Leucostim, 300 mcg/ml, solution for intravenous and subcutaneous administration, 1 ml, 1 pc.
It is not recommended for use in patients with severely impaired renal or liver function, because the effectiveness and safety of filgrastim in this category of patients has not been studied.
In patients with concomitant bone pathology and osteoporosis receiving filgrastim continuously for more than 6 months, monitoring of bone density is recommended.
The effectiveness of filgrastim in patients with significantly reduced numbers of myeloid progenitor cells has not been studied. Filgrastim increases the number of neutrophils by acting primarily on neutrophil precursor cells. Therefore, in patients with a reduced number 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.
Human G-CSF can induce the growth of myeloid cells in vitro. Similar effects may be observed in vivo in some non-myeloid cells. The safety and effectiveness of filgrastim in patients with myelodysplastic syndrome and chronic myeloid leukemia have not been established, so it is not indicated for these diseases. The differential diagnosis between blast transformation of chronic myeloid leukemia and acute myeloid leukemia should be especially carefully carried out.
During treatment, it is necessary to regularly determine the number of leukocytes. If, after passing the expected minimum, it exceeds 50,000/µl, filgrastim should be discontinued immediately. If filgrastim is used to mobilize peripheral blood hematopoietic progenitor cells, it should be discontinued when the leukocyte count exceeds 100,000/µl.
Use with extreme caution in patients receiving high-dose cytotoxic chemotherapy.
Filgrastim monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. It is recommended to regularly determine the platelet count and hematocrit. Particular caution should be exercised when using single or combination chemotherapy regimens known to cause severe thrombocytopenia.
Before using filgrastim for severe chronic neutropenia, a differential diagnosis with other hematological diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia, should be especially carefully carried out. Before starting treatment, a detailed blood test should be performed to determine the leukocyte formula and platelet count, as well as examine the morphological picture of the bone marrow and karyotype.
The blood picture should be carefully monitored, incl. platelet count, especially during the first few weeks of treatment with filgrastim. In case of thrombocytopenia (platelet count consistently below 100,000/μl), temporary discontinuation of filgrastim or dose reduction should be considered. There are also other changes in the blood count that require careful monitoring, incl. anemia and a transient increase in the number of myeloid progenitor cells.
During treatment, the size of the spleen should be regularly monitored and a urine test should be performed.
When assessing the number of progenitor cells mobilized in patients with filgrastim, special attention should be paid to the quantification method. The results of flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology, and caution should be exercised in making cell count recommendations based on studies performed in other laboratories.
There have been no specific studies of the effectiveness and safety of filgrastim in elderly patients.
The safety and effectiveness of use in newborns and patients with autoimmune neutropenia have not been established.
Leucostim
Instructions for use:
LEUCOSTIM®
Registration number:
Trade name of the drug:
Leucostim®.
International nonproprietary name:
filgrastim.
Dosage form:
solution for intravenous and subcutaneous administration.
Compound.
1 ml of solution contains:
active substance:
filgrastim (recombinant human granulocyte colony-stimulating factor) 600 mcg (60 million IU).
Excipients:
mannitol, dextran 60000, sodium acetate trihydrate, glacial acetic acid, polysorbate 80, water for injection.
Description.
Transparent, colorless solution.
Pharmacotherapeutic group.
Leukopoiesis stimulator.
ATX Code:
L03AA02.
Pharmacological properties.
Pharmacodynamics.
Filgrastim is a highly purified non-glycosylated protein consisting of 175 amino acids.
It is produced by a strain of Escherichia coli,
into the genome of which the gene for human granulocyte colony-stimulating factor (G-CSF), a glycoprotein that regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow, has been introduced using genetic engineering.
Leucostim containing recombinant G-CSF significantly increases the number of neutrophils in peripheral blood within the first 24 hours after administration, with a slight increase in the number of monocytes. In
patients with severe chronic neutropenia, Leukostim® may cause a slight increase in the number of circulating eosinophils and basophils. Leucostim® dose-dependently increases the number of neutrophils with normal or increased functional activity. After treatment, the number of neutrophils in the peripheral blood decreases by 50% within 1-2 days and returns to normal levels over the next 1-7 days. The duration of action when administered intravenously may be shortened. The clinical significance of this phenomenon with repeated administration of the drug is unclear.
The use of the drug Leukostim®, both independently and after chemotherapy, mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Autologous or allogeneic peripheral blood stem cell (PBSC) transplantation is performed after therapy with large doses of cytostatics, either instead of bone marrow transplantation or in addition to it. PSCC transplantation may also be indicated after (high-dose) myelosuppressive cytotoxic therapy. The use of PSCC mobilized using the drug Leukostim® 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 effectiveness and safety of Leukostim in adults and children receiving cytotoxic chemotherapy are the same.
