Zarsio solution for injection and infusion 48 million IU 0.5 ml in pre-filled syringe No. 5

Instructions for Zarsio solution for injection and infusion 48 million IU 0.5 ml in a pre-filled syringe No. 5

Composition

active substance: filgrastim (recombinant human granulocyte colony-stimulating factor);

1 ml of solution contains 60 million IU (600 μg) or 96 million IU (960 μg) of filgrastim;

pre-filled syringe (syringe dose) contains 30 million IU (300 μg) or 48 million IU (480 μg) of filgrastim in 0.5 ml;

Excipients: glutamic acid, sorbitol (E 420), polysorbate 80, water for injections.

Dosage form

Solution for injection or infusion.

Main physicochemical properties: clear colorless or slightly yellowish solution.

Pharmacotherapeutic group

Immunostimulants. Colony-stimulating factors. Filgrastim.

ATX code L0ЗА A02.

Pharmacological properties

Pharmacodynamics.

The active substance of the drug is filgrastim - recombinant human granulocyte colony-stimulating factor (G-CSF). Filgrastim has the same biological activity as endogenous human G-CSF, and differs from the latter only in that it is a non-glycosylated protein with an additional N-terminal methionine residue. Filgrastim, which is obtained by recombinant DNA technology, is isolated from Escherichia coli bacteria cells, into the genetic apparatus of which the gene encoding the G-CSF protein has been introduced.

Human granulocyte colony-stimulating factor – a glycoprotein – regulates the creation of functionally active neutrophil granulocytes and their release into the blood from the bone marrow. Filgrastim significantly increases the number of neutrophil granulocytes in the peripheral blood within the first 24 hours after administration and simultaneously leads to a slight increase in the number of monocytes. The increase in the number of neutrophil granulocytes when using the drug in the recommended dose range depends on the dose. Their functional properties are normal or enhanced, as evidenced by the results of the study of chemotaxis and phagocytosis. After the end of treatment with the drug, the number of neutrophil granulocytes in the peripheral blood decreases by 50% within 1–2 days and to normal levels within 1–7 days.

Filgrastim significantly reduces the frequency, severity and duration of neutropenia in patients after chemotherapy with cytostatics or myeloablative therapy followed by bone marrow transplantation. Filgrastim, both initially and after chemotherapy, activates peripheral blood hemocyte progenitor cells (PBPCs). These autologous PBPCs can be collected from the patient and administered after high-dose cytostatic treatment or instead of or in addition to bone marrow transplantation. Administration of PBPCs accelerates the recovery of hematopoiesis, reduces the risk of hemorrhagic complications and the need for platelet transfusions. In children and adults with TCN, filgrastim consistently increases the number of neutrophil granulocytes in the peripheral blood and reduces the frequency of infectious complications.

Pharmacokinetics.

Both intravenous and subcutaneous administration of the drug show a positive linear relationship between its plasma concentration and dose. After subcutaneous administration of the recommended doses of the drug, the serum concentration exceeds 10 ng/ml for 8–16 hours; the volume of distribution in the blood is about 150 ml/kg. After both subcutaneous and intravenous administration, the elimination of the drug from the body corresponds to 1st order kinetics. The average serum half-life of filgrastim is about 3.5 hours, and the clearance rate is approximately 0.6 ml/min per 1 kg. Continuous infusion for 28 days in patients recovering from autologous bone marrow transplantation was not accompanied by signs of cumulation and an increase in the half-life of the drug.

Indication

Reduction of the duration and severity of neutropenia in patients receiving intensive myelosuppressive chemotherapy with cytotoxic drugs for malignant neoplasms (except chronic myelogenous leukemia and myelodysplastic syndrome), and reduction of the duration of neutropenia in patients receiving high-dose chemotherapy with cytotoxic drugs followed by autologous or allogeneic bone marrow transplantation.

The safety and efficacy of filgrastim are similar in adults and children receiving cytotoxic chemotherapy.

