Filgrastim-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FILGRASTIM-VISTA (FILGRASTIM-VISTA)

Composition:

Active substance: filgrastim;

1 pre-filled syringe (0.5 mL solution) contains 300 mcg of filgrastim (30 million IU);

1 pre-filled syringe (0.8 mL solution) contains 480 mcg of filgrastim (48 million IU);

Excipients: glacial acetic acid, polysorbate 80, sodium hydroxide, sorbitol, water for injections.

Pharmaceutical form. Solution for injection or infusion.

Main physicochemical properties: colorless and clear solution.

Pharmacotherapeutic group. Immunostimulants. Colony-stimulating factors. Filgrastim. ATC code L03A A02.

Pharmacological Properties

Pharmacodynamics

Human granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that regulates the production and release of functional neutrophils from the bone marrow. FILGRASTIM-VISTA, containing r-metHuG-CSF (filgrastim), induces a marked increase in the number of peripheral blood neutrophils within twenty-four hours, with a slight increase in monocytes. In some patients with chronic neutropenia (CN), filgrastim may also cause a slight increase in circulating eosinophils and basophils compared to baseline levels; some of these patients may have eosinophilia or basophilia even prior to treatment. The increase in neutrophil count is dose-dependent at recommended doses. Neutrophils produced in response to filgrastim demonstrate normal or enhanced function, as shown by tests of chemotactic and phagocytic function. After discontinuation of filgrastim therapy, the number of circulating neutrophils decreases by 50% within 1–2 days and returns to normal levels within 1–7 days.

The use of filgrastim in patients undergoing cytotoxic chemotherapy significantly reduces the frequency, severity, and duration of neutropenia and febrile neutropenia. Filgrastim treatment significantly shortens the duration of febrile neutropenia, antibiotic use, and hospitalization following induction chemotherapy for acute myeloid leukemia or myeloablative therapy followed by bone marrow transplantation. However, the incidence of fever and the number of documented infection episodes were not reduced. The duration of fever was not reduced in patients undergoing myeloablative therapy followed by bone marrow transplantation.

Filgrastim administration, either alone or after chemotherapy, stimulates the mobilization of hematopoietic progenitor cells into peripheral blood. These autologous peripheral blood progenitor cells can be collected and reinfused after high-dose cytotoxic therapy, as an alternative or adjunct to bone marrow transplantation. Infusion of peripheral blood progenitor cells accelerates hematopoietic recovery, reducing the duration of risk for hemorrhagic complications and the need for platelet transfusions. In recipients of allogeneic peripheral blood progenitor cells mobilized with filgrastim, hematologic recovery occurs significantly faster, resulting in a significantly shorter time to unassisted platelet recovery compared to allogeneic bone marrow transplantation.

One retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukemias showed an increased risk of graft-versus-host disease (GvHD), treatment-related mortality (TRM), and overall mortality with G-CSF administration. In a separate retrospective international study involving patients with acute and chronic myeloid leukemia, no effect on the risk of GvHD, TRM, or mortality was observed. A meta-analysis of allogeneic transplantation studies, including nine prospective randomized trials, eight retrospective studies, and one controlled study, found no impact on the risks of acute GvHD, chronic GvHD, or early treatment-related mortality.

a The analysis includes studies involving bone marrow transplantation during this period; some studies used G-CSF.

b The analysis includes patients who received bone marrow transplantation during this period.

Use of filgrastim for mobilization of peripheral blood progenitor cells in healthy donors prior to allogeneic peripheral blood progenitor cell transplantation. In normal donors, a dose of 10 mcg/kg/day administered subcutaneously for 4–5 consecutive days allows collection of ≥ 4 × 10⁶ CD34⁺ cells/kg recipient body weight in most donors after two leukapheresis procedures.

Administration of filgrastim to patients, children or adults, with SCN (severe congenital, cyclic, and idiopathic neutropenia) results in a sustained increase in the absolute neutrophil count in peripheral blood and reduction in infections and infection-related complications. Administration of filgrastim to HIV-infected patients maintains normal neutrophil counts, allowing scheduled administration of antiviral and/or other myelosuppressive agents. There is no evidence that HIV replication increases in HIV-infected patients treated with filgrastim.

Like other hematopoietic growth factors, G-CSF has demonstrated in vitro stimulatory effects on human endothelial cells.

Pharmacokinetics

Filgrastim clearance has been shown to follow first-order pharmacokinetics after both subcutaneous and intravenous administration. The serum half-life of filgrastim is approximately 3.5 hours, and clearance is approximately 0.6 mL/min/kg. Continuous infusion of filgrastim for up to 28 days in patients recovering from autologous bone marrow transplantation did not result in drug accumulation, and the half-life remained comparable. A positive linear correlation exists between dose and serum filgrastim concentration, regardless of whether it is administered intravenously or subcutaneously. After subcutaneous administration of recommended doses, serum concentrations remained above 10 ng/mL for 8–16 hours. The volume of distribution in blood is approximately 150 mL/kg.

