Immugrast^® (Solution) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

ATC Code

L03AA02 (Filgrastim)

Active Substance

Filgrastim (Rec.INN registered by WHO)

Dosage Form

Immugrast®

Solution for intravenous and subcutaneous administration 30 million IU/1 ml: vial 1 pc. or syringe

Dosage Form, Packaging, and Composition

Solution for intravenous and subcutaneous administration transparent, colorless.

Excipients: D-sorbitol – 50 mg, polysorbate 80 – 0.04 mg, sodium acetate trihydrate – 0.204 mg, glacial acetic acid – 0.48 ml, water for injections – up to 1 ml.

1 ml – vials of colorless glass (1) – cardboard packs.
1 ml – syringes of colorless glass (1) – cardboard packs.

Clinical-Pharmacological Group

Leukopoiesis stimulant

Pharmacotherapeutic Group

Leukopoiesis stimulator

Pharmacological Action

Leukopoiesis stimulator. Filgrastim is a highly purified, non-glycosylated protein consisting of 175 amino acids. It is produced by a strain of Escherichia coli into whose genome the gene for human granulocyte colony-stimulating factor (G-CSF) – a glycoprotein that regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow – has been inserted by genetic engineering methods. Filgrastim, containing recombinant G-CSF, 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, Filgrastim may cause a slight increase in the number of circulating eosinophils and basophils.

Filgrastim increases the number of neutrophils with normal or increased functional activity in a dose-dependent manner. After the end of treatment, the number of neutrophils in the peripheral blood decreases by 50% within 1-2 days and returns to normal within the next 1-7 days. The duration of action after intravenous administration may be shorter. The clinical significance of this phenomenon with repeated administration of the drug is unclear.

The use of filgrastim, both alone and after chemotherapy, mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Autologous or allogeneic transplantation of peripheral blood stem cells (PBSC) is performed after therapy with high doses of cytostatics, either instead of bone marrow transplantation or in addition to it. PBSC transplantation may also be prescribed after (high-dose) myelosuppressive cytotoxic therapy. . The use of PBSC mobilized with filgrastim accelerates the recovery of hematopoiesis, reduces the severity and duration of thrombocytopenia, the risk of hemorrhagic complications, and the need for platelet transfusion after myelosuppressive or myeloablative therapy.

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

In children and adults with severe chronic neutropenia (severe congenital, cyclic, idiopathic neutropenia), Filgrastim consistently increases the number of neutrophils in the peripheral blood and reduces the frequency of infectious complications.

Prescribing filgrastim to patients with HIV infection helps maintain normal neutrophil counts and adhere to recommended doses of antiretroviral and/or other myelosuppressive therapy. No signs of increased HIV replication have been observed with the use of filgrastim.

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

Pharmacokinetics

Absorption and 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 in therapeutic doses, its plasma concentration exceeds 10 ng/ml for 8-16 hours. V_d– 150 ml/kg.

Elimination

Regardless of the route of administration, the elimination of filgrastim follows first-order kinetics. T_1/2 – 3.5 hours, clearance is 0.6 ml/min/kg. Long-term administration of filgrastim for up to 28 days after autologous bone marrow transplantation does not lead to accumulation or an increase in T_1/2.

Pharmacokinetics in Special Clinical Cases

In patients with end-stage renal failure, an increase in C_max and AUC and a decrease in V_d and clearance values are observed compared to healthy volunteers and patients with moderate renal failure.

Indications

• Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant neoplasms (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;
• Mobilization of peripheral blood stem cells, incl. after myelosuppressive therapy;
• Severe congenital, cyclic or idiopathic neutropenia (absolute neutrophil count ≤ 0.5×10⁹/L) in children and adults with a history of severe or recurrent infections;
• Persistent neutropenia (absolute neutrophil count ≤ 1.0×10⁹/L) in patients with advanced HIV infection to reduce the risk of bacterial infections when other treatment methods cannot be used.

ICD codes

Dosage Regimen

The drug is administered daily subcutaneously or as short intravenous infusions (30-minute). The drug can also be administered as 24-hour intravenous or subcutaneous infusions.

