Filgrastim - Nivestim; Granulocyte Colony Stimulating Factor, recombinant
Status - approved as a biosimilar in EU in June 2010
Organizations involved:
Hospira – Manuf.; R&D; Tech.; World mark.
Pliva d.d. – R&D; Tech.; Former
Teva Pharmaceuticals –Parent
Mayne Pharma Ltd. – R&D; Former
Cross ref.: See the filgrastim (Neupogen) for G-CSF-related information, and the other filgrastim entries.
Description: Nivestim refers to aqueous formulations of recombinant human granulocyte-colony stimulating factor produced in transformed E. coli BL21, yielding a non-glycosylated protein with an N-terminal methionyl extension (filgrastim). The protein is expressed in inclusion bodies followed by renaturation of protein and chromatographic purification steps.
See the Neupogen (Nivestim's reference product) entry for further information about the molecule.
Nivestim is available in three presentations - 48 MU (480 mcg), 30 MU (300 mcg) and a unique 12 MU (120 mcg) low weight presentation. Each ml of solution for injection or infusion contains 60 million units [MU] (600 micrograms) of filgrastim. Each pre-filled syringe contains 12 million units (MU) (120 micrograms) of filgrastim in 0.2 ml (0.6 mg/ml). Each ml of solution contains 50 mg of sorbitol. Other excipients are acetic acid, glacial; sodium hydroxide; polysorbate 80 (Tween 80); and Water for injections. Nivestim is stored and transported refrigerated (2°C - 8°C).
All presentations are available in a pre-filled syringe, allowing patients to self-administer Nivestim at home. Each syringe has an integrated needle-safe device to facilitate safer administration and is individually blister-packed to reduce the risk of contamination and provide tamper-evidence.
Nomenclature: G-CSF, rDNA/Hospira [BIO]; Nivestim [TR]; colony-stimulating factor (human clone 1034) , N-L-methionyl- [CAS]; Filgrastim [USAN INN BAN MESH]
135968-09-1 [CAS RN]; granulocyte colony stimulating factor, recombinant [SY]
Companies.: Nivestim was initially developed and is manufactured by PLIVA Hrvatska d.o.o. (Zagreb, Croatia), a subsidiary of Teva Pharmaceuticals.
In Nov. 2009, Hospira acquired full rights for Nivestim, including worldwide marketing and process development capabilities and a manufacturing plant in Croatia. The site has capacity sufficient to meet Hospira's worldwide filgrastim and pegfilgrastim requirements, along with expansion possibility for additional biogenerics manufacturing.
In March 2005, Barr Labs. joined with Pliva D.D. (Croatia) for development of generic G-CSF, with Barr receiving exclusive U.S. and Canadian marketing rights and intending to seek approval in the U.S. and Canada. Barr Labs., among the largest generic drug companies, acquired Pliva in Oct. 2006, and Barr was later acquired by Teva.
In April 2005, Pliva d.d. formed a collaboration with Mayne Pharma (Australia; later merged into Hospira) for development of biogeneric G-CSF, with Mayne paying Pliva €21 million over three years for certain marketing rights for G-CSF (and also biogeneric EPO), and receiving exclusive marketing rights in Western Europe, N. America, Middle East, and Asia/Pacific, with Pliva retaining other territories.
Status: Nivestim was developed (for the EU) as a “similar biological medicinal product” (biosimilar) according to Article 10 (4) and Annex 1, Part II, Chapter 4 of Directive 2001/83/EC as amended. The chosen reference medicinal product was Neupogen sourced from Amgen.
On June 10, 2010, biosimilar approval of Nivestim was granted by the EU. Hospira became the first U.S.-based company to receive a biosimilar EU approval.
Indications: [full text of the "Therapeutic indications:" section of the EMEA EPAR]':
Filgrastim is indicated for the reduction in the duration of neutropenia and the incidence of febrile neutropenia in patients treated with established cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes) and for the reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia.
The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.
Filgrastim is indicated for the mobilisation of peripheral blood progenitor cells (PBPC).
In patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia with an absolute neutrophil count (ANC) of 0.5 x 10.sup.9/L and a history of severe or recurrent infections, long term administration of filgrastim is indicated to increase neutrophil counts and to reduce the incidence and duration of infection-related events.
Filgrastim is indicated for the treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109 /l) in patients with advanced HIV infection, in order to reduce the risk of bacterial infections when other options to manage neutropenia are inappropriate.
Trials: In a large, randomized Phase lll study, Nivestim demonstrated comparable efficacy to Neupogen in the prevention of febrile neutropenia, and was as well tolerated, with a similar adverse event profile.
A randomised, open-label, single-dose, comparator-controlled, two-way crossover study in 46 healthy volunteers showed that the pharmacokinetic profile of Nivestim was comparable to that of the reference product, Neupogen, after subcutaneous and intravenous administration. Another randomised, double-blind, multiple-dose, comparator-controlled, two-way crossover study in 50 healthy volunteers showed that the pharmacokinetic profile of Nivestim was comparable to that of the reference product after subcutaneous administration.
Index Terms:
Companies involvement:
Full monograph
160.11 G-CSF, rDNA/Hospira
Nomenclature:
G-CSF, rDNA/Hospira [BIO]
Nivestim [TR]
colony-stimulating factor (human clone 1034) , N-L-methionyl- [CAS]
Filgrastim [USAN INN BAN MESH]
135968-09-1 [CAS RN]
granulocyte colony stimulating factor, recombinant [SY]
FDA Class: Biologic BLA
biopharmaceutical products
Biorex-70 resin
exempt from CBER lot release requirements
growth factors, hematopoietic
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
polysorbate 80 (Tween 80)
sodium hydroxide
somatropin, recombinant
Water for Injection
BHK-21 (C-13)
EU200 Currently Approved in EU EU777
UM999 Not Available/Not Marketed in US
US002 FDA application pending
EM001 Marketed Product in EU
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