Product Associated Variation in Generic Enoxaparin. Potential Clinical Implications

Abstract 1249

Recently the generic versions of enoxaparin brand (Sanofi-Aventis) have widely become available. Since enoxaparin is a biological product, minor compositional changes in these agents may potentially have clinical implications. Generic enoxaparins are manufactured by several companies and marketed under specific trade names. The purpose of this investigation was to determine the differences between generic products and within product variations in the same generic product. Eight generic products from India (Cutenox, Markaparin,

Clenox, Lomoparin, Lupenox, Lomorin-NX, Lomoh-40 and Troynoxa-40), four generic products from South America (Enoxalow, Versa, Heptron and Endocris), and one generic product from the USA (Enoxaparin sodium) were studied. The molecular weight profile of generic products showed relatively similar distribution profile with a molecular weight range of 3.9–4.9 kDa. The anti-FXa activity ranged from 87–110 U/mg, whereas wider variations were noted in anti-FIIa activity (28–41 U/mg). The anti-FXa:anti-FIIa ratio ranged from 3.1–4.2. Much wider variations (up to 60%) were noted in the anticoagulant assays (ACT, aPTT, Heptest, and thrombin time). Additionally the generic products also showed variations in the thrombin generation assay. Protamine and PF4 titration profile also showed variations. AT mediated inhibition of thrombin and FXa in the biochemical assays showed wider differences in IC₅₀ values. Heparinase digestion profile showed variable oligosaccharide composition and some of the products contained heparinase resistant glycosaminoglycans. A comparison of 5 batches of the branded enoxaparin (Clexane) and 5 batches of a generic enoxaparin showed that the generic product batches exhibited greater variation in the biologic assays despite a comparable anti-FXa profile. These observations suggest that despite the current regulatory requirements, product based differences in the generic enoxaparins exist, which may impact their safety and efficacy profile in cardiovascular and thrombotic indications for which the branded enoxaparin is approved. Additional pharmacodynamic studies and clinical validations of the safety and efficacy of each of the generic products maybe helpful in assuring a clinical equivalence of the generic products with the branded enoxaparin.