Лейкостим®

General characteristics. Structure:

Active ingredient: 300 mkg (30 million ME) or 600 mkg (60 million ME) of a filgrastim (recombinant granulotsitarny colony stimulating factor of the person).

Excipients: Mannitolum, a dextran 60000, acetate sodium trihydrate, acetic acid ice, polysorbate 80, water for injections.

Лейкостим® (to filgrasty - a recombinant granulotsitarny colony stimulating factor of the person) treats group of biologically active proteins regulating a differentiation and proliferation of cells.

Pharmacological properties:

Pharmacodynamics. Filgrastim is developed by a strain of a bacterium of Escherichia coli into which methods of genetic engineering entered a gene of a granulotsitarny colony stimulating factor of the person. Лейкостим® it is identical to a natural granulotsitarny colony stimulating factor of the person on biological activity, differing from it in lack of a glycosylation and existence of the additional N-trailer amino-acid rest of methionine.

Лейкостим® accelerates proliferation of granulotsitarny progenitors of a neutrophylic sprout of marrow (KOE-G), a differentiation in the direction of mature neutrophils and their exit in peripheral blood from marrow. Causes dozozavisimy increase in quantity of neutrophils in peripheral blood.

The neutrophils produced in response to administration of the drug Leykostim® have the normal or increased hemotaksichesky and phagocytal activity. Use of the drug Leykostim® allows to recover number of neutrophils in peripheral blood at a neutropenia at the patients receiving chemotherapy or at patients with a chronic neutropenia. Use of the drug Leykostim® in the preventive purposes allows to reduce the frequency, weight and duration of a neutropenia and febrile neutropenia after chemotherapy. It leads to prevention of infectious complications, reduction of terms of hospitalization and observance of the intervals between chemotherapy cycles provided by schemes of treatment.

Use of the drug Leykostim® both after chemotherapy, and irrespective of it, leads to mobilization in peripheral blood of progenitors of a hemogenesis. These cells can be collected by a cytapheresis and are entered to the patient after highly find out chemotherapy. Introduction of the hemopoietic stem cells allows to recover the hemopoietic and immune systems after miyeloablativny chemotherapy. After myelosuppressive chemotherapy introduction of the hemopoietic stem cells accelerates hemopoiesis recovery, reducing the frequency and weight of infectious and hemorrhagic complications.

Efficiency and safety of the drug Leykostim® at the adults and children receiving cytotoxic chemotherapy are identical.

At children and adults with a heavy chronic neutropenia the drug Leykostim® steadily increases number of neutrophils in peripheral blood, reducing the frequency of infectious complications.

Purpose of the drug Leykostim® to patients with HIV infection allows to support the normal level of neutrophils and to follow the recommended doses of anti-retrovirus and/or other myelosuppressive therapy. Signs of increase in replication of HIV at use of a filgrastim are noted.
 
Pharmacokinetics. Concentration of drug in a blood plasma is proportional to the entered dose. The elimination half-life of a filgrastim at hypodermic and intravenous administration makes 3-4 hours. After hypodermic introduction of therapeutic doses of a filgrastim, its concentration in serum exceeds 10 ng/ml within 8-16 hours. There is a direct dependence between concentration of a filgrastim in plasma and increase in quantity of neutrophils in peripheral blood.

Filgrastim, is generally metabolized to peptides and only in insignificant degree is brought with urine in not changed look (less than 1% of the entered dose). Prolonged use of a filgrastim during the period up to 28 days is not followed by signs of cumulation and increase in an elimination half-life.

Indications to use:

Drug is used on purpose:
• reductions of duration of a neutropenia of the II-IV degree and decrease in frequency of a febrile neutropenia at patients with not myeloproliferative new growths after chemotherapy cytostatic drugs;
• mobilization of hemopoietic progenitors in peripheral blood for the purpose of the subsequent their separation and transplantation after myelosuppressive chemotherapy;
• reductions of duration of a neutropenia and prevention of the related complications at the patients receiving miyeloablativny chemotherapy with the subsequent transplantation of marrow;
• treatments of a heavy chronic neutropenia for increase in number of neutrophils and decrease in frequency and duration of infectious complications;
• treatments of a resistant neutropenia at patients with the developed HIV infection stage (absolute number of neutrophils (≤ 1,0Õ109/l) for decrease in risk of bacterial infections.
• mobilization of hemopoietic progenitors in peripheral blood at healthy donors for the purpose of the subsequent their separation and allogenic transplantation.

