A randomized, single-dose, two-sequence, two-period, crossover study to assess the bioequivalence between two formulations of clonazepam tablet in healthy subjects

Abstract

Clonazepam is a benzodiazepine commonly prescribed to treat panic disorder, epilepsy, anxiety, depression and certain types of seizures. This study aimed to evaluate the bioequivalence between two formulations of clonazepam tablets in order to meet regulatory requirements for marketing in Colombia and other countries in Latin America. An open-label, randomized, single-dose, two-period, two-sequence, two-treatment crossover study was conducted in 36 healthy subjects of both genders. Subjects received a single dose of clonazepam 2 mg test tablet (Sanofi-Aventis de Colombia S.A.) and reference product (Rivotril®, Produtos Roche Químicos e Farmacêuticos S.A.) under fasting conditions according to a randomly assigned order with a 21-day washout period. Serial blood samples were collected up to 96 h post-dose. Plasma concentrations of clonazepam were obtained by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated using non-compartmental methods. A total of 36 healthy subjects were enrolled and 31 of them completed the study. Twenty-nine adverse events were reported (11 events with test product versus 18 events with reference product). There were no serious adverse events during the study. Geometric mean ratios (90% confidence intervals) for C_max and AUC_0–96h were 103.28% (98.10–108.64) and 102.50% (99.87–105.19), respectively. The test formulation of clonazepam 2 mg tablet manufactured by Sanofi-Aventis de Colombia S.A. was considered bioequivalent to reference product Rivotril^® (Produtos Roche Químicos e Farmacêuticos S.A.) according to regulatory requirements. Both formulations were safe and well-tolerated during the study.

Keywords:

• Clonazepam
• benzodiazepine
• bioequivalence
• pharmacokinetics
• bioavailability
• bioanalytical method

Acknowledgments

The authors thank the CAEP – Centro Avançado de Estudos e Pesquisas (Campinas, Brazil) team for technical support in Clinical, Analytical and Statistical phases of the bioequivalence study; and Genfar S.A. (Villa Rica, Colombia) for previous physicochemical assays and technical support in formulation manufacturing.

Disclosure statement

The authors declare that there is no conflict of interest regarding the publication of this article. The authors were fully responsible for all content and editorial decisions and did not receive financial support from Sanofi or any other form of compensation related to the development of this article.

Additional information

Funding

The bioequivalence study was financially supported by Sanofi-Aventis de Colombia S.A.