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

Filgrastim is a highly purified, non-glycosylated protein, consisting of 175 amino acids. It is produced by a strain Escherichia coli, at genome of which by genetic engineering methods introduced gene granulotsitarnogo colony-stimulating factor of human (G-CSF) - glycoprotein, regulating the formation of functionally active neutrophils and their release into the blood from the bone marrow. Leucostim®, containing recombinant G-CSF, significantly increases the number of neutrophils in peripheral blood as early as the first 24 hours after administration, with a slight increase in the number of monocytes. In patients with severe chronic neutropenia, Leucostim® can cause a slight increase in the number of circulating eosinophils and basophils.

Leucostim® dose-dependently increases the number of neutrophils with normal or increased functional activity. 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. The duration of action with intravenous administration may be shortened. The clinical significance of this phenomenon with repeated administration of the drug is unclear.

The use of Leucostim® 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) 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 PSKK, mobilized with the drug Leucostim®, accelerates the recovery of hematopoiesis, reduces the severity and duration of thrombocytopenia, the risk of hemorrhagic complications and the need for transfusion of platelet mass after myelosuppressive or myeloablative therapy.

The efficacy and safety of Leukostim® in adults and children receiving cytotoxic chemotherapy are the same.

In children and adults with severe chronic neutropenia (severe congenital, periodic, idiopathic neutropenia), Leucostim® steadily increases the number of neutrophils in peripheral blood, reduces the incidence of infectious complications. The administration of Leucostim® to patients with HIV infection helps maintain normal neutrophil counts and follow recommended doses of antiretroviral and / or other myelosuppressive therapy. Signs of increased replication of HIV with the use of the drug Leucostim® was not noted.

Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro.

Pharmacokinetics:

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

Regardless of the mode of administration, the elimination of filgrastim proceeds according to the rules of kinetics of the first order. The half-life is 3.5 hours, the clearance is 0.6 ml / min / kg.Long-term administration of filgrastim up to 28 days after autologous bone marrow transplantation does not result in cumulation and an increase in the half-life.

In patients with terminal stage of renal failure, an increase in the maximum concentration (C_mOh) and the area under the curve (AUC), and a decrease in the volume of distribution and clearance in comparison with healthy volunteers and patients with moderate-level renal failure.

Indications:

- Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant diseases (with the exception of chronic myelogenous leukemia and myelodysplastic syndrome), as well as neutropenia and its clinical consequences in patients receiving myeloablative therapy followed by allogeneic or autologous bone marrow transplantation.

- Mobilization of peripheral blood stem cells, including after myelosuppressive therapy.

- Severe congenital, periodic or idiopathic neutropenia (absolute number of neutrophils less than or equal to 0.5 × 10⁹/ l) in children and adults with severe or recurrent infections in the history.

- Persistent neutropenia (absolute number of neutrophils less than or equal to 1.0 × 10⁹/ l) in patients with advanced stage of HIV infection to reduce the risk of bacterial infections when ineffective or impossible to use other methods of treatment.

Contraindications:

- Hypersensitivity to filgrastimu or other components of the drug.

- Severe congenital neutropenia (Kostmann's syndrome) with cytogenetic disorders.

- The use of the drug in order to increase the doses of cytotoxic chemotherapeutic drugs is higher than recommended.

- Simultaneous administration with cytotoxic chemo- and radiotherapy.

- Terminal stage of chronic renal failure.

- Myelodysplastic syndrome (MDS) and chronic myelogenous leukemia (no data on efficacy and safety)

- Lactation.

- Newborn age (up to 28 days of life).

Carefully:

In pregnancy, malignant and premalignant diseases of myeloid nature (including acute myelogenous leukemia), sickle cell anemia, in combination with high-dosage chemotherapy.

Pregnancy and lactation:

Safety filgrastim for pregnant women is not established. Possible passage of the drug Leucostim® through the placental barrier in women. When prescribing Leukostim®, pregnant women should correlate the expected therapeutic effect with the possible risk to the fetus. In animal studies filgrastim did not have a teratogenic effect. There was an increased incidence of miscarriages, but no abnormalities of fetal development were noted.

