Instruction for use: Zarcio

Dosage form: Solution for intravenous and subcutaneous administration

Active substance: Filgrastimum

ATX

L03AA02 Filgrastim

Pharmacological group:

Stimulators of hemopoiesis

The nosological classification (ICD-10)

A49 Bacterial infection of unspecified site: Bacterial infection; Infectious diseases

B23.2 HIV disease, with manifestations of hematologic and immunological disorders, not elsewhere classified: Anemia in HIV-infected patients; Neutropenia in patients with AIDS

D72.8 Other specified disorders of white blood cells: Lymphocytopenia

D72.8.0 * Leukopenia: Autoimmune neutropenia; Congenital neutropenia; Granulocytopenia; Idiopathic and drug-induced leukopenia; Idiopathic neutropenia; Leukopenia aplastic; Leukopenia radiation; Leukopenia with radiation therapy; Radiation leukopenia; Hereditary neutropenia; Neutropenia in patients with AIDS; Periodic neutropenia; Radiation leukopenia; Persistent neutropenia; Febrile neutropenia; Two-stage cytopenia; Radiation cytopenia; Neutropenia is cyclic

Z51.1 Chemotherapy for neoplasm: Cystitis hemorrhagic, caused by cytostatics; Urotoxicity of cytostatics

Z52 Organ and tissue donors

Z94.8 Presence of another transplanted organ or tissue: Pancreas transplantation; Transplantation of spongy tissue; Bone marrow transplantation; A bone marrow transplant; Bone marrow transplantation; Xenotransplantation; TCM; Cell islet allotransplantation; Parathyroid autotransplantation

Composition

Solution for intravenous and subcutaneous administration 1 syringe (0.5 ml)

active substance: Filgrastim 30 million units (0.3 mg); 48 million units (0.48 mg)

Auxiliary substances: glutamic acid - 0.736 mg; Sorbitol - 25 mg; Polysorbate 80 - 0.02 mg; Sodium hydroxide - q.s up to pH; Water for injection - up to 0.5 m

Description of dosage form

Transparent colorless or yellowish solution.

Pharmachologic effect

Mode of action - Leukopoietic.

Pharmacodynamics

Filgrastim is a highly purified non-glycosylated protein consisting of 175 amino acids, or a recombinant human granulocyte colony-stimulating factor (r-h G-CSF). It is produced by the strain K12 Escherichia coli, the genome of which was introduced into the genome by genetic engineering methods of the granulocyte colony-stimulating factor (G-CSF) of a human. Human G-CSF regulates the production and release of neutrophils from the bone marrow to the peripheral blood. The use of filgrastim is accompanied by a significant increase in the number of neutrophils in the vascular bed within 24 hours, as well as a small increase in the number of monocytes. In some cases, there is an increase in the number of eosinophils and basophils, however, in some patients, eosinophilia and basophilia may be present before treatment begins. The increase in the number of neutrophils in the application of filgrastim in the recommended dose range is dose-dependent. Released neutrophils have normal or increased functional activity, which is confirmed by the tests of chemotaxis and phagocytosis. At the end of therapy, the number of neutrophils in peripheral blood is reduced by 50% within 1-2 days and returns to normal within the next 1-7 days. As well as other factors stimulating hematopoiesis, in vitro studies have shown that G-CSF has the ability to stimulate endothelial cells, since they have specific receptors for G-CSF. At the same time, it was established that G-CSF is the inducer of angiogenesis of vascular endothelial cells and accelerates the transport of neutrophils through the endothelium of the vessels. The use of filgrastim in patients receiving cytotoxic drugs is accompanied by a significant decrease in the frequency, severity and duration of neutropenia and febrile neutropenia and allows the use of antibiotics at lower doses compared with patients receiving only cytotoxic chemotherapy. Reduces the need for and duration of inpatient treatment in patients after induction chemotherapy with myeloleukemia or myeloablative therapy followed by bone marrow transplantation. The frequency of cases of body temperature increase did not decrease in patients after myeloablative therapy followed by bone marrow transplantation.

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

The use of Zarcio in children and adults with severe congenital neutropenia (periodic, idiopathic) stimulates a steady increase in the number of active neutrophils in peripheral blood and a decrease in the frequency of infectious and other complications.

The use of Zarcio in patients with HIV infection supports the number of neutrophils within normal limits, which allows to observe the necessary dosage regimen of antiretroviral drugs and myelosuppressive therapy. There are no signs of an increase in HIV replication with the use of Zarcio.

