Neupogen^® (Solution) Instructions for Use

ATC Code

L03AA02 (Filgrastim)

Active Substance

Filgrastim (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Leukopoiesis stimulant

Pharmacotherapeutic Group

Leukopoiesis stimulator

Pharmacological Action

Recombinant human G-CSF. Filgrastim is a hematopoietic growth factor – a highly purified, non-glycosylated protein consisting of 175 amino acids. It is produced by a strain of K12 Escherichia coli, into whose genome the gene for human granulocyte colony-stimulating factor (G-CSF) has been introduced by genetic engineering methods.

Human G-CSF is a glycoprotein that regulates the production of functionally active neutrophils and their release into the blood from the bone marrow. Neupogen^® significantly increases the number of neutrophils in the peripheral blood within the first 24 hours after administration, with a slight increase in the number of monocytes. In patients with severe chronic neutropenia (SCN), Neupogen^® may cause a slight increase in the number of circulating eosinophils and basophils. In some of these patients, eosinophilia or basophilia may be detected even before the start of therapy.

Neupogen^® increases the number of neutrophils with normal or increased functional activity in a dose-dependent manner, as revealed by assessing the chemotactic and phagocytic activity of neutrophils. After the end of treatment, the number of neutrophils in the peripheral blood decreases by 50% within 1-2 days and returns to normal levels within the next 1-7 days.

Neupogen^® significantly reduces the frequency, severity, and duration of neutropenia and febrile neutropenia, reducing the need for and duration of hospital treatment in patients receiving cytotoxic chemotherapy or myeloablative therapy followed by bone marrow transplantation.

Patients receiving Neupogen^® and cytotoxic chemotherapy require lower doses of antibiotics compared to patients receiving cytotoxic chemotherapy alone.

Treatment with Neupogen^® significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy, and hospitalization after induction chemotherapy for acute myeloid leukemia, without affecting the frequency of fever and infectious complications.

The use of Neupogen^®, both alone and after chemotherapy, mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Autologous peripheral blood stem cell (PBSC) transplantation is performed after high-dose cytotoxic therapy, either instead of bone marrow transplantation or in addition to it. PBSC transplantation can also be prescribed after (high-dose) myelosuppressive cytotoxic therapy. The use of PBSCs mobilized with Neupogen^® accelerates the recovery of hematopoiesis, reduces the risk of hemorrhagic complications and the need for platelet transfusion. In children and adults with SCN (severe congenital, cyclic, idiopathic neutropenia), Neupogen^® consistently increases the number of neutrophils in the peripheral blood and reduces the frequency of infectious complications.

Prescribing Neupogen^® to patients with HIV infection helps maintain normal neutrophil levels and adhere to the recommended doses of antiviral and/or other myelosuppressive therapy. No signs of increased HIV replication were noted with the use of Neupogen^®.

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

Preclinical safety data

The carcinogenic properties of filgrastim have not been studied. Filgrastim did not cause mutations in the bacterial genome, regardless of the presence of the enzyme system necessary for drug metabolism.

It has been found that some malignant cells have G-CSF receptors on their surface. The possibility that Filgrastim could serve as a growth factor for various types of tumors cannot be excluded.

In studies in rats of both sexes, no effect on fertility and pregnancy was found when filgrastim was used in doses up to 500 mcg/kg.

In studies in rats and rabbits, Filgrastim did not have a teratogenic effect. An increased frequency of miscarriages was observed in rabbits, but no fetal developmental abnormalities were noted.

Pharmacokinetics

Absorption

After subcutaneous administration, Filgrastim is rapidly absorbed and reaches its C_max in blood serum after 2-8 hours. T_1/2 after intravenous or subcutaneous administration is usually from 2 to 4 hours. Clearance and T_1/2 depend on the dose of the drug and the number of neutrophils. Considering the dependence of clearance on the number of neutrophils, its saturation with increasing filgrastim concentration and its decrease during neutropenia, it can be said that linear clearance and linear pharmacokinetics predominate. The absolute bioavailability after subcutaneous administration is 62% at a dose of 375 mcg and 72% at a dose of 750 mcg. After discontinuation of filgrastim administration, its concentration decreases to endogenous levels within 24 hours.

