Grazalva - instructions for use, dose, side effects, contraindications

The active substance of the drug is filgrastim - recombinant human granulocyte colony-stimulating factor (G-CSF). Filgrastim has the same biological activity as the endogenous human G-CSF, and differs from the latter only in that it is a non-glycosylated protein with an additional N-terminal methionine residue. Filgrastim, obtained by recombinant DNA technology, is isolated from the cells of the bacterium Escherichia coli, in the genetic apparatus of which a gene encoding the G-CSF protein was introduced.

Human granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow. Filgrastim, which has G-CSF activity,significantly increases the number of neutrophils in peripheral blood already in the first 24 hours after administration with a slight increase in the number of monocytes. In some patients with severe chronic neutropenia filgrastim can also cause a slight increase in the number of circulating eosinophils and basophils in comparison with the baseline.

In the range of recommended doses of filgrastim, a dose-dependent increase in the number of neutrophils with normal or increased chemotactic and phagocytic activity is observed. After the end of treatment, the number of neutrophils in peripheral blood is reduced by 50% within 1-2 days and returns to normal level during the next 1-7 days.

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

Filgrastim significantly reduces the duration of febrile neutropenia, the duration of antibiotic therapy and hospitalization after induction chemotherapy in acute myelogenous leukemia, and after myeloablative therapy followed by bone marrow transplantation,without affecting the frequency of fever and infectious complications and without reducing the duration of the febrile period in patients after myeloablative therapy followed by bone marrow transplantation.

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

The use of filgrastim in recipients of mobilized allogeneic PSKK results in a more rapid normalization of hematological parameters in comparison with allogeneic bone marrow transplantation. The normal number of platelets is restored and there is no need to control thrombocytopenia.

The appointment of filgrastim to healthy donors at 10 μg / kg body weight / day subcutaneously daily for 4-5 days usually allows for twoleukapheresis to obtain an amount of PSKK equal to or greater than 4x10⁶ CD34 + cells / kg body weight of the recipient.

In children and adults with severe chronic neutropenia (congenital, recurrent or idiopathic) filgrastim Stably increases the number of neutrophils in peripheral blood, reduces the incidence of infections and associated complications. The appointment of filgrastim to patients with HIV infection allows maintaining a normal level of neutrophils, which contributes to the systematic implementation of antiviral and / or myelosupressive therapy. There were no signs of an increase in HIV replication with filgrastim treatment.

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

Pharmacokinetics:

As with intravenous and subcutaneous administration of the drug, the elimination of filgrastim proceeds according to the rules of kinetics of the first order. The average half-life of filgrastim from serum is about 3.5 hours, the clearance is 0.6 ml / min / kg. With prolonged use of filgrastim up to 28 days after autologous bone marrow transplantation, no signs of cumulation and an increase in half-life were observed.

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

Indications:

Grazalvu is prescribed as a preventive and curative remedy for the following purposes:

- Reduction of the duration of neutropenia and a decrease in the frequency of febrile neutropenia in patients receiving cytotoxic chemotherapy for malignant diseases (with the exception of chronic myelogenous leukemia and myelodysplastic syndrome).

- Reduction of the duration of neutropenia in patients receiving myeloablative therapy with subsequent bone marrow transplantation.

- Mobilization of peripheral blood stem cells in patients.

- Long-term therapy to increase the number of neutrophils and reduce the frequency and duration of infectious complications in children and adults with severe chronic congenital, periodic or idiopathic neutropenia (absolute neutrophil count ≤0.5x10⁹/ l) and severe or recurrent infections in the history.

- Reduction of the risk of bacterial infections in persistent neutropenia (absolute number of neutrophils ≤1,0х10⁹/ l) in patients with developed stage of HIV infection with ineffectiveness of other neutropenia control agents.

- Mobilization of peripheral blood stem cells (PSSCs) in healthy donors for allogeneic transplantation of PMSC.

Contraindications:

- Hypersensitivity to filgrastimu or other components of the drug.

