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Drug Interactions between dabigatran and warfarin

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

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Interactions between your drugs

Major

warfarin dabigatran

Applies to: warfarin and dabigatran

GENERALLY AVOID: Drugs that can affect hemostasis such as glycoprotein IIb/IIIa inhibitors, thienopyridine antiplatelet agents, unfractionated and low molecular weight heparins, heparin derivatives, hirudin derivatives and analogs, thrombolytics, dextran, vitamin K antagonists, factor Xa inhibitors and other anticoagulants may potentiate the risk of bleeding complications associated with the use of dabigatran.

MANAGEMENT: In general, any agent that can enhance the risk of hemorrhage including other anticoagulants should be discontinued prior to initiation of dabigatran therapy. If coadministration is necessary, it should be undertaken with caution and only after thorough assessment of risks and benefits. A 24-hour interval is recommended before switching from dabigatran to parenteral anticoagulation. When switching from parenteral anticoagulation to dabigatran, the first dose of dabigatran should not be given before the next scheduled time of the parenteral anticoagulant dose. Unfractionated heparin may be used concomitantly at doses necessary to maintain intravenous or arterial catheter patency. Close clinical and laboratory observation for bleeding complications is recommended.

GENERALLY AVOID: In patients receiving neuraxial anesthesia or spinal puncture, the risk of developing an epidural or spinal hematoma during dabigatran therapy may be increased by the concomitant use of other drugs that affect coagulation. The development of epidural and spinal hematoma can lead to long-term or permanent paralysis.

MANAGEMENT: In patients undergoing neuraxial intervention, administration of dabigatran alone or with other drugs that can affect hemostasis should be approached with extreme caution and only after thorough assessment of risks and benefits. Besides bleeding complications, these patients should also be monitored frequently for signs and symptoms of neurologic impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), and bowel or bladder dysfunction. Urgent diagnosis and treatment (e.g., spinal cord decompression) are required if signs or symptoms of spinal hematoma develop. To reduce the potential risk of bleeding, placement or removal of an epidural catheter or lumbar puncture should ideally be performed when the anticoagulant effect of dabigatran is low. An optimal interval has not been established, but should take into consideration the pharmacokinetic profile of dabigatran.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. "Product Information. Pradax (dabigatran)." Boehringer Ingelheim (Canada) Ltd (2008):
  3. "Product Information. Pradaxa (dabigatran)." Boehringer-Ingelheim (2010):