In healthy volunteers and cancer patients before chemotherapy, a decrease in the plasma concentration of filgrastim was shown with its repeated administration. The increase in filgrastim clearance in this case is dose-dependent, and the degree of this increase may depend on the degree of neutrophilia in the recipients, which is consistent with data on an increase in neutrophil-dependent clearance with an increase in the neutrophil pool. In patients receiving Filgrastim after chemotherapy, the plasma concentration of the drug remained at the same level until the start of hematopoietic recovery.

Distribution

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

Elimination

Long-term administration of filgrastim (up to 28 days) after autologous bone marrow transplantation does not lead to accumulation or change in the half-life.

Regardless of the route of administration, the elimination of filgrastim follows first-order kinetics. T_1/2 is 3.5 hours, clearance is 0.6 ml/min/kg.

Pharmacokinetics in special patient groups

In children after chemotherapy, the pharmacokinetics of filgrastim are similar to those in adult patients receiving the same doses of the drug based on body weight, which allows us to conclude that the pharmacokinetics of filgrastim are independent of age.

Pharmacokinetic data in patients over 65 years of age are not available.

Studies on the use of filgrastim have shown that the pharmacodynamics and pharmacokinetics in patients with severe renal or hepatic impairment are similar to those in healthy subjects. Therefore, in these cases, there is no need for dose adjustment.

In patients with end-stage renal failure, there was a tendency towards an increase in the systemic exposure of filgrastim compared to healthy volunteers and patients with a creatinine clearance of 30-60 ml/min.

Indications

Adults and children

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

ICD codes

Dosage Regimen

Solution

Adults and children

Daily subcutaneously or as short intravenous infusions (30-minute) in 5% glucose solution until the neutrophil count passes the expected nadir and returns to the normal range. The subcutaneous route of administration is preferred.

Standard cytotoxic chemotherapy regimens

0.5 million IU (5 mcg)/kg once daily subcutaneously or as short intravenous infusions (30-minute) in 5% glucose solution. In most cases, the subcutaneous route of administration is preferred. There is evidence that intravenous administration of the drug shortens the duration of the effect. However, the clinical significance of these data remains unclear. The choice of route of administration should depend on the individual characteristics of the patient and the clinical picture of the disease. The first dose of Neupogen^® is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. Daily administration of Neupogen^® should be continued until the neutrophil count exceeds the expected nadir and reaches normal values. After a course of chemotherapy (standard regimens) for the treatment of solid tumors, lymphomas and lymphoid leukemia, the duration of therapy to achieve the desired effect is usually up to 14 days. After induction and consolidation therapy for acute myeloid leukemia, the duration of Neupogen^® use may increase to 38 days, depending on the type, doses and cytotoxic chemotherapy regimen used.

A transient increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Neupogen^®. To achieve a stable therapeutic effect, it is necessary to continue therapy with Neupogen^® until the neutrophil count exceeds the expected nadir and reaches normal values. It is not recommended to discontinue Neupogen^® prematurely, before the neutrophil count passes the expected nadir.

After myeloablative therapy followed by bone marrow transplantation

Daily subcutaneously or intravenously as an infusion in 20 ml of 5% glucose solution. The initial dose is 1.0 million IU (10 mcg)/kg per day intravenously by drip over 30 minutes or 24 hours, or by continuous subcutaneous infusion over 24 hours. The first dose of Neupogen^® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and in case of bone marrow transplantation – no later than 24 hours after bone marrow infusion. The duration of therapy is no more than 28 days (the efficacy and safety of therapy lasting more than 28 days have not been established).

After the maximum decrease in the neutrophil count (nadir), the daily dose is adjusted depending on the dynamics of the neutrophil content. If the neutrophil count exceeds 1.0×10⁹/L for three consecutive days, the dose of Neupogen^® is reduced to 0.5 million IU/kg per day; then, if the ANC exceeds 1.0×10⁹/L for 3 consecutive days, Neupogen^® is discontinued. If during treatment the ANC decreases to less than 1.0×10⁹/L, the dose of Neupogen^® should be increased again, in accordance with the above scheme.

Mobilization of peripheral blood stem cells (PBSC) in patients receiving myelosuppressive or myeloablative therapy followed by autologous PBSC transfusion with (or without) bone marrow transplantation

For PBSC mobilization – 1.0 million IU (10 mcg)/kg/day by subcutaneous injection once daily or continuous 24-hour subcutaneous infusion (in 20 ml of 5% glucose solution) for 5-7 consecutive days, with 1-2 consecutive leukapheresis procedures on days 5 and 6 usually being sufficient. In some cases, additional leukapheresis may be performed. Administration of Neupogen^® should be continued until the last leukapheresis.