The choice of route of administration depends on the specific clinical situation. The subcutaneous route of administration is preferred.

Standard Cytotoxic Chemotherapy Regimens

Administer at a dose of 5 mcg (0.5 million IU)/kg once daily subcutaneously or as short intravenous infusions. The first dose of the drug is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. A transient increase in the number of neutrophils is usually observed 1-2 days after starting treatment with Immugrast^®. To achieve a stable therapeutic effect, therapy with Immugrast^® must be continued until the neutrophil count passes the expected nadir and reaches normal values. If necessary, the duration of the course of therapy can be up to 14 days, depending on the severity of the disease and the severity of neutropenia. After induction and consolidation therapy for acute myeloid leukemia, the duration of Immugrast^® use may increase to 38 days depending on the type, doses and regimen of the cytotoxic drugs used.

It is not recommended to discontinue Immugrast^® prematurely, before the expected neutrophil nadir occurs.

After Myeloablative Chemotherapy Followed by Bone Marrow Transplantation

The recommended initial dose is 10 mcg (1.0 million IU)/kg, diluted in 20 ml of 5% dextrose solution, as a 30-minute or 24-hour intravenous infusion or by continuous subcutaneous infusion over 24 hours. The first dose of Immugrast^® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and in case of bone marrow transplantation – no later than 24 hours after the bone marrow infusion. The duration of therapy is no more than 28 days. After the maximum decrease in the neutrophil count, the daily dose is adjusted depending on the dynamics of their count. If the neutrophil count in the peripheral blood exceeds 1.0×10⁹/L for 3 consecutive days, the dose of Immugrast^® is reduced to 5 mcg (0.5 million IU)/kg; if at this dose the absolute neutrophil count exceeds 1.0×10⁹/L for another 3 consecutive days, Immugrast^® is discontinued. If during treatment the absolute neutrophil count decreases to less than 1.0×10⁹/L, the dose of Immugrast^® is increased again, according to the above scheme.

Mobilization of Peripheral Blood Stem Cells (PBSC) After Myelosuppressive Therapy Followed by Autologous PBSC Transfusion With (or Without) Bone Marrow Transplantation or in Patients With Myeloablative Therapy Followed by PBSC Transfusion

Administer at a dose of 10 mcg (1.0 million IU)/kg by subcutaneous injection once daily or by continuous 24-hour subcutaneous infusion for 6 consecutive days, with two consecutive leukapheresis procedures usually sufficient on the 5th and 6th days. In some cases, additional leukapheresis may be performed. Administration of Immugrast^® must be continued until the last leukapheresis.

PBSC Mobilization After Myelosuppressive Therapy

Administer at a dose of 5 mcg (0.5 million IU)/kg 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 absolute neutrophil count 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.

PBSC Mobilization in Healthy Donors for Allogeneic Transplantation

Administer at a dose of 10 mcg (1.0 million IU)/kg/day subcutaneously, for 4-5 days. Leukapheresis is performed from day 5 and if necessary until day 6 to obtain CD34+ cells in an amount of ≥ 4×10⁶ cells/kg of recipient body weight. The efficacy and safety of Immugrast^® in healthy donors under 16 and over 60 years of age have not been studied.

Severe Chronic Neutropenia (SCN)

Administer daily subcutaneously, as a single dose or divided into several administrations. For congenital neutropenia the initial dose is 12 mcg (1.2 million IU)/kg/day, for idiopathic or cyclic neutropenia – 5 mcg (0.5 million IU)/kg/day until a stable neutrophil count exceeds 1.5×10⁹/L. After achieving a therapeutic effect, the minimum effective dose to maintain this neutrophil level should be determined. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient’s response to therapy. Subsequently, the dose can be adjusted 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 faster dose increase can be used. In 97% of patients who responded positively to treatment, a full therapeutic effect is observed when filgrastim is prescribed at doses up to 24 mcg/kg/day. The daily dose of Immugrast^® should not exceed 24 mcg/kg.