Clinical Characteristics

Indications

• To reduce the duration of neutropenia and the incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignancies (with the exception of chronic myeloid leukemia and myelodysplastic syndrome).
• To reduce the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation, who are at high risk of prolonged severe neutropenia.
• For mobilization of peripheral blood progenitor cells (PBPC).
• For long-term therapy to increase neutrophil counts and reduce the frequency and duration of infectious complications in children and adults with severe congenital, cyclic, or idiopathic neutropenia (absolute neutrophil count ≤ 0.5×10⁹/L) and a history of severe or recurrent infections.
• To reduce the risk of bacterial infections in patients with persistent neutropenia (absolute neutrophil count ≤ 1.0×10⁹/L) during advanced stages of HIV infection when other means of controlling neutropenia have been ineffective.

Contraindications. Hypersensitivity to the active substance or to any of the excipients.

Safety precautions

Unused portions of the medicinal product should be disposed of according to current regulations.

Safety syringes should be disposed of according to current regulations.

Interaction with other medicinal products and other forms of interaction

The safety and efficacy of administering filgrastim on the same day as myelosuppressive cytotoxic agents have not been established. Due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, filgrastim should not be administered less than 24 hours before or earlier than 24 hours after administration of these agents. Preliminary data from a small number of patients who received filgrastim and 5-fluorouracil concurrently suggest an increased risk of worsening severity of neutropenia. Possible interactions with other hematopoietic growth factors and cytokines have not been studied in clinical trials.

Given that lithium stimulates neutrophil release, combination with filgrastim may enhance its effect. Although studies on this interaction have not been conducted, there is no evidence of harmful effects from such interaction.

Special precautions for use

Hypersensitivity

Hypersensitivity reactions, including anaphylactic reactions, have been observed in patients at the beginning or during continued treatment with filgrastim. If clinically significant hypersensitivity reactions occur, administration of filgrastim should be discontinued and not resumed thereafter. Filgrastim should not be administered to patients with a history of hypersensitivity to filgrastim or pegfilgrastim.

Pulmonary adverse reactions

Pulmonary adverse reactions, including interstitial lung disease, have been reported following administration of G-CSF. Patients with recent history of pulmonary infiltrates or pneumonia have a higher risk of such reactions. The onset of respiratory symptoms such as cough, fever, and dyspnea, in combination with radiological signs of pulmonary infiltrates and worsening of lung function, may be the first signs of acute respiratory distress syndrome (ARDS). Administration of filgrastim should be discontinued and appropriate treatment initiated.

Glomerulonephritis

Cases of glomerulonephritis have been reported in patients receiving filgrastim and pegfilgrastim. Glomerulonephritis usually resolves after dose reduction or discontinuation of filgrastim and pegfilgrastim. Regular urine analysis is recommended.

Capillary leak syndrome

Cases of capillary leak syndrome have been reported after administration of G-CSF. This condition is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration, and may be life-threatening if not treated promptly. Patients who develop symptoms of capillary leak syndrome should be closely monitored and provided with standard symptomatic treatment and, if necessary, intensive care.

Splenomegaly and splenic rupture

Asymptomatic cases of splenomegaly and isolated cases of splenic rupture have been observed in patients and healthy donors receiving filgrastim. Several cases of splenic rupture were fatal. Therefore, monitoring of spleen size (e.g., clinical examination, ultrasound) is recommended in such patients. The possibility of splenic rupture should be considered in donors or patients reporting pain in the upper left quadrant of the abdomen or left shoulder. Dose reduction of filgrastim slowed or halted spleen enlargement in patients with severe chronic neutropenia, and 3% of patients required splenectomy.

Growth of malignant cells

G-CSF may promote the growth of myeloid cells in vitro. Similar effects may be possible for certain non-myeloid cells.

Myelodysplastic syndrome or chronic myeloid leukemia

The safety and efficacy of filgrastim in patients with myelodysplastic syndrome or chronic myeloid leukemia have not been established. Filgrastim is not recommended for use in these conditions. Particular attention should be paid to differential diagnosis of blast crisis in chronic myeloid leukemia and acute myeloid leukemia.

Acute myeloid leukemia

The safety and efficacy of filgrastim in patients with secondary acute myeloid leukemia have not been sufficiently studied; therefore, filgrastim should be used with caution in these patients. Safety and efficacy of filgrastim in de novo acute myeloid leukemia in patients under 55 years of age with favorable cytogenetic factors [t(8;21), t(15;17), and inv(16)] have not been established.

Thrombocytopenia

Cases of thrombocytopenia have been reported in patients receiving filgrastim. Platelet counts should be closely monitored, especially during the first few weeks of filgrastim treatment. If thrombocytopenia (platelet count < 100×10⁹/L) develops in patients with severe chronic neutropenia, temporary discontinuation or dose reduction of filgrastim should be considered.

