Accofil®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACOFIL® (ACCOFIL®)

Composition:

Active substance: filgrastim;

One pre-filled syringe with a volume of 0.5 mL contains filgrastim* 30 million IU (300 mcg)/0.5 mL or 48 million IU (480 mcg)/0.5 mL;

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

* Recombinant human granulocyte colony-stimulating factor (G-CSF), produced by a laboratory strain of the bacterium Escherichia coli into which the G-CSF gene has been inserted using genetic engineering techniques.

Pharmaceutical form. Solution for injection or infusion.

Main physico-chemical properties: clear, colorless 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 functionally active neutrophils from the bone marrow. ACCOFIL**®**, containing methionyl recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) (filgrastim), significantly increases the number of neutrophils in peripheral blood within the first 24 hours after administration, along with a slight increase in monocyte count. In some patients with severe chronic neutropenia (SCN), filgrastim may cause a slight increase in circulating eosinophils and basophils relative to baseline levels; sometimes, eosinophilia or basophilia may already be observed prior to the initiation of therapy. Within the recommended dosage range of filgrastim, a dose-dependent increase in neutrophil count is observed. Neutrophils produced during filgrastim therapy have normal or enhanced functional capacity, as confirmed by chemotaxis and phagocytosis tests. Within 1–2 days after discontinuation of the drug, the number of circulating neutrophils typically decreases by 50% and returns to normal levels within 1–7 days.

The use of filgrastim in patients receiving cytotoxic chemotherapy leads to a significant reduction in the incidence, severity, and duration of neutropenia and febrile neutropenia. Filgrastim significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy, and hospitalization following induction chemotherapy for acute myeloid leukemia, as well as after myeloablative therapy followed by bone marrow transplantation, without affecting the frequency of fever and infectious complications or reducing the duration of the febrile period in patients after myeloablative therapy followed by bone marrow transplantation.

The use of filgrastim, either alone or following chemotherapy, mobilizes hematopoietic progenitor cells into peripheral blood. Collection and transplantation of such autologous peripheral blood progenitor cells (PBPCs) can be performed after high-dose chemotherapy, as an alternative to or in addition to bone marrow transplantation. Transplantation of peripheral blood progenitor cells accelerates hematopoietic recovery, thereby reducing the risk of hemorrhagic complications and the need for platelet transfusions.

Compared with allogeneic bone marrow transplantation, the use of allogeneic peripheral blood progenitor cells mobilized with filgrastim has demonstrated significantly faster hematological recovery in recipients, substantially reducing the time to platelet recovery without requiring platelet transfusion support.

A retrospective European study evaluating the use of G-CSF after allogeneic bone marrow transplantation in patients with acute leukemia showed an increased risk of graft-versus-host disease (GVHD), treatment-related mortality, and mortality after G-CSF administration. In another international retrospective study involving patients with acute and chronic myeloid leukemia, no impact of the drug on the risk of GVHD, treatment-related mortality, or overall mortality was observed. A meta-analysis of allogeneic transplantation studies, including results from 9 prospective randomized trials, 8 retrospective studies, and 1 case-control study, found no effect of therapy on the risk of acute or chronic GVHD or early treatment-related mortality. Information from these studies is summarized in Table 1.

Table 1

Relative risk (95 % CI) of graft-versus-host disease or treatment-related mortality following G-CSF use and bone marrow transplantation
Publication	Study period	No.	Acute graft-versus-host disease grade II–IV	Chronic graft-versus-host disease	Treatment-related mortality
Meta-analysis (2003)	1986–2001a	1198	1.08 (0.87, 1.33)	1.02 (0.82, 1.26)	0.70 (0.38, 1.31)
European retrospective study (2004)	1992–2002b	1789	1.33 (1.08, 1.64)	1.29 (1.02, 1.61)	1.73 (1.30, 2.32)
International retrospective study (2006)	1995–2000b	2110	1.11 (0.86, 1.42)	1.10 (0.86, 1.39)	1.26 (0.95, 1.67)

a The analysis includes studies in which bone marrow transplantation was performed during the specified period; in some studies, G-CSF was used.

b The analysis includes patients who underwent bone marrow transplantation during the specified period.

Use of filgrastim for mobilization of peripheral blood progenitor cells in healthy donors prior to allogeneic transplantation of peripheral blood progenitor cells

Administration of filgrastim to healthy donors at a dose of 10 mcg/kg/day subcutaneously daily for 4–5 days usually allows obtaining, during two leukapheresis procedures, a number of peripheral blood progenitor cells equal to or exceeding 4 × 10⁶ CD34+ cells/kg of recipient body weight.

Administration of filgrastim in children and adults with severe chronic neutropenia (severe congenital, cyclic, or idiopathic) results in a sustained increase in the absolute neutrophil count in peripheral blood, as well as reduction in the frequency of infections and other related events.

Use of filgrastim in HIV-infected patients enables maintenance of normal neutrophil levels to allow scheduled administration of antiviral and/or other myelosuppressive agents. No evidence of increased HIV replication has been observed in HIV-infected patients receiving filgrastim.

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

Pharmacokinetics

Absorption

After subcutaneous administration of recommended doses, filgrastim serum concentrations exceed 10 ng/mL for 8–16 hours.

Distribution

The volume of distribution in blood is approximately 150 mL/kg.

Elimination

Clearance of filgrastim after both subcutaneous and intravenous administration has been shown to follow first-order pharmacokinetic elimination. The serum half-life of filgrastim is approximately 3.5 hours, and the clearance rate is 0.6 mL/min/kg. With prolonged use of filgrastim for up to 28 days following autologous bone marrow transplantation, no evidence of drug accumulation or changes in half-life has been observed.

Linearity

A positive linear relationship between dose and serum concentration of filgrastim is observed after both intravenous and subcutaneous administration.

Preclinical safety data

Filgrastim was studied in repeat-dose toxicity studies of up to 1 year duration, which revealed changes related to its expected pharmacological effects, including increased leukocyte counts, myeloid hyperplasia in the bone marrow, extramedullary granulopoiesis, and spleen enlargement. All these changes were reversible upon discontinuation of treatment.