In children and adults with severe chronic neutropenia (severe congenital, periodic, idiopathic neutropenia), Leucostim® consistently increases the number of neutrophils in the peripheral blood and reduces the incidence of infectious complications. Prescribing Leukostim® to patients with HIV infection allows them to maintain normal neutrophil counts and follow the recommended doses of antiretroviral and/or other myelosuppressive therapy. There were no signs of increased HIV replication when using the drug Leucostim®. Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro.
Pharmacokinetics.
With intravenous and subcutaneous administration of filgrastim, a positive linear relationship is observed between the administered dose and serum concentration. After subcutaneous administration of therapeutic doses, its concentration exceeds 10 ng/ml for 8-16 hours. The volume of distribution is 150 ml/kg.
Regardless of the route of administration, the elimination of filgrastim proceeds according to the rules of 1st order kinetics. The half-life is 3.5 hours, clearance is 0.6 ml/min/kg. Long-term administration of filgrastim up to 28 days after autologous bone marrow transplantation does not lead to accumulation and an increase in the half-life. In patients with end-stage renal disease, there is an increase in maximum concentration (Cmax) and area under the curve (AUC), and a decrease in volume of distribution and clearance compared with healthy volunteers and patients with moderate renal failure.
Indications for use.
• Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant diseases (except for chronic myeloid leukemia and myelodysplastic syndrome), as well as neutropenia and its clinical consequences in patients receiving myeloablative therapy followed by allogeneic or autologous bone marrow transplantation.
• Mobilization of peripheral blood stem cells, including after myelosuppressive therapy.
• Severe congenital, recurrent or idiopathic neutropenia (absolute neutrophil count less than or equal to 0.5x109/L) in children and adults with a history of severe or recurrent infections.
• Persistent neutropenia (absolute neutrophil count less than or equal to 1.0x109/l) in patients with advanced HIV infection to reduce the risk of bacterial infections when other treatments are ineffective or impossible to use.
Contraindications.
• Hypersensitivity to filgrastim or other components of the drug.
• Severe congenital neutropenia (Kostmann's syndrome) with cytogenetic disorders.
• Use of the drug to increase doses of cytotoxic chemotherapy drugs above the recommended ones.
• Simultaneous administration with cytotoxic chemotherapy and radiation therapy.
• End-stage chronic renal failure.
• Myelodysplastic syndrome (MDS) and chronic myeloid leukemia (no data on efficacy and safety)
• Lactation.
• Newborn age (up to 28 days of life).
Carefully.
During pregnancy, malignant and precancerous diseases of a myeloid nature (including acute myeloid leukemia), sickle cell anemia, in combination with high-dose chemotherapy.
Use during pregnancy and lactation.
The safety of filgrastim in pregnant women has not been established. It is possible for the drug Leucostim to pass through the placental barrier in women. When prescribing Leucostim® to pregnant women, the expected therapeutic effect should be balanced against the possible risk to the fetus. In animal studies, filgrastim was not teratogenic. An increased rate of miscarriage was observed, but no fetal anomalies were noted.
There is no data on the penetration of filgrastim into breast milk. The use of Leucostim® in nursing mothers is not recommended.
Method of administration and dose.
Daily subcutaneously (SC) or as short intravenous (IV) infusions (30 minutes). The drug can also be administered as a 24-hour intravenous or subcutaneous infusion.
The choice of route of administration depends on the specific clinical situation. The preferred route of administration is subcutaneous.
Standard cytotoxic chemotherapy regimens.
At a dose of 5 mcg (0.5 million IU)/kg once a day daily subcutaneously or in the form of short intravenous infusions. The first dose of the drug is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. A transient increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Leukostim®. To achieve a stable therapeutic effect, it is necessary to continue therapy with Leucostim® until the number of neutrophils passes the expected minimum and reaches normal values. If necessary, the duration of therapy can be up to 14 days, depending on the severity of the disease and the severity of neutropenia. After induction and consolidation therapy for acute myeloid leukemia, the duration of therapy with Leukostim® may increase to 38 days, depending on the type, dose and mode of administration of the cytotoxic drugs used.
It is not recommended to discontinue Leucostim® prematurely, before the expected minimum number of neutrophils occurs.
After myeloablative chemotherapy followed by bone marrow transplantation.
