Tevagrastim

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TevaGrastim (TevaGrastimâ)

Composition:

Active substance: filgrastim;

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

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

Excipients: glacial acetic acid, polysorbate 80, sodium hydroxide, sorbitol (E 420), water for injections.

Pharmaceutical form. Solution for injection or infusion.

Main physicochemical characteristics: 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 of functionally active neutrophils and their release into the bloodstream from the bone marrow. TevaGrastim, containing recombinant G-CSF (filgrastim), 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. Filgrastim is produced using recombinant DNA technology in E. coli (K802). In some patients with severe chronic neutropenia, TevaGrastim may cause a slight increase in circulating eosinophils and basophils compared to baseline levels; eosinophilia or basophilia was observed in some of these patients prior to the start of treatment. TevaGrastim increases neutrophil counts in a dose-dependent manner when used at recommended doses. Neutrophils produced in response to filgrastim administration demonstrate normal or enhanced functional activity, as confirmed by assays of chemotactic and phagocytic functions. After discontinuation of filgrastim therapy, the number of neutrophils in peripheral blood decreases by 50% within 1–2 days and returns to normal levels within 1–7 days.

Filgrastim significantly reduces the frequency, severity, and duration of neutropenia and febrile neutropenia in patients undergoing cytotoxic chemotherapy. Treatment with filgrastim significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy, and hospitalization following induction chemotherapy for acute myeloid leukemia or myeloablative therapy followed by bone marrow transplantation. No effect of the drug on the frequency of fever and infectious complications has been demonstrated. The drug does not reduce the duration of fever in patients undergoing myeloablative therapy followed by bone marrow transplantation.

The use of filgrastim, either alone or after chemotherapy, mobilizes hematopoietic stem cells into the peripheral circulation. Autologous peripheral blood stem cell (PBSC) transplantation is performed after high-dose cytotoxic therapy, either instead of or in addition to bone marrow transplantation. Infusion of PBSC accelerates hematopoietic recovery, reducing the duration of risk for hemorrhagic complications and the need for platelet transfusions.

Compared with allogeneic bone marrow transplantation, the use of allogeneic PBSC mobilized with filgrastim has shown more rapid hematopoietic recovery in recipients, leading to a significant reduction in the time to platelet recovery.

A retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukemia found an increased risk of graft-versus-host disease (GvHD), as well as increased treatment-related mortality and overall mortality in patients receiving G-CSF. Another retrospective international study in patients with acute and chronic myeloid leukemia did not find an increased risk of GvHD, treatment-related mortality, or overall mortality. A meta-analysis of allogeneic transplantation studies, including 9 prospective randomized trials, 8 retrospective studies, and one case-control study, found no effect of the drug on the risk of acute or chronic GvHD or on treatment-related early mortality.

Administration of filgrastim to healthy donors at a dose of 10 mcg/kg body weight/day subcutaneously for 4–5 days typically allows the collection of sufficient PBSCs during 2 leukapheresis procedures to achieve 4×10⁶ CD34⁺ cells/kg recipient body weight.

In children and adults with severe chronic neutropenia (congenital, cyclic, or idiopathic), filgrastim stably increases the number of neutrophils in peripheral blood, reducing the frequency of infections and associated complications.

Administration of filgrastim to patients with HIV infection allows maintenance of normal neutrophil levels, facilitating the planned administration of antiviral and/or myelosuppressive therapy. No evidence of increased HIV replication has been observed during filgrastim treatment.

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

The efficacy and safety of TevaGrastim were evaluated in randomized, controlled phase III clinical trials in breast cancer, lung cancer, and non-Hodgkin's lymphoma. There was no significant difference between TevaGrastim and the reference product regarding the duration of severe neutropenia and the frequency of febrile neutropenia.

Pharmacokinetics

Randomized, blinded, single-dose, crossover clinical studies involving 196 healthy volunteers demonstrated comparable pharmacokinetic profiles of TevaGrastim and the reference product following either subcutaneous or intravenous administration.

