Grasalva (Solution) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Lemery, S.A. de C.V. (Mexico)

Packaged By

SICOR BIOTECH, UAB (Lithuania)

ATC Code

L03AA02 (Filgrastim)

Active Substance

Filgrastim (Rec.INN registered by WHO)

Dosage Forms

	Grasalva	Solution for intravenous and subcutaneous administration 30 million IU/1 ml: syringe 1 ml
		Solution for intravenous and subcutaneous administration 48 million IU/0.8 ml: syringe 0.8 ml

Dosage Form, Packaging, and Composition

Solution for intravenous and subcutaneous administration clear, colorless.

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

1 ml – single-use glass syringes (1) – blister packs (1) complete with a sterile needle in a blister – cardboard packs.

0.8 ml – glass syringes (1) – blister packs (1) complete with a sterile needle in a blister – cardboard packs.

Clinical-Pharmacological Group

Leukopoiesis stimulant

Pharmacotherapeutic Group

Leukopoiesis stimulator

Pharmacological Action

Recombinant human G-CSF. Filgrastim has the same biological activity as endogenous human G-CSF and differs from the latter only in that it is a non-glycosylated protein with an additional N-terminal methionine residue. Filgrastim, obtained by recombinant DNA technology, is isolated from cells of the bacterium Escherichia coli, into the genetic apparatus of which the gene encoding the G-CSF protein has been introduced.

Human G-CSF is a glycoprotein that regulates the production of functionally active neutrophils and their release into the blood from the bone marrow. Filgrastim, which has G-CSF activity, 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 severe chronic neutropenia, in some cases, Filgrastim may also cause a slight increase in the number of circulating eosinophils and basophils compared to baseline values.

Within the range of recommended doses of filgrastim, a dose-dependent increase in the number of neutrophils with normal or increased chemotactic and phagocytic activity is observed. 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.

Filgrastim significantly reduces the frequency, severity and duration of neutropenia and febrile neutropenia after cytotoxic chemotherapy.

Filgrastim significantly reduces the duration of febrile neutropenia, the duration of antibiotic therapy and hospitalization after 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 and without reducing the duration of the febrile period in patients after myeloablative therapy followed by bone marrow transplantation.

The use of filgrastim, both alone and after chemotherapy, mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Autologous or allogeneic peripheral blood stem cell (PBSC) transplantation can be performed after high-dose cytostatic treatment either instead of bone marrow transplantation or in addition to it. PBSC transplantation accelerates the recovery of hematopoiesis, reducing the risk of hemorrhagic complications and the need for platelet mass transfusion.

The use of filgrastim in recipients of mobilized allogeneic PBSCs leads to faster normalization of hematological parameters compared to allogeneic bone marrow transplantation. The normal platelet count is restored and the need to control thrombocytopenia is eliminated.

Administration of filgrastim to healthy donors at 10 mcg/kg/day subcutaneously daily for 4-5 days usually allows, with two leukapheresis procedures, to obtain a number of PBSCs equal to or exceeding 4×10⁶ CD34+ cells/kg of recipient body weight.

In children and adults with severe chronic neutropenia (congenital, cyclic or idiopathic), Filgrastim consistently increases the number of neutrophils in the peripheral blood, reducing the frequency of infections and associated complications. Prescribing filgrastim to patients with HIV infection helps maintain normal neutrophil levels, which contributes to the systematic implementation of antiviral and/or myelosuppressive therapy. No signs of increased HIV replication were observed during treatment with filgrastim.

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

Pharmacokinetics

Both with intravenous and subcutaneous administration of the drug, Filgrastim is eliminated according to first-order kinetics. The mean T_1/2 of filgrastim from blood serum is about 3.5 hours, clearance is 0.6 ml/min/kg. With long-term use of filgrastim for up to 28 days after autologous bone marrow transplantation, no signs of accumulation or increase in T_1/2 were observed.