Pharmacokinetics

Vd in the systemic circulation is about 150 ml / kg. With n / k and / in the introduction at the recommended doses, the concentration of filgrastim in the blood plasma remains above 10 ng / ml for 8-16 hours; And a direct linear relationship between the administered dose of filgrastim and its concentration in the blood plasma was noted

The withdrawal of filgrastim does not have a linear dependence, the rate of excretion of the drug decreases with an increase in the dose of the drug. The main way of deducing filgrastim is carried out with the participation of neutrophils, while the clearance increases at higher doses of the drug. The release rate of filgrastim increases with repeated use of the drug as long as the number of neutrophils increases. T1 / 2 filgrastim after a single SC administration is 2.7 hours (1 million units / kg, 10 mkg / kg) to 5.7 hours (0.25 million units / kg, 2.5 μg / kg) and After 7 days of application is 8.5 and 14 hours respectively.

Long-term therapy with filgrastim for more than 28 days in patients after autologous bone marrow transplantation was not accompanied by cumulation of the drug and had comparable T1 / 2 values.

Indication of the drug Zarcio

A reduction in the duration of neutropenia and febrile neutropenia in patients receiving cytotoxic chemotherapy for malignant neoplasm (with the exception of chronic myeloid leukemia and myelodysplastic syndromes), and a reduction in the duration of neutropenia in patients receiving myeloablative therapy followed by bone marrow transplantation, which is considered a risk factor for prolonged Severe neutropenia. The efficacy and safety of filgrastim are comparable in the conduct of cytotoxic chemotherapy in children and adults;

Mobilization of peripheral stem cells (PSKK), incl. After mielosupressivnoy therapy, as well as the mobilization of peripheral stem cells in healthy donors (allogeneic PSKK);

Hereditary periodic 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, prolonged treatment with filgrastim is indicated to increase the number of neutrophils and to reduce the frequency and duration of adverse effects Associated with infectious complications;

Prevention of bacterial infections and treatment of persistent neutropenia (absolute number of neutrophils, equal to 1 · 109 / L and less) in patients with developed stage of HIV infection with ineffectiveness of other methods of treatment.

Contraindications

Hypersensitivity to the drug or its components in the anamnesis;

Increased sensitivity to albumin and blood components in anamnesis in cases of albumin addition to solutions for intravenous infusions;

Hereditary intolerance to fructose (contains sorbitol);

Severe hereditary neutropenia (Costman's syndrome) with cytogenetic disorders and autoimmune neutropenia;

Use to increase doses of cytotoxic chemotherapeutic drugs above recommended;

Simultaneous radiation or chemotherapy;

Terminal stage of chronic renal failure (CRF);

Newborn period.

With caution: myelodysplastic syndrome; Chronic myelogenous leukemia; Secondary acute myeloblastic leukemia (patients under 55 years of age, without cytogenetic abnormalities); Excess nadir (the number of leukocytes in the blood test> 50 · 109 / l, for mobilization of PSKK -> 70 · 109 / l); Patients who receive high doses of chemotherapy drugs for malignant neoplasms (risk of intensifying toxic effects); Simultaneous application of single-component or combined chemotherapeutic drugs (risk of severe thrombocytopenia and anemia); Patients with significantly reduced number of myeloid progenitor cells (less than 2 × 10 6 CD34 + cells / kg - the application is not well understood); Thrombocytopenia (the number of platelets in the blood test is less than 100,000 / mm3); Splenomegaly (risk of rupture of the spleen); Infiltrative lung injury (risk of development / progression of infiltrative pneumonia); Sickle-cell disease, neutropenia, caused by bone marrow infectious disease or tumor tumors (lymphoma) (monotherapy is not established).

Application of pregnancy and breastfeeding

Data on the use of filgrastim during pregnancy are limited. There are indications of a possible passage of filgrastim through the placental barrier. In animal studies, filgrastim was not accompanied by a teratogenic effect. An increased incidence of miscarriages was noted, but fetal abnormalities were not noted.

When prescribing filgrastim, pregnant women should carefully evaluate the benefit-risk relationship by comparing the expected therapeutic effect to the mother with a possible risk to the fetus.

It is not established whether filgrastim penetrates breast milk. Therefore, if it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.