• The drug is indicated for the purpose of mobilizing peripheral blood stem cells (PBSCs).
• Long-term use is indicated in children and adults with severe congenital, cyclic or

idiopathic neutropenia and neutropenia with an absolute neutrophil count <0.5× 109/L to increase neutrophil counts and reduce the incidence of infections.

• Treatment of persistent neutropenia (absolute neutrophil count ≤1.0 × 109/L) in patients with advanced HIV infection to reduce the risk of bacterial infections when other treatments for neutropenia are inappropriate.

Contraindication

• Hypersensitivity to filgrastim, colony-stimulating factors, Escherichia coli or to any of the excipients.
• Severe hereditary neutropenia (Kostman syndrome) with cytogenetic abnormalities and autoimmune neutropenia.
• Chronic myelogenous leukemia and myelodysplastic syndrome.

Interaction with other medicinal products and other types of interactions

The safety and efficacy of Zarsio® administered on the same day as myelosuppressive cytotoxic chemotherapy have not been established. Due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to administer Zarsio® within 24 hours before or after the administration of these agents.

The severity of neutropenia may be increased when Zarsio® is administered concomitantly with 5-fluorouracil. Interactions with other hematopoietic growth factors and cytokines are unknown.

Since lithium stimulates the release of neutrophils, it is possible that the effect of Zarsio® may be enhanced when administered in combination, but such studies have not been conducted.

Due to pharmaceutical incompatibility, the drug should not be mixed with 0.9% sodium chloride solution.

Application features

Hypersensitivity

Hypersensitivity reactions, including anaphylactic reactions, occurring at the start of or during treatment, have been reported in patients receiving filgrastim. Zarcio® should be discontinued in patients who develop clinically significant hypersensitivity reactions.

Zarsio® should not be used in patients with a history of hypersensitivity to filgrastim or pegfilgrastim.

Pulmonary adverse reactions

There are rare reports of adverse respiratory effects, including interstitial pneumonia, with G-CSF. Patients with a recent history of infiltrative lung disease or pneumonia may be at increased risk. The presence of symptoms such as cough, fever and dyspnea, together with evidence of infiltrative lung lesions on chest x-ray and signs of progressive respiratory failure, suggests the presence of adult respiratory distress syndrome (ARDS). If ARDS is detected, filgrastim should be discontinued and appropriate treatment should be initiated.

Very rare cases of pulmonary adverse events (hemoptysis, pulmonary hemorrhage, pulmonary infiltration, dyspnea, and hypoxia) have been reported in post-marketing experience, particularly in healthy donors. If a pulmonary adverse event is suspected or confirmed, further use of filgrastim should be discontinued and the patient should be given appropriate medical care.

Glomerulonephritis

Glomerulonephritis has been reported in patients receiving filgrastim or pegfilgrastim. Glomerulonephritis usually resolves after dose reduction or discontinuation of filgrastim or pegfilgrastim. Periodic urinalysis is recommended.

Capillary loss syndrome

Cases of capillary leak syndrome, which can be life-threatening if treatment is delayed, have been reported following the use of G-CSF, characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop signs of capillary leak syndrome require close monitoring and symptomatic treatment, including resuscitation measures.

Splenomegaly and splenic rupture

Asymptomatic splenomegaly and splenic rupture have been reported in healthy donors and patients after administration of filgrastim. Splenic enlargement is a direct consequence of filgrastim administration. Palpable splenomegaly was observed in 31% of patients in the study. Several cases of fatal splenic rupture have been reported. Therefore, careful monitoring of splenic size (clinical and ultrasound examination) is necessary. Splenic rupture should be excluded in donors and/or patients who complain of left upper abdominal or left shoulder pain. Dose reduction slows or stops the progression of splenic enlargement; splenectomy was required in 3% of patients.

Growth of malignant cells

Since G-CSF is known to promote the growth of myeloid cells in vitro, similar effects may be observed for some non-myeloid cells in vitro.

