Filgrastim is produced by a strain of the bacteria Escherichia coli, in which genetically engineered gene is introduced human granulocyte colony-stimulating factor. Identical to natural granulocyte colony stimulating factor human biological activity, differing from it in the absence of glycosylation and the presence of an additional N-terminal amino acid residue of methionine.
Leykostim ® accelerates proliferation of neutrophilic bone marrow granulocytic progenitor cells (CFU-G), differentiation toward the mature neutrophils and output them to peripheral blood from bone marrow. It causes dose-dependent increase in the number of neutrophils in the peripheral blood. Neutrophils are produced in response to administration of the drug Leykostim ® , have normal or elevated phagocytic and chemotactic activity. Use of the drug Leykostim ® restores the number of neutrophils in the peripheral blood neutropenia in patients receiving chemotherapy or in patients with chronic neutropenia. Use of the drug testosterone suspension resultsas a preventive measure to reduce the frequency, severity and duration of neutropenia and febrile neutropenia after chemotherapy. This tends to prevent infectious complications, reduced hospital stays and compliance regimens prescribed intervals between cycles of chemotherapy.
Use of the drug after the chemotherapy, and independent of it, leads to a mobilization of peripheral blood hematopoietic progenitor cells. These cells can be collected by cytapheresis and administered to the patient after chemotherapy, the dose level high. Introduction of hematopoietic stem cells can restore the hematopoietic and immune systems following myeloablative chemotherapy. After myelosuppressive chemotherapy administration of hematopoietic stem cells accelerates restoration of hematopoiesis, reducing the frequency and severity of infectious and hemorrhagic complications.
The efficacy and safety of the drug in adults and children receiving cytotoxic chemotherapy are the same.
In children and adults with severe chronic neutropenia drug steadily increases the number of neutrophils in the peripheral blood, reducing the incidence of infectious complications.
The appointment of the drug in patients with HIV infection allows to maintain a normal neutrophil count and follow the recommended doses of antiretroviral and / or other myelosuppressive therapy. Signs of increased HIV replication is not noted in the application of filgrastim.
in plasma concentration of the drug is proportional to the administered dose. Filgrastim half-life after subcutaneous and intravenous injection is 3-4 hours. After subcutaneous administration of therapeutic doses of filgrastim, its concentration in the serum is greater than 10 ng / ml for 8-16 hours. There is a direct relationship between plasma concentration filgrastim and increase in the number of neutrophils in the peripheral blood.
Filgrastim mainly metabolized into peptides and only to a small extent excreted unchanged in the urine (less than 1% of the administered dose). Filgrastim prolonged use over a period of 28 days is not accompanied by signs of accumulation and increased half-life.
The drug is used to:
shortening the duration of neutropenia II-IV degree and reduce the incidence of febrile neutropenia in patients with nemieloproliferativnymi tumors after chemotherapy with cytotoxic drugs;
- mobilize hematopoietic progenitor cells into peripheral blood for the purpose of separation and their subsequent transplantation after myelosuppressive chemotherapy;
- shortening the duration of neutropenia and the prevention of its related complications in patients receiving myeloablative chemotherapy followed by bone marrow transplantation;
- treatment of severe chronic neutropenia, to increase the number of neutrophils and reduction of the frequency and duration of infectious complications;
- treatment of persistent neutropenia in patients with advanced HIV infection (absolute neutrophil count (≤ 1,0h10 9 / l) in order to reduce the risk of bacterial infections.
- mobilize hematopoietic progenitor cells into the peripheral blood of healthy donors with the purpose of their subsequent separation and allogeneic transplantation;Apply strictly on prescription.
: Hypersensitivity to the active substance (filgrastim), or other components of the preparation. Severe congenital neutropenia (Kostmann’s syndrome) with cytogenetic abnormalities. The newborn’s age (immediately after birth to 28 days of life).
With extreme caution filgrastim should be used for acute myeloid leukemia.
In myelodysplastic syndrome (MDS) and chronic myeloid leukemia efficacy and safety of filgrastim has not been established. Patients with the above diseases, as well as with the use of filgrastim is not recommended to precancerous lesions of myeloid blood, because the cells of some tumors can carry a receptor for G-CSF. Therefore, special attention should be paid to the differential diagnosis between the blast crisis of chronic myeloid leukemia and acute myeloid leukemia.
A small number of patients (less than 5%) treated with filgrastim, hyperskeocytosis observed (increase in the number of white blood cells more than 100×10 9 / L). Side effects directly associated with induced hyperskeocytosis filgrastim, is not described. However, given the potential risks associated with hyperskeocytosis, during treatment with filgrastim should be regularly to determine the number of leukocytes. By increasing the number of leukocytes over 50×10 9 / L filgrastim should be discontinued immediately. In the case of filgrastim for the mobilization of hematopoietic stem cells, the drug should be canceled when the number of white blood cells to exceed 70×10 9 / L.
