Expiration date: 05/2026
Dosage form:
solution for intravenous and subcutaneous administration of 60 million ml. IU/ml
Composition
Content per 1 ml:
active substance: filgrastim 60 million ME (corresponds to 600 mcg/ml);
auxiliary substances: glacial acetic acid 0.60 mg/ml, sorbitol 50.0 mg/ml, polysorbate 80 0.055 mg, sodium hydroxide up to pH 4.20, water for injection up to 1.00 ml.
Description
Transparent colorless liquid.
Pharmacotherapeutic group:
leukopoiesis stimulant.
ATX code:
L03AA02
Pharmacological properties
Pharmacodynamics
Filgrastim is a highly purified non—glycosylated protein consisting of 175 amino acids. It is produced by the Escherichia coli strain, in which the human granulocyte colony stimulating factor gene has been introduced into the genome by genetic engineering methods.
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. Filgrastim containing recombinant G-CSF significantly increases the number of neutrophils in peripheral blood in 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 decreases by 50% within 1-2 days and returns to normal levels within the next 1-7 days. The duration of action with intravenous administration may be shortened. Filgrastim significantly reduces the frequency, severity and duration of neutropenia and febrile neutropenia, reducing the need and duration of inpatient treatment in patients receiving cytostatic chemotherapy or myeloablative therapy followed by bone marrow transplantation.
Patients receiving filgrastim and cytotoxic chemotherapy require lower doses of antibiotics compared to patients receiving cytotoxic chemotherapy alone.
Filgrastim treatment 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 filgrastim both independently and after chemotherapy mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Autologous or allogeneic transplantation of peripheral blood stem cells (PCCs) is performed after therapy with high doses of cytostatics, either instead of bone marrow transplantation, or in addition to it. PCC transplantation may also be prescribed after (high-dose) myelosuppressive cytotoxic therapy. The use of PCCs mobilized with filgrastim 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 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 steadily increases the number of neutrophils in the peripheral blood, reduces the frequency of infectious complications.
The administration of filgrastim to patients with HIV infection allows maintaining normal neutrophil levels and following recommended doses of antiretroviral and/or other myelosuppressive therapy. There were no signs of increased HIV replication when using filgrastim.
Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro.
Pharmacokinetics
With intravenous and subcutaneous administration of filgrastim, there is a positive linear relationship 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 method of administration, the elimination of filgrastim proceeds according to the rules of kinetics of the 1st order. The half-life is 3.5 hours, the clearance is 0.6 ml/min /kg.
Prolonged 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 insufficiency, there is an increase in the maximum concentration (Cmax) and the area under the curve (AUC), and a decrease in the volume of distribution and clearance compared with healthy volunteers and patients with moderate renal insufficiency.
Indications for use:
Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant diseases (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, including after myelosuppressive therapy.
Severe congenital, periodic or idiopathic neutropenia (absolute number of neutrophils (ACNE) 0.5 x 109/l or less) in children and adults with a history of severe or recurrent infections.
Persistent neutropenia (ACNE 1.0 x 109/l or less) in patients with advanced stage of HIV infection to reduce the risk of bacterial infections if other treatment methods are not possible.
Contraindications:
Hypersensitivity to the active substance (filgrastim) or other components of the drug; severe congenital neutropenia (Kostmann syndrome) with cytogenetic disorders; use of the drug to increase doses of cytotoxic chemotherapeutic drugs above recommended; concomitant administration with cytotoxic chemotherapy and radiation therapy; terminal stage of chronic renal failure; breastfeeding period; newborn age (up to 28 days of life).
With caution
In pregnancy, malignant and precancerous diseases, including acute myeloid leukemia (insufficient data on efficacy and safety), sickle cell anemia, bone pathology (including osteoporosis), in combination with high-dose chemotherapy, with hereditary fructose intolerance (the drug contains sorbitol).
Use during pregnancy and breastfeeding
The safety of filgrastim for pregnant women has not been established. Filgrastim may pass through the placental barrier in women. When prescribing filgrastim to pregnant women, the expected therapeutic effect should be correlated with the possible risk to the fetus.
There is no data on the penetration of filgrastim into breast milk. It is not recommended to use filgrastim during breastfeeding.