Leukocytosis

In less than 5% of oncology patients receiving filgrastim at doses exceeding 0.3 million IU/kg/day (3 µg/kg/day), white blood cell counts increased to 100×10⁹/L or higher. No adverse reactions directly related to such leukocytosis have been described. However, due to the risk associated with high leukocytosis, white blood cell counts should be monitored regularly during filgrastim treatment. If white blood cell count exceeds 50×10⁹/L after the expected decline, filgrastim treatment should be discontinued immediately. However, if filgrastim is used for stem cell mobilization, it should be discontinued or the dose reduced when white blood cell count exceeds 70×10⁹/L.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The rate of antibody development against filgrastim is generally low. The appearance of binding antibodies is expected, as with other biological agents; however, data on their neutralizing activity are currently lacking.

Aortitis

Cases of aortitis have been reported after G-CSF administration in healthy individuals and cancer patients. Symptoms may include fever, abdominal pain, malaise, back pain, and may be accompanied by elevated inflammatory markers (e.g., C-reactive protein, white blood cell count). In most cases, aortitis was diagnosed by computed tomography and usually resolved after discontinuation of G-CSF.

Special precautions related to concomitant diseases

Sickle cell trait and sickle cell anemia

Cases of sickle cell crisis, sometimes fatal, have been observed in patients with sickle cell trait or sickle cell anemia receiving filgrastim. Therefore, filgrastim should be administered with caution in patients with sickle cell trait or sickle cell anemia.

Osteoporosis

Patients with concomitant osteoporosis receiving continuous filgrastim therapy for more than 6 months should undergo monitoring of bone mineral density.

Special warnings for patients with oncological diseases

Filgrastim should not be used to increase cytotoxic chemotherapy doses beyond established limits.

Risk associated with high-dose chemotherapy

Particular caution should be exercised when treating patients receiving high-dose chemotherapy, as treatment efficacy has not been established in these cases, while higher chemotherapy doses have shown increased toxicity, leading to cardiac, pulmonary, neurological, and dermatological reactions (see the package leaflet of the respective chemotherapeutic agent).

Effect of chemotherapy on erythrocytes and platelets

Monotherapy with filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher chemotherapy doses (e.g., full doses according to regimens), patients may be at increased risk of developing thrombocytopenia and anemia; therefore, platelet count and hematocrit should be monitored regularly. Single-agent or combination chemotherapy regimens that may cause severe thrombocytopenia should be used with particular caution.

The use of stem cells mobilized by filgrastim reduces the severity and duration of thrombocytopenia after myelosuppressive or myeloablative chemotherapy.

Myelodysplastic syndrome and acute myeloid leukemia in patients with breast cancer and lung cancer

In an observational post-marketing study, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were associated with the use of pegfilgrastim, an alternative G-CSF, in combination with chemotherapy and/or radiotherapy in patients with breast and lung cancer. A similar association between filgrastim and MDS/AML has not been observed. However, patients with breast cancer and patients with lung cancer should be monitored for signs and symptoms of MDS/AML.

Other special warnings

The effect of filgrastim in patients with significantly reduced numbers of myeloid precursor cells has not been studied. Filgrastim increases neutrophil counts by primarily affecting neutrophil precursor cells. Therefore, in patients with low numbers of precursor cells (e.g., those who have undergone intensive radiotherapy or chemotherapy, or those with tumor infiltration of bone marrow), the degree of neutrophil count increase may be reduced.

Vascular complications, including veno-occlusive disease and fluid imbalance, have occasionally been observed in patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation.

Cases of fatal graft-versus-host reaction have been reported in patients who received granulocyte colony-stimulating factor after allogeneic bone marrow transplantation.

Increased bone marrow hematopoietic activity in response to granulocyte colony-stimulating factor treatment, manifesting as transiently positive bone scans, has been reported. This should be considered when interpreting bone scan results.

Special warnings for patients undergoing stem cell mobilization

Mobilization

A prospective randomized comparison of two recommended mobilization methods (filgrastim alone or filgrastim in combination with myelosuppressive chemotherapy) in the same patient population has not been conducted. Individual patient characteristics across different studies and variability in laboratory determination of CD34+ cell counts make direct comparison of study results difficult. Therefore, it is difficult to recommend an optimal method. The mobilization method should be selected based on the patient's treatment goals.