Please note that the use of filgrastim is not preventing thrombocytopenia and anemia. Since thrombocytopenia and anemia are often the consequence of the application of high doses of chemotherapy, it is recommended on a regular basis to determine the number of platelets, and the number of red blood cells or hemoglobin level in the application of filgrastim after chemotherapy.
Particular attention should be paid to the differential diagnosis of severe chronic neutropenia from other hematologic disorders such as aplastic anemia ., myelodysplasia, and myeloid leukemia
in a small number (3%) of patients with severe congenital neutropenia (Kostmann’s syndrome) treated with filgrastim experienced MDS and leukemia.
MDS and leukemia – natural complications of the disease; their relationship to filgrastim treatment is unclear. Approximately 12% of patients with normal cytogenetics when re-examination detected abnormalities, including monosomy 7. If a patient with the syndrome Kostmann appear cytogenetic violations, it is necessary to carefully evaluate the benefits and risks of continuing filgrastim therapy. With the development of MDS or leukemia, filgrastim should be discontinued. It is not yet clear whether long-term treatment predisposes filgrastim in patients with severe congenital neutropenia (Kostmann’s syndrome) to the development of cytogenetic abnormalities, MDS and leukemia. Patients with the syndrome Kostmann is recommended at regular intervals (approximately every 12 months) to conduct morphological and cytogenetic studies of bone marrow.
Use during pregnancy and lactation
Safety of filgrastim in testosterone suspension results pregnant women has not been established, therefore its purpose pregnant can not be recommended. If necessary, the use of filgrastim during lactation, breast-feeding should be discontinued.
Dosing and Administration
Can be administered as a subcutaneous injection or intravenously. The method of administration and dosage will depend on the particular clinical situation, and determined by the attending physician. The preferred route of administration is subcutaneous. If necessary, the desired amount of intravenous drug is injected from the syringe into the vial or a plastic container with a 5% dextrose solution, then made a 30-minute infusion of diluted drug. Due to the increased sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy drugs, drug use is not recommended for less than 24 hours before the start of the course of chemotherapy earlier than 24 hours after completion of chemotherapy.
For the treatment of neutropenia after cytotoxic chemotherapy course Leykostim ® is administered once a day subcutaneously or intravenously at a dose of 5.0 mg (0.5 million IU.) Per 1 kg of body weight of the patient.
In patients receiving cytotoxic chemotherapy, a transient increase neutrophil count is usually observed after 1 – 2 days after initiation of treatment with Leykostim ® . To evaluate the effectiveness of treatment desired daily counting the number of neutrophils in the peripheral blood. To achieve a stable therapeutic effect should continue therapy with Leykostim ® as long as the number of neutrophils expected will not go low and does not reach normal values. After reaching an absolute neutrophil count greater than 2,0×10 9 / l of drug can be discontinued. If necessary, the course treatment duration may be up to 12 days, depending on the severity of the disease testosterone suspension results and severity of neutropenia. Following myeloablative chemotherapy followed by a bone marrow transplantation Leykostim ® is administered subcutaneously or intravenously at 10 mg (1.0 million. IU) per 1 kg of body weight. The first dose of drug Leykostim ® should be administered no sooner than 24 hours after cytotoxic chemotherapy and in bone marrow transplantation – not later than 24 hours after bone marrow infusion. After the time has elapsed maximum reduction in neutrophils, the daily dose is adjusted depending on the number of speakers. If the content of neutrophils in the peripheral blood exceeds 1,0h10 9 / L for three consecutive days, the dose of the drug Leykostim ® halved (to 5.0 mg (0.5 million. IU) per 1 kg of body weight).Then, if the absolute neutrophil count is greater than 1,0h10 9 / L for three consecutive days, Leykostim ® overturned. In the case of reducing the absolute number of neutrophils in the treatment of lower than 1.0 x 10 9 / L, the dose Leykostim again increased to 10 mg (1.0 million. IU) per 1 kg of body weight.
To mobilize hematopoietic stem cells Leykostim ® administered subcutaneously a daily dose of 5.0 mg (0.5 million. IU) per 1 kg of body weight (in patients undergoing myelosuppressive chemotherapy) or 10 mg (1.0 million. IU) per 1 kg of patient weight (without chemotherapy) within 5-7 consecutive days (number of injections depends on the rate of increase in the number of peripheral blood leukocytes and the separation efficiency). The day before the expected date of first separation (4th day of administration of the drug Leykostim ® ) and in the following days (until the day of final separation) estimated the number of leukocytes and neutrophils in the peripheral blood of the patient. Cytapheresis carried out in the case of increasing the number of white blood cells to 5×10 9 / l peripheral blood, starting from 5th day of the drug administration Leykostim ® . After each separation counts the number of nucleated cells and CD34 + cells in a sample intended for cryopreservation. Where the number of cryopreserved CD34 + cells, which is sufficient for transplantation (not less than 2×10 6 per kg weight of the patient), the introduction of Leykostim drug ® stops.
