Composition, form of production and packaging
The solution for the / in and / or the introduction of a transparent, colorless.
1 ml
filgrastim 30 million AD (300 Ојg)
Excipients: D-sorbitol - 50 mg, polysorbate 80 - 0.04 mg, sodium acetate trihydrate - 0.204 mg, glacial acetic acid - 0.48 ml, water d / u - up to 1 ml.
1 ml - bottles of colorless glass (1) - packs of cardboard.
1 ml - syringes of colorless glass (1) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
Leukopoiesis stimulant. Filgrastim is a highly purified non-glycosylated protein consisting of 175 amino acids. It is produced by the strain Escherichia coli, into the genome of which gene of granulocyte colony-stimulating factor of human (G-CSF) - glycoprotein, which regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow. Filgrastim, containing recombinant G-CSF, significantly increases the number of neutrophils in peripheral blood as early as the first 24 hours after administration, with a slight increase in the number of monocytes. In patients with severe chronic neutropenia filgrastim may cause a slight increase in the number of circulating eosinophils and basophils.
Filgrastim 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 is reduced by 50% within 1-2 days and returns to normal within the next 1-7 days. Duration of action with / in the introduction may be shortened.The clinical significance of this phenomena with repeated administration of the drug is unclear.
Application filgrastima both independently and after chemotherapy, mobilizes the yield of hematopoietic stem cells in the peripheral bloodstream. Autologous or allogeneic transplantation of peripheral blood stem cells (PSKK) is performed after therapy with large doses of cytostatics, or instead of bone marrow transplantation, or in addition to it. Transplantation of PSKK can also be administered after (high-dose) myelosuppressive cytotoxic therapy . The use of PSKK, mobilized with filgrastim, accelerates the restoration of hematopoiesis, reduces the severity and duration of thrombocytopenia, the risk of hemorrhagic complications and the need for transfusion of platelet mass after myelosuppressive or myeloablative therapy.
The efficacy and safety of filgrastim in adults and children receiving cytotoxic chemotherapy are the same.
In children and adults with severe chronic neutropenia (severe congenital, periodic, idiopathic neutropenia) filgrastim stably increases the number of neutrophils in peripheral blood, reduces the incidence of infectious complications.
The appointment of filgrastim to patients with HIV infection can support normal neutrophil count and follow recommended doses of antiretroviral and / or other myelosuppressive therapy. There are no signs of an increase in HIV replication with filgrastim.
Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro .
PHARMACOKINETICS
Suction and distribution
With iv and n / k administration of filgrastim a positive linear relationship between the administered dose and serum concentration is observed. After Рї / Рє administration in therapeutic doses, its plasma concentration exceeds 10 ng / ml for 8-16 hours. V d - 150 ml / kg.
Excretion
Regardless of the method of administration, the elimination of filgrastim proceeds according to the rules of kinetics of the first order. T 1/2 - 3.5 h, the clearance is 0.6 ml / min / kg. Long-term administration of filgrastim up to 28 days after autologous bone marrow transplantation does not result in cumulation and an increase in T 1/2.
Pharmacokinetics in special clinical cases
In patients with end-stage renal failure, an increase in C max and AUC and a decrease in V d and clearance are observed compared with healthy volunteers and patients with moderate-level renal failure.
INDICATIONS
- neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant neoplasms (with the exception of 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, incl. after myelosuppressive therapy;
- severe congenital, periodic or idiopathic neutropenia (absolute number of neutrophils is 0.5 Г— 10 9 / L) in children and adults with severe or recurrent infections in the anamnesis;
- persistent neutropenia (absolute number of neutrophils is 1.0 Г— 10 9 / L) in patients with developed stage of HIV infection to reduce the risk of bacterial infections when other methods of treatment are not possible.
DOSING MODE
The drug is administered daily s / c or in the form of short intravenous infusions (30-minute). Also, the drug can be administered in the form of 24-hour IV or infusion.
The choice of route of administration depends on the specific clinical situation. Preferably after the route of administration.
Standard schemes of cytotoxic chemotherapy
Enter in a dose of 5 Ојg (0.5 million IU) / kg 1 time / day daily sc, 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 beginning of treatment with the Immu- grastВ® preparation. To achieve a stable therapeutic effect, it is necessary to continue therapy with Immu- grast В® until the number of neutrophils passes the expected minimum and reaches normal values. If necessary, the duration of the course 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 of acute myelogenous leukemia, the duration of ImmugastВ® application may increase up to 38 days depending on the type, dosage and mode of administration of the cytotoxic drugs used.
