Enoxaparin sodium biosimilars

A low-molecular-weight heparin produced by alkaline depolymerisation of porcine intestinal mucosal heparin, a mixture of sulphated polysaccharide chains averaging about 4.5 kDa with a characteristic 1,6-anhydro end group on part of the chains. It is not a recombinant protein, which is why the United States treats it as a drug.

Binds antithrombin through a specific pentasaccharide sequence and accelerates its inhibition of factor Xa, with less effect on thrombin than unfractionated heparin, giving an anti-Xa to anti-IIa ratio of about four to one and a more predictable anticoagulant response.

Subcutaneous bioavailability of anti-Xa activity about 90%, peak activity at three to five hours and an elimination half-life of about four to five hours, mainly renal, so dose adjustment is needed in severe kidney impairment.

20 mg or 40 mg once daily for thromboprophylaxis; 1 mg/kg twice daily or 1.5 mg/kg once daily for treatment, in pre-filled syringes from 20 mg (2,000 IU) to 150 mg (15,000 IU). Dosing is expressed in mg or anti-Xa international units.

• Prophylaxis of venous thromboembolism in surgical and medical patients
• Treatment of deep vein thrombosis and pulmonary embolism
• Unstable angina and non-ST-elevation myocardial infarction
• ST-elevation myocardial infarction
• Prevention of clotting in the extracorporeal circuit during haemodialysis

Heparin-induced thrombocytopenia, an antibody-mediated reaction to heparin-platelet factor 4 complexes, is the immunological concern for all heparins. In the EU, comparative programmes for enoxaparin rely on analytical characterisation of the polysaccharide chains, pharmacodynamic equivalence of anti-Xa and anti-IIa activity in healthy volunteers, and an immunogenicity assessment; a comparative efficacy study has not been required. In the United States, generics established sameness through five criteria set by FDA in 2010.

Lovenox was approved by FDA on 29 March 1993 (NDA 020164) and Clexane nationally in EU member states from the 1980s; neither has an EMA product number. Because it is derived from animal tissue rather than produced by recombinant DNA, the United States regulates it as a drug and the first generic, from Sandoz, was approved by ANDA in July 2010. The EU treats it as a biological medicine: Inhixa from Techdow and Thorinane from Pharmathen were authorised as biosimilars in September 2016, and Thorinane's authorisation lapsed in 2019. In India, enoxaparin is licensed under the drug rules and does not appear in the r-DNA lists.

Sources: EMA medicines data (S017), EDE directory (S018); US regulatory history from FDA records and press reports.

Enoxaparin is the odd one in the Atlas and it earns its place for that reason: the same product is a biosimilar in Europe and a generic in the United States and India, and the dossier differs accordingly. Chinese heparin manufacturers dominate the supply chain, Techdow's Inhixa is registered in the UAE, and a second EU-sourced product, Ledraxen, reached the UAE in 2021. For an Indian company the route to Europe is the biosimilar one, with EMA's heparin-specific guideline as the standard.