The effects of filgrastim on embryofetal development were investigated in rats and rabbits. Intravenous administration (80 mcg/kg/day) of filgrastim to rabbits during the period of organogenesis was toxic to the dams and was associated with increased frequency of spontaneous abortions, post-implantation losses, and reduced average size of live offspring and fetal body weight.

Based on reported data from another filgrastim product similar to the medicinal product ACOFIL**®**, comparable results and increased fetal malformations were observed at a dose of 100 mcg/kg/day – a maternally toxic dose corresponding to systemic exposure approximately 50–90 times higher than that in patients receiving the clinical dose of 5 mcg/kg/day. The no-observed-adverse-effect level (NOAEL) for embryofetal development in this study was 10 mcg/kg/day, corresponding to systemic exposure approximately 3–5 times higher than that in patients receiving the clinical dose.

No toxic effects on dams or fetuses were observed in pregnant rats treated with doses up to 575 mcg/kg/day. Offspring of rats treated with filgrastim during the perinatal and lactation periods showed delayed external differentiation and growth retardation (≥ 20 mcg/kg/day) and slightly reduced survival (100 mcg/kg/day).

Filgrastim had no effect on fertility in male and female rats.

Clinical characteristics

Indications

ACCOFIL**®** is indicated to reduce the duration of neutropenia and the incidence of febrile neutropenia in patients receiving intensive cytotoxic chemotherapy for malignancies (with the exception of chronic myeloid leukemia and myelodysplastic syndrome), as well as to reduce the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation who are considered at risk of developing prolonged severe neutropenia. The safety and efficacy of ACCOFIL**®** are similar in adults and children receiving cytotoxic chemotherapy.

ACCOFIL**®** is indicated for the mobilization of peripheral blood progenitor cells.

Long-term therapy with ACCOFIL**®** is indicated 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 acute or recurrent infections.

ACCOFIL**®** is indicated for the treatment of persistent neutropenia (absolute neutrophil count ≤ 1.0 × 10⁹/L) in patients with progressive HIV infection to reduce the risk of bacterial infections when other treatments for neutropenia are inappropriate.

Contraindications

Known hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction

The safety and efficacy of administering filgrastim on the same day as myelosuppressive cytotoxic chemotherapy have not been definitively established. Due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, filgrastim should not be administered within 24 hours before or 24 hours after chemotherapy. Preliminary data from a small number of patients who received filgrastim and 5-fluorouracil simultaneously suggest an increased risk of severe neutropenia.

Potential interactions between filgrastim and other hematopoietic growth factors or cytokines have not been studied in clinical trials.

Since lithium stimulates neutrophil release, an enhanced effect of filgrastim is possible; however, such interaction has not been studied. Therefore, no conclusions can be drawn regarding the potential risks of combined use of these agents.

Special precautions for use

Traceability

To improve the traceability of biological medicinal products, it is mandatory to clearly record in the patient's medical file the name and batch number of the administered product.

Special considerations for use in various indications

Hypersensitivity reactions

Hypersensitivity reactions, including anaphylactic reactions, have been observed in patients receiving filgrastim, either at the beginning or during treatment. In the event of clinically significant hypersensitivity reactions, filgrastim should be permanently discontinued. The product is contraindicated in patients with a history of hypersensitivity reactions to filgrastim or pegfilgrastim.

Respiratory system adverse effects

Adverse effects on the respiratory system, including interstitial lung disease, have been reported after administration of G-CSF. The risk is higher in patients with recent history of lung infiltrates or pneumonia. The onset of respiratory symptoms such as cough, fever, and dyspnea, in combination with radiological signs of lung infiltrates and worsening lung function, may indicate acute respiratory distress syndrome (ARDS). In such cases, filgrastim should be discontinued and appropriate treatment initiated.

Glomerulonephritis

Cases of glomerulonephritis have been reported in patients treated with filgrastim and pegfilgrastim. Signs of glomerulonephritis typically resolved after dose reduction or discontinuation of filgrastim and pegfilgrastim. Urinalysis should be monitored in such patients.

Capillary leak syndrome

Cases of capillary leak syndrome have been reported following G-CSF administration, characterized by arterial hypotension, hypoalbuminemia, edema, and hemoconcentration. This syndrome can be life-threatening if not promptly treated.

Patients with capillary leak syndrome should be closely monitored and standard symptomatic therapy initiated, which may include intensive care (see section "Adverse reactions").

Splenomegaly and spleen rupture

Asymptomatic cases of splenomegaly and cases of spleen rupture have been reported in patients and healthy donors following filgrastim administration. Some cases of spleen rupture were fatal. Therefore, spleen size should be carefully monitored (e.g., by clinical or ultrasound examination). Donors or patients complaining of pain in the upper left quadrant of the abdomen or left shoulder should be evaluated for possible spleen rupture. Dose reduction of filgrastim slowed or halted further spleen enlargement in patients with severe chronic neutropenia, and 3% of patients required splenectomy.

Growth of malignant cells

G-CSF can stimulate 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; therefore, filgrastim is not indicated for use in these patients. Special attention should be paid to differential diagnosis between acute myeloid leukemia and blast transformation of chronic myeloid leukemia.

Acute myeloid leukemia

Due to limited safety and efficacy data on the use of filgrastim in patients with secondary acute myelocytic leukemia, the drug should be used with caution. The safety and efficacy of filgrastim in patients under 55 years of age with newly diagnosed acute myelocytic leukemia and 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 therapy. In patients with severe chronic neutropenia who develop thrombocytopenia (i.e., sustained platelet count reduction to < 100 × 10⁹/L), further treatment with filgrastim should be temporarily discontinued or the dose reduced.

