Warfarin with Fluconazole Interaction Details

Brand Names Associated with Warfarin

Brand Names Associated with Fluconazole

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 27, 2023

Interaction Effect

Increased INR and increased risk of bleeding events

Interaction Summary

The concomitant use of warfarin (a CYP2C9 and CYP3A4 substrate) with fluconazole (a CYP2C9 and CYP3A4 inhibitor) should be approached with caution as coadministration may result in increased warfarin plasma concentrations and increased INR and prothrombin time, which may lead to an increased risk for bleeding. Postmarketing cases of bruising, epistaxis, gastrointestinal bleeding, hematuria, and melena have been reported in patients who received fluconazole with warfarin . When possible, substitute fluconazole with an antifungal with less bleeding potential . If fluconazole therapy is required in a patient taking warfarin, more frequent monitoring of INR is recommended, especially when fluconazole is initiated and discontinued . Dose adjustments of warfarin may be necessary .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of fluconazole and warfarin should be approached with caution as this may result in increased INR and thereby increase the risk for bleeding. When possible, substitute fluconazole with an antifungal with a low-risk profile for bleeding. If concomitant use of fluconazole and warfarin is required, more frequent monitoring of the patient's INR and prothrombin time  is recommended, especially during initiation and discontinuation of fluconazole . Dose adjustments of warfarin may also be warranted .

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism of warfarin; inhibition of CYP2C9-mediated metabolism of warfarin

Literature Reports

A) A significant increase in mean INR of 0.83 (95% CI, 0.61 to 1.04) was observed in patients on warfarin who initiated treatment with oral fluconazole for oral candidiasis (n=413). The proportion of patients with an INR greater than 5 following initiation of systemic fluconazole significantly increased from 4.3% to 15.3%. The maximum INR increase was seen 2 weeks after fluconazole initiation and normalized after 4 weeks. Fluconazole is a strong inhibitor of CYP2C9, which catalyzes the metabolism of warfarin and leads to higher INR values .

B) Initiation of antibiotics in patients on continuous warfarin therapy resulted in a significantly increased risk of serious bleeding requiring hospitalization according to a nested case-control study of United States Medicare part D beneficiaries aged 65 years and older (n=38,762). Patients on warfarin who received any antibiotic were twice as likely to be hospitalized for bleeding compared with matched controls on warfarin who were not exposed to antibiotics (adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5). Additionally, continuous-warfarin users were twice as likely to have a bleeding event that required hospitalization within 60 days of antibiotic exposure compared with non-exposure. Antibiotic exposure greater than 60 days from the index bleed was not significantly associated with increased risk of bleeding. Specific antibiotics with the highest bleeding risk were azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), followed by cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05), cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21), and quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) .

C) The coadministration of fluconazole 200 mg/day for 14 days and a single 15-mg dose of warfarin in 13 healthy men resulted in a significant increase in prothrombin time (PT) response (area under the PT-time curve) compared with warfarin alone. In 12 subjects, there was a mean (+/- standard deviation) increase in the PT response of 7% +/- 4% (range: -2% to 13%). A 2-fold increase in PT response was reported in one other subject .

D) There was an association between prior fluconazole use and hospitalization for gastrointestinal bleed in a nested case-control study using United States Medicaid data (n=308,100). The adjusted odds ratios (OR) for the time period (time prescription was filled to the date of hospitalization) were 1.55 (95% CI 1.1 to 2.2) at 0 to 5 days; 1.89 (95% CI 1.35 to 2.64) at 6 to 10 days, 2.32 (95% 1.68 to 3.2) at 11 to 15 days, and 1.35 (95% CI 0.88 to 2.08) at 16 to 20 days. The OR were adjusted for age, gender, race, state, prior gastrointestinal bleed, chronic renal disease, liver disease, and use of proton pump inhibitors, metroNIDAZOLE, acetaminophen, and predniSONE. A case-crossover analysis of the data confirmed the association .

E) In a study of 6 healthy male volunteers, fluconazole was found to reduce the metabolic clearance of warfarin. The primary cytochrome P450 isozyme involved in the termination of the anticoagulant effect of S-warfarin, 2C9, was inhibited by 70% with the addition of fluconazole. Other metabolic hydroxylation pathways catalyzed by isozyme 3A4 were also found to be significantly inhibited by fluconazole. Fluconazole increased the mean plasma half-life of S-warfarin by 275% and R-warfarin by 210%. Fluconazole also increased the average AUC for the S- and R- enantiomers by 284% and 207%, respectively. The anticoagulant effect of warfarin, noted by an increase in prothrombin times, was markedly increased in all 6 subjects after addition of fluconazole .