Prior to administration of cytotoxic agents

In patients who have previously undergone active myelosuppressive therapy, adequate mobilization of stem cells to the recommended minimum level (≥ 2.0×10⁶ CD34+ cells/kg) or accelerated platelet count recovery may not occur. Some cytostatic agents have specific toxicity toward hematopoietic precursor cells and may negatively affect their mobilization. Agents such as melphalan, carmustine, and carboplatin, if administered over a prolonged period before stem cell mobilization attempts, may reduce mobilization efficacy. However, the use of melphalan, carboplatin, or carmustine in combination with filgrastim has proven effective in stem cell activation. If stem cell transplantation is planned, mobilization should be scheduled early in the treatment course. Particular attention should be paid to the number of stem cells mobilized in these patients prior to high-dose chemotherapy. If mobilization results according to the above criteria are insufficient, alternative treatments not requiring precursor cells should be considered.

Assessment of mobilized peripheral blood stem cells

When assessing the number of stem cells mobilized by filgrastim in patients, particular attention should be paid to the quantification method. Results of flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology; therefore, recommendations based on studies conducted in other laboratories should be approached with caution. Statistical analysis of the relationship between the number of infused CD34+ cells and the speed of platelet count recovery after high-dose chemotherapy indicates a complex but consistent correlation. The recommended minimum number of stem cells is ≥ 2.0×10⁶ CD34+ cells/kg, based on published data on adequate hematological recovery. A higher number of precursor cells appears to lead to faster recovery, whereas a lower number leads to slower blood count normalization.

Special warnings for healthy donors undergoing stem cell mobilization

Stem cell mobilization does not provide direct clinical benefit to healthy donors and should only be considered for the purpose of allogeneic stem cell transplantation.

Stem cell mobilization in donors should only be performed if standard clinical and laboratory criteria for stem cell donation are met, particularly hematological parameters and absence of infectious diseases.

The safety and efficacy of filgrastim in healthy donors under 16 years of age or over 60 years of age have not been evaluated.

Transient thrombocytopenia (platelet count < 100×10⁹/L) after filgrastim administration and leukapheresis was observed in 35% of subjects. Among them, two cases of thrombocytopenia with platelet count < 50×10⁹/L were associated with the leukapheresis procedure.

If more than one leukapheresis is required, particular attention should be paid to donors whose platelet count before leukapheresis is less than 100×10⁹/L; in general, apheresis should not be performed if platelet count is below 75×10⁹/L. Leukapheresis should not be performed in donors receiving anticoagulants or with coagulation disorders.

Donors receiving G-CSF for stem cell mobilization should be monitored until hematological parameters normalize.

Transient cytogenetic abnormalities have been observed in donors receiving G-CSF. The significance of these changes is unknown. However, the risk of stimulation of a malignant myeloid clone cannot be excluded. Apheresis centers are recommended to register and monitor stem cell donors for at least 10 years to ensure long-term safety monitoring.

Special warnings for recipients of allogeneic stem cells mobilized by filgrastim

Available data indicate that allogeneic stem cell transplantation is associated with a higher risk of acute and chronic graft-versus-host reaction compared to bone marrow transplantation.

Special warnings for patients with severe chronic neutropenia

Filgrastim should not be administered to patients with severe congenital neutropenia who develop leukemia or show signs of leukemia development.

Blood cell count determination

Other blood count changes may occur, including anemia and transient increase in myeloid precursor cells, requiring careful monitoring of cell counts.

Transformation to leukemia or myelodysplastic syndrome

Particular caution should be exercised in diagnosing severe chronic neutropenias. They should be differentiated from other hematological disorders such as aplastic anemia, myelodysplasia, and myeloleukemia. Before initiating treatment, a complete blood count with white blood cell differential and platelet count, as well as bone marrow morphology and karyotype, should be performed.

In clinical trials, myelodysplastic syndrome (MDS) or leukemia was observed in only a small number (3%) of patients with severe chronic neutropenia receiving filgrastim. This observation was made only in patients with congenital neutropenia. MDS and leukemia are common complications of this disease; their relationship to filgrastim treatment is not established. In approximately 12% of patients with initially normal cytogenetics, abnormalities including monosomy 7 were detected on repeat testing. It is currently unknown whether long-term filgrastim treatment promotes the development of cytogenetic abnormalities, MDS, or leukemia in patients with severe chronic neutropenia. In such patients, regular (approximately every 12 months) morphological and cytogenetic bone marrow examinations are recommended.

Other special warnings

Causes of transient neutropenia such as viral infections should be excluded.

Hematuria and/or proteinuria have been observed in a small number of patients; regular urine testing is recommended for monitoring.

The safety and efficacy of filgrastim in neonates and patients with autoimmune neutropenia have not been established.

Special warnings for patients with HIV infection

Blood cell count determination

Neutrophil counts should be closely monitored, especially during the first few weeks of filgrastim treatment. In some patients, a therapeutic effect is observed very quickly after the first injection, with a significant increase in neutrophil count. Monitoring of neutrophil counts is recommended daily during the first 2–3 days of filgrastim treatment, then at least twice weekly during the first two weeks, and at least once weekly or every two weeks during maintenance therapy. If a dose of 30 million IU (300 µg) filgrastim is administered less than daily, significant fluctuations in neutrophil count may occur over time. To determine the nadir of neutrophil count, blood samples should be taken immediately before the next dose of filgrastim.