Leukocytosis

In less than 5% of oncology patients receiving a daily filgrastim dose exceeding 0.3 million IU/kg (3 mcg/kg/day), leukocyte counts reached 100 × 10⁹/L or higher. There are no reports of adverse reactions directly caused by leukocytosis of this severity. However, due to the potential risks associated with severe leukocytosis, leukocyte counts should be regularly monitored during filgrastim therapy. If leukocyte counts exceed 50 × 10⁹/L after reaching the expected nadir, treatment should be immediately discontinued. During filgrastim use for mobilization of peripheral blood progenitor cells (PBPCs), if leukocyte counts increase to > 70 × 10⁹/L, the dose should be reduced or treatment discontinued.

Immunogenicity

All therapeutic proteins have the potential for immunogenicity. However, the risk of antibody development against filgrastim is low. Antibody binding occurs as expected, similar to other biological products. However, neutralizing activity has not been demonstrated to date.

Aortitis

Cases of aortitis have been reported after G-CSF administration in healthy donors and oncology patients. Symptoms included fever, abdominal pain, malaise, back pain, and elevated inflammatory markers (e.g., C-reactive protein and leukocyte count). In most cases, aortitis was diagnosed by CT scan and typically resolved after discontinuation of G-CSF (see section "Adverse reactions").

Special warnings and precautions related to concomitant diseases

Special safety measures in patients with sickle cell trait or sickle cell anemia

Sickle cell crises, some 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 safety measures for oncology patients

Filgrastim should not be used to increase cytotoxic chemotherapy doses beyond the established treatment regimen.

Risks associated with increased chemotherapy doses

The drug should be used with particular caution in patients receiving high-dose chemotherapy, as treatment efficacy has not been established in such cases, and high chemotherapy doses may cause increased toxicity, including cardiac, pulmonary, neurological, and dermatological reactions (see the prescribing information for the respective chemotherapeutic agent).

Effects of chemotherapy on erythrocytes and platelets

Filgrastim monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. When higher doses of chemotherapeutic agents (e.g., full doses according to prescribed regimens) are used, the risk of thrombocytopenia and anemia increases. In such cases, regular monitoring of platelet count and hematocrit is recommended. Particular caution should be exercised when using single-agent or combination chemotherapeutic regimens that may cause severe thrombocytopenia.

It has been demonstrated that transplantation of peripheral blood progenitor cells mobilized by filgrastim can reduce the severity and duration of thrombocytopenia following myelosuppressive or myeloablative chemotherapy.

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

In a post-marketing observational study, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were associated with the use of pegfilgrastim, an alternative G-CSF agent, in combination with chemotherapy and/or radiotherapy in breast and lung cancer patients. 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 myelodysplastic syndrome/acute myeloid leukemia.

Other special precautions

The effect of filgrastim in patients with markedly reduced numbers of myeloid progenitor cells has not been studied. Filgrastim increases neutrophil counts primarily by acting on neutrophil progenitor cells. Therefore, in patients with reduced numbers of neutrophil progenitor cells (e.g., due to intensive radiotherapy or chemotherapy or bone marrow infiltration by tumor cells), the response to the drug may be diminished.

In patients who underwent high-dose chemotherapy followed by transplantation, isolated cases of vascular disorders, including veno-occlusive disease and fluid imbalance, have been reported.

Cases of fatal graft-versus-host disease have been reported in patients receiving G-CSF after allogeneic bone marrow transplantation (see sections "Adverse reactions" and "Pharmacodynamics").

Enhanced hematopoiesis in the bone marrow in response to growth factor therapy may lead to transient pathological changes detectable by bone scintigraphy. This should be considered when interpreting bone scan images.

Special safety measures for patients undergoing mobilization of peripheral blood progenitor cells

Mobilization

Prospective, randomized, comparative studies of the two recommended mobilization methods (filgrastim alone or filgrastim in combination with myelosuppressive chemotherapy) in comparable patient groups have not been conducted. Individual patient characteristics across different studies and variability in laboratory determination of CD34+ cell counts complicate direct comparison of study data. Therefore, recommending an optimal mobilization method is difficult. The choice of mobilization method should depend on the overall treatment goals in each individual case.

Prior use of cytotoxic agents

In patients previously treated with intensive myelosuppressive chemotherapy, inadequate mobilization of peripheral blood progenitor cells to achieve the minimum recommended cell level (≥ 2.0 × 10⁶ CD34+ cells/kg) or delayed platelet recovery may occur.

Some cytotoxic agents have increased toxic effects on hematopoietic progenitor cells and may negatively affect their mobilization. Prolonged use of agents such as melphalan, carmustine (BCNU), and carboplatin prior to planned progenitor cell mobilization may reduce the procedure's effectiveness. However, the use of melphalan, carboplatin, or carmustine (BCNU) together with filgrastim promotes mobilization of blood progenitor cells. If peripheral blood progenitor cell transplantation is needed, stem cell mobilization should be planned early in the patient's treatment course. Special attention should be paid to the number of mobilized progenitor cells before initiating high-dose therapy. If mobilization results do not meet the above criteria, alternative treatment options not requiring progenitor cells should be considered.

Assessment of mobilized progenitor cell count

When assessing the number of mobilized progenitor cells in patients receiving filgrastim, special attention should be paid to the methodology used for quantification. Results of flow cytometric analysis of CD34+ cell counts vary depending on the methodology used; therefore, results based on studies conducted in other laboratories should be interpreted 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 recommendation for a minimum mobilized cell count of ≥ 2.0 × 10⁶ CD34+ cells/kg is based on published data on adequate hematological recovery. Faster recovery is observed when cell counts exceed the minimum level; recovery is slower when counts are below the recommended level.

Special safety measures for healthy donors undergoing mobilization of peripheral blood progenitor cells

Mobilization of peripheral blood progenitor cells does not provide direct clinical benefit to healthy donors and should be considered solely in the context of allogeneic stem cell transplantation.

Donors undergoing mobilization of peripheral blood progenitor cells must meet standard clinical and laboratory criteria for stem cell donors. Particular attention should be paid to hematological parameters and the presence of infectious diseases.

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

Transient thrombocytopenia (platelets < 100 × 10⁹/L) after filgrastim administration and leukapheresis was observed in 35% of studied patients. Two cases of platelet count reduction to 50 × 10⁹/L were associated with the leukapheresis procedure.

