Neupogen, syringe-tubes 30000000 units, 0.5ml

Pharmacological action

Hematopoietic.

Clinical pharmacology

Pharmacodynamics hematopoietic growth factor. Filgrastim is a highly purified non-glycosylated protein consisting of 175 amino acids. It is produced by the K12 strain of Escherichia coli, which has been genetically engineered to contain the human granulocyte colony-stimulating factor gene. Human granulocyte colony stimulating factor — G-CSF) is a glycoprotein that regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow. Neupogen® containing recombinant G-CSF significantly increases the number of neutrophils in the peripheral blood already in the first 24 hours after use, with a slight increase in the number of monocytes. In patients with severe chronic neutropenia, Neupogen® may cause a slight increase in the number of circulating eosinophils and basophils. Neupogen ® dose-dependently increases the number of neutrophils with normal or increased functional activity. After the end of treatment, the number of neutrophils in the peripheral blood decreases by 50% within 1-2 days and returns to normal levels within the next 1-7 days. The duration of action during intravenous use may be shortened. The clinical significance of this phenomenon with repeated use of the drug is unclear. Neupogen significantly reduces the frequency, severity, and duration of neutropenia and febrile neutropenia, reducing the need for and duration of inpatient treatment in patients receiving cytostatic chemotherapy or myeloablative therapy followed by bone marrow transplantation. Patients receiving Neupogen® and cytotoxic chemotherapy require lower doses of antibiotics compared to patients receiving cytotoxic chemotherapy alone. Treatment with Neupogen significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy and hospitalization after induction chemotherapy for acute myeloid leukemia, without affecting the frequency of fever and infectious complications. The use of Neupogen® both independently and after chemotherapy mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Autologous or allogeneic peripheral blood stem cell transplantation (PSCC) is performed after therapy with high doses of cytostatics, either instead of bone marrow transplantation, or in addition to it. PSCC transplantation can also be prescribed after (high-dose) myelosuppressive cytotoxic therapy. The use of PSCs mobilized with Neupogen ® accelerates the restoration of hematopoiesis, reduces the severity and duration of thrombocytopenia, the risk of hemorrhagic complications, and the need for platelet transfusion after myelosuppressive or myeloablative therapy. The efficacy and safety of Neupogen® in adults and children receiving cytotoxic chemotherapy are similar. In children and adults with severe chronic neutropenia (severe congenital, recurrent, idiopathic neutropenia) Neupogen® consistently increases the number of neutrophils in the peripheral blood, reduces the frequency of infectious complications. The use of Neupogen® in patients with HIV infection allows maintaining normal neutrophil levels and following the recommended doses of antiretroviral and/or other myelosuppressive therapy. There were no signs of increased HIV replication with Neupogen®. Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro. Pharmacokinetics With intravenous and subcutaneous use of filgrastim, there is a positive linear relationship between the administered dose and the concentration in the blood serum. After subcutaneous use of therapeutic doses, its concentration exceeds 10 ng / ml for 8-16 hours. The volume of distribution is 150 ml / kg. Regardless of the method of use, filgrastim elimination proceeds according to the rules of 1st-order kinetics. T 1/2 — 3.5 h, clearance is equal to 0.6 ml/min/kg. Long-term use of filgrastim up to 28 days after autologous bone marrow transplantation does not lead to accumulation and an increase in T 1/2. In patients with end-stage renal failure, there is an increase in Cmax and area under the curve (AUC), and a decrease in the values of volume of distribution and clearance compared with healthy volunteers and patients with moderate renal insufficiency.

Indications

Use during pregnancy and lactation

The drug is a category C. The safety of Neupogen® for pregnant women has not been established. It is possible for Neupogen® to pass through the placental barrier in women. When prescribing Neupogen® to pregnant women, the expected therapeutic effect should be correlated with the possible risk to the fetus. In studies on rats and rabbits, Neupogen® did not have a teratogenic effect. Rabbits had an increased miscarriage rate, but no fetal abnormalities were observed. It is not known whether Neupogen® penetrates into breast milk. The use of Neupogen® in nursing mothers is not recommended.

