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Drug Interaction Report

5 potential interactions and/or warnings found for the following 2 drugs:

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Major

ibuprofen warfarin

Applies to: ibuprofen, warfarin

GENERALLY AVOID: Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate the hypoprothrombinemic effect and bleeding risk associated with oral anticoagulants. In a one-year observational study of a population of coumarin users, the relative risk of bleeding complications due to concomitant NSAID use was 5.8 compared to coumarin use alone. Some investigators suggest that the risk of hemorrhagic peptic ulcers in particular may be substantially increased, especially in elderly or debilitated patients. A retrospective epidemiologic study of patients aged 65 years or older reported a nearly 13-fold increase in the risk of developing hemorrhagic peptic ulcer disease in concurrent users of oral anticoagulants and NSAIDs compared with nonusers of either drug. Fatalities have been reported. The pharmacologic effects of NSAIDs that contribute to this interaction include gastrointestinal irritation, prolongation of prothrombin time, and inhibition of platelet adhesion and aggregation. In addition, various NSAIDs have also been shown to alter the pharmacokinetics of warfarin and other oral anticoagulants, resulting in increased INR or prothrombin time. However, some studies failed to demonstrate any evidence of an interaction.

MANAGEMENT: NSAIDs should be administered with oral anticoagulants only if benefit outweighs risk. The INR should be checked frequently and oral anticoagulant dosage adjusted accordingly, particularly following initiation or discontinuation of NSAIDs in patients who are stabilized on their anticoagulant regimen. Patients should be advised to promptly report any signs of unusual bleeding or bruising to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, red or brown urine, or red or black stools. Salicylates (except aspirin) appear to have less effect on coagulation and may be preferable in patients treated with oral anticoagulants. Nevertheless, caution is advised and close monitoring for gastrointestinal bleeding is recommended, particularly in elderly or debilitated patients.

