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| |  Duloxetine Does Not Modify Anticoagulant Effects of Warfarin: Presented at ACCP By Crina Frincu-Mallos, PhD PHILADELPHIA -- September 17, 2008 -- Duloxetine was well tolerated when coadministered with warfarin in healthy subjects and dose adjustment of warfarin should not be required when duloxetine treatment is initiated in a patient on stable warfarin therapy, researchers reported here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting. Daily oral doses of 60 and 120 mg of duloxetine were considered to be well tolerated when coadministered with daily doses of 2 to 9 mg warfarin in healthy volunteers. Jill C. Chappell, PharmD, Eli Lilly and Company, Indianapolis, Indiana, presented the data here on September 14. Dr. Chappell and colleagues from i3 Statprobe, Burlington, Ontario, and Covance Clinical Research, Leeds, United Kingdom, sought to evaluate the anticoagulant effects of multiple doses of warfarin at steady state when taken concomitantly with duloxetine 60 or 120 mg using changes in the international normalised ratio (INR). Secondary objectives of the study were to evaluate the effect of duloxetine on the pharmacokinetics (PK) of warfarin, as well as to evaluate the safety and tolerability of the combination. The study also assessed platelet function by determining bleeding times using a modified Ivy method with a Surgicutt device, explained Dr. Chappell. Previous research suggested that duloxetine, a serotonin and norepinephrine reuptake inhibitor, could potentially have a pharmacodynamic interaction with warfarin.(1) But other researchers showed that a PK interaction between duloxetine and warfarin was unlikely.(2) Dr. Chappell and colleagues evaluated an initial cohort of 59 men and 1 woman in this open-label, randomised, 3-period, fixed-sequence study. Thirty subjects achieved a stable INR during period 1 and entered period 2, where they were randomised to receive a daily dose of warfarin in combination with duloxetine at a low dose (60 mg/day) or a high dose (120 mg/day). A total of 28 men and 1 woman between 19 and 62 years old completed the study. No statistically significant change in INR from baseline to day 14 could be detected, regardless of whether the low dose (P = .2) or high dose (P = .5) of duloxetine was coadministered with warfarin, said Dr. Chappell. Furthermore, she added, there was no statistically significant change in INR when looking at the combination versus warfarin alone (least squares [LS] mean [90% confidence interval (CI)] INR changes from baseline ranged from -0.12 to +0.14). In addition, the combination of warfarin plus high-dose duloxetine did not induce a statistically significant change in bleeding time, compared with warfarin alone (LS mean change: -0.30 minutes; 90% CI, -1.30 to 0.70). Interestingly, the prolongation in bleeding time was statistically significant when warfarin was coadministered with low-dose duloxetine, (LS mean change: 1.25 minutes; 90% CI, 0.25-2.24). However, the change did not have a clinical significance, according to the researchers. Looking at the effect of duloxetine on warfarin PK, the study confirms previous data showing that duloxetine has no effect on the PK of warfarin at steady state. In terms of safety, both doses of duloxetine were well tolerated. The most common adverse events were headache, dizziness, nausea, and fatigue. There were 2 cases of epistaxis; bleeding time on day 14 being <5 minutes and 7.5 minutes, respectively. Based on these data, the investigators concluded that no dose adjustment of warfarin and no additional monitoring of INR are necessary when warfarin is coadministered with duloxetine. However, patients should still be monitored closely when adding or discontinuing duloxetine, to ensure therapeutic anticoagulation, the researchers cautioned. Funding for this study was provided by Eli Lilly and Company. 1. Glueck CJ et al. JAMA. 2006;295:1517-1518.
[Presentation title: Evaluation of the Effect of Duloxetine on the Pharmacodynamics and Pharmacokinetics of Warfarin at Steady-State in Healthy Subjects. Abstract 105]
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