The recommended starting dose is 10 mcg (1.0 million IU)/kg, diluted in 20 ml of 5% dextrose solution, as a 30-minute or 24-hour intravenous infusion or by continuous subcutaneous infusion over 24 hours. First dose Leucostim® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and in case of bone marrow transplantation - no later than 24 hours after bone marrow infusions. The duration of therapy is no more than 28 days. After the maximum reduction in the number of neutrophils, the daily dose is adjusted depending on the dynamics of their number. If the content of neutrophils in peripheral blood exceeds 1.0 x109/l for three consecutive days, the dose of Leucostim® is reduced to 5.0 mcg (0.5 million IU)/kg; if at this dose the absolute number of neutrophils exceeds 1.0x109/l for three more days in a row, Leucostim® is discontinued. If during the treatment period the absolute number of neutrophils decreases to less than 1.0 xYue/l, the dose of Leucostim® is increased again in accordance with the above scheme.
Mobilization of peripheral blood stem cells (PBSCs) after myelosuppressive therapy followed by autologous PBSC transfusion with (or without) bone marrow transplantation or in patients with myeloablative therapy followed by PBSC transfusion.
At a dose of 10 mcg (1.0 million IU)/kg by subcutaneous injection once a day or continuous 24-hour subcutaneous infusion for 6 consecutive days, two consecutive leukapheresis procedures on the 5th, 6th are usually sufficient days. In some cases, additional leukapheresis may be performed. The prescription of Leukostim® must be continued until the last leukapheresis.
Mobilization of PSCC after myelosuppressive therapy.
At a dose of 5 mcg (0.5 million IU)/kg by daily subcutaneous injection, starting on the first day after completion of chemotherapy until the neutrophil count passes the expected minimum and reaches normal values. Leukapheresis should be performed during the period when the absolute neutrophil count rises from less than 0.5 x 109/L to more than 5.0 x 109/L. For patients who have not received intensive chemotherapy, leukapheresis alone is sufficient. In some cases, additional leukapheresis is recommended.
Mobilization of PSCCs from healthy donors for allogeneic transplantation.
At a dose of 10 mcg (1.0 million units)/kg per day subcutaneously, for 4-5 days. Leukapheresis is carried out from the 5th day and, if necessary, until the 6th day in order to obtain CD34+ cells in an amount of >4x106 cells/kg of the recipient’s body weight. The effectiveness and safety of Leucostim® in healthy donors under 16 and over 60 years of age have not been studied.
Severe chronic neutropenia (SCN).
Daily subcutaneously, once or divided into several injections. The initial dose for congenital neutropenia is 12 mcg (1.2 million IU)/kg per day, for idiopathic or periodic neutropenia - 5 mcg (0.5 million IU)/kg per day, until the number of neutrophils is stable above 1, 5x109/l. Once a therapeutic effect has been achieved, the minimum effective dose to maintain this neutrophil level should be determined. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient's response to therapy. Subsequently, dose adjustments can be made every 1 to 2 weeks to maintain the neutrophil count in the range of 1.5-10 x109/L.
In patients with severe infections, a more rapid dose escalation regimen may be used. In 97% of patients who responded positively to treatment, a full therapeutic effect is observed when filgrastim doses are prescribed up to 24 mcg/kg/day. The daily dose of Leucostim® should not exceed 24 mcg/kg.
Neutropenia in HIV infection.
The initial dose is 1-4 mcg (0.1-0.4 million IU)/kg per day once subcutaneously until the number of neutrophils normalizes (>2x109/l). Normalization of the number of neutrophils usually occurs after 2 days. After achieving a therapeutic effect, a maintenance dose of 300 mcg per day every other day. In the future, individual dose adjustment and long-term therapy with Leucostim® may be required to maintain the neutrophil count more than 2.0 x109/l.
Special dosage instructions.
Elderly age:
There are no special recommendations for elderly patients.
Children:
When used in pediatric practice in patients with severe chronic neutropenia and cancer, the safety profile of filgrastim did not differ from that in adults. Dosing recommendations for pediatric patients are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.
No dosage adjustment of filgrastim is required in patients with severe renal or hepatic impairment, as their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.
Recommendations for preparing a solution for intravenous administration.
If intravenous administration of the drug Leucostim® is necessary, the required amount of the drug is injected from a syringe into a vial or plastic container with a 5% dextrose solution.
Leucostim® cannot be diluted with 0.9% sodium chloride solution.