There is no data on the penetration of filgrastim into breast milk. Use Leukostim® in nursing mothers is not recommended.

Dosing and Administration:

Daily subcutaneously (sc) or in the form of short intravenous (IV) infusions (30-minute). Also, the drug can be administered in the form of 24-hour intravenous or subcutaneous infusion.

The choice of route of administration depends on the specific clinical situation. Preferably a subcutaneous route of administration.

Standard schemes of cytotoxic chemotherapy

In a dose of 5 mcg (0.5 million IU) / kg once a day daily sc, or in the form of short intravenous infusions. The first dose of the drug is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. A transient increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Leucostim®.To achieve a stable therapeutic effect, it is necessary to continue therapy with Leukostim® until the number of neutrophils passes the expected minimum and does not reach normal values. If necessary, the duration of the course of therapy can be up to 14 days, depending on the severity of the disease and the severity of neutropenia. After induction and consolidation therapy of acute myeloid leukemia, the duration of therapy with Leucostim® can increase up to 38 days, depending on the type, dosage and mode of administration of the cytotoxic drugs used.

It is not recommended to cancel Leukostim® prematurely, before the expected minimum of neutrophil count.

After myeloablative chemotherapy followed by bone marrow transplantation:

The recommended initial dose is 10 μg (1.0 million IU) / kg diluted in 20 ml of a 5% dextrose solution in the form of a 30-minute or 24-hour intravenous infusion or by continuous subcutaneous infusion for 24 hours. The first dose of the drug Leucostim® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and with bone marrow transplantation - no later than 24 hours after bone marrow infusion. The duration of therapy is no more than 28 days.After the maximum reduction in the number of neutrophils, the daily dose is adjusted depending on the dynamics of their number. If the neutrophil count in peripheral blood exceeds 1.0 x 10⁹/ l for three consecutive days, the dose of Leucostim is reduced to 5.0 μg (0.5 million IU) / kg; if at this dose the absolute number of neutrophils exceeds 1.0x10⁹/ l for another three consecutive days, Leucostim® is canceled. If during the treatment period the absolute number of neutrophils decreases less than 1.0 x 10⁹/ l, the dose of Leucostim® is increased again, in accordance with the above scheme.

Mobilization of peripheral blood stem cells after myelosuppressive therapy followed by autologous transfusion of PSKK with or without bone marrow transplantation or in patients with myeloablative therapy followed by transfusion with PSKK:

At a dose of 10 μg (1.0 million IU) / kg by subcutaneous injection once a day or continuous 24-hour subcutaneous infusion for 6 consecutive days, usually two procedures of leukapheresis are sufficient in a row for the 5 th, 6 th days. In some cases, additional leukapheresis is possible. The appointment of Leucostim® should be continued until the last leukapheresis.

Mobilization of PMSC after myelosuppressive therapy:

In a dose of 5 μg (0.5 million)ME) / kg by daily subcutaneous injections, starting from the first day after completion of chemotherapy and until the amount of neutrophils passes through the expected minimum and reaches normal values. Leukapheresis should be performed during the period when the absolute number of neutrophils rises from less than 0.5 x 10⁹/ l to more than 5.0 х10⁹/ l. Patients who did not receive intensive chemotherapy, it is enough to have one leukapheresis. In some cases, additional leukapheresis is recommended.

Mobilization of PSKC in healthy donors for allogeneic transplantation:

In a dose of 10 mcg (1.0 million units) / kg per day subcutaneously, for 4-5 days. Leukapheresis is carried out from the 5th day and, if necessary, until the 6th day in order to obtain Cd34+ cells in an amount> 4x10⁶ cells / kg body weight of the recipient. The efficacy and safety of using Leucostim® in healthy donors under the age of 16 and older than 60 years have not been investigated.

Severe chronic neutropenia (THC)

Daily subcutaneously, once or divided into several administrations. The initial dose for congenital neutropenia is 12 μg (1.2 million IU) / kg per day, with idiopathic or intermittent neutropenia - 5 μg (0.5 million IU) / kg per day, to a stable excess of the number of neutrophils 1.5 × 10⁹/ l.After achieving the therapeutic effect, the minimum effective dose should be determined to maintain this level of neutrophils. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient's response to therapy. Subsequently, every 1 to 2 weeks, a dose adjustment can be performed to maintain the amount of neutrophils in the range of 1.5-10 x 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 the treatment, the full therapeutic effect is observed with the appointment of filgrastim doses up to 24 μg / kg / day. The daily dose of Leucostim® should not exceed 24 μg / kg.

