Warfarin with Acetaminophen Interaction Details

Brand Names Associated with Warfarin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Feb 25, 2024

Interaction Effect

An increased risk of bleeding

Interaction Summary

The concurrent use of acetaminophen has been associated with an increased hypoprothrombinemic effect of warfarin. It has been proposed that acetaminophen may inhibit the metabolism of warfarin or acetaminophen may interfere with formation of clotting factors. Gingival bleeding and hematuria have been observed in case reports when acetaminophen is given with warfarin[1][2][3][4][5]. Acetaminophen at a dose of 4 grams daily, enhanced the anticoagulant effects of warfarin in a randomized, double-blind, placebo-controlled study [6]. In another double-blind, randomized, placebo-controlled studies, doses of acetaminophen 2 to 4 g/day in patients on stable warfarin therapy led to clinically significant INR elevations [7]. However, due to lack of a safer alternative, acetaminophen is still the analgesic and antipyretic of choice in patients receiving warfarin therapy, as long as excessive amounts and prolonged administration are avoided [8]. Clinicians may consider early and frequent monitoring of INR for several weeks when acetaminophen is added or discontinued in patients on warfarin therapy [6].

Severity

Moderate

Onset

Delayed

Evidence

Established

How To Manage Interaction

Patients receiving warfarin or other coumarin anticoagulants should be cautioned to limit their intake of acetaminophen. Elevations in INR have occurred within 1-2 weeks of initiating acetaminophen at moderate to high doses (2 and 4 g/day) in patients on stable warfarin therapy[7]. Consider early and frequent monitoring of INR for several weeks when acetaminophen is added or discontinued in patients on warfarin therapy [6].

Mechanism Of Interaction

Inhibition of warfarin metabolism or interference with clotting factor formation

Literature Reports

A) In a double-blind, randomized, placebo-controlled study (n=36), initiation of acetaminophen (APAP) at doses of 2 to 4 g/day in adults on stable warfarin therapy led to clinically significant INR elevations. Patients received either APAP 2 g/day (n=12), APAP 4 g/day (n=12), or placebo (n=12) for 4 weeks. Patients were withdrawn from the study if they had a significant deviation (INR of 1.8 or less or 3.3 or more for target INR of 2-3, and an INR of either 2.2 or less or 3.8 or more for target INR of 2.5-3.5). The primary endpoint was the difference in mean INR between groups at weekly intervals. The study was terminated early due to slow enrollment and evidence of INR increases. An intent to treat analysis showed a statistically significant increase in mean INR of 0.7 (95% confidence interval (CI), 0.27-1.2; p=0.01) between the placebo and APAP 2 g/day groups at week 2. For the 4 g/day group, there were statistically significant placebo-subtracted increases in mean INR at weeks 1, 2, and 3 of 0.5 (95% CI, 0.08-0.9), 0.6 (95% CI, 0.21-1), and 1 (95% CI, 0.48-0.15), respectively. The INR increase from baseline in the APAP groups ranged from 0.6-2.8. Among secondary endpoints, 54% (n=13) of patients in the APAP groups had an INR increase of 0.3 or more above the upper limit of their target range versus 17% (n=2) in the placebo group. One and 2 patients in the APAP 2 and 4 g/day groups, respectively, had INR values higher than 4. Among 12 of 13 patients with elevated INRs in the APAP groups, discontinuing APAP and keeping the same warfarin dose led to INR values within target range in about 2 weeks in 10 patients, while elevations persisted in 2 patients. A 7% warfarin dose decrease in addition to discontinuing APAP in 1 patient led to a therapeutic INR during follow-up. Both patients with elevated INRs in the placebo group were kept on the same warfarin dose with persistent INR elevations [7].

B) In a randomized, double-blind, placebo-controlled, crossover study, coadministration of acetaminophen (4 g/day) enhanced warfarin's anticoagulant effects. Patients (n=20) over 18 years of age, taking 2-9 mg of warfarin for at least one month (target INR 2-3), and with no recent/ongoing diseases were randomized to receive either acetaminophen 1 g orally 4 times daily (n=10) or placebo (n=10) for 14 days, and were then crossed over to the other treatment arm following a 2-week washout period. Other medications, including those known to affect INR, were allowed during the study as long as doses were kept constant. Among evaluable patients (n=18), the change in INR from baseline, analyzed using the area under the INR changes-time curve (AUC INR) from day 0-14 (primary endpoint), was significantly higher in the acetaminophen period vs the placebo period, and the mean AUC INRs (+/- standard deviation (SD)) were 6.64 +/- 5.28 and -1.02 +/- 3.22, respectively (p less than 0.001). Increases in INR occurred within 2 days of acetaminophen administration, continued through day 7, and remained elevated for the remainder of the study. The maximum mean +/- SD increase from baseline INR was 1.2 +/- 0.62 vs 0.37 +/- 0.48 for the patients on acetaminophen vs placebo, respectively (p less than 0.001). Significant reductions also occurred in the vitamin K-sensitive clotting factors II, VII, IX, and X during the 14-day period. Despite elevations in INR, the warfarin and acetaminophen combination was well tolerated and no bleeding events were noted during the study. Inhibition of enzymes involved in the vitamin K-dependent clotting factor synthesis by acetaminophen or its metabolites is postulated as a plausible mechanism for this interaction [6].