Method of administration and dosage
Daily subcutaneously (subcutaneously) or in the form of short intravenous (IV) infusions (30 minutes) in 5% dextrose solution (see "Instructions for dilution") until the number of neutrophils exceeds the expected minimum (nadir) and returns to the range of normal values. The choice of route of administration depends on the specific clinical situation. The n/a route of administration is preferred.
If necessary, the required amount of the drug is injected from a syringe into a vial or plastic container with a 5% dextrose solution, then a 30-minute infusion of the diluted drug is performed. Syringes with Tevagrastim are intended for single use only.
Breeding instructions
The drug Tevagrastim is diluted with only 5% dextrose solution, it cannot be diluted with 0.9% sodium chloride solution. The diluted preparation can be adsorbed by glass and plastics. If the drug is diluted to a concentration of less than 15 micrograms /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, the total dose of Tevagrastim is less than 300 mcg (less than 30 million mg). ME) should be administered with the addition of 0.2 ml of a 20% solution of human albumin. Tevagrastim should not be diluted to a final concentration of less than 2 micrograms / ml (less than 0.2 million mg). IU/ml).
The finished solution of the drug Tevagrastim should be stored at a temperature of 2 to 8 ° C for no more than a day.
Standard cytotoxic chemotherapy regimens
At a dose of 5 micrograms (0.5 million IU) / kg once a day, daily, subcutaneously or intravenously in the form of short infusions (30 minutes) on 5% dextrose solution. The first dose of the drug is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. 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 consolidating therapy of acute myeloid leukemia, the duration of use of Tevagrastim may increase to 38 days, depending on the type, doses and cytotoxic chemotherapy regimen used.
A transient increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Tevagrastim. To achieve a stable therapeutic effect, it is necessary to continue therapy with Tevagrastim until the number of neutrophils exceeds the expected minimum and reaches normal values.
It is not recommended to cancel the drug Tevagrastim prematurely, before the number of neutrophils passes the expected minimum. Treatment should be discontinued if ACNE after nadir has reached 1.0 x 109 / l.
After myeloablative chemotherapy followed by bone marrow transplantation
Subcutaneous or intravenous infusion in 20 ml of 5% dextrose solution. The initial dose is 10 mcg (1.0 million IU) / kg intravenously for 30 minutes or 24 hours or by continuous subcutaneous infusion for 24 hours. The first dose of Tevagrastim should be administered no earlier than 24 hours after cytotoxic chemotherapy, and in bone marrow transplantation - no later than 24 hours after bone marrow infusion. The duration of therapy is no more than 28 days. After the maximum decrease in the number of neutrophils (nadir), the daily dose is adjusted depending on the dynamics of their number. If the number of neutrophils in peripheral blood exceeds 1.0 x 109 / l for three consecutive days, the dose of Tevagrastim is reduced to 5.0 mcg (0.5 million IU) / kg; then, if ACNE exceeds 1.0 x 109 / l for three consecutive days, Tevagrastim is discontinued. If, during the treatment period, ACNE decreases to less than 1.0 x 109 / l, the dose of Tevagrastim is increased again, in accordance with the above scheme.
Mobilization of peripheral blood stem cells (PCCs) after myelosuppressive therapy followed by autologous PCC transfusion with (or without) bone marrow transplantation or in patients with myeloablative therapy followed by PCC transfusion
At a dose of 10 mcg (1.0 million IU) / kg by subcutaneous injection 1 time per day or continuous 24-hour subcutaneous infusion for 6 consecutive days, while two leukapheresis procedures in a row on the 5th and 6th days are usually sufficient. In some cases, additional leukapheresis may be performed. The use of the drug Tevagrastim should be continued until the last leukapheresis.
Mobilization of PCCs after myelosuppressive therapy
At a dose of 5 micrograms (0.5 million IU) / kg by daily injection, starting from the first day after completion of chemotherapy and until the number of neutrophils passes through the expected minimum and reaches normal values. Leukapheresis should be performed during a period when ACNE 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, one leukapheresis may be enough. In some cases, additional leukapheresis is recommended.
Mobilization of PCCs in healthy donors for allogeneic transplantation
At a dose of 10 mcg (1.0 million units) / kg / day n / a, for 4-5 days. Leukapheresis is performed from day 5 and, if necessary, until day 6 in order to obtain CD34+ cells in an amount of at least 4 x 106 cells / kg of body weight of the recipient. The efficacy and safety of Tevagrastim in healthy donors under 16 and over 60 years of age have not been studied.
