Zarcio - instructions for use, doses, side effects, contraindications

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 strain K12 Escherichia coli, the genome of which by genetic engineering methods introduced gene granulotsitarnogo colony-stimulating factor (G-CSF) rights.

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 of hemopoiesis stimulation, in studies in vitro It has been 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, 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 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 with subsequent 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 (PSCC) spend 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 PSMCs mobilized with Zarcio®, accelerates the restoration 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.

Application of the drug 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 maintains the number of neutrophils within normal limits, which allows to observe the necessary dosage regimen of antiretroviral drugs and myelosuppressive therapy. Signs of increased HIV replication with Zarcio® not noted.

Pharmacokinetics:

The volume of distribution in the systemic circulation is about 150 ml / kg. With subcutaneous and intravenous administration at recommended doses, the concentration of filgrastim in blood plasma is maintained above 10 ng / ml for 8-16 hours; and a direct linear relationship was observed between the administered dose of filgrastim and its concentration in the blood plasma.

The withdrawal of filgrastim has no linear dependence, the rate of excretion of the drug decreases with an increase in the dose of the drug. The main way to deduce filgrastim is carried out with the participation of neutrophils, while the clearance increases at higher doses of the drug.filgrastim elimination rate increases with repeated use of the drug as long as increasing the number of neutrophils. Half-life (T_1/2) Filgrastim after single subcutaneous administration of from 2.7 h (1.0 million U / kg, 10 mg / kg) to 5.7 h (0,250,000 U / kg, 2.5 mg / kg) and 7 days of application is 8.5-14 hours, respectively.

Long filgrastim therapy for more than 28 days in patients after autologous bone marrow transplantation was not associated with accumulation of the drug, and had comparable values T_1/2.

Indications:

- Reduction in the duration of neutropenia and febrile neutropenia in patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukemia and myelodysplastic syndromes), as well as the reduction of neutropenia duration in patients treated with myeloablative therapy followed by bone marrow transplantation, which is considered to be a factor in increasing the risk of long-term 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), including after myelosupressive therapy, as well as mobilization of peripheral stem cells in healthy donors (allogeneic PSKK).

- Hereditary periodic or idiopathic neutropenia in adults and children with an absolute number of neutrophils 0.5X10⁹/ l and 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 (the absolute number of neutrophils is 1.0x10⁹/ l and less) in patients with the expanded stage of HIV infection with the ineffectiveness of other treatments.

Contraindications:

- Hypersensitivity to the drug or its components in history;

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

- hereditary fructose intolerance (contains sorbitol);

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

- the drug should not be used to increase the doses of cytotoxic chemotherapeutic drugs above those recommended;

- simultaneous radiation or chemotherapy;

- terminal stage of chronic renal failure (CRF);

- newborn periodcti.

Carefully:

Myelodysplastic syndrome, chronic myelogenous leukemia, secondary acute myeloblastic leukemia (in patients under 55 years old, without cytogenetic abnormalities), nadir excess (number of leukocytes in a blood test> 50 x 10⁹/ l, for mobilization of PSKK -> 70 x 10⁹/ l), in patients who receive high doses of chemotherapy drugs for malignant neoplasms (the risk of intensifying toxic effects), simultaneous use of single-component or combined chemotherapeutic drugs (risk of severe thrombocytopenia and anemia), in patients with a significantly reduced number of myeloid progenitor cells less than 2,0х10⁶ Cd34+ cells / kg - insufficiently studied), thrombocytopenia (with a platelet count of less than 100,000 / mm in the blood test³), Splenomegaly (risk infiltrative pulmonary lesion ruptured spleen) (risk of development / progression infiltrative pneumonia), sickle cell disease, neutropenia due to bone marrow lesions of infectious origin or a tumor (lymphoma) (monotherapy has not been established).

Pregnancy and lactation:

Data on filgrastim during pregnancy are limited.

There are indications suggesting a possible passage of filgrastim through the placental barrier. In animal studies, filgrastim was not accompanied by a teratogenic effect. An increased incidence of miscarriage, but fetal abnormalities were noted.

When assigning pregnant filgrastim should be carefully weighed against the benefit-risk, comparing the expected therapeutic effect for the mother and the possible risk to the fetus.

It is not established whether the filgrastim in breast milk. Therefore, if necessary, the appointment during lactation should stop breastfeeding.

