Zettrol Drug Interactions

In preclinical studies, it has been shown that Ezetimibe does not induce cytochrome P450 drug metabolising enzymes.
No clinically significant pharmacokinetic interactions have been observed between Ezetimibe and drugs known to be metabolised by cytochromes P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.
In clinical interaction studies, Ezetimibe had no effect on the pharmacokinetics of dapsone, dextromethorphan, digoxin, oral contraceptives (ethinyl estradiol and levonorgestrel), glipizide, tolbutamide, or midazolam during co-administration. Cimetidine, co-administered with Ezetimibe, had no effect on the bioavailability of Ezetimibe.
Antacids: Concomitant antacid administration decreased the rate of absorption of Ezetimibe but had no effect on the bioavailability of Ezetimibe. This decreased rate of absorption is not considered clinically significant.
Cholestyramine: Concomitant cholestyramine administration decreased the mean area under the curve (AUC) of total Ezetimibe (Ezetimibe + Ezetimibe glucuronide) approximately 55%. The incremental low density lipoprotein cholesterol (LDL-C) reduction due to adding Ezetimibe to cholestyramine may be lessened by this interaction (see Dosage & Administration).
Fibrates: In patients receiving fenofibrate and Ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease (see Precautions and Adverse Reactions).
If cholelithiasis is suspected in a patient receiving Ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued (see Adverse Reactions).
Concomitant fenofibrate or gemfibrozil administration modestly increased total Ezetimibe concentrations (approximately 1.5 and 1.7-fold respectively).
Co-administration of Ezetimibe with other fibrates has not been studied.
Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In animal studies, Ezetimibe sometimes increased cholesterol in the gallbladder bile but not in all species (see Pharmacology: Toxicology: Preclinical safety study under Actions). A lithogenic risk associated with the therapeutic use of Ezetimibe cannot be ruled out.
Statins: No clinically significant pharmacokinetic interactions were seen when Ezetimibe was co-administered with atorvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or rosuvastatin.
Ciclosporin: In a study of eight post-renal transplant patients with creatinine clearance of >50 mL/min on a stable dose of ciclosporin, a single 10 mg dose of Ezetimibe resulted in a 3.4-fold (range 2.3 to 7.9-fold) increase in the mean AUC for total Ezetimibe compared to a healthy control population, receiving Ezetimibe alone, from another study (n=17). In a different study, a renal transplant patient with severe renal impairment who was receiving ciclosporin and multiple other medications demonstrated a 12-fold greater exposure to total Ezetimibe compared to concurrent controls receiving Ezetimibe alone. In a two-period crossover study in twelve healthy subjects, daily administration of 20 mg Ezetimibe for 8 days with a single 100 mg dose of ciclosporin on Day 7 resulted in a mean 15% increase in ciclosporin AUC (range 10% decrease to 51% increase) compared to a single 100-mg dose of ciclosporin alone. A controlled study on the effect of coadministered Ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted. Caution should be exercised when initiating Ezetimibe in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving Ezetimibe and ciclosporin (see Precautions).
Anticoagulants: Concomitant administration of Ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. However, there have been post-marketing reports of increased International Normalised Ratio (INR) in patients who had Ezetimibe added to warfarin or fluindione. If Ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione, INR should be appropriately monitored (see Precautions).
Paediatric population: Interaction studies have only been performed in adults.