Myelodysplastic syndrome (MDS) or chronic myeloid leukemia

The safety and efficacy of filgrastim in patients with myelodysplastic syndrome and chronic myeloid leukemia have not been established, therefore the use of the drug is not indicated in these diseases. Particular attention should be paid to the differential diagnosis between blast transformation of chronic myeloid leukemia and acute myeloid leukemia.

Acute myelocytic leukemia (AML)

As data on the safety and efficacy of filgrastim in patients with secondary acute myeloid leukemia (AML) are limited, the drug should be prescribed with caution.

The safety and efficacy of de novo filgrastim administration in patients with AML < 55 years of age with favorable cytogenetics [t(8;21), t(15;17) and inv(16)] have not been established.

Thrombocytopenia

Thrombocytopenia has been reported very commonly in patients receiving filgrastim. Close monitoring of platelet counts is necessary, especially during the first weeks of filgrastim therapy. In cases of thrombocytopenia in patients with TCH, i.e. a persistent decrease in platelet count to < 100 × 109/l, further filgrastim therapy should be temporarily discontinued or the dose reduced.

The number of leukocytes in the blood reaches or exceeds 100 × 109/l in less than 5% of patients receiving a daily dose of the drug above 0.3 million IU/kg (3 μg/kg) of body weight. There are no data on any adverse reactions directly caused by the development of leukocytosis of this severity. However, given the possible risk associated with severe leukocytosis, regular monitoring of the number of leukocytes is necessary during treatment with filgrastim. If the number of leukocytes exceeds 50 × 109/l after reaching the expected level, the drug should be discontinued immediately. In the case of use of the drug for mobilizing PSCC, it should be discontinued or the dose adjusted if the number of leukocytes increases to > 70 × 109/l.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The rate of antibody development to filgrastim is generally low. Binding antibodies have been identified, as with all biologics; however, they are not currently associated with neutralizing activity.

Special warnings and precautions related to concomitant diseases

Special precautions for sickle cell trait and sickle cell disease

Sickle cell crises, in some cases fatal, have been reported with filgrastim in patients with sickle cell trait or sickle cell disease. Physicians should exercise caution when prescribing filgrastim to patients with sickle cell trait or sickle cell disease.

In patients with sickle cell anemia, cases of acute hemolytic crisis (an increase in the number of altered cells), sometimes fatal, have been reported. Filgrastim should be administered with caution to such patients and appropriate clinical and laboratory parameters should be closely monitored during therapy, with particular attention to possible spleen enlargement and the development of blood vessel thrombosis.

Osteoporosis

In patients with concomitant bone pathology and osteoporosis, regular monitoring of bone density is recommended during long-term (more than 6 months) use of filgrastim.

Special precautions in patients with cancer

Filgrastim should not be used to increase the dose of cytotoxic chemotherapy beyond established dosing regimens.

Risk associated with increasing chemotherapy dose.

Particular caution should be exercised when treating patients with malignant neoplasms receiving high doses of cytostatics, since in these cases the effectiveness of treatment has not been established. It is known that increased doses of chemotherapy drugs have shown more pronounced toxicity, leading to the development of cardiovascular, pulmonary, neurological and dermatological adverse reactions (see instructions for medical use of concomitant cytostatic drugs).

The effect of chemotherapy on red blood cells and platelets

Filgrastim monotherapy does not prevent the development of thrombocytopenia and anemia caused by myelosuppressive chemotherapy. In the case of the use of higher doses of chemotherapy (e.g. full doses according to the prescribed regimen), the risk of severe thrombocytopenia and anemia is increased.

Regular monitoring of clinical blood parameters such as hematocrit and platelet count is recommended. Particular caution should be exercised when using single or combination chemotherapeutic agents that may cause severe thrombocytopenia.

When filgrastim was used for PSC mobilization, a reduction in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloablative chemotherapy was observed.

Other special precautions

The efficacy of the drug in patients with significantly reduced numbers of myeloid progenitor cells has not been studied. Filgrastim increases the number of neutrophils by acting primarily on neutrophil progenitor cells. Therefore, in patients with reduced numbers of progenitor cells (for example, as a result of intensive radiotherapy, chemotherapy or as a result of bone marrow infiltration by tumor cells), the number of neutrophils produced may be reduced.

Vascular disorders, such as venous occlusion and water metabolism disorders, have occasionally been reported in patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation.

There are data on the development of graft-versus-host disease and fatalities in patients receiving G-CSF after allogeneic bone marrow transplantation.

Increased bone marrow hematopoiesis in response to growth factor therapy is associated with transient pathological changes seen on bone scintigraphy. This should be considered when interpreting diagnostic bone images.

Aortitis has been reported following administration of filgrastim, both in healthy subjects and in cancer patients. The following symptoms were noted: fever, abdominal pain, malaise, back pain, and elevated inflammatory markers (e.g., elevated C-reactive protein and leukocytosis). In most cases, aortitis was diagnosed by CT scan and usually resolved after discontinuation of filgrastim.

Special precautions for patients requiring PSCC mobilization

There is no randomized comparison of the two recommended mobilization methods (filgrastim alone or in combination with myelosuppressive chemotherapy) within the same patient population. The degree of variation between individual patients and between laboratory assays of CD34+ cells means that direct comparisons between studies are difficult. It is therefore difficult to recommend the optimal method. The choice of mobilization method should be considered in relation to the overall treatment goals for the individual patient.

Previous exposure to cytotoxic agents

In patients who have previously received intensive myelosuppressive therapy, the use of filgrastim for PSC mobilization may not result in an increase in PSC counts to the recommended minimum level (≥ 2.0 × 106 CD34+ cells/kg) or an increase in the rate of platelet recovery.

Some cytotoxic agents are particularly toxic to hematopoietic progenitor cells and have a negative effect on their mobilization. Long-term use of melphalan, carboplatin or carmustine (BCNU) before progenitor cell mobilization may lead to poorer results. However, concomitant use of melphalan, carboplatin or BCNU with filgrastim is effective in PSCC mobilization. If PSCC transplantation is planned, it is recommended to perform stem cell mobilization early in the patient's treatment. Particular attention should be paid to the number of progenitor cells activated in such patients before the use of high-dose chemotherapy. If the mobilization results according to the above criteria are insufficient, alternative treatments that do not require the use of progenitor cells should be considered.

Estimation of the number of progenitor cells

When assessing the number of PSCs mobilized in patients treated with filgrastim, special attention should be paid to the method of quantification. Flow cytometric analysis of CD34+ cell counts varies considerably depending on the methodology used, and therefore, counts obtained in other laboratories should be interpreted with caution.

Statistical analysis of the relationship between the number of CD34+ cells administered and the rate of platelet recovery after high-dose chemotherapy suggests a complex but consistent relationship. The recommendation to maintain a minimum level of ≥ 2.0 × 106 CD34+ cells/kg is based on published experience with adequate hematological recovery. Higher levels than the recommended minimum result in faster recovery, while lower levels result in slower recovery.

Special precautions for healthy donors undergoing PSC mobilization

Mobilization of PSCs from healthy donors affects their health status and is used exclusively to obtain allogeneic stem cells for transplantation.

Donors undergoing PSC mobilization for transplantation should meet the standard clinical and laboratory requirements for stem cell donors. Particular attention should be paid to blood counts and the presence of infectious diseases. The safety and efficacy of filgrastim in healthy donors aged <16 years and >60 years have not been evaluated.

Transient thrombocytopenia (platelet count < 100 x 109/L) following filgrastim administration and leukapheresis was observed in 35% of patients. Among these, two cases of platelet counts < 50 x 109/L were reported and attributed to the leukapheresis procedure.