It is not recommended to cancel Immugrast В® prematurely, before the expected minimum of neutrophil count.
After myeloablative chemotherapy followed by bone marrow transplantation
The recommended initial dose is 10 Ојg (1.0 million IU) / kg diluted in 20 ml of a 5% dextrose solution in the form of a 30-minute or 24-hour IV infusion or by continuous subcutaneous infusion for 24 hours. The first dose of Immugast В® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and when bone marrow transplantation - no later than 24 hours after the infusion of the bone marrow. 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 neutrophil count in the peripheral blood exceeds 1.0 Г— 10 9 / L for 3 consecutive days, the dose of ImmugastВ® is reduced to 5 Ојg (0.5 million IU) / kg; if at this dose the absolute number of neutrophils exceeds 1.0 Г— 10 9 / L for another 3 consecutive days, Immugrast В® is canceled. If during the treatment period the absolute number of neutrophils decreases less than 1.0 Г— 10 9 / l, the dose of ImmugastВ® is increased again, in accordance with the above scheme.
Mobilization of peripheral blood stem cells after myelosuppressive therapy followed by autologous transfusion of PSKK with or without bone marrow transplantation or in patients with myeloablative therapy followed by transfusion of PSKK
Enter a dose of 10 Ојg (1.0 million IU) / kg by injection 1 time / day or a continuous 24-hour infusion for 6 consecutive days, with two leukapheresis procedures in a row at the 5th, 6th days. In some cases, additional leukapheresis is possible. The appointment of Immugast В® should be continued until the last leukapheresis.
Mobilization of PSKC after myelosuppressive therapy
Enter a dose of 5 Ојg (0.5 million IU / kg) by daily injections, starting from the first day after completion of chemotherapy and until the amount of neutrophils passes through the expected minimum and reaches normal values. Leukapheresis should be performed during the period when the absolute number of neutrophils rises from less than 0.5 Г— 10 9 / L to more than 5.0 Г— 10 9 / L. Patients who did not receive intensive chemotherapy, it is enough to have one leukapheresis. In some cases, additional leukapheresis is recommended.
Mobilization of PSKC in healthy donors for allogeneic transplantation
Enter a dose of 10 mcg (1.0 million AD) / kg / day p / c, for 4-5 days. Leukapheresis is performed from the 5th day and, if necessary, until the 6th day in order to obtain CD34 + cells in an amount of? 4 Г— 10 6 cells / kg body weight of the recipient. The efficacy and safety of Immugast В® in healthy donors under the age of 16 and older than 60 years have not been investigated.
Severe chronic neutropenia (THC)
Enter daily s / to, once or divided into several introductions. With congenital neutropenia, the initial dose of 12 Ојg (1.2 million IU) / kg / day, with idiopathic or periodic neutropenia - 5 Ојg (0.5 million IU) / kg / day to a stable excess of the number of neutrophils 1.5 Г— 10 9 / l. After achieving the therapeutic effect, the minimum effective dose should be determined to maintain this level of neutrophils. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient's response to therapy. Subsequently, every 1-2 weeks, you can make a dose adjustment to maintain the number of neutrophils in the range of 1.5-10 Г— 109 / l.
In patients with severe infections, a scheme with a faster increase in dose can be used. In 97% of patients who responded positively to the treatment, the full therapeutic effect is observed when prescribing doses of filgrastim up to 24 mcg / kg / day. The daily dose of Immugast В® should not exceed 24 mcg / kg.
Neutropenia in HIV infection
The initial dose of 1-4 mcg (0.1-0.4 million MIU) / kg / day once p / to the normalization of the number of neutrophils (? 2 Г— 10 9 / l). Normalization of the number of neutrophils usually occurs in 2 days. After reaching the therapeutic effect, a maintenance dose of 300 Ојg / day every other day. In the future, individual dose adjustment and long-term therapy with Immu- grastВ® may be required to maintain a neutrophil count of more than 2.0 Г— 10 9 / L.
Dosing in special clinical cases
For elderly patients, there are no special recommendations for dosing.