C) A prospective case-control study was developed to identify factors associated with an INR greater than 6.0 among outpatients taking warfarin whose target INR was 2.0 to 3.0. Ninety-three case patients were interviewed with an INR of greater than 6.0 and 196 controls with an INR in the range of 1.7 to 3.3. INRs increased from 3.5 for 2275-4549 mg intake of acetaminophen per week (95% confidence interval (CI), 1.2-10.0), to 6.9 for 4550 mg to 9099 mg intake per week (95% CI, 2.6-37.9). For those patients taking the highest dose of acetaminophen, 9100 mg/week or more, the odds increased 10-fold of having an INR greater than 6.0 (95% CI, 2.6-37.9). Other factors independently associated with an INR greater than 6.0 were new medication known to potentiate warfarin, advanced malignancy, recent diarrheal illness, decreased oral intake, and taking more warfarin than prescribed. Higher intake of vitamin K and alcohol consumption from 1 to 2 drinks per day were associated with decreased risk. Acetaminophen is an under-recognized cause of over anticoagulation. Regular monitoring of INR values may reduce the frequency of high levels of anticoagulation. Modification of the risk factors should reduce the frequency of overanticoagulation as well [1].

D) In a double-blind study, 20 patients were placed on placebo or acetaminophen 500 mg four times a day while on coumarin therapy. A significant increase in clotting times in patients taking acetaminophen was seen. The mechanism of this drug interaction is unknown and the authors of this study suggest that acetaminophen may interfere with the hepatic synthesis of factors II, VII, IX, and X [3].

E) Healthy male volunteers receiving acetaminophen 4 g daily for one day or two weeks did not show an altered disposition of either the (R)- or (S)-enantiomers of warfarin. During a two-phase randomized crossover study, twenty subjects received a single dose of racemic warfarin 20 mg alone, a 22-day regimen of acetaminophen 1 gram four times daily, and a single 20 mg oral dose of warfarin administered on days 2 and 16 of acetaminophen. Acute and chronic acetaminophen dosing had no effect on the maximum serum concentrations or time to maximum serum concentration of either warfarin enantiomer. Prothrombin time (PT) changes ranged from 1.1 seconds to 6.4 seconds, with the greatest change occurring with the first exposure of warfarin. Factor VII concentrations were not significantly altered between acetaminophen treatments. Additionally, urinary excretion of acetaminophen and its metabolites was unchanged, suggesting that warfarin does not affect acetaminophen metabolism [9].

F) A 74-year-old patient receiving warfarin for atrial fibrillation experienced an increase in INR from 2.3 to 6.4 after acetaminophen therapy (4 g/day for 3 days). The patient's warfarin plasma concentration did not significantly change from 1.54 mcg/mL before treatment to 1.34 mcg/mL after treatment. The author concludes that acetaminophen at dosages exceeding 2 g/day may cause excessive anticoagulation in patients who have previously achieved a stable INR while receiving warfarin. Patients should be advised to have additional INR measurements performed when taking acetaminophen at dosages exceeding 2 g/day [10].

References

1 ) Hylek EM, Heiman H, Skates S, et al: Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279:657-662.

2 ) Bartle WR & Blakely JA: Potentiation of warfarin anticoagulation by acetaminophen (letter). JAMA 1991; 265:1260.

3 ) Boeijinga JJ, Boerstra EE, Ris P, et al: Interaction between paracetamol and coumarin anticoagulants. Lancet 1982; 1:506.

4 ) Jones RV: Warfarin and distalgesic interaction. Br Med J 1976; 1:460.

5 ) Antlitz AM, Mead JA Jr., & Tolentino MA: Potentiation of oral anticoagulant therapy by acetaminophen. Curr Therap Res 1968; 10:501-507.

6 ) Mahe I, Bertrand N, Drouet L, et al: Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica 2006; 91(12):1621-1627.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

7 ) Parra D, Beckey NP, & Stevens GR: The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007; 27(5):675-683.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

8 ) Shek KLA, Chan LN, & Nutescu E: Warfarin-acetaminophen drug interaction revisited. Pharmacotherapy 1999; 19:1153-1158.

9 ) Kwan D, Bartle WR, & Walker SE: The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39:68-75.

10 ) Gebauer M, Nyfort-Hansen K, Henschke P, et al: Warfarin and acetaminophen interaction. Pharmacotherapy 2003; 23(1):109-112.

Warfarin Overview

• Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.