If the drug is diluted to a concentration of less than 15 mcg/ml (less than 1.5 million IU/ml), then human serum albumin should be added to the solution so that the final albumin concentration is 2 mg/ml. For example, with a final solution volume of 20 ml, a total dose of Leucostim® less than 300 mcg (less than 30 million IU) should be administered with the addition of 0.2 ml of a 20% solution of human albumin. Leukostim® should not be diluted to a final concentration of less than 2 mcg/ml (less than 0.2 million IU/ml).
Leucostim®, when diluted with a 5% dextrose solution or a 5% dextrose solution and albumin, is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (a copolymer of polypropylene and polyethylene) and polypropylene.
Syringes with Leukostim® are intended for single use only.
The prepared solution of Leucostim® is stored at a temperature of 2 to 8°C for no more than 24 hours.
Side effect.
Adverse reactions are listed according to the following gradation: very often (> 10%); often (> 1% - < 10%); infrequently (> 0.1% - < 1%); rare (>0.01% to <0.1%); very rare (<0.01%).
From the hematopoietic organs:
very often - neutrophilosis and leukocytosis (as a consequence of the pharmacological action of filgrastime), with long-term administration - anemia, splenomegaly; often - thrombocytopenia; very rarely - rupture of the spleen.
From the respiratory system:
often - cough; very rarely - infiltrates in the lungs, adult respiratory distress syndrome.
From the musculoskeletal system:
often - pain in bones, muscles, joints; often - osteoporosis; very rarely - exacerbation of rheumatoid arthritis, pseudogout (pyrophosphate arthropathy)
From the cardiovascular system:
very rarely - decreased or increased blood pressure, skin vasculitis (with long-term therapy in patients with SCN).
From the digestive system:
often – diarrhea, hepatomegaly.
From the genitourinary system:
rarely – hematuria, proteinuria; very rarely - dysuria.
From the skin and its appendages:
often – skin rash, with long-term use alopecia; rarely - Sweet's syndrome (acute febrile neutrophilic dermatosis, connection with taking filgrastim has not been established).
Allergic reactions:
very rarely - skin rash, urticaria, facial swelling, wheezing, shortness of breath, low blood pressure, tachycardia.
From the laboratory parameters:
very often - reversible, weak Moderate increase in the activity of gammaglutamyltransferase, alkaline phosphatase, lactate dehydrogenase, increase in the concentration of uric acid in the blood serum, transient hypoglycemia; rarely - increased aspartate aminotransferase activity.
Others:
often - headache, increased fatigue, general weakness, reactions at the injection site (less than 2% of patients with SCN).
Overdose.
There have been no cases of filgrastim overdose. 1-2 days after discontinuation of the drug, the number of circulating neutrophils usually decreases by 50% and returns to normal levels after 1-7 days.
Interaction with other drugs.
The effectiveness and safety of administering filgrastim on the same day as cytotoxic chemotherapy have not been established. Due to the high sensitivity of actively proliferating myeloid cells to antitumor cytotoxic drugs, it is not recommended to prescribe filgrastim 24 hours before or after the administration of these drugs. There are isolated reports of increased severity of neutropenia with simultaneous administration of filgrastim and 5-fluorouracil. There is currently no data on possible interactions with other hematopoietic growth factors and cytokines.
Given that lithium stimulates the release of neutrophils, the effect of filgrastim may be enhanced when used in combination. Interaction studies between lithium and filgrastim have not been conducted.
Filgrastim is not pharmaceutically compatible with 0.9% sodium chloride solution.
When using filgrastim to mobilize hematopoietic stem cells after chemotherapy, it should be taken into account that when cytostatics such as melphalan, carmustine and carboplatin are prescribed for a long time, the effectiveness of mobilization may be reduced.
Special instructions.
Treatment with Leukostim® should be carried out under the supervision of a physician experienced in the use of colony-stimulating factors, if the necessary diagnostic capabilities are available. Cell mobilization and apheresis procedures should be performed in specialized medical institutions.
In myelodysplastic syndrome (MDS) and chronic myeloid leukemia, the effectiveness and safety of filgrastim have not been established. For patients with the above diseases, the use of filgrastim is not indicated. Particular attention should be paid to the differential diagnosis between blast crisis of chronic myeloid leukemia and acute myeloid leukemia.
Particular care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematological diseases such as aplastic anemia, myelodysplasia and myeloid leukemia.