- Chronic myelogenous leukemia and myelodysplastic syndrome (see "Special instructions and precautions").

- Severe congenital neutropenia (Costman's syndrome) with cytogenetic disorders (see "Special instructions and precautions").

- Use to increase doses of cytotoxic chemotherapeutic drugs above recommended.

- Lactation.

Pregnancy and lactation:

Safety filgrastim for pregnant women is not established. There are published data on the penetration of filgrastim through the placental barrier. Data on the teratogenicity of filgrastim in studies on rats and rabbits have not been obtained. In rabbits who received filgrastim, there was an increased incidence of miscarriages, but there was no abnormality of development.

When prescribing Grazalva, pregnant women should correlate the expected therapeutic effect with the possible risk to the fetus.

Dosing and Administration:

Patients receiving cytotoxic chemotherapy for malignant diseases

The recommended dose is 0.5 million ME (5 μg) / kg body weight once a day. The first dose should be administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. Grazalva can be administered by daily injections or daily short (30-minute) IV infusions on a 5% glucose solution (see "Instructions for Use.") Preferably the route of administration, with iv administration of filgrastim can be shortened.

The Grazalva is injected daily until the number of neutrophils exceeds the expected minimum (nadir) and reaches the normal range. In patients receiving cytotoxic chemotherapy for solid tumors, lymphomas and lymphocytic leukemia, the duration of therapy is up to 14 days. After induction and consolidation therapy of acute myelogenous leukemia, the duration of Grazalva's application can increase up to 38 days.The duration of treatment with Grazalva depends on the type, doses and the used scheme of cytotoxic chemotherapy.

Usually a transient increase in the number of neutrophils is observed 1-2 days after the initiation of treatment with filgrastim. To achieve a stable therapeutic effect, it is necessary to continue Grasalva therapy until the amount of neutrophils exceeds the expected minimum (nadir) and reaches the normal level. It is not recommended to cancel treatment prematurely, until the number of neutrophils passes through the nadir.

Patients receiving myeloablative therapy followed by bone marrow transplantation

The initial dose of 1 million IU (10 μg) / kg of body weight per day is given in the form of a 30-minute or continuous 24-hour IV infusion or continuous 24-hour infusion. For intravenous infusion and infusion of Gracalva dilute 20 ml of 5% glucose solution (see "Instructions for use").

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

After the moment of the maximum decrease in the number of neutrophils passes, the daily dose is corrected depending on the dynamics of the neutrophil content as follows:

Number of neutrophils	The dose of filgrastim
More than 1,0х10⁹/ l for 3 consecutive days	Reduce to 0.5 million ME (5 μg) / kg / day
More than 1,0х10⁹/ l for the next 3 consecutive days	Filgrastim is canceled
If during treatment the absolute amount of neutrophils decreases to less than 1.0 × 10⁹/ l, the dose of the drug is increased again in accordance with the above scheme.

Mobilization of peripheral blood stem cells (SBSC) in patients receiving myelosuppressive or myeloablative therapy followed by autologous transfusion of PSKK

To mobilize PSKK as an independent therapy, 1 million IU (10 μg) / kg per day in the form of a continuous 24-hour infusion or by way of injection once a day for 5-7 consecutive days. For infusion Grasalva dilute 20 ml of 5% glucose solution (see "Instructions for use"). Usually enough one or two leukapheresis on the 5th or 6th days. In the case of additional leukapheresis, the appointment of Grazalva in the same dose should be continued until the final leukapheresis.

To mobilize PSKC after mielosupressivnoy chemotherapy, 0.5 million ME (5 μg) / kg per day by daily injections, starting from the first day after completion of chemotherapy and until the amount of neutrophils passes through the expected minimum and does not reach normal values.Leukapheresis should be performed during the period of increasing the number of neutrophils with <0.5x10⁹/ l to> 5.0x10⁹/ l. Patients who did not receive intensive chemotherapy, it is enough to have one leukapheresis. In some cases, additional leukapheresis is recommended.

