Zarcio, 48 million units /0.5 ml 0.5 ml syringes 5 pcs

Phylgrastim is a highly purified non-glycosylated protein consisting of 175 amino acids, or recombinant human granulocytic colony-stimulating factor (r-h G-CSF). It is produced by the K12 strain of Escherichia coli, which has been genetically engineered to contain the human granulocytic colony-stimulating factor (G-CSF) gene.

Human G-CSF regulates the production and release of neutrophils from the bone marrow into the peripheral blood. Administration of filgrastim is accompanied by a significant increase in the number of neutrophils in the vascular bed within 24 hours, as well as a slight increase in the number of monocytes.

In some cases, an increase in eosinophils and basophils is also noted, but eosinophilia and basophilia may be present in some patients before the start of treatment. The increase in neutrophil counts with filgrastim in the recommended dose range is dose-dependent. Released neutrophils have normal or increased functional activity as evidenced by chemotaxis and phagocytosis tests.

After the end of therapy, the number of neutrophils in peripheral blood decreases by 50% within 1-2 days and returns to a normal value within the next 1-7 days. Like other factors stimulating hematopoiesis, in vitro studies it has been shown that G-CSF has the ability to stimulate endothelial cells because they have specific receptors for G-CSF.

At the same time it was found that G-CSF is an inducer of angiogenesis of vascular endothelial cells and accelerates neutrophil transport through the vascular endothelium.

The use of filgrastim in patients receiving cytotoxic drugs is accompanied by a significant reduction in the frequency, severity and duration of neutropenia and febrile neutropenia and allows the use of antibiotics at lower doses compared to patients receiving only cytotoxic chemotherapy.

Limits the need and duration of hospital treatment in patients after induction chemotherapy for myeloleukemia or myeloablative therapy followed by bone marrow transplantation. The incidence of body temperature did not decrease in patients after myeloablative therapy followed by a bone marrow transplant.

The use of Zarcio both in monotherapy and after chemotherapy mobilizes the output of hematopoietic stem cells into the peripheral blood stream. Autologous or allogeneic peripheral blood stem cell (PBSC) transplantation is performed after high-dose cytostatic therapy, either instead of or in addition to bone marrow transplantation.

Bone marrow transplantation can also be prescribed after (high-dose) myelosuppressive cytotoxic therapy. The use of hMSCs mobilized with Zarsio accelerates recovery of hematopoiesis, reduces the severity and duration of thrombocytopenia, reduces the risk of hemorrhagic complications and the need for platelet transfusions after myelosuppressive or myeloablative therapy.

The use of Zarsio in children and adults with severe congenital neutropenia (recurrent, idiopathic) promotes a steady increase of the number of active neutrophils in peripheral blood and reduces the incidence of infectious and other complications.

The use of Zarsio in patients with HIV infection maintains the number of neutrophils within normal values, which allows to observe the necessary dosing regime of antiretroviral drugs and means of myelosuppressive therapy. There are no signs of increased HIV replication when using Zarsio.

Indications

– reduction of neutropenia duration and frequency of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignancy (except for chronic myeloleukosis and myelodysplastic syndromes) as well as reduction of neutropenia duration in patients receiving myeloablative therapy with subsequent bone marrow transplantation, which is considered to be an increased risk factor for long-term severe neutropenia.

The efficacy and safety of filgrastim are comparable in cytotoxic chemotherapy in children and adults;

– mobilization of peripheral stem cells (PSCs), including after myelosuppressive therapy, as well as mobilization of peripheral stem cells from healthy donors (allogeneic PSCC);

– hereditary recurrent or idiopathic neutropenia in adults and children with an absolute neutrophil count of 0.5 × 109/L or less, with a history of severe recurrent infections, long-term treatment with filgrastim is indicated to increase neutrophil counts and to reduce the frequency and duration of adverse effects associated with infectious complications;

Prevention of bacterial infections and treatment of persistent neutropenia (absolute neutrophil counts of 1 × 109/L or less) in patients with advanced HIV infection when other treatments have failed.

Active ingredient

How to take, the dosage

The Zarsio therapy can be performed in collaboration with oncology center physicians who have experience with granulocyte colony-stimulating factor (G-CSF) therapy, as well as experience treating patients with hematologic diseases, in a treatment facility with the necessary diagnostic equipment.