In children with severe chronic neutropenia and oncological diseases, the profile of filgrastim safety did not differ from that in adults. Recommendations for dosing for children are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.
Correction of filgrastim dose is not required in patients with severe renal or hepatic insufficiency , their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.
Rules for the preparation of a solution for intravenous administration
If necessary, in / in the introduction of Immugast В®, the required amount of the drug is injected from the syringe into a vial or plastic container with 5% dextrose solution.
Immugast В® can not be diluted with 0.9% sodium chloride solution.
If the drug is diluted to less than 15 Ојg / ml (less than 1.5 million IU / ml), then serum albumin should be added to the solution so that the final concentration of albumin is 2 mg / ml. For example, with a final solution volume of 20 ml, the total dose of ImmugastВ® preparation should be less than 300 Ојg (less than 30 million ME) with the addition of 0.2 ml of a 20% human albumin solution. Do not dilute Immugrast В® to a final concentration of less than 2 Ојg / ml (less than 0.2 million IU / ml).
ImmouragistВ® when diluted with 5% dextrose solution or 5% dextrose solution and albumin is compatible with glass and a number of plastics, in t.ch.polyvinylchloride, polyolefin (copolymer of polypropylene and polyethylene) and polypropylene.
Syringes with Immugast В® are for single use only.
A ready-made solution of Immugast В® is stored at a temperature of 2 to 8 В° C for no more than a day.
SIDE EFFECT
Determination of the frequency of adverse reactions: very often (> 10%); often (> 1%, <10%); infrequently (> 0.1%, <1%); rarely (> 0.01%, <0.1%); very rarely (> 0.01%).
From the hemopoietic system: very often - neutrophilia and leukocytosis (as a consequence of the pharmacological action of filgrastim), with prolonged use - anemia, splenomegaly; often - thrombocytopenia; very rarely - rupture of the spleen.
On the part of the respiratory system: often - cough; very rarely - infiltrates in the lungs, adult respiratory distress syndrome.
From the musculoskeletal system: often - pain in the bones, muscles, joints, osteoporosis; very rarely - exacerbation of rheumatoid arthritis, pseudogout (pyrophosphate arthropathy).
From the cardiovascular system: very rarely - a decrease or increase in blood pressure, cutaneous vasculitis (with prolonged therapy in patients with THC).
On the part of 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 prolonged use - alopecia; rarely - Sweet syndrome (acute febrile neutrophilic dermatosis, connection with filgrastim is not established).
Allergic reactions: very rarely - skin rash, hives, face swelling, wheezing, shortness of breath, lowering blood pressure, tachycardia.
On the part of laboratory indicators: very often - reversible, weak and moderate increase in GGT, APP, LDH, an increase in the concentration of uric acid in the blood serum, transient hypoglycemia; rarely - increase of ACT activity.
Other: often - headache, fatigue, general weakness, reactions at the injection site (less than 2% of patients with TCN).
CONTRAINDICATIONS
- severe congenital neutropenia (Costman's syndrome) with cytogenetic disorders;
- use of the drug in order to increase the doses of cytotoxic chemotherapeutic drugs above recommended;
- simultaneous appointment with cytotoxic chemo- and radiotherapy;
- terminal stage of chronic renal failure;
- Myelodysplastic syndrome (MDS) and chronic myeloid leukemia (no data on efficacy and safety);
- the period of lactation (breastfeeding);
- Newborn age (up to 28 days of life);
- Hypersensitivity to the components of the drug.
Caution should be prescribed in pregnancy, malignant and premalignant diseases of the myeloid nature (including acute myeloid leukemia), sickle cell anemia, in combination with high-dosage chemotherapy.
PREGNANCY AND LACTATION
Safety filgrastim for pregnant women is not established. Perhaps the passage of filgrastim through the placental barrier in women. When prescribing ImmugastВ®, pregnant women should correlate the expected therapeutic effect to the mother with a possible risk to the fetus.
In animal studies, filgrastim did not have a teratogenic effect. There was an increased incidence of miscarriages, but no abnormalities of fetal development were noted.
There is no data on the penetration of filgrastim into breast milk. Apply Immugast В® during breastfeeding is not recommended.
