A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Zetia Side Effects, and Drug Interactions - Ezetimibe
Zetia Side Effects, and Drug Interactions - Ezetimibe
SIDE EFFECTS
ZETIA has been evaluated for safety in more than 4700 patients
in clinical trials. Clinical studies of ZETIA (administered alone or with an
HMG-CoA reductase inhibitor) demonstrated that ZETIA was generally well tolerated.
The overall incidence of adverse events reported with ZETIA was similar to that
reported with placebo, and the discontinuation rate due to adverse events was
also similar for ZETIA and placebo.
Monotherapy
Adverse experiences reported in ³2%
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 8.
Table 8* Clinical Adverse Events Occurring in ³2%
of Patients Treated with ZETIA and at an Incidence Greater than Placebo, Regardless
of Causality
|
Body System/Organ Class Adverse Event
|
Placebo (%) n = 795
|
ZETIA 10 mg (%) n = 1691
|
|
Body as a whole – general disorders
|
|
Fatigue
|
1.8
|
2.2
|
|
Gastro-intestinal system disorders
|
|
Abdominal pain
|
2.8
|
3.0
|
|
Diarrhea
|
3.0
|
3.7
|
|
Infection and infestations
|
|
Infection viral
|
1.8
|
2.2
|
|
Pharyngitis
|
2.1
|
2.3
|
|
Sinusitis
|
2.8
|
3.6
|
|
Musculo-skeletal system disorders
|
|
Arthralgia
|
3.4
|
3.8
|
|
Back pain
|
3.9
|
4.1
|
|
Respiratory system disorders
|
|
Coughing
|
2.1
|
2.3
|
* Includes patients who received placebo or ZETIA alone reported in
Table 9.
The frequency of less common adverse events was comparable
between ZETIA and placebo.
Combination with an HMG-CoA reductase Inhibitor
ZETIA has been evaluated for safety in combination studies
in more than 2000 patients.
In general, adverse experiences were similar between ZETIA
administered with HMG-CoA reductase inhibitors and HMG-CoA reductase inhibitors
alone. However, the frequency of increased transaminases was slightly higher
in patients receiving ZETIA administered with HMG-CoA reductase inhibitors than
in patients treated with HMG-CoA reductase inhibitors alone. (See PRECAUTIONS,
Liver Enzymes.) Clinical adverse experiences reported in ³2%
of patients and at an incidence greater than placebo in four placebo-controlled
trials where ZETIA was administered alone or initiated concurrently with various
HMG-CoA reductase inhibitors, regardless of causality assessment, are shown
in Table 9.
Table 9* Clinical Adverse Events occurring in ³2%
of Patients and at an Incidence Greater than Placebo, Regardless of Causality,
in ZETIA/Statin Combination Studies
|
Body System/Organ Class Adverse Event
|
Placebo (%) n=259
|
ZETIA 10 mg (%) n=262
|
All Statins** (%) n=936
|
ZETIA + All Statins** (%) n=925
|
|
Body as a whole – general disorders
|
|
Chest pain
|
1.2
|
3.4
|
2.0
|
1.8
|
|
Dizziness
|
1.2
|
2.7
|
1.4
|
1.8
|
|
Fatigue
|
1.9
|
1.9
|
1.4
|
2.8
|
|
Headache
|
5.4
|
8.0
|
7.3
|
6.3
|
|
Gastro-intestinal system disorders
|
|
Abdominal pain
|
2.3
|
2.7
|
3.1
|
3.5
|
|
Diarrhea
|
1.5
|
3.4
|
2.9
|
2.8
|
|
Infection and infestations
|
|
Pharyngitis
|
1.9
|
3.1
|
2.5
|
2.3
|
|
Sinusitis
|
1.9
|
4.6
|
3.6
|
3.5
|
|
Upper respiratory tract infection
|
10.8
|
13.0
|
13.6
|
11.8
|
|
Musculo-skeletal system disorders
|
|
Arthralgia
|
2.3
|
3.8
|
4.3
|
3.4
|
|
Back pain
|
3.5
|
3.4
|
3.7
|
4.3
|
|
Myalgia
|
4.6
|
5.0
|
4.1
|
4.5
|
* Includes four placebo-controlled combination studies
in which ZETIA was initiated concurrently with an HMG-CoA reductase inhibitor.
** All Statins = all doses of all HMG-CoA reductase
inhibitors.
Post-marketing Experience
The following adverse reactions have been reported in post-marketing experience:
Hypersensitivity reactions, including angioedema and rash.
DRUG INTERACTIONS
(See also CLINICAL PHARMACOLOGY, Drug Interactions.)
Cholestyramine: Concomitant cholestyramine administration decreased
the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction
due to adding ezetimibe to cholestyramine may be reduced by this interaction.
Fibrates: The safety and effectiveness of ezetimibe administered
with fibrates have not been established.
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 ANIMAL
PHARMACOLOGY). Co-administration of ZETIA with fibrates is not recommended
until use in patients is studied.
Fenofibrate: In a pharmacokinetic study, concomitant fenofibrate
administration increased total ezetimibe concentrations approximately 1.5-fold.
Gemfibrozil: In a pharmacokinetic study, concomitant
gemfibrozil administration increased total ezetimibe concentrations approximately
1.7-fold.
HMG-CoA reductase inhibitors: No clinically significant
pharmacokinetic interactions were seen when ezetimibe was co-administered with
atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin.
Cyclosporine: The total ezetimibe level increased 12-fold
in one renal transplant patient receiving multiple medications, including cyclosporine.
Patients who take both ezetimibe and cyclosporine should be carefully monitored.
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 times 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 times 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 times the human exposure at 10 mg daily based on
AUC0-24hr for total ezetimibe).
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 times 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 times 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
HMG-CoA reductase inhibitors (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 HMG-CoA reductase inhibitors are contraindicated in pregnant
and nursing women. When ZETIA is administered with an HMG-CoA reductase inhibitor
in a woman of childbearing potential, refer to the pregnancy category and package
labeling for the HMG-CoA reductase inhibitor. (See CONTRAINDICATIONS.)
Labor and Delivery
The effects of ZETIA on labor and delivery in pregnant women
are unknown.
Nursing Mothers
In rat studies, exposure to total ezetimibe in nursing pups
was up to half of that observed in maternal plasma. It is not known whether
ezetimibe is excreted into human breast milk; therefore, ZETIA should not be
used in nursing mothers unless the potential benefit justifies the potential
risk to the infant.
Pediatric Use
The pharmacokinetics of ZETIA in adolescents (10 to 18 years)
have been shown to be similar to that in adults. Treatment experience with ZETIA
in the pediatric population is limited to 4 patients (9 to 17 years) in the
sitosterolemia study and 5 patients (11 to 17 years) in the HoFH study. Treatment
with ZETIA in children (<10 years) is not recommended. (See CLINICAL
PHARMACOLOGY, Special Populations.)
Geriatric Use
Of the patients who received ZETIA in clinical studies, 948
were 65 and older (this included 206 who were 75 and older). The effectiveness
and safety of ZETIA were similar between these patients and younger subjects.
Greater sensitivity of some older individuals cannot be ruled out. (See CLINICAL
PHARMACOLOGY, Special Populations, and ADVERSE
REACTIONS.)
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