Dosing and Administration:

Therapy with Zarcio® can be carried out by interacting with cancer center physicians who have experience with the use of a granulocyte colony-stimulating factor (G-CSF) preparation, as well as the experience of treating patients with hematological diseases in a medical facility that has 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 (0.300 mg) and 48 million units / 0.5 ml (0.480 mg).

Cytotoxic chemotherapy

The recommended daily dose of Zarcio® is 0.5 million units / kg (0.005 mg / kg) of body weight.

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

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, in order 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 1.0 million units / kg (0.010 mg) of body weight per 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.

Table 1. Selection of the dose of Zarcio® in response to the nadir

Absolute number of neutrophils (AFN)	Adjusting the dose of Zarsio®
АЧН> 1,0х10⁹/ l for 3 consecutive days	Dose reduction to 0.5 million units / kg (0.005 mg / kg) of body weight per day
АЧН> 1,0х10⁹/ l for the next 3 days in a row	Abolition of the drug
If during treatment, the AFN decreases to <1.0 × 10⁹/ l, the dose of Zarcio® is increased again according to the above scheme

Mobilization of peripheral blood stem cells (PSSC)

Patients receiving myelosuppressive or myeloablative therapy with subsequent autologous transplantation of PMSC

To mobilize PSKK when using Zarcio® as a monotherapy, the recommended dose is 1.0 million units / kg (0.010 mg / kg) of body weight per day for 5-7 consecutive days. Conduct 1-2 sessions of leukapheresis on the 5th and 6th day. In some cases, one additional leukapheresis session is performed. Do not change the dose of Zarcio® until the final leukapheresis.

To mobilize PBSC after myelosuppressive chemotherapy Zarsio® recommended dose of the drug is 0.5 MU / kg (0.005 mg / kg) of body weight per day, every day, starting the first day after completion of chemotherapy and as long as the number of neutrophils can not pass the expected nadir and will not reach the norm. Leukapheresis should be carried out during the period of an increase in ACHN with <0.5x10⁹/ l to> 5.0x10⁹/ l. Patients not receiving intensive chemotherapy, spend 1 session leukapheresis. In some cases, additional sessions of leukapheresis are recommended.

Healthy donors before allogeneic transplantation of PSKK

To mobilize PBSC prior to allogeneic transplantation in healthy donors PSCC recommended dose Zarsio® preparation is 1.0 MU / kg (0.010 mg / kg) of body weight per day n / k for 4-5 consecutive days. Leukapheresis was carried out the 5th day and, if necessary, continue to 6th day in order to obtain 4x10⁶ Cd34+ cells / kg body weight of the recipient.

Severe chronic neutropenia (THC)

Congenital neutropenia

The recommended starting dose of 1.2 Mill. U / kg (0.012 mg / kg) of body weight per day in single or divided doses.

Idiopathic and periodic neutropenia

The recommended initial dose is 0.5 million units / kg (0.005 mg / kg) of body weight per day once or in divided doses.

Selection of the dose:

The drug Zarcio® is administered daily until a stable and exceedingly high neutrophil count of 1.5x10⁹/ l. Once the therapeutic effect is achieved, 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, an individual dose adjustment is performed every 1-2 weeks to maintain the average number of neutrophils in the range of 1.5x10⁹/ l to 10x10⁹/ 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 with the appointment of doses up to 24 mcg / kg per day. The daily dose of Zarcio® should not exceed 24 mcg / kg.

HIV infection

Recovery of the number of neutrophils

The recommended initial dose of Zarcio® is 0.1 million units / kg (0.001 mg / kg) of body weight inday with increasing dose to a maximum of 0.4 million units / kg (0.004 mg / kg) of body weight to normalize the number of neutrophils (ACHN> 2.0 × 10⁹/ l). Normalization of the number of neutrophils usually occurs in 2 days. In rare cases (<10% of patients) to restore the number of neutrophils, the dose of the drug can be increased to 1.0 million units / kg (0.010 mg / kg) of body weight per day.

Maintaining the normal number of neutrophils

After reaching the therapeutic effect, a maintenance dose of 0.300 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> 2.0 × 10⁹/ l.

Special categories of patients

Patients with impaired renal / hepatic function

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

Children with severe chronic neutropenia (TCN) 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

Zarcio® is used in the form of subcutaneous injections or intravenous infusions for 30 minutes 1 time per day. Additional guidance on dilution of the drug in a 5% solution (50 mg / ml) of dextrose for intravenous administration is given in the section "Special instructions". In most cases, the subcutaneous route of administration is preferred. With intravenous administration 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 followed by bone marrow transplantation

Zarcio® is diluted in 20 ml of 5% (50 mg / ml) dextrose solution and used as a short intravenous infusion for 30 minutes, or a prolonged subcutaneous or intravenous infusion for 24 hours. Additional guidance on dilution of the drug in a 5% solution (50 mg / ml) of dextrose for intravenous infusion is given in the section "Special instructions".

