Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Ratiopharm GmbH, Graf-Arco-Straße 3, 89079 Ulm, Germany
Pharmacotherapeutic group: Immunostimulants, colony stimulating factors
ATC code: L03AA02
Ratiograstim is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu.
Human G-CSF is a glycoprotein which regulates the production and release of functional neutrophils from the bone marrow. Ratiograstim containing r-metHuG-CSF (filgrastim) causes marked increases in peripheral blood neutrophil counts within 24 hours, with minor increases in monocytes. In some SCN patients, filgrastim can also induce a minor increase in the number of circulating eosinophils and basophils relative to baseline; some of these patients may present with eosinophilia or basophilia prior to treatment. Elevations of neutrophil counts are dose-dependent at recommended doses. Neutrophils produced in response to filgrastim show normal or enhanced function as demonstrated by tests of chemotactic and phagocytic function. Following termination of filgrastim therapy, circulating neutrophil counts decrease by 50% within 1 to 2 days, and to normal levels within 1 to 7 days.
Use of filgrastim in patients undergoing cytotoxic chemotherapy leads to significant reductions in the incidence, severity and duration of neutropenia and febrile neutropenia. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, antibiotic use and hospitalisation after induction chemotherapy for acute myelogenous leukaemia or myeloablative therapy followed by bone marrow transplantation. The incidence of fever and documented infections were not reduced in either setting. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.
Use of filgrastim, either alone or after chemotherapy, mobilises haematopoietic progenitor cells into peripheral blood. These autologous PBPCs may be harvested and infused after high-dose cytotoxic therapy, either in place of or in addition to bone marrow transplantation. Infusion of PBPCs accelerates haematopoietic recovery reducing the duration of risk for haemorrhagic complications and the need for platelet transfusions.
Recipients of allogeneic PBPCs mobilised with filgrastim experienced significantly more rapid haematological recovery, leading to a significant decrease in time to unsupported platelet recovery, when compared with allogeneic bone marrow transplantation.
One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukaemias suggested an increase in the risk of GvHD, treatment related mortality (TRM) and mortality when G-CSF was administered. In a separate retrospective international study in patients with acute and chronic myelogenous leukaemias, no effect on the risk of GvHD, TRM and mortality was seen. A meta-analysis of allogeneic transplant studies, including the results of nine prospective randomized trials, 8 retrospective studies and 1 case-controlled study, did not detect an effect on the risks of acute GvHD, chronic GvHD or early treatment-related mortality.
Relative risk (95% CI) of GvHD and TRM following treatment with G-CSF after bone marrow transplantation:
| Publication | Period of study | N | Acute grade II-IV GvHD | Chronic GvHD | TRM |
|---|---|---|---|---|---|
| Meta-analysis (2003) | 1986-2001a | 1198 | 1.08 (0.87, 1.33) | 1.02 (0.82, 1.26) | 0.70 (0.38, 1.31) |
| European retrospective study (2004) | 1992-2002b | 1789 | 1.33 (1.08, 1.64) | 1.29 (1.02, 1.61) | 1.73 (1.30, 2.32) |
| International retrospective study (2006) | 1995-2000b | 2110 | 1.11 (0.86, 1.42) | 1.10 (0.86, 1.39) | 1.26 (0.95, 1.67) |
a Analysis includes studies involving bone marrow transplant during this period; some studies used GM-CSF (granulocyte-macrophage–colony stimulating factor)
b Analysis includes patients receiving bone marrow transplant during this period
Prior to allogeneic PBPC transplantation, use of filgrastim for the mobilisation of PBPC in normal donors allows a collection of ≥4 × 106 CD34+ cells/kg recipient body weight in the majority of the donors after two leukapheresis. Normal donors are given a dose of a 10 μg/kg/day, administered subcutaneously for 4 to 5 consecutive days.
Use of filgrastim in patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic neutropenia) induces a sustained increase in absolute neutrophil counts in peripheral blood and a reduction of infection and related events.
Use of filgrastim in patients with HIV infection maintains normal neutrophil counts to allow scheduled dosing of antiviral and/or other myelosuppressive medication. There is no evidence that patients with HIV infection treated with filgrastim show an increase in HIV replication.
As with other haematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.
The efficacy and safety of Ratiograstim has been assessed in randomised, controlled phase III studies in breast cancer, lung cancer and Non-Hodgkin-Lymphoma. There were no relevant differences between Ratiograstim and the reference product with regard to duration of severe neutropenia and incidence of febrile neutropenia.
Randomised, single-blind, single dose, crossover studies in 196 healthy volunteers showed that the pharmacokinetic profile of Ratiograstim was comparable to that of the reference product after subcutaneous and intravenous administration.
Clearance of filgrastim has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration. The serum elimination half-life of filgrastim is approximately 3.5 hours, with a clearance rate of approximately 0.6 mL/min/kg. Continuous infusion with filgrastim over a period of up to 28 days, in patients recovering from autologous bone-marrow transplantation, resulted in no evidence of drug accumulation and comparable elimination half-lives. There is a positive linear correlation between the dose and the serum concentration of filgrastim, whether administered intravenously or subcutaneously. Following subcutaneous administration of recommended doses, serum concentrations were maintained above 10 ng/mL for 8 to 16 hours. The volume of distribution in blood is approximately 150 mL/kg.
In cancer patients, the pharmacokinetic profile of Ratiograstim and the reference product was comparable after single and repeated subcutaneous administration.
Filgrastim was studied in repeated dose toxicity studies up to 1 year in duration which revealed changes attributable to the expected pharmacological actions including increases in leukocytes, myeloid hyperplasia in bone marrow, extramedullary granulopoiesis and splenic enlargement. These changes all reversed after discontinuation of treatment.
Effects of filgrastim on pre-natal development have been studied in rats and rabbits. Intravenous (80 µg/kg/day) administration of filgrastim to rabbits during the period of organogenesis was maternally toxic and increased spontaneous abortion, post-implantation loss, and decreased mean live litter size and foetal weight were observed.
Based on reported data for another filgrastim product similar to the reference product, comparable findings plus increased foetal malformations were observed at 100 µg/kg/day, a maternally toxic dose which corresponded to a systemic exposure of approximately 50-90 times the exposures observed in patients treated with the clinical dose of 5 µg/kg/day. The no observed adverse effect level for embryo-foetal toxicity in this study was 10 µg/kg/day, which corresponded to a systemic exposure of approximately 3-5 times the exposures observed in patients treated with the clinical dose.
In pregnant rats, no maternal or foetal toxicity was observed at doses up to 575 µg/kg/day. Offspring of rats administered filgrastim during the peri-natal and lactation periods, exhibited a delay in external differentiation and growth retardation (≥20 µg/kg/day) and slightly reduced survival rate (100 µg/kg/day).
Filgrastim had no observed effect on the fertility of male or female rats.
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