Severe chronic neutropenia (TN)
Daily n / a, about once or divided into several introductions. In congenital neutropenia: the initial dose is 12 mcg (1.2 million IU) / kg / day, in idiopathic or periodic neutropenia - 5 mcg (0.5 million IU) / kg / day, until the stable excess of the number of neutrophils is 1.5 x 109 / L. After achieving a therapeutic effect, the minimum effective dose should be determined to maintain this number 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, dose adjustments can be made every 1-2 weeks to maintain the number of neutrophils in the range of 1.5-10 x 109/l.
In patients with severe infections, a regimen with a faster dose increase can be applied. In 97% of patients who responded positively to treatment, the full therapeutic effect is observed with doses of filgrastim up to 24 mcg / kg / day. The daily dose of Tevagrastim should not exceed 24 mcg / kg / day.
Neutropenia in HIV infection
The initial dose is 1-4 mcg (0.1-0.4 million IU) / kg / day, once, n / a until the neutrophil count is normalized (at least 2 x 109 / l). Normalization of the number of neutrophils usually occurs after 2 days. After achieving the therapeutic effect, the maintenance dose is 300 mcg per day 2-3 times a week according to the alternating scheme (every other day). In the future, individual dose adjustment and long-term therapy with Tevagrastim may be required to maintain the number of neutrophils over 2.0 x 109/ l.
Special instructions for dosing
There are no special dosage recommendations for elderly patients.
Children's age: in children with CKD and oncological diseases, the safety profile of filgrastim did not differ from that of adults. The dosage recommendations for children are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.
Dose adjustment of filgrastim is not required in patients with severe renal or hepatic insufficiency, since their pharmacokinetic and pharmacodynamic parameters are similar to those in healthy volunteers.
Side effect
Side effects are distributed according to the classification by frequency of occurrence: very common (? 1/10); often (? 1/100, but < 1/10); infrequently (? 1/1000, but < 1/100); rarely (? 1/10000, but < 1/100); very rare (< 1/10000); unknown frequency (cannot be determined based on available data).
Patients with cancer
The most common adverse effects associated with the use of filgrastim at the recommended dose were mild or moderate musculoskeletal pain (in 10% of patients) and severe musculoskeletal pain (in 3% of patients). Musculoskeletal pain was usually eliminated with standard analgesic treatment. Less frequent adverse effects were urinary disorders (mainly mild to moderate dysuria).
Filgrastim did not increase the frequency of adverse reactions associated with cytotoxic chemotherapy. Undesirable effects were observed with equal frequency in patients with filgrastim/chemotherapy and placebo/chemotherapy, including nausea and vomiting, alopecia, diarrhea, fatigue, lack of appetite, inflammation of the mucous membranes (mucositis), headache, cough, skin rash, chest pain, general weakness, sore throat, constipation and nonspecific pain.
Reversible, dose-dependent and usually mild to moderate increases in lactate dehydrogenase (LDH), alkaline phosphatase (alkaline phosphatase), uric acid concentration and gamma-glutamyltransferase (GGT) activity in blood plasma were observed when filgrastim was used at recommended doses in approximately 50%, 35%, 25% and 10% of patients, respectively.
Occasionally, there was a transient decrease in blood pressure (BP), which did not require therapeutic intervention.
A graft-versus-host reaction and death of patients receiving HCF after allogeneic bone marrow transplantation have been reported.
Sometimes, vascular disorders, including venoocclusive disease and disorders associated with water metabolism in the body, were noted in patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation. A causal relationship with the use of filgrastim in these cases has not been established.
Very rare cases of cutaneous vasculitis have been reported in patients receiving filgrastim. The mechanism of development of vasculitis in patients receiving filgrastim has not been established.
There are rare reports of the development of Sweet syndrome (acute fibrillation dermatosis). Since a significant proportion of these patients suffered from leukemia, which is known to be associated with Sweet syndrome, a causal relationship with filgrastim has not been established.
In some cases, an exacerbation of rheumatoid arthritis was observed.
Pseudopodagra has been reported in patients with cancer treated with filgrastim.
Rare adverse effects from the lungs, including interstitial pneumonia, pulmonary edema and pulmonary infiltrates, have been reported in isolated cases with an adverse outcome in the form of respiratory failure or adult respiratory distress syndrome (RDSV), including fatal.