For PBSC mobilization after myelosuppressive chemotherapy – 0.5 million IU (5 mcg)/kg/day by daily subcutaneous injections, starting from the first day after completion of chemotherapy and until the neutrophil count passes the expected nadir and reaches normal values. Leukapheresis should be performed during the period when the ANC rises from less than 0.5×10⁹/L to more than 5.0×10⁹/L. For patients who have not received intensive chemotherapy, one leukapheresis may be sufficient. In some cases, additional leukapheresis procedures are recommended.

Mobilization of PBSC in healthy donors for allogeneic transplantation

1 million IU (10 mcg)/kg/day subcutaneously for 4-5 days. Leukapheresis is performed from day 5 and, if necessary, up to day 6 in order to obtain CD34+ ≥ 4×10⁶ cells/kg of recipient body weight. The efficacy and safety of using Neupogen^® for PBSC mobilization in healthy donors under 16 and over 60 years of age have not been studied.

Severe chronic neutropenia (SCN)

Daily, subcutaneously, as a single dose or divided into several administrations. For congenital neutropenia: initial dose – 1.2 million IU (12 mcg)/kg/day; for idiopathic or cyclic neutropenia: 0.5 million IU (5 mcg)/kg/day until a stable neutrophil count exceeds 1.5×10⁹/L. After achieving a 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 desired neutrophil count. After 1-2 weeks of treatment, depending on the patient’s response to therapy, the initial dose can be doubled or halved. Subsequently, individual dose adjustments can be made every 1-2 weeks to maintain the neutrophil count in the range of 1.5-10×10⁹/L. In patients with severe infections, a regimen with a more rapid dose increase can be used. In 97% of patients who responded positively to treatment, a full therapeutic effect is observed when doses up to 24 mcg/kg per day are prescribed. The safety of long-term administration of Neupogen^® in doses above 24 mcg/kg per day in patients with SCN has not been established.

Neutropenia in HIV infection

Initial dose – 0.1-0.4 million IU (1-4 mcg)/kg per day as a single subcutaneous injection to achieve and maintain a normal neutrophil count (greater than 2.0×10⁹/L). In more than 90% of patients who responded positively to treatment, normalization of the neutrophil count usually occurs within 2 days. A small number of patients (less than 10%) required doses of the drug up to 1.0 million IU (10 mcg)/kg/day (maximum daily dose not more than 10 mcg/kg) to achieve a normal neutrophil count. After achieving a therapeutic effect, the minimum effective dose must be administered to maintain a normal neutrophil count. The recommended maintenance dose is 300 mcg per day subcutaneously on average 3 times a week on an alternating schedule (every other day). Subsequently, individual dose adjustment and long-term administration of the drug may be required to maintain an average neutrophil count >2.0×10⁹/L.

Use in children

Standard cytotoxic chemotherapy regimens: the safety and efficacy profiles of Neupogen^® in children receiving cytotoxic chemotherapy did not differ from those in adults.

Patients after myelosuppressive or myeloablative therapy followed by autologous PBSC transfusion the safety and efficacy of Neupogen^® in healthy donors under 16 years of age have not been assessed.

Patients with SCN and cancer: the efficacy and safety of Neupogen^® in newborns with SCN have not been established.

Severe congenital, cyclic or idiopathic neutropenia (ANC less than or equal to 0.5×10⁹/L) is an indication for long-term use of Neupogen^® in children with a history of severe or recurrent infections to increase the number of neutrophils, as well as to reduce the frequency and duration of infection-related complications.

In clinical studies, the efficacy of Neupogen^® was proven in patients under 18 years of age with SCN and cancer. The safety profile of the drug in children for the treatment of SCN did not differ from that in adults.

Dosage recommendations for pediatric patients are the same as for adults receiving myelosuppressive cytotoxic chemotherapy.

Elderly age

A small number of elderly patients participated in the studies; no special studies of this group of patients were conducted. There are no special recommendations for elderly patients.

The safety and efficacy of Neupogen^® in healthy donors over 60 years of age have not been assessed.

Patients with renal or hepatic impairment

No dose adjustment is required in patients with severe renal or hepatic impairment, as their pharmacokinetic and pharmacodynamic parameters were similar to those in healthy volunteers.

Instructions for dilution

Neupogen^® is diluted only with 5% glucose solution. Dilution with 0.9% sodium chloride solution is not allowed. The drug should not be diluted to a final concentration of less than 5 mcg in 1 ml.