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

Indications

As a prophylactic and therapeutic agent:

• To reduce the duration of neutropenia and the incidence of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignant diseases (except for chronic myeloid leukemia and myelodysplastic syndrome);
• To reduce the duration of neutropenia in patients receiving myeloablative therapy followed by bone marrow transplantation;
• For the mobilization of peripheral blood stem cells in patients;
• For long-term therapy to increase the number of neutrophils and reduce the frequency and duration of infectious complications in children and adults with severe chronic congenital, cyclic or idiopathic neutropenia (absolute neutrophil count ≤0.5×10⁹/L) and a history of severe or recurrent infections;
• To reduce the risk of bacterial infections in persistent neutropenia (absolute neutrophil count ≤1×10⁹/L) in patients with advanced HIV infection when other means of controlling neutropenia are ineffective;
• For the mobilization of PBSCs in healthy donors for allogeneic PBSC transplantation.

ICD codes

Dosage Regimen

Patients receiving cytotoxic chemotherapy for malignant diseases

The recommended dose is 0.5 million IU (5 mcg)/kg body weight once daily. The first dose should be administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. Grasalva can be administered by daily subcutaneous injections or daily short (30-minute) intravenous infusions in a 5% dextrose (glucose) solution. . The subcutaneous route of administration is preferable; with intravenous administration, the effect of filgrastim may be shortened.

Grasalva is administered daily until the neutrophil count exceeds the expected minimum (nadir) and reaches the range of normal values. In patients receiving cytotoxic chemotherapy for solid tumors, lymphomas and lymphocytic leukemia, the duration of therapy is up to 14 days. After induction and consolidation therapy for acute myeloid leukemia, the duration of Grasalva use may increase to 38 days. The duration of treatment with Grasalva depends on the type, doses and regimen of cytotoxic chemotherapy used.

A transient increase in the number of neutrophils is usually observed 1-2 days after starting treatment with Grasalva. To achieve a stable therapeutic effect, it is necessary to continue therapy with Grasalva until the neutrophil count exceeds the expected minimum (nadir) and reaches a normal level. It is not recommended to discontinue treatment prematurely, before the neutrophil count passes through the nadir.

Patients receiving myeloablative therapy followed by bone marrow transplantation

The initial dose – 1 million IU (10 mcg)/kg body weight per day – is prescribed as a 30-minute or continuous 24-hour intravenous infusion or a continuous 24-hour subcutaneous infusion. For intravenous and subcutaneous infusion, Grasalva is diluted with 20 ml of 5% dextrose (glucose) solution.

The first dose of Grasalva should be administered no earlier than 24 hours after chemotherapy and no later than 24 hours after bone marrow transplantation.

After the moment of maximum decrease in the number of neutrophils has passed, the daily dose should be adjusted depending on the dynamics of the neutrophil content as follows

If during treatment the absolute neutrophil count decreases to a level of less than 1 x 10⁹/L, the drug dose is increased again in accordance with the above scheme.

Mobilization of PBSCs in patients receiving myelosuppressive or myeloablative therapy followed by autologous PBSC transfusion

For PBSC mobilization performed as monotherapy, the drug is prescribed at a dose of 1 million IU (10 mcg)/kg/day as a continuous 24-hour subcutaneous infusion or by subcutaneous injection once daily for 5-7 consecutive days. For infusion, Grasalva is diluted with 20 ml of 5% dextrose (glucose) solution. . Usually one or two leukapheresis procedures on the 5th or 6th days are sufficient. In case of additional leukapheresis, administration of Grasalva at the same dose must be continued until the final leukapheresis.

For PBSC mobilization after myelosuppressive chemotherapy, 0.5 million IU (5 mcg)/kg/day is prescribed by daily subcutaneous injections, starting from the first day after completion of chemotherapy and until the neutrophil count passes the expected minimum and reaches normal values. Leukapheresis should be performed during the period of increasing neutrophil count from 0.5 x10⁹/L to >5 x10⁹/L. For patients who have not received intensive chemotherapy, one leukapheresis procedure is usually sufficient. In some cases, additional leukapheresis procedures are recommended.

Patients with severe chronic neutropenia (SCN)

For congenital neutropenia, Grasalva is prescribed at an initial dose of 1.2 million IU (12 mcg)/kg/day by subcutaneous injections once or divided into several administrations.

For idiopathic or cyclic neutropenia, the drug is prescribed at an initial dose of 0.5 million IU (5 mcg)/kg/day subcutaneously once or by several administrations.

Dose adjustment: Grasalva is administered daily until a stable excess of the neutrophil count of 1.5×10⁹/L is achieved. After achieving a therapeutic effect, the minimum effective dose to maintain this level is determined. Long-term daily administration of the drug is required to maintain the required neutrophil count. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the effect of therapy. Subsequently, individual dose adjustment is carried out every 1-2 weeks to maintain the average neutrophil count in the range from 1.5×10⁹/L to 10×10⁹/L. In patients with severe infections, a regimen with a faster dose increase can be used. The safety of using Grasalva for long-term treatment of patients with SCN at doses above 2.4 million IU (24 mcg)/kg/day has not been established.

Patients with HIV infection

To restore the neutrophil count, the initial dose is 0.1 million IU (1 mcg)/kg/day daily by a single subcutaneous injection, with the dose increased to a maximum of 0.4 million IU (4 mcg)/kg/day – until the neutrophil count normalizes (more than 2×10⁹/L).

To maintain a normal neutrophil count: after the neutropenia has ended, the minimum effective dose of the drug to maintain a normal neutrophil count is determined. It is recommended to start with the administration of 30 million IU (300 mcg) (regardless of body weight) subcutaneously every other day. It is necessary to maintain the neutrophil count above 2.0×10⁹/L, so subsequent individual dose adjustment may be required depending on the patient’s neutrophil level. Usually, this dose is sufficient to be administered 3 times a week; sometimes, long-term administration of the drug is required to maintain the neutrophil count >2.0×10⁹/L.

Mobilization of PBSCs in healthy donors for allogeneic PBSC transplantation

The recommended dose is 1 million IU (10 mcg)/kg/day by 24-hour subcutaneous infusion or subcutaneous injection once daily for 4-5 consecutive days. Leukapheresis is performed from the 5th day and, if necessary, up to the 6th day in order to obtain 4×10⁶ CD34+ cells/kg of recipient body weight.

There are no data on the safety and efficacy of filgrastim use in donors under 16 and over 60 years of age.

In children with SCN and oncological diseases, Grasalva is used in the same doses as in adults receiving myelosuppressive cytotoxic chemotherapy.

For elderly patients, no specific recommendations have been established due to insufficient research.

Rules for preparation and administration of infusion solutions

Grasalva should be diluted only with 5% dextrose (glucose) solution; dilution with 0.9% sodium chloride solution is not allowed.

The drug after dilution may be adsorbed onto glass and plastics.

If Grasalva is diluted to a concentration of less than 1.5 million IU (15 mcg) in 1 ml, human serum albumin must be added to prevent adsorption, so that the final albumin concentration is 2 mg/ml. For example, when diluting a total dose of Grasalva of less than 30 million IU (300 mcg) to a final solution volume of 20 ml, 0.2 ml of 20% albumin solution should be added. Grasalva should not be diluted to a concentration of less than 0.2 million IU (2 mcg)/ml.

Grasalva properly diluted with 5% dextrose (glucose) solution or 5% dextrose (glucose) solution with albumin is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (copolymer of polypropylene and polyethylene) and polypropylene.

The diluted Grasalva solution can be stored at a temperature from 2°C (35.6°F) to 8°C (46.4°F) for no more than 24 hours.

After use, the syringe with the remaining solution is destroyed.

The drug should be administered daily at the same time. To avoid pain, it is best to change the injection site daily.

Adverse Reactions

Patients with oncological diseases

Musculoskeletal system often – bone and muscle pain, usually mild or moderate (10%), but sometimes severe (3%), in most cases relieved by conventional analgesics.

Urinary system urinary disorders (mainly mild or moderate dysuria).

Metabolism: reversible, dose-dependent and usually mild or moderate increase in LDH, ALP, serum uric acid, GGT levels in 50%, 35%, 25% and 10% of patients, respectively.

Cardiovascular system rarely – transient decrease in blood pressure, not requiring treatment.

Dermatological reactions in some cases – cutaneous vasculitis, the mechanism of which is unclear.

Respiratory system: in some patients, the formation of infiltrates in the lungs was noted, leading to the development of pulmonary failure or adult respiratory distress syndrome, which could be fatal.

Allergic reactions rare cases of symptoms indicating allergic-type reactions have been described, with about half of them associated with the administration of the first dose. Such reactions were more frequent after intravenous administration of the drug. Sometimes resumption of treatment was accompanied by a relapse of symptoms.

Other in some cases – exacerbation of rheumatoid arthritis.

According to randomized placebo-controlled clinical trials, Filgrastim did not increase the frequency of adverse reactions to cytotoxic chemotherapy. Adverse events, noted with equal frequency in patients receiving Filgrastim/chemotherapy and placebo/chemotherapy, included nausea, vomiting, alopecia, diarrhea, lethargy, general weakness, anorexia, inflammation of the mucous membranes, headache, cough, skin rash, chest pain, sore throat, constipation and nonspecific pain (without a specified diagnosis).

Sometimes in patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation, vascular disorders were noted, such as veno-occlusive disease and water balance disorders. Their causal relationship with filgrastim has not been established.

Cases of Sweet’s syndrome (acute febrile neutrophilic dermatosis) have been reported. The causal relationship with filgrastim in these cases is unknown, since a significant proportion of them were in leukemia patients, and Sweet’s syndrome is characteristic of this disease.

Patients with SCN

Musculoskeletal system most often – bone and muscle pain; less than 2% – joint pain, osteoporosis.

From the digestive system: splenomegaly is possible, which may progress in a small number of patients; less than 10% – diarrhea shortly after initiation of filgrastim therapy; less than 2% – hepatomegaly.

From the hematopoietic system thrombocytopenia is possible; less than 10% – anemia and epistaxis after long-term therapy.

From the CNS less than 10% – headaches shortly after initiation of filgrastim therapy; less than 2% – headaches during subsequent therapy.

From metabolism transient and asymptomatic increases in serum uric acid, LDH and ALP activity, and a transient moderate decrease in postprandial blood glucose levels are possible.

Dermatological reactions less than 2% – alopecia, skin rash; 2% – cutaneous vasculitis during long-term therapy.

From the urinary system very rarely during long-term therapy – proteinuria and/or hematuria.

Other less than 2% – injection site reactions.

The frequency of the aforementioned symptoms decreased over time in some patients with SCN.

HIV-infected patients

From the musculoskeletal system most commonly – bone and muscle pain, usually mild or moderate. The frequency of symptoms is approximately the same as in cancer patients.

From the digestive system less than 3% – mild or moderate splenomegaly with a favorable clinical course; hypersplenism, as well as splenectomy, did not occur in any of the patients. Since splenomegaly is common in HIV infection and AIDS, the relationship of this phenomenon with filgrastim administration remains unclear.

Healthy donors during PBSC mobilization

From the musculoskeletal system most commonly – mild or moderate bone and muscle pain; in isolated cases – symptoms of arthritis exacerbation.

From the hematopoietic system 41% – leukocytosis (more than 50×10⁹/L); 35% – transient thrombocytopenia (platelet count less than 100×10⁹/L) was observed after filgrastim administration and leukapheresis.

From metabolism in isolated cases – asymptomatic increases in ALP, LDH, AST activity and uric acid levels.

From the CNS headache.

From the digestive system in isolated cases – splenic rupture.

Other very rarely – severe allergic reactions.

Contraindications

• Chronic myeloid leukemia and myelodysplastic syndrome;
• Severe congenital neutropenia (Kostmann syndrome) with cytogenetic abnormalities;
• Use for the purpose of increasing doses of cytotoxic chemotherapeutic drugs above recommended levels;
• Lactation (breastfeeding);
• Hypersensitivity to the drug components.

