Duloxetine and Betrixaban: Interaction Details

a) No clinically significant changes in INR or bleeding time were observed with coadministration of DULoxetine and warfarin (at steady state conditions) compared with warfarin alone in healthy subjects (n=30; age range, 19 to 62 years). All subjects received warfarin 10 on day 1 then individualized dosing (range, 2 to 9 mg) daily on days 2 to 9 for a goal INR range of 1.5 to 2.0 for 3 consecutive days. After warfarin steady state was achieved, all subjects received DULoxetine 60 mg once daily for 4 days, then either continued 60 mg daily (n=15; group 1) or increased to 120 mg daily (n=15; group 2) for 10 days. Warfarin was discontinued on day 14. During concomitant administration among group 1 and 2, the mean INR changes from baseline ranged from -0.05 to +0.07 (90% confidence interval, -0.12 to +0.14). Additionally, mean INR changes from baseline were not significantly affected by dosage increase or by duration of DULoxetine therapy. Notably, a statistically significant prolongation in bleeding time was observed at day 14 in group 1 compared with warfarin alone; however, the difference was considered small (less than 2 minutes); whereas, no prolongation in bleeding time was observed in group 2. Additionally, the AUC (steady state) of warfarin R- and S-enantiomers was not affected with either dosage of DULoxetine. One subject discontinued due to mild epistaxis ⁴.

b) A population-based, case-controlled study of new coumarin users (acenocoumarol and phenprocoumon) with concomitant selective serotonin reuptake inhibitors (SSRIs) resulted in an increased risk of hospitalization due to non-gastrointestinal bleeding. Using national pharmacy and hospitalization records, Netherlands researchers identified 1848 cases that were admitted for abnormal bleeding and compared them with 5818 control subjects also taking coumarins. Median duration of treatment in patients was 220 days (range, 1 to 4690 days). Patients on SSRIs showed greater risk for hospitalization for non-gastrointestinal bleeding (adjusted odds ratio (OR) 1.7, 95% confidence interval (CI), 1.1 to 2.5), however, the rate of gastrointestinal bleeding (adjusted OR 0.8, 95% CI, 0.4 to 1.5) was not significantly different ¹.

c) A case report describes a 44-year-old female patient maintained on warfarin (INR 2.2) who developed petechiae/purpura (INR 5) after 55 days of concomitant DULoxetine treatment. Warfarin was initiated one year prior following ischemic stroke. Her daily, stable medication regimen included atorvastatin 10 mg, warfarin 7.5 mg to 10 mg, lamoTRIgine 50 mg, topiramate 200 mg, clonazePAM 2 mg, and albuterol extended-release 4 mg twice a day. DULoxetine 30 mg/day was added to treat depression-related insomnia. On day 58, only the warfarin was discontinued, and by day 85 the patient's INR exceeded 19. At this time, plasma warfarin level was 5.3 mcg/mL (17 mcmol/L; therapeutic range 2 to 8 mcg/mL (6 to 30 mcmol/L). Intravenous vitamin K 10 mg was administered, briefly decreasing the INR. By day 94, the INR was again elevated at 6.4, vitamin K-dependent clotting factors II, VII, and X were critically low, and fibrinogen level was normal. DULoxetine was then discontinued and 4 days later the INR measured 1.2, factor II increased to 48% and factor X increased to 54%. INR was 0.9 by day 105, and warfarin was restarted on day 110. By day 140, INR was stable at 2.2, with the patient again maintained on 7.5 to 10 mg/day. According to the Naranjo algorithm, the probability score for this adverse event was 12, or highly probable. The authors suggest that DULoxetine may have an effect on the CYP1A2 metabolism of warfarin, may have displaced warfarin from its protein-binding sites, or may have unique metabolic properties not yet determined ⁵.