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

Excipients: mannitol 50 mg, dextran 60,000 15 mg, sodium acetate trihydrate 0.23 mg, acetic acid ice to pH 4.0, polysorbate 80 0.04 mg, water for injection up to 1 ml.

Description:

A clear, colorless or pale yellow solution.

Pharmacotherapeutic group:leukopoiesis stimulant

ATX: & nbsp

L.03.A.A.02 Filgrastim

Pharmacodynamics:

Leucostim® (filgrastim - recombinant human granulocyte colony-stimulating factor (G-CSF)) belongs to the group of biologically active proteins that regulate cell differentiation and proliferation.

Leucostim® is produced by a strain of the bacterium Escherichia coli, into which gene of granulocyte colony-stimulating factor of a person has been introduced by genetic engineering methods. Leucostim® is identical to the natural granulocyte colony-stimulating factor of a human in biological activity, differing from it by the absence of glycosylation and the presence of an additional N-terminal amino acid residue of methionine.

Leucostim® accelerates the proliferation of granulocyte precursor cells of the neutrophilic bone marrow germ, differentiation in the direction of mature neutrophils, and their release into the peripheral blood from the bone marrow. Causes a dose-dependent increase in the number of neutrophils in peripheral blood. Neutrophils produced in response to the administration of Leukostema ® have normal or increased chemotactic and phagocytic activity.

The use of Leucostim® allows to restore the number of neutrophils in the peripheral blood for neutropenia in patients receiving antitumor chemotherapy, or in patients with chronic neutropenia.

Application of the drug

Leucostim® for preventive purposes can reduce the frequency, severity and duration of neutropenia and febrile neutropenia after antitumor chemotherapy. This leads to the prevention of infectious complications, a reduction in the length of hospitalization, and adherence to the intervals prescribed in the treatment regimens between cycles of chemotherapy.

The use of Leukostim® as after antitumor chemotherapy, and independently of it, leads to mobilization in the peripheral. blood of progenitor cells of hemopoiesis.These cells can be collected by cytapheresis and administered to the patient after high-dose chemotherapy, which accelerates the recovery of hematopoies, reducing the incidence and severity of infectious and hemorrhagic complications.

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

In children and adults with severe chronic neutropenia filgrastim Stably increases the number of neutrophils in peripheral blood, reducing the frequency of infectious complications.

The use of filgrastim in patients with HIV infection allows maintaining normal neutrophil count in peripheral blood and following recommended doses of antiretroviral and / or other myelosuppressive therapy. There are no signs of an increase in HIV replication with filgrastim.

Pharmacokinetics:

The concentration of filgrastim in the blood plasma is proportional to the administered dose. The half-life of filgrastim with subcutaneous and intravenous administration is 3-4 hours. After subcutaneous administration of therapeutic doses of filgrastim, its concentration in the serum exceeds 10ng / ml for 8-16 hours.There is a direct relationship between the concentration of filgrast in the plasma and the increase in the number of neutrophils in the peripheral blood.

In patients with end-stage renal failure, an increase in the maximum Stach concentration and AUC of the "area under the curve" is noted, and a decrease in the volume of distribution and clearance compared to healthy volunteers and patients with moderate-level renal failure.

Long-term use of filgrastim for up to 28 days is not accompanied by signs of cumulation and an increase in the half-life.

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 anamnesis.

- Persistent neutropenia (absolute number of neutrophils less than or equal to 1.0х10⁹/ l) in patients with developed stage of HIV infection to reduce the risk of bacterial infections if other methods of treatment can not be used.

Contraindications:

- Hypersensitivity to the drug or its components in an anamnesis.

- Severe congenital neutropenia (Costman's syndrome) with cytogenetic violations.

- Filgrastim should not be used to increase the doses of cytotoxic chemotherapeutic drugs above recommended.

- Simultaneous administration with cytotoxic chemo- and radiotherapy.

- Terminal stage of chronic renal failure.

- Lactation.

- Newborn age (immediately after birth until 28 days of life).

Carefully:

Use with caution in pregnancy, malignant and premalignant diseases of the myeloid nature (including acute myelogenous leukemia de novo and secondary), as well as in combination with high-dose chemotherapy.