APPLICATION FOR FUNCTIONS OF THE LIVER
Correction of filgrastim dose is not required in patients with severe renal insufficiency . their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Correction of filgrastim dose is not required in patients with severe hepatic insufficiency , their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.
APPLICATION FOR CHILDREN
Contra-indication: newborn (up to 28 days of life).
In children with severe chronic neutropenia and oncological diseases, the profile of filgrastim safety did not differ from that in adults. Recommendations for dosing for children are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.
APPLICATION IN ELDERLY PATIENTS
For elderly patients, there are no special recommendations for dosing.
SPECIAL INSTRUCTIONS
Treatment with Immugast В® should only be carried out under the supervision of a doctor who has experience with colony-stimulating factors, provided that the necessary diagnostic capabilities are available. Procedures for mobilization and apheresis of cells should be carried out in specialized medical institutions.
With MDS and chronic myeloid leukemia, the efficacy and safety of filgrastim have not been established. Patients with the abovementioned diseases of filgrastim not shown. Particular attention should be paid to a differential diagnosis between the blast crisis of chronic myelogenous leukemia and acute myelogenous leukemia.
Particular care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematologic diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia.
In a small number (3%) of patients with severe congenital neutropenia (Costman's syndrome) who received filgrastim, MDS and leukemia were observed. MDS and leukemia are natural complications of this disease; their connection with treatment with filgrastim is not clear. Approximately 12% of patients with initially normal cytogenetics were found to have anomalies during a second examination, including. monosomy 7. If patients with Kostmann syndrome appear cytogenetic abnormalities, as well as the development of MDS or leukemia, filgrastim should be discontinued. It is not yet clear whether long-term treatment predisposes filgrastim in patients with Kostmann 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.
Cytogenetic abnormalities, leukemia and osteoporosis have been found long-term use of filgrastim (> 5 years) in 9.1% of patients with severe chronic neutropenia. Their connection with the drug intake is not clear.
Filgrastim treatment should be performed under regular control of blood count with the counting of leukocyte and platelet count (before treatment and then 2 times per week with standard chemotherapy and at least 3 times a week for mobilization PSCC with or without subsequent bone marrow transplantation). By increasing the number of leukocytes greater than 50 x 10 9 / L, filgrastim should be discontinued immediately. If filgrastim used to mobilize hematopoietic stem cells, it is necessary to cancel, at excess leukocyte count 70 x 10 9 / l.
Monotherapy filgrastim did not prevent the development of thrombocytopenia and anemia due to myelosuppressive chemotherapy. It is recommended to regularly twice a week to carry out a blood test to determine platelet count and hematocrit in the application of filgrastim after chemotherapy.
It is necessary to carefully monitor the number of platelets, especially during the first few weeks of treatment with filgrastim. When TXH during the first weeks of therapy initial CBC and platelet counts determined two times per week, at a stable condition of the patient - 1 time per month. If a patient develops thrombocytopenia (platelet count consistently below 100 Г— 10 9/ L), should be considered a temporary drug discontinuation or dose reduction. There are also other changes in blood counts, requiring careful control, including anemia and a transient increase in the number of myeloid progenitor cells.
It is necessary to eliminate the causes of transient neutropenia, such as viral infections.
During treatment with filgrastim should be regularly urine (for proteinuria and hematuria exceptions) and to control the size of the spleen.
Safety and efficacy of filgrastim in neonates and patients with autoimmune neutropenia have not been established.
After bone marrow transplantation carried out blood and platelet counts determined 3 times a week.
In patients who in the past been actively pursued myelosuppressive therapy is sufficient to increase the PSCC recommended minimum may not occur (? 2.0 x 10 6CD34 +-cells / kg). In this regard, such patients when the need for transplantation PSCC, it is recommended to plan their mobilization in the early course of treatment stages, while if the result of the mobilization before the introduction of high-dose chemotherapy was not possible to obtain a sufficient number of PBSC, you should consider alternative treatments that do not require the use of cells precursor.
When using mobilized PBSC filgrastim observed reduction in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloablative chemotherapy.
There is a complex but stable statistical relationship between the number of introduced CD34 + cell, and platelet counts rate normalization after high-dose chemotherapy.
Minimum number PSCC equal to or greater than 2 Г— 10 6 of CD34 + -cells / kg, leads to sufficient hematological recovery.