If more than one leukapheresis procedure is required, special attention should be paid to donors whose platelet count prior to leukapheresis is < 100 × 109/L; leukapheresis is generally not recommended for platelet counts < 75 × 109/L.

Leukapheresis should not be performed on donors who require anticoagulant therapy or who have hemostatic disorders.

Monitoring of donors receiving G-CSF for PSC mobilization should continue until hematological parameters normalize.

Transient cytogenetic changes have been observed in healthy donors following G-CSF administration. The significance of these changes is unknown.

The long-term safety of the drug when administered to donors is still being determined. The risk of promoting the formation of malignant myeloid cell clones cannot be excluded. Apheresis centers are recommended to systematically monitor stem cell donors for at least 10 years to ensure long-term safety monitoring.

Special precautions for recipients undergoing filgrastim-based PSC mobilization

Evidence suggests that the immunological interaction between allogeneic PSCC and the recipient is associated with a higher risk of acute and chronic graft-versus-host disease compared with bone marrow transplantation.

Special precautions for patients with THN

Filgrastim should not be used in patients with severe congenital neutropenia who have developed leukemia or in patients who have evidence of leukemic transformation.

Blood composition research

Transformation into leukemia or pre-leukemia

Special care is required in the diagnosis of THN to differentiate it from other hematological diseases such as aplastic anemia, myelodysplasia, and myeloid leukemia. Before starting treatment, a complete blood count should be performed to determine the leukocyte formula and platelet count, as well as to determine the morphological picture of the bone marrow and karyotype.

The occurrence of myelodysplastic syndrome (MDS) or leukemia in patients with severe chronic neutropenia who participated in clinical trials of filgrastim is rare (approximately 3%). These disorders were observed only in patients with congenital neutropenia. MDS and leukemia are common complications of the disease, their relationship to filgrastim therapy is uncertain. Approximately 12% of patients (without cytogenetic abnormalities before the start of therapy) had abnormalities in the results of subsequent tests, including monosemium 7. In cases of cytogenetic abnormalities in a patient with severe chronic neutropenia, the benefit-risk ratio of continued use of filgrastim should be carefully weighed. Further administration of filgrastim should be discontinued in patients who develop MDS or leukemia. It is unknown whether long-term treatment with filgrastim in patients with severe chronic neutropenia increases the risk of cytogenetic abnormalities, MDS, or transformation to leukemia. Morphological and cytogenetic examination of the bone marrow of patients should be performed regularly, at intervals of approximately every 12 months.

Other special precautions

Other causes of neutropenia, such as viral infections, should be ruled out.

Hematuria was observed frequently and proteinuria was observed in a small number of patients. Regular urinalysis is necessary for timely detection of these phenomena.

Safety and efficacy in neonates and patients with autoimmune neutropenia have not been established.

Special precautions for patients with HIV infection

Blood formula

Careful monitoring of the absolute neutrophil count (ANC) is necessary, especially during the first weeks of filgrastim therapy. Some patients have a very rapid response with a significant increase in neutrophil count in response to the first dose of filgrastim. Daily ANC determination is recommended for the first 2-3 days of filgrastim administration. Subsequently, ANC determination is recommended at least 2 times a week for the first 2 weeks, then once a week and every 2 weeks during maintenance therapy. During the next administration of filgrastim at an individually determined dose and at a dose of 30 million IU/day (300 μg/day), larger fluctuations in the patient's ANC value are possible. To determine the minimum (lowest ANC values), it is recommended to obtain blood samples from the patient for ANC analysis immediately before the scheduled administration of filgrastim.

Risk associated with the use of myelosuppressive drugs at increased doses

Filgrastim administration alone does not exclude the possibility of thrombocytopenia and anemia due to myelosuppressive chemotherapy. The risk of thrombocytopenia and anemia in patients receiving higher doses of chemotherapy or the use of more of these drugs in combination with filgrastim may increase. Regular monitoring of blood counts is recommended.