The mobilization and apheresis procedures must be performed in collaboration with specialists from the Hematology Oncology Center who have adequate experience in this field and the ability to monitor hematopoietic progenitor cells as needed.

The drug Zarsio is available in the following dosages: 30 million IU/0.5 ml (0.3 mg) and 48 million IU/0.5 ml (0.48 mg).

Cytotoxic chemotherapy

The recommended daily dose of Zarsio is 0.5 million IU/kg (0.005 mg/kg) of body weight.

The first dose of the drug should not be given before 24 hours after a course of cytotoxic chemotherapy.

The drug Zarsio should be given daily until the total neutrophil count in the clinical blood count exceeds the expected nadir and reaches normal values.

After chemotherapy for solid tumors, lymphoma and lympholeukemia, the duration of treatment is up to 14 days until these values are reached. After induction and consolidation therapy for acute myeloid leukemia the duration of treatment may be significantly longer (up to 38 days) and is determined depending on the type, dose and regimen of cytotoxic chemotherapy used.

In patients receiving cytotoxic chemotherapy, a transient increase in neutrophil counts is usually observed 1-2 days after the start of treatment with Zarcio. Nevertheless, in order to achieve a stable therapeutic effect, it is necessary to continue Zarzio therapy until neutrophil counts exceed the expected nadir and reach normal values. Premature termination of treatment with the drug before the neutrophil count has crossed the nadir is not recommended.

Patients receiving myeloablative therapy followed by a bone marrow transplant: The recommended starting dose of Zarcio is 1 million IU/kg (0.01 mg) of body weight/day.

The first dose of Zarsio should be given no earlier than 24 hours after cytotoxic chemotherapy and no later than 24 hours after a bone marrow transplant.

Dose adjustment: After a maximum decrease in neutrophil count (nadir), the daily dose of Zarcio should be adjusted according to the change in neutrophil count as follows.

Table 1. Adjustment of Zarcio drug dose in response to achievement of nadir

Peripheral blood stem cell (PBSC) mobilization

Patients receiving myelosuppressive or myeloablative therapy followed by autologous PBSC transplantation

For PBSC mobilization using Zarzio as monotherapy, the recommended dose is 1 million units/kg (0.01.001 mg/kg). IU/kg (0.01 mg/kg) of body weight/day for 5-7 consecutive days. One or two sessions of leukapheresis are performed on days 5 and 6. In some cases, 1 additional session of leukapheresis is performed. The dose of Zarcio should not be changed before the final leukapheresis.

To mobilize PSCC after myelosuppressive chemotherapy, the recommended dose of Zarcio is 0.5 million IU/kg (0.005 mg/kg) of body weight daily, starting on day 1 after completion of chemotherapy and until neutrophil counts have passed the expected nadir and have reached normal.

Leukapheresis should be performed during the period of increasing ACH from <0.5 ×109/l to >5 × 109/l. Patients who have not received intensive chemotherapy should receive 1 session of leukapheresis. Additional leukapheresis sessions are recommended in individual cases.

Healthy donors before allogeneic HSCC transplantation

For HSCC mobilization before allogeneic HSCC transplantation in healthy donors the recommended dose of Zarcio is 1 million IU/kg (0.01 mg/kg) of body weight per day by injection for 4-5 consecutive days. Leukapheresis is carried out from day 5 and, if necessary, continues until day 6 in order to obtain 4 × 106 CD34+ cells/kg of the recipient’s body weight.

Severe chronic neutropenia (TCN)

Congenital neutropenia

The recommended starting dose is 1.2 million IU/kg (0.012 mg/kg) of body weight/day once or in fractional doses.

Idiopathic and recurrent neutropenia

The recommended starting dose is 0.5 million IU/kg (0.005 mg/kg) of body weight/day in a single or divided dose.

Preparation dosage selection

Zarzio is given daily until a neutrophil count of 1.5 × 109 is achieved and stable. Once a therapeutic effect has been achieved, a minimum effective dose to maintain this level is determined. Prolonged daily administration of the drug is required to maintain the desired neutrophil count.