A small number (3%) of patients with severe congenital neutropenia (Kostmann's syndrome) treated with filgrastim have developed MDS and leukemia. MDS and leukemia are natural complications of this disease; their relationship to filgrastim treatment is unclear. In approximately 12% of patients with initially normal cytogenetics, anomalies were discovered upon re-examination, including monosomy 7. If cytogenetic abnormalities appear in a patient with Kostmann's syndrome, or if MDS or leukemia develops, filgrastim should be discontinued. It is not yet clear whether long-term treatment with filgrastim predisposes patients with Kostmann syndrome to the development of cytogenetic abnormalities, MDS and leukemia. Patients with Kostmann syndrome are recommended to undergo morphological and cytogenetic studies of the bone marrow at regular intervals (approximately every 12 months).
Cytogenetic disorders, leukemia and osteocorosis were found with long-term use of filgrastim (>5 years) in 9.1% of patients with severe chronic neutropenia. Their connection with taking the drug has not been clarified.
Treatment with filgrastim should be carried out under regular monitoring of a complete blood count with counting the leukocyte formula and platelet count (before starting therapy and then 2 times a week with standard chemotherapy and at least 3 times a week with mobilization of PSCC with or without subsequent bone marrow transplantation). If the leukocyte count increases to more than 50x109/l, filgrastim should be discontinued immediately. If filgrastim is used to mobilize hematopoietic stem cells, it must be discontinued if the leukocyte count exceeds 70 x109/l.
Filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. It is recommended to regularly perform blood tests twice a week to determine platelet count and hematocrit while using filgrastim after chemotherapy.
Platelet counts should be carefully monitored, especially during the first few weeks of treatment with filgrastim. In case of SCN, during the first weeks of initial therapy, a clinical blood test and platelet count are determined 2 times a week, and if the patient’s condition is stable - once a month. If the patient develops thrombocytopenia (platelet count consistently below 100×10%), temporary discontinuation of the drug or dose reduction should be considered. There are also other changes in the blood count that require careful monitoring, incl. anemia and a transient increase in the number of myeloid progenitor cells.
Causes of transient neutropenia such as viral infections should be excluded.
During treatment with filgrastim, urine tests should be performed regularly (to exclude hematuria and proteinuria) and the size of the spleen should be monitored.
The safety and effectiveness of filgrastim in neonates and patients with autoimmune neutropenia have not been established.
After bone marrow transplantation, a blood test is performed and the platelet count is determined 3 times a week.
Patients who have received active myelosuppressive therapy in the past may not have a sufficient increase in PSCC to the recommended minimum level (>2.0x106CD34+/
Kr). In this regard, in such patients, if it is necessary to undergo PSCC transplantation, it is recommended to plan their mobilization at an early stage of the course of treatment, and if, as a result of mobilization before the introduction of high-dose chemotherapy, it was not possible to obtain a sufficient number of PSCCs, then alternative types of treatment should be considered, not requiring the use of progenitor cells.
When using filgrastim-mobilized PSCC, a decrease in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloablative chemotherapy is observed.
There is a complex; but a stable statistical relationship between the number of introduced CO34+ cells and the rate of normalization of the platelet count after high-dose chemotherapy.
A minimum number of PSCC equal to or exceeding 2.0 × 106 CO34+ cells/kg leads to a sufficient restoration of hematological parameters.
Mobilization of PSKs can only be considered in those healthy donors whose clinical and laboratory parameters, especially hematological parameters, meet the criteria for selecting donors for mobilization of PSKs.
Transient leukocytosis (leukocytes more than 50x109/l) is observed in 41% of healthy donors, more than 75x109/l - in 2% of healthy donors. Transient thrombocytopenia (platelet count less than 100x109/l) after administration of filgrastim and leukapheresis is observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50 xl09/l were noted after the leukapheresis procedure.
If more than one leukapheresis is required, special care should be taken if the donor's platelet count before leukapheresis is less than 100x109/L. Leukapheresis is not recommended if the platelet count is less than 75 xl0/l, as well as in donors with impaired hemostasis or receiving anticoagulants.
Filgrastim should be discontinued or its dose reduced if the white blood cell count exceeds 70 x109/L.
In healthy donors, it is necessary to regularly monitor all blood test parameters until they normalize.
Considering isolated cases of splenic rupture after the administration of granulocyte colony-stimulating factor to healthy donors, it is recommended to monitor its size (palpation, ultrasound).
During long-term observation of the safety of filgrastim use in healthy donors up to 4 years after filgrastim administration, no cases of hematopoiesis disorders were noted. However, the risk of stimulating the emergence of a clone of malignant myeloid cells cannot be excluded, and therefore, in apheresis centers it is recommended to systematically monitor healthy stem cell donors for at least 10 years.
Special instructions for recipients of allogeneic PSCC obtained with filgrastim:
the use of allogeneic PSCC graft may be associated with an increased risk of acute or chronic graft-versus-host disease compared with bone marrow transplantation.