Side effects

The following side effects are distributed according to the classification of organs and systems and the frequency of occurrence: very often (≥1 / 10); Often (≥1 / 100 - <1/10); Infrequently (≥1 / 1000 - <1/100); Rarely (≥1 / 10000 - <1/1000); Very rarely (<1/10000), the frequency is unknown (cannot be estimated from the available data).

On the part of the immune system: very rarely (in patients) and infrequently (in donors before mobilization of PSKK) - hypersensitivity reactions, including anaphylactic reactions, skin rash, urticaria, angioedema, dyspnea and BP

From hemopoiesis: very often anemia, splenomegaly (progressing in a number of cases), donors before mobilization of PSKK - leukocytosis (> 50 · 109 / L) and transient thrombocytopenia (<100 · 109 / L) - as a consequence of the pharmacological action of filgrastim ; Often - thrombocytopenia, splenomegaly (asymptomatic, in donors and patients); Infrequently - a violation of the function of the spleen; Very rarely - rupture of the spleen.

From the nervous system: very often - a headache.

From the CVS side: infrequently - transient decrease in blood pressure; Rarely - vascular disorders, incl. Veno-occlusive disease and an increase in bcc.

On the part of the respiratory system: very often - nosebleeds; Very rarely - pulmonary edema, interstitial pneumonia, infiltrates in the lungs; In donors - hemoptysis, pulmonary hemorrhage, dyspnea, hypoxemia.

From the skin and its appendages: often - vasculitis (with prolonged use), alopecia, rash; Very rarely - Sweet syndrome (acute febrile dermatosis, connection with filgrastim is not established).

From the musculoskeletal system: very often - pain in the bones, joints and muscles (weak or moderate, in donors - transient); Often - pain in the bones, joints and muscles (severe), osteoporosis, arthralgia; Infrequently (in donors) and very rarely (in patients) - exacerbation of rheumatoid arthritis.

On the part of the digestive system: often - diarrhea, hepatomegaly.

From the genitourinary system: infrequently - hematuria, proteinuria; Very rarely - dysuria.

Laboratory indicators: very often (in patients) and often (in the case of donors) - reversible, dose-dependent, weak or moderate increase in activity of AP, LDH, in patients - glutamyltransferase, hyperuricemia, decrease in glucose concentration in the blood (moderate, reversible); Infrequently in donors - a reversible, weak increase in the activity of AST and uric acid.

Other: often - pain at the injection site, fatigue, reactions at the injection site (less than 2% of patients with TCN.

Interaction

The safety and effectiveness of Zarcio's administration on the same day as myelosuppressive cytotoxic chemotherapy drugs have not been established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, Zarcio preparation should not be administered within 24 hours before or after administration of these drugs. With the simultaneous administration of Zarsio and fluorouracil, the severity of neutropenia may worsen. Possible interaction with other hematopoietic growth factors and cytokines is not known. Given that lithium stimulates the release of neutrophils, it is possible to enhance the effect of Zarcio's drug with a combined prescription, but such studies have not been conducted.

Due to pharmaceutical incompatibility, Zarcio preparation cannot be mixed with 0.9% sodium chloride solution.

Dosing and Administration

IV, SC.

Zarcio therapy can be performed by interacting with cancer center physicians who have experience using a drug containing G-CSF, as well as the experience of treating patients with hematological diseases in a medical institution where there is the necessary diagnostic equipment.

Mobilization and apheresis procedures should be carried out in cooperation with specialists of the oncology-hematology center, who have appropriate experience in this field and the possibility of the necessary monitoring of hematopoietic progenitor cells.

Zarcio is available in the following doses: 30 million units / 0.5 ml (0.3 mg) and 48 million units / 0.5 ml (0.48 mg).

Cytotoxic chemotherapy. The recommended daily dose of Zarcio is 0.5 million units / kg (0.005 mg / kg).

The first dose of the drug should be administered no earlier than 24 hours after the course of cytotoxic chemotherapy.

The drug Zarcio is administered daily until the total number of neutrophils in a clinical blood test exceeds the expected nadir and reaches normal values. After chemotherapy for solid tumors, lymphomas and lymphocytic leukemia, the duration of treatment before reaching these values is up to 14 days. After induction and consolidation therapy of acute myeloid leukemia, the treatment time can be significantly increased (up to 38 days) and determined depending on the type, dose and scheme of the cytotoxic chemotherapy used.

