When ezetimibe is to be administered with a statin, refer to the information for that particular statin.
Liver Enzymes: In controlled co-administration trials in patients receiving ezetimibe with a statin, consecutive transaminase elevations [≥3 x the upper limit of normal (ULN)] have been observed. When ezetimibe is co-administered with a statin, liver function tests should be performed at initiation of therapy and according to the recommendations of the statin. (See Side Effects).
Hepatic Insufficiency: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic insufficiency, ezetimibe is not recommended in these patients (see Special Populations under Actions).
Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established, therefore, co-administration of ezetimibe and fibrates is not recommended (see Interactions).
Cyclosporine: Caution should be exercised when initiating ezetimibe in the setting of cyclosporine (see Interactions).
Skeletal Muscle: In clinical trials, there was no excess of myopathy or rhabdomyolysis associated with ezetimibe compared with the relevant control arm (placebo or HMG-CoA reductase inhibitor alone). However, myopathy and rhabdomyolysis are known adverse reactions to HMG-CoA reductase inhibitors and other lipid-lowering drugs. In clinical trials, the incidence of CPK >10 x ULN was 0.2% for ezetimibe versus 0.1% for placebo, and 0.1% for ezetimibe co-administered with an HMG-CoA reductase inhibitor versus 0.4% for HMG-CoA reductase inhibitor.
Use in pregnancy: There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.
In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 times the human exposure at 10 mg daily based on AUC0-24 hr 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 AUC0-24 hr 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.
Use in lactation: Studies in rats have shown that ezetimibe is excreted in milk. It is not known whether ezetimibe is excreted into human breast milk, therefore, ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.