If Neupogen^® is diluted to a concentration of less than 1.5 million IU (15 mcg) in 1 ml, then human serum albumin should be added to the solution in an amount such that the final albumin concentration is 2 mg/ml. For example, with a final solution volume of 20 ml, total doses of filgrastim less than 30 million IU (300 mcg) should be administered with the addition of 0.2 ml of 20% albumin solution.

Reconstituted Neupogen^® may be adsorbed by glass and plastics. However, Neupogen^® when diluted with a 5% glucose solution is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (a copolymer of polypropylene and polyethylene), and polypropylene.

The prepared Neupogen^® solution should be stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for no more than 24 hours.

Adverse Reactions

Clinical trial data

Definition of adverse reaction frequency: very common (> 10%), common (1-10%), uncommon (< 1%), rare (< 0.01%).

Patients with cancer

Neupogen^® does not increase the frequency of adverse reactions to cytotoxic chemotherapy. Adverse events occurred with equal frequency in patients receiving Neupogen^®/chemotherapy and placebo/chemotherapy.

General disorders and administration site conditions: common – fatigue, general weakness, mucosal inflammation (mucositis), anorexia; uncommon – non-specific pain; rare – exacerbation of rheumatoid arthritis.

Musculoskeletal and connective tissue disorders: common – chest pain, bone pain (especially in bones with active hematopoiesis) and muscle pain (mild or moderate (10%), sometimes severe (3%), which in most cases is relieved by common analgesics).

Gastrointestinal disorders: very common – nausea, vomiting; common – constipation, diarrhea.

Cardiac disorders: in isolated cases – transient arterial hypotension not requiring medical correction, vascular disorders (veno-occlusive disease, disorders associated with changes in body fluid content in patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation; a relationship with Neupogen^® administration has not been established).

Respiratory, thoracic and mediastinal disorders: common – cough, sore throat; rare – pulmonary infiltrates, interstitial pneumonia, pulmonary edema, in isolated cases with an adverse outcome in the form of respiratory failure or adult respiratory distress syndrome (may be fatal).

Skin and subcutaneous tissue disorders: common – alopecia, skin rash; rare – Sweet’s syndrome (febrile acute dermatosis); cutaneous vasculitis (the mechanism of development in patients receiving Neupogen^® is unknown).

Nervous system disorders: common – headache.

Immune system disorders: rare – allergic reactions. About half of the allergic reactions are associated with the administration of the first dose, more often after IV administration of the drug. Sometimes resumption of treatment is accompanied by a recurrence of symptoms.

Renal and urinary disorders: rare – urination disorders (mainly mild to moderate dysuria).

Laboratory findings: very common – increased LDH, ALP, GGT activity, increased serum uric acid concentration (reversible dose-dependent changes, usually mild or moderate).

Patients with HIV infection

Musculoskeletal and connective tissue disorders: very common – bone and muscle pain (myalgia), mainly mild or moderate (frequency similar to that in patients with cancer).

Blood and lymphatic system disorders common – splenomegaly (relationship with drug administration less than 3% of cases; in all cases, physical examination revealed mild or moderate splenomegaly with a favorable clinical course; no cases of hypersplenism were noted, splenectomy was not performed in any case). Splenomegaly is quite common in patients suffering from HIV infection, and also occurs to varying degrees of severity in most patients with AIDS; in such cases, a relationship with Neupogen^® administration has not been established.

Healthy donors (mobilization of allogeneic PBPC)

General disorders and administration site conditions: rare – exacerbation of rheumatoid arthritis.

Musculoskeletal and connective tissue disorders: very common – bone and muscle pain, mainly mild or moderate.

Respiratory, thoracic and mediastinal disorders: rare – hemoptysis, pulmonary infiltrates.

Nervous system disorders: very common – headache.

Immune system disorders: uncommon – severe allergic reactions.

Blood and lymphatic system disorders very common – leukocytosis (more than 50 x 10⁹/L) was observed in 41% of healthy donors, transient thrombocytopenia (less than 100 x 10⁹/L) was observed in 35% of healthy donors; common – splenomegaly (without clinical manifestations); uncommon – splenic function disorders.

Laboratory findings: common – transient slight increase in LDH, ALP activity; uncommon – slight increase in AST activity (without clinical consequences), hyperuricemia.

Patients with SCN

The frequency of adverse events with Neupogen^® in patients with SCN decreases over time.