After 1-2 weeks of treatment, the initial dose may be doubled or halved depending on the effectiveness of therapy. Subsequently, individual dose adjustments are made every 1 to 2 weeks to maintain an average neutrophil count between 1.5 × 109 and 10 × 109. In patients with severe infections, a regimen with a more rapid dose increase may be used.

In 97% of patients who responded positively to treatment, full therapeutic effect is observed when doses up to 24 mcg/kg/day are administered. The daily dose of Zarsio should not exceed 24 mcg/kg/day.

HIV infection

Reconstitution of neutrophil counts

The recommended starting dose of Zarsio is 0.1 million IU/kg (0.001 mg/kg) of body weight/day with increasing the dose to a maximum of 0.4 million IU/kg (0.004 mg/kg) of body weight until neutrophil count normalization (ACH > 2 × 109). Normalization of neutrophil counts usually occurs after 2 days. In rare cases (<10% of patients) for restoration of neutrophil count the drug dose can be increased up to 1 million units/kg (0.01 mg/kg) of body weight/day.

Maintenance of normal neutrophil counts

After therapeutic effect is achieved, maintenance dose of 0.3 mg/day 2-3 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 of > 2 × 109/L.

Particular categories of patients

Patients with impaired renal/liver function

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

Children with severe chronic neutropenia (TCN) and malignancies

When used in pediatric patients with TCN and cancer, the safety profile of Zarsio did not differ from that of adults. Dosing recommendations for pediatric patients are the same as for adults receiving myelosuppressive cytotoxic chemotherapy.

Elderly patients

Because of the limited number of elderly patients in clinical trials, there are no specific recommendations for the use of Zarsio in elderly patients. No additional studies have been performed in this category of patients.

Means of administration

Cytotoxic chemotherapy

Zarcio is given as a pelvic injection or intravenous infusion for 30 minutes once daily. For additional information on dilution of the drug in 5% (50 mg/ml) dextrose solution for IV administration, see section “Special Precautions”. In most cases, the p/c route of administration is preferable.

The duration of effect may be shortened if a single dose is administered intravenously. The clinical significance of these data with regard to the use of multiple doses of the drug has not been established. The choice of route of administration depends on the characteristics of the individual clinical situation and is determined for each patient individually.

Patients receiving myeloablative therapy followed by bone marrow transplantation

The drug Zarsio is diluted in 20 ml of 5% (50 mg/ml) dextrose solution and given as a short IV infusion over 30 minutes or as a long term p/v or IV infusion over 24 hours. For additional instructions on dilution of the drug in 5% dextrose solution (50 mg/ml) for IV infusion, see section “Special Precautions”.

PSCC mobilization.

For mobilization of HSCC in patients undergoing myelosuppressive or myeloablative therapy followed by autologous HSCC transplantation, Zarcio may also be administered as a prolonged p/c infusion for 24 hours. Before infusion, the drug is diluted in 20 ml of 5% (50 mg/ml) dextrose solution. Additional instructions for dilution of the drug in 5% (50 mg/ml) dextrose solution for infusion are given in the section “Special notes”.

TXP/HIV infection

The initial dose is 0.1-0.4 million IU (0.001-0.004 mg/kg) once daily by injection until neutrophil count normalizes (usually within 2 days). After therapeutic effect is achieved, the maintenance dose is 30 million IU (0.3 mg)/day every other day. Thereafter, individual dose adjustment and long-term therapy with Zarcio may be required to maintain neutrophil count > 2 ×10%.

Interaction

The safety and efficacy of Zarsio administration on the same day as myelosuppressive cytotoxic chemotherapy have not been established. Because of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, administration of Zarsio 24 hours before or after administration of these drugs is not recommended.

The severity of neutropenia may be increased if Zarsio and fluorouracil are administered concomitantly.

Possible interaction with other hematopoietic growth factors and cytokines is unknown.

With lithium stimulating the release of neutrophils, it is possible that the effects of Zarcio may be enhanced with combined administration, but no such studies have been conducted.

Pharmaceutical incompatibilities mean that Zarsio should not be mixed with 0.9% sodium chloride solution.

Directions for use

Before using the drug, a visual check of the contents in the pre-filled syringe is performed. The solution should be clear with no visible particles. The product does not contain preservatives. To avoid microbial contamination, please note that Zarsio in a pre-filled syringe is for single use only.

