Tevagrastim, 60 ml/ml 0.5 ml

Pharmacotherapeutic group: leukopoiesis stimulator

Code ATX: L03AA02

Pharmacological properties

Pharmacodynamics

Filgrastim, a recombinant hematopoietic growth factor closely related to granulocyte colony stimulating factor (G-CSF), is a highly purified non-glycosylated protein composed of 175 amino acids. It is produced by a strain of Escherichia coli in whose genome the gene for human granulocytic colony-stimulating factor has been inserted by genetic engineering methods.

Human 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.

Philgrastim dose-dependently increases the number of neutrophils with normal or increased functional activity. After treatment termination the number of neutrophils in peripheral blood decreases by 50% within 1-2 days and returns to the normal level during the next 1-7 days. The duration of action when administered intravenously may be shortened. Filgrastim significantly reduces the frequency, severity and duration of neutropenia and febrile neutropenia, reducing the need and duration of hospital 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.

The treatment with filgrastim significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy and hospitalization after induction chemotherapy for acute myeloleukemia, without affecting the frequency of fever and infectious complications.

The use of filgrastim, both alone and after chemotherapy, mobilizes the output of hematopoietic stem cells into the peripheral blood stream. Autologous or allogeneic transplantation of peripheral blood stem cells (PBSCs) is performed after therapy with high doses of cytostatics, either instead of or in addition to bone marrow transplantation. HSCC transplantation can also be prescribed after (high-dose) myelosuppressive cytotoxic therapy. The use of PSCs mobilized with filgrastim accelerates hematopoiesis recovery, 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 filgrastim in adults and children receiving cytotoxic chemotherapy is similar.

In children and adults with severe chronic neutropenia (severe congenital, recurrent, idiopathic neutropenia), filgrastim consistently increases the number of neutrophils in peripheral blood and reduces the incidence of infectious complications.

Prescribing filgrastim to patients with HIV infection allows to maintain normal neutrophil counts and follow recommended doses of antiretroviral and/or other myelosuppressive therapy. There is no evidence of increased HIV replication with filgrastim.

Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro.

Pharmacokinetics

In intravenous and subcutaneous administration of filgrastim, there is a positive linear relationship between administered dose and serum concentration. After subcutaneous administration of therapeutic doses, its concentration exceeds 10 ng/ml within 8-16 hours. The volume of distribution is 150 ml/kg.

Independent on the method of administration, the elimination of filgrastim follows the rules of 1st order kinetics. Period of half-life is 3.5 hours and clearance is 0.6 ml/min/kg.

Long-term administration of filgrastim up to 28 days after autologous bone marrow transplantation does not cause cumulation and increase of half-life.

In patients with end-stage renal failure, there is an increase in maximum concentration (C_max) and area under the curve (AUC), and a decrease in volume distribution and clearance compared to healthy volunteers and patients with moderate renal failure.

Indications

Adults and children

Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant diseases (except for chronic myeloid leukemia and myelodysplastic syndrome); – neutropenia and its clinical consequences in patients receiving myeloablative therapy followed by allogeneic or autologous bone marrow transplantation, with an increased risk of developing prolonged and severe neutropenia;
neutropenia in patients with acute myeloid leukemia receiving induction or consolidation chemotherapy to reduce its duration and clinical consequences;
mobilization of peripheral blood stem cells (autologous PSCC), including after myelosuppressive therapy, as well as mobilization of peripheral blood stem cells in healthy donors (allogeneic PSCC);
severe congenital, periodic or idiopathic neutropenia (absolute neutrophil count (ANC) ≤ 0.5 x 109/L) in patients with a history of severe or recurrent infections to increase the number of neutrophils, as well as to reduce the frequency and duration of infectious complications;
persistent neutropenia (ANN ≤ 1.0 x 109/l) in patients with advanced stage HIV infection to reduce the risk of bacterial infections when other treatment methods cannot be used.

Use strictly as prescribed by your doctor.

Pharmacological effect

Pharmacotherapeutic group: leukopoiesis stimulator

ATX code: L03AA02

Pharmacological properties

Pharmacodynamics

Filgrastim, a recombinant hematopoietic growth factor close to granulocyte colony-stimulating factor (G-CSF), 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 human granulocyte colony-stimulating factor gene has been introduced using genetic engineering methods.