Contraindications

With caution:

Side effects

Interaction

The safety and efficacy of Neupogen use on the same day as myelosuppressive cytotoxic chemotherapy drugs have not been established. Due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to prescribe Neupogen® at an interval of 24 hours before or after the use of these drugs. Neutropenia may increase in severity when Neupogen and 5-fluorouracil are co-administered. Possible interactions with other hematopoietic growth factors and cytokines are unknown.Given that lithium stimulates the release of neutrophils, it is possible to increase the effect of Neupogen® with combined use, but such studies have not been conducted. Due to pharmaceutical incompatibilities, do not mix with 0.9% sodium chloride solution.

How to take, course of use and dosage

Daily subcutaneous or in the form of short intravenous infusions (30 minutes) in 5% dextrose solution (see “Dilution instructions”) until the neutrophil count passes the expected minimum (nadir) and returns to the normal range. The choice of route of use depends on the specific clinical situation. The subcutaneous route of use is preferred. Neupogen® vials and syringes are intended for single use only. Standard regimens of cytotoxic chemotherapy.

After myeloablative therapy followed by autologous or allogeneic bone marrow transplantation

Mobilization of peripheral blood stem cells (PSCs) after myelosuppressive therapy followed by autologous PSCs transfusion with or without bone marrow transplantation or in patients with myeloablative therapy followed by PSCS transfusion

PSCC mobilization after myelosuppressive chemotherapy

Mobilization of PSCs from healthy donors for allogeneic transplantation

Severe chronic neutropenia (TCN)

Neutropenia in HIV infection

Special dosage instructions

Instructions for DILUTIONNEPOGEN® is diluted only with 5% dextrose solution, it is not allowed to dilute with 0.9% sodium chloride solution. Diluted Neupogen® can be absorbed by glass and plastics. If Neupogen® is diluted to a concentration of less than 1.5 million units (15 micrograms) in 1 ml, then human serum albumin should be added to the solution in an amount that the final albumin concentration is 2 mg/ml. For example, if the final volume of the solution is 20 ml, total doses of Neupogen® less than 30 million units (300 mcg) should be administered with the addition of 0.2 ml of 20% albumin solution. Neupogen® when diluted with 5% dextrose solution or 5% dextrose solution and albumin is compatible with glass and a number of plastics, including PVC, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene. Do not dilute the drug to a final concentration of less than 0.2 million units (2 micrograms) in 1 ml. The finished Neupogen® solution is stored at a temperature of 2° to 8 °C for no more than a day.

Overdose

No cases of overdose have been reported. After 1-2 days after discontinuation of the drug, the number of circulating neutrophils usually decreases by 50% and returns to normal levels in 1-7 days.

Description

Clear, colorless or slightly yellowish liquid, odorless or slightly odorless.