Use in Pregnancy and Lactation

The safety of filgrastim in pregnant women has not been established. There are literature data on the penetration of filgrastim through the placental barrier. The use of Grasalva during pregnancy is not recommended; however, if it is necessary to use the drug, the expected benefit of therapy for the mother and the potential risk to the fetus should be carefully assessed.

In experimental studies in rats and rabbits, no data on the teratogenicity of filgrastim were obtained. An increased frequency of miscarriages was observed in rabbits, but no developmental abnormalities were noted.

It is not recommended to use Grasalva during lactation (breastfeeding).

Use in Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment.

Use in Renal Impairment

No dose adjustment is required in patients with renal impairment.

Pediatric Use

There are no data on the safety and efficacy of filgrastim use in donors under 16 years of age.

In childrenwith SCN and cancer, Grasalva is used in the same doses as in adults receiving myelosuppressive cytotoxic chemotherapy.

Geriatric Use

No specific recommendations have been established for elderly patients due to insufficient number of studies.

There are no data on the safety and efficacy of filgrastim use in donors over 60 years of age.

Special Precautions

Treatment with Grasalva should be carried out only in cooperation with an oncology center with specialists experienced in the treatment of patients with hematological diseases with filgrastim and with the necessary diagnostic capabilities.

Mobilization and apheresis procedures should be carried out in cooperation with an oncology or hematology center with specialists with sufficient experience in this field and the ability to adequately monitor hematopoietic progenitor cells.

Filgrastim may cause the growth of myeloid cells in vitro. Similar effects may be observed in vitro and on some non-myeloid cells.

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

The safety and efficacy of filgrastim in patients with secondary acute myeloid leukemia have not been sufficiently studied, therefore Grasalva should be prescribed to them with caution.

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

Patients with concomitant bone pathology and osteoporosis receiving continuous treatment with Grasalva for more than 6 months should be monitored for bone mineral density.

No dose adjustment is required in patients with renal or hepatic impairment.

During treatment with filgrastim, the development of adult respiratory distress syndrome is possible, the first signs of which may be cough, fever and dyspnea. The formation of pulmonary infiltrates detectable by radiography and respiratory dysfunction are also possible. In this case, Grasalva should be discontinued and necessary treatment should be prescribed.

Special precautions in patients with malignant diseases

Leukocytosis

In patients receiving cytotoxic chemotherapy, given the possible risk associated with high leukocytosis, the leukocyte count should be regularly monitored during treatment with Grasalva. During the first 2-3 days of treatment, it is recommended to determine the neutrophil count daily, then during the first two weeks of therapy – at least 2 times a week, and during maintenance therapy – at least once a week or every other week. If the leukocyte count exceeds 50×10⁹/L after passing the expected nadir, treatment with Grasalva should be discontinued immediately. However, if Filgrastim is used for PBSC mobilization, the drug is discontinued or the dose is reduced if the leukocyte count exceeds 70×10⁹/L.

Risk associated with high-dose chemotherapy

Particular caution should be exercised when treating patients receiving high-dose chemotherapy, since in these cases an improvement in the outcome of the malignant neoplasm has not been established, while chemotherapeutic drugs in increased doses have more pronounced toxicity with the development of cardiac, pulmonary, neurological and dermatological reactions.

Monotherapy with filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapeutic drugs (e.g., full doses according to regimens), the patient may be at greater risk of developing thrombocytopenia and anemia, so it is recommended to regularly determine the platelet count and hematocrit.

Particular caution should be exercised when using single-agent or combination chemotherapy regimens known for their ability to cause severe thrombocytopenia.

The use of PBSC mobilized with filgrastim reduces the severity and duration of thrombocytopenia after myelosuppressive or myeloablative chemotherapy.

Other precautions

The effect of filgrastim in patients with a significantly reduced number of myeloid progenitor cells has not been studied. The drug 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, or with tumor infiltration of the bone marrow), the degree of increase in neutrophil count may be reduced.