When treating HIV-infected patients with neutropenia with filgrastim, it is necessary to regularly conduct a complete blood count (absolute neutrophil count (ANC), 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. Given fluctuations in the ANC value, to determine the true maximum reduction in ANC (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 by infectious pathogens (for example, Mycobacterium avium complex) or with tumor lesions of the bone marrow (lymphoma), filgrastim therapy is carried out simultaneously with therapy directed against these conditions.
In patients with sickle cell anemia, blood tests should be performed regularly and the possibility of splenomegaly and vascular thrombosis should be taken into account.
In patients with bone pathology and osteoporosis receiving continuous treatment with filgrastim for more than 6 months, bone density monitoring is indicated.
The effect of filgrastim in patients with a significantly reduced number of myeloid progenitor cells is not known. Filgrastim increases the number of neutrophils by acting primarily on neutrophil precursor cells. Therefore, in patients with a reduced number 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.
A history of pneumonia or pulmonary infiltrates may be risk factors for interstitial lung disease during filgrastim therapy. The appearance of cough, fever and shortness of breath associated with the appearance of infiltrates in the lungs may be the first signs of the development of adult respiratory distress syndrome. If these signs appear, filgrastim should be discontinued and appropriate treatment should be prescribed.
The effect of the drug on the ability to drive vehicles and maintain machinery.
There was no effect of filgrastim on the ability to drive vehicles and operate machinery.
Release form.
Solution for intravenous and subcutaneous administration 600 mcg/ml (60 million IU/ml). 0.8 ml of a drug with a concentration of 600 mcg/ml (60 million IU/ml), containing 480 mcg (48 million IU) of filgrastim in neutral glass syringes with soldered needles and a butyl rubber stopper laminated with a fluoropolymer, sealed with tips on pistons.
1 or 5 syringes complete with pistons (1 or 5, respectively) in a blister pack made of PVC film, along with instructions for use in a cardboard box.
Storage and transportation conditions.
At temperatures from 2 to 8 °C. Keep out of the reach of children.
Best before date.
2 years. Do not use after the expiration date stated on the package.
Conditions for dispensing from pharmacies.
Dispensed by prescription.
Manufacturer. LLC "Biocad", Petrovo-Dalneye, Moscow region.
www.biocad.ru and www.leucostim.ru
Leucostim®
Treatment with Leukostim® 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 at an oncology or hematology center with experience in this field and the ability to adequately monitor hematopoietic progenitor cells.
Infrequent cases of splenic rupture, in some cases with a fatal outcome, have been described during the use of G-CSF (filgrastim). Given these data, careful monitoring of the size of the spleen using clinical examination (palpation) and instrumental methods (for example, ultrasound) is recommended. It is necessary to carry out targeted diagnosis if a splenic rupture or splenomegaly is suspected in case of complaints from patients or healthy donors of pain in the upper quadrant of the abdomen or upper shoulder region.
According to the literature, the presence of sickle cell anemia and a high white blood cell count is an unfavorable prognostic factor. In such patients, blood tests should be performed regularly and the possibility of splenomegaly and vascular thrombosis should be taken into account.
Cases of sickle cell crises have been described during the use of filgrastim, some with a fatal outcome. Caution should be exercised in patients with sickle cell disease when prescribing Leucostim® (filgrastim), carefully assessing the benefits and possible risks.
Due to the frequent incidence of thrombocytopenia in patients treated with filgrastim, careful monitoring of platelet counts is recommended.
Patients with bone tissue pathology, including osteoporosis, receiving continuous treatment with Leucostim® for more than 6 months are advised to monitor bone density.
The effect of Leukostim® in patients with a significantly reduced number of myeloid progenitor cells is unknown. Leukostim® increases the number of neutrophils by acting primarily on neutrophil precursor cells, so in patients with reduced numbers of progenitor cells (for example, those who have undergone intensive radiation or chemotherapy), the degree of increase in the number of neutrophils may be lower.
The effect of Leukostim® on graft-versus-host disease has not been established.
When symptoms such as cough, fever and dyspnea occur, in combination with radiological findings in the form of pulmonary infiltrates and deterioration of lung function, the development of adult respiratory distress syndrome can be assumed. In this case, drug therapy should be discontinued and appropriate treatment should be prescribed.
Growth of malignant cells
The safety and effectiveness of Leukostim® in patients with myelodysplastic syndrome and chronic myeloid leukemia have not been established, therefore it is not indicated for these diseases. Particular 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 may be observed in vitro
in some non-myeloid cells. Leukostim® should be used with caution in patients with secondary acute myeloid leukemia, due to limited data on safety and effectiveness in this case.