To apply strictly on doctor's orders.

Route of administration and doses:

Лейкостим® it can be entered both subcutaneously, and intravenously. The way of introduction and a dose depend on a specific clinical situation and are defined by the attending physician. The hypodermic way of introduction is preferable. In need of intravenous administration the required amount of the drug is administered from the syringe in a bottle or a plastic container from 5% by dextrose solution, then 30-minute infusion of divorced drug is made. Due to the hypersensitivity of quickly sharing myeloid cells to cytotoxic himiopreparata, use of the drug Leykostim® is not recommended less than in 24 hours prior to the beginning of a course of chemotherapy and earlier, than in 24 hours after the termination of a course of chemotherapy.
 
Instructions on cultivation. Лейкостим® it is impossible to part 0,9% with chloride sodium solution; drug is dissolved by 5% with dextrose solution. If drug gets divorced to concentration less than 15 mkg/ml (less than 1,5 million ME/ml), then it is necessary to add a seralbumin of the person that final concentration of albumine made 2 mg/ml to solution. For example, at the final volume of solution of 20 ml, a total dose of the drug Leykostim® less than 300 mkg (less than 30 million ME) it is necessary to enter 0,2 ml of 20% of solution of albumine of the person with addition.
 
It is impossible to part filgrasty to final concentration less than 2 mkg/ml (less than 0,2 million ME/ml).

The recommended doses. For treatment of a neutropenia after a course of cytotoxic chemotherapy Leykostim® enter once a day subcutaneously or intravenously in a dose of 5,0 mkg (0,5 million ME) on 1 kg of body weight of the patient.

At the patients receiving cytotoxic chemotherapy, passing increase in number of neutrophils is observed usually in 1 - 2 day after an initiation of treatment by the drug Leykostim®. For assessment of efficiency of treatment daily calculation of quantity of neutrophils in peripheral blood is desirable. For achievement of stable therapeutic effect it is necessary to continue therapy by the drug Leykostim® until the number of neutrophils does not pass the expected minimum and will not reach normal values. After achievement of the absolute number of neutrophils exceeding 2,0x109/l drug it is possible to cancel. If necessary duration of a course of therapy can make up to 12 days, depending on disease severity and expressiveness of a neutropenia. After miyeloablativny chemotherapy with the subsequent bone marrow transplantation of Leykostim® enter subcutaneously or intravenously at the rate of 10 mkg (1,0 million ME) on 1 kg of body weight.

The first dose of the drug Leykostim® should be entered not earlier than in 24 hours after cytotoxic chemotherapy, and at transplantation of marrow - not later, than in 24 hours after infusion of marrow. After there passes the moment of the maximum decrease in number of neutrophils, the daily dose is adjusted depending on dynamics of their number. If the maintenance of neutrophils in peripheral blood exceeds 1,0Õ109/l within three days in a row, the dose of the drug Leykostim® is reduced twice (to 5,0 mkg (0,5 million ME) by 1 kg of body weight). Then, if the absolute number of neutrophils exceeds 1,0Õ109/l within three days in a row, Leykostim® cancel. In case of reduction of absolute number of neutrophils in the course of treatment lower than 1,0 x 109/l, the drug dose Leykostim is increased to 10 mkg (1,0 million ME) by 1 kg of body weight again.

For mobilization of the hemopoietic stem cells of Leykostim® enter subcutaneously in a daily dose 5,0 mkg (0,5 million ME) on 1 kg of body weight (at patients after myelosuppressive chemotherapy) or 10 mkg (1,0 million ME) on 1 kg of mass of the patient (for lack of chemotherapy) within 5-7 consecutive days (the number of introductions depends on the speed of increase of quantity of leukocytes in peripheral blood and effectiveness of separation). A day before the estimated term of the first separation (the 4th day of administration of the drug Leykostim®) and in the next days (about day of the last separation) the quantity of leukocytes and neutrophils in peripheral blood of the patient is estimated. Tsitaferez is carried out in case of increase in number of leukocytes up to 5Õ109/l peripheral blood, since 5th day of administration of the drug Leykostim®. After each separation the number of yadrosoderzhashchy cells and CD34+ of cells in the sample intended for a cryopreservation is counted. At achievement of quantity of the cells cryopreserved by CD34+ which is enough for performing transplantation (not less than 2x106 on kg of mass of the patient) administration of the drug Leykostim® stops.

