Acetaminophen And Codeine and Warfarin: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 1, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Acetaminophen And Codeine
Warfarin
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Your pain medicine here contains acetaminophen (the same ingredient as Tylenol), and you also take warfarin, a blood thinner. When you take a lot of acetaminophen regularly, it can make warfarin work a little too strongly, which raises your chance of bleeding. People have noticed things like bleeding gums or blood in the urine.
The good news is this is very manageable. Acetaminophen is actually the preferred pain reliever for people on warfarin, as long as you don't take large amounts for a long time. Please check with your pharmacist or doctor, since they may want to watch your blood test (INR) a bit more closely for a few weeks.
Effect: Acetaminophen can potentiate warfarin's anticoagulant effect, increasing INR and bleeding risk. (The codeine component is not the interacting agent here.)
Mechanism: Proposed inhibition of warfarin metabolism and/or interference with vitamin K dependent clotting factor synthesis (a PD/PK effect).
- Direction: Increased warfarin effect (higher INR).
- Magnitude: Clinically significant INR rises with acetaminophen 2 to 4 g/day; dose and duration dependent.
- Onset: Delayed, typically within 1 to 2 weeks.
- Evidence: Established (RCT and case-report data).
Management: Warfarin is narrow therapeutic index. Limit acetaminophen dose/duration; monitor INR early and frequently for several weeks when acetaminophen is started or stopped.
What happens
An increased risk of bleeding
Interaction Deep Dive
Taking acetaminophen together with warfarin has been linked to a heightened hypoprothrombinemic response to warfarin. Two mechanisms have been suggested: acetaminophen might suppress warfarin metabolism, or it could interfere with the production of clotting factors. Case reports have documented gingival bleeding and hematuria when the two drugs are administered together37489. In a randomized, double-blind, placebo-controlled trial, acetaminophen given at 4 grams per day intensified warfarin's anticoagulant action 2. Separate double-blind, randomized, placebo-controlled studies found that acetaminophen doses of 2 to 4 g/day produced clinically significant rises in INR among patients maintained on stable warfarin regimens 1. Nevertheless, because no safer option exists, acetaminophen remains the preferred analgesic and antipyretic for patients on warfarin, provided that excessive quantities and prolonged use are avoided 10. When acetaminophen is started or stopped in patients receiving warfarin, clinicians may wish to monitor INR early and often over the course of several weeks 2.
Why it happens (mechanism)
Inhibition of warfarin metabolism or interference with clotting factor formation
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise. Acetaminophen is still the safest pain and fever reliever for people on warfarin, so this combination is often used on purpose.
- Limit the amount and how long you use acetaminophen. Occasional or short-term use is generally lower risk than high daily doses (2 to 4 g/day) taken for weeks.
- Your team may check your INR more often, especially in the first couple of weeks after you start or stop acetaminophen, and your warfarin dose may be adjusted and individualized as needed.
- Tell your prescriber or pharmacist about any bleeding signs such as bleeding gums, easy bruising, or blood in urine or stool.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
6 reports — tap to read
a) In a double-blind, randomized, placebo-controlled trial (n=36), starting acetaminophen (APAP) at 2 to 4 g/day in adults who were on stable warfarin produced clinically significant rises in INR. Participants were given APAP 2 g/day (n=12), APAP 4 g/day (n=12), or placebo (n=12) over 4 weeks. Individuals were removed from the trial for a significant deviation (INR of 1.8 or less or 3.3 or more for a target INR of 2-3, and an INR of either 2.2 or less or 3.8 or more for a target INR of 2.5-3.5). The main outcome was the difference in mean INR across groups measured at weekly points. The trial ended prematurely because of slow enrollment and signs of INR elevation. An intent to treat analysis demonstrated a statistically significant rise 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. In the 4 g/day group, statistically significant placebo-subtracted increases in mean INR were seen 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 rise in INR from baseline in the APAP groups spanned 0.6-2.8. Among the secondary outcomes, 54% (n=13) of patients in the APAP groups experienced an INR rise of 0.3 or more above the upper boundary of their target range compared with 17% (n=2) in the placebo group. One and 2 patients in the APAP 2 and 4 g/day groups, respectively, had INR readings above 4. Of 12 of 13 patients with raised INRs in the APAP groups, stopping APAP while maintaining the same warfarin dose brought INR back within the target range in roughly 2 weeks in 10 patients, whereas elevations continued in 2 patients. A 7% reduction in warfarin dose together with discontinuing APAP in 1 patient produced a therapeutic INR during follow-up. Both patients with raised INRs in the placebo group remained on the same warfarin dose with continued INR elevations 1.
b) In a randomized, double-blind, placebo-controlled, crossover trial, giving acetaminophen (4 g/day) alongside warfarin strengthened warfarin's anticoagulant action. Patients (n=20) older than 18 years, taking 2-9 mg of warfarin for at least one month (target INR 2-3), and without recent or ongoing illnesses were randomized to receive either acetaminophen 1 g orally 4 times daily (n=10) or placebo (n=10) for 14 days, then were switched to the alternate treatment arm after a 2-week washout period. Other drugs, including those known to influence INR, were permitted during the study provided their doses stayed constant. Among the evaluable patients (n=18), the change in INR from baseline, examined using the area under the INR changes-time curve (AUC INR) from day 0-14 (main outcome), was significantly greater during the acetaminophen period than 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). INR increases appeared within 2 days of acetaminophen administration, persisted through day 7, and stayed elevated for the rest of the study. The maximum mean +/- SD increase from baseline INR was 1.2 +/- 0.62 versus 0.37 +/- 0.48 for patients on acetaminophen versus placebo, respectively (p less than 0.001). Significant declines also happened in the vitamin K-sensitive clotting factors II, VII, IX, and X over the 14-day span. Despite the INR elevations, the warfarin plus acetaminophen combination was well tolerated and no bleeding episodes were recorded during the study. Inhibition by acetaminophen or its metabolites of enzymes involved in synthesizing vitamin K-dependent clotting factors is proposed as a plausible mechanism for this interaction 2.