Patients with severe chronic neutropenia (THC)

With congenital neutropenia, Grazalva is prescribed at an initial dose of 1.2 million IU (12 μg) / kg per day by injections once or divided into several injections.

For idiopathic or intermittent neutropenia, an initial dose of 0.5 million IU (5 μg) / kg / day is given once or by several administrations.

Correction of dose: Grazalva is injected daily until the neutrophil count is 1.5 × 10⁹/ 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 effect of therapy. Subsequently, every 1-2 weeks, an individual dose adjustment is performed to maintain the average number of neutrophils in the range of 1.5x10⁹/ l up to 10x10⁹/ l.In patients with severe infections, a scheme with a faster increase in dose can be used. The safety of filgrastim with prolonged treatment of patients with TCN doses greater than 2.4 million ME (24 μg) / kg per day is not established.

Patients with HIV infection

To restore the number of neutrophils

The initial dose is 0.1 million IU (1 μg) / kg per day daily by single injection, with a maximum dose of up to 0.4 million ME (4 μg) / kg / day until the neutrophil count more than 2,0x10⁹/ l).

To maintain a normal amount of neutrophils

At the end of neutropenia, the minimum effective dose of the drug is determined to maintain the normal amount of neutrophils. It is recommended to start with the introduction of 30 million ME (300 μg) (regardless of body weight) after a day. It is necessary to maintain the number of neutrophils more than 2.0x10⁹/ l, therefore later individual dose adjustment may be required depending on the level of neutrophils in the patient. Usually this dose is sufficient to administer 3 times a week, sometimes to maintain the amount of neutrophils> 2.0x10⁹/ l requires a long-term administration of the drug.

Mobilization of peripheral blood stem cells (PSSC) in healthy donors for allogeneic transplantation of PMSC

The recommended dose is 1 million.ME (10 μg) / kg per day by 24-hour infusion (see "Instructions for Use") or SC injection once a day for 4-5 consecutive days. Leukapheresis is carried out from the 5th day and, if necessary, until the 6th day in order to obtain 4x10⁶ CD34 + cells / kg body weight of the recipient.

Data on the safety and efficacy of filgrastim in donors under the age of 16 and older than 60 years are not available.

Special instructions for dosing

Children: Grazalva is used in patients with TCN and oncological diseases at the same doses as in adults receiving myelosuppressive cytotoxic chemotherapy.

Elderly age: special recommendations for senile patients are not established due to insufficient number of studies.

Instructions for use

Grazalva is bred only with 5% glucose solution (dextrose), it is not allowed to dilute with 0.9% sodium chloride solution.

The preparation after dilution can be adsorbed by glass and plastics.

If Grazalva is diluted to a concentration of less than 1.5 million IU (15 μg) in 1 ml, to prevent adsorption, it is necessary to add whey human albumin in an amount such that the final concentration of albumin is 2 mg / ml. For example, when the total dose of Grazalva is diluted, less than 30 million.ME (300 μg) to a final solution volume of 20 ml, 0.2 ml of a 20% solution of albumin should be added.

Do not dilute Grasalva to a concentration of less than 0.2 million IU (2 μg) / mL.

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

The diluted solution of Grazalva can be stored at a temperature of 2 to 8 ° C for no more than 24 hours. After use, the syringe with the rest of the solution is destroyed.

Preferred areas of the body for subcutaneous administration of Grasalva are shown in the figure:

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

Side effects:

In cancer patients

Treatment with filgrastim in recommended doses is often accompanied by pain in the bones and muscles. As a rule, they are mild or moderate (10%), but sometimes they are strong (3%), and in most cases are stopped by usual analgesics. Less common side effects include micturition disorders (mainly mild or moderate dysuria).

According to randomized placebo-controlled clinical trials filgrastim did not increase the incidence of adverse reactions to cytotoxic chemotherapy. Adverse events with the same frequency observed in patients receiving filgrastim / chemotherapy and placebo / chemotherapy included nausea, vomiting, alopecia, diarrhea, lethargy, general weakness, anorexia, mucositis, headache, cough, skin rash, pain in the thoracic cage, sore throat, constipation and nonspecific pain (without indicating the diagnosis).