Conducting mobilization PBSC can only be considered for those healthy donors who have clinical and laboratory parameters, especially haematological, meet the criteria for the selection of donors to mobilize PBSC.
Transient leukocytosis (? Leukocytes 50 10 9 / L) was observed in 41% of healthy donors more than 75 10? 9 / l - 2% of healthy donors. Transient thrombocytopenia (platelet count of less than 100 x 10 9/ L) after administration of filgrastim and leukapheresis conduct is observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50 x 10 9 / l after leukapheresis procedure.
If required more than one conducting leukapheresis necessary to control the platelet count before each apheresis procedure, particularly if the platelet count below 100 x 10 9 / l. Undergo leukapheresis is not recommended if the platelet count less than 75 Г— 10 9 / l, as well as donors, in violation of hemostasis or receiving anticoagulants.
Filgrastim should be discontinued or the dose should be reduced if the leukocyte count exceeds 70 x 10 9 / l.
In healthy donors, all parameters of blood analysis to their normalization must be checked regularly.
Given the isolated cases of splenic rupture after administration of G-CSF from healthy donors, it is recommended to control its size (palpation, ultrasound).
With long-term monitoring of the safety of the use of filgrastim in healthy donors up to 4 years after the application of filgrastim, violations of hematopoiesis was observed. However, to eliminate the risk of occurrence of stimulation clones of malignant myeloid cells is impossible, so it is recommended apheresis centers systematically observe healthy donor stem cells for at least 10 years.
Specific guidance for recipients of allogeneic PBSC obtained by filgrastim:PSCC application allograft may be associated with increased risk of developing acute or chronic reaction "graft versus host" as compared to bone marrow transplantation.
Filgrastim in the treatment of HIV-infected patients with neutropenia should be regularly full 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 every week or every other week during maintenance therapy. Considering fluctuations ANC values to determine the true maximum reduction of ANC (nadir), blood sampling should be carried out before assigning the next dose.
In patients with infectious diseases and bone marrow infiltration of infectious agents (e.g., complex Mycobacterium avium) or tumorous lesions of the bone marrow (lymphoma) filgrastim therapy is performed simultaneously with therapy directed against these conditions.
Patients with sickle cell disease should regularly carry out a blood test and consider the possibility of splenomegaly and thrombosis.
Patients with bone disease and osteoporosis receiving filgrastim continuous treatment for more than 6 months, shows control bone density.
Effect of filgrastim in patients with severely reduced the number of myeloid progenitor cells is not known. Filgrastim increases the number of neutrophils by acting primarily on precursor cells of neutrophils. Therefore, in patients with a reduced content of progenitor cells (for example, those subjected to 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 a factor in the risk of interstitial lung disease on the background of filgrastim therapy. The emergence of a cough, fever and shortness of breath associated with the appearance of pulmonary infiltrates may be the first signs of adult respiratory distress syndrome. When these signs filgrastim should be discontinued and appropriate treatment.
Impact on the ability to drive vehicles and manage mechanisms
There was no effect of filgrastim on ability to drive and use machines.
OVERDOSE
Cases of filgrastim overdose are not marked. After 1-2 days after the drug is usually the number of circulating neutrophils is reduced by 50% and returns to normal after 1-7 days.
DRUG INTERACTION
The efficacy and safety of filgrastim administration in one day with cytotoxic chemotherapy have not been established. Due to the high sensitivity of actively proliferating myeloid cells to cytotoxic anticancer drugs assign filgrastim for 24 hours before or after administration of these drugs is not recommended.
There are some reports on strengthening the severity of neutropenia, while the use of filgrastim and fluorouracil.
Data on possible interactions with other hematopoietic growth factors and cytokines no.
Given that lithium promotes the release of neutrophils, may increase filgrastim action when combined appointment. Studies on the interaction of lithium and filgrastim not conducted.
Filgrastim pharmaceutically incompatible with 0.9% sodium chloride solution.
In the application of filgrastim mobilization of hematopoietic stem cells after the chemotherapy should be noted that when administered for a long time cytostatics such as melphalan, carmustine and carboplatin, mobilization efficiency may be reduced.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be kept out of reach of children at a temperature of from 2 В° to 8 В° C; Do not freeze. Shelf life - 2 years.
Transported at a temperature of from 2 В° to 8 В° C in a cold box; Do not freeze.