c) A prospective case-control study was designed to identify factors linked with an INR above 6.0 among outpatients on warfarin whose target INR was 2.0 to 3.0. Ninety-three case patients were interviewed with an INR exceeding 6.0 and 196 controls with an INR within the range of 1.7 to 3.3. INRs rose from 3.5 for 2275-4549 mg of acetaminophen intake 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 patients taking the highest acetaminophen amount, 9100 mg/week or more, the odds of having an INR above 6.0 increased 10-fold (95% CI, 2.6-37.9). Additional factors independently linked with an INR above 6.0 were a new medication known to potentiate warfarin, advanced malignancy, recent diarrheal illness, reduced oral intake, and taking more warfarin than prescribed. Greater intake of vitamin K and alcohol consumption of 1 to 2 drinks per day were associated with lowered risk. Acetaminophen is an under-recognized cause of over anticoagulation. Routine monitoring of INR values may lessen the frequency of high anticoagulation levels. Modifying the risk factors should also reduce the frequency of overanticoagulation 3.
d) In a double-blind study, 20 patients were assigned to placebo or acetaminophen 500 mg four times a day while receiving coumarin therapy. A significant rise in clotting times was observed in patients taking acetaminophen. The mechanism of this drug interaction is unknown, and the authors of this study propose that acetaminophen may interfere with the hepatic production of factors II, VII, IX, and X 4.
e) Healthy male volunteers taking acetaminophen 4 g daily for one day or two weeks showed no change in the disposition of either the (R)- or (S)-enantiomer of warfarin. In a two-phase randomized crossover study, twenty subjects received a single dose of racemic warfarin 20 mg alone, a 22-day course of acetaminophen 1 gram four times daily, and a single 20 mg oral dose of warfarin given on days 2 and 16 of acetaminophen. Acute and chronic acetaminophen dosing did not affect the maximum serum concentrations or the time to maximum serum concentration of either warfarin enantiomer. Prothrombin time (PT) changes ranged from 1.1 seconds to 6.4 seconds, with the largest change occurring at the first warfarin exposure. Factor VII concentrations were not significantly changed between acetaminophen treatments. In addition, urinary excretion of acetaminophen and its metabolites was unchanged, indicating that warfarin does not alter acetaminophen metabolism 5.
f) A 74-year-old patient taking warfarin for atrial fibrillation had an INR rise from 2.3 to 6.4 after acetaminophen therapy (4 g/day for 3 days). The patient's plasma warfarin concentration did not change significantly, from 1.54 mcg/mL before treatment to 1.34 mcg/mL afterward. The author concludes that acetaminophen at doses above 2 g/day may lead to excessive anticoagulation in patients who had previously reached a stable INR on warfarin. Patients should be counseled to obtain additional INR measurements when taking acetaminophen at doses above 2 g/day 6.
Common questions
Can I take Acetaminophen And Codeine and Warfarin together?
Regular or high-dose acetaminophen can strengthen warfarin and raise bleeding risk, so limit how much you use and expect your care team to check your INR more closely when you start or stop it. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Acetaminophen And Codeine and Warfarin interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Acetaminophen And Codeine and Warfarin interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise. Acetaminophen is still the safest pain and fever reliever for people on warfarin, so this combination is often used on purpose. Limit the amount and how long you use acetaminophen. Occasional or short-term use is generally lower risk than high daily doses (2 to 4 g/day) taken for weeks. Your team may check your INR… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Acetaminophen And Codeine or Warfarin need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (10)
- 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
- 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.
- Hylek EM, Heiman H, Skates S, et al: Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279:657-662. PubMed
- Boeijinga JJ, Boerstra EE, Ris P, et al: Interaction between paracetamol and coumarin anticoagulants. Lancet 1982; 1:506. PubMed
- Kwan D, Bartle WR, & Walker SE: The effects of acetaminophen on pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39:68-75. PubMed
- Gebauer M, Nyfort-Hansen K, Henschke P, et al: Warfarin and acetaminophen interaction. Pharmacotherapy 2003; 23(1):109-112. PubMed
- Bartle WR & Blakely JA: Potentiation of warfarin anticoagulation by acetaminophen (letter). JAMA 1991; 265:1260. DOI
- Jones RV: Warfarin and distalgesic interaction. Br Med J 1976; 1:460.
- Antlitz AM, Mead JA Jr. & Tolentino MA: Potentiation of oral anticoagulant therapy by acetaminophen. Curr Therap Res 1968; 10:501-507.
- Shek KLA, Chan LN, & Nutescu E: Warfarin-acetaminophen drug interaction revisited. Pharmacotherapy 1999; 19:1153-1158. PubMed
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