Following both subcutaneous and intravenous administration, filgrastim elimination follows first-order kinetics. The mean serum half-life of filgrastim is approximately 3.5 hours, and clearance is 0.6 mL/min/kg. With prolonged use of filgrastim (up to 28 days) after autologous bone marrow transplantation, no evidence of drug accumulation or increased half-life was observed.

With both intravenous and subcutaneous administration of filgrastim, a positive linear relationship between dose and serum concentration is observed. After subcutaneous administration of therapeutic doses, serum concentrations exceed 10 ng/mL for 8–16 hours. The volume of distribution in blood is approximately 150 mL/kg.

In cancer patients, the pharmacokinetic profile of TevaGrastim was comparable to that of the reference product following both single and repeated subcutaneous administrations.

Clinical characteristics.

Indications.

• Reduction of the duration of neutropenia and reduction of the incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignant diseases (with the exception of chronic myeloid leukemia and myelodysplastic syndrome).
• Reduction of the duration of neutropenia in patients receiving myeloablative therapy followed by bone marrow transplantation, who are at high risk of prolonged severe neutropenia.
• Mobilization of peripheral blood stem cells (PBSC).
• 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 with severe or recurrent infections in history.
• Reduction of the risk of bacterial infections in patients with persistent neutropenia (absolute neutrophil count ≤ 1.0×10⁹/L) at the stage of advanced HIV infection when other methods of controlling neutropenia are ineffective.

Contraindications.

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

Special safety precautions.

Disposal of unused medicinal product residues must be carried out in accordance with national requirements. For syringes without a safety injection device, do not recap the needle after use. Used syringes should be placed in a puncture-resistant container with solid walls and stored in a place inaccessible to children. The filled container should be disposed of in accordance with national requirements. Used syringes must not be discarded in household waste.

For syringes with a safety injection device, the protective mechanism prevents needlestick injuries after use, so no special disposal precautions are required. Syringes with a safety injection device should be disposed of in accordance with national requirements.

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 simultaneously suggest a risk of increased 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, an enhanced effect of filgrastim may occur when used concomitantly. Although studies on this interaction have not been conducted, there is no evidence of harmful effects from this interaction.

Special precautions for use.

Hypersensitivity

Hypersensitivity reactions, including anaphylactic reactions, have been observed in patients at the beginning or during further treatment with filgrastim. If clinically significant hypersensitivity reactions occur, filgrastim administration must 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 after administration of G-CSF. Patients with recent history of pulmonary infiltrates or pneumonia may have an increased 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 pulmonary function, may be the first signs of acute respiratory distress syndrome (ARDS). 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 urinalysis 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 developing symptoms of capillary leak syndrome should be closely monitored and provided with standard symptomatic treatment, which may include 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. Splenic rupture should be considered in donors and/or patients reporting pain in the upper left quadrant of the abdomen or left shoulder tip. Dose reduction of filgrastim slows or stops spleen enlargement in patients with severe chronic neutropenia, and splenectomy was required in 3% of patients.

Growth of malignant cells

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

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 between 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. The safety and efficacy of filgrastim in de novo acute myeloid leukemia in patients under 55 years of age with favorable cytogenetic prognostic 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 develops in patients with severe chronic neutropenia (platelet count < 100×10⁹/L), 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 mcg/kg/day), white blood cell counts increased to 100×10⁹/L or higher. No adverse reactions directly associated with such leukocytosis have been described. However, due to the potential risks associated with high leukocytosis, white blood cell counts should be regularly monitored during filgrastim therapy. If white blood cell counts exceed 50×10⁹/L after the expected decline, filgrastim treatment should be discontinued immediately. However, if filgrastim is used for stem cell mobilization, the drug should be discontinued or the dose reduced when white blood cell counts exceed 70×10⁹/L.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The rate of antibody formation against filgrastim is generally low. The appearance of binding antibodies is expected, as with other biological products; 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

Special warnings in sickle cell disorder and sickle cell anemia

Sickle cell crises, sometimes fatal, have been observed in patients with sickle cell trait or sickle cell anemia during filgrastim therapy. Therefore, filgrastim should be administered with caution to 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 oncology patients

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

Risk associated with high-dose chemotherapy

Particular caution is required 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).