Human 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 within 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 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. Filgrastim significantly reduces the incidence, severity and duration of neutropenia and febrile neutropenia, reducing the need and duration of hospital treatment in patients receiving cytotoxic 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.

Treatment with filgrastim significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy and hospitalization after induction chemotherapy for acute myeloid leukemia, without affecting the incidence 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 peripheral blood stem cell transplantation (PBSC) 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 with filgrastim accelerates the recovery 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 are similar in adults and children receiving cytotoxic chemotherapy.

In children and adults with severe chronic neutropenia (severe congenital, periodic, idiopathic neutropenia), filgrastim consistently increases the number of neutrophils in peripheral blood and reduces the incidence of infectious complications.

Prescribing filgrastim 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 with filgrastim use.

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 within 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.

Special instructions

Treatment with Tevagrastim 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.

Glomerulonephritis

There have been reports of the development of glomerulonephritis in patients receiving filgrastim, lenograstim or pegfilgrastim. Typically, cases of glomerulonephritis resolve after dose reduction or discontinuation of filgrastim, lenograstim, or pegfilgrastim. Monitoring of urinalysis parameters is recommended.

There are reports of the development of aortitis after administration of G-CSF. Symptoms may include fever, abdominal pain, malaise, back pain, and may be accompanied by elevated levels of inflammatory markers (eg, C-reactive protein and white blood cell count). In most cases, aortitis was diagnosed using computed tomography and resolved after discontinuation of G-CSF.

Precautions for patients with acute myeloid leukemia

Growth of malignant cells

Human G-CSF can stimulate the growth of myeloid cells in vitro. Similar effects may be observed in vitro in some non-myeloid cells.

In myelodysplastic syndrome (MDS) and chronic myeloid leukemia, the effectiveness and safety of filgrastim have not been established. For patients with the above diseases, as well as with precancerous lesions of the myeloid lineage of hematopoiesis, 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.

Caution should be exercised when using Tevagrastim in patients with secondary myelocytic leukemia (AML) as safety and efficacy data 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

For patients with osteoporosis that has developed as a result of bone disease, with long-term (more than 6 months) use of the drug Tevagrastim, it is recommended to regularly monitor bone density.

There are rare reports of adverse respiratory reactions with the use of G-CSF, in particular interstitial pneumonia. Patients who have recently had infiltrative pulmonary 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 identified by X-ray examination and signs of deterioration in pulmonary function may be the first signs of ARDS. If ARDS develops, use of Tevagrastim is discontinued and appropriate therapy is administered.

The development of capillary hyperpermeability syndrome has been reported with the use of G-CSF, which is accompanied by a decrease in blood pressure, hypoalbuminemia, edema and hemoconcentration. The condition of patients who develop capillary leak syndrome should be monitored, symptomatic treatment and resuscitation should be carried out if necessary.

Precautions for patients with cancer

Leukocytosis

In a small number of patients (less than 5%) receiving filgrastim in doses above 3 mcg (0.3 million IU)/kg per day, leukocytosis (white blood cell count 100 x 109/L or more) was observed. Side effects directly related to filgrastim-induced leukocytosis have not been described. However, given the possible risk associated with leukocytosis, the white blood cell count should be determined regularly during treatment with filgrastim. If, after passing the expected minimum, it exceeds 50 x 109/l, filgrastim should be discontinued immediately. If filgrastim is used to mobilize hematopoietic stem cells, the drug should be discontinued when the leukocyte count exceeds 70 x 109/L.

Risk associated with high-dose chemotherapy

Particular caution should be exercised when treating patients receiving high-dose chemotherapy, since higher doses of chemotherapy 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 (eg, full doses according to regimens), the patient may be at greater risk of developing thrombocytopenia and anemia. It is recommended to regularly perform blood tests twice a week, determine the platelet count and hematocrit during the use of filgrastim after chemotherapy. Particular caution should be exercised when using single-component or combination chemotherapy regimens that can cause severe thrombocytopenia.

When filgrastim was used to mobilize PSCC, a decrease in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloblastic chemotherapy was found.

Other Precautions

The effect of filgrastim in patients with significantly reduced numbers of myeloid progenitor cells is not known. Filgrastim increases the number of neutrophils by acting primarily on neutrophil precursor cells. Therefore, in patients with reduced progenitor cell counts (for example, those who have undergone intense radiation therapy or chemotherapy), the degree of increase in neutrophil counts may be lower.

