Characteristic
Filgrastim is a highly purified non-glycosylated polypeptide containing 175 amino acid residues.
MTPLGPASSLPQSFLLKCLEQ-VRKIQDGGAAL-
QEKLCATYKLCHPEELVLLGH-SLGIPWAPLSS-
CPSQALQLAGCLSQLHSGLFL-YQGLLQALEGI-
SPELGPTLDTLQLDVADFATT-IWQQMEELGMA-
PALQPTQGAMPAFASAFQRRA-GGVLVASHLQS-
FLEVSYRVLRHLAQP
C 845 H one thousand three hundred thirty-six O 242 N 223 S 9 M.m.: 18798
It is produced by a genetically modified culture of Escherichia coli BL21 (DE3) / pES3-7, which contains the human granulocyte colony-stimulating factor (G-CSF) gene.
Human G-CSF regulates the formation of functionally active neutrophils and their entry into the blood from the bone marrow.
Filstim, which contains recombinant G-CSF, significantly increases the number of neutrophils in the peripheral blood within the first 24 hours after administration and simultaneously causes a slight increase in the number of monocytes.
The increase in the number of neutrophils and their functional characteristics depend on the dose.
The use of filgrastim preparations significantly reduces the frequency and duration of neutropenia in patients after chemotherapy with cytostatics, myeloablative therapy followed by bone marrow transplantation.
Patients who received the drug required hospitalization less often, spent less time in the hospital, and took lower doses of antibiotics compared to patients who received only cytotoxic therapy.
The use of Filstim (both primary and after chemotherapy) activates peripheral blood progenitor cells (PBPCs).
In children and adults with severe chronic neutropenia (severe congenital, recurrent and malignant neutropenia), the drug stably increases the number of peripheral blood neutrophils and reduces the frequency of infectious complications.
After the end of treatment with the drug, the number of neutrophils in the peripheral blood decreases by 50% within 1-2 days and returns to normal levels within 1-7 days.
Pharmacological properties
Pharmacokinetics. After subcutaneous administration of the drug at recommended doses, its serum concentration exceeds 10 ng/ml for 8-16 hours; the volume of distribution in the blood is about 150 ml/kg. The average half-life of filgrastim from serum is about 3.5 hours, and the clearance rate is about 0.6 ml/min per 1 kg. Continuous infusion for 28 days in patients recovering from autologous bone marrow transplantation was not accompanied by signs of cumulation and an increase in the half-life of the drug.
Indication
To reduce the duration and frequency of neutropenia, including that accompanied by a febrile reaction, in patients receiving chemotherapy with cytotoxic agents for non-myeloid malignant diseases.
To reduce the duration of neutropenia and its clinical consequences in patients receiving myeloablative therapy followed by bone marrow transplantation.
For the mobilization of autologous PBPCs, including after myelosuppressive therapy, to accelerate the restoration of hematopoiesis by administering these cells after myelosuppression or myeloablation.
With long-term therapy aimed at increasing the number of neutrophils, to reduce the frequency and shorten the duration of infectious complications in children and adults with severe congenital, periodic or malignant neutropenia (absolute neutrophil count 500 in 1 mm 3) and with a history of severe or recurrent infections.
Application
When conducting cytotoxic chemotherapy according to standard regimens, the drug is prescribed at a dose of 0.5 million units (5 mcg) per 1 kg of body weight once a day subcutaneously or by intravenous administration.
In myeloablative therapy followed by bone marrow transplantation, the initial dose of filgrastim - 1 million IU (10 mcg) per 1 kg of body weight per day - is administered intravenously drip over 30 minutes or by continuous intravenous infusion over 24 hours, or subcutaneously.
Before intravenous administration, the drug is diluted in 20 ml of 5% glucose solution; the first dose is administered no earlier than 24 hours after cytotoxic therapy or bone marrow transplantation.
Filstim is administered daily until the neutrophil count reaches the expected minimum and then normal values. The duration of treatment can be up to 14 days depending on the type of doses and regimen of cytotoxic chemotherapy.
Due to cytotoxic chemotherapy, an increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Filstim. However, to obtain a stable therapeutic effect, it is necessary to continue therapy until the number of neutrophils passes the expected minimum and reaches normal values. It is not recommended to cancel the drug prematurely, before reaching the required minimum value of the number of neutrophils.