If more than one leukapheresis procedure is required, special attention should be paid to donors whose platelet count before leukapheresis is < 100 × 10⁹/L. In general, leukapheresis is not recommended if platelet count is < 75 × 10⁹/L, especially when anticoagulants are used or coagulation disorders are diagnosed.

Donors receiving G-CSF for mobilization of peripheral blood progenitor cells should be monitored until hematological parameters normalize.

Special safety measures for recipients of allogeneic peripheral blood progenitor cells mobilized by filgrastim

Current data indicate that allogeneic peripheral blood progenitor cells mobilized by filgrastim are associated with a higher incidence of acute and chronic graft-versus-host disease compared to bone marrow transplantation.

Special safety measures for patients with severe chronic neutropenia

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

Blood cell counts

Other changes in blood cell counts, including anemia and transient increase in myeloid progenitor cells, may occur and require careful monitoring.

Transformation to leukemia or myelodysplastic syndrome

Special attention is required in diagnosing severe chronic neutropenia to differentiate it from other hematological disorders such as aplastic anemia, myelodysplasia, and myeloleukemia. Before initiating treatment, a complete blood count with differential leukocyte count and platelet count, as well as bone marrow morphology and karyotype, should be evaluated.

In patients with severe chronic neutropenia participating in clinical trials of filgrastim, a low incidence of myelodysplastic syndrome or leukemia (approximately 3%) was observed. These disorders occurred only in patients with congenital neutropenia. Myelodysplastic syndrome and leukemia are common complications of this disease and have not been definitively linked to filgrastim use. Approximately 12% of patients without cytogenetic abnormalities before treatment initiation later developed abnormalities, including monosomy 7. It is currently unknown whether long-term filgrastim therapy in patients with severe chronic neutropenia increases the risk of cytogenetic abnormalities, myelodysplastic syndrome, or disease transformation to leukemia. These patients should undergo regular (approximately every 12 months) morphological and cytogenetic bone marrow examinations.

Other special precautions

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

Hematuria or proteinuria has been observed in a small number of patients. Urinalysis should be performed regularly to monitor these conditions.

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

Special safety measures for HIV-infected patients

Blood cell counts

Absolute neutrophil count should be closely monitored, especially during the first few weeks of filgrastim therapy. Some patients may exhibit a very rapid response to the initial filgrastim dose with a significant increase in neutrophil count. During the first 2–3 days of filgrastim use, absolute neutrophil count should be monitored daily. Thereafter, during the first two weeks, it should be assessed at least twice weekly, then once weekly or once every two weeks during maintenance therapy. With intermittent administration of filgrastim at 30 million IU (300 mcg)/day, significant fluctuations in absolute neutrophil count may occur over time. Blood samples for determining the minimum absolute neutrophil count should be collected immediately before the scheduled filgrastim dose.

Risks associated with use of high-dose myelosuppressive agents

Filgrastim monotherapy does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. The risk of thrombocytopenia and anemia may increase in patients receiving higher doses of chemotherapeutic agents or combinations of such agents with filgrastim. Regular monitoring of blood parameters is recommended (see above).

Infections and malignancies causing myelosuppression

Neutropenia may result from bone marrow infiltration by opportunistic pathogens such as Mycobacterium avium complex or by malignant tumors such as lymphoma. If bone marrow-infiltrating infections or malignancies are diagnosed, appropriate treatment for these conditions should be initiated in addition to filgrastim for neutropenia management. The efficacy of filgrastim in treating neutropenia caused by bone marrow-infiltrating infections or malignancies has not been established.

All patients

AKKOFIL**®** contains sorbitol (D-sorbitol). The product should not be administered to patients with hereditary fructose intolerance (HFI), unless clinically essential.

Children under 2 years of age may not yet have been diagnosed with HFI. Intravenous administration of medicinal products containing sorbitol/fructose may be life-threatening; therefore, their use is contraindicated in this population, except in cases of clinical necessity and lack of alternatives.

The possibility of HFI symptoms in the patient's history should be considered before administering this medicinal product.

AKKOFIL**®** contains less than 1 mmol sodium (23 mg) per dose and is considered practically sodium-free.

The needle cap of the pre-filled syringe contains dry natural rubber (a latex derivative), which may cause serious allergic reactions.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of filgrastim in pregnant women are limited or absent. Increased embryo loss was observed in rabbits at multiples of clinical exposure and in the presence of maternal toxicity (see section "Pharmacological properties"). There are reports that filgrastim can cross the placental barrier. Filgrastim is not recommended during pregnancy.

Breastfeeding

It is unknown whether filgrastim or its metabolites are excreted in breast milk. Risks to newborns and 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

Filgrastim did not affect reproductive performance or fertility in male or female rats (see section "Pharmacological properties").

Ability to affect reaction speed when driving or operating machinery

AKKOFIL**®** may have a minor influence on reaction speed when driving or operating machinery. Dizziness may occur after administration of AKKOFIL**®** (see section "Adverse reactions").

Method of Administration and Dosage

Treatment with the medicinal product AKKOFIL® must be conducted only in specialized medical facilities equipped with appropriate diagnostic equipment and by physicians experienced in hematology and the use of G-CSF. Cell mobilization and apheresis procedures must be performed in specialized medical institutions by specialists with sufficient experience in this field and with the possibility of adequate monitoring of hematopoietic progenitor cells.

Dosage

Intensive chemotherapy with cytotoxic agents

The recommended daily dose of the medicinal product AKKOFIL® is 0.5 million IU (5 mcg)/kg body weight/day. The first dose should be administered no earlier than 24 hours after completion of cytotoxic chemotherapy. In randomized clinical trials, a dose of 230 mcg/m²/day (4.0–8.4 mcg/kg body weight/day) was administered subcutaneously.

Filgrastim should be administered daily until the neutrophil count exceeds the expected nadir and recovers to normal levels. After intensive chemotherapy for solid tumors, lymphomas, and lympholeukosis, the duration of treatment to achieve these criteria is typically within 14 days. Following induction and consolidation therapy for acute myeloid leukemia, the treatment duration may be significantly prolonged (up to 38 days), depending on the type, dose, and regimen of the cytotoxic chemotherapy administered.