Isolated cases of symptoms indicating allergic reactions, including anaphylaxis, skin rash, urticaria, Quincke's edema, shortness of breath, decreased blood pressure, developing with the introduction of the first dose or subsequent use of filgrastim, have been reported in patients receiving filgrastim. There were more such reactions after intravenous administration. In some cases, the symptoms recurred after repeated use of filgrastim, which indicates a causal relationship. The use of filgrastim should be discontinued in patients who have developed severe allergic reactions.
Isolated cases of sickle cell crises have been reported in patients with sickle cell anemia.
On the part of the immune system:
very rarely - allergic reactions.
From the side of metabolism and nutrition:
very often - an increase in the activity of LDH, alkaline phosphatase, an increase in the concentration of uric acid in plasma.
From the nervous system:
often - headache.
From the vascular side:
infrequently - syndrome of increased capillary permeability; rarely - vascular disorders, angiopathy.
From the respiratory system:
often - cough, sore throat; very rarely - infiltrates in the lungs.
From the gastrointestinal tract:
very often - nausea, vomiting; often - constipation, diarrhea, anorexia, mucositis.
From the liver and biliary tract:
very often - an increase in GGT activity.
From the skin and subcutaneous fat:
often - alopecia, skin rash; very rarely - Sweet syndrome, cutaneous vasculitis.
From the musculoskeletal system:
often - chest pain, musculoskeletal pain;
very rarely, an exacerbation of rheumatoid arthritis.
From the urinary system:
very rarely, there is a violation of urination.
Other: often - fatigue, general weakness; infrequently - nonspecific pain.
Healthy donors during the mobilization of the PSC
Transient mild or moderate musculoskeletal pain was very often observed. Leukocytosis (more than 50 x 109/l) was observed in 41% of healthy donors and transient thrombocytopenia (less than 100 x 109/l l) after filgrastim and leukophoresis was observed in 35% of healthy donors. Transient slight increases in the activity of alkaline phosphatase, LDH, aspartate aminotransferase (ACT) and uric acid concentration in blood plasma were reported in healthy donors receiving filgrastim (without clinical consequences).
Occasionally, an exacerbation of arthritis has been reported. Occasionally, symptoms indicating severe allergic reactions have been reported. Headache, believed to be associated with the use of filgrastim, has been reported in healthy donors during the mobilization of PCCs in studies.
Frequent, mostly asymptomatic cases of splenomegaly and very rare cases of rupture of the spleen have been reported in healthy donors and patients after administration of G-CSF. In healthy donors, adverse respiratory events (hemoptysis, pulmonary hemorrhage, infiltrates in the lungs, shortness of breath and hypoxia) were observed very rarely when using filgrastim in the post-registration period.
In the post-registration period, cases of increased capillary permeability syndrome have been reported with the use of G-CSF. They were usually observed in patients with advanced malignant disease, sepsis, taking several chemotherapy drugs at the same time or undergoing apheresis. The syndrome of increased capillary permeability can be life-threatening if treatment is delayed. Infrequently (? 1/1000 to < 1/100), this syndrome was observed in healthy donors during the mobilization of PCCs after administration of G-CSF.
From the blood and lymphatic system:
very often - leukocytosis, thrombocytopenia;
infrequently, disorders of the spleen.
On the part of the immune system:
infrequently - severe allergic reactions.
From the side of metabolism and nutrition:
often - increased activity of alkaline phosphatase, LDH;
infrequently, an increase in the activity of ACT.
From the nervous system:
very often it is a headache.
From the vascular side:
infrequently - syndrome of increased capillary permeability.
From the musculoskeletal system:
very often - musculoskeletal pain;
infrequently, an exacerbation of rheumatoid arthritis.
Patients with THN
The frequency of adverse effects associated with the use of filgrastim in patients with TN tends to decrease over time.
The most common adverse effects associated with the use of filgrastim were bone and muscle pain. There was also an enlargement of the spleen, progressive in some cases, and thrombocytopenia. Headache and diarrhea were usually observed shortly after the start of filgrastim treatment in less than 10% of patients. Anemia and nosebleeds have also been reported.
There was a transient increase in uric acid concentration, LDH activity, and alkaline phosphatase in blood plasma without clinical consequences. There was also a transient moderate decrease in blood glucose concentration after eating.
