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Drug Interactions between dicumarol and diflunisal

This report displays the potential drug interactions for the following 2 drugs:

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Major

diflunisal dicumarol

Applies to: diflunisal and dicumarol

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
  23. Ermer JC, Hicks DR, Wheeler SC, Kraml M, Jusko WJ (1994) "Concomitant etodolac affects neither the unbound clearance nor the pharmacologic effect of warfarin." Clin Pharmacol Ther, 55, p. 305-16
  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
  31. (2001) "Product Information. Mobic (meloxicam)." Boehringer-Ingelheim
  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 and food interactions

Moderate

dicumarol food

Applies to: dicumarol

MONITOR: Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants. Vitamin K is a cofactor in the synthesis of blood clotting factors that are inhibited by oral anticoagulants, thus intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants. Resistance to oral anticoagulants has been associated with consumption of foods or enteral feedings high in vitamin K content. Likewise, a reduction of vitamin K intake following stabilization of anticoagulant therapy may result in elevation of the INR and bleeding complications. Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables. Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil. Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption. Whether these foods can alter the effect of oral anticoagulants has not been extensively studied. One small study found that moderate consumption (1.5 servings/day) does not significantly affect the INR after one week in patients receiving long-term anticoagulation.

Consumption of large amounts of mango fruit has been associated with enhanced effects of warfarin. The exact mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin. In one report, thirteen patients with an average INR increase of 38% reportedly had consumed one to six mangos daily 2 to 30 days prior to their appointment. The average INR decreased by 17.7% after discontinuation of mango ingestion for 2 weeks. Rechallenge in two patients appeared to confirm the interaction.

Limited data also suggest a potential interaction between warfarin and cranberry juice resulting in changes in the INR and/or bleeding complications. The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice. At least a dozen reports of suspected interaction have been filed with the Committee on Safety of Medicines in the U.K. since 1999, including one fatality. In the fatal case, the patient's INR increased dramatically (greater than 50) six weeks after he started drinking cranberry juice, and he died from gastrointestinal and pericardial hemorrhage. However, the patient was also taking cephalexin for a chest infection and had not eaten for two weeks prior to hospitalization, which may have been contributing factors. Other cases involved less dramatic increases or instabilities in INR following cranberry juice consumption, and a decrease was reported in one, although details are generally lacking. In a rare published report, a 71-year-old patient developed hemoptysis, hematochezia, and shortness of breath two weeks after he started drinking 24 ounces of cranberry juice a day. Laboratory test results on admission revealed a decrease in hemoglobin, an INR greater than 18, and prothrombin time exceeding 120 seconds. The patient recovered after warfarin doses were withheld for several days and he was given packed red blood cells, fresh-frozen plasma, and subcutaneous vitamin K. It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.

There have been several case reports in the medical literature of patients consuming grapefruit, grapefruit juice, or grapefruit seed extract who experienced increases in INR. R(+) warfarin, the less active of the two enantiomers of warfarin, is partially metabolized by CYP450 3A4. Depending on brand, concentration, dose and preparation, grapefruit juice may be considered a moderate to strong inhibitor of CYP450 3A4, thus coadministration with warfarin may decrease the clearance of R(+) warfarin. However, the clinical significance of this effect has not been established. A pharmacokinetic study found no effect on the PT or INR values of nine warfarin patients given 8 oz of grapefruit juice three times a day for one week.

A patient who was stabilized on warfarin developed a large hematoma in her calf in association with an elevated INR of 14 following consumption of approximately 3 liters of pomegranate juice in the week prior to admission. In vitro data suggest that pomegranate juice can inhibit CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the biologically more active S(-) enantiomer of warfarin. In rats, pomegranate juice has also been shown to inhibit intestinal CYP450 3A4, the isoenzyme that contributes to the metabolism of R(+) warfarin.

Black currant juice and black currant seed oil may theoretically increase the risk of bleeding or bruising if used in combination with anticoagulants. The proposed mechanism is the antiplatelet effects of the gamma-linolenic acid constituent in black currants.

Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin. The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K. Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia. No other changes in diet or medications were noted during this time. The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.

An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg/day for 4.5 years. The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days. The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.

MANAGEMENT: Intake of vitamin K through supplements or diet should not vary significantly during oral anticoagulant therapy. The diet in general should remain consistent, as other foods containing little or no vitamin K such as mangos and soy milk have been reported to interact with warfarin. Some experts recommend that continuous enteral nutrition should be interrupted for one hour before and one hour after administration of the anticoagulant dose and that enteral formulas containing soy protein should be avoided. Patients should also consider avoiding or limiting the consumption of cranberry juice or other cranberry formulations (e.g., encapsulated dried cranberry powder), pomegranate juice, black currant juice, and black currant seed oil.