Risk associated with use of high-dose myelosuppressive agents

Monotherapy with filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses or quantities of chemotherapeutic agents together with filgrastim, patients may be at increased risk of developing thrombocytopenia and anemia; therefore, regular blood cell count monitoring is recommended (see above).

Infections and malignancies causing myelosuppression

Neutropenia may be due to bone marrow infiltration by opportunistic infection agents (e.g., Mycobacterium avium complex) or tumors (lymphoma). In addition to filgrastim for neutropenia treatment, such patients should receive specific treatment for the underlying disease. The effect of filgrastim on neutropenia caused by infectious agents or malignant bone marrow tumors has not been sufficiently studied.

Other warnings

Traceability. To improve traceability of granulocyte colony-stimulating factors, the brand name of the prescribed medicinal product and the batch number of the administered product should be clearly documented in the patient's medical record.

Important information on excipients

Sorbitol. The medicinal product contains sorbitol. The additive effect of concomitant use of medicinal products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered.

For intravenous use. Filgrastim should not be administered to patients with hereditary fructose intolerance (HFI), except in cases of extreme necessity. HFI may not yet be diagnosed in infants and young children (under 2 years of age). Medicinal products for intravenous use containing sorbitol/fructose may be life-threatening and should not be prescribed to this patient group, except in cases of acute clinical necessity and lack of alternatives. A detailed medical history regarding symptoms of HFI should be obtained from each patient before prescribing this medicinal product.

Sodium. One pre-filled syringe contains less than 1 mmol (23 mg) of sodium, i.e., the medicinal product is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of filgrastim in pregnant women are limited or absent. Animal studies have shown reproductive toxicity. Increased embryo loss was observed in animals at multiple high doses and in the presence of maternal toxicity. There are reports of filgrastim crossing the placental barrier. Filgrastim is not recommended during pregnancy.

Breastfeeding. It is unknown whether filgrastim or its metabolites are excreted in human breast milk. Risk to breastfed newborns/infants cannot be excluded. The decision to discontinue breastfeeding or interrupt/stop filgrastim therapy should be made considering the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility. Animal studies have shown that filgrastim does not affect reproductive function or fertility.

Ability to affect reaction speed when driving or operating machinery

Filgrastim may have a minor influence on the ability to drive or operate machinery. Dizziness may occur after administration of filgrastim (see section "Adverse reactions").

Method of Administration and Dosage

Treatment should be conducted in collaboration with an oncology center equipped with appropriate diagnostic facilities and staffed by specialists experienced in hematology and in the use of human granulocyte colony-stimulating factor. Procedures for cell mobilization and apheresis should be performed by specialists with adequate experience in this field and with appropriate monitoring of hematopoietic progenitor cells.

Conventional Cytotoxic Chemotherapy

Dosage

The recommended dose of filgrastim is 0.5 million IU (5 µg) / kg body weight once daily. The first dose should be administered no sooner than 24 hours after completion of cytotoxic chemotherapy. In randomized clinical trials, a subcutaneous dose of 23 million IU (230 µg) / m² / day (4.0–8.4 µg / kg body weight per day) was used.

The medicinal product should be administered daily until neutrophil counts, following the expected nadir, recover to normal levels. In patients receiving cytotoxic chemotherapy for solid tumors, lymphomas, and lympholeukemia, the expected duration of therapy required to meet these criteria is up to 14 days. After induction and consolidation therapy for acute myeloid leukemia, the duration of treatment may be significantly longer (up to 38 days), depending on the type, dosage, and regimen of cytotoxic chemotherapy used.

A transient increase in neutrophil count is usually observed within 1–2 days after initiating filgrastim treatment in patients receiving cytotoxic chemotherapy. However, to achieve a stable therapeutic effect, filgrastim therapy should not be interrupted before neutrophil counts have recovered to normal levels following the expected nadir. Premature discontinuation of treatment, before the expected nadir in neutrophil count, is not recommended.

Method of Administration

The medicinal product can be administered via daily subcutaneous injections or daily short (30-minute) intravenous infusions in 5% glucose solution. Subcutaneous administration is preferred, as clinical trial data from single-dose studies indicate that intravenous administration may reduce the duration of filgrastim's effect. The clinical relevance of these findings for multiple-dose regimens has not been established. The route of administration should be selected based on the individual clinical circumstances.

Subcutaneous Administration

1

2

Syringe with a safety device preventing needlestick injury and reuse (Fig. 1, 2).

3

4

Preferred body sites for subcutaneous injection (Fig. 3, 4).

5

6

Subcutaneous administration of the medicinal product (Fig. 5–6).