Undesirable effects possibly associated with the use of filgrastim, and usually observed in less than 2% of patients with TN, were injection site reactions, headache, liver enlargement, joint pain, alopecia, osteoporosis, and skin rash. During long-term use of filgrastim, the development of cutaneous vasculitis has been reported in 2% of patients with TN, as well as very rare cases of proteinuria/hematuria.
From the blood and lymphatic system:
very often - anemia, splenomegaly;
often - thrombocytopenia;
infrequently, disorders of the spleen.
From the side of metabolism and nutrition:
very often - a decrease in blood glucose concentration, an increase in alkaline phosphatase, LDH, hyperuricemia.
From the nervous system:
often - headache.
From the respiratory system:
very often - nosebleeds.
From the digestive system:
often - diarrhea, hepatomegaly.
From the skin and subcutaneous tissues:
often - alopecia, skin rash, cutaneous vasculitis, pain at the injection site.
From the musculoskeletal system:
very often - pain in bones and muscles;
It is often osteoporosis.
From the kidneys and urinary tract:
infrequently - hematuria, proteinuria.
Patients with HIV infection
Mild to moderate musculoskeletal pain and myalgia associated with the use of filgrastim were constantly observed. The frequency of pain is similar to that of patients with cancer.
An enlargement of the spleen associated with the use of filgrastim was observed in less than 3% of patients. In all cases, mild to moderate splenomegaly with a favorable clinical course was observed during physical examination; there were no cases of hypersplenism and splenectomy. Splenomegaly is quite common in patients suffering from HIV infection, and is also present in varying degrees of severity in most patients with AIDS. In these cases, the relationship of splenomegaly with the use of filgrastim remains unclear.
From the blood and lymphatic system:
often there is a violation on the part of the spleen.
From the musculoskeletal system:
very often - musculoskeletal pain.
Overdose
Cases of overdose of filgrastim have not been noted. 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 medicinal products
The efficacy and safety of filgrastim administration on the same day with cytotoxic chemotherapy drugs 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 administration of these drugs.
Fluorouracil increases the severity of neutropenia when administered concomitantly with filgrastim. Possible interaction with other hematopoietic growth factors and cytokines is unknown.
Given that lithium stimulates the release of neutrophils, it is possible to enhance the effect of filgrastim with combined administration, but such studies have not been conducted.
Filgrastim is not pharmacologically compatible with 0.9% sodium chloride solution. When using filgrastim to mobilize hematopoietic stem cells after chemotherapy, it should be borne in mind that when prescribing cytostatics such as melphalan, carmustine and carboplatin for a long time, the effectiveness of mobilization may be reduced.
Special instructions
Treatment with Tevagrastim should be carried out only 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 oncological or hematology center with experience in this field and the ability to adequately monitor hematopoiesis progenitor cells.
The syringe containing the solution can be equipped with an additional needle safety device or be without it. An additional safety device is designed to prevent injuries and injections with already used syringes (needles) and does not require any special precautions. To inject the solution, slowly and evenly press down on the plunger of the syringe. The pressure on the piston is maintained until the recommended dose is administered and the syringe is removed from the injection site. Used syringes are disposed of in accordance with the instructions of a medical institution or a doctor. Syringes without a safety device are placed in a container made of durable material before disposal.
Precautions for patients with acute myeloid leukemia
The growth of human G-CSF malignant cells can stimulate the growth of myeloid cells in vitro. Similar effects can be observed in vitro with respect to some non-myeloid cells.
In myelodysplastic syndrome (MDS) and chronic myeloid leukemia, the efficacy and safety of filgrastim have not been established. In patients with the above diseases, as well as with precancerous lesions of the myeloid germ of hematopoiesis, the use of filgrastim is not indicated. Special attention should be paid to the differential diagnosis between the blast crisis of chronic myeloid leukemia and acute myeloid leukemia.
Caution should be exercised when using the drug Tevagrastim in patients with secondary myelocytic leukemia (AML) because data on safety and efficacy are limited.
The safety and efficacy of Tevagrastim, first used in patients with AML under the age of 55 years without cytogenetic abnormalities [t(8; 21), t(15; 17) and inv(16)], have not been established.
Other precautions
Patients with osteoporosis developed as a result of bone tissue disease, with prolonged (more than 6 months) use of the drug Tevagrastim, it is recommended to regularly monitor bone density.