General disorders and administration site conditions: common – reactions (including pain) at the injection site (< 2%), arthralgia (< 2%).

Musculoskeletal and connective tissue disorders: very common – bone and muscle pain; common – osteoporosis (< 2%).

Gastrointestinal disorders common – diarrhea (usually after initiation of therapy), hepatomegaly (< 2%).

Skin and subcutaneous tissue disorders: common – alopecia (< 2%), rash (< 2%), cutaneous vasculitis (2%).

Nervous system disorders: common – headache (< 2%, usually after initiation of therapy).

Blood and lymphatic system disorders: very common – anemia, splenomegaly (may progress in some cases); common – thrombocytopenia; uncommon – splenic function disorders. Cases of epistaxis were also identified.

Renal and urinary disorders: uncommon – hematuria, proteinuria.

Laboratory findings: very common – transient increase in LDH, ALP activity without clinical manifestations, transient moderate postprandial hypoglycemia, hyperuricemia.

Post-marketing experience

Immune system disorders: in rare cases – allergic reactions, including anaphylaxis, skin rash, urticaria, which may develop at the start of therapy or during subsequent treatment with filgrastim. In some cases, resumption of treatment was accompanied by a recurrence of symptoms, suggesting a causal relationship between the drug and the adverse event. If serious allergic reactions occur, filgrastim therapy should be discontinued.

Blood and lymphatic system disorders isolated cases of sickle cell crises, some fatal, have been reported during filgrastim administration. Isolated cases of splenic rupture have been reported in healthy donors and patients with cancer receiving G-CSF (filgrastim).

Skin and subcutaneous tissue disorders in rare cases (≥ 0.01% and < 0.1%) – Sweet’s syndrome (febrile acute dermatosis). Cases of cutaneous vasculitis have been reported in patients with cancer receiving filgrastim (estimated reporting frequency 0.001%).

Metabolism and nutrition disorders isolated cases of pseudogout (chondrocalcinosis) have been reported in patients with cancer receiving filgrastim.

Laboratory findings: reversible increases in serum uric acid concentration, ALP and LDH activity without clinical manifestations (usually mild or moderate) have been observed in patients receiving Filgrastim after cytotoxic chemotherapy.

Contraindications

• Severe congenital neutropenia (Kostmann’s syndrome) with cytogenetic abnormalities;
• Use for the purpose of increasing doses of cytotoxic chemotherapeutic agents above recommended levels;
• Concomitant administration with cytotoxic chemotherapy and radiation therapy;
• Hypersensitivity to the components of the drug.

Use in Pregnancy and Lactation

Category C.

The safety of Neupogen^® during pregnancy has not been established. Filgrastim may cross the placental barrier in women. Reproductive toxicity was identified in animal studies. When prescribing Neupogen^® to pregnant women, the expected therapeutic effect should be weighed against the potential risk to the fetus.

In studies in rats of both sexes, no effect on fertility and pregnancy was found with the use of filgrastim at doses up to 500 mcg/kg.

In studies in rats and rabbits, Neupogen^® did not have a teratogenic effect. An increased frequency of miscarriages was observed in rabbits, but no fetal abnormalities were noted.

It is not known whether Filgrastim is excreted in breast milk. Neupogen^® is not recommended for use in nursing mothers.

Use in Hepatic Impairment

No dose adjustment is required in patients with severe hepatic impairment, as their pharmacokinetic and pharmacodynamic parameters were similar to those of healthy volunteers.

Use in Renal Impairment

No dose adjustment is required in patients with severe renal impairment, as their pharmacokinetic and pharmacodynamic parameters were similar to those of healthy volunteers.

Pediatric Use

Can be used according to indications and in recommended doses.

Geriatric Use

A small number of elderly patients participated in the studies; no specific studies of this patient group have been conducted. There are no specific recommendations for elderly patients.

The safety and efficacy of Neupogen^® in healthy donors over 60 years of age have not been evaluated.

Special Precautions

Treatment with Neupogen^® should be carried out only under the supervision of an oncologist or hematologist experienced in the use of G-CSF, with the necessary diagnostic capabilities. Cell mobilization and apheresis procedures should be performed in an oncology or hematology center with experience in this field and the ability to adequately monitor hematopoietic progenitor cells.

