Comparative in vitro antimicrobial potency, stability, colouration and dissolution time of generics versus innovator of meropenem in Europe

Abstract

Meropenem generics are often imposed on prescribers, however scarce information is available on key properties such as antimicrobial potency, stability and colouration in solution, and dissolution time. This study aimed to generate comparative information for products available in Europe. The originator (AS-TRA) and four generics (HOSPIRA, SANDOZ, FRESENIUS and AUROVIT) were compared for: (i) MICs against Pseudomonas aeruginosa clinical isolates (range, 0.125-191 mg/L); (ii) colouration (visual and photometry) and stability of concentrated solutions for prolonged or continuous infusion and maintained at 25-37 °C for up to 8 h (acceptable limit, ≥90% of original concentration); and (iii) dissolution time of concentrated solutions (50 mg/mL [for bolus administration]: turbidimetry and nursing personnel assessment). No significant difference was observed for MICs (except 2/80 isolates). For concentrated solutions storage: (i) SANDOZ produced about two times more yellow-coloured degradation products than the other preparations; (ii) meropenem loss was time-, concentration-and temperature-dependent; (iii) FRESENIUS was the least stable (limit for 1 g/48 mL, ~8 h at 25 °C and 4.5 h at 37 °C); (iv) at 2 g/48 mL, the storage time limit was 5-6 h at 25 °C and ~3 h at 37 °C for all preparations. Complete dissolution (turbidimetry) required 240 s for generics (120 s for ASTRA), and nurses reported longer but highly variable times for generics. Substantial differences between innovator and generics have been identified that could impact on their clinical use and/or make multicentric studies difficult to interpret, requiring suitability studies in the environments of their intended use.

Comparison of Pharmaceutical Characteristics between Brand-Name Meropenem and Its Generics

“…Differences between brand-name meropenem and meropenem generics marketed in foreign countries, including Japan [19], India [22], and European countries [11], have been reported by several studies [11,[19][20][21][22]. This study, for the first time, characterized critical pharmaceutical features, including particle morphologies, solubility, numbers of insoluble particles, stability, residual solvents, and antimicrobial effects, of BNM and six major GPs marketed in China.…”

“…The brand-name products might be required to conduct additional post-marketing studies [10] after they are on the market to test their safety and effectiveness in a large number of people. In order to achieve in vivo clinical equivalence, the quality of the brand-name drug and the generics should be consistent in vitro [11]. Based on the data of pharmaceutical consistency and bioequivalence (BE) studies, the generic products can be approved quickly.…”

“…Meropenem generics have been widely used across the world. Previous studies have characterized differences between brand-name meropenem and its generics marketed overseas in terms of pharmaceutical features as well as therapeutical efficacies [11,[19][20][21][22]. Previous studies compared brand-name meropenem and its generics in Colombia and found that the therapeutic nonequivalence of meropenem products might be attributed to the different susceptibility to dihydropeptidase I (DHP-I) hydrolysis [20].…”

“…Studies conducted in Japan showed that brand-name meropenem and its generic products are different in dissolution time, which might be associated with the differences in the size of bulk particles and the amount of solubilizer [19]. In addition, it has been characterized that meropenem generics marketed in Europe had different dissolution times and stability compared to its originator product [11]. Studies conducted in India [22] described a method for the determination of relative potency of various generic brands of antibiotics and showed that in terms of active pharmaceutical ingredient, not all generics are inferior.…”

Meropenem: continuous or extended infusion?

“…Thus, CI does not offer significant PK/ PD advantages over EI for meropenem. On a practical point of view, CI of meropenem needs a dedicated intravenous line access (which is not always obvious in critically ill patients) and frequent infusion syringes changes (every 5-8 h) due to stability issues, particularly at temperatures ≥ 25°C [5].…”