Drug interactions between Miradon and sulfamethoxazole

sulfamethoxazole ↔ anisindione

Applies to:sulfamethoxazole and Miradon (anisindione)

MONITOR CLOSELY: Coadministration with a sulfonamide may increase the plasma concentrations and hypoprothrombinemic effects of coumarin anticoagulants. The proposed mechanism is sulfonamide inhibition of coumarin metabolism via CYP450 2C9 and possibly also displacement of coumarin derivatives from plasma protein binding sites. The interaction has been reported in controlled studies in healthy volunteers and has been associated with significant bleeding and elevation of prothrombin time in several case reports. A retrospective cohort study of acutely ill warfarin patients at a U.S. Veteran's Affairs Medical Center also revealed a significantly increased risk and severity of overanticoagulation following initiation of sulfamethoxazole-trimethoprim (SMX-TMP) compared to a control agent, terazosin. Specifically, a mean INR increase of 1.76 was observed in the SMX-TMP group (n=16), compared to a mean decrease of 0.15 in the terazosin group (n=29). Elevations in INR beyond therapeutic levels were seen in 69% of SMX-TMP patients versus 5% of the terazosin patients, and INR elevations beyond 4 were seen in 44% of the SMX-TMP patients versus 0% of the terazosin patients. Within the SMX-TMP group, 38% showed a mean change in INR of 2 or more points, and 31% showed a rise of 5 or more points. Adverse bleeding events occurred in 13% of the SMX-TMP patients, while none occurred in the controls. These results are supported by a case-control study that found SMX-TMP to be one of only two medications to significantly increase the risk of overanticoagulation in previously stable outpatients treated with phenprocoumon or acenocoumarol. In that study, 300 outpatients at a Netherlands anticoagulant clinic who presented with an INR value greater than or equal to 6.0 (median value 6.8) were compared with 302 randomly selected matched controls with INR values within the target range (median value 3.2), and changes in the use of 87 potentially interacting drugs or drug classes in the four weeks prior to the index day were identified and analyzed. A course of SMX-TMP strongly increased the risk of overanticoagulation even after adjustment for potential confounding factors, particularly in patients treated with acenocoumarol. A follow-up study focusing on antibiotic use in outpatients treated with phenprocoumon or acenocoumarol at a different Netherlands anticoagulant clinic also identified SMX-TMP use as a risk factor for overanticoagulation, with the relative risk most strongly increased four days or more after start of the antibiotic.

MANAGEMENT: Patients receiving coumarin anticoagulants should be closely monitored during concomitant therapy with sulfonamides. The INR should be checked frequently and coumarin dosage adjusted accordingly, particularly following initiation or discontinuation of sulfonamide therapy in patients who are stabilized on their anticoagulant regimen. The same precaution may be applicable during therapy with other oral anticoagulants (e.g., indandiones), although clinical data are lacking. Patients should be advised to promptly report any signs of bleeding to their physician, 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.