Warfarin with Azathioprine Interaction Details

Brand Names Associated with Warfarin

Brand Names Associated with Azathioprine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 07, 2023

Interaction Effect

Decreased anticoagulant effectiveness

Interaction Summary

There have been several case reports published that indicate a reduction in the anticoagulant activity of warfarin when azathioprine are used concurrently.

Severity

Moderate

Onset

Delayed

Evidence

Probable

How To Manage Interaction

In patients receiving oral anticoagulant therapy with warfarin, the prothrombin time ratio or international normalized ratio (INR) should be closely monitored with the addition and withdrawal of treatment with azathioprine, and should be reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.

Mechanism Of Interaction

Impaired warfarin absorption; enhanced warfarin metabolism

Literature Reports

A) A 30-year-old woman was receiving daily prednisolone 5 mg, azathioprine 150 mg, and warfarin 20 mg . When azathioprine was reduced to 100 mg, a reduction in the warfarin dose to 15 mg was required; a reduction in warfarin was again required when azathioprine was reduced to 50 mg daily. At a later date, a higher dose of azathioprine was reinstated and the international normalized ratio (INR) decreased to 1.3, necessitating an increase in warfarin from 11 mg to 17 mg to attain an INR of approximately 2.4.

B) A 50-year-old female stabilized on warfarin 40 mg weekly for two years because of a recurrent pulmonary embolism had an international normalized ratio (INR) of approximately 3.0. Other medications included prednisone 40 mg daily for an unspecified autoimmune disease. Azathioprine therapy was initiated at 100 mg daily as a steroid-sparing treatment, but no change in the prednisone dose or general health of the patient was noted. One week after azathioprine was started, the INR had decreased to 1.1. The warfarin dose was gradually increased to 100 mg weekly over the course of two months with a corresponding INR of 1.95. Following the discontinuation of azathioprine, the INR increased to 8.3 while the warfarin dose was still maintained at 100 mg weekly. Warfarin was decreased down to 30 mg weekly with resulting stabilized INR values of 2.8 .

C) A case of warfarin resistance due to azathioprine was reported in a 32-year-old female with a history of deep vein thrombosis (DVT), steroid-dependent ulcerative colitis, and osteoporosis. The patient was stabilized on warfarin 35 mg/week until 6 weeks postpartum to treat an initial DVT. Azathioprine 75 mg/day was initiated ten days after completing warfarin therapy. The patient developed a recurrent DVT nine days later. Warfarin therapy was reinstated and an increase in warfarin dosage to 120 mg/week was necessary to achieve an INR of 2.0-3.0. She did not use any over-the-counter products. The author suggests that the decrease in effect of warfarin with concurrent use of azathioprine may be due to decreased bioavailability, enhanced warfarin metabolism, or increased prothrombin and Factor II activity .

D) A case of warfarin-resistance due to azathioprine was reported in a 29-year-old female with Cogan’s syndrome. Prior to initiating azathioprine, the patient presented with thrombosis of the left carotid artery. Anticoagulation (target INR 2 to 3) was achieved with warfarin at an average weekly dose of 39 mg/wk. After 6 months of stable warfarin therapy, her INR decreased to 1.9 with no reported explanation and her warfarin dose was increased to 40.25 mg/wk. Two months later, her cyclophosphamide was switched to azathioprine (150 mg daily dose) and without other changes in her normal regimen or diet the patient’s INR level dropped from 1.9 to 1 after 3 weeks. Her warfarin dose was then increased by 30%, however her INR remained at 1.1 four days later. Administration of azathioprine and warfarin was then separated by 1 hour, however the patient’s INR remained at 1.2 when measured 5 days later. Warfarin dosages were titrated up to 112 mg/wk over the next several weeks, and the patient achieved an INR of 2.5. Following liver enzyme elevations, azathioprine was decreased to 100 mg/day resulting in an increase in INR to 3.4 over 2 weeks. Warfarin dosages were then adjusted to 105 mg/wk, and the patient’s INR stabilized to a therapeutic level. Authors concluded that azathioprine was responsible for inducing warfarin resistance; a conclusion substantiated by the Naranjo probability scale and the Drug Interaction Probability scale. Study authors also conducted a literature review and found six case reports of patients who were on stable doses of warfarin that later required increases in warfarin maintenance doses in order for the patient’s to maintain a therapeutic INR following azathioprine initiation .

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.

Azathioprine Overview

• Azathioprine is used with other medications to prevent transplant rejection (attack of the transplanted organ by the immune system) in people who received kidney transplants. It is also used to treat severe rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) when other medications and treatments have not helped. Azathioprine is in a class of medications called immunosuppressants. It works by decreasing the activity of the body's immune system so it will not attack the transplanted organ or the joints.

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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.