The sorbitol contained in the drug in an amount of 50 mg/ml should not have a negative effect on patients with hereditary fructose intolerance. However, Grasalva should be used with caution in such patients.

Special precautions in patients undergoing PBSC mobilization

Mobilization

No prospective randomized studies comparing the 2 recommended mobilization methods (Filgrastim alone or in combination with myelosuppressive chemotherapy) in the same patient population have been conducted. Individual patient characteristics in different studies and the degree of discrepancy in the results of laboratory determination of CD34+ cell count make direct comparison of the results of these studies difficult. Therefore, it is difficult to recommend an optimal method. The choice of mobilization method should be made depending on the treatment goals for a given patient.

Before prescribing cytotoxic agents

In patients who have previously received active myelosuppressive therapy, sufficient activation of PBSC to the recommended minimum level (> 2 x10⁶ CD34+ cells/kg) or acceleration of platelet count normalization may not occur.

Some cytostatics are particularly toxic to hematopoietic progenitor cells and may negatively affect their mobilization. Agents such as melphalan, carmustine and carboplatin, if administered for a long time prior to stem cell mobilization attempts, may reduce its effectiveness. However, the use of melphalan, carboplatin or carmustine in combination with filgrastim has been effective in activating stem cells. If PBSC transplantation is planned, it is recommended to schedule stem cell mobilization at an early stage of the treatment course. Particular attention should be paid to the number of stem cells activated in such patients prior to high-dose chemotherapy. If the mobilization results according to the above criteria are insufficient, alternative treatment options not requiring the use of progenitor cells should be considered.

Assessment of the number of mobilized peripheral blood stem cells

When assessing the number of PBSC mobilized in patients with filgrastim, special attention should be paid to the quantification method. The results of flow cytometric analysis of CD34+ cell count vary depending on the specific methodology, so caution should be exercised regarding recommendations on their number based on studies conducted in other laboratories.

The rate of platelet count normalization after high-dose chemotherapy depends on the number of CD34+ cells reinfused. The recommended minimum number of PBSC is > 2 x10⁶ CD34+ cells/kg. A number of progenitor cells exceeding this value appears to be associated with faster normalization, while a number below the specified value is associated with slower blood count normalization.

Special precautions in healthy donors undergoing PBSC mobilization

PBSC mobilization is not indifferent to the health of donors and is used only before transplantation of allogeneic progenitor cells.

PBSC mobilization can be performed in donors only if they meet the usual clinical and laboratory criteria for hematopoietic progenitor cell donation, with particular attention to hematological parameters and the presence of infectious diseases.

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

If more than one leukapheresis is required, special attention should be paid to donors whose platelet count before leukapheresis 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.

Grasalva should be discontinued or the dose reduced if the leukocyte count is more than 70×10⁹/L.

The donor observation period should be long to assess drug safety. Donors who have taken Filgrastim for PBSC mobilization should be monitored until hematological parameters normalize.

Furthermore, the risk of stimulating a malignant myeloid clone cannot be excluded. Apheresis centers are recommended to register and monitor PBSC donors to ensure further collection of data on the safety of the drug use.

After filgrastim administration, splenic rupture is possible in healthy donors. In this regard, it is recommended to monitor their spleen size (palpation, ultrasound). The possibility of splenic rupture should be considered in case of complaints of pain in the upper left part of the abdomen or in the left shoulder.

Special precautions in recipients of allogeneic PBSC mobilized with filgrastim

Literature data indicate that the immunological interaction of allogeneic PBSC and the recipient is characterized by a greater degree of risk of developing acute graft-versus-host reaction compared to bone marrow transplantation.

Special precautions in patients with SCN

Blood count examination

Platelet count should be carefully monitored, especially during the first few weeks of filgrastim therapy. If the patient exhibits 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 may also be observed, including anemia and a transient increase in the number of myeloid progenitor cells.