Dosing and Administration:

Daily subcutaneously or in the form of short (30-minute) intravenous infusions on a 5% dextrose solution (see "Instructions for breeding"), until the number of neutrophils passes minimum (nadir) and returns to the normal range.

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

Recommended doses

After standard schemes of cytotoxic chemotherapy

For 0.5 million units (5 μg) / kg 1 time per day daily subcutaneously or in the form of 30-minute intravenous infusions on a 5% solution of dextrose. The first dose of filgrastim is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. Duration of therapy up to 14 days. After induction and consolidation therapy of acute myelogenous leukemia, the duration of filgrastim administration can be increased up to 38 days, depending on the type, dosage and the used scheme of cytotoxic chemotherapy. A transient increase in the number of neutrophils is usually observed 1 to 2 days after initiation of treatment with filgrastim.To achieve a stable therapeutic effect, it is necessary to continue therapy with filgrastim until the number of neutrophils exceeds the expected minimum and reaches normal values. It is not recommended to cancel filgrastim prematurely, until the number of neutrophils passes through the expected minimum. Treatment should be discontinued if the absolute number of neutrophils (DCA) after nadir reached 1,0x10⁹/ l.

After mieloablative therapy followed by autologous or allogeneic bone marrow transplantation

Subcutaneously or intravenously in the form of infusion in 20 ml of a 5% solution of dextrose (see "Instructions for breeding"). The initial dose is 1.0 million units (10 μg) / kg / day drip for 30 minutes or 24 hours, or by continuous infusion within 24 hours. The first dose of filgrastim should be administered no earlier than 24 hours after cytotoxic chemotherapy, and when bone marrow transplantation - no later than 24 hours after the infusion of the bone marrow. The duration of therapy is no more than 28 days. After the maximum reduction in the number of neutrophils (nadir), the daily dose is corrected depending on the dynamics of the neutrophil content.If the number of neutrophils exceeds 1.0x10⁹/ l. for three consecutive days, the dose of filgrastim is reduced to 0.5 million units / kg / day; then, if the absolute number of neutrophils exceeds 1.0x10⁹/ liter for three consecutive days, filgrastim cancel. If during the treatment period the absolute amount of neutrophils decreases less than 1.0x10⁹/ l, the dose of filgrastim should be 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 of PSKK

For 1.0 million units (10 μg) / kg per day 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 5-6 days. In some cases, additional leukapheresis is possible. The appointment of filgrastim should continue until the last leukapheresis.

Mobilization of PSKC after myelosuppressive chemotherapy

For 0.5 million units (5 μg) / kg per day 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 does not reach normal values. Leukapheresis should be performed during the period when the absolute number of neutrophils rises from less than 0.5 × 10⁹/ l to more than 5.0х10⁹/ 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

For 1 million units (10 μg) kg / day subcutaneously, for 4-5 days. Leukapheresis is carried out from 5 days and, if necessary, up to 6 days in order to obtain ≥ 4x10⁶ CD34 + cells / kg body weight of the recipient. Efficacy and safety in healthy individuals under the age of 16 and older than 60 years has not been investigated.

Severe chronic neutropenia (THC)

Daily, subcutaneously, once or divided into several administrations. With congenital neutropenia: the initial dose is 1.2 million units (12 μg) / kg per day, with idiopathic or intermittent neutropenia: 0.5 million units (5 μg) / kg per day until the neutrophil count is 1.5 × 10⁹/ l. After achieving a therapeutic effect, the minimum effective dose should be determined to maintain this level.To maintain the required number of neutrophils requires a long daily administration of the drug. After 1-2 weeks of treatment, depending on the response of the patient to therapy, the initial dose can be doubled or halved. Subsequently, every 1-2 weeks, individual dose adjustment can be performed to maintain the number of neutrophils in the range of 1.5-10 × 10⁹/ l. In patients with severe infections, a scheme with a faster increase in dose can be used. In 97% of patients who responded positively to treatment, the full therapeutic effect is observed with the appointment of doses up to 24 mcg / kg per day. The daily dose of filgrastim should not exceed 24 mcg / kg.