Neutropenia in HIV infection:

The initial dose of 1-4 μg (0.1-0.4 million IU) / kg per day once subcutaneously to normalize the amount of neutrophils (> 2 × 10⁹/ l). Normalization of neutrophil counts usually occurs after 2 days. After reaching the therapeutic effect, a maintenance dose of 300 μg per day every other day. In the future, individual dose adjustment and long-term therapy with Leucostim® may be required to maintain neutrophil counts in excess of 2.0 x 10⁹/ l.

Special instructions for dosing

Elderly age: special recommendations for elderly patients are absent.

Children: when applied in pediatric practice in patients with severe chronic neutropenia and oncological diseases, the safety profile of filgrastym did not differ from that in adults. Recommendations for dosing for children of the same age are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.

Correction of filgrastim dose is not required in patients with severe renal or hepatic insufficiency, since their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.

Recommendations for the preparation of a solution for intravenous administration

If you need intravenous injection of Leucostim®, the required amount of the drug is injected from the syringe into a vial or plastic container with 5% dextrose solution.

Leucostim® can not be diluted with 0.9% sodium chloride solution.

If the preparation is diluted to a concentration of less than 15 μg / ml (less than 1.5 million IU / ml), serum human albumin, so that the final concentration of albumin is 2 mg / ml.For example, with a final solution volume of 20 ml, the total dose of Leucostim® is less than 300 μg (less than 30 million ME) should be administered with the addition of 0.2 ml of a 20% solution of human albumin. Do not dilute Leukostim® to a final concentration of less than 2 μg / ml (less than 0.2 million IU / mL).

Leucostim®, when diluted with 5% dextrose or 5% dextrose and albumin, is compatible with glass and a range of plastics, including polyvinyl chloride, polyolefin (polypropylene-polyethylene) and polypropylene.

Syringes with Leukostim® are for single use only.

The ready-made solution of the Leucostim® preparation is stored at a temperature of 2 to 8 ° C for no more than a day.

Side effects:

Adverse reactions are listed according to the following gradation: very often (> 10%); often (> 1% - <10%); infrequently (> 0.1% - <1%); rarely (> 0.01% to <0.1%); very rarely (<0.01%).

On the part of the organs of hematopoiesis: very often - neutrophilia and leukocytosis (as a consequence of the pharmacological action of filgrastim), with long-term administration - anemia, splenomegaly; often - thrombocytopenia; very rarely - rupture of the spleen.

On the part of the respiratory system: often - cough; very rarely - infiltrates in the lungs, adult respiratory distress syndrome.

From the musculoskeletal system: often - pain in the bones, muscles, joints; Often - osteoporosis; very rarely - exacerbation of rheumatoid arthritis, pseudogout (pyrophosphate arthropathy)

From the side of the cardiovascular system: very rarely - a decrease or increase in blood pressure, skin vasculitis (with prolonged therapy in patients with TCN).

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

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

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

Allergic reactions: very rarely - skin rash, hives, face swelling, wheezing, shortness of breath, lowering of blood pressure, tachycardia.

From the laboratory indicators: very often - reversible, weak and moderate increase in the activity of gamma glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, increased uric acid concentration in blood serum, transient hypoglycemia; rarely - increased activity of aspartate aminotransferase.

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

Overdose:

Filgrastim overdose cases are not noted. 1-2 days after drug withdrawal, the number of circulating neutrophils usually decreases by 50% and returns to normal level after 1-7 days.

Interaction:

The efficacy and safety of filgrastim administration in one day with cytotoxic chemotherapeutic agents have not been established. Due to the high sensitivity of actively proliferating myeloid cells to antitumor cytotoxic drugs, filgrastim 24 hours before or after the administration of these drugs is not recommended. 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 currently not available.

Given that lithium stimulates the release of neutrophils, it is possible to increase the action of filgrastim in a combined application. Studies on the interaction of lithium and filgrastim were not conducted.

