Drug interaction between warfarin and acetaminophen?

The management of anticoagulant therapy is an important component of the treatment of various disease states. Maintaining the narrow therapeutic range required for the safe and effective use of warfarin is essential to avoid suboptimal dosing and adverse events. Numerous drug interactions with warfarin are present due to alterations in absorption, distribution, and metabolism.  The severity of interactions with warfarin varies greatly and dictates very different recommendations for management and monitoring. In the most insignificant interactions, no change in dosage or monitoring is necessary, whereas some interactions require a significant empiric reduction in warfarin dosage and close monitoring of INR.

Reports of the interaction between acetaminophen and warfarin are sparse and generally have small sample sizes.  Prospective studies have associated acetaminophen with elevated INR values in patients receiving warfarin with previously stable INR values. In these patients, elevations in INR generally occurred with the administration of acetaminophen 2–4 g/day for several days and returned to the therapeutic range within days of discontinuing the acetaminophen. One troublesome aspect of the interaction between acetaminophen and warfarin is the wide availability and use of acetaminophen. One study identified that 18.5% of a large number of patients taking warfarin also used acetaminophen-containing products.  The presence of acetaminophen in a patient’s drug regimen may be neglected unintentionally as it is present in countless combination over-the-counter and prescription products.

Mechanism of interaction

Warfarin is available as a racemic mixture of R and S-enantiomers. Both R- and S-warfarin are metabolized by various hepatic enzymes to inactive metabolites. Interactions that increase S-warfarin, which has 3-fold higher potency, are known to increase the anticoagulant effect, whereas the resulting effects of interactions that solely increase R-warfarin are controversial (eg. ciprofloxacin inhibits metabolism of R-warfarin but generally does not affect the INR). S-warfarin is predominantly metabolized by CYP2C9 and minimally by CYP3A4, and R-warfarin is metabolized by CYP3A4 and CYP1A2, and minimally by CYP2C19. Acetaminophen undergoes metabolism primarily by glucuronidation and sulfation with up to 15% metabolized by CYP1A2, CYP2E1, and CYP3A4. Acetaminophen does not interact directly with warfarin metabolism at CYP2C9 but has been observed to inhibit CYP3A4 in vitro.  This is a suggested mechanism of the interaction with acetaminophen, as acetaminophen interacts with both enantiomers at CYP3A4 and the R-warfarin at CYP1A2.  Additional components of the interaction include the observation that R-warfarin has been seen to inhibit CYP2C9 in vitro, potentially increasing the concentration of S-warfarin.

If acetaminophen is necessary at doses near or greater than 2 g/day for more than 1 day, extra attention to the INR may be prudent. Extra care should be taken in patients susceptible to fluctuations in INR, such as geriatric patients or those at high risk for bleeding or who have a history of significant bleeding.

Take away points:

• Some patients are likely to be susceptible to increases in INR due to a warfarin-acetaminophen interaction
• Acetaminophen ≥2 g/day for multiple days has been repeatedly shown to elevate the INR in those on warfarin
• Acetaminophen is present in many over-the-counter products a person might not mention at first during a medication history
• Some medications that inhibit CYP2C9 with serious impact on the INR are: amiodarone, fluconazole (Diflucan) capecitabine (Xeloda), sulfamethoxazole/trimethoprim (Bactrim), fluvoxamine (Luvox), metronidazole (Flagyl), voriconazole (VFEND)

References:

Hughes GJ, Patel PN, Saxena N.  Effect of Acetaminophen on International Normalized Ratio in Patients Receiving Warfarin Therapy.   Pharmacotherapy 2011;31(6):591-7.

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