Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial

Abstract

Objectives: To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results.

Methods: This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49.

Results: One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84).

Conclusions: Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents.

Trial registration: ClinicalTrials.gov NCT02017197.

Fig 1. Participant flow in the WARFA trial by allocation sequence and study period.

INR: international normalized ratio; M: Marevan; NOAC: novel anticoagulant; TW: Teuto warfarin; UQW: União Química warfarin. ^a One patient with CHA₂DS₂VASc = 0, one participant using warfarin along with aspirin and clopidogrel and one patient already enrolled in another clinical trial. ^b Warfarin switched for a NOAC due to arrhythmia ablation procedures and not because of adverse events. ^c Patient developed hypersensitivity type I reaction to TW and decided to switch back to UQW. ^d One patient with CHA2DS2VASc = 0. ^e One patient of childbearing potential. ^f Patient withdrew due to study visits not fitting into his personal schedule.