Neutropenia in HIV Infection

Initial dose 1-4 mcg (0.1-0.4 million IU)/kg/day once subcutaneously until normalization of the neutrophil count (≥2×10⁹/L). Normalization of the neutrophil count usually occurs within 2 days. After achieving a therapeutic effect, the maintenance dose is 300 mcg/day every other day. Subsequently, individual dose adjustment and long-term therapy with Immugrast^® may be required to maintain the neutrophil count above 2.0×10⁹/L.

Dosing in Special Clinical Cases

For elderly patients, there are no specific dosing recommendations.

In children with severe chronic neutropenia and oncological diseases, the safety profile of filgrastim did not differ from that in adults. Dosing recommendations for children are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.

Dose adjustment of filgrastim is not required in patients with severe renal or hepatic impairment, because their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.

Rules for Preparing the Solution for Intravenous Administration

If intravenous administration of Immugrast^® is necessary, the required amount of the drug is injected from the syringe into a vial or plastic container with 5% dextrose solution.

Immugrast^® should not be diluted with 0.9% sodium chloride solution.

If the drug is diluted to a concentration of less than 15 mcg/ml (less than 1.5 million IU/ml), then human serum albumin should be added to the solution so that the final albumin concentration is 2 mg/ml. For example, with a final solution volume of 20 ml, a total dose of Immugrast^® of less than 300 mcg (less than 30 million IU) should be administered with the addition of 0.2 ml of 20% human albumin solution. Do not dilute Immugrast^® to a final concentration of less than 2 mcg/ml (less than 0.2 million IU/ml).

Immugrast^® when diluted with 5% dextrose solution or 5% dextrose solution and albumin is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (copolymer of polypropylene and polyethylene) and polypropylene.

Syringes with Immugrast^® are for single use only.

The prepared solution of Immugrast^® is stored at a temperature of 2 to 8°C (46.4°F) for no more than 24 hours.

Adverse Reactions

Definition of frequency of adverse reactions: very common (>10%); common (>1%, <10%); uncommon (>0.1%, <1%); rare (>0.01%, <0.1%); very rare (>0.01%).

From the hematopoietic system: very common – neutrophilia and leukocytosis (as a consequence of the pharmacological action of filgrastim), with long-term use – anemia, splenomegaly; common – thrombocytopenia; very rare – splenic rupture.

From the respiratory system: common – cough; very rare – pulmonary infiltrates, adult respiratory distress syndrome.

From the musculoskeletal system: common – bone, muscle, joint pain, osteoporosis; very rare – exacerbation of rheumatoid arthritis, pseudogout (pyrophosphate arthropathy).

From the cardiovascular system: very rare – decrease or increase in blood pressure, cutaneous vasculitis (with long-term therapy in patients with SCN).

From the digestive system: common – diarrhea, hepatomegaly.

From the urinary system: rare – hematuria, proteinuria; very rare – dysuria.

From the skin and its appendages: common – skin rash, with long-term use – alopecia; rare — Sweet’s syndrome (acute febrile neutrophilic dermatosis, relationship with filgrastim intake not established).

Allergic reactions: very rare – skin rash, urticaria, facial edema, wheezing, shortness of breath, decreased blood pressure, tachycardia.

From laboratory parameters: very common – reversible, mild and moderate increase in the activity of GGT, ALP, LDH, increase in the concentration of uric acid in the blood serum, transient hypoglycemia; rare – increase in AST activity.

Other: common – headache, increased fatigue, general weakness, injection site reactions (in less than 2% of patients with SCN).

Contraindications

• Severe congenital neutropenia (Kostmann syndrome) with cytogenetic abnormalities;
• Use of the drug to increase the doses of cytotoxic chemotherapeutic drugs above recommended;
• Simultaneous administration with cytotoxic chemo- and radiotherapy;
• End-stage chronic renal failure;
• Myelodysplastic syndrome (MDS) and chronic myeloid leukemia (no data on efficacy and safety);
• Lactation period (breastfeeding);
• Neonatal period (up to 28 days of life);
• Hypersensitivity to the components of the drug.

Use with caution in pregnancy, malignant and pre-neoplastic diseases of myeloid nature (including acute myeloid leukemia), sickle cell anemia, in combination with high-dose chemotherapy.