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

When filgrastim is used to mobilize hematopoietic stem cells after chemotherapy, it should be borne in mind that with long-term administration of such cytostatics as melphalan, carmustine and carboplatin, mobilization efficiency can be reduced.

Special instructions:

Treatment with Leucostim® should be performed under the supervision of a doctor who has experience with colony-stimulating factors, provided that the necessary diagnostic capabilities are available. Procedures for mobilization and apheresis of cells should be carried out in specialized medical institutions.

With myelodysplastic syndrome (MDS) and chronic myeloid leukemia, the efficacy and safety of filgrastim have not been established. Patients with the above diseases, filgrastim not shown. Particular attention should be paid to a differential diagnosis between the blast crisis of chronic myelogenous leukemia and acute myelogenous leukemia.

Particular care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematologic diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia.

A small number (3%) of patients with severe congenital neutropenia (Costman's syndrome) who received filgrastim, MDS and leukemia were observed. MDS and leukemia are natural complications of this disease; their connection with treatment with filgrastim is unclear. Approximately 12% of patients with initially normal cytogenetics had anomalies during a second examination, including monosomy 7. If a patient with Costman's syndrome develops cytogenetic disorders, as well as with the development of MDS or leukemia filgrastim should be canceled. It is not yet clear whether long-term treatment with filgrastim predisposes patients with Kostmann's syndrome to the development of cytogenetic abnormalities, MDS and leukemia. Patients with Costman's syndrome are recommended to perform morphological and cytogenetic studies of the bone marrow at regular intervals (approximately every 12 mS).

Cytogenetic disorders, leukemia and osteoporosis were detected with prolonged use of filgrastim (> 5 years) in 9.1% of patients with severe chronic neutropenia. Their connection with the drug is not clear.

Treatment with filgrastim should be carried out under regular supervision of a general blood count with countingof the leukocyte formula and the number of platelets (before the start of therapy and further 2 times a week with standard chemotherapy and at least 3 times per week in mobilizing PSKK with or without a subsequent bone marrow transplantation). With an increase in the number of leukocytes more than 50x10⁹/ l, filgrastim should be immediately canceled. If filgrastim It is used for the mobilization of hematopoietic stem cells, it must be canceled, if the number of white blood cells is exceeded 70 x 10⁹/ l.

Filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. It is recommended to perform regular blood tests twice a week and determine the number of platelets and hematocrit in the filgrastim application after chemotherapy.

It is necessary to carefully monitor the number of platelets, especially during the first few weeks of treatment with filgrastim. At TCHN during the first weeks of initial therapy, a clinical blood test and the number of platelets are determined 2 times a week, with a stable patient - 1 time per month. If the patient has thrombocytopenia (the number of platelets stably below 100 x 10⁹/ l), consideration should be given to the temporary withdrawal of the drug or a reduction in the dose. There are also other changes in the blood formula, which require its careful monitoring, incl. anemia and a transient increase in the number of myeloid progenitor cells.

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

During treatment with filgrastim, urine analysis should be performed regularly (to exclude hematuria and proteinuria) and control the size of the spleen.

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

After bone marrow transplantation, a blood test is performed and the platelet count is determined 3 times a week.

Patients who have undergone active myelosuppressive therapy in the past may not have a sufficient increase in PSMC to the recommended minimum level (> 2.0 x10⁶ Cd34 + / kg). Therefore, such patients should plan their mobilization at an early stage of treatment if it is necessary to perform transplantation of PSKK, and if the mobilization prior to the introduction of high-dose chemotherapy failed to obtain sufficient PSKK, alternative treatments should be considered,not requiring the use of progenitor cells.

With the use of mobilized filgrastim PSKK there is a decrease in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloablative chemotherapy.

There is a complex but stable statistical relationship between the number of CD34 entered⁺cells and rate of normalization of the number of platelets after high-dose chemotherapy.

The minimum amount of UCSA is equal to or greater than 2.0x10⁶ CD34⁺cells / kg, leads to a sufficient recovery of hematological parameters.