Recommendations for dilution

Zarcio may be administered diluted in 5% (50 mg/ml) dextrose solution. The drug must be diluted immediately before insertion, but dilution to below 0.2 million units/ml (0.002 mg/ml) is not recommended.

If diluted to a concentration of 1.5 million units/ml (0.015 mg/ml), additional human albumin must be added to reach a concentration of 2 mg/ml. For example, to reach a solution volume of 20 ml and a total dose of Zarcio of 30 million units (0.300 mg), an additional addition of an albumin solution of 200 mg/ml (20% solution) is required.

When diluted in dextrose solution, the drug is not absorbed by glass and other materials used for infusion.

Do not use sodium chloride solution to dilute Zarsio!

The drug can be stored at a temperature not exceeding 25°C for 72 hours during its shelf life.

After dilution, use within 24 hours.

Special Instructions

Treatment with Zarcio should only be performed 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.

Cytotoxic chemotherapy

The growth of malignant cells

Because G-CSF can stimulate growth of myeloid cells in vitro, the following information is recommended.

The safety and effectiveness of Zarsio in patients with myelodystplastic syndrome (MDS) and chronic myeloleukemia have not been established. Therefore, the use of Zarsio is not indicated in these diseases. Particular attention is needed in the differential diagnosis between blast-transforming chronic myeloleukemia and acute myeloleukemia.

Because data on the safety and efficacy of Zarsio in patients with secondary acute myelocytic leukemia (AML) are limited, Zarsio should be administered with caution.

The safety and efficacy of Zarcio, first prescribed in patients with OML under 55 years of age without cytogenetic abnormalities [t(8; 21), t(15; 17), and inv(16)], have not been established.

Leukocytosis

The number of leukocytes in the blood reaches or exceeds 100 × 109/L in less than 5% of patients who received a daily dose of Zarcio greater than 0.3 million units/kg (0.0003 mg/kg) of body weight. There are no reports of any adverse effects directly attributable to the development of leukocytosis of this severity. However, given the possible risks associated with severe leukocytosis, the leukocyte count should be monitored regularly during treatment with Zarsio. If the leukocyte count exceeds 50 × 109/L after reaching the expected nadir, the drug should be stopped immediately. If Zarsio is used to mobilize PSCC, the drug should be discontinued or the dose should be reduced when the white blood cell count increases to >70 × 109/L.

The risks associated with increasing the dose of ongoing chemotherapy

. Particular caution should be exercised when treating patients with malignancies who receive high doses of chemotherapy drugs, as no significant additional effect of high doses on disease outcome has been confirmed, but there is a high likelihood of more severe toxic effects on the cardiovascular, respiratory, nervous system, and skin (see (See the instructions for medical use of the chemotherapy drugs used).

Monotherapy with Zarsio does not prevent thrombocytopenia and anemia due to myelosuppressive chemotherapy. If higher doses of chemotherapy (e.g., full doses according to prescribed regimens) are used, the risk of severe thrombocytopenia and anemia increases. Regular monitoring of clinical blood counts such as hematocrit and platelet counts is recommended. Particular caution should be exercised when using single-component or combined chemotherapeutic agents that may cause severe thrombocytopenia.

The severity and duration of thrombocytopenia due to myelosuppressive or myeloablative chemotherapy has been shown to decrease when Zarsio is used to mobilize PSCC.

Other precautions

The efficacy of Zarsio in patients with significantly reduced myeloid progenitor cell counts has not been studied. Zarsio increases neutrophil counts by acting primarily on neutrophil precursor cells. Therefore, in patients with a reduced number of progenitor cells (e.g., as a result of intensive radiation therapy or chemotherapy, or due to bone marrow infiltration by tumor cells) the number of neutrophils produced may be lower. There are data on the development of graft vs. host reaction (GVHD) and lethal outcomes in patients treated with G-CSF after allogeneic bone marrow transplantation.

Peripheral blood stem cell (PBSC) mobilization

Pre-treatment with cytotoxic agents

. Patients who have previously received intensive myelosuppressive therapy may not experience an increase in the number of PSCCs sufficient to the recommended minimum level (≥2 × 106 CD34+ cells/kg) or an increase in platelet recovery rate when Zarsio is used to mobilize PSCCs.