Use in Pregnancy and Lactation

The safety of filgrastim for pregnant women has not been established. Filgrastim may cross the placental barrier in women. When prescribing Immugrast^® to pregnant women, the expected therapeutic benefit for the mother should be weighed against the potential risk to the fetus.

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

There are no data on the penetration of filgrastim into breast milk. The use of Immugrast^® during breastfeeding is not recommended.

Use in Hepatic Impairment

Dose adjustment of filgrastim is not required in patients with severe hepatic impairment, because their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.

Use in Renal Impairment

Dose adjustment of filgrastim is not required in patients with severe renal impairment, because their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.

Pediatric Use

Contraindication: neonatal period (up to 28 days of life).

In children with severe chronic neutropenia and oncological diseases, the safety profile of filgrastim did not differ from that in adults. Dosing recommendations for children are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.

Geriatric Use

For elderly patients, there are no specific dosing recommendations.

Special Precautions

Treatment with Immugrast^® should be carried out only under the supervision of a physician experienced in the use of colony-stimulating factors, with the necessary diagnostic capabilities. Cell mobilization and apheresis procedures should be performed in specialized medical institutions.

For MDS and chronic myeloid leukemia, the efficacy and safety of filgrastim have not been established. The use of filgrastim is not indicated for patients with the above diseases. Particular attention should be paid to the differential diagnosis between the blast crisis of chronic myeloid leukemia and acute myeloid leukemia.

Particular caution should be exercised when diagnosing severe chronic neutropenia to differentiate it from other hematological diseases, such as aplastic anemia, myelodysplasia, and myeloleukemia.

In a small number (3%) of patients with severe congenital neutropenia (Kostmann’s syndrome) treated with Filgrastim, MDS and leukemia were observed. MDS and leukemia are natural complications of this disease; their relationship to Filgrastim treatment is not clear. 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, as well as if MDS or leukemia develops, Filgrastim should be discontinued. It is not yet clear whether long-term treatment with Filgrastim in patients with Kostmann’s syndrome predisposes to the development of cytogenetic abnormalities, MDS, and leukemia. Patients with Kostmann’s syndrome are recommended to undergo morphological and cytogenetic examinations of the bone marrow at regular intervals (approximately every 12 months).

Cytogenetic abnormalities, leukemia, and osteoporosis were detected with long-term use of Filgrastim (> 5 years) in 9.1% of patients with severe chronic neutropenia. Their relationship to the drug has not been established.

Treatment with Filgrastim should be carried out under regular monitoring of a complete blood count with a leukocyte differential and platelet count (before starting therapy and then twice a week during standard chemotherapy and at least 3 times a week during hematopoietic stem cell mobilization with or without subsequent bone marrow transplantation). If the leukocyte count rises above 50×10⁹/L, Filgrastim should be discontinued immediately. If Filgrastim is used for mobilization of hematopoietic stem cells, it must be discontinued if the leukocyte count exceeds 70×10⁹/L.

Monotherapy with Filgrastim does not prevent the development of thrombocytopenia and anemia caused by myelosuppressive chemotherapy. It is recommended to regularly perform blood tests twice a week to determine platelet count and hematocrit during the use of Filgrastim after chemotherapy.

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

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

During treatment with Filgrastim, urinalysis (to rule out hematuria and proteinuria) should be performed regularly and spleen size should be monitored.

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

After bone marrow transplantations, blood tests and platelet counts are performed 3 times a week.

In patients who have previously undergone active myelosuppressive therapy, a sufficient increase in HSCs to the recommended minimum level (≥ 2.0×10⁶ CD34⁺ cells/kg) may not occur. In this regard, for such patients requiring HSC transplantation, it is recommended to plan their mobilization at an early stage of the treatment course; if it is not possible to obtain a sufficient number of HSCs as a result of mobilization prior to high-dose chemotherapy, alternative treatment options not requiring the use of progenitor cells should be considered.

When using Filgrastim-mobilized HSCs, a reduction in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloablative chemotherapy is observed.