References

  1. Flessner MF, Knight H (1988) "Prolongation of prothrombin time and severe gastrointestinal bleeding associated with combined use of warfarin and ketoprofen." JAMA, 259, p. 353
  2. Ku LL, Ward CO, Durgin SJ (1970) "A clinical study of drug interaction and anticoagulant therapy." Drug Intell Clin Pharm, 4, p. 300-6
  3. Koch-Weser J, Sellers EM (1971) "Drug interactions with coumarin anticoagulants (second of two parts)." N Engl J Med, 285, p. 547-58
  4. Cryst C, Hammar S (1988) "Acute granulomatous interstitial nephritis due to co-trimoxazole." Am J Nephrol, 8, p. 483-8
  5. Aggeler PM, O'Reilly RA, Leong L, Kowitz PE (1967) "Potentiation of anticoagulant effect of warfarin by phenylbutazone." N Engl J Med, 276, p. 496-501
  6. Serlin MJ, Mossman S, Sibeon RG, Tempero KF, Breckeridge AM (1980) "Interaction between diflunisal and warfarin." Clin Pharmacol Ther, 28, p. 493-8
  7. Rhodes RS, Rhodes PJ, Klein C, Sintek CD (1985) "A warfarin-piroxicam drug interaction." Drug Intell Clin Pharm, 19, p. 556-8
  8. Dahl SL, Ward JR (1982) "Pharmacology, clinical efficacy, and adverse effects of piroxicam, a new nonsteroidal anti-inflammatory agent." Pharmacotherapy, 2, p. 80-9
  9. Loftin JP, Vesell ES (1979) "Interaction between sulindac and warfarin: different results in normal subjects and in an unusual patient with a potassium-losing renal tubular defect." J Clin Pharmacol, 19, p. 733-42
  10. Self TH, Evans WE, Ferguson T (1975) "Drug enhancement of warfarin activity." Lancet, 2, p. 557-8
  11. Buchanan GR, Martin V, Levine PH, et al. (1977) "The effects of "anti-platelet" drugs on bleeding time and platelet aggregation in normal human subjects." Am J Clin Pathol, 68, p. 355-9
  12. Udall JA (1970) "Drug interference with warfarin therapy." Clin Med, 77, p. 20-5
  13. Schulman S, Henriksson K (1989) "Interaction of ibuprofen and warfarin on primary haemostasis." Br J Rheumatol, 28, p. 46-9
  14. Bull J, Mackinnon J (1975) "Phenylbutazone and anticoagulant control." Practitioner, 215, p. 767-72
  15. O'Reilly RA (1982) "Phenylbutazone and sulfinpyrazone interaction with oral anticoagulant phenprocoumon." Arch Intern Med, 142, p. 1634-7
  16. O'Reilly RA, Goulart DA (1981) "Comparative interaction of sulfinpyrazone and phenylbutazone with racemic warfarin: alteration in vivo of free fraction of plasma warfarin." J Pharmacol Exp Ther, 219, p. 691-4
  17. Kaufman DW, Kelly JP, Sheehan JE, Laszlo A, Wiholm BE, Alfredsson L, Koff RS, Shapiro S (1993) "Nonsteroidal anti-inflammatory drug use in relation to major upper gastrointestinal bleeding." Clin Pharmacol Ther, 53, p. 485-94
  18. Koren JF, Cochran DL, Janes RL (1987) "Tolmetin-warfarin interaction." Am J Med, 82, p. 1278-80
  19. Self TH, Soloway MS, Vaughn D (1978) "Possible interaction of indomethacin and warfarin." Drug Intell Clin Pharm, 12, p. 580-2
  20. Stricker BH, Delhez JL (1982) "Interaction between flurbiprofen and courmarins." Br Med J, 285, p. 812-3
  21. Mieszczak C, Winther K (1993) "Lack of interaction of ketoprofen with warfarin." Eur J Clin Pharmacol, 44, p. 205-6
  22. Davis LJ, Kayser SR, Hubsher J, Williams RL (1984) "Effect of oxaprozin on the steady-state anticoagulant activity of warfarin." Clin Pharm, 3, p. 295-7
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  24. Wells PS, Holbrook AM, Crowther NR, Hirsh J (1994) "Interactions of warfarin with drugs and food." Ann Intern Med, 121, p. 676-83
  25. Serlin MJ, Breckenridge AM (1983) "Drug interactions with warfarin." Drugs, 25, p. 610-20
  26. Brouwers JRBJ, Desmet PAGM (1994) "Pharmacokinetic-pharmacodynamic drug interactions with nonsteroidal anti-inflammatory drugs." Clin Pharmacokinet, 27, p. 462-85
  27. Schafer AI (1995) "Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis." J Clin Pharmacol, 35, p. 209-19
  28. Gabb GM (1996) "Fatal outcome of interaction between warfarin and a non-steroidal anti-inflammatory drug." Med J Aust, 164, p. 700-1
  29. Pardo A, GarciaLosa M, FernandezPavon A, delCastillo S, PascualGarcia T, GarciaMendez E, DalRe R (1999) "A placebo-controlled study of interaction between nabumetone and acenocoumarol." Br J Clin Pharmacol, 47, p. 441-4
  30. Dennis VC, Thomas BK, Hanlon JE (2000) "Potentiation of oral anticoagulation and hemarthrosis associated with nabumetone." Pharmacotherapy, 20, p. 234-9
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  32. Knijff-Dutmer EA, Schut GA, van de Laar MA (2003) "Concomitant coumarin-NSAID therapy and risk for bleeding." Ann Pharmacother, 37, p. 12-6
  33. Shorr RI, Ray WA, Daugherty JR, Griffin MR (1993) "Concurrent use of nonsteroidal anti-inflammatory drugs and oral anticoagulants places elderly persons at high risk for hemorrhagic peptic ulcer disease." Arch Intern Med, 153, p. 1665-70
  34. Held H, Kaminski B, von Oldersausen HF (1970) "Die beeinflussung der elimination von glycodiazin durch leber- und nierenfunctionssorungen und durch eine behandlung mit phenylbutazone, phenprocumarol und doxycyclin." Diabetologia, 6, p. 386-91
  35. Penning-van Beest F, Erkens J, Petersen KU, Koelz HR, Herings R (2005) "Main comedications associated with major bleeding during anticoagulant therapy with coumarins." Eur J Clin Pharmacol, 61, p. 439-44
View all 35 references

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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