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Drug and food interactions

Moderate

warfarin food

Applies to: warfarin

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 "Predictable reduction in anticoagulant activity of warfarin by small amounts of vitamin K." Acta Med Scand 198 (1975): 269-70
  2. Westfall LK "An unrecognized cause of warfarin resistance." Drug Intell Clin Pharm 15 (1981): 131
  3. Lee M, Schwartz RN, Sharifi R "Warfarin resistance and vitamin K." Ann Intern Med 94 (1981): 140-1
  4. Zallman JA, Lee DP, Jeffrey PL "Liquid nutrition as a cause of warfarin resistance." Am J Hosp Pharm 38 (1981): 1174
  5. Griffith LD, Olvey SE, Triplett WC "Increasing prothrombin times in a warfarin-treated patient upon withdrawal of ensure plus." Crit Care Med 10 (1982): 799-800
  6. Kempin SJ "Warfarin resistance caused by broccoli." N Engl J Med 308 (1983): 1229-30
  7. Watson AJ, Pegg M, Green JR "Enteral feeds may antagonise warfarin." Br Med J 288 (1984): 557
  8. Walker FB "Myocardial infarction after diet-induced warfarin resistance." Arch Intern Med 144 (1984): 2089-90
  9. Howard PA, Hannaman KN "Warfarin resistance linked to enteral nutrition products." J Am Diet Assoc 85 (1985): 713-5
  10. Karlson B, Leijd B, Hellstrom K "On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment." Acta Med Scand 220 (1986): 347-50
  11. Pedersen FM, Hamberg O, Hess K, Ovesen L "The effect of dietary vitamin K on warfarin-induced anticoagulation." J Intern Med 229 (1991): 517-20
  12. Parr MD, Record KE, Griffith GL, et al. "Effect of enteral nutrition on warfarin therapy." Clin Pharm 1 (1982): 274-6
  13. Wells PS, Holbrook AM, Crowther NR, Hirsh J "Interactions of warfarin with drugs and food." Ann Intern Med 121 (1994): 676-83
  14. O'Reilly RA, Rytand DA ""Resistance" to warfarin due to unrecognized vitamin K supplementation." N Engl J Med 303 (1980): 160-1
  15. Kazmier FJ, Spittell JA Jr "Coumarin drug interactions." Mayo Clin Proc 45 (1970): 249-55
  16. Chow WH, Chow TC, Tse TM, Tai YT, Lee WT "Anticoagulation instability with life-threatening complication after dietary modification." Postgrad Med J 66 (1990): 855-7
  17. MacLeod SM, Sellers EM "Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants." Drugs 11 (1976): 461-70
  18. Sullivan DM, Ford MA, Boyden TW "Grapefruit juice and the response to warfarin." Am J Health Syst Pharm 55 (1998): 1581-3
  19. Harrell CC, Kline SS "Vitamin K-supplemented snacks containing olestra: Implication for patients taking warfarin." Jama J Am Med Assn 282 (1999): 1133-4
  20. Beckey NP, Korman LB, Parra D "Effect of the moderate consumption of olestra in patients receiving long-term warfarin therapy." Pharmacotherapy 19 (1999): 1075-9
  21. Monterrey-Rodriguez J "Interaction between warfarin and mango fruit." Ann Pharmacother 36 (2002): 940-1
  22. Cambria-Kiely JA "Effect of soy milk on warfarin efficacy." Ann Pharmacother 36 (2002): 1893-6
  23. MHRA. Mediciines and Healthcare products Regulatory Agency. Committee on Safety of Medicines "Possible interaction between warfarin and cranberry juice. http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/currentproblems/currentproblems.htm" (2003):
  24. Suvarna R, Pirmohamed M, Henderson L "Possible interaction between warfarin and cranberry juice." BMJ 327 (2003): 1454
  25. Kuykendall JR, Houle MD, Rhodes RS "Possible warfarin failure due to interaction with smokeless tobacco." Ann Pharmacother 38 (2004): 595-7
  26. Grant P "Warfarin and cranberry juice: an interaction?" J Heart Valve Dis 13 (2004): 25-6
  27. Rindone JP, Murphy TW "Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding." Am J Ther 13 (2006): 283-4
  28. Brandin H, Myrberg O, Rundlof T, Arvidsson AK, Brenning G "Adverse effects by artificial grapefruit seed extract products in patients on warfarin therapy." Eur J Clin Pharmacol 63 (2007): 565-70
  29. Agencia EspaƱola de Medicamentos y Productos Sanitarios Healthcare "Centro de informaciĆ³n online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html" (2008):
  30. Griffiths AP, Beddall A, Pegler S "Fatal haemopericardium and gastrointestinal haemorrhage due to possible interaction of cranberry juice with warfarin." J R Soc Health 128 (2008): 324-6
  31. Guo LQ, Yamazoe Y "Inhibition of cytochrome P450 by furanocoumarins in grapefruit juice and herbal medicines." Acta Pharmacol Sin 25 (2004): 129-36
  32. Hamann GL, Campbell JD, George CM "Warfarin-cranberry juice interaction." Ann Pharmacother 45 (2011): e17
  33. Jarvis S, Li C, Bogle RG "Possible interaction between pomegranate juice and warfarin." Emerg Med J 27 (2010): 74-5
  34. Roberts D, Flanagan P "Case report: Cranberry juice and warfarin." Home Healthc Nurse 29 (2011): 92-7
  35. Ge B, Zhang Z, Zuo Z "Updates on the clinical evidenced herb-warfarin interactions." Evid Based Complement Alternat Med 2014 (2014): 957362
  36. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm 66 (2009): 1438-67
  37. Bodiford AB, Kessler FO, Fermo JD, Ragucci KR "Elevated international normalized ratio with the consumption of grapefruit and use of warfarin." SAGE Open Med Case Rep 0 (2013): 1-3
View all 37 references

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Moderate

warfarin food

Applies to: warfarin

MONITOR: Enhanced hypoprothrombinemic response to warfarin has been reported in patients with acute alcohol intoxication and/or liver disease. The proposed mechanisms are inhibition of warfarin metabolism and decreased synthesis of clotting factors. Binge drinking may exacerbate liver impairment and its metabolic ability in patients with liver dysfunction. The risk of bleeding may be increased. Conversely, reductions in INR/PT have also been reported in chronic alcoholics with liver disease. The proposed mechanism is that continual drinking of large amounts of alcohol induces the hepatic metabolism of anticoagulants. Effects are highly variable and significant INR/PT fluctuations are possible.

