Warfarin with Leflunomide Interaction Details
Brand Names Associated with Warfarin
- Coumadin®
- Jantoven®
- Warfarin
Brand Names Associated with Leflunomide
- Arava®
- Leflunomide
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 07, 2023
Interaction Effect
Increased risk of bleeding
Interaction Summary
Concomitant administration of leflunomide and warfarin has resulted in elevation in international normalized ratio (INR) in 2 patients. This interaction can be attributed to inhibition of the CYP2C9-mediated metabolism of warfarin by leflunomide may result in decreased clearance of warfarin, thereby enhancing warfarin's anticoagulant effect and increasing the risk of bleeding. Caution is advised if these agents are coadministered. Consider monitoring INR more frequently and adjust the warfarin dose accordingly to achieve desired level of anticoagulation .
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Concomitant administration of leflunomide and warfarin has resulted in elevation in international normalized ratio (INR). Monitor patient for signs and symptoms of increased bleeding. Consider monitoring INR more frequently and adjust the warfarin dose as necessary to maintain the desired level of anticoagulation.
Mechanism Of Interaction
Inhibition of CYP2C9-mediated metabolism of warfarin by leflunomide
Literature Reports
A) Addition of leflunomide therapy in a 61-year-old Caucasian woman receiving warfarin resulted in an elevated international normalized ratio (INR). The woman, who had a history of recurrent thromboembolism and atrial fibrillation, was receiving warfarin (36 mg/week) for 4 months and had a stable INR (goal INR 2-3) prior to initiation of leflunomide. Concomitant medications also included ramipril, hydrochlorothiazide, propafenone, prednisone, sulindac, buspirone, folic acid, calcium and potassium supplementation. Leflunomide for rheumatoid arthritis was initiated at 100 mg/day for 3 days, followed by 20 mg/day thereafter. Subsequently, during a routine follow-up visit, the patient's INR had increased to 7.3 and this result was confirmed by using a separate laboratory testing method. Liver and renal function tests were normal and the patient had not experienced any recent illness or bleeding problems. Additionally, the patient reported to being compliant with warfarin and all other drug/disease-related contributors to INR elevation were ruled out. Subsequently, warfarin was withheld for 3 doses, followed by a decrease in warfarin dose from 36 to 32 mg/week. Repeat testing a week later resulted in an INR of 2 and over the next 10 weeks, with continual warfarin dosage reductions, the patient's INR (goal INR 2-3) stabilized at a warfarin dose of 28 mg/week. Inhibition of the CYP2C9-mediated metabolism of warfarin by leflunomide was proposed as the mechanism for this interaction .
B) A case report described an increase in a patient's international normalized ratio (INR) following concomitant use of leflunomide and warfarin. A 49-year-old man with resistant rheumatoid arthritis began taking leflunomide 100 mg daily for 3 days. His INR had been stable for a year while taking warfarin. Two days before treatment with leflunomide was initiated his INR was 3.4. He developed gross hematuria after taking two doses of leflunomide, requiring hospitalization. His INR rose to 11 and warfarin was discontinued. The hematuria resolved and his hemoglobin concentration was satisfactory. On the third day of hospital admission he was given vitamin K 1 mg intravenously. His ratio decreased to 1.9 which coincided with the change in leflunomide maintenance dose of 20 mg daily. Warfarin was prescribed at 1 mg daily, sufficient to maintain his INR within the recommended range. Leflunomide caused the increase in the patient's ratio and the subsequent lower warfarin doses required to maintain the ratio within the normal range .
Warfarin Overview
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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.
Leflunomide Overview
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Leflunomide is used alone or in combination with other medications to treat rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function). Leflunomide is in a class of medications called disease-modifying antirheumatic drugs (DMARDs). It works by decreasing inflammation and slowing the progress of the condition, which can help improve the physical activity of people with rheumatoid arthritis.
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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:
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.