In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil count is usually observed 1–2 days after initiating filgrastim. However, therapy must be continued to achieve a sustained therapeutic response until the neutrophil count exceeds the expected nadir and returns to normal levels. Premature discontinuation of filgrastim is not recommended until the neutrophil count has exceeded the expected nadir.

Patients undergoing myeloablative therapy followed by bone marrow transplantation

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

After reaching the minimum neutrophil level, the daily dose of filgrastim should be adjusted according to the neutrophil response (see Table 2).

Table 2

Neutrophil count	Adjustment of filgrastim dose
> 1.0 × 109/L for 3 consecutive days	Reduce to 0.5 million IU (5 mcg)/kg/day
If absolute neutrophil count remains > 1.0 × 109/L for 3 consecutive days	Discontinue filgrastim
If during treatment the absolute neutrophil count decreases to < 1.0 × 109/L, the dose of the drug should be increased again according to the above scheme.

Mobilization of peripheral blood progenitor cells (PBPCs) in patients receiving myelosuppressive or myeloablative therapy followed by autologous transplantation of peripheral blood progenitor cells

The recommended dose of the medicinal product ACCOPHIL® for mobilization of peripheral blood progenitor cells when used as monotherapy is 1.0 million IU (10 mcg)/kg/day for 5–7 consecutive days. Usually, one or two leukapheresis procedures on day 5 and day 6 of treatment are sufficient. Additional leukapheresis sessions may be performed in some cases. The dose of the drug should not be changed before completion of the final leukapheresis session.

The recommended dose of filgrastim for mobilization of peripheral blood progenitor cells following myelosuppressive chemotherapy is 0.5 million IU (5 mcg)/kg/day, administered starting on the first day after completion of chemotherapy and continued until the neutrophil count exceeds the expected nadir and returns to normal levels. Leukapheresis should be performed during the period when the absolute neutrophil count increases from < 0.5 × 10⁹/L to > 5.0 × 10⁹/L. For patients who have not received intensive chemotherapy, usually one leukapheresis session is sufficient. In other cases, additional leukapheresis sessions may be required.

Mobilization of peripheral blood progenitor cells in healthy donors prior to allogeneic transplantation of peripheral blood progenitor cells

For mobilization of peripheral blood progenitor cells in healthy donors, filgrastim is administered at a dose of 1.0 million IU (10 mcg)/kg/day for 4–5 consecutive days. To collect 4 × 10⁶ CD34+ cells/kg of recipient body weight, leukapheresis is initiated on day 5 of therapy and, if necessary, continued until day 6.

Long-term therapy to increase neutrophil counts and reduce the frequency and duration of infectious complications in children and adults with severe chronic neutropenia – congenital, cyclic, or idiopathic

Congenital neutropenia

Congenital neutropenia: the recommended initial dose is 1.2 million IU (12 mcg)/kg/day as a single dose or divided into multiple doses.

Idiopathic or cyclic neutropenia

The recommended initial dose is 0.5 million IU (5 mcg)/kg/day as a single dose or divided into multiple doses.

Dose adjustment

Filgrastim is administered daily by subcutaneous injection until the neutrophil count reaches and stably exceeds 1.5 × 10⁹/L. After response is achieved, the minimum effective dose required to maintain this level should be determined. Long-term daily administration of the drug is recommended to maintain adequate neutrophil counts. After 1–2 weeks of treatment, the initial dose may be doubled or halved depending on therapeutic efficacy. Thereafter, individual dose adjustments may be made every 1–2 weeks to maintain the average neutrophil count within the range of 1.5 × 10⁹/L to 10 × 10⁹/L. An accelerated dose escalation scheme may be used for patients with severe infections. In clinical studies, 97% of patients demonstrated a complete response with doses ≤ 24 mcg/kg/day. The safety of long-term use of filgrastim doses exceeding 24 mcg/kg/day in patients with severe chronic neutropenia has not been established.

HIV-infected patients

Restoration of neutrophil count

The recommended initial dose of filgrastim is 0.1 million IU (1 mcg)/kg/day, increased up to a maximum of 0.4 million IU (4 mcg)/kg/day. Treatment should continue until normal neutrophil counts are achieved and maintained (absolute neutrophil count > 2.0 × 10⁹/L). In clinical studies, over 90% of patients receiving these doses demonstrated a therapeutic response, with neutrophil count recovery achieved on average within 2 days.

A small number of patients (less than 10%) required doses up to 1.0 million IU (10 mcg)/kg/day to restore neutrophil counts.

Maintenance of normal neutrophil count

After neutrophil count recovery, the minimum effective dose required to maintain normal neutrophil counts should be determined. The recommended initial dose is 30 million IU (300 mcg) administered every other day. Subsequent individual dose adjustments may be necessary based on the patient's absolute neutrophil count to maintain levels > 2.0 × 10⁹/L. In clinical studies, a dose of 30 million IU (300 mcg) administered 1 to 7 days per week was sufficient to maintain the absolute neutrophil count > 2.0 × 10⁹/L, with an average administration frequency of three times per week. Long-term administration of the drug may be required to maintain the absolute neutrophil count > 2.0 × 10⁹/L.

Special patient groups

Elderly patients

Clinical studies of filgrastim included a small number of elderly patients. Specific studies in this patient group have not been conducted; therefore, no specific dosing recommendations for filgrastim are available.

Renal or hepatic impairment

Studies of filgrastim use in patients with severe renal or hepatic impairment have shown that the pharmacokinetic and pharmacodynamic profile of the drug in these patients corresponds to that in patients without such disorders. Therefore, dose adjustment in this patient group is not required.

Use of the drug in children with severe chronic neutropenia and oncological diseases

In the clinical study program for severe chronic neutropenia, 65% of patients were under 18 years of age. For this age group, which primarily included children with congenital neutropenia, treatment efficacy was evident. The safety profiles of the drug in children with severe chronic neutropenia did not differ.