Impact of chemotherapy on erythrocytes and platelets

Filgrastim monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapeutic agents (e.g., full doses according to regimens), patients may be at increased risk of developing thrombocytopenia and anemia; therefore, regular monitoring of platelet count and hematocrit is recommended. 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 following myelosuppressive or myeloablative chemotherapy.

Myelodysplastic syndrome and acute myeloid leukemia in patients with breast 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. Nevertheless, 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 markedly reduced numbers of myeloid precursor cells has not been studied. The drug increases neutrophil counts primarily by acting on 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 bone marrow tumor infiltration), the degree of neutrophil 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.

Fatal graft-versus-host reaction has been reported in patients receiving 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 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 choice of mobilization method should depend on the patient's treatment goal.

Prior to cytotoxic agents

In patients who have previously undergone intensive 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 mobilization. If stem cell transplantation is planned, stem cell 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 are insufficient according to the above criteria, alternative treatments not requiring precursor cells should be considered.

Assessment of mobilized peripheral blood stem cell count

When assessing the number of stem cells mobilized by filgrastim in patients, particular attention should be paid to the method of quantitative determination. Results of flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology; therefore, recommendations on cell counts 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 shows a complex but consistent correlation. The recommended minimum stem cell count is ≥ 2.0×10⁶ CD34+ cells/kg, based on published data on adequate hematological recovery. A higher number of precursor cells appears to be associated with faster recovery, whereas a lower number is associated with slower blood count normalization.

Special warnings for healthy donors undergoing stem cell mobilization

Stem cell mobilization provides no 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 they meet standard clinical and laboratory criteria for stem cell donation, 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 less than 100×10⁹/L) after filgrastim administration and leukapheresis was observed in 35% of subjects. Among them, 2 cases of thrombocytopenia with platelet count below 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 the platelet count is below 75×10⁹/L.

Leukapheresis should not be performed in donors receiving anticoagulants or those with coagulation disorders.

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

Special warnings for recipients of allogeneic stem cells mobilized by filgrastim

Available data indicate that allogeneic stem cell transplantation carries a higher risk of acute and chronic graft-versus-host disease 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 changes in blood count 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 is required in diagnosing severe chronic neutropenias. Differential diagnosis from other hematological disorders such as aplastic anemia, myelodysplasia, and myeloleukemia is necessary. Before initiating treatment, a complete blood count with leukocyte differential and platelet count, as well as bone marrow morphology and karyotype, should be performed.

In clinical trials, 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 association with filgrastim treatment is not established. In approximately 12% of patients with initially normal cytogenetics, abnormalities including monosomy 7 were detected upon repeated 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. These patients are recommended to undergo regular (approximately every 12 months) morphological and cytogenetic bone marrow examinations.

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 urinalysis is recommended for monitoring.

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

Special warnings for HIV-infected patients

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. Neutrophil counts should be monitored 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 mcg) of filgrastim is administered to a patient not on a daily basis, significant fluctuations in neutrophil count may occur over time. To determine the decrease in neutrophil count or the true nadir, blood samples should be taken immediately before the next dose is administered.

Risk associated with use of high-dose myelosuppressive agents

Filgrastim monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapeutic agents in combination 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 caused by bone marrow infiltration by opportunistic infection agents (such as Mycobacterium avium complex) or tumors (lymphoma). In addition to filgrastim for neutropenia treatment, these patients should receive specific treatment for the underlying condition. The effect of filgrastim on neutropenia caused by infectious agents or malignant bone marrow tumors has not been sufficiently studied.

Other warnings

Sorbitol. Tevagrastim contains sorbitol (E 420). The additive effect of concomitant administration of medicinal products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered.