Growth of malignant cells

The safety and efficacy of Neupogen^® in patients with myelodysplastic syndrome and chronic myeloid leukemia have not been established, therefore it is not indicated for these diseases. Particular attention should be paid to the differential diagnosis between acute myeloid leukemia and the blast crisis of chronic myeloid leukemia.

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

Neupogen^® should be used with caution in patients with secondary acute myeloid leukemia, due to limited safety and efficacy data in this case.

The safety and efficacy of Neupogen^® in patients with de novo acute myeloid leukemia under 55 years of age with prognostically favorable cytogenetic factors (translocations t (8;21), t (15;17), inv (16)) have not been established.

Patients receiving cytotoxic chemotherapy

Leukocytosis: in less than 5% of patients receiving Neupogen^® at doses greater than 0.3 million IU (3 mcg/kg/day), the white blood cell count increased to 100×10⁹/L or more. No adverse events directly related to such leukocytosis have been described. However, given the possible risk associated with high leukocytosis, the white blood cell count should be monitored regularly (e.g., 2-3 times a week) during treatment with Neupogen^®. If the white blood cell count exceeds 50 x 10⁹/L after the expected nadir, Neupogen^® should be discontinued immediately. If Neupogen^® is used for PBPC mobilization, its dose should be reduced or completely discontinued if the white blood cell count exceeds 70×10⁹/L.

Risk associated with high-dose chemotherapy: particular caution should be exercised when treating patients receiving high-dose chemotherapy, since improvement in the outcome of the malignant neoplasm has not been noted, while increased doses of chemotherapeutic agents have more pronounced toxicity, including skin reactions and adverse effects on the cardiovascular, nervous and respiratory systems.

Monotherapy with Neupogen^® 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), the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly perform blood tests and determine platelet count and hematocrit. Particular caution should be exercised when using single-agent or combination chemotherapy regimens that can cause severe thrombocytopenia.

The use of Neupogen^® for PBPC mobilization has been shown to reduce the degree and duration of thrombocytopenia that developed as a result of myelosuppressive or myeloablative chemotherapy.

Patients with SCN

Transformation to leukemia or preleukemia (myelodysplastic syndrome): particular caution should be exercised in diagnosing SCN, and it should be differentiated from other hematological diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia. Before starting treatment, a complete blood count with differential and platelet count should be performed, and the bone marrow morphology and karyotype should be examined.

A small number (3%) of patients with severe congenital neutropenia (Kostmann’s syndrome) treated with Neupogen^® developed myelodysplastic syndrome and leukemia. Myelodysplastic syndrome and leukemia are natural complications of this disease. Their relationship with Neupogen^® treatment is unclear. Approximately 12% of patients with initially normal cytogenetics were found to have abnormalities upon re-examination, including monosomy 7. If a patient with Kostmann’s syndrome develops cytogenetic abnormalities, the benefits and risks of continuing Neupogen^® therapy should be carefully assessed. If myelodysplastic syndrome or leukemia develops, Neupogen^® should be discontinued. It is not yet clear whether long-term treatment with Neupogen^® in patients with severe congenital neutropenia (Kostmann’s syndrome) predisposes to the development of cytogenetic abnormalities, myelodysplastic syndrome and leukemia. Patients with Kostmann’s syndrome are recommended to undergo regular (approximately every 12 months) morphological and cytogenetic examinations of the bone marrow.

Cytogenetic abnormalities, leukemia and osteoporosis were detected with long-term use of Neupogen^® (>5 years) in patients (9.1%) with SCN. The relationship of these phenomena with the use of the drug has not been elucidated.

Blood count: platelet count should be carefully monitored, especially during the first few weeks of treatment with Neupogen^®. In SCN, during the first weeks of initial therapy, a complete blood count and platelet count are determined twice a week, and in a stable patient condition – once a month. If a patient develops thrombocytopenia (platelet count consistently below 100 x 10⁹/L), temporary discontinuation of the drug or dose reduction should be considered. Other changes in the blood count are also observed, requiring its careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

Other: such causes of transient neutropenia as viral infections should be excluded. Spleen enlargement is a direct consequence of treatment with Neupogen^®. During clinical trials, splenomegaly was detected by palpation in 31% of patients with SCN. On radiography, an increase in volume is detected soon after the start of treatment and tends to stabilize. Dose reduction slows or stops the increase in spleen size; splenectomy may be required in 3% of patients. Spleen size should be monitored regularly by palpation.

A small number of patients had hematuria and proteinuria. To monitor these parameters, urinalysis should be performed regularly.

