Status: approved in EU as as biosimilar

Organizations involved:

Sandoz GmbH – Manuf.; R&D; Tech.

Novartis AG –Intl. mark.; Parent

Rentschler Arzneimittel GmbH & Co. – Manuf.

Lek – Manuf.

Cross ref.: See the entries for EPO Products and other EPO product entries, particularly Eprex (#136). See also the EPO rDNA/Medice (Abseamed) entry, with Abseamed containing the same active agent as Binocrit.

Description: Benicrit is biosimilar version (essentially a copy) of Eprex from Ortho/Johnson & Johnson. Like Eprex this product contains recombinant human EPO (HX-575) expressed by transformed Chinese hamster ovary (CHO) cell culture.

Nomenclature: rDNA/Sandoz [BIO]; Binocrit [TR]; erythropoietin, recombinant [SY]; Epoetin alfa [INN]; HX-575 [SY]; HX575 [SY]; epoetin lambda [Official name in Austria]

Biological.: Amgen has reported differences between HX575 (Binocrit and Abseamed) and the EPO in Eprex including differences in glycosylation; higher levels of high mannose-type structures; lower levels of N-glycolyl-neuramic acid and diacetylated neuramic acids; and peptide mapping showing differences in O-linked glycan due to higher sialylation and lower content of oxidized variant.

Companies.: This product was developed by Sandoz GmbH, the generics subsidiary of Novartis AG, which handles marketing in the European Union and internationally.

HX575, the active agent (epoetin alfa) is manufactured under contract by Rentschler Arzneimittel GmbH & Co. Rentschler also provides HX575 to Medice for its epoetin alfa biosimilar product, Binocrit.

In Feb. 2010, Lek (Slovenia), a Sandoz/Novartis subsidiary, opened a 430 m manufacturing facility in Slovenia to produce epoetin alfa drug substance for use in the biosimilars marketed by its parent company, Sandoz invested $3.75m (€2.77m) in Lek’s site in Menge in central Slovenia. In 2009, Lek opened a €13m packaging center to supply European markets.

Manufacture: See the manufacture section of the Abseamed entry above for further information about HX575 (epoetin alfa) manufacture.

Status: Sandoz filed with the European Union (EU) for approval of this product under EU “biosimilar” regulations, which allow abbreviated filings based largely on comparisons, including phamacokinetic/bioavailability trials, with an already-approved product, rather than full, Phase III-like placebo-controlled and other studies. EMEA review of this and two other biosimilar EPO products (from Hexal and Medice, see related entries) began on March 29, 2006. On June 22, 2007, the Committee for Medicinal Products for Human Use, European Medicines Agency (EMEA), EU, recommended approval of Binocrit.

On Aug. 31, 2007, EMEA/EU granted approval under biosimilar regulations for all Indications: for which the reference EPO (Eprex) is approved in the EU. These include use in patients with renal anemia and those receiving cancer chemotherapy. However, as with Eprex, this excludes the subcutaneous administration for patients with chronic kidney disease and the use to increase the yield of autologous blood from patients in a predonation program.

Regarding biosimilarity, the EMA EPAR noted, "“Differences were observed at the glycosylation level. Phosphorylated high mannose type structures in HX575 were detected at higher levels than in Eprex/Erypo”. Market: Sandoz market Binocrit in some European counties, while Hexal, another Novartis subsidiary handles others.

In Aug. 2010, Hospira reported, " Retacrit, introduced in 2008, now has a more than 50% share of the total short-acting EPO biosimilar market in Europe.".

Binocrit was launched in Germany, its major market in late 2007. Sandoz launched it with a 15% discount relative to Eprex and other branded/innovator EPO products. After other products reduced their prices, the cost of Binocrit was reduced to a 33% discount. As of mid-2009, Binocrit has gained 30% share of the intravenous EPO market in Germany.

In German pharmacies, a package of six 0.5 ml vials dosed 1.000 IU cost 74.21 euros ($105; pharmacy prices), about a 20% or more discount relative to Eprex and other branded/innovator EPO products.

Marketing of Binocrit and other biosimilar EPO products in Europe has been slowed by prominent decisions by countries, including France, Spain and the Netherlands to ban pharmacists from substituting a biosimilar version if a physician has prescribed the reference product. This reaffirmed to many that biosimilars were not equivalent to their reference products.

Technically, physicians in most European countries must specifically prescribe this product, i.e., they can not simply write an ambiguous, generic prescription for "epoetin alfa." Similarly, this product has not been ruled therapeutically equivalent or substituable with Eprex, so pharmacies cannot on their own fill prescriptions for Eprex with this product. However, EU member and other European countries may adopt their own policies concerning product names and substitution.