Some cytotoxic agents are particularly toxic to hematopoietic progenitor cells and may have adverse effects on their mobilization. Prolonged use of drugs such as melphalan, carboplatin or carmustine before progenitor cell mobilization can lead to poorer results. However, simultaneous use of melphalan, carboplatin or carmustine with filgrastim is effective in mobilizing PSCC.

If PSCC transplantation is planned, it is recommended to perform stem cell mobilization early in the patient’s treatment. Particular attention should be paid to the number of progenitor cells activated in such patients prior to the use of high-dose chemotherapy drugs. If the results of mobilization according to the above criteria are insufficient, alternative therapies that do not require the use of progenitor cells should be considered.

The evaluation of the number of peripheral blood stem cells

When evaluating the number of PSCs mobilized in patients on Zarzio, special attention should be paid to the method of quantification. The results of flow cytometric analysis for CD34+ cell counts vary depending on the method chosen, and therefore, results obtained in different laboratories should be interpreted with caution.

Statistical analysis has shown that there is a complex but consistent relationship between the number of CD34+ cells injected in reinfusion and the rate of platelet count recovery after high-dose chemotherapy drugs. A minimum number of >2 ×106 CD34+ cells/kg results in sufficient hematological recovery and is recommended based on published data. A CD34+ cell count greater than this value is associated with a more rapid normalization; if the cell count does not reach this level, the blood counts recover more slowly.

Healthy donors before allogeneic PSCC transplantation

PSCC mobilization has no immediate clinical outcome for healthy donors and can only be performed for the purpose of allogeneic stem cell transplantation.

PSCC mobilization can only be administered to donors who meet standard clinical and laboratory criteria for stem cell donation, with special attention to hematologic parameters and the presence of infectious diseases.

The safety and efficacy of Zarcio in healthy donors under the age of 16 years and over 60 years has not been studied.

Transient thrombocytopenia (platelet count <100 × 109/l) after administration of Zarcio and leukapheresis was observed in 35% of donors. Among them, 2 cases of thrombocytopenia with platelet count <50 × 109/L after leukapheresis were observed. If more than one session of leukapheresis is required, donors with platelet counts less than 100 × 109/L should be particularly closely monitored; as a rule, apheresis is not recommended for neutrophil counts below 75 × 109/L.

Leukapheresis should not be performed on donors who are taking anticoagulants or who have hemostasis disorders.

The dose of Zarsio should be withdrawn or reduced if the white blood cell count increases >70 × 109/L.

In donors receiving G-CSF for PSCC mobilization, all clinical blood counts should be monitored regularly until they normalize.

In healthy donors treated with G-CSF, transient cytogenetic changes have been reported. The significance of these manifestations is not known.

The safety of Zarcio in healthy donors is still under review. At this time, the risk of malignant myeloid clone development in donors cannot be excluded. Medical centers performing apheresis procedures are advised to systematically monitor stem cell donors for a minimum of 10 years to monitor the safety of Zarcio in the long-term.

There are reports of frequent, mostly asymptomatic cases of splenomegaly, as well as very rare cases of spleen rupture in healthy donors and patients receiving G-CSF. Some cases of spleen rupture have been fatal. Therefore, the size of the spleen should be carefully monitored (clinical examination and ultrasound). The risk of spleen rupture in donors and/or patients with upper left abdominal or upper arm pain should be considered.

In the post-marketing period, very rare cases of adverse respiratory effects (hemoptysis, pulmonary hemorrhage, pulmonary infiltrative changes, dyspnea and hypoxia) have been reported in healthy donors. If the presence of the above symptoms is suspected, the appropriateness of further use of the drug and the need for appropriate treatment should be considered.

Recipients of allogeneic PSCC derived from Zarcio-stimulated mobilization

The immunologic interaction of allogeneic PSCC grafts has been reported to be associated with a higher risk of acute and chronic graft versus host reaction (RTPH) when compared to bone marrow transplantation.