Transformation to leukemia or myelodysplastic syndrome

Particular caution should be exercised when diagnosing severe chronic neutropenias; they must be differentiated from other hematological diseases such as aplastic anemia, myelodysplasia and myeloid leukemia. Before starting treatment, a complete clinical blood count with leukocyte differential and platelet count should be performed, and the bone marrow morphological picture and karyotype should be examined.

If cytogenetic abnormalities appear in patients with SCN, the benefits and risks of continuing therapy should be carefully assessed. If myelodysplastic syndrome (MDS) or leukemia develops, Grasalva should be discontinued. It is currently unclear whether long-term treatment with filgrastim in patients with severe chronic neutropenia predisposes to the development of cytogenetic abnormalities, MDS and leukemia. Such patients are recommended to undergo regular (approximately every 12 months) morphological and cytogenetic studies of the bone marrow.

Other cases

Such causes of transient neutropenia as viral infections should be excluded.

Splenomegaly is a direct consequence of filgrastim treatment; dose reduction slows or stops the increase in spleen size. Spleen size should be monitored regularly; abdominal palpation is sufficient to detect abnormal splenic volume enlargement.

Hematuria and/or proteinuria were detected in a small number of patients; regular laboratory urine tests should be performed to monitor them.

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

Special precautions in HIV infection

Blood cell examination

Neutrophil count should be carefully monitored, especially during the first few weeks of filgrastim therapy. In some patients, the therapeutic effect appears very quickly after the first injection and the neutrophil count increases significantly. It is recommended to monitor the neutrophil count during the first 2-3 days of filgrastim therapy daily, then during the first two weeks of therapy – at least 2 times a week, and during maintenance therapy – at least once a week or every two weeks.

If the dose of 30 million IU (300 mcg) per day is not administered to the patient daily, strong fluctuations in the neutrophil count begin to be observed after some time. To determine a decrease in neutrophil count or the true nadir level, it is recommended to take the patient’s blood samples for analysis immediately before the administration of the next dose of the drug.

Risk associated with high-dose myelosuppressive therapy

Monotherapy with filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using a larger amount of chemotherapeutic drugs or their high doses in combination with filgrastim, the patient may be at greater risk of developing thrombocytopenia and anemia, in connection with which it is recommended to regularly determine blood cell counts, as indicated above.

Infections and malignant neoplasms causing myelosuppression

In patients with neutropenia caused by bone marrow infiltration with infectious agents (e.g., disseminated Mycobacterium avium complex infection) or tumor involvement of the bone marrow (lymphoma), specific treatment should be applied in addition to filgrastim administration. The effect of filgrastim on neutropenia caused by infectious agents or malignant tumors of the bone marrow has not been sufficiently studied.

Special precautions in patients with sickle cell anemia

Literature data indicate that a high leukocyte count in sickle cell anemia is a prognostically unfavorable factor. Therefore, Filgrastim should be prescribed with caution to patients with sickle cell anemia, and relevant clinical and laboratory parameters should be carefully monitored during therapy, with particular attention to possible splenomegaly and the development of vascular thrombosis.

Effect on ability to drive and operate machinery

The effect on the ability to drive vehicles or operate machinery has not been established.

Overdose

The effect of Grasalva in case of overdose has not been established. After discontinuation of the drug, the number of circulating neutrophils usually first decreases and then returns to normal.

Drug Interactions

The safety and efficacy of administering filgrastim on the same day as myelosuppressive antitumor drugs have not been established. Due to the sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapeutic drugs, it is not recommended to administer Filgrastim within 24 hours before their use or earlier than 24 hours after the end of administration of these drugs.

There are isolated reports of increased severity of neutropenia with simultaneous administration of filgrastim and 5-fluorouracil.

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

Lithium, which stimulates neutrophil release, may enhance the effect of filgrastim. This interaction has not been studied, but there is no information on its adverse consequences.

Pharmaceutical Interaction

Grasalva is pharmaceutically incompatible with 0.9% sodium chloride solution.

Storage Conditions

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

Shelf Life

The shelf life is 2 years.

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.