Clinical study data on the use of filgrastim in children indicate that the drug has similar safety and efficacy profiles in children and adults receiving cytotoxic chemotherapy.

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

Method of administration

Intensive cytotoxic chemotherapy

Filgrastim may be administered daily as subcutaneous injections or by intravenous infusion with 5% glucose solution for infusion (50 mg/mL) over 30 minutes (the dilution procedure is described below). In most cases, subcutaneous administration is recommended. Studies of single-dose filgrastim have shown that intravenous administration may result in a shorter duration of action. The clinical significance of these findings for repeated administration is unknown. The route of administration should be selected based on the specifics of each clinical case.

Patients receiving myeloablative therapy followed by bone marrow transplantation

Filgrastim may be administered by 30-minute or 24-hour intravenous infusion, or by continuous 24-hour subcutaneous infusion. Filgrastim must be diluted in 20 mL of 5% glucose solution for infusion (50 mg/mL).

Mobilization of peripheral blood progenitor cells (PBPCs) in patients receiving myelosuppressive or myeloablative therapy followed by autologous transplantation of peripheral blood progenitor cells

Filgrastim may be administered by continuous 24-hour subcutaneous infusion or by subcutaneous injection. For infusion, the drug must be diluted in 20 mL of 5% glucose solution for infusion (50 mg/mL).

Mobilization of peripheral blood progenitor cells after myelosuppressive chemotherapy

Filgrastim is administered by subcutaneous injection.

Mobilization of peripheral blood progenitor cells in healthy donors prior to allogeneic transplantation of peripheral blood progenitor cells

Filgrastim is administered by subcutaneous injection.

Long-term therapy to increase neutrophil counts and reduce the frequency and duration of infectious complications in children and adults with severe chronic neutropenia – congenital, cyclic, or idiopathic

Congenital, idiopathic, or cyclic neutropenia: filgrastim is administered by subcutaneous injection.

HIV-infected patients

To restore and maintain normal neutrophil counts, filgrastim is administered by subcutaneous injection.

Information on patient self-administration of the drug

This section contains information on how to self-administer injections of the medicinal product ACCOPHIL®. It is important that you do not attempt to perform self-injection unless you have received specific training from your doctor or nurse. It is also important that you dispose of the syringe in a sharps container (puncture-resistant). If you are unsure about self-injection or have any questions, please consult your doctor or nurse.

How to self-administer the medicinal product ACCOPHIL®?

Important! Do not attempt to perform self-injection unless you have been trained by a doctor or nurse in the proper technique. Before administering the drug:

1. Remove the pre-filled syringe with ACCOPHIL® from the refrigerator.
2. Check the expiration date on the label of the pre-filled syringe (EXP). Do not use if the date has passed or if it has been stored outside the refrigerator for more than 15 days, or if the expiration date has otherwise expired.
3. Check the appearance of the ACCOPHIL® medicinal product. It should be a clear, colorless solution. Do not use if particles are present.
4. For more comfortable injection, leave the pre-filled syringe at room temperature for 30 minutes or hold it gently in your hand for several minutes. Do not heat ACCOPHIL® by any other method (e.g., in a microwave or hot water).
5. Wash your hands thoroughly.
6. Find a comfortable, well-lit place and place all necessary items for injection (pre-filled syringe with the medicinal product and alcohol swab) where you can easily access them.

Before injecting ACCOPHIL®, ensure that the pre-filled syringe has not been dropped on hard surfaces. Ensure that the needle cap remains on the syringe until you are ready to inject. Perform the following steps to administer the injection.

Step 1. Check system integrity

Ensure that the system is undamaged. Do not use the product if there is any damage (to the syringe or needle protective cap), loss of system components, or if the needle protective cap is in the protective position as shown in Figure 8 – this indicates prior handling of the system. The system must not be used if it does not match the image in Figure 1. If the system does not match the image in Figure 1, dispose of it in a biological hazard (sharps) container.

Fig. 1

Step 2. Remove the needle protective cap

1. Remove the protective cap as shown in Figure 2. Hold the body of the needle protective cap in one hand with the needle tip pointing away from you, ensuring the cap does not touch the needle during removal. With the other hand, pull the cap straight off. After removing the needle protective cap, dispose of it in a biological hazard (sharps) container.
2. You may notice a small air bubble in the pre-filled syringe. It is not necessary to remove the air bubble before injection. Injection of the solution with an air bubble is harmless.
3. There may be more liquid in the syringe than needed. Use the scale on the syringe barrel to correctly set the dose of ACCOPHIL® prescribed by your doctor. Remove excess liquid by pressing the plunger head to the mark (mL) on the syringe corresponding to the prescribed dose.
4. Check again to ensure the correct dose of ACCOPHIL® is in the syringe.
5. The pre-filled syringe is now ready for use.

Fig. 2

The most suitable injection sites are (Figure 3):

• anterior thigh;
• abdomen, excluding the area around the navel.

Fig. 3

If someone else is administering the injection, the upper back area may also be used as an injection site (Figure 4).

Fig. 4

It is recommended to rotate injection sites to avoid tissue hardening at the injection site.

Step 3. Inserting the needle

1. Disinfect the injection site with an alcohol wipe before needle insertion.
2. Gently pinch the skin at the injection site between your thumb and index finger of one hand, but do not compress it (Figure 5).

Fig. 5

1. With the other hand, insert the needle at the injection site without touching the plunger head (at an angle of 45–90º) (Figure 6).

Fig. 6

1. Gently pull back on the plunger to check whether a blood vessel has been punctured. If blood appears in the syringe, remove the needle and inject at another site.
2. Inject only the dose prescribed by your doctor, following the instructions below.

Step 4. Injection

Place your thumb on the plunger head. Press on the plunger head, increasing pressure at the end of the injection, and ensure the syringe is completely emptied (see Figure 7). Hold the skin fold until the injection is complete.

Fig. 7

Step 5. Needlestick injury protection using the needle guard

The needle guard covers the needle after injection to prevent needlestick injury. It does not affect the normal function of the syringe.