For intravenous use. This product 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). Intravenous medicinal products 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 HFI symptoms should be obtained from each patient before prescribing this medicinal product.

Sodium. One pre-filled syringe of Tevagrastim contains less than 1 mmol (23 mg) of sodium, i.e., essentially "sodium-free".

Traceability. To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

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 high multiples of clinical exposure 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 benefits of breastfeeding for the child and the benefits of treatment 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").

Administration and Dosage

Treatment should be conducted in collaboration with an oncology center equipped with appropriate diagnostic equipment 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 sufficient experience in this field and with adequate monitoring of hematopoietic progenitor cells.

Standard Cytotoxic Chemotherapy

Dosing

The recommended dose of TevaGraStim 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/day) was used.

TevaGraStim should be administered daily until neutrophil counts recover to normal levels following the expected nadir. 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, dose, and regimen of cytotoxic chemotherapy used.

A transient increase in neutrophil count is usually observed within 1–2 days after initiating filgrastim therapy in patients receiving cytotoxic chemotherapy. However, to achieve a stable therapeutic effect, filgrastim therapy should not be discontinued 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.

Administration Method

TevaGraStim may 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 on single-dose administration suggest that the duration of filgrastim effect may be reduced with intravenous administration. The clinical relevance of these findings for multiple-dose regimens has not been established. The route of administration should be selected based on the specifics of each clinical case.

For Subcutaneous Administration

1a 1b

2a 2b

Syringe without safety device to prevent needlestick injuries or reuse (Fig. 1a, 1b)

Syringe with safety device to prevent needlestick injuries or reuse (Fig. 2a, 2b)

3 4

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

5 6 7

Subcutaneous administration of the drug (Fig. 5–7)

1. Disinfect the injection site with an alcohol swab. Pinch a fold of skin between the thumb and index finger without compressing it (Fig. 5).
2. Insert the needle fully into the skin (Fig. 6 – injection with syringe without safety device; Fig. 7 – injection with syringe with safety device).
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.

The drug should be administered daily at the same time.

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

Syringes without safety device

The drug should be injected slowly and evenly, while holding the skin fold between fingers.

After injection, first withdraw the needle, then release the skin.

A new syringe must be used for each subsequent injection. Re-injection of any remaining TevaGraStim from the same syringe is prohibited.

8

Syringes with safety device

The drug should be injected slowly and evenly, while holding the skin fold between fingers, until the full dose is delivered and the syringe plunger stops moving.

Excessive force when depressing the plunger must be avoided.

After injection, withdraw the needle while continuing to press on the plunger, then release the skin (Fig. 8).

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

A new syringe must be used for each subsequent injection. Re-injection of any remaining TevaGraStim from the same syringe is prohibited.

Myeloablative Therapy Followed by Bone Marrow Transplantation

Dosing

The recommended initial dose is 1.0 million IU (10 µg)/kg body weight per day.

The first dose of TevaGraStim should be administered no sooner than 24 hours after cytotoxic chemotherapy and no sooner than 24 hours after bone marrow transplantation.

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

Table 1

Method of Administration

TevaGrastrim can be administered via a 30-minute or 24-hour intravenous infusion or by continuous 24-hour subcutaneous infusion. TevaGrastrim 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 transplantation of PBSCs

Dosing

For mobilization of PBSCs as monotherapy, the recommended dose of filgrastim is 1.0 million IU (10 mcg)/kg/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 be continued until the final leukapheresis.

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

Method of Administration

When filgrastim is used for mobilization of PBSCs as monotherapy, the drug may be administered as a continuous 24-hour subcutaneous infusion or by subcutaneous injection. For infusion, the medicinal product TevaGrastrim is diluted in 20 ml of 5% glucose solution for infusion.

When filgrastim is used for mobilization of PBSCs after myelosuppressive chemotherapy, the drug should be administered by subcutaneous injection.

