Do All Histamine2-Antagonists Cause a Warfarin Drug Interaction?

Abstract

Cimetidine, the first marketed histamine2-receptor antagonist, has been shown to decrease the clearance of warfarin consistently through inhibition of cytochrome P-450 metabolism. The clinical significance of this drug–drug interaction has been questioned due to: (1) the lowering of the warfarin therapeutic range, (2) the lowering of the total daily therapeutic cimetidine dosage, (3) the advent of once-daily cimetidine dosing, and (4) the demonstration that the clearance of the less active warfarin R-enantiomer is decreased to a greater extent than the more active S-enantiomer. Ranitidine has been implicated in both increasing and decreasing warfarin's hypoprothrombinemic effect (noted in the warfarin package insert), despite the majority of investigations demonstrating no warfarin clearance changes. Careful examination of the implicating data indicates that the majority of the warfarin pharmacodynamic and pharmacokinetic variance that occurs with combined ranitidine-warfarin therapy cannot be attributed to a drug–drug interaction. No data are available to implicate the newer histamine2-antagonists, famotidine and nizatidine, in causing a decrease in warfarin metabolism.