Efficacy and safety of Leykostim drug ® in healthy donors younger than 16 and older than 60 years have not been studied.
In severe chronic neutropenia (TXH) Leykostim ® should be administered subcutaneously daily until the neutrophil count is not consistently exceed 1.5x 10 9 / l (with congenital neutropenia – at a dose of 12 micrograms (1.2 million IU) per 1 kg of weight. patient per day subcutaneously for one or more administrations, with periodic or idiopathic neutropenia -5.0 g (0.5 million IU.) per 1 kg of weight per day). After achieving a therapeutic effect is necessary to determine the minimum effective dose to maintain this level of neutrophils. This requires a long period of daily administration. After 1 – 2 weeks of treatment, the starting dose can be halved or doubled depending on the patient’s response to therapy. Subsequently, every 1 – 2 weeks should correct the dose to maintain the number of neutrophils in the range 1,5-10h10 9/ L. When neutropenia associated with HIV infection: initial dose of 1 – 4 mg (0.1-0.4 million. IU) per 1 kg of body weight per day subcutaneously once to normalize the number of neutrophils (> 2×10 9 / l).Normalization of the number of neutrophils usually occurs within 2 days. With the ineffectiveness of the initial dose escalation carried her up to 5.0 micrograms (0.5 million. IU) per 1 kg of body weight once a day subcutaneously. After achieving a therapeutic effect is supportive drug therapy Leykostim ® in a dose of 1 – 4 mg (0.1 – 0.4 million IU.) Per 1 kg of weight per day, 2-3 times a week. In the future, may require individual adjustment of dose and long-term drug therapy Leykostim ® to maintain the number of neutrophils more 2,0×10 9 / l. Specific guidance on dosing: In the application of filgrastim in pediatric practice in patients with severe chronic neutropenia and cancer safety profile of filgrastim did not differ from that in adults. Dosing recommendations for patients with childhood are the same as for adults receiving myelosuppressive cytotoxic chemotherapy or. No dose adjustment is not required filgrastim in patients with severe renal or hepatic impairment, as their pharmacokinetic and pharmacodynamic indices are similar to those in healthy volunteers.
Treatment with Leykostim ® in the recommended doses may be accompanied by tenderness at the injection site, pain in the bones and muscles.
In a clinical study of the drug Leykostim ® in 7.5% of patients had mild or moderate musculoskeletal pain, which either did not require dosage adjustment, They were cropped or nonsteroidal anti-inflammatory drugs. Severe pain have been reported.
According to the literature, in rare cases, can be identified of delayed-type hypersensitivity at the site of injection, accompanied by the appearance of erythema and edema. In case of such reactions, use of the drug should be discontinued.
In rare cases, the use of filgrastim observed headache, fatigue, diarrhea, hepatomegaly, micturition disorders (mostly slight or moderate dysuria). There are isolated reports of transient decrease in blood pressure, do not require treatment. There may be reversible, dose-dependent and usually mild or moderate increase in lactate concentrations, alkaline phosphatase, serum uric acid, γ-glutamyl transferase, reduction in the number of platelets in peripheral blood.
Occasionally there may be a skin rash, enlargement of the spleen in patients with initially not enlarged spleen, vasculitis, vascular thrombosis. Cases of the appearance of infiltrates in the lungs with the development of adult respiratory distress syndrome; These events were more common after chemotherapy regimens including bleomycin, their connection with the reception of filgrastim has not been established. Very rarely following use of filgrastim observed cases of proteinuria and hematuria.
Extremely rarely observed exacerbation of rheumatoid arthritis during treatment with filgrastim and splenic rupture, thrombocytopenia and anemia with prolonged use of filgrastim. When long-term therapy filgrastim in 2% of patients experienced TXH cutaneous vasculitis.
Overdose Cases of filgrastim is not marked.
Interactions with other drugs
Because of the high sensitivity of actively proliferating myeloid cells to anticancer cytostatic drugs in the appointment of filgrastim should be observed in the interval of 24 hours before or after administration of myelosuppressive drugs. Efficacy and safety of filgrastim administration in one day with cytotoxic chemotherapy have not been established. 5-fluorouracil increases the severity of neutropenia, while the appointment with filgrastim.
Filgrastim pharmaceutically is not compatible with 0.9% sodium chloride solution.
In the application of filgrastim for the mobilization of hematopoietic stem cells after chemotherapy should be noted that when administered for a long time such cytostatics as melphalan , carmustine (BCNU) and carboplatin, the effectiveness of mobilization can be reduced.
Effect on ability to drive vehicles and maintenance mechanisms
Given the mechanism of pharmacological (immunological) activities filgrastim, its impact on the ability to drive and use machines is highly unlikely.