Neutropenia in HIV infection

The initial dose of 0.1-0.4 million units (1-4 μg) / kg / day once subcutaneously to normalize the number of neutrophils. The maximum daily dose is not more than 10 μg / kg. Normalization of neutrophil counts usually occurs after 2 days. After reaching the therapeutic effect, a maintenance dose of 300 mcg / 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.

Correction of the dosing regimen

Elderly age: special recommendations for elderly patients are absent.

Children: when applied in pediatric practice in patients with TCN and oncological diseases, the safety profile of filgrastim 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.

Dose adjustment is not required in patients with severe renal or hepatic insufficiency, since their pharmacokinetic and pharmacodynamic parameters were similar to those of healthy volunteers.

Breeding instructions

Filgrastim diluted with only 5% dextrose solution, do not allow dilution with 0.9% sodium chloride solution. Diluted filgrastim can be adsorbed by glass and plastics. If filgrastim dilute to a concentration of less than 1.5 million units (15 μg) in 1 ml, then the solution should be added with whey human albumin in an amount such that the final concentration of albumin is 2 mg / ml. For example, with a final solution volume of 20 ml, total doses of filgrastim less than 30 million units (300 μg) should be administered with the addition of 0.2 ml of a 20% albumin solution. Filgrastim when diluted with 5% dextrose solution or 5% dextrose solution and albumin is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (polypropylene-polyethylene copolymer) and polypropylene. Do not dilute the drug to a final concentration of less than 0.2 million units (2 μg) in 1 ml. The filgrastim solution is stored at a temperature of 2 to 8 ° C for no more than a day.

Side effects:

Common reactions: headache; fatigue, fever.

Musculoskeletal system: weak or moderate (10%), sometimes severe (3%) pain in the bones and muscles, which in most cases are stopped by usual analgesics; arthralgia, osteoporosis, acute gouty arthritis, exacerbation of rheumatoid arthritis.

Gastrointestinal tract: diarrhea, hepatomegaly.

The cardiovascular system: transient arterial hypotension, which does not require medical correction; cutaneous vasculitis (with prolonged therapy in 2% of patients with severe chronic neutropenia); arrhythmia (there is no connection with taking the drug), vascular disorders (vein-occlusive disease, connection with filgrastim is not established).

Respiratory system: infiltrates in the lungs, adult respiratory distress syndrome, respiratory failure; interstitial pneumonia, possibly with an unfavorable prognosis (after chemotherapy, especially those involving bleomycin; connection with reception filgrastima not established);

Skin and its appendages: reactions at the injection site - infiltration, tenderness, swelling and / or densification. Alopecia, skin rash, Sweet syndrome (febrile acute dermatosis, connection with filgrastim is not established).

Blood and lymphatic system: splenomegaly, pain in the upper left quadrant of the abdomen; vascular thrombosis; rupture of the spleen; thrombocytopenia, anemia and nasal bleeding (with long-term administration), hyperleukocytosis, myelodysplastic syndrome and leukemia (in 3% of patients with severe congenital neutropenia (Costman's syndrome) (no connection with the drug intake).

Genitourinary system: mild or moderate dysuria.

Hypersensitivity reactions: rash.

More than half of the reactions Hypersensitivity is associated with the administration of the first dose, more often after intravenous administration of the drug. Sometimes the resumption of treatment is accompanied by a relapse of symptoms.

Laboratory indicators: reversible, dose-dependent, weak or moderate increase in the activity of lactate dehydrogenase, alkaline phosphatase, γ-glutamyltransferase; hyperuricemia, transient hypoglycemia after eating; proteinuria, hematuria.

Filgrastim does not increase the incidence of adverse reactions to cytotoxic chemotherapy. The undesirable effects observed with the same frequency in patients receiving filgrastim / chemotherapy and placebo / chemotherapy included nausea and vomiting, alopecia, diarrhea, lethargy, anorexia, mucosal inflammation, headache, cough, skin rash, chest pain, total weakness, sore throat, constipation and nonspecific pain (without indicating the diagnosis).

Overdose:

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

Interaction:

The safety and efficacy of filgrastim administration on the same day as myelosuppressive cytotoxic chemotherapeutic agents have not been established. In view of the sensitivity of rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy,use filgrastim in the interval 24 hours before or after the administration of these drugs is not recommended.