In the treatment with filgrastim, a reversible, dose-dependent and usually mild or moderate increase in the concentrations of lactate dehydrogenase, alkaline phosphatase, serum uric acid and γ-glutamyltransferase, respectively, in 50%, 35%, 25% and 10% of patients was observed at recommended doses.

Occasionally, a transient reduction in blood pressure that does not require treatment is possible.

Sometimes, patients who received high-dose chemotherapy followed by autologous bone marrow transplantation, had vascular disorders, for example, veno-occlusive disease and water metabolism disorders. Their causal relationship with filgrastim was not established.

In rare cases, those who received filgrastim patients had skin vasculitis, the mechanism of which is unclear.

There were cases of Sweet syndrome (acute febrile neutrophilic dermatosis). There is no known causal relationship with filgrastim in these cases, since a significant proportion of them belonged to patients with leukemia, and Sweet syndrome is characteristic of this disease.

In some cases, there was an exacerbation of rheumatoid arthritis.

Some patients noted the formation of infiltrates in the lungs, leading to the development of pulmonary insufficiency or adult respiratory distress syndrome, which can result in death.

Rare cases of the appearance of symptoms indicating allergic-type reactions are described, and about half of them were associated with the administration of the first dose. There were more such reactions after intravenous administration of the drug. Sometimes the resumption of treatment was accompanied by a relapse of symptoms.

In patients with THC

The most frequent adverse reaction attributed to filgrastim is bone pain, sometimes along with muscle pain.

Other side effects include enlargement of the spleen, which in a small number of patients may progress, as well as thrombocytopenia.

Headaches and diarrhea were described soon after initiation of filgrastim treatment in less than 10% of patients, anemia and nasal haemorrhage after long-term treatment were approximately the same frequency.

There was a transient and clinically asymptomatic increase in serum concentrations of uric acid, lactate dehydrogenase and alkaline phosphatase, as well as a transient moderate decrease in blood glucose after eating.

Adverse events associated with treatment with filgrastim and occurred in less than 2% of patients with THC included reactions at the injection site, headache, enlargement of the liver, joint pain, alopecia, osteoporosis and skin rash. With prolonged therapy, skin vasculitis was observed in 2% of patients with TCN, and in very rare cases - proteinuria and / or hematuria.

The frequency of the above symptoms in some patients with TCN decreased over time.

In HIV-infected

Clinical studies have established that the most common undesirable reaction that can be attributed to filgrastim is pain in the bones and muscles, usually weak or moderate. The frequency of symptoms is about the same as in cancer patients.

Less than 3% of patients receiving filgrastim treatment have a slight or average increase in the spleen with a favorable clinical course; hypersplenism, as well as splenectomy, was not found in any of the patients. Since with HIV infection and AIDS usually the spleen is increased, the connection of this phenomenon with filgrastim remains unexplained.

In healthy donors in the mobilization of peripheral blood stem cells (PSSC)

In healthy SUBSD donors, adverse reactions to filgrastim most often manifested a weak or moderately severe pain in the bones and muscles. 41% of donors had leukocytosis (more than 50x10⁹/ l), and in 35% - after administration of filgrastim and carrying out of leukapheresis, transient thrombocytopenia was detected (the number of platelets less than 100x10⁹/ l).

In some healthy donors, there was a clinically asymptomatic increase in the concentrations of alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase and uric acid.

In rare cases, there were symptoms of exacerbation of arthritis, very rarely severe allergic reactions.

Headache, noted by donors of PMSC, is believed to be associated with filgrastim.

In isolated cases in healthy donors of PMSC who received a granulocyte colony-stimulating factor, a rupture of the spleen occurred.

Overdose:Action Grazalva in case of an overdose is not established. After the drug is discontinued, the number of circulating neutrophils usually first decreases and then returns to normal.