The safety mechanism activates after fully depressing the plunger head:

• Hold the syringe steady and slowly lift your thumb off the plunger head.
• The plunger rod and plunger head will rise upward with your thumb, and the spring will retract the needle into the needle guard (see Figure 8).

Fig. 8

Remember!

If you experience any problems, ask your doctor or nurse for assistance.

Special safety precautions

If necessary, ACCOPHIL® may be diluted in 5% glucose. Dilution to a final concentration below 0.2 MIU (2 mcg)/mL is not recommended under any circumstances.

The solution should be visually inspected before use. Only clear, particle-free solutions should be used. Do not shake.

For patients receiving filgrastim diluted to concentrations below 1.5 MIU (15 mcg)/mL, human serum albumin should be added to a final concentration of 2 mg/mL. For example: In a final injection volume of 20 mL, total filgrastim doses below 30 MIU (300 mcg) should be administered with 0.2 mL of 200 mg/mL (20%) human albumin solution.

ACCOPHIL® does not contain preservatives. Due to the potential risk of microbial contamination, pre-filled syringes of ACCOPHIL® are intended for single use only.

When diluted in 5% glucose solution, ACCOPHIL® is compatible with glass and various plastics, including PVC, polyolefin (copolymer of polypropylene and polyethylene), and polypropylene.

Disposal of used syringes

The needle guard prevents needlestick injury after use; therefore, there are no special disposal requirements. Dispose of the syringe as instructed by your doctor, nurse, or pharmacist.

If more ACCOPHIL® is administered than prescribed

Do not increase the dose prescribed by your doctor. If you think you have administered more than required, contact your doctor as soon as possible.

If you forget to inject ACCOPHIL®

If you miss an injection or administer too little of the medicinal product, contact your doctor as soon as possible. Do not administer a double dose to compensate for a missed dose.

Children

Use of the drug in children with severe chronic neutropenia and oncological diseases

In the clinical study program for severe chronic neutropenia, 65% of patients were under 18 years of age. For this age group, which primarily included children with congenital neutropenia, treatment efficacy was evident. The safety profiles of the drug in children with severe chronic neutropenia did not differ.

Clinical study data on the use of filgrastim in children indicate that the drug has similar safety and efficacy profiles in children and adults receiving cytotoxic chemotherapy.

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

Overdose

Symptoms of ACCOPHIL® overdose are unknown.

One to two days after discontinuation of the drug, circulating neutrophil counts usually decrease by 50%, and return to normal levels within 1–7 days.

Adverse Reactions

Safety Profile Overview

The most serious adverse reactions that may occur during filgrastim therapy include: anaphylactic reaction, serious respiratory adverse reactions (including interstitial pneumonia and ARDS), capillary leak syndrome, severe splenomegaly/rupture of the spleen, transformation to leukemia or myelodysplastic syndrome in patients with severe chronic neutropenia, graft-versus-host reaction in patients undergoing allogeneic bone marrow transplantation or peripheral blood progenitor cell transplantation, and sickle cell crisis in patients with sickle cell anomalies.

The most commonly reported adverse reactions are: pyrexia, musculoskeletal pain (including bone pain, back pain, arthralgia, myalgia, limb pain, muscle pain, chest pain, neck pain), anaemia, vomiting, and nausea. In clinical trials, 10% of oncology patients experienced mild or moderate musculoskeletal pain, and 3% experienced severe pain.

Description of Adverse Reactions

Below are adverse reactions reported from clinical studies and spontaneous reports.

Within each frequency group, adverse reactions are listed in descending order of severity.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000).

Infections and Infestations

Common: sepsis, bronchitis, upper respiratory tract infections, urinary tract infections.

Disorders of the Blood and Lymphatic System

Very common: thrombocytopenia, anaemia.

Common: splenomegaly^a, decreased hemoglobin level^d.

Uncommon: leukocytosis^a.

Rare: splenic rupture^a, sickle cell anaemia with crisis, extramedullary hematopoiesis.

Immune System Disorders

Uncommon: hypersensitivity, drug hypersensitivity^a, graft-versus-host reaction^b.

Rare: anaphylactic reaction.

Disorders of the Digestive System and Metabolism

Common: decreased appetite^d, increased blood lactate dehydrogenase levels.

Uncommon: hyperuricemia, increased blood uric acid levels.

Rare: decreased blood glucose levels, pseudogout (pyrophosphate arthropathy)^a, fluid volume disorder.

Psychiatric Disorders

Common: insomnia.

Nervous System Disorders

Very common: headache^a.

Common: dizziness, hypoesthesia, paraesthesia.

Cardiovascular Disorders

Common: arterial hypertension, hypotension.

Uncommon: veno-occlusive disease^g.

Rare: capillary leak syndrome^a, aortitis.

Respiratory, Thoracic and Mediastinal Disorders

Common: haemoptysis, dyspnoea, cough^a, oropharyngeal pain^a,d, epistaxis.

Uncommon: acute respiratory distress syndrome^a, respiratory failure^a, pulmonary oedema^a, pulmonary haemorrhage, interstitial lung disease^a, pulmonary infiltrates^a, hypoxia.

Gastrointestinal Disorders

Very common: diarrhoea^a,d, vomiting^a,d, nausea^a.

Common: mouth pain^e, constipation^d.

Hepatobiliary Disorders

Common: hepatomegaly, increased blood alkaline phosphatase levels.

Uncommon: increased blood aspartate aminotransferase and gamma-glutamyltransferase levels.

Skin and Subcutaneous Tissue Disorders

Very common: alopecia^a.

Common: rash^a, erythema.

Uncommon: maculopapular rash.

Rare: cutaneous vasculitis^a, Sweet’s syndrome (acute febrile neutrophilic dermatosis).

Musculoskeletal and Connective Tissue Disorders

Very common: musculoskeletal pain^v.

Common: muscle spasms.

Uncommon: osteoporosis.

Rare: decreased bone density, exacerbation of rheumatoid arthritis.

Renal and Urinary Disorders

Common: dysuria, haematuria.