There have been reports of cases of graft-versus-host disease and deaths in patients receiving G-CSF after allogeneic bone marrow transplantation.

Dynamic radiography of bone tissue revealed an increase in hematopoietic activity of the bone marrow in response to therapy with human G-CSF. These data should be taken into account when analyzing the results of bone radiography.

Precautions for 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. The degree of variation in laboratory CD34+ cell count results means that direct comparisons between different studies are difficult. Therefore, it is difficult to recommend the optimal method. The choice of mobilization method should be based on the overall treatment goals of the 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 (at least 2.0 x 106 CD34+ cells/kg) or increase the rate of platelet count normalization.

Some cytostatics are particularly toxic to hematopoietic progenitor cells and may adversely affect their mobilization. Long-term use of drugs such as melphalan, carboplatin, or carmustine before mobilization of progenitor cells may lead to worse results. However, the simultaneous use of melphalan, carboplatin and carmustine with filgrastim is effective in mobilizing PSCC. If transplantation of PSCCs is planned, it is recommended to plan their mobilization early in the patient’s course of treatment. Particular attention should be paid to the number of progenitor cells activated in such patients before high-dose chemotherapy is administered. If mobilization fails to obtain sufficient numbers of PSCCs, alternative treatments that do not require the use of progenitor cells should be considered.

Estimation of the number of PSCC

When estimating the number of PSCC mobilized in patients using the drug Tevagrastim, special attention should be paid to the method of quantitative determination. The results of flow cytometric analysis of CD34+ cell counts vary depending on the method chosen, and therefore results obtained from different laboratories must be interpreted with caution.

There is a complex but consistent statistical relationship between the number of reinfused CD34+ cells and the rate of platelet count recovery after high-dose chemotherapy.

A minimum number of PSCC equal to or greater than 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 this value, the recovery of blood counts occurs more slowly.

Precautions for healthy donors when mobilizing PSCC

Cell mobilization and apheresis procedures should be performed at a center with experience in this field.

Mobilization of PSCCs has no immediate clinical benefit when used in healthy donors and can only be performed for the purpose of allogeneic stem cell transplantation.

PSCC mobilization can only be performed from donors who meet standard clinical and laboratory criteria for stem cell donation. Particular attention should be paid to hematological parameters and the presence of infectious diseases.

The safety and effectiveness of Tevagrastim in healthy donors under the age of 16 years and over 60 years of age have not been studied.

Transient leukocytosis (white blood cells more than 50 x 109/l) was observed in 41% of patients. Transient thrombocytopenia (platelet count less than 100 x 109/L) after the use 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 particularly 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 if there are hemostatic disorders.

The dose of Tevagrastim should be discontinued or reduced if the leukocyte count is more than 70 x 109/L.

In healthy donors who receive G-CSF to mobilize PSCC, all clinical blood test parameters should be regularly monitored until they normalize.

Monitoring the safety of Tevagrastim in healthy donors continues. At present, the risk of developing a myeloid malignant clone in donors cannot be excluded. Medical centers performing apheresis procedures are recommended to systematically monitor the condition of stem cell donors for at least 10 years in order to monitor the long-term safety of Tevagrastim.

There is information about private, mostly asymptomatic cases of splenomegaly, as well as very rare cases of splenic rupture in healthy donors and patients after administration of G-CSF. Some cases of splenic rupture 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 splenic rupture should be considered in donors and patients who experience pain in the upper left abdomen or upper left shoulder.

During the post-registration period, very rare cases of adverse effects of G-CSF on the respiratory system (hemoptysis, pulmonary hemorrhage, pulmonary infiltrates, shortness of breath and hypoxia) were observed in healthy donors. If you suspect the presence of these symptoms, you should consider the advisability of further use of the drug and the need for appropriate treatment.

Precautions for recipients of allogeneic PSCCs obtained with filgrastim

With allogeneic transplantation of PSCC, the risk of developing acute or chronic graft-versus-host disease is higher than with allogeneic bone marrow transplantation.

Precautions for patients with SCN

Blood cell count

The platelet count should be carefully monitored, especially during the first few weeks of treatment with the drug. If a patient develops thrombocytopenia (platelet count less than 100 x 109/L for a long time), temporary discontinuation of the drug or reduction of its dose should be considered.