Safety and efficacy of Leukostim® in patients with de novo
under 55 years of age in the case of prognostically favorable cytogenetic factors (translocations t(8;21), t(l5;17), inv(16)) have not been established.
Patients receiving cytotoxic chemotherapy
Leukocytosis:
in less than 5% of patients receiving Leukostim® in doses of more than 0.3 million units (3 mcg/kg per day), the number of leukocytes increased to 100 x 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 leukocyte count should be monitored regularly (for example, 2-3 times a week) during treatment with Leukostim®. If, after passing the expected minimum, it exceeds 50 x 109/l, Leucostim® should be discontinued immediately.
If Leucostim® is used to mobilize PSCC, it is discontinued when the leukocyte count exceeds 70 x 109/L.
Risks associated with high-dose chemotherapy:
Particular caution should be exercised when treating patients receiving high-dose chemotherapy, since no improvement in cancer outcome has been observed, while higher doses of chemotherapy have greater toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems (see instructions for the use of specific chemotherapy drugs).
Monotherapy with Leukostim® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapy drugs (eg, full doses according to regimens), the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly perform blood tests twice a week to determine the platelet count and hematocrit. Particular caution should be exercised when using single-component or combination chemotherapy regimens that can cause severe thrombocytopenia.
It has been shown that the use of Leukostim® for the mobilization of PSCC leads to a decrease in the degree and duration of thrombocytopenia that develops as a result of myelosuppressive or myeloablative chemotherapy.
Patients with SCN
Transformation into leukemia or preleukemia (myelodysplastic syndrome):
Particular 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 examine the morphological picture of the bone marrow and karyotype.
Myelodysplastic syndrome and leukemia have been observed in a small number (3%) of patients with severe congenital neutropenia (Kostmann's syndrome) treated with Leucostim®. Myelodysplastic syndrome and leukemia are natural complications of this disease; their relationship to filgrastim treatment is unclear. Approximately 12% of patients with initially normal cytogenetics were found to have abnormalities upon re-examination, including monosomy 7. If a patient with Kostmann's syndrome develops cytogenetic abnormalities, the benefits and risks of continuing therapy with Leukostim should be carefully assessed. If myelodysplastic syndrome or leukemia develops, Leucostim® should be discontinued. It is unknown whether long-term treatment with Leucostim predisposes patients with severe congenital neutropenia (Kostmann's syndrome) to the development of cytogenetic abnormalities, myelodysplastic syndrome and leukemia. Patients with Kostmann syndrome are recommended to undergo regular (approximately every 12 months) morphological and cytogenetic studies of the bone marrow.
Cytogenetic abnormalities, leukemia and osteoporosis were found with long-term use of filgrastim (>5 years) in patients (9.1%) with severe chronic neutropenia. The connection between these phenomena and the use of the drug has not been clarified.
Blood formula:
The platelet count should be carefully monitored, especially during the first few weeks of treatment with Leukostim®. In case of severe chronic neutropenia, during the first weeks of initial therapy, a clinical blood test and platelet count are determined 2 times a week, if the patient’s condition is stable - once a month. If the patient develops thrombocytopenia (platelet count consistently below 100 x 109/L), temporary discontinuation of the drug or dose reduction should be considered. There are also other changes in the blood count 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 treatment with filgrastim. During clinical studies, 31% of patients with SCN had splenomegaly on palpation. When radiographically, the increase in volume is detected soon 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, urine tests should be performed regularly.
The safety and effectiveness of the drug in newborns and patients with autoimmune neutropenia have not been established.
Patients undergoing PSCC mobilization
After bone marrow transplantation, a blood test is performed and the platelet count is determined 3 times a week.
Mobilization:
The two recommended mobilization methods (filgrastim alone or in combination with myelosuppressive chemotherapy) have not been compared in the same patient population. Direct comparison of results from different studies is difficult due to individual differences between patients and also due to differences between CD34+ values obtained using laboratory tests. Therefore, it is quite difficult to recommend any optimal mobilization method. The choice of mobilization method should be made depending on the overall goals of treatment for a given patient.
Previous treatment with cytotoxic agents:
Patients who have received active myelosuppressive therapy in the past may not sufficiently increase PBMC to the recommended minimum level (≥2.0 x 106 CD34+ cells/kg) or accelerate platelet count normalization.
