Warfarin and Azathioprine: Interaction Details

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 ².

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 ³.

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 ⁴.

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 ⁵.

e) In a case report, an 81-year-old man whose INR was stable required multiple re-titrations of his warfarin dosage while receiving 3 separate 12-week cycles of mercaptopurine for acute promyelocytic leukemia. At the start of chemotherapy, a 25% increase in the warfarin maintenance dosage was required. In between the chemotherapy cycles, the patient's warfarin dosage was difficult to stabilize, but he did require decreases in the warfarin dosage while not receiving mercaptopurine ⁶.

f) Anticoagulant effects of warfarin are reduced when concurrently used with mercaptopurine. A 62-year-old man previously stabilized on 4 to 10 mg warfarin daily for venous thrombosis for a period of 3 years, was treated with mercaptopurine. The Thrombotest suddenly rose above the therapeutic range with the addition of mercaptopurine. This effect was abolished by increasing the dose of warfarin. However, when the dose of mercaptopurine was increased, the Thrombotest again began to rise. Mercaptopurine was discontinued and the Thrombotest fell sharply. The patient was continued to be treated satisfactorily with original warfarin doses and no further mercaptopurine administration. It is possible that mercaptopurine may inhibit the gastrointestinal absorption of warfarin. However, it is more likely that mercaptopurine stimulates microsomal enzymes to increase the rate of metabolism of warfarin. More data is required to evaluate the significance of this interaction ⁷.

g) There have been case reports published that indicate a reduction in the anticoagulant activity of warfarin when mercaptopurine is used concurrently ⁸.