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

Patients undergoing PBPC mobilization

After bone marrow transplantation, blood count and platelet count are performed 3 times a week.

Mobilization: a comparison of the two recommended mobilization methods (Filgrastim alone or in combination with myelosuppressive chemotherapy) in the same patient population has not been conducted. Direct comparison of the results of different studies is difficult due to individual differences between patients, as well as due to differences between CD34+ values obtained by laboratory tests. Therefore, it is quite difficult to recommend any optimal mobilization method. The choice of mobilization method should be made depending on the overall treatment goals for a given patient.

Prior treatment with cytotoxic agents: in patients who have previously received active myelosuppressive therapy, a sufficient increase in PBPC to the recommended minimum level (≥ 2.0×10⁶ CD34+/kg) or acceleration of platelet count normalization may not occur.

Some cytostatics have particular toxicity to hematopoietic progenitor cells and may negatively affect their mobilization. The use of drugs such as melphalan, carmustine and carboplatin for a long period before the start of mobilization may reduce the degree of its expression. However, the use of melphalan, carboplatin or carmustine together with Neupogen^® is effective in activating PBPC. If PBPC transplantation is planned, it is recommended to schedule their mobilization at an early stage of the treatment course. Particular attention should be paid to the number of progenitor cells activated in such patients before high-dose chemotherapy. If the mobilization results according to the above criteria are insufficient, alternative treatment options that do not require the use of progenitor cells should be considered.

Assessment of the quantity (“yield”) of peripheral blood stem cells: when assessing the number of PBPC mobilized in patients with Neupogen^®, special attention should be paid to the quantification method. The results of flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology, and caution should be exercised regarding recommendations on their number based on studies conducted in other laboratories.

There is a complex but stable statistical relationship between the number of CD34+ cells administered in the reinfusion and the rate of platelet count normalization after high-dose chemotherapy.

A minimum PBPC quantity equal to or greater than 2.0×10⁶ CD34+ cells/kg leads to sufficient recovery of hematological parameters. A quantity exceeding this value appears to be accompanied by faster normalization, while a quantity less than the specified one is accompanied by slower normalization of the blood picture.

PBPC mobilization in healthy donors

The PBPC mobilization procedure does not provide direct benefit to healthy donors and should be performed only for the purpose of allogeneic transplantation.

Cell mobilization and apheresis procedures should be performed in a medical center with experience in this field. HPC mobilization is only possible if laboratory parameters, especially the donor’s hematological parameters, meet the selection criteria; special attention should also be paid to the presence of infectious diseases.

Transient leukocytosis (leukocytes greater than 50×10⁹/L) is observed in 41% of healthy donors. Transient thrombocytopenia (platelet count less than 100×10⁹/L) after filgrastim administration and leukapheresis is observed in 35% of donors. Furthermore, 2 cases of thrombocytopenia less than 50×10⁹/L after the leukapheresis procedure have been noted.

If more than one leukapheresis is required, the platelet count should be monitored before each apheresis procedure, especially if the platelet count is less than 100×10⁹/L. Leukapheresis is not recommended if the platelet count is less than 75×10⁹/L, when anticoagulants are prescribed, or in cases of known hemostasis disorders.

Neupogen^® should be discontinued or its dose reduced if the leukocyte count is greater than 70×10⁹/L.

In healthy donors, all blood count parameters should be regularly monitored until they normalize.

Given the rare cases of splenic rupture after G-CSF administration to healthy donors, it is recommended to monitor its size (palpation, ultrasound examination).

The risk of the emergence of a clone of malignant tumor cells cannot be excluded. Systematic long-term safety monitoring of the drug’s use in healthy donors is recommended at the apheresis center.

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

Special Instructions for Recipients of Allogeneic HPCs Obtained Using Neupogen^®

The use of allogeneic HPC grafts may be associated with an increased risk of developing acute or chronic graft-versus-host disease compared to bone marrow transplantation.

Neutropenia in HIV Patients

With a very rapid positive response to therapy, a significant increase in the number of neutrophils may occur after the initial doses of Neupogen^®. During treatment with Neupogen^®, a complete blood count (including ANC, red blood cell count, platelet count) should be performed regularly daily for the first 2-3 days, then twice a week for the first 2 weeks, and weekly or every other week during maintenance therapy. During maintenance therapy at 300 mcg/day on an alternating schedule, significant fluctuations in the neutrophil count may occur. Considering the fluctuations in ANC values, blood sampling to determine the true maximum decrease in ANC (nadir) should be performed before the administration of the next dose of the drug.