There may be other changes in the blood count that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

Development of acute leukemia or MDS

It is necessary to carry out timely diagnosis of SCN and differentiate this diagnosis from other disorders of the hematopoietic 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 platelet count, as well as determine the bone marrow morphology and karyotype.

During clinical trials, MDS and leukemia were observed in a small number (approximately 3%) of patients with SCN treated with filgrastim. These results were obtained only when observing patients with congenital neutropenia (Kostman syndrome). MDS and leukemia are the most common complications of SCN, and their relationship with filgrastim treatment has not been determined. Approximately 12% of patients with initially normal cytogenetics were found to have abnormalities on re-evaluation, including monosomy 7. If a patient with SCN exhibits cytogenetic abnormalities, it is necessary to carefully evaluate the expected benefit versus the possible risk of continuing therapy with Tevagrastim. The drug should be discontinued if MDS or leukemia develops. It is currently unclear whether long-term use of Tevagrastim provokes the development of cytogenetic disorders, MDS or leukemia in patients with SCN. It is recommended to regularly (after approximately 12 months) conduct morphological and cytogenetic studies of the bone marrow.

With long-term (more than 5 years) use of filgrastim, cytogenetic disorders, leukemia and osteoporosis were found in 9.1% of patients with SCN. A relationship with the use of filgrastim has not been established.

Other Precautions

It is necessary to exclude causes of transient neutropenia such as viral infections.

Splenic enlargement is a likely effect associated with filgrastim treatment. During clinical studies, splenomegaly was detected in 31% of patients upon palpation. On radiography, an increase in the size of the spleen is detected soon after the start of treatment with filgrastim and tends to stabilize. Reducing the dose of the drug has been noted to slow or stop the increase in spleen size; splenectomy may be necessary in 3% of patients. It is necessary to regularly monitor the size of the spleen during clinical examination.

Hematuria/proteinuria was observed in a small number of patients. To exclude these manifestations, a general urine test should be regularly monitored.

The safety and effectiveness of the drug in newborns and patients with autoimmune neutropenia have not been established.

Precautions for patients with HIV infection

Blood cell count

ACN should be closely monitored, especially during the first weeks of therapy with Tevagrastim. Some patients may experience a very rapid and significant increase in ANC with the initial dose of Tevagrastim. During the first 2-3 days of using the drug, it is recommended to measure the ANC daily. Thereafter, the ACN should be checked at least twice a week for the first 2 weeks and then every week or every other week throughout the course of maintenance therapy. If there is a break in the use of the drug Tevagrastim at a dose of 30 million IU/day (300 mcg/day), the patient may experience significant fluctuations in ANC during treatment. In order to determine the minimum ACN (nadir), it is recommended to monitor a complete blood count before each administration of the drug Tevagrastim.

Risk associated with the use of high doses of myelosuppressive drugs (MSDM)

Monotherapy with Tevagrastim is not used to prevent the development of thrombocytopenia and anemia during the use of MSLP. When higher doses or multiple MSLPs are used simultaneously in combination with Tevagrastim therapy, the risk of developing thrombocytopenia and anemia increases. Regular monitoring using a complete blood count is recommended.

Development of myelosuppression due to infections or neoplasms

Neutropenia may be due to bone marrow damage due to opportunistic infections such as Mycobacterium avium complex or malignancies such as lymphoma. If an infiltrative lesion of the bone marrow, an inflammatory lesion or a malignant neoplasm is detected, simultaneously with the use of the drug Tevagrastim for the treatment of neutropenia, it is necessary to use appropriate therapy for the 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 Disease

In patients with sickle cell anemia, there have been cases of hemolytic crisis (an increase in the number of changed cells), sometimes with death. Patients with sickle cell disease should use Tevagrastim only if the expected benefit outweighs the possible risk of using Tevagrastim.

Effect of excipients

The sorbitol contained in Tevagrastim 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.

Impact on the ability to drive vehicles and machinery

There was no effect of filgrastim on the ability to drive vehicles and operate machinery.

Active ingredient

Filgrastim

Composition

1 ml of solution contains: active ingredient: filgrastim 60 million IU/ml (corresponding to 600 μg/ml); excipients: glacial acetic acid 0.60 mg/ml, sorbitol 50.0 mg/ml, polysorbate 80 0.055 mg/ml, sodium hydroxide up to pH 4.20, water for injection up to 1.00 ml.