Mobilization of PSCC

Subcutaneous administration.

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

TCH / HIV infection

Subcutaneous administration.

The initial dose of 0.1-0.4 million units (0.001-0.004 mg / kg) once subcutaneously to normalize the number of neutrophils (usually within 2 days). After achieving the therapeutic effect, the maintenance dose is 30 million units (0.300 mg) per day every other day.In the future, individual dose adjustment and prolonged therapy with Zarcio® may be required to maintain the number of neutrophils> 2.0 × 10⁹/ l.

Side effects:

According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

Oncological patients

From the immune system

often: reactions hypersensitivity¹including anaphylactic reactions, skin rash, urticaria, angioedema, dyspnea and lowering of blood pressure (BP);

infrequently: graft versus host response².

¹unwanted reactions occurred after intravenous administration of the drug. In some cases relapses were observed with the resumption of treatment. When the occurrence of a serious allergic reaction, the drug should be temporarily discontinued.

²there are reports of fatal outcomes in patients receiving G-CSF after allogeneic bone marrow transplantation.

On the part of the organs of hematopoiesis

infrequently: splenomegaly, rupture spleen (incl.with a fatal outcome), sickle-cell crisis *.

* Individual cases were noted in patients with sickle cell disease.

From the nervous system

Often: headache.

From the side of the cardiovascular system

often: lowering blood pressure;

infrequently: a syndrome of increased permeability of capillaries, veno-occlusive disease and an increase in the volume of circulating blood.

On the part of the respiratory system

Often: sore throat, cough, shortness of breath;

often: hemoptysis;

infrequently: acute respiratory distress syndrome adults (ARDS), respiratory failure, pulmonary edema *, interstitial lung disease *, pulmonary bleeding, infiltrates in the lung *.

* In some cases, these adverse events led to the arrest of respiration or to acute respiratory failure (including fatal).

From the skin and its appendages

Often: rash, alopecia;

infrequently: Sweet syndrome (acute febrile dermatosis, connection with filgrastim is not established), cutaneous vasculitis (with prolonged use, the mechanism of development in patients receiving filgrastim, unknown).

From the musculoskeletal system

Often: pain in the bones *, joints and muscles (weak or moderate);

infrequently: exacerbation of rheumatoid arthritis.

* includes pain in the bones, back pain, pain in the limbs, chest pain, neck pain.

From the side of the digestive system

Often: nausea, vomiting, constipation, diarrhea.

From the genitourinary system

often: dysuric disorders infrequently: change in the analysis of urine.

Co hand laboratory indicators

Often: increased activity of gamma-glutamyltransferase (G-GT), increased uric acid concentration, increased activity of alkaline phosphatase, lactate dehydrogenase;

infrequently: pseudogout.

General reactions

Often: asthenia, inflammation of mucous membranes, increased fatigue, decreased appetite;

often: pain in the chest;

infrequently: pain.

Donors

From the immune system

infrequently: anaphylactic reactions.

On the part of the organs of hematopoiesis

Often: leukocytosis (> 50x10⁹/ l, was observed in 41% of healthy donors) and transient thrombocytopenia (<100x10⁹/ l, was observed in 35% of healthy donors) - as a consequence of the pharmacological action of filgrastrim;

often: splenomegaly (asymptomatic);

infrequently: rupture of the spleen (including fatal outcome).

From the nervous system

very often: headache.

From the side of the cardiovascular system

infrequently: syndrome of increased permeability of capillaries.

* as a rule, in patients with extantaMr.malignant tumors, sepsis, repeatedly undergoing chemotherapy or apheresis.

On the part of the respiratory system

often: dyspnea;

infrequently: pulmonary hemorrhage, infiltrates in the lungs, hemoptysis, hypoxic conditions.

From the musculoskeletal system

Often: pain in the bones *, joints and muscles (transient);

infrequently: exacerbation of rheumatoid arthritis.

* includes pain in the bones, back pain, pain in the limbs, chest pain, neck pain.