There are rare reports of undesirable adverse reactions from the respiratory system when using G-CSF, in particular interstitial pneumonia. Patients who have recently suffered from infiltrative lung disease or pneumonia may be at high risk. The appearance of symptoms such as cough, fever and shortness of breath against the background of infiltrates in the lungs detected during X-ray examination, and signs of deterioration in lung function, may be the first signs of RDSV. In case of development of RDSV, the use of the drug Tevagrastim is discontinued and appropriate therapy is performed
The development of increased capillary permeability syndrome has been reported with the use of G-CSF, which is accompanied by a decrease in blood pressure, hypoalbuminemia, edema and hemoconcentration. It is necessary to monitor the condition of patients who develop a syndrome of increased capillary permeability, carry out symptomatic treatment and resuscitation, if necessary.
Precautions for patients with cancer and diseases
Leukocytosis
A small number of patients (less than 5%) receiving filgrastim at doses above 3 micrograms (0.3 million IU)/kg per day had leukocytosis (leukocyte count 100 x 109/l or more). Side effects directly related to filgrastim-induced leukocytosis have not been described. However, given the possible risk associated with leukocytosis, the number of white blood cells should be regularly determined during treatment with filgrastim. If, after passing the expected minimum, it exceeds 50 x 109/l, filgrastim should be canceled immediately. If filgrastim is used to mobilize hematopoietic stem cells, the drug must be discontinued when the number of white blood cells exceeds 70 x 109 / l.
The risk associated with high-dose chemotherapy
Particular caution should be exercised in the treatment of patients receiving high-dose chemotherapy, since increased doses of chemotherapy drugs have more pronounced toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems (see instructions for use of specific chemotherapy drugs).
Filgrastim monotherapy does not prevent the development of 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 developing thrombocytopenia and anemia. It is recommended to conduct a blood test regularly twice a week, determine the number of platelets and hematocrit during the use of filgrastim after chemotherapy. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens capable of causing severe thrombocytopenia. When filgrastim was used to mobilize PSCs, a decrease in the severity and duration of thrombocytopenia due to myelosuppressive or myeloblastic chemotherapy was revealed.
Other precautions
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 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.
There have been reports of graft-versus-host reactions and deaths in patients receiving G-CSF after allogeneic bone marrow transplantation.
Bone tissue X-ray revealed an increase in the hematopoietic activity of the bone marrow in response to human G-CSF therapy. These data should be taken into account when analyzing the results of bone radiography.
Precautions for patients undergoing PCC mobilization
After bone marrow transplantation, a blood test is performed and the number of platelets is determined 3 times a week.
Mobilisation
Two recommended mobilization methods (filgrastim alone or in combination with myelosuppressive chemotherapy) were not compared in the same patient population. The degree of difference in the results of laboratory determination of the number of CD34+ cells means that direct comparison of different studies is difficult. Therefore, it is difficult to recommend the optimal method. The choice of the mobilization method should be made depending on the general goals of the patient's treatment.
Previous treatment with cytotoxic agents
In patients who have had active myelosuppressive therapy in the past, there may not be a sufficient increase in PSCC to the recommended minimum level (at least 2.0 x 106 CD34+ cells / kg) or an increase in the rate of normalization of platelet count.
Some cytostatics are particularly toxic to hematopoiesis progenitor cells and may adversely affect their mobilization. Prolonged use of drugs such as melphalin, carboplatin or carmustine before the mobilization of progenitor cells can lead to worse results. However, the simultaneous use of menphalan, carboplatin and carmustine with filgrastim is effective in mobilizing PSCs. If the transplantation of PCCs is planned, it is recommended to plan their mobilization at an early stage of the patient's treatment course. Particular attention should be paid to the number of progenitor cells activated in such patients before the use of high-dose chemotherapy. If, as a result of mobilization, it was not possible to obtain a sufficient amount of PCCs, then alternative treatments that do not require the use of progenitor cells should be considered.
Estimation of the number of PSCs
When assessing the number of PCCs mobilized in patients with Tevagrastim, 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 chosen method, and therefore it is necessary to interpret the results obtained during research in different laboratories with caution.
There is a complex but stable statistical relationship between the number of CD34+ cells reinfused and the rate of platelet count recovery after high-dose chemotherapy.
A minimum amount of PCCs equal to or exceeding 2 x 106 CD34+ cells/kg leads to sufficient recovery of hematological parameters and is recommended based on published data. The number of CD34+ cells exceeding this value is apparently accompanied by a faster normalization, if the number of cells is less than the specified value, the recovery of blood parameters is slower.