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

Dosing

For mobilization of PBSCs in healthy donors, filgrastim should be administered at a dose of 1.0 million IU (10 mcg)/kg/day for 4–5 consecutive days. Leukapheresis should begin on day 5 of treatment and, if necessary, continue on day 6 to achieve 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/day as a single or divided dose.

Idiopathic or cyclic neutropenia. The recommended initial dose is 0.5 million IU (5 mcg)/kg/day 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 minimum effective dose to maintain this level should be determined. Long-term daily administration of the drug is required to maintain the required 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. A more rapid dose escalation regimen may be used in patients with severe infections. In clinical studies, 97% of patients who responded to treatment achieved a complete response with a dose ≤ 2.4 million IU (24 mcg)/kg/day. The safety of long-term treatment with filgrastim at doses exceeding 2.4 million IU (24 mcg)/kg/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/day, with dose escalation up to a maximum of 0.4 million IU (4 mcg)/kg/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 a dose up to 1.0 million IU (10 mcg)/kg/day to correct neutropenia.

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

Method of Administration

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

Special patient populations

Use in elderly patients

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

Use in patients with renal or hepatic impairment

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

Use in children with severe chronic neutropenia and oncological diseases

65% of patients enrolled in the clinical study program for the 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 have demonstrated comparable efficacy and safety of filgrastim in both adults and children receiving cytotoxic chemotherapy.

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

Handling instructions

TevaGrastrim 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 may 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.

TevaGrastrim does not contain preservatives. Therefore, due to the potential risk of microbial contamination, syringes containing the drug are intended for single use only.

TevaGrastrim diluted with 5% glucose solution is compatible with glass and several plastics, including polyvinyl chloride (PVC), polyolefin (a copolymer of polypropylene and polyethylene), and polypropylene.

The chemical and physical stability of the diluted infusion solution is 24 hours when stored at 2–8°C. From a microbiological standpoint, the drug should be used immediately. If not administered immediately after dilution, the duration and conditions of storage prior to use are the responsibility of the user and generally should not exceed 24 hours at 2–8°C, unless dilution was performed under controlled and validated aseptic conditions.

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

Children.

Clinical trial data indicate that the safety and efficacy of filgrastim treatment are identical in adults and children receiving cytotoxic chemotherapy.

The recommended dose for children and adults receiving myelosuppressive cytotoxic chemotherapy is the same.

Overdose.

The effects of filgrastim overdose have not been established. After discontinuation of the drug, the circulating neutrophil count usually 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 adverse reactions (including interstitial pneumonitis and ARDS), 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 frequently reported adverse reactions were: pyrexia, musculoskeletal pain (including bone pain, back pain, arthralgia, myalgia, limb pain, musculoskeletal pain, chest musculoskeletal 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 trials and spontaneous reports are listed in Table 2. Within each frequency subgroup, adverse reactions are listed in order of decreasing severity.

Table 2

aSee section "Description of selected adverse reactions".

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

cIncludes bone pain, back pain, arthralgia, myalgia, limb pain, musculoskeletal pain, musculoskeletal chest pain, neck pain.

dCases occurred during the post-marketing period in patients who underwent bone marrow transplantation or PBPC mobilization.

eAdverse reactions occurring more frequently in patients receiving filgrastim compared to placebo group, and associated with 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 at the beginning or during continued administration of the drug in clinical trials and in the post-marketing period. Such reactions were generally more frequent after intravenous administration. In some cases, re-administration of the drug was followed by recurrence of symptoms, indicating a causal relationship. If serious allergic reactions occur, filgrastim should be discontinued and not re-initiated.

Respiratory system adverse reactions

Adverse reactions affecting the lungs, including interstitial lung disease, pulmonary edema, pulmonary infiltrates, sometimes leading to respiratory failure or acute respiratory distress syndrome, potentially fatal, have been reported during clinical trials and in the post-marketing period (see section "Special warnings and precautions for use").

Splenomegaly and splenic rupture

Cases of splenomeg游戏副本