Interaction:

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

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

Data on the possible interaction with other hematopoietic growth factors and cytokines are not available.

Lithium, stimulating the release of neutrophils, can enhance the action of filgrastim. This interaction has not been investigated, but there is no information about its undesirable consequences.

Grasalva is not pharmaceutically compatible with 0.9% sodium chloride solution.

Special instructions:

Treatment Grazalva should be carried out only in cooperation with a cancer center that has specialists with experience fillograstim patients with hematological diseases and with the necessary diagnostic capabilities.

Procedures for mobilization and apheresis of cells should be carried out in cooperation with an oncological or hematological center, which has specialists with sufficient experience in this field and the possibilities of adequate monitoring of hematopoietic progenitor cells.

Growth of malignant cells

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

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

The safety and efficacy of filgrastim in patients with secondary acute myelogenous leukemia have not been adequately studied, and therefore Grazalva should be administered with caution.

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

Other Precautions

Patients with concomitant osteal pathology and osteoporosis receiving continuous treatment with Grazalva for more than 6 months are shown to control bone density.

In patients with impaired renal or hepatic function, dose adjustment is not required.

In the treatment with filgrastim, the development of adult respiratory distress syndrome (ARDS) is possible, the first signs of which can be cough, fever and shortness of breath, it is also possible to form lung infiltrates detected by roentgenology and respiratory distress. In this case, you should cancel Grazalva and prescribe the necessary treatment.

Special precautions for cancer patients

Leukocytosis

In patients receiving chemotherapy with cytotoxic agents

Considering the possible risk associated with high leukocytosis, during treatment with Grazalva, the number of leukocytes must be regularly monitored. In the first 2-3 days of treatment it is recommended to determine the number of neutrophils daily, then during the first two weeks of therapy - at least twice a week, and during maintenance treatment - at least once a week or a week. If the number of white blood cells after passing the expected minimum exceeds 50x10⁹/ l, treatment Grazalva should be immediately canceled. However, if filgrastim It is used to mobilize PSKK, the drug is canceled or the dose is reduced in excess of the number of white blood cells 70x10⁹/ l.

The risk associated with high-dose chemotherapy

Particular caution should be exercised in the treatment of patients receiving high-dose chemotherapy, since in these cases, the improvement in the outcome of malignant neoplasm has not been established, while increased doses of chemotherapeutic agents had more pronounced toxicity, leading to the development of cardiac, pulmonary, neurological and dermatological reactions.

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

Particular caution should be exercised when applying single-component or combination chemotherapeutic regimens, known for their ability to cause severe thrombocytopenia.

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

Other precautions

The effect of filgrastim in patients with a significantly reduced number of myeloid progenitor cells has not been studied. The drug increases the number of neutrophils by primarily affecting the neutrophil precursor cells. Therefore, in patients with a low content of progenitor cells (for example, who underwent intensive radiation therapy or chemotherapy, as well as with tumor infiltration of the bone marrow), the degree of increase in the number of neutrophils can be reduced.

Hereditary intolerance to fructose. Contained in the preparation sorbitol in the amount of 50 mg / ml should not have a negative effect on patients with hereditary intolerance to fructose. However, Grazalva should be used with caution in such patients.

Special precautions in patients undergoing mobilization of peripheral blood stem cells (JSSC)

Mobilization

Prospective randomized trials compared two recommended mobilization methods (only filgrastim or in combination with myelosuppressive chemotherapy) were not performed on the same contingent of patients. The individual characteristics of patients in various studies and the degree of discrepancy in the results of laboratory determination of the number of CD34 + cells make it difficult to directly compare the results of these studies. Therefore, it is difficult to recommend an optimal method. The choice of method of mobilization should be carried out depending on the purposes of treatment of the given patient.

Before the appointment of cytotoxic agents

Patients who have undergone active myelosuppressive therapy in the past may not have sufficient activation of PSMC up to the recommended minimum level (≥ 2.0x10⁶CD34 + cells / kg) or the acceleration of normalization of the number of platelets.