Severe chronic neutropenia (TCN)

The number of blood cells

The number of platelets should be monitored closely, especially during the first weeks of therapy with the drug. If a patient is found to have thrombocytopenia and his platelet count is less than 100,000/mm3 for a long time, consideration should be given to withdrawing Zarsio for a short time or reducing its dose.

There may be other changes in the blood count that require close monitoring, including anemia and a transient increase in myeloid progenitor cell counts.

The development of acute leukemia or myelodysplastic syndrome (MDS)

The timely diagnosis of TCH and the differentiation of this diagnosis from other disorders of the hematopoietic system, such as aplastic anemia, MDS and myeloleukemia, must be made. Prior to treatment, a complete clinical work-up with determination of the white blood cell count and platelet count, bone marrow morphology and karyotype should be performed.

In clinical studies, a small number (approximately 3%) of patients with TCH who received filgrastim have seen MDS or leukemia. These results were only observed in patients with congenital neutropenia. MDS and leukemia are the most frequent complications of TCH, and their association with filgrastim therapy has not been determined. Approximately 12% of patients with initially unchanged cytogenetic parameters were found to have changes, including monosomia in the 7th chromosome pair, when re-examined. If a patient with TCH shows cytogenetic abnormalities, the risk-benefit ratio of continuing Zarsio therapy should be carefully evaluated; the drug should be discontinued if MDS or leukemia develops. It is currently unclear whether long-term use of Zarsio induces cytogenetic abnormalities, MDS, or leukemia in patients with TCN. It is recommended that morphologic and cytogenetic studies of the bone marrow be performed regularly (approximately every 12 months).

Other precautions

The causes of transient neutropenia, such as viral infections, must be excluded.

Enlargement of the spleen is a likely effect associated with treatment with Zarsio. During clinical studies, 31% of patients showed splenomegaly on palpation. On radiography, an increase in spleen size was detected soon after the start of filgrastim treatment and tended to stabilize. It has been noted that decreasing the dose of Zarcio slows or stops the increase in spleen size; splenectomy may be necessary in 3% of patients. Spleen size should be monitored regularly by clinical examination.

A small number of patients have had hematuria/proteinuria. To exclude these manifestations, regular monitoring of total urinalysis should be performed.

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

HIV infection

Blood cell count

The absolute neutrophil count (ANR) should be strictly monitored, especially during the first weeks of therapy with Zarcio. Some patients may experience a very rapid and significant increase in BUN at the initial dose of Zarsio. During the first 2-3 days of using the drug, it is recommended to measure ACH daily. Subsequently, the ACH should be checked at least twice a week during the first 2 weeks and then every week or every other week during the whole course of maintenance therapy. If Zarcio is interrupted at a dose of 30 million IU/day (0.300 mg/day), the patient may experience significant swings in the ACN during treatment. In order to determine the minimum NAD (nadir), it is recommended to monitor the blood count before each administration of Zarzio.

Risk of using high doses of myelosuppressive medications

Monotherapy with Zarsio is not indicated to prevent thrombocytopenia and anemia with myelosuppressive medications. If higher doses or multiple myelosuppressive drugs are used concomitantly with Zarsio therapy, the risk of thrombocytopenia and anemia increases. Regular monitoring of gross blood counts is recommended.

The development of myelosuppression due to infections or tumor entities

Neutropenia may be due to bone marrow lesions in opportunistic infections caused by pathogens such as Mycobacterium avium complex, or malignancies such as lymphoma. If infiltrative bone marrow lesions of inflammatory origin or malignant neoplasms are detected, simultaneously with the use of Zarsio for treatment of neutropenia, the appropriate therapy of the diagnosed diseases must be prescribed. The efficacy of Zarsio use in treatment of neutropenia caused by bone marrow lesions of infectious origin or tumor neoplasms has not been established.

Other precautions

There have been reports of rare cases of adverse effects on the respiratory organs, particularly the development of interstitial pneumonia with G-CSF. Patients who have recently had infiltrative lung disease or pneumonia may have a high risk. The appearance of symptoms such as cough, fever and dyspnea, combined with the detected infiltrative lung lesion on radiological examination and signs of progressive respiratory failure, suggest the presence of adult respiratory distress syndrome (ARDS). If RDSD is detected, Zarsio should be discontinued and appropriate treatment administered.