In patients receiving cytotoxic chemotherapy, a transient increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Zarcio. Nevertheless, to achieve a stable therapeutic effect, it is necessary to continue therapy with Zarcio until the number of neutrophils exceeds the expected nadir and reaches normal values. It is not recommended to abolish prematurely drug treatment before the transition of neutrophils through the nadir.

Patients receiving myeloablative therapy with subsequent bone marrow transplantation. The recommended initial dose of Zarcio is 1 million units / kg (0.010 mg) / day.

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

Dose adjustment. After the maximum reduction in the number of neutrophils (nadir), the daily dose of Zarcio should be adjusted depending on the change in the number of neutrophils as follows.

Selection of the dose of Zarcio in response to the nadir. At ACCH> 1 · 109 / L for 3 consecutive days, the dose should be reduced to 0.5 million U / kg / day (0.005 mg / kg / day); At À×Í> 1 · 109 / l for 3 consecutive days in a row the drug should be canceled. If during treatment AFH decreases to <1 · 109 / l, the dose of Zarcio is increased again according to the above scheme.

Mobilization of PSKK. Patients receiving myelosuppressive or myeloablative therapy followed by autologous transplantation of PSKK. To mobilize PSKK when using Zarcio as a monotherapy, the recommended dose is 1 million units / kg (0.010 mg / kg) / day for 5-7 consecutive days. Conduct 1-2 sessions of leukapheresis on the 5th and 6th day. In some cases, an additional 1 session of leukapheresis is performed. Do not change the dose of Zarcio until the final leukapheresis.

To mobilize PSKC after myelosuppressive chemotherapy, the recommended dose of Zarcio is 0.5 million units / kg (0.005 mg / kg) / day daily, starting from the first day after completion of chemotherapy and until the expected number of neutrophils passes the expected nadir and Will reach the norm. Leukapheresis should be carried out during the period of the increase in ACHN from <0.5 · 109 / L to> 5 · 109 / L. Patients who did not receive intensive chemotherapy, are treated with 1 session of leukapheresis. In some cases, additional sessions of leukapheresis are recommended.

Healthy donors before allogeneic transplantation of PSKK. To mobilize PSKK before allogeneic transplantation of PSKC in healthy donors, the recommended dose of Zarcio is 1 million units / kg (0.010 mg / kg) / day for 4-5 consecutive days. Leukapheresis is carried out from the 5th day and, if necessary, continues until the 6th day in order to obtain 4 × 106 CD34 + cells / kg.

Severe chronic neutropenia (THC). The recommended initial dose is 1.2 million units / kg (0.012 mg / kg) / day once or in divided doses.

Idiopathic and periodic neutropenia. The recommended initial dose is 0.5 million units / kg (0.005 mg / kg) / day once or in divided doses.

Selection of the dose of the drug. The drug Zarcio is administered daily until a stable and exceedingly high neutrophil count of 1.5 × 10%. After achieving the therapeutic effect, the minimum effective dose is determined to maintain this level. To maintain the right amount of neutrophils requires a long daily administration of the drug. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the effectiveness of the therapy. Subsequently, every 1-2 weeks, an individual dose adjustment is performed to maintain the average number of neutrophils in the range from 1.5 · 109 / L to 10 · 109 / L. In patients with severe infections, a scheme with a faster increase in dose can be used. In 97% of patients who responded positively to treatment, the full therapeutic effect is observed when doses are prescribed up to 24 mcg / kg / day. The daily dose of Zarcio should not exceed 24 mcg / kg.

HIV infection

Restoration of the number of neutrophils. The recommended initial dose of Zarcio is 0.1 million units / kg (0.001 mg / kg) / day, with a dose increase of up to 0.4 million units / kg (0.004 mg / kg) to normalize the number of neutrophils (ACHH> 2 · 109 / L). Normalization of the number of neutrophils usually comes in 2 days. In rare cases (<10% of patients) to restore the number of neutrophils, the dose of the drug can be increased to 1 million units / kg (0.010 mg / kg) / day.

Maintaining a normal number of neutrophils. After reaching the therapeutic effect, the maintenance dose is 0.3 mg / day 2-3 times a week according to the alternating schedule (every other day). Subsequently, individual dose adjustment and long-term administration of the drug may be required to maintain the average number of neutrophils> 2 · 109 / L.