Some cytotoxic agents have a particular toxicity to the precursor cells of hemopoiesis and can adversely affect their mobilization. Such tools as melphalan, carmustine (BCNU) and carboplatin, if they have been prescribed for a long time before attempts to mobilize stem cells, can reduce its effectiveness. However, the use of melphalan, carboplatin or carmustine together with filgrastim was effective in the activation of stem cells. If it is planned to transplant PSKK, it is recommended to plan mobilization of stem cells at an early stage of treatment. Particular attention should be paid to the number of stem cells activated in such patients before high-dose chemotherapy. If the results of mobilization in accordance with the above criteria are not sufficient, alternative treatments that do not require the use of progenitor cells should be considered.

Assessment of the number of mobilized peripheral blood stem cells

Estimating the number of PSMCs mobilized in patients with filgrastim, special attention should be given to the quantification method.The results of flow cytometric analysis of the number of CD34 + cells differ depending on the specific technique, so care should be taken for recommendations based on the number of studies conducted in other laboratories.

The rate of normalization of platelet count after high-dose chemotherapy depends on the number of CD34 + cells injected into reinfusion. The recommended minimum amount of PSKK is ≥2,0x10⁶ CD34 + cells / kg. The number of progenitor cells exceeding this value seems to be accompanied by faster normalization, while the amount less than that indicated by a slower normalization of the blood composition.

Special precautions for healthy donors undergoing the mobilization of PSKK

Mobilization of PSKC in donors is not indifferent to their health and is used only before transplantation of allogeneic progenitor cells.

Mobilization of PMSC can be carried out by donors only if it meets the usual clinical and laboratory criteria for the donation of hematopoietic progenitor cells, in particular, attention should be paid to hematological indicators and the presence of infectious diseases.

The safety and efficacy of filgrastim in healthy donors under the age of 16 and older than 60 years have not been evaluated.

Grazalva is not recommended for pregnant and lactating women.

If more than one leukapheresis is needed, special attention should be paid to donors whose platelet counts to less than 100x10⁹/ l. Conduction of leukapheresis is not recommended if the number of platelets is less than 75x10⁹/ l, with the appointment of anticoagulants or known violations of hemostasis.

Grazalva should be canceled or the dose of the drug is reduced if the number of white blood cells is more than 70x10⁹/ l.

The monitoring period for the donor should be long to assess the safety of the drug. Donors who filgrastim for the mobilization of PSKK, should be monitored prior to the normalization of hematological parameters.

In addition, the risk of stimulating a malignant myeloid clone is not ruled out. The centers of apheresis are recommended to register and monitor the PSKK donors to ensure further data collection on the safety of the drug.

After applying filgrastim in healthy donors, rupture of the spleen is possible. In this regard, they are recommended to control the size of the spleen (palpation, ultrasound). It should be borne in mind the possibility of rupture of the spleen with complaints of pain in the upper left part of the abdomen or in the left shoulder.

Special precautions for recipients of allogeneic PSCCs mobilized with filgrastim

The literature data indicate that the immunological interaction of allogeneic PSKK and the recipient is characterized by a greater risk of developing an acute graft-versus-host response compared to bone marrow transplantation.

Special precautions in patients with THC

Investigation of blood composition

It is necessary to carefully monitor the number of platelets, especially during the first few weeks of treatment with filgrastim. If the patient manifests thrombocytopenia (the number of platelets stably below 100x10⁹/ l), consideration should be given to the temporary cancellation of the drug or the reduction of the dose. There may be other changes in the blood formula that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

Transformation into leukemia or myelodysplastic syndrome

Particular care should be exercised in the diagnosis of severe chronic neutropenia, it is necessary to differentiate them from other hematological diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia. Before the start of treatment should be a complete clinical analysis of the blood with the definition of the leukocyte formula and the number of platelets, as well as to explore the morphological picture of the bone marrow and karyotype.