After the maximum decrease in the number of neutrophils has passed, the daily dose should be adjusted taking into account the dynamics of their number: if the number of neutrophils exceeds 1000 in 1 mm 3 for 3 consecutive days, the dose of the drug is reduced to 0.5 million IU (5 μg) / kg per day; then, if the absolute number of neutrophils exceeds 1000 in 1 mm 3 also for 3 days, the drug is canceled. If during the treatment the absolute number of neutrophils decreases to 1000 in 1 mm 3, the dose of the drug should be increased again according to the above scheme.
In severe congenital neutropenia, the drug is administered at an initial dose of 1.2 million IU (12 mcg) / kg per day s / c once or divide the daily dose into several injections.
Patients with severe chronic neutropenia should receive daily subcutaneous administration until the neutrophil count is consistently above 1500/mm3. After achieving a therapeutic effect, the effective minimum maintenance dose is determined. To maintain the required number of neutrophils, long-term daily administration of the drug is required. After 1-2 weeks of treatment, the initial dose can be doubled or halved depending on the patient's response to therapy. In the future, individual dose adjustments can be made every 1-2 weeks to maintain the average neutrophil count in the range of 1500-10,000/mm3. For patients with severe infections, a regimen with a more rapid dose increase can be used.
After preparation, diluted drug solutions should be stored in a refrigerator at 2-8°C for no more than 24 hours.
Contraindication
Hypersensitivity to the drug. Severe congenital neutropenia (Kostman syndrome) with cytogenetic abnormalities.
Side effects
In patients receiving cytotoxic chemotherapy, treatment with filgrastim is often accompanied by bone and muscle pain, usually mild to moderate, sometimes severe. In most cases, the pain is relieved by taking analgesics. Less common side effects are urinary disorders (mainly mild to moderate dysuria). There are isolated reports of a temporary decrease in pain that did not require treatment.
Reversible, dose-dependent, usually mild to moderate increases in serum LDH, LF, uric acid, and γ-glutamyltransferase concentrations may often be observed.
Sometimes in patients who received high-dose chemotherapy with subsequent autologous bone marrow transplantation, vascular disorders (for example, veno-occlusive disease and disturbances of water and electrolyte balance) are noted. The causal relationship of their occurrence with the use of the drug has not been established. Isolated cases of allergic-type reactions have been described, and about half of them were associated with the administration of the first dose. These cases were more often observed after intravenous administration of the drug. Sometimes the resumption of treatment was accompanied by a relapse of allergic symptoms.
Adverse reactions resulting from the use of filgrastim have been described in patients with severe chronic neutropenia, and in some of them the frequency of these reactions decreased over time.
The most common adverse reactions are bone pain and generalized musculoskeletal pain; other adverse reactions include splenic enlargement, which may progress in a small number of patients, and thrombocytopenia; headache and diarrhea have been reported shortly after initiation of filgrastim treatment. There have also been reports of anemia and epistaxis, which occur only with long-term use of the drug.
A transient and clinically asymptomatic increase in serum concentrations of uric acid, LDH and LF was observed, as well as a moderate and reversible decrease in postprandial blood glucose levels.
In patients with severe chronic neutropenia, side effects possibly related to filgrastim were usually observed in less than 2% of patients and included injection site reactions, liver enlargement, joint pain, hair loss, osteoporosis, and skin rash.
During long-term therapy, 2% of patients with severe chronic neutropenia experienced skin vasculitis, and in very rare cases, proteinuria and hematuria.
Special instructions
G-CSF promotes the growth of myeloid cells in vitro. A similar effect in vitro can be observed in some non-myeloid cells. The safety and efficacy of filgrastim in patients with myelodysplasia, acute and chronic myeloid leukemia have not been established. Due to the possible potentiation of tumor growth, filgrastim should be used with caution in malignant myeloid diseases. In any myeloproliferative disease, filgrastim should be used with caution, taking into account the possible risk of leukemia. During treatment with filgrastim, it is necessary to regularly monitor the number of leukocytes; if it exceeds 5000 in 1 mm 3, the drug should be immediately discontinued. If the drug is used for mobilization of PBPC, it is canceled if the number of leukocytes exceeds 10,000 in 1 mm 3.
