Interactions

Active ingredient Ezetimibe interacts in the following cases:

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.

Coumarin anticoagulants

If ezetimibe is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored. 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.

Fibrates

In patients receiving fenofibrate and ezetimibe, physicians should be aware of the possible risk of cholelithiasis and gallbladder disease. If cholelithiasis is suspected in a patient receiving Ezetimibe and fenofibrate, gallbladder investigations are indicated and this therapy should be discontinued.

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. A lithogenic risk associated with the therapeutic use of Ezetimibe cannot be ruled out.

Colestyramine

Concomitant colestyramine 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 colestyramine may be lessened by this interaction.

Ciclosporin

Caution should be exercised when initiating ezetimibe in the setting of ciclosporin. Ciclosporin concentrations should be monitored in patients receiving ezetimibe and 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 medicinal products, 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 co-administered ezetimibe on ciclosporin exposure in renal transplant patients has not been conducted.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.

Pregnancy

Ezetimibe should be given to pregnant women only if clearly necessary. No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on the use of ezetimibe in monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, birth or postnatal development.

Nursing Mothers

Ezetimibe should not be used during lactation. Studies on rats have shown that ezetimibe is secreted into breast milk. It is not known if ezetimibe is secreted into human breast milk.

Carcinogenesis, Mutagenesis and Fertility

Fertility

No clinical trial data are available on the effects of ezetimibe on human fertility. Ezetimibe had no effect on the fertility of male or female rats.

Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machines, it should be taken into account that dizziness has been reported.