Does Tylenol Increase INR?
Yes, acetaminophen (Tylenol) can increase INR in patients taking warfarin, particularly at doses of 2 grams per day or higher taken for several consecutive days. 1
Mechanism and Dose-Dependent Effect
The interaction between acetaminophen and warfarin appears to occur through inhibition of vitamin K-dependent activation of coagulation factors, specifically reducing functional factor VII and factor IX. 2 This is not simply a hepatotoxic effect, as INR elevations occur even without hepatic injury. 2
The risk is clearly dose-dependent:
- Daily doses exceeding 2 grams significantly increase INR 1
- Doses of 9,100 mg/week or more increase the odds of having an INR >6.0 by 10-fold 3
- Both 2 g/day and 3 g/day regimens produce statistically significant INR increases (mean increase of 0.70 and 0.67 respectively) starting by day 3 of therapy 4
Clinical Significance
When NSAIDs are combined with anticoagulants, there is a 3- to 6-fold increased risk of GI bleeding, and INR can increase by up to 15%. 1 While this guideline statement refers primarily to NSAIDs, the NCCN guidelines specifically note that acetaminophen can increase the therapeutic effects of warfarin when taken in daily doses exceeding 2 grams. 1
The INR elevation typically:
- Becomes significant after several consecutive days of use 5
- Requires warfarin dose adjustment and enhanced monitoring in clinical practice 5
- Can occur even in patients on stable warfarin therapy 4
Monitoring Recommendations
If acetaminophen use is necessary in patients taking warfarin:
- Anticipate an increase in INR and monitor accordingly 1
- Check INR within 3-7 days of starting acetaminophen at doses ≥2 g/day 4
- Consider more frequent monitoring if acetaminophen is used regularly 5, 3
- Maintain target INR of 2.0-3.0 with time in therapeutic range (TTR) ≥65% 1
Common Pitfalls
Do not assume acetaminophen is completely safe in anticoagulated patients. Despite being recommended as a first-line analgesic alternative to NSAIDs 6, acetaminophen is an underrecognized cause of overanticoagulation in outpatient settings. 3
The interaction is often missed because:
- Acetaminophen is ubiquitous and available over-the-counter 5
- Patients may not report acetaminophen use when asked about medications 3
- The effect requires several days of consecutive use to manifest 5, 4
Risk Stratification
Patients at highest risk for clinically significant INR elevation:
- Those taking acetaminophen ≥2 g/day for multiple consecutive days 1, 5
- Patients with advanced malignancy (16-fold increased odds of INR >6.0) 3
- Those with recent diarrheal illness or decreased oral intake 3
- Patients taking other medications that potentiate warfarin 3
Protective factors include: