Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Chugai Pharma UK Ltd, Mulliner House, Flanders Road, Turnham Green, London W4 1NN
Pharmacotherapeutic group: Cytokines
ATC code: L03AA10
Lenograstim (rHuG-CSF) belongs to the cytokine group of biologically active proteins which regulate cell differentiation and cell growth.
rHuG-CSF is a factor that stimulates neutrophil precursor cells as demonstrated by the CFU-S and CFU-GM cell count which increases in peripheral blood.
GRANOCYTE induces a marked increase in peripheral blood neutrophil counts within 24 hours of administration.
Elevations of neutrophil count are dose-dependent over the 1-10 µg/kg/day range. At the recommended dose, repeated doses induce an enhancement of the neutrophil response. Neutrophils produced in response to GRANOCYTE show normal chemotactic and phagocytic functions.
As with other hematopoietic growth factors, G-CSF has shown in vitro stimulating properties on human endothelial cells.
Use of GRANOCYTE in patients who underwent Bone Marrow Transplantation or who are treated with cytotoxic chemotherapy leads to significant reductions in duration of neutropenia and its associated complications.
Use of GRANOCYTE either alone or after chemotherapy mobilises haematopoietic progenitor cells into the peripheral blood. These autologous Peripheral Blood Progenitor Cells (PBPCs) can be harvested and infused after high dose cytotoxic chemotherapy, either in place of, or in addition to bone marrow transplantation.
Reinfused PBPCs, as obtained following mobilisation with GRANOCYTE have been shown to reconstitute haemopoiesis and reduce the time to engraftment, leading to a marked decrease of the days to platelets independence when compared to autologous bone marrow transplantation.
A pooled analysis of data from 3 double-blind placebo-controlled studies conducted in 861 patients (n=411 ≥55 years) demonstrated a favourable benefit/risk ratio of lenograstim administration in patients over 55 years of age undergoing conventional chemotherapy for de novo acute myeloid leukaemia, in the exception of AML with good cytogenetics, i.e. t (8;21), t (15;17) and inv (16).
The benefit in the sub-group of patients over 55 years appeared in terms of lenograstim-induced acceleration of neutrophil recovery, increase in the percentage of patients without infectious episode, reduction in infection duration, reduction in the duration of hospitalisation, reduction in the duration of IV antibiotherapy. However, these beneficial results were not associated with decreased severe or life-threatening infections incidence, nor with decreased infection-related mortality.
Data from a double-blind placebo-controlled study conducted in 446 patients with de novo AML showed that, in the 99 patients subgroup with good cytogenetics, the event-free survival was significantly lower in the lenograstim arm than in the placebo arm, and there was a trend towards a lower overall survival in the lenograstim arm when compared to data from the not good cytogenetics subgroup.
The pharmacokinetics of GRANOCYTE are dose and time dependent.
During repeated dosing (IV and SC routes), peak serum concentration (immediately after IV infusion or after SC injection) is proportional to the injected dose. Repeated dosing with GRANOCYTE by the two administration routes showed no evidence of drug accumulation.
At the recommended dose, the absolute bioavailability of GRANOCYTE is 30%. The apparent volume of distribution (Vd) is approximately 1 L/kg body weight and the mean residence time close to 7 h following subcutaneous dosing.
The apparent serum elimination half-life of GRANOCYTE (S.C. route) is about 3-4 h, at steady state (repeated dosing) and is shorter (1-1.5 h) following repeated IV infusion.
Plasma clearance of rHuG-CSF increased 3-fold (from 50 up to 150 mL/min) during repeated S.C. dosing. Less than 1% of lenograstim is excreted in urine unchanged and it is considered to be metabolised to peptides. During multiple S.C. dosing, peak serum concentrations of lenograstim are close to 100 pg/mL/kg body weight at the recommended dosage. There is a positive correlation between the dose and the serum concentration of GRANOCYTE and between the neutrophil response and the total amount of lenograstim recovered in serum.
In animals, acute toxicity studies (up to 1000 µg/kg/day in mice) and sub-acute toxicity studies (up to 100 µg/kg/day in monkey) showed the effects of overdose were restricted to an exaggerated and reversible pharmacological effect.
There is no evidence from studies in rats and rabbits that GRANOCYTE is teratogenic. An increased incidence of embryo-loss has been observed in rabbits, but no malformation has been seen.
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