With the simultaneous use of filgrastim and 5-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 increase the action of filgrastim in a combined application, but such studies have not been conducted.

Due to pharmaceutical incompatibility, it should not be mixed with 0.9% sodium chloride solution.

Special instructions:

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

a) Growth of malignant cells

The safety and efficacy of filgrastim in patients with myelodysplastic syndrome and chronic myelogenous leukemia have not been established, therefore, with these diseases it is not shown. Particular attention should be paid to differential diagnosis between acute myelogenous leukemia and an imperious crisis of chronic myelogenous leukemia.

Granulocyte colony stimulating factor of a person can stimulate the growth of myeloid cells in vitro. Similar effects can be observed in vitro and for some non-myeloid cells.

b) Patients receiving cytotoxic chemotherapy

Leukocytosis: less than 5% of patients who received filgrastim in doses of more than 0.3 million units (3 μg / kg per day), the number of leukocytes increased to 100 × 10⁹/ l and more. There are no side effects directly associated with such leukocytosis, not described. However, given the possible risk associated with high leukocytosis, during treatment with filgrastim, the number of leukocytes should be regularly determined. If after passing the expected minimum, it will exceed 50х10⁹/ l, filgrastim should be immediately canceled. If filgrastim It is used to mobilize PSKK, it is canceled if the number of leukocytes exceeds 70x10⁹/ l.

The risk associated with from high-dose chemotherapy:

extra care should be shown in the treatment of patients receiving high-dose chemotherapy because improvement in the outcome of malignant neoplasm has not been observed,while increased doses of chemotherapy have more pronounced toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems (see instructions for the use of: specific chemotherapy drugs)

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 thrombocytopenia and anemia. It is recommended to perform regular blood tests twice a week and determine the number of platelets and hematocrit. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens capable of causing severe thrombocytopenia.

c) Patients with THC

Transformation into leukemia or pre-leukemia: special care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematologic diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia.Prior to treatment should be carried out with the full blood count and determination of leukocyte platelet counts, as well as explore morphologic picture of bone marrow and karyotype. A small number (3%) of patients with severe congenital neutropenia (Costman's syndrome) who received filgrastim, myelodysplastic syndrome (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 were found to have anomalies during a second examination, including monosomy 7. If a patient with Costman's syndrome develops cytogenetic disorders, it is necessary to carefully evaluate the benefits and risk of continuing therapy with filgrastim. With the development of MDS or leukemia filgrastim should be canceled. It is not known whether long-term treatment with filgrastim predisposes patients with severe congenital neutropenia (Costman's syndrome) to the development of cytogenetic abnormalities, MDS and leukemia. Patients with Costman's syndrome are encouraged to conduct regular (approximately every 12 months) morphological and cytogenetic studies of the bone marrow.Cytogenetic disorders, leukemia and osteoporosis were detected with prolonged use of filgrastim (> 5 years) in patients (9.1%) with severe chronic neutropenia. Their connection with the drug is not clear.

Blood formula: you need to carefully control the number of platelets, especially during the first few weeks of treatment with filgrastim. In severe chronic neutropenia during the first weeks of initial therapy, a clinical blood test and platelet count are determined 2 times a week, with a stable patient condition - once a month. If the patient has thrombocytopenia (the number of platelets stably below 100x10⁹/ 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 that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

Other: should exclude such causes of transient neutropenia, as viral infections. The enlargement of the spleen is a direct consequence of the treatment with filgrastim. During clinical trials, 31% of patients with THC showed palpation with splenomegaly.In radiography, the increase in volume is detected soon after the start of treatment and tends to stabilize. Reducing the dose slows or stops the increase in the size of the spleen; splenectomy may be required in 3% of patients. The size of the spleen should be monitored regularly by palpation. A small number of patients had hematuria and proteinuria. To monitor these indicators, urine tests should be done regularly. Safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established.

d) Patients undergoing the mobilization of PMSC

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

Mobilization: comparison of two recommended mobilization methods (only filgrastim or in combination with myelosuppressive chemotherapy) were not performed on the same contingent of patients. The choice of method of mobilization should be made depending on the overall goals of the treatment of the patient.