Infectious and malignant diseases causing myelosuppression

Neutropenia may result from infiltration of the bone marrow by opportunistic infections such as Mycobacterium avium or from malignancies such as lymphoma. In patients with infectious diseases or malignancies affecting the bone marrow, appropriate therapy for the disease should be used in addition to filgrastim to correct neutropenia. The effect of filgrastim on the resolution of neutropenia caused by infectious diseases or malignancies affecting the bone marrow has not been determined.

Excipients

Zarsio® contains sorbitol, therefore patients with rare hereditary problems of fructose intolerance should not use this medicine.

The protective cap contains a derivative of natural rubber latex. Although the medicinal product itself does not contain natural rubber latex, the safety of the product in patients sensitive to latex has not been studied.

In order to improve the traceability of G-CSF, the name of the administered medicinal product should be clearly stated in the patient file.

Use during pregnancy or breastfeeding

The safety of filgrastim in pregnant women has not been established. There is evidence that filgrastim crosses the placental barrier. There is no evidence of teratogenicity of filgrastim in animal studies. Animal studies have shown reproductive toxicity. An increased incidence of miscarriages has been observed in animals treated with filgrastim.

It is not known whether filgrastim and its metabolites are excreted in human milk, therefore a risk to the nursing infant cannot be excluded. Therefore, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from filgrastim therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Animal studies have shown that filgrastim does not affect the reproductive system or fertility.

Ability to influence reaction speed when driving vehicles or other mechanisms

Filgrastim may have a minor influence on the reactions when driving vehicles or using other mechanisms, namely possible dizziness.

Method of administration and doses

Zarsio® therapy can be performed in medical institutions with the necessary diagnostic equipment. Physicians should have experience in the use of granulocyte colony-stimulating factor (G-CSF)-containing medicinal products and the treatment of patients with hematological diseases.

Mobilization and apheresis procedures should be performed in collaboration with physicians who have the appropriate experience and the ability to properly monitor hematopoietic progenitor cells.

Neutropenia in patients receiving cytotoxic chemotherapy for malignant diseases.

The recommended daily dose of the drug is 0.5 million IU/kg (5 mcg/kg) of body weight once a day. The first dose of the drug should be administered no earlier than 24 hours after a course of cytotoxic chemotherapy. The drug should be used until the total number of neutrophils in the clinical blood test exceeds the expected level and reaches the norm. After chemotherapy for solid tumors, lymphomas and lymphocytic leukemia, the duration of treatment to achieve the specified values is up to 14 days. After induction and consolidation therapy for acute myeloid leukemia, the duration of treatment can be significantly increased (up to 38 days) depending on the type, dose and regimen of cytotoxic chemotherapy used.

In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil count is usually observed 1-2 days after the start of treatment with Zarsio®. However, to achieve a stable therapeutic effect, therapy should be continued until the neutrophil count exceeds the expected minimum and reaches the norm. It is not recommended to prematurely discontinue treatment with the drug before the neutrophil count passes the expected minimum.

Method of administration

Zarsio® should be administered as a subcutaneous injection or intravenous infusion (diluted in 5% glucose solution) over 30 minutes once daily. In most cases, the subcutaneous route of administration is preferred. With intravenous administration of a single dose, the duration of the drug's effect may be shortened. The clinical significance of these data regarding the use of multiple doses of the drug has not been established. The choice of route of administration depends on the specific clinical situation and is determined for each patient individually.

Patients receiving myeloablative therapy followed by bone marrow transplantation.

The recommended starting dose of Zarsio® is 1 million IU/kg (10 mcg/kg) of body weight per day. The first dose should be administered no earlier than 24 hours after cytotoxic chemotherapy and no earlier than 24 hours after bone marrow transplantation.

After the maximum decrease in neutrophil count (nadir), the daily dose of Zarsio® should be adjusted depending on the change in neutrophil count (see table).

Dose adjustment of Zarsio® in response to reaching the nadir.