Special categories of patients

Patients with impaired renal / hepatic function. Dose correction is not required in patients with severe renal or hepatic insufficiency, Their pharmacokinetic and pharmacodynamic parameters were similar to those of healthy volunteers.

Children with THC and malignant neoplasms. When used in pediatric practice in patients with TCN and oncological diseases, the safety profile of Zarcio did not differ from that in adults. Recommendations for dosing for children of the same age are the same as for adults receiving myelosuppressive cytotoxic chemotherapy.

Elderly patients. Due to the limited number of elderly patients in clinical trials, there are no specific recommendations for the use of Zarcio in elderly patients. There were no additional studies in this category of patients.

Method of administration

Cytotoxic chemotherapy. The drug Zarcio is used in the form of SC injections or IV infusions for 30 minutes 1 time per day. Additional guidance on the dilution of the drug in a 5% solution (50 mg / ml) of dextrose for IV administration is given in the section "Special instructions". In most cases, the route of administration is preferred. With iv injection of a single dose, the duration of the effect of the drug may decrease. The clinical significance of these data regarding the use of multiple doses of the drug has not been established. The choice of the method of administration depends on the specific clinical situation and is determined for each patient individually.

Patients receiving myeloablative therapy with subsequent bone marrow transplantation. Zarcio preparation is diluted in 20 ml of 5% (50 mg / ml) of dextrose solution and applied in the form of a short IV infusion for 30 minutes or a prolonged SC or IV infusion for 24 hours. Additional instructions for dilution of the drug in 5% solution (50 mg / ml) of dextrose for intravenous infusions is given in the section "Special instructions".

Mobilization of PSCC

A / c introduction. To mobilize PSKK, patients who undergo myelosuppressive or myeloablative therapy followed by autologous transplantation of PSKK, Zarcio can also be administered as a continuous infusion for 24 hours. Before infusion, the drug is diluted in 20 ml of a 5% (50 mg / ml) solution Dextrose. Additional guidance on the dilution of the drug in a 5% solution (50 mg / ml) of dextrose for infusions is given in the section "Special instructions".

TCH / HIV infection

A / c introduction. The initial dose is 0.1-0.4 million units (0.001-0.004 mg / kg) once, until the neutrophil count is normalized (usually within 2 days). After achieving the therapeutic effect, the maintenance dose is 30 million units (0.3 mg) / day every other day. In the future, individual dose adjustment and prolonged therapy with Zarcio may be required to maintain the neutrophil count> 2 · 109 / L.

Overdose

Filgrastim overdose cases are not registered.

Special instructions

Treatment with Zarcio should only be performed under the supervision of an oncologist or hematologist with experience in the use of G-CSF, provided that the necessary diagnostic capabilities are available. Procedures for mobilization and apheresis of cells should be performed in an oncological or hematological center with experience in this field and the possibility of adequate monitoring of hematopoietic progenitor cells.

Cytotoxic chemotherapy

Growth of malignant cells. Due to the fact that G-CSF can stimulate the growth of myeloid cells in vitro, it is recommended to consider the following information:

- safety and efficacy of Zarcio preparation in patients with myelodysplastic syndrome (MDS) and chronic myeloid leukemia have not been established. Therefore, for these diseases, the use of Zarcio is not shown. Particular attention is needed when conducting a differential diagnosis between the blast-transformation of chronic myelogenous leukemia and acute myelogenous leukemia;

- Since data on the safety and efficacy of Zarcio preparation for patients with secondary acute myelocytic leukemia (AML) are limited, Zarcio preparation should be administered with caution.

- safety and efficacy of Zarcio, first prescribed for patients with AML at the age of 55 years without pathogenetic anomalies [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 over 0.3 million units / kg (0.0003 mg / kg). There is no information about any side effects directly caused by the development of leukocytosis of this severity. However, considering the possible risk associated with severe leukocytosis, during treatment with Zarcio, the number of leukocytes must be regularly monitored. If the number of white blood cells exceeds 50 · 109 / l after reaching the expected nadir, immediately discontinue the drug. If the Zarcio drug is used to mobilize PSKK, it should be abolished or reduced with an increase in the number of white blood cells to> 70 · 109 / L.

The risk associated with increasing the dose of chemotherapy. Special care must be taken in the treatment of patients with malignant tumors who receive high doses of chemotherapy drugs, since no significant additional effect of high doses on the outcome of the disease has been confirmed, but the likelihood of a more pronounced toxic effect on CAS, respiratory system, nervous system and skin Instructions for the medical use of the chemotherapeutic drugs used).