Efficiency and safety of use of the drug Leykostim® for healthy donors are younger 16 and 60 years are more senior were not investigated.

At the heavy chronic neutropenia (HCN) of Leykostim® it is necessary to enter daily subcutaneously until the number of neutrophils does steadily not exceed 1,5kh 109/l (at an inborn neutropenia - in a dose of 12 mkg (1,2 million ME) on 1 kg of mass of the patient a day subcutaneously for one or several introductions; at an idiopathic or periodic neutropenia of-5,0 mkg (0,5 million ME) on 1 kg of weight a day). After achievement of therapeutic effect it is necessary to define a minimal effective dose for maintenance of this level of neutrophils. For this purpose long daily administration of drug is required. In 1 - 2 weeks of treatment the initial dose can be doubled or to reduce half, depending on reaction of the patient to therapy. Afterwards each 1 - 2 weeks it is necessary to make dose adjustment for maintenance of number of neutrophils in the range 1,5-10Õ109/l.

At the neutropenia associated with HIV infection: an initial dose of 1 - 4 mkg (0,1-0,4 million ME) on 1 kg of body weight a day once subcutaneously before normalization of number of neutrophils (> 2Õ109/l). Normalization of number of neutrophils usually occurs in 2 days. At inefficiency of an initial dose escalation to 5,0 mkg (0,5 million ME) on 1 kg of weight a day once subcutaneously is carried out it. After achievement of therapeutic effect the maintenance therapy by the drug Leykostim® in a dose of 1 - 4 mkg (0,1 - 0,4 million ME) on 1 kg of weight a day 2-3 times a week is carried out. Further individual dose adjustment and long therapy by the drug Leykostim® for maintenance of number of neutrophils more than 2,0x109/l can be required.

Special instructions on dosing. At use of a filgrastim in children's practice at patients with a heavy chronic neutropenia and oncological diseases the profile of safety of a filgrastim did not differ from that at adults. Recommendations about dosing for patients of children's age same, as for the adults receiving myelosuppressive or cytotoxic chemotherapy.

Dose adjustment of a filgrastim is not required from patients with a heavy renal or liver failure as their pharmacokinetic and pharmakodinamichesky indicators are similar to those at healthy volunteers.

Features of use:

With extra care filgrasty should apply at an acute myeloleukemia.

At a miyelodisplastichesky syndrome (MDS) and a myelosis efficiency and safety of use of a filgrastim are not established. And also with pretumor defeats of a myeloid sprout of a hemopoiesis, use of a filgrastim is not recommended to patients with above-mentioned diseases as cells of some tumors can bear a receptor to G-KSF. Thereof, special attention should be paid on the differential diagnosis between blast crisis of a myelosis and an acute myeloleukemia.

At a small number of patients (less than 5%) receiving filgrasty the hyperleukocytosis was observed (increase in number of leukocytes over 100Õ109/l). The by-effects which are directly connected with the hyperleukocytosis induced filgrastimy are not described. However, considering the possible risk connected with a hyperleukocytosis during treatment filgrastimy it is necessary to define number of leukocytes regularly. At increase in number of leukocytes over 50x109/l filgrasty should cancel immediately. In case of use of a filgrastim for mobilization of the hemopoietic stem cells, drug needs to be cancelled when the number of leukocytes exceeds 70x109/l.

It is necessary to consider that use of a filgrastim does not prevent thrombocytopenia and anemia. As thrombocytopenia and anemia often are a consequence of use of high doses of himiopreparat, it is regularly recommended to define number of thrombocytes, and also number of erythrocytes or level of hemoglobin in the course of use of a filgrastim after chemotherapy.

Special attention should be paid to differential diagnosis of heavy chronic neutropenias from other hematologic diseases, such as aplastic anemia, a myelodisplasia and a myeloleukemia.

At a small number (3%) of the patients with a heavy inborn neutropenia (Kostmann's syndrome) receiving filgrasty MDS and a leukosis was observed.