Method of administration

The drug should be dissolved in 20 ml of 5% glucose solution and administered as a short intravenous infusion over 30 minutes or as a long subcutaneous or intravenous infusion over 24 hours.

Mobilization of peripheral blood stem cells (PBSCs) in patients receiving myelosuppressive or myeloablative therapy followed by autologous PBSC transfusion

Patients receiving myelosuppressive or myeloablative therapy followed by autologous PSCC transplantation.

For mobilisation of PSCs after myelosuppressive chemotherapy, the recommended dose of Zarsio® is 0.5 million IU/kg (5 mcg/kg) body weight per day, starting on the first day after completion of chemotherapy until the neutrophil count has passed the expected nadir and returned to normal. Leukapheresis should be performed during the period of ANC increase from < 0.5 × 109/l to > 5 × 109/l. In patients who have not received intensive chemotherapy, 1 leukapheresis session is usually sufficient. In some cases, additional leukapheresis sessions are recommended.

Method of administration

Filgrastim for PSCC mobilization, when used alone, can be administered as a continuous subcutaneous infusion over 24 hours or as a subcutaneous injection. For infusions, filgrastim should be diluted in 20 ml of 5% glucose solution.

Filgrastim for PSCC mobilization after myelosuppressive chemotherapy should be administered subcutaneously.

Mobilization of PSCs in healthy donors before allogeneic PSC transplantation.

For PSC mobilization prior to allogeneic PSC transplantation in healthy donors, the recommended dose of Zarsio® is 1 million IU/kg (10 mcg/kg) of body weight per day for 4-5 consecutive days. Leukapheresis should be performed from day 5 and, if necessary, continued until day 6 to obtain 4 × 106 CD34+ cells/kg of recipient body weight.

Method of administration

Filgrastim should be administered as a subcutaneous injection.

In patients with severe chronic neutropenia (SCN)

Hereditary neutropenia

The recommended initial dose is 1.2 million IU/kg (12 mcg/kg) of body weight per day by single subcutaneous injection or in divided doses.

Idiopathic and intermittent neutropenia

The recommended initial dose is 0.5 million IU/kg (5 mcg/kg) of body weight per day as a single dose or in divided doses.

Dose selection

Zarsio® should be administered daily as a subcutaneous injection until a neutrophil count of 1.5 × 109/l is achieved and maintained above that level. After achieving a therapeutic effect, determine the minimum effective dose to maintain this level. Long-term daily administration of the drug is required to maintain the required number of neutrophils. After 1-2 weeks of treatment, the initial dose can be doubled or halved depending on the effectiveness of therapy. In the future, individual dose adjustments should be made every 1-2 weeks to stabilize the average neutrophil count in the range of 1.5 × 109/l to 10 × 109/l. Patients with severe infections may benefit from a more rapid dose escalation regimen. The safety of filgrastim in long-term treatment of patients with Zarsio® doses higher than 2.4 million IU (24 mcg/kg) per day has not been established.

Method of administration

Filgrastim should be administered as a subcutaneous injection.

In patients with HIV infection

Neutrophil count recovery

The recommended initial dose of the drug is 0.1 million IU/kg (1 μg/kg) of body weight per day, with an increase in the dose to 0.4 million IU (4 μg/kg) of body weight per day by a single subcutaneous injection until the neutrophil count normalizes (ANC > 2.0 × 109/l). Normalization of the neutrophil count usually occurs after 2 days. In a small number of cases (< 10% of patients) the dose of the drug may be increased to 1 million IU/kg (10 μg/kg of body weight per day) to restore the neutrophil count.

Maintaining normal neutrophil counts

When neutropenia is resolved, the minimum effective dose should be established to maintain a normal neutrophil count. After achieving a therapeutic effect, the maintenance dose is 300 mcg/day 2-3 times a week on an alternate schedule (every other day). In the future, individual dose adjustment and long-term use of the drug may be necessary to maintain a mean neutrophil count > 2.0 × 109/l.

Method of administration

Filgrastim should