Monotherapy with Zarcio does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. If higher doses of chemotherapy are used (for example, full doses according to the prescribed regimens), the risk of severe thrombocytopenia and anemia increases. It is recommended to regularly monitor such indicators of clinical blood analysis as hematocrit and platelet count. Particular care should be taken when using single-component or combined chemotherapeutic drugs that can cause severe thrombocytopenia.

When Zarcio was used to mobilize PSKK, a decrease in the severity and duration of thrombocytopenia due to myelosuppressive or myeloablative chemotherapy was found.

Other precautions. The effectiveness of Zarcio in patients with significantly reduced number of myeloid progenitor cells has not been studied. Zarcio drug increases the number of neutrophils by affecting, primarily, the neutrophil precursor cells. Therefore, in patients with a decrease in the number of progenitor cells (for example, as a result of intensive radiation therapy or chemotherapy treatment or as a consequence of bone marrow infiltration by tumor cells), the amount of neutrophils formed may be lower.

There are data on the development of graft-versus-host (GVHD) and lethal outcomes in patients receiving G-CSF after allogeneic bone marrow transplantation.

Mobilization of PSCC

Prior treatment with cytotoxic agents. In patients who had previously undergone intensive myelosuppressive therapy, against the backdrop of the use of Zarcio preparation for mobilization of PSKK, there may not be an increase in the number of PSDM sufficient to the recommended minimum level (> 2 × 106 CD34 + cells / kg) or an increase in the rate of platelet recovery.

Some cytotoxic agents have particular toxicity to hematopoietic progenitor cells and may have a negative effect on their mobilization. Long-term use of such drugs as melphalan, carboplatin or carmustine before the mobilization of progenitor cells can lead to poor results. However, simultaneous use of melphalan, carboplatin or carmustine with filgrastim is effective in mobilizing PSKK.

If it is planned to transplant PSKK, it is recommended to mobilize stem cells at an early stage of treatment of the patient. Particular attention should be paid to the number of progenitor cells activated in such patients prior to the use of chemotherapy drugs in high doses. If the results of mobilization in accordance with the above criteria are insufficient, consideration should be given to the use of alternative therapies that do not require the use of progenitor cells.

Estimate of the amount of PSKK. When assessing the number of PSKK, mobilized in patients with the use of Zarcio, special attention should be given to the method of quantitative determination. The results of flow-cytometric analysis on the number of CD34 + cells differ depending on the chosen method, and therefore it is necessary to interpret with care the results obtained during the research in different laboratories.

Statistical analysis showed that there is a complex but stable relationship between the number of CD34 + cells introduced into reinfusion and the rate of platelet count recovery after the use of high doses of chemotherapy drugs. The minimal amount (> 2 × 106 CD34 + cells / kg) leads to a sufficient recovery of hematological parameters and is recommended based on the published data. The number of CD34 + cells exceeding the indicated value is accompanied by faster normalization; If the number of cells does not reach this level, recovery of blood counts is slower.

Healthy donors before the allogeneic transplantation of PSKK. Mobilization of PSKC does not have a direct clinical result for healthy donors and can only be carried out for the purpose of allogeneic stem cell transplantation.

MOPS mobilization can be assigned only to donors that meet standard clinical and laboratory criteria for stem cell donation, with particular attention to hematological indicators and the presence of infectious diseases.

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

Transient thrombocytopenia (platelet count <100 · 109 / L) after Zarcio's appointment and leukapheresis is observed in 35% of donors. Among them, 2 cases of thrombocytopenia with a platelet count <50 · 109 / l after leukapheresis were noted. If more than one leukapheresis session is required, the condition of donors with platelet counts less than 100 · 109 / L should be carefully monitored; As a rule, with the number of neutrophils to 75 · 109 / L apheresis is not recommended.

Leukapheresis should not be administered to donors taking anticoagulants or having hemostasis disorders.

It is necessary to cancel or reduce the applied dose of Zarcio if the number of leukocytes increases> 70 · 109 / l.

Donors receiving G-CSF to mobilize PSKK should regularly monitor all indicators of the clinical blood test prior to their normalization.

In healthy donors who used G-CSF, cases of transient cytogenetic changes were noted. The significance of these manifestations is unknown.