Precautions for healthy supplements during the mobilization of PCCs
Cell mobilization and apheresis procedures should be carried out at a center with experience in this field.
The mobilization of PCCs does not have a direct clinical result when used in healthy donors and can be carried out exclusively for the purpose of long-term stem cell transplantation.
The mobilization of PCCs can only be carried out in donors who meet the standard clinical and laboratory criteria for stem cell donation. Special attention should be paid to hematological parameters and the presence of infectious diseases.
The safety and efficacy of Tevagrastim in healthy donors under the age of 16 and over 60 years has not been studied.
Transient leukocytosis (leukocytes greater than 50 x 109/l) was observed in 41% of patients. Transient thrombocytopenia (platelet count less than 100 x 109/l) after filgrastim administration and leukapheresis is observed in 35% of donors. In addition, there were 2 cases of thrombocytopenia less than 50 x 109/ l after the leukapheresis procedure.
If more than one leukapheresis is required, the platelet count should be monitored especially carefully 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 using anticoagulants or there are hemostatic disorders.
The dose of Tevagrastim should be discontinued or reduced if the number of white blood cells is more than 70 x 109 / l.
In healthy donors who receive GKSF for the mobilization of PCCs, all clinical blood test parameters should be regularly monitored until they are normalized. Monitoring of the safety of Tevagrastim in healthy donors continues. Currently, the risk of developing a myeloid malignant clone in donors cannot be excluded. Medical centers that perform apheresis procedures. It is recommended to carry out systematic monitoring of the condition of stem cell donors for at least 10 years in order to monitor the safety of the use of Tevagrastim in the long term.
There is information about private, mostly asymptomatic cases of splenomegaly, as well as very rare cases of rupture of the spleen in healthy donors and patients after administration of G-CSF. Some cases of rupture of the spleen have been fatal. In this regard, it is necessary to carefully monitor the size of the spleen (during clinical examination (palpation) and ultrasound examination). The risk of rupture of the spleen in donors and patients should be taken into account when they experience pain in the upper left part of the abdominal cavity or the upper part of the left shoulder.
In the post-registration period, very rare cases of adverse effects of G-CSF on the respiratory system (hemoptysis, pulmonary hemorrhage, infiltrates in the lungs, shortness of breath and hypoxia) were noted in healthy donors. If these symptoms are suspected, the expediency of further use of the drug and the need for appropriate treatment should be considered.
Precautions for recipients of allogeneic PCCs obtained with filgrastim
With allogeneic PSCC transplantation, the risk of developing an acute or chronic graft-versus-host reaction is higher than with allogeneic bone marrow transplantation.
Precautions for patients with TN
The number of blood cells
It is necessary to carefully monitor the number of platelets, especially during the first few weeks of treatment with the drug. If the patient develops thrombocytopenia (the number of platelets for a long time is less than 100 x 109 / l), consideration should be given to temporarily discontinuing the drug or reducing its dose.
There may be other changes in the blood formula that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.
The development of acute leukemia or MDS
It is necessary to carry out timely diagnosis of TNF and differentiate this diagnosis from other disorders of the hematopoiesis system, such as aplastic anemia, MDS and myeloid leukemia. Before starting therapy, a general blood test should be performed to determine the leukocyte formula and the number of platelets, as well as to determine the morphology of the bone marrow and karyotype.
During clinical trials, a small number (approximately 3%) of patients with TNF treated with filgrastim had MDS and leukemia. These results were obtained only when monitoring patients with congenital neutropenia (Kostman syndrome). MDS and leukemia are the most common complications of TNF; and their relationship to filgrastim treatment has not been determined. Approximately 12% of patients with initially normal cytogenetics had abnormalities, including monosomy 7, upon repeated examination. If a patient with THC exhibits cytogenetic disorders, it is necessary to carefully assess the ratio of the expected benefit and possible risk from continuing therapy with Tevagrastim. The drug should be discontinued in case of MDS or leukemia. It is currently unclear whether long-term use of the drug Tevagrastim provokes the development of cytogenetic disorders, MDS or leukemia in patients with THC. It is recommended to conduct morphological and cytogenetic bone marrow studies regularly (after about 12 months).