Patients with concomitant bone disease and osteoporosis, with long-term (more than 6 months) use of Zarsio it is recommended to monitor bone density regularly.

In patients with sickle cell disease there have been cases of acute hemolytic crisis (increased number of altered cells), sometimes with fatal outcome. Patients with sickle cell disease should prescribe Zarsio with caution.

Bone tissue radiography revealed an increase in bone marrow hematopoietic activity in response to growth factor therapy. These data should be taken into account when analyzing the results of bone radiography.

Synopsis

Contraindications

– hereditary fructose intolerance (contains sorbitol);

– severe hereditary neutropenia (Kostmann syndrome) with cytogenetic disorders and autoimmune neutropenia;

– The drug should not be used to increase doses of cytotoxic chemotherapy drugs above the recommended doses;

– concurrent radiation or chemotherapy;

– terminal stage of chronic renal failure (CKF);

– period of newborn.

– history of hypersensitivity to the drug or its components;

– history of hypersensitivity to albumin and blood components when albumin is added to solutions for intravenous infusion.

With caution

Myelodysplastic syndrome, chronic myeloleukemia, secondary acute myeloblastic leukemia (in patients under age 55, without cytogenetic abnormalities), excess nadir (leukocyte count in blood test >50 × 109/l, for PSCC mobilization – >70 × 109/l), in patients who receive high doses of chemotherapy drugs for malignancies (risk of increased toxic effects), the simultaneous use of single-component or combined chemotherapy drugs (risk of severe thrombocytopenia and anemia), in patients with significantly reduced myeloid progenitor cell count (less than 2 × 106 CD34+ cells/kg – use is not well studied), thrombocytopenia (with platelet count in blood test less than 100,000/mm3), splenomegaly (risk of spleen rupture), infiltrative lung disease (risk of development/progression of infiltrative pneumonia), sickle cell disease, neutropenia due to bone marrow lesions of infectious genesis or tumor neoplasms (lymphoma) (effectiveness of monotherapy is not established).

Side effects

The side effects shown below are categorized according to organ and system classification and frequency of occurrence: Very common (≥1/10); common (≥1/100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1000); very rare (<1/10 000), frequency unknown (cannot be estimated based on available data).

Immune system disorders: very rare (in patients) and infrequent (in donors prior to PSCC mobilization) – hypersensitivity reactions, including anaphylactic reactions, skin rash, urticaria, angioedema, dyspnea and decreased BP.

Hematopoietic organs: very common – anemia, splenomegaly (progressive in some cases), in donors before PSCC mobilization – leukocytosis (> 50 × 109/l) and transient thrombocytopenia (< 100 × 109/L) – as a consequence of the pharmacological action of filgrastim; frequently – thrombocytopenia, splenomegaly (asymptomatic, in donors and patients); infrequently – spleen dysfunction; very rarely – spleen rupture.

Nervous system disorders: very common – headache.

Cardiovascular system disorders: infrequent – transient decrease of BP; rare – vascular disorders, including veno-occlusive disease and increase of the blood circulation.

Respiratory system: very common – nasal bleeding; very rare – pulmonary edema, interstitial pneumonia, lung infiltrates; in donors – hemoptysis, pulmonary bleeding, dyspnea, hypoxemia.

The skin and its appendages: often – vasculitis (with long-term use), alopecia, rash; very rare – Sweet’s syndrome (acute febrile dermatosis, relationship with taking filgrastim is not established).

Muscular system disorders: very common – pain in bones, joints and muscles (mild to moderate, in donors – transient); common – pain in bones, joints and muscles (severe), osteoporosis, arthralgia; infrequent in donors and very rare in patients – exacerbation of rheumatoid arthritis.

In the digestive system: often – diarrhea, hepatomegaly.

Urogenital system disorders: infrequent – hematuria, proteinuria; very rare – dysuria.

Laborary parameters: very common in patients and common in donors – reversible, dose-dependent, mild to moderate increase of ALP activity, LDH, in patients – GGT, hyperuricemia, decrease of blood glucose concentration (moderate, reversible); uncommon in donors – reversible, mild increase of AST and uric acid activity.

Others: frequent – pain at the injection site, increased fatigue, reactions at the injection site (less than 2% of patients with TCH).

Overdose