Special instructions

Treatment with Neupogen should only be carried out under the supervision of an oncologist or hematologist with experience in the use of G-CSF, if the necessary diagnostic capabilities are available. Cell mobilization and apheresis procedures should be performed in an oncology or hematology center that has experience in this area and is able to adequately monitor hematopoiesis progenitor cells. a) Growth of malignant cells The safety and efficacy of Neupogen® in patients with myelodysplastic syndrome and chronic myeloid leukemia have not been established, so it is not indicated for these diseases. Special attention should be paid to the differential diagnosis between acute myeloid leukemia and blast crisis of chronic myeloid leukemia. Human G-CSF can stimulate the growth of myeloid cells in vitro. Similar effects can be observed in vitro for some non-myeloid cells. b) Patients receiving cytotoxic chemotherapyleukocytosis: less than 5% of patients receiving Neupogen® in doses of more than 0.3 million units (3 mcg/kg / day), the number of white blood cells increased to 100·109/l or more. No side effects directly related to such leukocytosis have been described. However, given the possible risk associated with high leukocytosis, the number of white blood cells should be measured regularly during treatment with Neupogen®. If it exceeds 50·109/L after passing the expected minimum, Neupogen® should be discontinued immediately. If Neupogen® is used to mobilize PSCs, it is canceled when the number of white blood cells exceeds 70 * 109/l. Risk associated with high-dose chemotherapy: special caution should be exercised in the treatment of patients receiving high-dose chemotherapy, since there is no improvement in the outcome of the malignancy, while increased doses of chemotherapy drugs have more pronounced toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems (seeinstructions for the use of specific chemotherapy drugs). Neupogen monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapy drugs (for example, full doses according to the regimens), the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly perform a blood test twice a week and determine the number of platelets and hematocrit. Special care should be taken when using single-component or combined chemotherapy regimens that can cause severe thrombocytopenia. c) Patients with TNF transformation into leukemia or pre-leukemia: special care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematological diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia. Before starting treatment, a detailed blood test should be performed to determine the leukocyte formula and platelet count, as well as to study the morphological picture of the bone marrow and karyotype. A small number (3%) of patients with severe congenital neutropenia (Kostmann’s syndrome) treated with Neupogen® experienced myelodysplastic syndrome (MDS) and leukemia. MDS and leukemia are natural complications of this disease, and their association with Neupogen® treatment is unclear. Approximately 12% of patients with initially normal cytogenetics showed abnormalities, including monosomy 7. If a patient with Kostmann’s syndrome develops cytogenetic disorders, the benefits and risks of continuing Neupogen therapy should be carefully evaluated. If MDS or leukemia develops, Neupogen should be discontinued. It is not yet clear whether long-term treatment with Neupogen® predisposes patients with Kostmann’s syndrome to the development of cytogenetic abnormalities, MDS and leukemia. Patients with Kostmann’s syndrome are recommended to conduct regular morphological and cytogenetic studies of the bone marrow (approximately every 12 months). Cytogenetic disorders, leukemia, and osteoporosis were detected with prolonged use of Neupogen® (>5 years) in patients (9.1%) with severe chronic neutropenia. Their connection with taking the drug is not clear. Blood formula: platelet counts should be carefully monitored, especially during the first few weeks of Neupogen treatment. In TCH, during the first weeks of initial therapy, a clinical blood test and platelet count are determined 2 times a week, in a stable patient’s condition-1 time a month. If the patient develops thrombocytopenia (the platelet count is consistently below 100 * 109/L), temporary discontinuation of the drug or a reduction in the dose should be considered. There are also other changes in the blood formula that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells. Other: causes of transient neutropenia such as viral infections should be excluded. Spleen enlargement is a direct consequence of Neupogen®treatment. During clinical studies, splenomegaly was detected on palpation in 31% of patients with TCH. Radiography reveals an increase in spleen volume shortly after the start of treatment and tends to stabilize. Reducing the dose slows or stops the increase in spleen size; splenectomy may be required in 3% of patients. The size of the spleen should be monitored regularly by palpation. Hematuria and proteinuria were observed in a small number of patients. To monitor these indicators, a urine test should be performed regularly. The safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established. d) Patients undergoing PSCC mobilizationafter bone marrow transplantation perform a blood test and determine the number of platelets 3 times a week. Mobilisation: The two recommended mobilisation methods (filgrastim alone or in combination with myelosuppressive chemotherapy) were not compared in the same cohort of patients. The choice of mobilization method should be made depending on the general goals of treatment of this patient. Previous treatment with cytotoxic agents: patients who have previously received active myelosuppressive therapy may not experience a sufficient increase in PSCC to the recommended minimum level (≥2.0 * 106 CD34+/kg) or an acceleration in platelet count normalization. Some cytostatics are particularly toxic