1. Disinfect the injection site with an alcohol wipe. Pinch the skin between the thumb and index finger without compressing it (Fig. 5).
2. Insert the needle fully into the skin (Fig. 6).
3. Gently pull back on the syringe plunger to check whether a blood vessel has been punctured. If blood appears in the syringe, withdraw the needle, and re-inject at another site.

Filgrastim should be administered daily at the same time.

To avoid pain, the injection site should be rotated daily.

7

Syringes with safety devices

Filgrastim should be injected slowly and evenly, with the skin pinched between the fingers, until the full dose is administered and the syringe plunger stops moving.

Excessive force on the plunger must not be applied.

After administering the medicinal product, withdraw the needle while continuing to press on the plunger, then release the skin (Fig. 7).

Once the finger is removed from the plunger, the syringe's safety mechanism will quickly cover the needle to prevent injury.

A new syringe must be used for each subsequent injection. Re-injection of any remaining filgrastim in the syringe is prohibited.

Myeloablative Therapy Followed by Bone Marrow Transplantation

Dosage

The recommended initial dose is 1.0 million IU (10 µg) / kg body weight per day. The first dose of filgrastim should be administered no sooner than 24 hours after cytotoxic chemotherapy and no sooner than 24 hours after bone marrow transplantation.

After the neutrophil nadir, the daily dose should be adjusted according to changes in neutrophil count (see Table 1).

Table 1

Method of Administration

The medicinal product can be administered by 30-minute or 24-hour intravenous infusion or by continuous 24-hour subcutaneous infusion. Filgrastim should be diluted in 20 mL of 5% glucose solution for infusion.

Mobilization of peripheral blood stem cells in patients receiving myelosuppressive or myeloablative therapy followed by autologous stem cell transplantation

Dosing

When filgrastim is used as monotherapy for mobilization of stem cells, the recommended dose is 1.0 million IU (10 mcg)/kg per day for 5–7 consecutive days. Usually, one or two leukapheresis procedures on day 5 or 6 are sufficient. If additional leukapheresis is required, filgrastim administration at the same dose should continue until the final leukapheresis.

For mobilization of stem cells after myelosuppressive chemotherapy, the recommended dose is 0.5 million IU (5 mcg)/kg per day, starting on the first day after completion of chemotherapy and continuing until the neutrophil count, after the expected nadir, recovers to normal levels. Leukapheresis should be performed during the period of neutrophil recovery from less than 0.5×10⁹/L to more than 5.0×10⁹/L. In patients who have not received intensive chemotherapy, a single leukapheresis may sometimes be sufficient. In other cases, additional leukapheresis procedures are recommended.

Method of Administration

When filgrastim is used as monotherapy for mobilization of stem cells, it may be administered as a continuous 24-hour subcutaneous infusion or by subcutaneous injection. For infusion, the medicinal product should be diluted in 20 mL of 5% glucose solution for infusion. When filgrastim is used for mobilization of stem cells after myelosuppressive chemotherapy, it should be administered by subcutaneous injection.

Mobilization of peripheral blood stem cells in healthy donors for allogeneic stem cell transplantation

Dosing

For mobilization of stem cells in healthy donors, filgrastim should be administered at a dose of 1.0 million IU (10 mcg)/kg per day for 4–5 consecutive days. Leukapheresis should begin on day 5 of treatment and, if necessary, continue on day 6 to achieve a yield of 4×10⁶ CD34⁺ cells/kg of recipient body weight.

Method of Administration

Filgrastim should be administered by subcutaneous injection.

Severe Chronic Neutropenia

Dosing

Congenital neutropenia. The recommended initial dose is 1.2 million IU (12 mcg)/kg per day given as a single or divided dose.

Idiopathic or cyclic neutropenia. The recommended initial dose is 0.5 million IU (5 mcg)/kg per day given as a single or divided dose.

Dose Adjustment. Filgrastim should be administered daily by subcutaneous injection until the neutrophil count reaches and stably exceeds 1.5×10⁹/L. After achieving the therapeutic effect, the minimal effective dose to maintain this level should be determined. Long-term daily administration of filgrastim is required to maintain the desired neutrophil count. After 1 or 2 weeks of treatment, the initial dose may be doubled or halved depending on the therapeutic response. Thereafter, individual dose adjustments should be made every 1–2 weeks to maintain the average neutrophil count within the range of 1.5×10⁹/L to 10×10⁹/L. In patients with severe infections, a more rapid dose escalation regimen may be used. In clinical studies, a complete response was observed in 97% of patients who responded to treatment at doses ≤ 2.4 million IU (24 mcg)/kg per day. The safety of long-term use of filgrastim at doses exceeding 2.4 million IU (24 mcg)/kg per day in patients with severe chronic neutropenia has not been established.

Method of Administration

Congenital, idiopathic, or cyclic neutropenia. Filgrastim should be administered by subcutaneous injection.