If patients with TCN have cytogenetic disorders, it is necessary to carefully evaluate the benefits and risks of continuing therapy. With the development of myelodysplastic syndrome (MDS) or leukemia Grazalvu should be canceled. At present, it is not clear whether long-term treatment with filgrastim predisposes patients with severe chronic neutropenia to the development of cytogenetic abnormalities, MDS and leukemia. Such patients are recommended to carry out morphological and cytogenetic studies of the bone marrow regularly (approximately every 12 months).

Other cases

It is necessary to exclude such causes of transient neutropenia as viral infections.The enlargement of the spleen is a direct consequence of the treatment with filgrastim, a decrease in dose slows or stops the increase in the size of the spleen. The size of the spleen must be monitored regularly, in order to detect an abnormal increase in the volume of the spleen, it is enough to produce a palpation of the abdomen.

A small number of patients showed hematuria and / or proteinuria, and urine testing should be performed regularly to monitor them.

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

Special precautions for HIV infection

Examination of blood cells

It is necessary to carefully monitor the amount of neutrophils, especially during the first few weeks of treatment with filgrastim. In some patients, after the first injection, the therapeutic effect is very quickly manifested and the amount of neutrophils increases significantly. It is recommended to monitor the number of neutrophils in the first 2-3 days of filgrastim treatment daily, then in the first two weeks of treatment - at least twice a week, and during maintenance treatment - at least once a week or 2 weeks.

If the dose of 30 million.ME (300 μg) per day is not administered to the patient every day, after a while, strong fluctuations in the number of neutrophils begin to occur. To determine the reduction in the number of neutrophils or the true minimum level (nadir), it is recommended to take samples of the patient's blood for analysis immediately before the administration of the next dose of the drug.

Risk due to high-dose myelosuppressive therapy

Monotherapy with filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Because of the possibility of using more of chemotherapy drugs together with filgrastim or their high doses, the patient may be at greater risk of developing thrombocytopenia and anemia, and therefore it is recommended to regularly determine the number of blood cells (see above).

Infections and malignant neoplasms that cause myelosuppression

In patients with neutropenia caused by infiltration of the bone marrow by infectious agents (eg, with disseminated infection by the bacteria of the group Mycobacterium avium) or a tumor lesion of the bone marrow (lymphoma), in addition to filgrastim, specific treatment should be applied.The effect of filgrastim on neutropenia caused by infectious agents or malignant bone marrow tumors has not been adequately studied.

Special precautions in patients with sickle cell anemia

The literature published data that a large number of leukocytes in the case of sickle cell anemia is a prognostically unfavorable factor. Therefore sick sickle cell anemia filgrastim should be administered with caution, and during therapy carefully monitor the relevant clinical and laboratory indicators, paying special attention to the possible increase in the spleen and the development of blood vessel thrombosis.

Effect on the ability to drive transp. cf. and fur:Influence on ability to drive vehicles or work with mechanisms is not established.

Form release / dosage:Solution for intravenous and subcutaneous administration, 48 million IU / 0.8 mL.

Packaging:

Grazalva 48 million IU / 0.8 ml:

0.8 ml (48 million IU, corresponding to 480 μg filgrastim) in a single-use glass syringe (Glass I of type according to Hearth F. 3.2.1), graduated to 1 ml (scale division 0.1 ml), with a fixed injection needle covered with a protective cap, with a piston seal in the cylinder of a syringe made of elastomer type I (according to Hebrews 3.2.9).The syringe is placed in a contour mesh box made of PVC. One syringe with the preparation in a contour squeeze box made of PVC together with the instruction for use is placed in a cardboard box.

Storage conditions:

At a temperature of 2 ° C to 8 ° C in a dark place.

Keep out of the reach of children.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-006476/08

Date of registration:13.08.2008

Expiration Date:Unlimited

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

LEMERY, S.A. de C.V. Mexico

Representation: & nbspTeva Teva Israel

Information update date: & nbsp09.05.2017

Illustrated instructions

Instructions

Grazalva (Grasalva)