Some cytostatics are particularly toxic to hematopoietic progenitor cells and may negatively affect their mobilization. The use of drugs such as melphalan, carmustine and carboplatin for a long period before the onset of mobilization can reduce its severity. However, the use of melphalan, carboplatin or carmustine together with the drug Leukostim® is effective in activating PSCC.
If transplantation of PSCC is planned, 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 such patients before high-dose chemotherapy. If mobilization results are insufficient according to the above criteria, alternative treatments that do not require the use of progenitor cells should be considered.
Estimation of the number (“harvest”) of peripheral blood stem cells:
When assessing the number of PSCCs mobilized in patients using the drug Leukostim®, special attention should be paid to the method of quantitative determination. Results from flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology, and data on cell counts based on studies performed in other laboratories should be used with caution.
There is a complex but stable statistical relationship between the number of reinfused CD34+ cells and the rate of platelet count normalization after high-dose chemotherapy. A minimum number of PSCC equal to or greater than 2.0 x 106 CD34+ cells/kg leads to sufficient restoration of hematological parameters. An amount exceeding this value is apparently accompanied by a faster normalization; an amount less than this is accompanied by a slower normalization of the blood picture.
Mobilization of PSCCs in healthy donors
The PSCC mobilization procedure does not directly benefit healthy donors and should only be performed for the purpose of allogeneic transplantation.
Cell mobilization and apheresis procedures should be performed at a center with experience in this field. Mobilization of PSCC is possible only if laboratory parameters, especially hematological parameters of the donor, meet the selection criteria, and special attention should be paid to the presence of infectious diseases.
Transient leukocytosis (leukocytes more than 50 x 109/l) is observed in 41% of healthy donors, more than 75 x 109/l - in 2% of healthy donors. Transient thrombocytopenia (platelet count less than 100 x 109/l) after administration of filgrastim and leukapheresis is observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50 x 109/L were noted after the leukapheresis procedure.
If more than one leukapheresis is required, the platelet count should be monitored before each apheresis procedure, especially if the platelet count is less than 100 x 109/L. Leukapheresis is not recommended if the platelet count is less than 75 x 109/L, when anticoagulants are prescribed or when there are known hemostasis disorders.
Leukostim® should be discontinued or its dose reduced if the leukocyte count is more than 70 x 109/L.
In healthy donors, it is necessary to regularly monitor all blood test parameters until they normalize.
Considering isolated cases of splenic rupture after the administration of G-CSF to healthy donors, it is recommended to monitor its size (palpation, ultrasound).
The risk of the emergence of a clone of malignant tumor cells cannot be excluded. It is recommended that the apheresis center systematically monitor the long-term safety of the drug in healthy donors.
The safety and effectiveness of Leukostim® in healthy donors under 16 and over 60 years of age has not been assessed.
Special instructions for recipients of allogeneic PSCC obtained with filgrastim
The use of allogeneic PSCC graft may be associated with an increased risk of acute or chronic graft-versus-host disease compared with bone marrow transplantation.
Neutropenia in HIV patients
With a very rapid positive response to therapy, a significant increase in the number of neutrophils is possible after the administration of initial doses of Leukostim®.
When treating with Leucostim®, it is necessary to regularly conduct a complete blood count (absolute count of neutrophils, 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 for time of maintenance therapy. When carrying out maintenance therapy of 300 mcg per day according to an alternating regimen, significant fluctuations in the number of neutrophils are possible.
Given fluctuations in the absolute neutrophil count, to determine the true maximum reduction in neutrophil count (nadir), blood sampling should be performed before prescribing the next dose of the drug.
Monotherapy with Leukostim® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapy (eg, full doses according to regimens) or more of them in combination therapy, the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly perform blood tests and determine the platelet count and hematocrit.
In patients with infectious diseases and infiltration of the bone marrow by infectious pathogens (for example, Mycobacterium avium complex) or with a tumor lesion of the bone marrow (lymphoma), filgrastim therapy is carried out simultaneously with therapy directed against these conditions. The effectiveness of Leukostim® in the treatment of neutropenia caused by infiltration of the bone marrow by infectious agents (osteomyelitis) or tumor lesions has not been established.
Instructions for use, handling and disposal
Vigorous shaking should be avoided.
Before administration, the Leucostim® solution should be inspected for the presence of foreign visible particles. It is allowed to administer the solution only without the presence of foreign visible particles.
Vials and pre-filled syringes with Leucostim® are intended for single use only.
The release of medicinal products into the environment should be minimized. Disposal of Leucostim® through wastewater or household waste is not permitted. Where possible, special systems should be used to dispose of medications.