Co hand laboratory indicators

often: increased activity of alkaline phosphatase, lactate dehydrogenase;

infrequently: increased activity of aspartate aminotransferase, increased concentration of uric acid.

Patients with THC

On the part of the organs of hematopoiesis

Often: anemia, splenomegaly (progressing in a number of cases);

often: thrombocytopenia, rupture of the spleen.

From the nervous system

very often: headache (less than 2% of patients).

On the part of the respiratory system

Often: nose bleed.

From the skin and its appendages

Often: rash (less than 2% of patients);

often: alopecia (less than 2% of patients), cutaneous vasculitis (with prolonged use, in 2% of patients).

From the musculoskeletal system

Often: pain in the bones¹, joints and muscles (weak or moderate), arthralgia (less than 2% of patients);

often: osteoporosis² (less than 2% of patients).

¹includes pain in the bones, pain in the blue, pain in the extremities, chest pain, pain in the neck.

²also in pediatric patients with TCH, receiving long-term treatment with filgrastim, described frequent cases of a decrease in bone density and the development of osteoporosis.

From the side of the digestive system

Often: diarrhea, hepatomegaly (less than 2% of patients).

From the genitourinary system

often: hematuria;

infrequently: proteinuria.

Co hand laboratory indicators

Often: rise concentration of uric acid, increased activity of alkaline phosphatase, lactate dehydrogenase, increased glucose concentration.

Other

often: pain at the injection site, increased fatigue, reactions at the injection site (less than 2% of patients).

Patients with HIV

On the part of the blood and lymphatic system

often: splenomegaly¹;

frequency is unknown: sickle cell crisis.

From the side of musculoskeletal systems

Often: bone pain² and muscles.

¹ the association of splenomegaly with the drug was observed in less than 3% of patients. In all cases, during medical examination, splenomegaly was of mild or moderate severity with a benign clinical current; no cases of hypersplenism were noted, no patient underwent splenectomy. Since splenomegaly is often present in patients with HIV and to some extent in most AIDS patients, the relationship with filgrastim is not clear.

²includes pain in the bones, back pain, pain in the limbs, chest pain, neck pain.

Overdose:

Symptoms of filgrastim overdose are not established.

Interaction:

The safety and efficacy of Zarcio® on the same day as myelosuppressive cytotoxic chemotherapeutic agents have not been established.

Due to the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to prescribe Zarcio® within 24 hours before or after the administration of these drugs.

With the simultaneous administration of Zarcio® 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® with a combined prescription, but such studies have not been conducted.

Due to pharmaceutical incompatibility, Zarcio® can not be mixed with 0.9% sodium chloride solution.

Special instructions:

Treatment with Zarcio® should only be performed under the supervision of an oncologist or hematologist who has experience with the use of G-CSF,agnostic possibilities.

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

Since data on the safety and efficacy of Zarcio® for patients with secondary acute myelocytic leukemia (AML) are limited, Zarcio® should be given with caution. Safety and efficacy of Zarcio®, first prescribed for patients with AML at the age of 55 years without cytogenetic abnormalities [t(8; 21), t(l 5; 17) and inv(16)] have not been established.

Leukocytosis

The number of leukocytes in the blood reaches or exceeds 100 x 10⁹/ L in less than 5% of patients who received a daily dose of Zarcio® more than 0.3 million units / kg (0.0003 mg / kg) of body weight. There is no information about any side effects, directly

Due to 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 leukocytes exceeds 50x10⁹ After reaching the expected nadir, immediately discontinue the drug. If Zarzio ® is used to mobilize GTSKK, it must be canceled or reduced dose with an increase in the number of white blood cells to> 70x10⁹.

The risk associated with increasing the dose of chemotherapy

Special care must be taken when treating 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 more toxic effects on the cardiovascular system, respiratory system, nervous system and skin (see instructions for the medical use of used chemotherapeutic drugs).

Monotherapy with Zarcio® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy.If higher doses of chemotherapy are used (eg, full doses according to the prescribed regimens), the risk of severe thrombocytopenia and anemia increases.

It is recommended to regularly monitor such indicators of a clinical blood test, as hematocrit and the number of platelets. 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 efficacy of Zarcio® in patients with a significantly reduced number of myeloid progenitor cells has not been studied.

Zarcio® increases the number of neutrophils by primarily affecting 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 result of bone marrow infiltration by tumor cells), the amount of neutrophils formed may be lower.There are data on the development of the "graft-versus-host" (GVHD) and lethal outcomes in patients receiving G-CSF after allogeneic bone marrow transplantation.