Monitoring of the safety of the use of Zarcio in healthy donors continues. At present, the risk of developing a malignant myeloid clone in donors cannot be ruled out. Medical centers that conduct apheresis procedures recommend systematic monitoring of the status of stem cell donors for a minimum of 10 years in order to monitor the safety of the use of Zarsio in the long-term.

There are reports of frequent, mostly asymptomatic cases of splenomegaly, as well as very rare cases of rupture of the spleen in healthy donors and patients taking G-CSF. Some cases of rupture of the spleen were accompanied by lethal outcomes. In this regard, it is necessary to carefully monitor the size of the spleen (with clinical examination and ultrasound). The risk of rupture of the spleen in donors and / or patients should be taken into account if they have pain in the upper left part of the abdominal cavity or upper arm.

In the postmarketing period, very rare cases of adverse effects on respiratory organs (hemoptysis, pulmonary hemorrhage, infiltrative changes in the lungs, dyspnea and hypoxia) were noted in healthy donors. If you suspect a presence of these symptoms, you should consider the advisability of further use of the drug and the need for appropriate treatment.

Recipients of allogeneic PSKK, obtained by mobilization, stimulated by the drug Zarcio

According to available data, the immunological interaction of the allogeneic graft of PMSC may be associated with a higher risk of developing acute and chronic GVHD when compared with bone marrow transplantation.

THC

The number of blood cells. It is necessary to strictly control the number of platelets, especially during the first weeks of therapy with the drug. If the patient is diagnosed with thrombocytopenia and the platelet count is less than 100,000 / mm3 for a long time, consideration should be given to a short-term withdrawal of Zarcio or a reduction in its dose.

There are other possible changes in the blood formula, which require careful monitoring, incl. Anemia and a transient increase in the number of myeloid progenitor cells.

Development of acute leukemia or MDS. It is necessary to perform timely diagnosis of TCN and to differentiate this diagnosis from other disorders of the hematopoietic system, such as aplastic anemia, MDS and myeloid leukemia. Before the start of treatment, a general clinical analysis should be carried out to determine the leukocyte formula and the number of platelets, to determine the bone marrow morphology and karyotype.

During clinical trials, a small number (approximately 3%) of patients with TCN receiving filgrastim observed MDS or leukemia. These results were obtained only when observing patients with congenital neutropenia. MDS and leukemia are the most frequent complications of TCN, and their relationship to filgrastim therapy is not defined. Approximately 12% of patients with initially unchanged cytogenetic parameters in the second survey showed changes, incl. Monosomy in the 7th pair of chromosomes. If a patient with TCN exhibits cytogenetic disorders, it is necessary to carefully evaluate the relationship between risk and benefit from continuing therapy with Zarcio; The drug should be withdrawn in the case of MDS or leukemia. Currently, it is unclear whether the long-term use of Zarcio drug provokes the development of cytogenetic disorders, MDS or leukemia in patients with THC. It is recommended to conduct regular (approximately every 12 months) morphological and cytogenetic studies of the bone marrow.

Other precautions. It is necessary to exclude such causes of transient neutropenia as viral infections.

The increase in the spleen is a probable effect associated with the treatment with Zarcio. During clinical trials, 31% of patients with palpation showed splenomegaly. In radiography, an increase in the size of the spleen is detected soon after the initiation of treatment with filgrastim and tends to stabilize. It was noted that a decrease in the dose of Zarcio slows or stops the increase in the size of the spleen; In 3% of patients, splenectomy may be necessary. It is necessary to regularly monitor the size of the spleen during clinical examination.

A small number of patients had hematuria / proteinuria. To exclude these manifestations, a general urine test should be monitored regularly. The safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established.

HIV infection

The number of blood cells. It is necessary to strictly control ASC, especially during the first weeks of therapy with Zarcio. In some patients, a very rapid and significant increase in AEC can be observed with the initial dose of Zarcio. During the first 2-3 days of application of the drug, it is recommended to measure AHN daily. Subsequently, ACN should be checked at least 2 times a week for the first 2 weeks and then every week or one week throughout the course of maintenance therapy. If there is a break in the use of Zarcio in a dose of 30 million units per day (0.3 mg / day), the patient may experience significant fluctuations in AFN during treatment. In order to determine the minimum AHN (nadir), it is recommended that a general blood test be performed before each injection of Zarcio.

