Is there enough evidence of interaction between ranitidine and warfarin?

Fråga: Is there enough evidence of interaction between ranitidine and warfarin?

Sammanfattning: There is not enough evidence to prove the existence of a practically important interaction between ranitidine and warfarin.

Svar: Cimetidine has been shown to potentiate the action of warfarin by inhibiting its hepatic metabolism and been used as a positive control in a few studies in the same aspect as for ranitidine.

Serlin et al (1) has reported that in five volunteers taking daily subtherapeutic doses of warfarin (mean value 3.4 mg) for 2 weeks the addition of ranitidine 200 mg twice daily for another 2 weeks did not affect prothrombin time or plasma warfarin concentration (mean prothrombin time 18.2 (SE = 0.5 second) when taking warfarin alone and 17.1 (SE = 0.4 second) with warfarin plus ranitidine).

O´Reilly (2) has also shown that in 11 healthy volunteers ranitidine 150 mg twice a day did not influence the prothrombin time. The areas under the curves of prothrombin time over 7 days after drug intake were 84 on average (SD = 6) with warfarin alone and 83 (SD = 8) plus ranitidine. There was a significant increase to 101 (SD = 8) when cimetidin was given. The mean value of warfarin plasma area under the curve was 467 (SD = 38) mgxh/l with warfarin alone and 469 (SD = 37) mgxh/l plus ranitidine. While in the same subjects cimetidine 300 mg, four times a day for 4 days significantly augmented both the hypoprothrombinemia and the blood concentrations of single dose of racemic warfarin 1.5 mg/kg.

More recently, a comparative effect of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man was reported by Toon et al (3). They found in 8 male healthy volunteers ranitidine 300 mg daily for 9 days had no effect on prothrombin time and Factor VII clotting time or the pharmacokinetics of the individual warfarin enantiomers when a single 25 mg oral dose of racemic warfarin was administered on Day 4 of the ranitidine regimen. Cimetidine (single 800 mg daily) with the same protocol as ranitidine produced no statistically significant change in the anticoagulant effect of warfarin or in the pharmacokinetics of a (s)enantiomer which is more potent pharmacologically, but produced a statistically significant decrease in the clearance of the (R)enantiomer. However, five of the 8 subjects showed an increased response during the cimetidine phase and great inter- and intrasubject variability in response was observed (3).

Some animal data concerning interactions between ranitidine and warfarin were also available. Serlin et al showed that ranitidine had no effect on the single dose pharmacodynamics and pharmacokinetics of warfarin in the rat and no effect on pentobarbitone sleeping time in the rat whereas an equivalent dose of cimetidine produced a significant prolongation of sleeping time (1).

There was only one report showing a decreased oral warfarin clearance after ranitidine and cimetidine. In five healthy subjects ranitidine at 150 mg twice daily for one week induced a 27 per cent (66.7 ml/h to 48.7 ml/h) fall in apparent oral warfarin (10 mg) clearance. In the same subjects cimetidine 200 mg three times a day and 400 mg at night induced a 36 per cent (66.7 ml/h to 42.9 ml/h) decrease in warfarin clearance. A dose related effect was seen in 2 subjects with high dose of ranitidine (750 mg/day) and in another 2 subjects receiving lower dose of cimetidine (200 mg twice daily). However, no measurement of pharmacodynamics was performed (4).

No interaction has been observed between famotidine and warfarin in rat (5).

In summary, there is no double blind and randomized clinical study on the possible interaction between ranitidine and warfarin. Most of the data from a few available studies showed no influence of ranitidine on the effect of warfarin, but a significant interaction between cimetidine and warfarin. There is however one study showing a decreased warfarin clearance after ranitidine and warfarin were given to a small number of subjects and without any pharmacodynamic measurement. 1 Serlin MJ, Sibeon RG, Breckenridge AM: Lack of effect of ranitidine on warfarin action. Br J Clin Pharmacol 1981; 12: 791-794 2 O´Reilly RA: Comparative interaction of cimetidine and ranitidine with racemic warfarin in man. Arch Intern Med 1984; 144: 989-991 3 Toon S, Hopkins KJ, Garstang FM, Rowland M: Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man. Eur J Clin Pharmacol 1987; 32: 165-172 4 Desmond PV, Mashford ML, Harman PJ, Morphett BJ, Breen KJ, Wang YM: Decreased oral warfarin clearance after ranitidine and cimetidine. Clin Pharmacol Ther 1984; 35: 338-341 5 Lin JH, Cocchetto DM, Yeh KC, Duggan DE: Comparative effects of H2-receptor antagonists on drug interaction in rats. Drug Metab Dispos 1986; 14: 649-653