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
Fibrates: The safety and effectiveness of ezetimibe administered with fibrates have not been
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a
preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Co-administration of ZETIA 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
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
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 Category: C
There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetrol 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). Ezetrol 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.
Labor and Delivery
The effects of ZETIA on labor and delivery in pregnant women are unknown.
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.
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.
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.