Uncommon: proteinuria.

Rare: glomerulonephritis, pathological changes in urine analysis.

General Disorders and Administration Site Conditions

Very common: increased fatigue^a, mucositis^a, pyrexia.

Common: chest pain^a, pain^a, asthenia^a, malaise^d, peripheral oedema^d.

Uncommon: injection site reaction.

Injury, Poisoning and Procedural Complications

Common: transfusion reaction^d.

^a See below "Description of Adverse Reactions".

^b Cases of graft-versus-host reaction, including fatal cases, have been reported in patients after allogeneic bone marrow transplantation (see below "Description of Adverse Reactions").

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

^g Cases reported during post-marketing use in patients who underwent bone marrow transplantation or mobilization of peripheral blood progenitor cells.

^d Adverse reactions occurring more frequently in patients receiving filgrastim compared to placebo group and associated with underlying oncological disease or cytotoxic chemotherapy treatment.

Description of Adverse Reactions

Graft-versus-Host Reaction

Cases of graft-versus-host reaction with fatal outcomes have been reported in patients receiving G-CSF after allogeneic bone marrow transplantation (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

Capillary Leak Syndrome

Cases of capillary leak syndrome have been reported in patients after administration of G-CSF. These cases generally occurred in patients with malignancies, sepsis, during chemotherapy or apheresis (see section "Special Warnings and Precautions for Use").

Sweet’s Syndrome

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

Respiratory System Adverse Reactions

During clinical trials and post-marketing use, adverse events affecting the lungs, including interstitial lung disease, pulmonary oedema and pulmonary infiltrates, have been observed. In some cases, these complications led to respiratory failure or acute respiratory distress syndrome (ARDS), which may be fatal (see section "Special Warnings and Precautions for Use").

Splenomegaly and Splenic Rupture

Cases of splenomegaly and splenic rupture have been observed after filgrastim administration. Some cases of splenic rupture were fatal (see section "Special Warnings and Precautions for Use").

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, rash, urticaria, angioedema, dyspnoea and hypotension, have been reported at the beginning or during therapy in clinical trials and post-marketing use. Most such reactions occurred after intravenous administration. In some cases, symptoms recurred upon re-administration, suggesting a causal relationship. In case of serious allergic reactions, filgrastim should be discontinued permanently.

Cutaneous Vasculitis

Cases of cutaneous vasculitis have been reported in patients receiving filgrastim. The mechanism of vasculitis in these patients is unknown. Cutaneous vasculitis occurred in 2% of patients with congenital neutropenia during long-term treatment.

Pseudogout (Pyrophosphate Chondrocalcinosis)

Cases of pseudogout have been reported in oncology patients receiving filgrastim.

Leukocytosis

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

Children

Clinical trial data indicate that filgrastim demonstrates similar safety and efficacy profiles in children and adults receiving cytotoxic chemotherapy, suggesting no age-related differences in filgrastim pharmacokinetics. The only commonly reported adverse reaction in children was musculoskeletal pain, which did not differ in presentation from that observed in adults.

Currently, there is insufficient data to further evaluate the use of filgrastim in children.

Other Special Populations

Elderly Patients

No differences in safety and efficacy of filgrastim use in patients aged over 65 years compared to younger adults (aged 18 years and older) receiving cytotoxic chemotherapy have been observed; clinical practice has not revealed differences in therapeutic response between these two age groups. Currently, there is insufficient data to evaluate the use of filgrastim in elderly patients for other approved indications.

Children with Congenital Neutropenia

In paediatric patients with severe chronic neutropenia receiving long-term filgrastim therapy, cases of decreased bone mineral density and osteoporosis have been reported.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf Life. 3 years.

When diluted with 5% glucose solution (50 mg/mL) for infusion, filgrastim is compatible with glass and various plastics, including polyvinyl chloride, polyolefin (copolymer of polypropylene and polyethylene), and polypropylene.

Chemical and physical stability of the diluted infusion solution has been demonstrated for 30 hours at 25 °C ± 2 °C. From a microbiological standpoint, the solution should be used immediately. If not used immediately, storage time and conditions prior to administration are the responsibility of the user and must not exceed 30 hours at 25 °C ± 2 °C, provided dilution was performed under controlled and validated aseptic conditions.

Storage Conditions

Store in a refrigerator at 2–8 °C. Do not freeze.

Accidental single freezing for up to 24 hours does not affect the stability of the medicinal product. However, if freezing lasted longer than 24 hours or occurred more than once, the medicinal product MUST NOT be used.

During the shelf life, for outpatient use, the patient may remove the medicinal product from the refrigerator and store it at room temperature (not exceeding 25 °C) for one period of up to 15 days. At the end of this period, the product must not be returned to the refrigerator and should be disposed of.

Store the syringe in its original packaging, protected from light.

Keep out of reach of children.

Proposed Storage Conditions After First Opening of Packaging

AККОФІL® does not contain preservatives. Therefore, due to the risk of microbial contamination, syringes are intended for single use only. After use, syringes containing residual solution must be disposed of according to local requirements.

Incompatibilities

AККОФІL® must not be diluted with sodium chloride solutions.

Glass and plastic may adsorb diluted filgrastim.

The medicinal product must not be mixed with other medicinal products except as specified in the section "Method of Administration and Dosage".

Packaging

0.5 mL (30 million IU) or 0.5 mL (48 million IU) in a pre-filled syringe with an injection needle equipped with a needle safety device, 1 pre-filled syringe per blister, 5 blisters with alcohol wipes per carton.

Prescription Category. Prescription only.

Manufacturer

Accord Healthcare Polska Sp. z o.o. Importer's Address / Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's Location and Address of Business Operations

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorisation Holder. Accord Healthcare S.L.U.

Inquiries regarding poor quality of the medicinal product; safety concerns or improper use of the medicinal product or complaints are accepted 24/7 via phone: +380993100335 or by email at: [email protected].

Marketing Authorisation Holder's Location

World Trade Center, Moll de Barcelona, s/n, Edifici Est, 6th floor, 08039 Barcelona, Spain.