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

A minimum HSC count equal to or exceeding 2×10⁶ CD34⁺ cells/kg leads to sufficient recovery of hematological parameters.

HSC mobilization may only be considered in those healthy donors whose clinical and laboratory parameters, especially hematological parameters, meet the criteria for selection of donors for HSC mobilization.

Transient leukocytosis (leukocytes more than 50×10⁹/L) is noted in 41% of healthy donors, more than 75×10⁹/L – in 2% of healthy donors. Transient thrombocytopenia (platelet count less than 100×10⁹/L) after administration of Filgrastim and leukapheresis is observed in 35% of donors. Furthermore, 2 cases of thrombocytopenia less than 50×10⁹/L after the leukapheresis procedure were noted.

If more than one leukapheresis is required, 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, as well as in donors with impaired hemostasis or receiving anticoagulants.

Filgrastim should be discontinued or its dose should be reduced if the leukocyte count exceeds 70×10⁹/L.

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

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

During long-term safety follow-up of Filgrastim use in healthy donors for up to 4 years after Filgrastim use, no cases of impaired hematopoiesis were noted. However, the risk of stimulating the emergence of a clone of malignant myeloid cells cannot be ruled out; therefore, it is recommended to systematically monitor healthy stem cell donors in apheresis centers for at least 10 years.

Special instructions for recipients of allogeneic HSCs obtained using Filgrastim: the use of an allogeneic HSC graft may be associated with an increased risk of developing acute or chronic graft-versus-host disease compared to bone marrow transplantation.

When treating HIV-infected patients with neutropenia with Filgrastim, a detailed blood test (absolute neutrophil count (ANC), red blood cells, platelets, etc.) should be performed regularly daily for the first few days, then twice a week for the first 2 weeks and every week or every other week during maintenance therapy. Given fluctuations in ANC values, blood sampling should be performed before the next dose of the drug to determine the true maximum decrease in ANC (nadir).

In patients with infectious diseases and bone marrow infiltration with infectious agents (e.g., Mycobacterium avium complex) or with tumor involvement of the bone marrow (lymphoma), Filgrastim therapy is carried out simultaneously with therapy directed against these conditions.

In patients with sickle cell anemia, blood tests should be performed regularly and the possibility of splenomegaly and vascular thrombosis should be considered.

Patients with bone pathology and osteoporosis receiving continuous Filgrastim treatment for more than 6 months are indicated for bone density monitoring.

The effect of Filgrastim in patients with a significantly reduced number of myeloid progenitor cells is unknown. Filgrastim 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.

A history of pneumonia or pulmonary infiltrates may be a risk factor for the occurrence of interstitial lung disease during Filgrastim therapy. The appearance of cough, fever, and shortness of breath associated with the appearance of pulmonary infiltrates may be the first signs of the development of adult respiratory distress syndrome. If these signs appear, Filgrastim should be discontinued and appropriate treatment should be prescribed.

Effect on ability to drive vehicles and operate machinery

No effect of Filgrastim on the ability to drive vehicles and operate machinery has been noted.

Overdose

No cases of Filgrastim overdose have been reported. 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 efficacy and safety of administering Filgrastim on the same day as cytotoxic chemotherapeutic agents have not been established. Due to the high sensitivity of actively proliferating myeloid cells to antitumor cytotoxic drugs, it is not recommended to administer Filgrastim within 24 hours before or after the administration of these drugs.

There are isolated reports of increased severity of neutropenia with the simultaneous use of Filgrastim and fluorouracil.

There are currently no data on possible interactions with other hematopoietic growth factors and cytokines.

Given that lithium stimulates neutrophil release, the effect of Filgrastim may be enhanced when administered in combination. Studies on the interaction between lithium and Filgrastim have not been conducted.

Filgrastim is pharmaceutically incompatible with 0.9% sodium chloride solution.

When using Filgrastim for hematopoietic stem cell mobilization after chemotherapy, it should be taken into account that long-term administration of cytostatics such as melphalan, carmustine, and carboplatin may reduce mobilization efficacy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 2 years.

Transport at a temperature from 2°C (35.6°F) to 8°C (46.4°F) in thermal containers; do not freeze.

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.