Pregnancy

The safety of filgrastim in pregnant women has not been established. It may pass through the placental barrier in women. When prescribing the drug to pregnant women, the expected therapeutic effect should be weighed against the possible risk to the fetus.
There is no data on the penetration of filgrastim into breast milk. It is not recommended to use the drug during breastfeeding.

Contraindications

History of hypersensitivity to the drug and its components; severe congenital neutropenia (Kostmann syndrome) with cytogenetic disorders; simultaneous administration with cytotoxic chemotherapy and radiation therapy; the drug should not be used to increase doses of cytotoxic chemotherapy drugs above the recommended ones, end-stage chronic renal failure; breastfeeding period; newborn age (up to 28 days of life).

With caution

During pregnancy, malignant and precancerous diseases, patients with sickle cell anemia, bone tissue pathologies (including osteoporosis), with secondary acute myeloid leukemia (due to limited data on safety and effectiveness), when treating patients receiving high-dose chemotherapy, hereditary fructose intolerance (the drug contains sorbitol).

Side Effects

Side effects are distributed according to the classification by frequency of occurrence: very often (≥ 1/10); often (≥ 1/100, but < 1/10); uncommon (≥ 1/1000, but < 1/100); rare (≥ 1/10000, but < 1/100); very rare (< 1/10000); unknown frequency (cannot be determined from available data).

Patients with cancer

The most common adverse effects associated with the use of filgrastim at the recommended dose were mild to moderate musculoskeletal pain (in 10% of patients) and severe musculoskeletal pain (in 3% of patients). Musculoskeletal pain was usually managed with standard analgesic treatment. Less common adverse effects were urinary disturbances (mainly mild to moderate dysuria).

Filgrastim did not increase the incidence of adverse reactions associated with cytotoxic chemotherapy. Adverse effects were observed at similar rates in patients receiving 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 plasma lactate dehydrogenase (LDH), alkaline phosphatase (ALP), uric acid concentrations and gamma-glutamyl transferase (GGT) activity were observed with filgrastim at recommended doses in approximately 50%, 35%, 25% and 10% of patients, respectively.

Occasionally, a transient decrease in blood pressure (BP) was observed, which did not require therapeutic intervention.

Graft-versus-host disease and death have been reported in patients receiving G-CSF after allogeneic bone marrow transplantation.

Occasionally, vascular disorders, including veno-occlusive disease and disorders associated with water metabolism in the body, have been noted in patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation. A cause-and-effect 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’s syndrome (acute febrile dermatosis). Because a significant proportion of these patients suffered from leukemia, which is known to be associated with Sweet’s syndrome, a causal relationship with filgrastim has not been established.

In some cases, exacerbation of rheumatoid arthritis was observed.

The development of pseudogout has been reported in patients with cancer receiving filgrastim.

Rare pulmonary adverse effects have been reported, including interstitial pneumonia, pulmonary edema and pulmonary infiltrates, with isolated cases of adverse outcomes such as respiratory failure or adult respiratory distress syndrome (ARDS), including death.

Isolated cases of symptoms indicating allergic-type reactions, including anaphylaxis, skin rash, urticaria, Quincke’s edema, shortness of breath, and decreased blood pressure, developing upon administration of the first dose or subsequent use of filgrastim, have been described. There were more such reactions after intravenous use. In some cases, symptoms recurred after repeated use of filgrastim, suggesting a causal relationship. Filgrastim should be discontinued in patients who develop severe allergic reactions.

Isolated cases of sickle cell crises have been reported in patients with sickle cell disease.

From the immune system: very rarely – allergic reactions.

From the side of metabolism and nutrition: very often – increased activity of LDH, alkaline phosphatase, increased concentration of uric acid in plasma.

From the nervous system: often – headache.

From the side of blood vessels: infrequently – syndrome of increased capillary permeability; rarely – vascular disorders, angiopathy, aortitis.

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 – increased GGT activity.

From the skin and subcutaneous fat: often – alopecia, skin rash; very rarely – Sweet’s syndrome, cutaneous vasculitis.

From the musculoskeletal system: often – chest pain, musculoskeletal pain; very rarely – exacerbation of rheumatoid arthritis.

From the urinary system: very rarely – urinary disturbance.

Other: often – fatigue, general weakness; infrequently – nonspecific pain.