Prior treatment cytotoxic agents: in patients who have undergone active myelosuppressive therapy in the past,There may not be a sufficient increase in PSMC to the recommended minimum level (2,0x10⁶ FROMD34⁺-cells / kg) or the acceleration of the normalization of the number thrombocytes. Some cytostatics have a particular toxicity to the precursor cells of hemopoiesis and can adversely affect their mobilization. If it is planned to transplant PSKK, it is recommended to schedule their mobilization at an early stage of treatment. Particular attention should be paid to the number of progenitor 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 ("yield") of peripheral blood stem cells: Estimating the number of PSMCs mobilized in patients with filgrastim should pay special attention to the quantification method. The results of a flow optometric analysis of the number CD34⁺-cells differ depending on the specific methodology, and one must be cautious about data on their number based on research,conducted in other laboratories.

There is a complex but stable statistical relationship between the number of C injected into reinfusionD34⁺cells and rate of normalization of the number of platelets after high-dose chemotherapy. The minimum amount of PSKK, equal to or exceeding 2.0х10⁶ FROMD34⁺cells / kg, leads to a sufficient recovery of hematological indicators. The quantity exceeding this value seems to be accompanied by a faster normalization, the amount less indicated - a slower normalization of the blood picture.

e) Mobilization of PSKC in healthy donors

Procedures for mobilization and apheresis of the scrolls should be conducted in a center with experience in this area. Mobilization of PMSC is possible only if the laboratory parameters, especially the hematological parameters donor, selection criteria. Transient leukocytosis (leukocytes more than 50х10⁹/ l) is observed in 41% of healthy donors, more than 75x10⁹/ 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 50x10⁹/ l after the procedure of leukapheresis. If more than one leukapheresis is required, the number of platelets must be monitored before each apheresis procedure, especially if the platelet count is less than 100x10⁹/ l. Conducting leukapheresis is not recommended if the number of neutrophils is less than 75x10⁹/ l, with the appointment of anticoagulants or known violations of hemostasis. Filgrastim should be canceled, or its dose should be reduced if the number of white blood cells is more than 70x10⁹/ 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 G-CSF to healthy donors, it is recommended to control its size (palpation, ultrasound).

There are no data on cases of violation of hemopoiesis in healthy donors up to 4 beds after the administration of filgrastim. However, in the center of apheresis, systematic monitoring of long-term safety of the drug in healthy donors is recommended.

Special instructions for recipients of allogeneic PSKK, obtained with filgrastim.

The use of an allogeneic graft Associate with an increased risk of developing an acute or chronic "graft versus host" response compared to bone marrow transplantation.

f) Neutropenia in HIV patients

In the treatment with filgrastim, a thorough blood test (absolute number of neutrophils, erythrocytes, platelets, etc.) should be performed regularly on a daily basis for the first few days, then 2 times a week for the first 2 weeks, and every week or week during a maintenance therapy. Given the fluctuations in the neutrophil count, the blood sample must be taken before the next dose is administered to determine the true maximum reduction in the number of neutrophils (nadir). In patients with infectious diseases and infiltration of the bone marrow by infectious agents (for example, the complex Mycobacterium avium) or with a bone marrow (lymphoma) tumor, filgrastim therapy is administered concomitantly with therapy directed against these conditions.

g) Other special precautions

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, patients undergoing intensive radiation therapy or chemotherapy), the degree of increase in the number of neutrophils may be lower.

If a respiratory distress syndrome occurs in adults, the drug should be discontinued and prescribed appropriate treatment.

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

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

Form release / dosage:

Solution for intravenous and subcutaneous administration, 300 μg / ml (30 million IU / ml).

Packaging:

For 0.5 ml (150 μg (15 million) ME)) or 1 ml (300 μg (30 million ME)) in a sterile syringe made of neutral glass with a soldered injection needle covered with a protective protective cap or rigid,ukuporennyh tip of butyl rubber, laminated fluoropolymer equipped with a piston. For each syringe stick a label.

For 1 or 5 filled syringes in a contiguous 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:LS-002011

Date of registration:29.07.2011

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® )