F) Additional evidence of a reaction between warfarin and fluconazole was reported in a 73-year-old female nursing home resident. The patient had received warfarin 2.5 mg daily for 10 years after undergoing aortic valve replacement. Five days after starting a regimen of fluconazole 200 mg daily for extensive candida dermatitis, the patient had an INR of 12.9, and the warfarin therapy was discontinued. Seven days after initiation of fluconazole therapy, the patient developed a lower gastrointestinal bleed and her INR was 10.6 upon admission to the hospital. After discontinuation of fluconazole and treatment with fresh frozen plasma and packed red blood cells, the patient's INR had decreased to 2.2 by the third hospital day. The patient returned to the nursing home and was eventually restarted on warfarin 2.5 mg daily without further bleeding complications or INR elevations beyond therapeutic values .

G) An interaction between fluconazole and warfarin was reported in a 39-year-old man who had undergone renal transplantation 3 years earlier. The patient developed an occluded lower left extremity artery that was treated with urokinase and subsequent warfarin therapy. The patient was given warfarin doses ranging from 5 mg to 7.5 mg per day to maintain an INR between 2.0 and 3.0. Eight days after warfarin therapy was started, the patient developed a fungal urinary tract infection and was started on fluconazole 100 mg on the first day and 50 mg per day thereafter. Two days after the initiation of fluconazole therapy, the patient's INR increased from 2.8 to 3.8. Despite decreasing the warfarin dose to 2.5 mg on day 3 of fluconazole therapy, the INR increased to 4.7. After discontinuation of warfarin, the INR increased to 5.2 on the fourth day of therapy. Fluconazole therapy was discontinued after 7 days, and the patient was discharged from the hospital with warfarin 2.5 mg daily. The INR values subsequently decreased to 1.5 .

H) The effect of fluconazole on the CYP2C9 isozyme has been studied to develop an approach to the safe management of the warfarin-fluconazole drug interaction. A stepped reduction of warfarin over 5 days to a final target daily dose that is determined by the fluconazole dose level has been proposed. Simulation studies indicated that a warfarin stepped-dose reduction schedule was superior to a one-time dose reduction .

I) Two case reports describe patients who experienced an increase in their prothrombin time (PT) and INR within 2 days of adding fluconazole to a previously stable warfarin regimen. Patient 1, a 78-year-old woman, was stabilized on warfarin 2 mg daily with a PT and INR of 15.4 seconds and 1.67, respectively. Fluconazole 400 mg daily was initiated while she was hospitalized for acute cellulitis, and her PT and INR increased to 23.7 seconds and 3.67, respectively, 1 day later. Fluconazole was decreased to 400 mg every other day 2 days later, and on the sixth day of concurrent fluconazole and warfarin therapy, her PT and INR were 42 seconds and 10.4, respectively. Warfarin and fluconazole were both discontinued, and vitamin K was administered. The second patient, a 67-year-old woman, had been taking warfarin 5 mg daily with a corresponding PT and INR of 20.4 seconds and 2.79, respectively. Within 48 hours of initiating therapy with intravenous fluconazole 400 mg daily while hospitalized for an infected central venous catheter, the PT and INR had increased to 43.5 seconds and 11.1, respectively. Both medications were discontinued, and fresh frozen plasma was given to correct the coagulopathy .

Warfarin Overview

• Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

Fluconazole Overview

• Fluconazole is used to treat fungal infections, including yeast infections of the vagina, mouth, throat, esophagus (tube leading from the mouth to the stomach), abdomen (area between the chest and waist), lungs, blood, and other organs. Fluconazole is also used to treat meningitis (infection of the membranes covering the brain and spine) caused by fungus. Fluconazole is also used to prevent yeast infections in patients who are likely to become infected because they are being treated with chemotherapy or radiation therapy before a bone marrow transplant (replacement of unhealthy spongy tissue inside the bones with healthy tissue). Fluconazole is in a class of antifungals called triazoles. It works by slowing the growth of fungi that cause infection.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.