Drug interactions between Cymbalta and warfarin
Interactions between your drugs
warfarin ↔ duloxetine
Applies to:warfarin and Cymbalta (duloxetine)
MONITOR: Limited data suggest that duloxetine may potentiate the hypoprothrombinemic effects of warfarin. The mechanism of interaction is unknown. In one case report, a 44-year-old woman who had been treated uneventfully with warfarin (7.5 to 10 mg/day) for one year demonstrated a significantly increased INR after initiation of duloxetine (30 mg/day) for depression. Her other medications included atorvastatin (10 mg/day), lamotrigine (50 mg/day), topiramate (200 mg/day), clonazepam (2 mg/day), and albuterol (extended-release tablets 4 mg twice a day), all of which she had been taking without incident. Fifty-five days after starting duloxetine, the patient developed petechiae and purpura in association with an INR of 5.0. Warfarin, but not duloxetine, was stopped on day 58. Her INR continued to increase and was greater than 19 on day 85, with a plasma warfarin level of 5.3 mcg/mL. She was given intravenous vitamin K, whereupon her INR decreased briefly but increased again to 6.4 on day 94. At that point, her levels of vitamin K-dependent clotting factors were critically low. Duloxetine was stopped, and INR decreased to 1.2 by day 98. Warfarin was restarted on day 110. By day 140, her INR was stable at 2.2 while maintained on her original dosage of warfarin. The time course described in the case report supports an interaction between duloxetine and warfarin. Other potential causes such as thyroid disease, hepatic or renal impairment, platelet dysfunction, alternative self-medication, and warfarin self-intoxication were excluded.
MANAGEMENT: Until more data are available, caution may be advisable if duloxetine is used in combination with warfarin. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of duloxetine in patients who are stabilized on their warfarin regimen. The same precaution may be applicable during therapy with other oral anticoagulants, although clinical data are lacking. 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, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.
- Glueck CJ, Khalil Q, Winiarska M, Wang P "Interaction of duloxetine and warfarin causing severe elevation of international normalized ratio." JAMA 295 (2006): 1517-8
Drug and food interactions
Applies to: Cymbalta (duloxetine)
GENERALLY AVOID: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.
MANAGEMENT: Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol. Duloxetine should generally not be prescribed to patients with substantial alcohol use.
- "Product Information. Cymbalta (duloxetine)." Lilly, Eli and Company, Indianapolis, IN.
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.
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.
- Lee M, Schwartz RN, Sharifi R "Warfarin resistance and vitamin K." Ann Intern Med 94 (1981): 140-1
- Suvarna R, Pirmohamed M, Henderson L "Possible interaction between warfarin and cranberry juice." BMJ 327 (2003): 1454
- Kempin SJ "Warfarin resistance caused by broccoli." N Engl J Med 308 (1983): 1229-30
- 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
- Harrell CC, Kline SS "Vitamin K-supplemented snacks containing olestra: Implication for patients taking warfarin." Jama J Am Med Assn 282 (1999): 1133-4
- Grant P "Warfarin and cranberry juice: an interaction?" J Heart Valve Dis 13 (2004): 25-6
- Westfall LK "An unrecognized cause of warfarin resistance." Drug Intell Clin Pharm 15 (1981): 131
- Kuykendall JR, Houle MD, Rhodes RS "Possible warfarin failure due to interaction with smokeless tobacco." Ann Pharmacother 38 (2004): 595-7
- 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
- Walker FB "Myocardial infarction after diet-induced warfarin resistance." Arch Intern Med 144 (1984): 2089-90
- 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
- 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
- Zallman JA, Lee DP, Jeffrey PL "Liquid nutrition as a cause of warfarin resistance." Am J Hosp Pharm 38 (1981): 1174
- Wells PS, Holbrook AM, Crowther NR, Hirsh J "Interactions of warfarin with drugs and food." Ann Intern Med 121 (1994): 676-83
- MHRA. Mediciines and Healthcare products Regulatory Agency. Committee on Safety of Medicines "Possible interaction between warfarin and cranberry juice. Available from: URL: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/currentproblems/currentproblems.htm." ([2003 Sept]):
- Ministerio de Sanidad y Consumo. Gobierno de España "AEMPS. Agencia Española de Medicamentos y Productos Sanitarios. Available from: URL: https://sinaem4.agemed.es/consaem/fichasTecnicas.do?metodo=detalleForm."
- 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
- Watson AJ, Pegg M, Green JR "Enteral feeds may antagonise warfarin." Br Med J 288 (1984): 557
- Kazmier FJ, Spittell JA Jr "Coumarin drug interactions." Mayo Clin Proc 45 (1970): 249-55
- O'Reilly RA, Rytand DA ""Resistance" to warfarin due to unrecognized vitamin K supplementation." N Engl J Med 303 (1980): 160-1
- Cambria-Kiely JA "Effect of soy milk on warfarin efficacy." Ann Pharmacother 36 (2002): 1893-6
- Monterrey-Rodriguez J "Interaction between warfarin and mango fruit." Ann Pharmacother 36 (2002): 940-1
- 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
- Hamann GL, Campbell JD, George CM "Warfarin-cranberry juice interaction." Ann Pharmacother 45 (2011): e17
- Andersen P, Godal HC "Predictable reduction in anticoagulant activity of warfarin by small amounts of vitamin K." Acta Med Scand 198 (1975): 269-70
- MacLeod SM, Sellers EM "Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants." Drugs 11 (1976): 461-70
- 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
- Jarvis S, Li C, Bogle RG "Possible interaction between pomegranate juice and warfarin." Emerg Med J 27 (2010): 74-5
- Roberts D, Flanagan P "Case report: Cranberry juice and warfarin." Home Healthc Nurse 29 (2011): 92-7
- Parr MD, Record KE, Griffith GL, et al "Effect of enteral nutrition on warfarin therapy." Clin Pharm 1 (1982): 274-6
- Howard PA, Hannaman KN "Warfarin resistance linked to enteral nutrition products." J Am Diet Assoc 85 (1985): 713-5
- Rindone JP, Murphy TW "Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding." Am J Ther 13 (2006): 283-4
Therapeutic duplication warnings
No therapeutic duplications were found for your selected drugs.
Drug Interaction Classification
|Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.|
|Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.|
|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.|
|No information available.|
Do not stop taking any medications without consulting your healthcare provider.
Disclaimer: Every effort has been made to ensure that the information provided by Multum is accurate, up-to-date and complete, but no guarantee is made to that effect. In addition, the drug information contained herein may be time sensitive and should not be utilized as a reference resource beyond the date hereof. This material does not endorse drugs, diagnose patients, or recommend therapy. Multum's information is a reference resource designed as supplement to, and not a substitute for, the expertise, skill, knowledge, and judgement of healthcare practitioners in patient care. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective, or appropriate for any given patient. Multum Information Services, Inc. does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. Copyright 2000-2018 Multum Information Services, Inc. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse, or pharmacist.