HIV-Infected Patients

Dosing

For correction of neutropenia. The recommended initial dose is 0.1 million IU (1 mcg)/kg per day, with dose escalation up to a maximum of 0.4 million IU (4 mcg)/kg per day until sustained normalization of the neutrophil count (absolute neutrophil count > 2.0×10⁹/L). In clinical studies, more than 90% of patients responded to this dosing regimen, achieving neutrophil recovery within a median of 2 days.

A small number of patients (less than 10%) required doses up to 1.0 million IU (10 mcg)/kg per day to correct neutropenia.

For maintenance of normal neutrophil counts. After correction of neutropenia, the minimal effective dose of filgrastim to maintain normal neutrophil counts should be determined. It is recommended to start with 30 million IU (300 mcg) every other day. Subsequently, individual dose adjustments may be necessary based on the patient’s neutrophil levels to maintain counts above 2.0×10⁹/L. In clinical studies, a dose of 30 million IU (300 mcg) administered on days 1 to 7 of each week was sufficient to maintain an absolute neutrophil count > 2.0×10⁹/L with a median administration frequency of 3 times per week. Long-term use of filgrastim may be required to maintain an absolute neutrophil count > 2.0×10⁹/L.

Method of Administration

Correction of neutropenia or maintenance of normal neutrophil counts. Filgrastim should be administered by subcutaneous injection.

Special Patient Populations

Elderly Patients

Clinical studies of filgrastim included a limited number of elderly patients, and no specific studies have been conducted in this patient group. Therefore, no specific dosing recommendations can be made.

Patients with Renal or Hepatic Impairment

Patients with severe renal or hepatic impairment do not require dose adjustment, as studies have shown that their pharmacokinetic and pharmacodynamic parameters are similar to those in healthy volunteers.

Children with Severe Chronic Neutropenia and Oncological Diseases

65% of patients enrolled in the clinical studies program for treatment of severe chronic neutropenia were under 18 years of age. Treatment efficacy was evident in this age group, which included the majority of patients with congenital neutropenia. There were no differences in safety profiles between children treated for severe chronic neutropenia. Clinical studies demonstrated comparable efficacy and safety of filgrastim in children and adults receiving cytotoxic chemotherapy.

Dosing recommendations for children are the same as for adults receiving myelosuppressive cytotoxic chemotherapy.

Accidental single freezing of syringes does not affect the stability of filgrastim.

Special Handling Instructions

The medicinal product should be diluted, if necessary, with 5% (50 mg/mL) glucose solution for infusion. Dilution to a final concentration below 0.2 million IU (2 mcg)/mL is not recommended under any circumstances. The solution should be visually inspected before administration. Only clear, particle-free solutions should be used.

If filgrastim is diluted to a concentration below 1.5 million IU (15 mcg)/mL, human serum albumin should be added to achieve a final concentration of 2 mg/mL. For example, when diluting a total filgrastim dose of less than 30 million IU (300 mcg) to a final volume of 20 mL, 0.2 mL of 20% (200 mg/mL) human albumin solution should be added.

The product contains no preservatives. Therefore, due to the risk of microbial contamination, syringes containing filgrastim are intended for single use only. Filgrastim diluted with 5% glucose solution is compatible with glass and several plastics, including polyvinyl chloride (PVC), polyolefin (copolymer of polypropylene and polyethylene), and polypropylene. Chemical and physical stability of the diluted infusion solution is maintained for 24 hours at 2–8°C.

From a microbiological standpoint, the product should be used immediately. If filgrastim is not administered immediately after dilution, the time and conditions of storage prior to use are the responsibility of the user and should generally not exceed 24 hours at 2–8°C, unless dilution was performed under controlled and validated aseptic conditions.

Children

Clinical trial data indicate that the safety and efficacy of filgrastim treatment in children receiving cytotoxic chemotherapy are not different from those in adults. The recommended dose for children and adults receiving myelosuppressive cytotoxic chemotherapy is the same.

Overdose

Symptoms. The effects of filgrastim in overdose have not been established.

Treatment. After discontinuation of the medicinal product, the circulating neutrophil count typically decreases by 50% within 1–2 days and then returns to normal within 1–7 days.

Adverse Reactions

The most serious adverse reactions that may occur during treatment with filgrastim include: anaphylactic reaction, serious pulmonary reactions (including interstitial pneumonitis and acute respiratory distress syndrome), capillary leak syndrome, severe splenomegaly/rupture of the spleen, transformation to myelodysplastic syndrome or leukemia in patients with severe chronic neutropenia, graft-versus-host reaction in patients who have undergone allogeneic bone marrow transplantation or peripheral blood stem cell transplantation, and sickle cell crisis in patients with sickle cell anemia.

The most commonly reported adverse reactions were: hyperthermia, musculoskeletal pain (including bone pain, back pain, arthralgia, myalgia, limb pain, musculoskeletal pain, musculoskeletal chest pain, neck pain), anemia, vomiting, nausea. In clinical studies involving oncology patients, musculoskeletal pain was mild or moderate in 10% of patients and severe in 3% of patients.