Particular caution should be exercised when treating patients receiving high-dose chemotherapy. Filgrastim monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy, but allows the use of chemotherapy drugs in higher doses (according to the regimens), as a result of which the patient is at high risk of developing thrombocytopenia and anemia. It is recommended to regularly determine the platelet count and hematocrit. Particular caution should be exercised when using single-component or combination chemotherapy regimens that can cause thrombocytopenia.
Special attention should be paid to the diagnosis of severe forms of chronic neutropenia. It is necessary to differentiate them from such hematological diseases as hypoplastic anemia, myelodysplasia and myeloid leukemia. Before treatment, a comprehensive blood test with a leukocyte formula and platelet count, as well as a study of the morphological composition of the bone marrow and karyotype are indicated.
In patients with severe congenital neutropenia (Kostman syndrome) who received filgrastim, in some cases the development of myelodysplastic syndrome and leukemia was observed, but their relationship to treatment with filgrastim has not been established. If cytogenetic abnormalities are detected in patients with Kostman syndrome, the risk and benefit of continuing filgrastim therapy should be carefully weighed; if myelodysplastic syndrome or leukemia is detected, the drug should be discontinued. It has not yet been established whether long-term treatment with filgrastim in patients with Kostman syndrome contributes to the development of leukemia, therefore, patients with this pathology are recommended to regularly (approximately every 12 months) to conduct morphological and cytogenetic bone marrow studies.
Peripheral platelet counts should be closely monitored, especially during the first few weeks of filgrastim therapy. If thrombocytopenia (platelet count consistently below 100,000/mm3) is detected, consideration should be given to temporarily discontinuing the drug or reducing the dose.
Other changes in blood composition that require constant monitoring are also observed, including anemia and a transient increase in the number of immature myeloid cells.
A cause of transient neutropenia, such as viral infections, should be excluded.
Spleen enlargement is a direct consequence of filgrastim treatment, so regular abdominal palpation is necessary to determine spleen size. When the dose of the drug is reduced, spleen enlargement slowed down and did not progress. Hematuria and proteinuria were detected in a small number of patients. To monitor them, regular laboratory urine tests should be performed.
The safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established.
In patients who have previously received active myelosuppressive therapy, there may not be sufficient activation of the CPP to the recommended minimum level (2 10 6 CD34-positive cells / kg) or acceleration of normalization of the platelet count.
Some cytotoxic agents are particularly toxic to PBMCs and may interfere with their mobilization. Agents such as melphalan, carmustine (BCNU), and carboplatin, if administered for a prolonged period prior to attempting PBMC mobilization, may reduce its effectiveness. However, the use of melphalan, carboplatin, or carmustine in combination with filgrastim has been shown to be effective in activating PBMCs.
If a transplant of the PBPC is planned, it is recommended to perform stem cell mobilization at the beginning of the course of treatment. Particular attention should be paid to the number of progenitor cells activated in such patients before the use of high-dose chemotherapy. If the results of mobilization according to the above criteria are insufficient, alternative treatments that do not require the use of progenitor cells should be considered. When assessing the number of progenitor cells mobilized in patients with filgrastim, special attention should be paid to the method of quantification. The results of a flow study of the number of CD34-positive cells vary depending on the technique used, and caution should be exercised when making recommendations based on studies conducted in different laboratories.
Patients with osteoporosis and concomitant bone pathology who receive continuous treatment with filgrastim for 6 months or more are advised to monitor bone density.
Filgrastim increases neutrophil counts primarily by affecting their progenitor cells. Therefore, in patients with reduced progenitor cell counts (e.g. after intensive radiation or chemotherapy), the degree of increase in neutrophil counts may be less.
Incompatibility. Not studied.
Use during pregnancy and breastfeeding. The safety of Filstim during pregnancy has not been established, it is not known whether Filstim passes into breast milk, therefore its use during breastfeeding is not recommended.
Effect on the ability to drive vehicles. Not studied.
Interactions
The safety and efficacy of administering Filstim on the same day as myelosuppressive cytotoxic chemotherapy have not been established. Given the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, administering Filstim within 24 hours before and after the administration of these drugs is not recommended.
Overdose
Symptoms of an overdose of Filstim are unknown.
Storage conditions
In a place protected from light at a temperature of 2-8 °C.