The mobilization of PSKK can only be considered in those healthy donors whose clinical and laboratory parameters, especially hematological parameters, meet the criteria for selecting donors for mobilizing CPM.

Transient leukocytosis (leukocytes more than 50 x 10⁹/ l) is observed in 41% of healthy donors, more than 75 x10⁹/ l - in 2% of healthy donors. Transient thrombocytopenia (number of platelets less than 100x10⁹/ l) after the appointment of filgrastim and the conduct of leukapheresis is observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50 x 10⁹/ l after the procedure of leukapheresis.

If more than one leukapheresis is required, special care should be taken with the number of platelets in the donor before carrying out leukapheresis less than 100 x 10⁹/ l. Conduction of leukapheresis is not recommended if the number of platelets is less than 75x10⁹/ l, as well as in donors, with a violation of hemostasis or receiving anticoagulants.

Filgrastim should be withdrawn or its dose should be reduced if the number of leukocytes exceeds 70 x10⁹/ l.

In healthy donors, it is necessary to regularly monitor all blood test parameters prior to their normalization.

Given single cases of rupture of the spleen after the appointment of a granulocyte colony-stimulating factor to healthy donors, it is recommended to control its size (palpation, ultrasound).

With long-term monitoring of the safety of filgrastim in healthy donors up to 4 years after the appointment filgrastima, cases of violation of hemopoiesis is not noted. However, it is impossible to exclude the risk of stimulation of a clone of malignant myeloid cells, and therefore it is recommended that in the centers of apheresis, it is recommended to follow the healthy donors of stem cells systematically for a minimum of 10 years.

Specific guidance for recipients of allogeneic PSKK obtained with filgrastim: the use of an allogeneic graft may be associated with an increased risk of developing an acute or chronic "graft versus host" response compared to bone marrow transplantation.

When treating filgrastim with HIV-infected patients with neutropenia, a thorough blood test (absolute number of neutrophils (ASC), erythrocytes, platelets, etc.) should be performed on a daily basis for the first few days, then 2 times a week for the first 2 weeks and every week or a week during maintenance therapy. Taking into account fluctuations in the value of AChN, in order to determine the true maximum decrease in AFN (nadir), blood sampling should be performed before the next dose of the drug is prescribed.

In patients with infectious diseases and infiltration of bone marrow by infectious agents (for example, complex Mycobacterium avium) or with a bone marrow (lymphoma) tumor, filgrastim therapy is administered concomitantly with therapy directed against these conditions.

Patients with sickle-cell anemia should regularly perform a blood test and take into account the possibility of developing splenomegaly and thrombosis of blood vessels.

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

The effect of filgrastim in patients with significantly reduced number of myeloid progenitor cells is not known. Filgrastim increases the number of neutrophils by first affecting the neutrophil precursor cells. Therefore, in patients with a reduced content of progenitor cells (for example, those subjected to intensive radiation therapy or chemotherapy), the degree of increase in the number of neutrophils may be lower.

Presence in the anamnesis of a pneumonia or infiltrates in lungs can be the risk factors of occurrence of an intersticial disease of lungs against therapy filgrastimom. The appearance of cough, fever and shortness of breath associated with the appearance of infiltrates in the lungs may be the first signs of the development of adult respiratory distress syndrome. When these signs appear filgrastim should be canceled and appropriate treatment prescribed.

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

It is not noted the influence of filgrastim on the ability to drive vehicles and work with mechanisms.

Form release / dosage:

Solution for intravenous and subcutaneous administration, 600 μg / ml (60 million IU / ml).

Packaging:

0.5 ml (300 μg (30 million) ME)) or 0.8 ml (480 μg (48 million ME)) of the preparation in a sterile syringe made of neutral glass with a soldered injection needle covered with a protective cap elastic or rigid, sealed with a butyl rubber tip, a laminated fluoropolymer equipped with a piston. For each syringe stick a label.

For 1 or 5 filled syringes in a contour acheive box with instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of 2 to 8 ° C.

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-008806/10

Date of registration:27.08.2010

The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia

Manufacturer: & nbsp

BIOCAD, CJSC Russia

Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia

Information update date: & nbsp22.09.2015

Illustrated instructions

Instructions

Leucostim® (Leucostim® )