Mobilization of peripheral blood stem cells (PSSC)

There have been no prospective randomized studies devoted to the selection of the optimal method of mobilization (filgrastim in monotherapy or in combination with myelosuppressive therapy). The choice of method of mobilization should be carried out taking into account the individual characteristics of the patient.

Prior treatment cytotoxic agents

In patients who had previously undergone intensive myelosuppressive therapy, against the backdrop of the use of Zarcio® to mobilize PSKK, there may not be an increase in the number of PSDM sufficient to the recommended minimum concentration (> 2.0x10⁶ CD34 + cells / kg) or increased platelet recovery rate. 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 carmustia 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 a CPCK transplant is planned, it is recommended that stem cells be mobilized early in the 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 not sufficient, consideration should be given to the use of alternative therapies that do not require the use of progenitor cells.

Estimation of the number of peripheral blood stem cells

When assessing the number of PSKCs that have been mobilized in patients with Zarcio®, special attention should be given to the quantification method. Results of flow-cytometric analysis by quantity 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 has shown that there is a complex but stable relationship between the amount injected into reinfusion Cd34+ cells and the rate of recovery of platelet count after the use of high doses of chemotherapy drugs. Minimal number> 2,0х10⁶ Cd34+ cells / kg leads to a sufficient recovery of hematological parameters and is recommended based on published data. amount Cd34+ cells, exceeding the indicated value, is accompanied by faster normalization; if the number of cells does not reach this concentration, recovery of blood counts is slower.

Healthy donors before conducting an allogeneic transplantmacentnersuu PSCC

Mobilization of PSKC does not have a direct clinical result for healthy donors and can be performed solely for the purpose of allogeneic stem cell transplantation.

Mobilization of PSKC can be prescribed 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.

There have been reports of very frequent cases of thrombocytopenia in healthy donors.

It is necessary to strictly control the number of platelets. Transient thrombocytopenia (number of platelets <100x10⁹/ l) after the appointment of Zarcio® and the conduct of leukapheresis is observed in 35% of donors. Among them, 2 cases of thrombocytopenia with a platelet count <50x10⁹/ l after carrying out of a leukapheresis.

If more than one leukapheresis session is required, the condition of donors with a platelet count of less than 100x10⁹/ l ; with a platelet count of less than 75x10⁹/ l apheresis is not recommended.

Leukapheresis should not be given 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> 70x10⁹/ 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, there were cases of transient cytogenetic changes. The significance of these manifestations is not known.

Monitoring of the safety of Zarcio® in healthy donors continues. At present, the risk of developing a malignant myeloid clone in donors can not be ruled out. Medical centers conducting 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 Zarcio® in a remote period.

There are reports of frequent, mostly asymptomatic cases of splenomegaly, as well as of infrequent 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). Consider the risk of rupture of the spleen in donors and / or patients if they have pain in the upper left part of the abdominal cavity or upper arm.

In the post-gastritis period, healthy donors have very rare cases of adverse effects on the respiratory system (hemoptysis, pulmonary hemorrhage,infiltrative changes in the lungs, dyspnea and hypoxia). 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 Zarcio®

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

In patients receiving high-dose chemotherapy before transplantation, cases of veno-occlusive disease are described.

Severe chronic neutropenia (THC)

Number of blood cells

There have been reports of frequent cases of thrombocytopenia.

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

There are other possible changes in the blood formula that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

The development of acute leukemia or myelodysplastic syndrome (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 should be a general clinical analysis with the definition of the leukocyte formula and the number of platelets, determine the morphology of the bone marrow and karyotype. During clinical trials, a small number (approximately 3%) of patients with TCN receiving flngrastim were 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 connection with filgrastim therapy is not determined. Approximately 12% of patients with initially unchanged cytogenetic parameters in the second survey showed changes, including monosomia in 7 pairs of chromosomes.

If a patient with TCN exhibits cytogenetic disorders,it is necessary to carefully evaluate the relationship between risk and benefit from continued therapy with Zarcio®; The drug should be withdrawn in the case of development of MDS or leukemia. It is currently unclear whether the prolonged use of Zarcio®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.

There have been reports of very frequent cases of splenomegaly and spleen rupture. In connection with this, it is necessary to take into account the risk of enlargement or rupture of the spleen in patients with TXH if they have pain in the upper left part of the abdominal cavity or upper arm. Increased spleen is a likely effect associated with treatment with Zarcio®. During clinical trials, 31% of patients showed palpation with 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; 3% of patients may need splenectomy. 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.