Monotherapy with Neupogen^® 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) or a greater number of them in combination therapy, the patient may be at greater risk of thrombocytopenia and anemia. Regular blood tests and determination of platelet count and hematocrit are recommended.

In patients with infectious diseases and bone marrow infiltration by infectious agents (e.g., Mycobacterium avium complex) or with tumor involvement of the bone marrow (lymphoma), filgrastim therapy is administered concurrently with therapy directed against these conditions. The efficacy of Neupogen^® in treating neutropenia caused by bone marrow infiltration by infectious agents (osteomyelitis) or tumor involvement has not been established.

Other Special Precautions

Rare cases of splenic rupture have been described in healthy donors and patients with cancer receiving G-CSF (filgrastim), in some cases with fatal outcomes. Given these data, careful monitoring of spleen size by clinical examination (palpation) and instrumental methods (e.g., ultrasound examination) is recommended. Targeted diagnostics should be performed if splenic rupture or splenomegaly is suspected in cases where patients or healthy donors complain of pain in the upper left quadrant of the abdomen or the upper shoulder area.

According to literature data, the presence of sickle cell anemia and a high leukocyte count is an unfavorable prognostic factor. In such patients, blood tests should be performed regularly, and the possibility of splenomegaly and vascular thrombosis should be considered. Cases of sickle cell crises during filgrastim administration have been described, some with fatal outcomes. Therefore, in patients with sickle cell anemia, caution should be exercised when prescribing Neupogen^® (filgrastim), carefully weighing the benefits and potential risks.

Patients with bone pathology and osteoporosis receiving continuous treatment with Neupogen^® for more than 6 months should have their bone density monitored.

The effect of Neupogen^® in patients with a significantly reduced number of myeloid progenitor cells is unknown. Neupogen^® increases the number of neutrophils primarily by acting on neutrophil progenitor cells. Therefore, in patients with a reduced content of progenitor cells (e.g., those who have undergone intensive radiation therapy or chemotherapy), the degree of increase in neutrophil count may be lower.

The effect of Neupogen^® on graft-versus-host disease has not been established.

Neupogen^® contains sorbitol at a concentration of 50 mg/mL. It is unlikely that sufficient sorbitol will be administered to cause a toxic reaction due to monotherapy with Neupogen^®; however, patients with hereditary fructose intolerance should be cautious.

If symptoms such as cough, fever, and dyspnea occur, combined with radiological findings of pulmonary infiltrates and worsening pulmonary function, the development of adult respiratory distress syndrome can be suspected. In this case, therapy with the drug should be discontinued and appropriate treatment initiated.

Instructions for Use, Handling, and Disposal

Vigorous shaking should be avoided.

Before administration, the Neupogen^® solution should be inspected for the presence of foreign visible particles. The solution should only be administered if no foreign visible particles are present.

Vials and syringe tubes with Neupogen^® are intended for single use only.

The release of medicinal products into the environment should be minimized. Disposal of Neupogen^® via wastewater or with household waste is not permitted. If possible, special systems for drug disposal should be used.

Effect on Ability to Drive and Use Machines

No effect of Neupogen^® on the ability to drive vehicles or operate machinery has been observed.

Overdose

Cases of overdose have not been reported. In bone marrow transplantation studies, Neupogen^® was administered to patients at doses up to 138 mcg/kg/day without the development of toxic effects. Within 1-2 days after discontinuation of the drug, the number of circulating neutrophils usually decreases by 50% and returns to normal levels within 1-7 days.

Drug Interactions

The safety and efficacy of administering Neupogen^® on the same day as myelosuppressive cytotoxic chemotherapeutic agents have not been established. Due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to administer Neupogen^® within the 24-hour interval before or after the administration of these drugs. When Neupogen^® and fluorouracil are administered concomitantly, the severity of neutropenia may increase. Possible interaction with other hematopoietic growth factors and cytokines is unknown.

Given that lithium stimulates neutrophil release, an enhancement of the effect of Neupogen^® may be possible with combined administration, but such studies have not been conducted.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy leads to transient positive changes in bone imaging, which should be taken into account when interpreting the results.

Due to pharmaceutical incompatibility, it must not be mixed with 0.9% sodium chloride solution.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Transport at a temperature between 2°C (35.6°F) and 8°C (46.4°F).

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.