The risk caused by the use of high doses of myelosuppressive drugs. Monotherapy with Zarcio is not used to prevent the development of thrombocytopenia and anemia when taking myelosuppressive drugs. In the case of higher doses or simultaneously several myelosuppressive drugs in combination with Zarcio therapy, the risk of developing thrombocytopenia and anemia is increased. It is recommended that regular monitoring of the expanded blood test be performed.

Development of myelosuppression due to infections or tumor formations. Neutropenia may be due to bone marrow damage in opportunistic infections that are caused by pathogens such as Mycobacterium avium complex, or malignant tumors, such as lymphoma. In detecting infiltrative lesions of bone marrow of inflammatory origin or malignant neoplasm, concomitantly with the use of Zarsio preparation for the treatment of neutropenia, appropriate therapy of diagnosed diseases is necessary. The effectiveness of Zarcio in the treatment of neutropenia due to bone marrow infection of infectious genesis or tumor neoplasms has not been established.

Other precautions. There are reports of rare cases of adverse effects on the respiratory system, in particular, the development of interstitial pneumonia in the background of the use of G-CSF. Patients newly infected with infiltrative lung disease or pneumonia may have a high risk. The appearance of such symptoms as cough, fever and shortness of breath, in combination with the revealed infiltrative lung lesion during X-ray examination and signs of progressive respiratory failure, suggest the presence of adult respiratory distress syndrome (ARDS). In the case of ARDS, the use of Zarcio is stopped and appropriate treatment is prescribed.

Patients with concomitant osteal pathology and osteoporosis with prolonged (more than 6 months) use of Zarcio are encouraged to regularly monitor bone density.

In patients with sickle-cell disease, cases of development of an acute hemolytic crisis (an increase in the number of altered cells), sometimes with a fatal outcome, were noted. Patients with sickle cell disease should be cautious about prescribing Zarcio.

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

Recommendations before use

Before using the drug, visual control of the contents in a pre-filled syringe is performed. The solution should be clear, without visible particles. The drug does not contain preservatives. To avoid microbial contamination, it should be borne in mind that the Zarcio preparation in a pre-filled syringe is only intended for single use.

Recommendations for breeding the drug

The drug Zarsio can be administered in diluted form in a 5% (50 mg / ml) solution of dextrose. Dilution of the drug is carried out immediately before administration, but dilution to a concentration of less than 0.2 million units / ml (0.002 mg / ml) is not recommended. When diluted at a concentration of 1.5 million U / ml (0.015 mg / ml), human albumin should be added additionally to a concentration of 2 mg / ml. For example, to achieve a solution volume of 20 ml and a total dose of Zarcio 30 million ED (0.3 mg), additional addition of an albumin solution in a volume of 200 mg / ml (20% solution) is necessary.

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

It is forbidden to use sodium chloride solution for dilution of Zarcio!

Once during the expiration date, the drug can be stored at a temperature of no higher than 25 ° C for 72 hours.

After breeding, use within 24 hours.

Impact on the ability to manage vehicles and mechanisms. No cases of adverse effects of Zarcio's drug on the rate of psychomotor reactions were observed; The effect of the drug on the ability to drive vehicles and mechanisms has not been established.

Release form

Solution for intravenous and subcutaneous injection. For 0.5 ml of the drug (30 million or 48 million units) in a syringe of colorless transparent borosilicate glass type I with a capacity of 1 ml, equipped with a stopper for the piston of gray bromobutyl rubber coated with fluoropolymer and a non-removable (integrated in the syringe) needle for subcutaneous Injection of stainless steel with a rubber protective cap and a cap made of polypropylene. 1 or 5 syringes per blister. For 1 or 2 blisters are placed in a pack of cardboard.

Manufacturer

Ai Di Tee Biologie GmbH, Am Farmpark, 06861, Dessau-Rosslau, Germany.

A legal entity in whose name the registration certificate was issued: Sandoz GmbH, Austria, Kundl, A-6250, Biohemistraße, 10.

Issued quality control: Sandoz GmbH, Austria.

To obtain additional information about the preparation, as well as to send your complaints and information about undesirable phenomena, you can go to the following address in Russia: ZAO Sandoz, Russia, Moscow

Storage conditions of the drug Zarcio

In the dark place at a temperature of 2-8 ° C, in the original packaging.

Keep out of the reach of children.

Shelf life of the drug Zarcio

3 years. 72 hours (at a temperature not exceeding 25 deg.)

Do not use after the expiry date printed on the package.