Brand Name versus Generic Warfarin

A Systematic Review of the Literature

Francesco Dentali, M.D.; Marco P. Donadini, M.D.; Nathan Clark, Pharm.D.; Mark A. Crowther, M.D.; David Garcia, M.D.; Elaine Hylek, M.D.; Dan M. Witt, Pharm.D.; Walter Ageno, M.D.

Disclosures

Pharmacotherapy. 2011;31(4):386-393. 

In This Article

Discussion

This is, to our knowledge, the first systematic review that compared the efficacy and safety of brand name and generic warfarin products. We failed to detect substantial differences between brand name and generic warfarin. When, in three RCTs, the average INR was compared between patients assigned to brand name or generic warfarin, the CIs of the differences in the pooled INRs fell within the prespecified range for bioequivalence (80–125%).[6,7,13]

Results of observational studies are more conflicting, suggesting different features for different generic warfarin products. The first study that compared anticoagulation control in patients maintained on oral anticoagulation with brand name warfarin and in patients switched to generic warfarin (Panwarfarin) found worse control in the generic group, questioning the advisability of this substitution.[3] However, this study examined a generic warfarin not currently registered in the United States or Europe, and the findings were not confirmed in a subsequent study with similar design that compared brand name warfarin with an FDA-approved generic warfarin compound (Barr Laboratories). Other observational studies compared anticoagulation control and the number of thromboembolic and hemorrhagic complications in patients receiving oral anticoagulant therapy before and after the switch to a generic warfarin product. One study found generic warfarin (Taro-warfarin) to be associated with a reduced warfarin sensitivity, suggesting a reduced bioavailability of the new formulation[4] (although this was well within the limits defining bioavailability). Two other studies found time in the therapeutic range to be similar or only slightly reduced compared with the period before substitution[5,8] (the observed difference was statistically significant in one study, but it was not deemed to be clinically significant[5]). In these three studies, the number of thromboembolic and hemorrhagic complications before and after the switch was similar. These results were further confirmed by an ecologic study that found a similar rate of thromboembolic and hemorrhagic complications after introduction of two generic warfarin formulations (Apo-warfarin and Taro-warfarin) to over 30,000 warfarin-treated patients.

Our analysis has significant limitations. Caution is necessary since all included studies (except the Canadian ecologic study) have small sample sizes and thus the analyses lack power to detect even large differences in clinical event rates. This consideration may be true especially for some generic warfarin brands used in one single small study.[3,12,13] The three crossover RCTs that measured the differences in the mean INR when brand name or generic warfarin was administered reported data as pooled averages, which do not reflect individual responses.[6,7,13] As demonstrated in one observational study, substantial changes in individual INR control can occur despite minimal differences in the overall mean INR response.[5] This highlights the need to monitor individual patients at the time of changing warfarin brands to allow timely adjustments of warfarin dosage.

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