Adverse reactions identified from clinical studies and spontaneous reports are listed in Table 2. Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 2

a See section "Description of selected adverse reactions".

b Cases of graft-versus-host reaction and fatal events have been reported in patients after allogeneic bone marrow transplantation (see section "Description of selected adverse reactions" below).

c Includes bone pain, back pain, arthralgia, myalgia, limb pain, musculoskeletal pain, musculoskeletal chest pain, neck pain.

d Cases occurred in the post-marketing period in patients who underwent bone marrow transplantation or hematopoietic progenitor cell mobilization.

e Adverse reactions occurring more frequently in patients receiving filgrastim compared to placebo group, and associated with the consequences of the underlying oncological disease or cytotoxic chemotherapy.

Description of selected adverse reactions

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, rash, urticaria, angioedema, dyspnea, and hypotension, have been observed during clinical trials and in the post-marketing period, developing either early or during continued administration of filgrastim. Such reactions were generally more frequent after intravenous administration of filgrastim. In some cases, re-administration of filgrastim was followed by recurrence of symptoms, indicating a causal relationship. If serious allergic reactions occur, filgrastim should be discontinued and not restarted.

Respiratory system adverse reactions

During clinical trials and in the post-marketing period, adverse reactions affecting the lungs have been reported, including interstitial lung disease, pulmonary edema, pulmonary infiltrates, sometimes leading to respiratory failure or acute respiratory distress syndrome, which may be fatal (see section "Special precautions").

Splenic enlargement and splenic rupture

Cases of splenomegaly and splenic rupture have been reported with filgrastim use. Some cases of splenic rupture were fatal (see section "Special precautions").

Capillary leak syndrome

Cases of capillary leak syndrome have been reported with granulocyte colony-stimulating factor administration. These usually occur in patients with progressive malignancies, sepsis, those receiving multiple chemotherapeutic agents simultaneously, or undergoing apheresis (see section "Special precautions").

Cutaneous vasculitis

Cases of cutaneous vasculitis have been reported in patients receiving filgrastim. The mechanism of vasculitis in patients receiving filgrastim is not fully understood. With long-term use, cutaneous vasculitis occurred in 2% of patients with severe chronic neutropenia.

Leukocytosis

Leukocytosis (white blood cell count > 50×10⁹/L) was observed in 41% of healthy donors. Transient thrombocytopenia (platelet count < 100×10⁹/L) after filgrastim administration and leukapheresis was observed in 35% of donors (see section "Special precautions").

Sweet’s syndrome

Cases of Sweet’s syndrome (acute febrile neutrophilic dermatosis) have been reported in patients receiving filgrastim.

Pseudogout (chondrocalcinosis)

Pseudogout (chondrocalcinosis) has been reported in cancer patients receiving filgrastim.

Graft-versus-host reaction

Cases of graft-versus-host reaction with fatal outcome have been reported in patients receiving G-CSF after allogeneic bone marrow transplantation (see sections "Pharmacodynamics", "Special precautions").

Children

Clinical trial data in pediatric patients demonstrate similar efficacy and safety of filgrastim in children and adults receiving cytotoxic chemotherapy, indicating no age-related differences in filgrastim pharmacokinetics. The only consistently reported adverse reaction was musculoskeletal pain, which did not differ from that observed in adults. There is insufficient data to further evaluate the use of filgrastim in children.

Other special patient categories

Elderly patients

No overall differences in safety and efficacy were observed in patients aged 65 years and older compared to younger adults (>18 years) receiving cytotoxic chemotherapy. Clinical experience has not revealed differences in therapeutic response between elderly patients and younger adult patients. There is insufficient data to evaluate the use of filgrastim in geriatric patients for other approved indications.

Pediatric patients with severe chronic neutropenia

Cases of decreased bone mineral density and osteoporosis have been reported in children with severe chronic neutropenia receiving long-term filgrastim therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2.5 years.

Storage conditions. Store in the original packaging at a temperature of 2 °C to 8 °C. Keep out of reach of children.

Incompatibilities

The medicinal product must not be diluted with sodium chloride solutions.

The medicinal product must not be mixed with other medicinal products except those specified in the section "Instructions for use and dosage".

Filgrastim may adsorb to glass and certain plastics after dilution; this does not occur when dilution is performed as specified in the section "Instructions for use and dosage".

Packaging

0.5 mL (30 million IU) in a pre-filled syringe with a safety device for administration; packs of 5 pre-filled syringes with a safety device.

0.8 mL (48 million IU) in a pre-filled syringe with a safety device; packs of 5 pre-filled syringes with a safety device.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Industries Ltd.

Manufacturer’s address and location of operations. Industrial Zone, 18 Eli Hurvitz Street, P.O. Box 353, Kfar Saba, 4410202, Israel.