehouse Station, NJ 08889, USA
Spl Patient Package Insert Section
ZETIA® (ezetimibe)
Tablets
Patient Information about ZETIA (zĕt´-ē-ă)
Generic name: ezetimibe (ĕ-zĕt´-ĕ-mīb)
Read this information carefully before you start taking ZETIA and each time
you get more ZETIA. There may be new information. This information does not take
the place of talking with your doctor about your medical condition or your
treatment. If you have any questions about ZETIA, ask your doctor. Only your
doctor can determine if ZETIA is right for you.
What is ZETIA?
ZETIA is a medicine used to lower levels of total cholesterol and LDL (bad)
cholesterol in the blood. ZETIA is for patients who cannot control their
cholesterol levels by diet and exercise alone. It can be used by itself or with
other medicines to treat high cholesterol. You should stay on a
cholesterol-lowering diet while taking this medicine.
ZETIA works to reduce the amount of cholesterol your body absorbs. ZETIA does
not help you lose weight. ZETIA has not been shown to prevent heart disease or
heart attacks.
For more information about cholesterol, see the "What should
I know about high cholesterol?" section that follows.
Who should not take ZETIA?
Do not take ZETIA if you are allergic to ezetimibe, the active ingredient in
ZETIA, or to the inactive ingredients. For a ul of inactive ingredients, see
the "Inactive ingredients" section that follows.
If you have active liver disease, do not take ZETIA while taking
cholesterol-lowering medicines called statins.
If you are pregnant or breast-feeding, do not take ZETIA while taking a
statin.
If you are a woman of childbearing age, you should use an effective method
of birth control to prevent pregnancy while using ZETIA added to statin
therapy.
ZETIA has not been studied in children under age 10.
What should I tell my doctor before and while taking
ZETIA?
Tell your doctor about any prescription and non-prescription medicines you
are taking or plan to take, including natural or herbal remedies.
Tell your doctor about all your medical conditions including allergies.
Tell your doctor if you:
ever had liver problems. ZETIA may not be right for you.
are pregnant or plan to become pregnant. Your doctor will discuss with you
whether ZETIA is right for you.
are breast-feeding. We do not know if ZETIA can pass to your baby through
your milk. Your doctor will discuss with you whether ZETIA is right for
you.
experience unexplained muscle pain, tenderness, or weakness.
How should I take ZETIA?
Take ZETIA once a day, with or without food. It may be easier to remember to
take your dose if you do it at the same time every day, such as with breakfast,
dinner, or at bedtime. If you also take another medicine to reduce your
cholesterol, ask your doctor if you can take them at the same time.
If you forget to take ZETIA, take it as soon as you remember. However, do
not take more than one dose of ZETIA a day.
Continue to follow a cholesterol-lowering diet while taking ZETIA. Ask your
doctor if you need diet information.
Keep taking ZETIA unless your doctor tells you to stop. It is important that
you keep taking ZETIA even if you do not feel sick.
See your doctor regularly to check your cholesterol level and to check for
side effects. Your doctor may do blood tests to check your liver before you
start taking ZETIA with a statin and during treatment.
What are the possible side effects of ZETIA?
In clinical studies patients reported few side effects while taking ZETIA.
These included diarrhea, joint pains, and feeling tired.
Patients have experienced severe muscle problems while taking ZETIA, usually
when ZETIA was added to a statin drug. If you experience unexplained muscle
pain, tenderness, or weakness while taking ZETIA, contact your doctor
immediately. You need to do this promptly, because on rare occasions, these
muscle problems can be serious, with muscle breakdown resulting in kidney
damage.
Additionally, the following side effects have been reported in general use:
allergic reactions (which may require treatment right away) including swelling
of the face, lips, tongue, and/or throat that may cause difficulty in breathing
or swallowing, rash, and hives; raised red rash, sometimes with target-shaped
lesions; joint pain; muscle aches; alterations in some laboratory blood tests;
liver problems; stomach pain; inflammation of the pancreas; nausea; dizziness;
tingling sensation; depression; headache; gallstones; inflammation of the
gallbladder.
Tell your doctor if you are having these or any other medical problems while
on ZETIA. For a complete ul of side effects, ask your doctor or pharmacist.
What should I know about high
cholesterol?
Cholesterol is a type of fat found in your blood. Your total cholesterol is
made up of LDL and HDL cholesterol.
LDL cholesterol is called "bad" cholesterol because it can build up in the
wall of your arteries and form plaque. Over time, plaque build-up can cause a
narrowing of the arteries. This narrowing can slow or block blood flow to your
heart, brain, and other organs. High LDL cholesterol is a major cause of heart
disease and one of the causes for stroke.
HDL cholesterol is called "good" cholesterol because it keeps the bad
cholesterol from building up in the arteries.
Triglycerides also are fats found in your blood.
General information about ZETIA
Medicines are sometimes prescribed for conditions that are not mentioned in
patient information leaflets. Do not use ZETIA for a condition for which it was
not prescribed. Do not give ZETIA to other people, even if they have the same
condition you have. It may harm them.
This summarizes the most important information about ZETIA. If you would like
more information, talk with your doctor. You can ask your pharmacist or doctor
for information about ZETIA that is written for health professionals.
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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