Structure and haemostatic effects of generic versions of enoxaparin available for clinical use in Brazil: Similarity to the original drug

Summary

Patent protection for enoxaparin has expired. Generic preparations are developed and approved for clinical use in different countries. However, there is still skepticism about the possibility of making an exact copy of the original drug due to the complex processes involved in generating low-molecular-weight heparins. We have undertaken a careful analysis of generic versions of enoxaparin available for clinical use in Brazil. Thirty-three batches of active ingredient and 70 of the final pharmaceutical product were obtained from six different suppliers. They were analysed for their chemical composition, molecular size distribution, in vitro anticoagulant activity and pharmacological effects on animal models of experimental thrombosis and bleeding. Clearly, the generic versions of enoxaparin available for clinical use in Brazil are similar to the original drug. Only three out of 33 batches of active ingredient from one supplier showed differences in molecular size distribution, resulting from a low percentage of tetrasaccharide or the presence of a minor component eluted as monosaccharide. Three out of 70 batches of the final pharmaceutical products contained lower amounts of the active ingredient than that declared by the suppliers. Our results suggest that the generic versions of enoxaparin are a viable therapeutic option, but their use requires strict regulations to ensure accurate standards.

Keywords

Low-molecular-weight-heparins - generic drugs - anticoagulants - heparin - antithrombotic agents

• References

• 1 Weitz JI.. Low-molecular-weight heparins. N Engl J Med 1997; 337: 688-698.
• 2 Bisio A, Vecchietti D, Citterio M. et al. Structural features of low-molecular-weight heparins affecting their affinity to antithrombin. Thromb Haemost 2009; 102: 865-873.
• 3 Fareed J, Leong WL, Hoppensteadt DA. et al. Generic low-molecular-weight heparins: some practical considerations.. Semin Thromb Haemost 2004; 30: 703-713.
• 4 Harenberg J, Kakkar A, Bergqvist D. et al. Recommendations on biosimlar low-molecular-weight-heparins.. J Thromb Haemost 2009; 7: 1222-1225.
• 5 Jeske WP, Walenga JM, Hoppensteadt DA. et al. Differentiating low-molecular-weight heparins based on chemical, biological and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins.. Semin Thromb Haemost 2008; 34: 74-85.
• 6 Dische Z.. A specific color reaction for glucuronic acid. J Biol Chem 1947; 167: 189-198.
• 7 Aquino RS, Pereira MS, Vairo BC. et al. Heparins from porcine and bovine intestinal mucosa: are they similar drugs?. Thromb Haemost 2010; 103: 1005-1015.
• 8 Komatsu H, Takahata T, Tanaka M. et al. Determination of the molecular-weight distribution of low-molecular-weight heparins using high-performance gel permeation chromatography. Biol Pharm Bull 1993; 16: 1189-1193.
• 9 Olson ST, Björk I, Shore JD.. Kinetic Characterization of Heparin-Catalyzed and Uncatalyzed Inhibition of Blood Coagulation Proteinases by Antithrombin. Methods Enzymol 1993; 222: 525-559.
• 10 Fonseca RJ, Oliveira SN, Pomin VH. et al. Effects of oversulfated and fucosylated chondroitin sulfates on coagulation. Challenges for the study of anticoagulant polysaccharides. Thromb Haemost 2010; 103: 994-1004.
• 11 Herbert JM, Bernat A, Maffrand JP.. Importance of platelets in experimental venous thrombosis in the rat. Blood 1992; 80: 2281-2286.
• 12 Guerrini M, Guglieri S, Naggi A. et al. Low molecular weight heparins: structural differentiation by bidimensional nuclear magnetic resonance spectroscopy.. Semin Thromb Haemost 2007; 33: 478-487.
• 13 Guerrini M, Guglieri S, Naggi A. et al. Oversulfated chondroitin sulfate is a contaminant in heparin associated with adverse clinical events.. Nat Biotechnol 2008; 26: 669-675.
• 14 Collignon F, Frydman A, Caplain H. et al. Comparison of the pharmacokinetic profiles of three low molecular mass heparins - dalteparin, enoxaparin and nadroparin - administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 73: 630-640.
• 15 Gray E, Mulloy B.. Biosimilar low molecular weight heparin products.. J Thromb Haemost 2009; 7: 1218-1221.
• 16 Gomes M, Ramacciotti E, Litinas E. et al. Concerns on generic enoxaparin use in acute coronary syndrome.. Arq Bras Card 2010; 95: 551-552.
• 17 Lever R, Page CP.. Novel drug development opportunities for heparin. Nature reviews: Drug Discov 2002; 1: 140-148.