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

There were cases of a syndrome of increased capillary permeability (Clarkson's disease), whose clinical manifestations include lowering of arterial pressure, hypoapinebuminemia, generalized edema and haemoconcentration. Patients who have the above symptoms should be carefully observed, intensive therapy may be necessary.

HIV infection

Number of blood cells

It is necessary to strictly control the absolute number of neutrophils (ASC), especially during the first weeks of therapy with Zarcio®. In some patients, there can be a very rapid and significant increase in ACN at the initial dose of Zarcio®.During the first 2-3 days of drug administration, it is recommended to measure ACN daily. Subsequently, ACN should be tested 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 an interruption in the use of Zarcio® at a dose of 30 million ED / day (0.300 mg / day), the patient may experience significant fluctuations in AFN during treatment. In order to determine the minimum ACN (nadir), it is recommended that a general blood test be performed before each injection of Zarcio®.

There have been reports of frequent cases of splenomegaly in patients with HIV infection. Consider the risk of enlargement or rupture of the spleen in patients with pain in the upper left part of the abdominal cavity or upper arm.

Risk, caused by the use of high doses of myelosuppressive medicines

Monotherapy with Zarcio® is not used to prevent the development of thrombocytopenia and anemia with the use of myelosuppressive drugs. In the case of higher doses or several myelosuppressive drugs in combination with Zarcio® therapy,the risk of developing thrombocytopenia and anemia is increased. Regular monitoring of a detailed blood test is recommended.

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 neoplasms, for example, lymphoma. In detecting infiltrative lesions of bone marrow of inflammatory origin or malignant neoplasm, concomitantly with the use of Zarcio® 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 involvement of infectious genesis or neoplastic tumors 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 who have recently had 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 acute respiratory distress syndrome (ARDS). In case of ARDS detection, the use of Zarcio® is stopped and appropriate treatment is prescribed.

Patients with concomitant bone disease and osteoporosis, with prolonged (more than 6 months) use of Zarcio®, it is recommended 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.

After withdrawal of therapy with Zarcio®, a decrease in the number of circulating neutrophils by approximately 50% is usually observed within 1-2 days. Their number is normalized within 1-7 days.

There are reports of infrequent cases of splenomegaly and splitting of the spleen in cancer patients. Some cases of rupture of the spleen were accompanied by lethal outcomes. In this regard, it is necessary to take into account the risk of enlargement or rupture of the spleen in such patients if they have pain in the upper left part of the abdominal cavity or upper arm.

Effect on the ability to drive transp. cf. and fur:

There were no cases of adverse effects of Zarcio® on the rate of psychomotor reactions; The effect of the drug on the ability to drive vehicles and mechanisms has not been established.

Form release / dosage:Solution for intravenous and subcutaneous administration, 30 million units / 0.5 ml, 48 million units / 0.5 ml.

Packaging:

Primary packaging

For 0.5 ml of the preparation (30 million units and 48 million units) in a syringe of colorless transparent borosilicate glass type I with a capacity of 1 ml, equipped with a limiter of the piston stroke of bromobutyl rubber, coated with fluoropolymer,and a non-removable (integrated into the syringe body) hypodermic injection needle made of stainless steel with a rubber protective cap and a polypropylene cap, as well as a special safety cap for the needle after the injection (to prevent trauma due to needle mischief by negligence) or without it.

Secondary packaging

1, 2 or 3 syringes per blister.

For 1 or 2 blisters with 1 syringe together with instructions for use in a pack of cardboard.

For 1 blister with 2 syringes and 1 blister with 3 syringes together with instructions for use in a pack of cardboard.

2 blisters with 2 syringes and 2 blisters with 3 syringes together with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C.

It is recommended to store it in a cardboard box.

Keep out of the reach of children place.

Shelf life:

3 years.

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

Note: it is possible to store the drug once at room temperature (not above 25 ° C) for 72 hours. After 72 hours, the drug should not be used it is recommended and it must be recycled.

Terms of leave from pharmacies:On prescription

Registration number:LP-001302

Date of registration:29.11.2011

The owner of the registration certificate:Sandoz GmbHSandoz GmbH Austria

Manufacturer: & nbsp

IDT BIOLOGIKA, GmbH Germany

SANDOZ, GmbH Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp22.09.2015

Illustrated instructions

Instructions

Zarcio® (Zarcio®)