Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study.
OBJECTIVE
Paracetamol (acetaminophen) has occasionally been reported to interact with warfarin. The primary end-point of this study was to investigate whether paracetamol initiation potentiates the anticoagulant effect of warfarin and the mechanism of the interaction.


METHODS
In a double-blind placebo-controlled, randomized, cross-over study, 20 patients on stable oral anticoagulant therapy with warfarin for at least 1 month were randomized to receive placebo or paracetamol 1g four times daily for 14 days. International Normalized Ratio (INR) and clotting factors activities were measured before the first administration and then on days 2, 4, 7, 9, 11,14.


RESULTS
Mean INR rose rapidly after the start of paracetamol and was significantly increased within one week of paracetamol intake compared to placebo, p=0.0002. The INR values reached a mean maximum of 3.45+/-0.78 with paracetamol versus 2.66+/-0.73 with placebo (p=0.03), corresponding to a maximum increase from baseline of 1.20+/-0.62 with paracetamol versus 0.37+/-0.48 with placebo (p<0.001). Together with the rise in INR on paracetamol treatment there were significant reductions in the vitamin K-dependent clotting factors II, VII, IX and X.


CONCLUSIONS
The most plausible hypothesis to explain the in vivo interaction is that paracetamol (or its metabolites) interfere with enzymes involved in vitamin K-dependent coagulation factor synthesis. Paracetamol at 4 g daily (a dose higher than that used in clinical practice) potentiates the anticoagulant response produced by warfarin. Clinicians should be aware of this clinically significant and underestimated interaction.
Mahé
Isabelle
I
Unité de Recherches Thérapeutiques, Hôpital Lariboisière, 2, rue Ambroise Paré, 75010 Paris, France. isabelle.mahe@lrb.aphp.fr
Bertrand
Nathalie
N
Drouet
Ludovic
L
Bal Dit Sollier
Claire
C
Simoneau
Guy
G
Mazoyer
Elizabeth
E
Caulin
Charles
C
Bergmann
Jean-François
JF
D000082:Acetaminophen / Q000097:blood* / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D014859:Warfarin / Q000097:blood* / Q000493:pharmacokinetics*
D000082:Acetaminophen; D014859:Warfarin