Warfarin
Ezetimibe (Zetia) Interactions
Ezetimibe lacks significant inhibitor or inducer effects on cytochrome P-450 isoenzymes. Ezetimibe coadministration has no significant effect on specific probe drugs (caffeine, dextromethorphan, tolbutamide, and midazolam) known to be metabolized by cytochrome P-450 enzymes (1A2, 2D6, 2C8/9 and 3A4 isoenzymes). In addition, cimetidine (a non-specific cytochrome P-450 inhibitor) has no effect on the bioavailability of ezetimibe or total ezetimibe. Ezetimibe has no significant interactions when administered concomitantly with digoxin, glipizide, or oral contraceptives. Coadministration of ezetimibe has no significant effect on the bioavailability of ethinyl estradiol or levonorgestrel. Ezetimibe has no significant effect on the bioavailability or electrophysiologic effects of digoxin. Ezetimibe has no significant effect on the pharmacokinetics and pharmacodynamics of glipizide; glipizide also has no significant effect on the systemic exposure of total ezetimibe or ezetimibe.
Antacids (e.g., 20 ml aluminum hydroxide; magnesium hydroxide) have no significant effect on the oral bioavailability of total ezetimibe (ezetimibe plus ezetimibe-glucuronide), ezetimibe-glucuronide, or ezetimibe based on AUC values. However, the peak plasma concentration (Cmax) of total ezetimibe is decreased by 30%. The effect of the antacids in this regard is not expected to have a significant effect on the ability of ezetimibe to lower cholesterol. However, to limit any potential interaction, it would be prudent to administer ezetimibe at least 1 hour before or 2 hours after administering antacids.
The effects of combined therapy with ezetimibe and HMG-CoA reductase inhibitors (’statins’) are synergistic, resulting in greater LDL reductions than either ezetimibe or statin monotherapy. This interaction is utilized for therapeutic benefits to enhance LDL-lowering of antilipemic therapy. When used in combination with 10 - 80 mg of either simvastatin or atorvastatin, combined use with ezetimibe achieved LDL-reductions of approximately 51% or 56%, respectively, compared to 36% or 44% with simvastatin or atorvastatin monotherapy, respectively. When used in combination with 10 - 40 mg of either pravastatin or lovastatin, combined use with ezetimibe achieves LDL reductions of approximately 39% or 40%, respectively, compared to LDL reductions of 25% with either pravastatin or lovastatin monotherapy. No clinically significant pharmacokinetic interactions were noted when ezetimibe was coadministered with the HMG-CoA reductase inhibitors studied (i.e., atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, or simvastatin). Concomitant administration of ezetimibe has no significant effect on the bioavailability of these statins; the bioavailability of total ezetimibe is also unaffected.
The safety and effectiveness of ezetimibe when coadministered with fibric acid derivatives (’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. Coadministration of ezetimibe with fibrates is not recommended until clinical trials have been conducted. In a pharmacokinetic study, concomitant fenofibrate or gemfibrozil administration increased total ezetimibe concentrations by approximately 1.5 or 1.7-fold, respectively. However, ezetimibe does not affect the pharmacokinetics of fenofibrate or the bioavailability of gemfibrozil.
The oral absorption of ezetimibe may be decreased by the concomitant administration of the bile acid sequestrants (’resin’ type cholesterol medications); the incremental LDL-cholesterol reduction expected to occur by adding ezetimibe to bile acid sequestrant therapy may be reduced by this interaction. In a study of 40 hypercholesterolemic adult subjects, concomitant cholestyramine (4 grams PO twice daily) administration decreased the mean AUC values of total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and ezetimibe by approximately 55% and 80%, respectively. A similar effect might be expected to occur with the concomitant administration of colestipol or colesevelam with ezetimibe; however, this potential interaction has not been studied. To limit a potential interaction, ezetimibe should be administered at least 2 hours before or 4 hours after administration of a bile acid sequestrant.
Cyclosporine may significantly increase ezetimibe serum concentrations. In addition, ezetimibe can increase cyclosporine serum concentrations. In a study of twelve healthy subjects, daily administration of 20 mg ezetimibe for 8 days and a single dose of 100 mg cyclosporine on day 7 resulted in a mean 15% increase in cyclosporine AUC (up to 51%) compared to a single dose of 100 mg cyclosporine alone. In a study of eight post-renal transplant patients with mildly impaired or normal renal function (CrCl > 50 mL/min), stable doses of cyclosporine (75 to 150 mg twice daily) increased the mean AUC and Cmax values of total ezetimibe 3.4-fold (range 2.3-fold to 7.9-fold) and 3.9-fold (range 3.0-fold to 4.4-fold), respectively, compared to a historical healthy control population (n=17). In a different study, a renal transplant patient with severe renal insufficiency (creatinine clearance of 13.2 mL/min/1.73 m2) who was receiving multiple medications, including cyclosporine, demonstrated a 12-fold greater exposure to total ezetimibe compared to healthy subjects. The degree of increase in ezetimibe exposure may be greater in patients with severe renal insufficiency. In patients treated with cyclosporine, the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the antilipemic benefits provided by ezetimibe. Patients who take cyclosporine concurrently with ezetimibe should be closely monitored for serum cyclosporine concentrations and for potential adverse effects of ezetimibe and cyclosporine.
Coadministration with ezetimibe has not demonstrated significant effects on the bioavailability or the anticoagulant effects (prothrombin time) of warfarin when studied in 12 healthy adult males. However, there have been post-marketing reports of increased INR in patients who had ezetimibe added to warfarin therapy. Most of these patients were also receiving other medications. The manufacturer recommends that if ezetimibe is added to warfarin, the INR should be appropriately monitored.
[ Last revised: 12/30/2005 2:54:00 PM ]
References
. Sudhop T, Von Bergmann K. Cholesterol absorption inhibitors for the treatment of hypercholesterolaemia. Drugs 2002;62:2333 - 47.
. Kosoglou T, Meyer I, Veltri EP, et al. Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin. Br J Clin Pharmacol 2002;54:309 - 19.
. Gagne C, Gaudet D, Bruckert E, et al. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469 - 75.
. Zetia™ (ezetimibe) package insert. Kenilworth, NJ: Schering Corporation; 2003 Mar.
. Vytorin™ (ezetimibe; simvastatin) package insert. North Wales, PA: MERCK/Schering-Plough Pharmaceuticals; 2005 Dec.
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