References

  1. Andersen P, Godal HC (1975) "Predictable reduction in anticoagulant activity of warfarin by small amounts of vitamin K." Acta Med Scand, 198, p. 269-70
  2. Westfall LK (1981) "An unrecognized cause of warfarin resistance." Drug Intell Clin Pharm, 15, p. 131
  3. Lee M, Schwartz RN, Sharifi R (1981) "Warfarin resistance and vitamin K." Ann Intern Med, 94, p. 140-1
  4. Zallman JA, Lee DP, Jeffrey PL (1981) "Liquid nutrition as a cause of warfarin resistance." Am J Hosp Pharm, 38, p. 1174
  5. Griffith LD, Olvey SE, Triplett WC (1982) "Increasing prothrombin times in a warfarin-treated patient upon withdrawal of ensure plus." Crit Care Med, 10, p. 799-800
  6. Kempin SJ (1983) "Warfarin resistance caused by broccoli." N Engl J Med, 308, p. 1229-30
  7. Watson AJ, Pegg M, Green JR (1984) "Enteral feeds may antagonise warfarin." Br Med J, 288, p. 557
  8. Walker FB (1984) "Myocardial infarction after diet-induced warfarin resistance." Arch Intern Med, 144, p. 2089-90
  9. Howard PA, Hannaman KN (1985) "Warfarin resistance linked to enteral nutrition products." J Am Diet Assoc, 85, p. 713-5
  10. Karlson B, Leijd B, Hellstrom K (1986) "On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment." Acta Med Scand, 220, p. 347-50
  11. Pedersen FM, Hamberg O, Hess K, Ovesen L (1991) "The effect of dietary vitamin K on warfarin-induced anticoagulation." J Intern Med, 229, p. 517-20
  12. Parr MD, Record KE, Griffith GL, et al. (1982) "Effect of enteral nutrition on warfarin therapy." Clin Pharm, 1, p. 274-6
  13. Wells PS, Holbrook AM, Crowther NR, Hirsh J (1994) "Interactions of warfarin with drugs and food." Ann Intern Med, 121, p. 676-83
  14. O'Reilly RA, Rytand DA (1980) ""Resistance" to warfarin due to unrecognized vitamin K supplementation." N Engl J Med, 303, p. 160-1
  15. Kazmier FJ, Spittell JA Jr (1970) "Coumarin drug interactions." Mayo Clin Proc, 45, p. 249-55
  16. Chow WH, Chow TC, Tse TM, Tai YT, Lee WT (1990) "Anticoagulation instability with life-threatening complication after dietary modification." Postgrad Med J, 66, p. 855-7
  17. MacLeod SM, Sellers EM (1976) "Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants." Drugs, 11, p. 461-70
  18. Sullivan DM, Ford MA, Boyden TW (1998) "Grapefruit juice and the response to warfarin." Am J Health Syst Pharm, 55, p. 1581-3
  19. Harrell CC, Kline SS (1999) "Vitamin K-supplemented snacks containing olestra: Implication for patients taking warfarin." Jama J Am Med Assn, 282, p. 1133-4
  20. Beckey NP, Korman LB, Parra D (1999) "Effect of the moderate consumption of olestra in patients receiving long-term warfarin therapy." Pharmacotherapy, 19, p. 1075-9
  21. Monterrey-Rodriguez J (2002) "Interaction between warfarin and mango fruit." Ann Pharmacother, 36, p. 940-1
  22. Cambria-Kiely JA (2002) "Effect of soy milk on warfarin efficacy." Ann Pharmacother, 36, p. 1893-6
  23. MHRA. Mediciines and Healthcare products Regulatory Agency. Committee on Safety of Medicines (2003) Possible interaction between warfarin and cranberry juice. http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/currentproblems/currentproblems.htm
  24. Suvarna R, Pirmohamed M, Henderson L (2003) "Possible interaction between warfarin and cranberry juice." BMJ, 327, p. 1454
  25. Kuykendall JR, Houle MD, Rhodes RS (2004) "Possible warfarin failure due to interaction with smokeless tobacco." Ann Pharmacother, 38, p. 595-7
  26. Grant P (2004) "Warfarin and cranberry juice: an interaction?" J Heart Valve Dis, 13, p. 25-6
  27. Rindone JP, Murphy TW (2006) "Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding." Am J Ther, 13, p. 283-4
  28. Brandin H, Myrberg O, Rundlof T, Arvidsson AK, Brenning G (2007) "Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy." Eur J Clin Pharmacol, 63, p. 565-70
  29. Agencia EspaƱola de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de informaciĆ³n online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  30. Griffiths AP, Beddall A, Pegler S (2008) "Fatal haemopericardium and gastrointestinal haemorrhage due to possible interaction of cranberry juice with warfarin." J R Soc Health, 128, p. 324-6
  31. Guo LQ, Yamazoe Y (2004) "Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines." Acta Pharmacol Sin, 25, p. 129-36
  32. Hamann GL, Campbell JD, George CM (2011) "Warfarin-cranberry juice interaction." Ann Pharmacother, 45, e17
  33. Jarvis S, Li C, Bogle RG (2010) "Possible interaction between pomegranate juice and warfarin." Emerg Med J, 27, p. 74-5
  34. Roberts D, Flanagan P (2011) "Case report: Cranberry juice and warfarin." Home Healthc Nurse, 29, p. 92-7
  35. Ge B, Zhang Z, Zuo Z (2014) "Updates on the clinical evidenced herb-warfarin interactions." Evid Based Complement Alternat Med, 2014, p. 957362
  36. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT (2009) "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm, 66, p. 1438-67
  37. Bodiford AB, Kessler FO, Fermo JD, Ragucci KR (2013) "Elevated international normalized ratio with the consumption of grapefruit and use of warfarin." SAGE Open Med Case Rep, p. 1-3
View all 37 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.