MANAGEMENT: Patients taking oral anticoagulants should be counseled to avoid large amounts of ethanol, but moderate consumption (one to two drinks per day) are not likely to affect the response to the anticoagulant in patients with normal liver function. Frequent INR/PT monitoring is recommended, especially if alcohol intake changes considerably. It may be advisable to avoid oral anticoagulant therapy in patients with uncontrollable drinking problems. Patients should be advised to promptly report any signs of bleeding to their doctor, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

References

  1. Breckenridge A "Clinical implications of enzyme induction." Basic Life Sci 6 (1975): 273-301
  2. Karlson B, Leijd B, Hellstrom K "On the influence of vitamin K-rich vegetables and wine on the effectiveness of warfarin treatment." Acta Med Scand 220 (1986): 347-50
  3. Udall JA "Drug interference with warfarin therapy." Clin Med 77 (1970): 20-5
  4. "Product Information. Coumadin (warfarin)." DuPont Pharmaceuticals PROD (2001):
  5. Havrda DE, Mai T, Chonlahan J "Enhanced antithrombotic effect of warfarin associated with low-dose alcohol consumption." Pharmacotherapy 25 (2005): 303-7
  6. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  7. Canadian Pharmacists Association "e-CPS. http://www.pharmacists.ca/function/Subscriptions/ecps.cfm?link=eCPS_quikLink" (2006):
  8. Pharmaceutical Society of Australia "APPGuide online. Australian prescription products guide online. http://www.appco.com.au/appguide/default.asp" (2006):
View all 8 references

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Moderate

warfarin food

Applies to: warfarin

MONITOR: Multivitamin preparations containing vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants in some patients. Vitamin K1 in its active, reduced form serves as a cofactor in the generation of functional clotting factors, during which it becomes oxidized. It is reactivated in a process that is inhibited by oral anticoagulants, thus intake of additional vitamin K through supplements or diet can reverse the action of oral anticoagulants. Although the amount of vitamin K in over-the-counter multivitamin preparations is generally well below the dose thought to affect anticoagulation, there have been isolated case reports of patients stabilized on warfarin whose INR decreased following initiation of a multivitamin supplement and returned to therapeutic levels upon cessation of the multivitamin. Increases in warfarin dosage were required in some cases when the multivitamin was continued. One patient whose warfarin dosage was increased developed a subcapsular hematoma in her right kidney two weeks after she discontinued the multivitamin without informing her physician. Her INR was 13.2 and she was treated with vitamin K and fresh frozen plasma. It is possible that patients with low vitamin K status may be particularly susceptible to the interaction. Investigators have shown that vitamin K deficiency can cause an oversensitivity to even small increases in vitamin K intake. In one study where warfarin-stabilized patients were given a multivitamin tablet containing 25 mcg of vitamin K1 daily for 4 weeks, subtherapeutic INRs occurred in 9 of 9 patients with low vitamin K1 levels (<1.5 mcg/L) and only 1 of 7 patients with normal vitamin K1 levels (>4.5 mcg/L). INR decreased by a median of 0.51 and warfarin dosage had to be increased by 5.3% in patients with low vitamin K1 levels, whereas INR and warfarin dosage did not change significantly in patients with normal vitamin K1 levels. The prevalence of vitamin K deficiency may be small, but significant in the anticoagulated population. In a survey of 179 consecutive ambulatory patients on stable warfarin therapy attending an anticoagulation clinic, 22 (12.3%) were found to have vitamin K1 deficiency (<0.1 ng/mL).

MANAGEMENT: The potential for multivitamin supplements containing even low levels of vitamin K to affect anticoagulation should be recognized. In particular, elderly and/or malnourished patients may require more frequent monitoring of INR following the initiation or discontinuation of a multivitamin supplement, and the anticoagulant dosage adjusted as necessary.

References

  1. Kurnik D, Loebstein R, Rabinovitz H, Austerweil N, Halkin H, Almog S "Over-the-counter vitamin K1-containing multivitamin supplements disrupt warfarin anticoagulation in vitamin K1-depleted patients. A prospective, controlled trial." Thromb Haemost 92 (2004): 1018-24
  2. Kumik D, Lubetsky A, Loebstein R, Almog S, Halkin H "Multivitamin supplements may affect warfarin anticoagulation in susceptible patients." Ann Pharmacother 37 (2003): 1603-6
  3. Ducharlet KN, Katz B, Leung S "Multivitamin supplement interaction with warfarin therapy." Australas J Ageing 30 (2011): 41-2

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Therapeutic duplication warnings

Therapeutic duplication is the use of more than one medicine from the same drug category or therapeutic class to treat the same condition. This can be intentional in cases where drugs with similar actions are used together for demonstrated therapeutic benefit. It can also be unintentional in cases where a patient has been treated by more than one doctor, or had prescriptions filled at more than one pharmacy, and can have potentially adverse consequences.

Duplication

Anticoagulants

Therapeutic duplication

The recommended maximum number of medicines in the 'anticoagulants' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'anticoagulants' category:

  • dabigatran
  • warfarin

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.


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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.