to hematopoiesis progenitor cells and may negatively affect their mobilization. The use of melphalan, carboplatin or carmustine together with Neupogen® is effective in activating PSCs. If PSCs are to be transplanted, it is recommended to plan their mobilization at an early stage of the course of treatment. Particular attention should be paid to the number of progenitor cells activated in these patients prior to high-dose chemotherapy. If the mobilization results are insufficient in accordance with the above criteria, alternative treatments that do not require the use of progenitor cells should be considered. Evaluation of the number (“harvest”) of peripheral blood stem cells: when evaluating the number of PSCs mobilized in patients with Neupogen®, special attention should be paid to the method of quantitative determination. The results of flow cytometric analysis of the number of CD34+cells vary depending on the specific methodology, and recommendations for their number based on studies conducted in other laboratories should be treated with caution. There is a complex but stable statistical relationship between the number of CD34+cells reinfused and the rate of platelet count normalization after high-dose chemotherapy. A minimum number of PSCs equal to or greater than 2.0 * 106 CD34+cells / kg leads to a sufficient recovery of hematological parameters. The amount exceeding this value is apparently accompanied by a faster normalization, the amount less than the specified value is accompanied by a slower normalization of the blood picture. e) Mobilization of PSCs from healthy donors Procedures for cell mobilization and apheresis should be performed in a center with experience in this field. PSCC mobilization is possible only if the laboratory parameters, especially the hematological parameters of the donor, meet the selection criteria. Transient leukocytosis (leukocytes greater than 50·109/l) is observed in 41% of healthy donors, more than 75·109/l-in 2% of healthy donors. Transient thrombocytopenia (platelet count less than 100·109/l) after the appointment of filgrastim and leukapheresis is observed in 35% of donors. In addition, there were 2 cases of thrombocytopenia less than 50·109/l after the leukapheresis procedure. If more than one leukapheresis is required, it is necessary to monitor the platelet count before each apheresis procedure, especially if the platelet count is less than 100 * 109/l. Leukapheresis is not recommended if the number of neutrophils is less than 75 * 109 / l, when prescribing anticoagulants or known hemostatic disorders. Neupogen® should be discontinued or its dose should be reduced if the number of white blood cells is more than 70 * 109/l. In healthy donors, it is necessary to regularly monitor all blood test parameters until they normalize. Taking into account isolated cases of spleen rupture after G-CSF use to healthy donors, it is recommended to monitor its size (palpation, ultrasound). Long-term monitoring of the safety of Neupogen® use in healthy donors continues. There are no data on cases of impaired hematopoiesis in healthy donors up to 4 years after Neupogen ® use. However, the apheresis center recommends systematic monitoring of the long-term safety of the drug in healthy donors. Special instructions for recipients of allogeneic PSCs obtained with Neupogen®The use of an allogeneic PSCC graft may be associated with an increased risk of developing an acute or chronic graft-versus-host reaction compared to bone marrow transplantation. Neutropenia in HIV patients When treated with Neupogen®, it is necessary to regularly perform a detailed blood test (ACN, red blood cells, platelets, etc. ) daily for the first few days, then 2 times a week for the first 2 weeks and every week or every other week during maintenance therapy. Taking into account fluctuations in the ACN value, to determine the true maximum reduction in ACN (nadir), blood sampling should be performed before prescribing the next dose of the drug. In patients with infectious diseases and infiltration of the bone marrow with infectious pathogens (for example, Mycobacterium avium complex) or with a tumor lesion of the bone marrow (lymphoma), filgrastim therapy is performed simultaneously with therapy directed against these conditions. g) Other special precautions In patients with sickle cell anemia, blood tests should be performed regularly and the possibility of splenomegaly and vascular thrombosis should be considered. Patients with bone pathology and osteoporosis receiving continuous treatment with Neupogen® for more than 6 months should be monitored for bone density. The effect of Neupogen® in patients with a significantly reduced number of myeloid progenitor cells is not known. Neupogen® increases the number of neutrophils by acting primarily on neutrophil progenitor cells. Therefore, in patients with a reduced content of progenitor cells (for example, those who have undergone intensive radiation therapy or chemotherapy), the degree of increase in the number of neutrophils may be lower. Neupogen® contains sorbitol at a concentration of 50 mg / ml, caution should be exercised in patients with hereditary fructose intolerance. If adult respiratory distress syndrome occurs, therapy with the drug should be discontinued and appropriate treatment should be prescribed. Influence on the ability to drive vehicles and work with machines and mechanisms.There was no effect of Neupogen® on the ability to drive a car or work with mechanisms.

Form of production

Solution for subcutaneous use,1 syringe-tube:

Packaging: 0.5 ml 1 piece syringe tube, complete with injection needle; in a cardboard pack.

Storage conditions

At a temperature of 2-8 °C. Keep out of reach of children.

Shelf

life is 2 years. Do not use after the expiration date indicated on the package.

Active ingredient

Filgrastim

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as prescribed by a doctor, for children as prescribed by a doctor

Indications

Cancer