A comparative study of the therapeutic equivalence (efficacy, safety, and tolerability) and pharmacokinetics of brand-name and generic rivaroxaban in patients with non-valvular atrial fibrillation

Aim. To study the therapeutic equivalence (efficacy, safety, and tolerability) and pharmacokinetics of the brand-name and generic rivaroxaban 20 mg in patients with non-valvular atrial fibrillation and a high risk of thromboembolic complications.

Material and methods. This open-label, randomized, crossover comparative study of two 20 mg rivaroxaban tablet formulations registered in Russia, Riqulatron (Gedeon Richter OJSC, Hungary) and Xarelto® (Bayer Pharma AG, Germany), included 30 patients (16 men), with a median age of 66 years and a СHA2DS2-VASc score of 3.0 (2.3-4.0). The clinical part consisted of: a screening period (1-7 days before randomization), two 42-day rivaroxaban treatment periods with a visit on day 14±1 of each, an interim visit for drug switching, and a final visit. Patients completed a drug intake diary and an adherence questionnaire. Quantitative determination of rivaroxaban concentration in patient plasma was performed using high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS). Data were processed using StatSoft Statistica 13.0 (USA).

Results. Data are presented for 29 patients. The steady-state trough and peak concentrations were 22.29 (3.78-101.76) ng/ml and 197.04 (118.00-376.78) ng/ml for the generic, and 20.55 (5.02-82.29) ng/ml and 179.38 (102.80-335.71) ng/ml for the brand-name drug, respectively. The 90% confidence intervals for the ratios of trough and peak concentrations were 0.93-1.25 and 0.99-1.21, respectively. Mean laboratory values for patients, regardless of the treatment sequence, were within reference ranges except for peak prothrombin time. Rivaroxaban concentration was a significant predictor of prothrombin time (p<0.001), with a strong direct correlation between these parameters. No thromboembolic events were recorded in any patient during the observation period. Hemorrhagic complications (gingival bleeding, hematuria) were recorded in ten patients; five events occurred while taking the brand-name drug and seven while taking the generic; no rivaroxaban discontinuation was required. Other adverse events (laboratory value deviations from reference ranges, decompensation of chronic heart failure, paroxysm of atrial fibrillation, diarrhea) also did not require rivaroxaban discontinuation.

Conclusion. The comparative study of the two rivaroxaban formulations demonstrated similar efficacy, safety, tolerability, and pharmacokinetics for Riqulatron (Gedeon Richter OJSC, Hungary) and Xarelto® (Bayer Pharma AG, Germany) at a 20 mg dose in patients with non-valvular atrial fibrillation.

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