MDS and leukosis - natural complications of this disease; their communication with treatment filgrastimy is not clear. Approximately anomalies, including a monosomy 7 were found in 12% of patients with initially normal cytogenetics at repeated inspection. If the patient with a syndrome Kostmann has cytogenetic disturbances, it is necessary to estimate carefully advantages and risk of continuation of therapy filgrastimy. At development of MDS or a leukosis by filgrasty it is necessary to cancel. For the present it is not clear whether prolonged treatment filgrastimy patients with a heavy inborn neutropenia (Kostmann's syndrome) contributes to development of cytogenetic anomalies, MDS and a leukosis. With Kostmann's syndrome it is recommended to patients through regular periods (approximately each 12 months) to conduct morphological and cytogenetic researches of marrow.
 
Use during pregnancy and a lactation.  Safety of a filgrastim for pregnant women is not established therefore its appointment cannot be recommended to pregnant women. In need of use of a filgrastim during a lactation, breastfeeding should be stopped.

Influence of drug on ability to control of vehicles and to service of mechanisms. Considering the mechanism of pharmacological (immunological) action of a filgrastim, its influence on ability to manage vehicles and to work with mechanisms it is represented extremely improbable.

Side effects:

Treatment by the drug Leykostim® in the recommended doses can be followed by morbidity in the place of an injection, ostealgias and muscles.

In clinical trial of the drug Leykostim® at 7,5% of patients mild or moderate musculoskeletal pains which or did not demand medicinal correction were noted, or were stopped by reception of non-steroidal anti-inflammatory drugs. Severe pains were not noted.

According to literature, the reactions of hypersensitivity of the slowed-down type in a drug injection site which are followed by emergence of an erythema and hypostasis can be in rare instances revealed. In case of identification of such reactions use of drug should be stopped.

In rare instances at use of a filgrastim the headache, fatigue, diarrhea, a hepatomegalia, frustration of an urination were observed (mainly, a weak or moderate dysuria). There are separate messages on the passing lowering of arterial pressure which was not demanding treatment. Reversible, dozozavisimy and usually weak or moderate increase in concentration of a lactate dehydrogenase, alkaline phosphatase, serumal uric acid and a γ-glutamiltransferaza, decrease in number of thrombocytes in peripheral blood can be observed.

Skin rash, increase in a spleen at patients with initially not increased spleen, a vasculitis, thrombosis of vessels can seldom be observed. Cases of emergence of infiltrates in lungs with development respiratory a distress syndrome of adults are described; these phenomena were more often observed after the schemes of chemotherapy including Bleomycinum, their connection with reception of a filgrastim is not established. Very seldom after use of a filgrastim cases of a proteinuria and a hamaturia were observed.

The pseudorheumatism aggravation against the background of use of a filgrastim, and also a rupture of a spleen, thrombocytopenia and anemia was exclusively seldom observed at prolonged use of a filgrastim. At long therapy filgrastimy at 2% of sick THN the skin vasculitis was observed.

Interaction with other medicines:

Due to the high sensitivity of actively proliferating myeloid cells to antineoplastic cytostatic drugs at purpose of a filgrastim it is necessary to observe an interval at 24 hours to or after purpose of myelosuppressive drugs. Efficiency and safety of introduction of a filgrastim in one day with cytotoxic himiopreparata are not established. 5-ftoruratsit increases weight of a neutropenia at co-administration with filgrastimy.

Filgrastim is pharmaceutical not compatible from 0,9% chloride sodium solution.

At use of a filgrastim for mobilization of the hemopoietic stem cells after chemotherapy it is necessary to consider that at purpose for a long time of such tsitostatik as Melphalanum, кармустин (BCNU) and карбоплатин, efficiency of mobilization can be reduced.

Contraindications:

Hypersensitivity to active agent (filgrasty) or other components of drug. A heavy inborn neutropenia (Kostmann's syndrome) with cytogenetic disturbances. Newborn age (right after the birth up to 28 days of life).

Overdose:

Cases of overdose of a filgrastim are noted.

Storage conditions:

At a temperature from 2 to 8 °C. List B. To store in the place, unavailable to children. A period of validity - 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 0,5 ml of the drug with concentration of 300 mkg/ml containing 150 mkg (15 million ME) of a filgrastim; on 1 ml of the drug with concentration of 300 mkg/ml containing 300 mkg (30 million ME) of a filgrastim in the syringes from neutral glass with the sealed needles covered with caps protective elastic or rigid corked by the tips on pistons from rubber butyl laminated by a ftorpolimer.

On 1 or 5 syringes complete with pistons (1 or 5 respectively) in a blister strip packaging from a PVC film, together with the application instruction in a pack from a cardboard.