Healthy donors during PSCC mobilization

Transient mild or moderate musculoskeletal pain was very common.

Leukocytosis (more than 50 x 109/L) was observed in 41% of healthy donors and transient thrombocytopenia (less than 100 x 109/L) after the use of filgrastim and leukophoresis was observed in 35% of healthy donors. Transient minor increases in ALP, LDH, aspartate aminotransferase (AST) activity and plasma uric acid concentrations have been reported in healthy donors receiving filgrastim (without clinical consequences).

There are rare reports of exacerbation of arthritis.

Rarely, symptoms suggestive of severe allergic reactions have been reported.

Headache believed to be associated with filgrastim use has been reported in healthy donors during PSCC mobilization studies.

Frequent, mostly asymptomatic, cases of splenomegaly and very rare cases of splenic rupture have been reported in healthy donors and patients after administration of G-CSF.

In healthy donors, adverse events from the respiratory system (hemoptysis, pulmonary hemorrhage, pulmonary infiltrates, shortness of breath and hypoxia) were observed very rarely when using filgrastim in the post-marketing period.

During the post-registration period, cases of capillary leak syndrome have been reported with the use of G-CSF. They were typically observed in patients with advanced malignancy, sepsis, taking multiple chemotherapy drugs at the same time, or undergoing apheresis. Leaky capillary syndrome can be life-threatening if treatment is delayed. Infrequently (≥ 1/1000 to < 1/100) this syndrome was observed in healthy donors when mobilizing PSCC after administration of G-CSF.

From the blood and lymphatic system: very often – leukocytosis, thrombocytopenia; infrequently – disorders of the spleen.

From the immune system: rarely – severe allergic reactions.

From the side of metabolism and nutrition: often – increased activity of alkaline phosphatase, LDH; infrequently – increased AST activity.

From the nervous system: very often – headache.

From the side of blood vessels: infrequently – capillary hyperpermeability syndrome, rarely – aortitis.

From the musculoskeletal system: very often – musculoskeletal pain; infrequently – exacerbation of rheumatoid arthritis.

Patients with SCN

The incidence of adverse effects associated with the use of filgrastim in patients with SCN tends to decrease over time.

The most common adverse effects associated with filgrastim were bone and muscle pain. Spleen enlargement, progressive in some cases, and thrombocytopenia were also observed. Headache and diarrhea typically occurred soon after initiation of filgrastim treatment in less than 10% of patients. Anemia and nosebleeds have also been reported.

There was a transient increase in the concentration of uric acid, LDH activity, and alkaline phosphatase in the blood plasma without clinical consequences. A transient moderate decrease in blood glucose concentration after meals was also observed.

Adverse effects possibly associated with filgrastim use, and generally observed in less than 2% of patients with SCN, 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 SCN, 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 – decreased concentration of glucose in the blood, increased 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; often – osteoporosis.

From the kidneys and urinary tract: infrequently – hematuria, proteinuria.

Patients with HIV infection

Mild to moderate musculoskeletal pain and myalgia associated with filgrastim use were consistently observed. The incidence of pain is similar to that in patients with cancer.

Splenic enlargement associated with filgrastim use was observed in less than 3% of patients. In all cases, physical examination revealed mild to moderate splenomegaly with a favorable clinical course; There were no cases of hypersplenism or splenectomy.

Splenomegaly is quite common in patients suffering from HIV infection, and is also present to varying degrees in most patients with AIDS. In these cases, the relationship of splenomegaly to filgrastim use remains unclear.

From the blood and lymphatic system: often – a violation of the spleen.

From the musculoskeletal system: very often – musculoskeletal pain.

Interaction

The effectiveness and safety of administering filgrastim on the same day as cytotoxic chemotherapy has 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.

Fluorouracil increases the severity of neutropenia when administered simultaneously with filgrastim. Possible interactions with other hematopoietic growth factors and cytokines are unknown.

Given that lithium stimulates neutrophil release, it is possible that the effects of filgrastim may be enhanced when administered in combination, but such studies 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 prescribing cytostatics such as melphalan, carmustine and carboplatin for a long time, the effectiveness of mobilization may be reduced.

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.

Storage conditions

Store at temperatures from 2°C to 8°C, protected from light.
Keep out of the reach of children!

Shelf life

2.5 years.
Do not use after expiration date.

Manufacturer

Teva Pharmaceutical Enterprises Ltd., Israel