With prolonged (more than 5 years) use of filgrastim, cytogenetic disorders, leukemia and osteoporosis were found in 9.1% of patients with CKD. The connection with the use of filgrastim has not been established.
Other precautions
It is necessary to exclude such causes of transient neutropenia as viral infections.
Enlargement of the spleen is a likely effect associated with filgrastim treatment. During clinical trials, splenomegaly was detected on palpation in 31% of patients. During radiography, an increase in the size of the spleen is detected shortly after the start of filgrastim treatment and tends to stabilize. It has been noted that reducing the dose of the drug slows down or stops the increase in the size of the spleen; splenectomy may be necessary in 3% of patients. It is necessary to regularly monitor the size of the spleen during a clinical examination.
A small number of patients had hematuria/proteinuria. To exclude these manifestations, regular monitoring of the general urine test should be carried out.
The safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established.
Precautions for patients with HIV infection
The number of blood cells
It is necessary to strictly control ACNE, especially during the first weeks of therapy with Tevagrastim. Some patients may experience a very rapid and significant increase in ACNE at the initial dose of Tevagrastim. During the first 2-3 days of using the drug, it is recommended to measure ACNE daily. Subsequently, ACNE should be checked at least 2 times a week for the first 2 weeks and then every week or every other week throughout the course of maintenance therapy. With a break in the use of the drug Tevagrastim at a dose of 30 million mg. IU/day (300 mcg/day) the patient may experience significant fluctuations in ACNE during treatment. In order to determine the minimum ACNE (nadir), it is recommended to monitor the total blood count before each administration of the drug Tevagrastim.
The risk associated with the use of high doses of myelosuppressive drugs (MSLP)
Monotherapy with Tevagrastim is not used to prevent the development of thrombocytopenia and anemia against the background of the use of MSLP. If higher doses are used or several MSLPS are used simultaneously in combination with Tevagrastim therapy, the risk of thrombocytopenia and anemia increases. Regular monitoring of a detailed blood test is recommended.
The development of myelosuppression due to infections or neoplasms
Neutropenia can be caused by damage to the bone marrow in opportunistic infections caused by pathogens such as Mycobacterium avium complex, or malignant neoplasms. for example, lymphoma. If an infiltrative lesion of the bone marrow is detected, an inflammatory lesion or a malignant neoplasm, simultaneously with the use of the drug Tevagrastim for the treatment of neutropenia, it is necessary to use appropriate therapy for diagnosed diseases. The effectiveness of Tevagrastim in the treatment of neutropenia caused by bone marrow damage of infectious origin or tumor neoplasms has not been established.
Precautions for patients with sickle cell anemia
Patients with sickle cell anemia have cases of hemolytic crisis (an increase in the number of altered cells), sometimes with fatal outcome. Patients with sickle cell disease should use Tevagrastim only if the expected benefit exceeds the possible risk when using Tevagrastim.
The effect of excipients
The Tevagrastim sorbitol contained in the preparation in an amount of 50 mg / ml should not have a negative effect on patients with hereditary fructose intolerance. However, Tevagrastim should be used with caution in such patients.
Influence on the ability to drive vehicles and mechanisms
The effect of filgrastim on the ability to drive vehicles and work with mechanisms has not been noted.
Product form:
Solution for intravenous and subcutaneous administration of 60 million ml. IU/ml.
0.5 ml each (30 million ME, which corresponds to 300 micrograms of filgrastim) or 0.8 ml (48 million ME, which corresponds to 480 micrograms of filgrastim) of the drug in a glass graduated disposable syringe (type I glass according to Eur.F.), graduated to 1 ml (scale division 0.1 ml) with a fixed injection needle covered with a protective cap with a rubber insert, with a piston seal made of type I elastomer (according to Eur.F..). The syringe can be additionally equipped with a needle safety device or be without it.
1.5, 10 syringes with the drug (with or without a needle safety device) are placed in a cardboard holder or a plastic contour cell package, or 10 syringes (with or without a needle safety device) are placed 5 each in 2 cardboard holders or 2 plastic contour cell packages. All types of syringes can be sealed in a transparent blister, which is used only for automatic packaging.
Syringes are placed together with the instructions for medical use in a cardboard pack.
Storage conditions
At a temperature from 2 ° C to 8 ° C in a place protected from light.
Keep out of reach of children.
Expiration date
2.5 years old.
Do not use after the expiration date indicated on the package.
