Granocyte® 34 (Granocyte® 34)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLenograstimLenograstim
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  • Granocyte® 34
    lyophilizate in / in PC 
    Shugai Sanofi Aventis     France
    • Dosage form: & nbsplyophilizate for the preparation of solution for intravenous and subcutaneous administration
    Composition:

    One bottle contains:

    active substance: lenograstim - 33.6 million. ME (263 μg);

    Excipients: mannitol (D-mannitol) - 25 mg, polysorbate 20-0.1 mg, arginine (L-arginine) - 10 mg, phenylalanine (L-phenylalanine) 10 mg, methionine (L-methionine) - 1 mg, hydrochloric acid - to pH 6.5.

    Composition of the applied solvent: water for injections.

    Description:

    Liofilizate white.

    Pharmacotherapeutic group:Leukopoiesis stimulant
    ATX: & nbsp

    L.03.A.A   Colony-stimulating factors

    L.03.A.A.10   Lenograstim

    Pharmacodynamics:

    Granocyte® 34 preparation (recombinant human granulocyte colony-stimulating factor [G-CSF]) belongs to the group of cytokines, biologically active proteins regulating cell differentiation and proliferation.

    G-CSF is a factor that stimulates the precursor cells of the neutrophilic bone marrow germ, as evidenced by an increase in the number of colony-stimulating units of the spleen (CFU-C) and colony-stimulating granulocyte units (CFU-G) in the bone marrow. The preparation Granocyte® 34 causes a marked increase in the number of neutrophils in the peripheral blood within 24 hours after administration, which is dose-dependent at a dosage range of 1-10 μg / kg body weight / day.Repeated administration of the drug at recommended doses causes an additional increase in the neutrophil count in the blood. Neutrophils produced in response to Granocyte® 34 administration have normal chemotactic properties and phagocytic activity.

    Like other hematopoietic growth factors, in vitro G-CSF is able to stimulate the proliferation of human endothelial cells. The use of Granocyte ® 34 both after bone marrow transplantation and after cytotoxic chemotherapy leads to a significant reduction in the duration of neutropenia and associated complications.

    The introduction of Granocyte® 34 both after chemotherapy and independently of it, leads to the mobilization (exit) in the peripheral blood of precursor cells of hematopoiesis (progenitor cells), which can be isolated from the blood and injected intravenously to the patient after high-dose cytotoxic chemotherapy to restore damaged hematopoiesis instead of or in addition to bone marrow transplantation.

    It was shown that the introduction of autologous progenitor cells of hematopoiesis from the peripheral blood to the patient,obtained through the stimulation of Granotitis ® 34, promotes a faster recovery of hematopoiesis and a reduction in the engraftment time, which also significantly reduces the duration of neutropenia and thrombocytopenia in comparison with bone marrow autotransplantation.
    Pharmacokinetics:

    The pharmacokinetics of lenograstim depends on the dose of the drug and the duration of its administration. There is a direct relationship between the dose and plasma concentration of lenograstim and between the neutrophil response and the concentration of lenograstim in the blood plasma.

    With repeated administration (intravenous or subcutaneous), the maximum concentration of the drug in the blood plasma is proportional to the administered dose; cumulation of the drug is not revealed.

    In recommended doses, the absolute bioavailability of lenograstim is 30%. The distribution volume is approximately 1 l / kg. The average retention time of lenograstim in the body with subcutaneous injection is 7 h.

    Lenograstim, in general, is metabolized to peptides, which are difficult to distinguish from other endogenous polypeptides.

    Lenograstim is slightly excreted in the urine in unchanged form (less than 1% of the administered dose).The half-life of lenograstim with subcutaneous administration is approximately 3-4 hours, with intravenous repeated administration - 1-1.5 hours.

    Studies of the pharmacokinetics of lenograstm in patients with impaired hepatic or renal function were not performed.

    Indications:

    Granocyte® 34 is used for:

    - reduction in the period of neutropenia and related complications in patients with non-myeloid malignancies who underwent myelosuppressive chemotherapy followed by autologous or allogeneic bone marrow transplantation (TCM) and those at increased risk of developing prolonged severe neutropenia;

    - reduction in the duration of severe neutropenia and related complications in patients with non-myeloid malignancies after standard cytotoxic chemotherapy;

    - mobilization of progenitor cells of hemopoiesis in peripheral blood (including in healthy donors).

    Contraindications:

    - Hypersensitivity to lenograstimu or other components of the drug.

    - Breastfeeding period.

    - Myeloid neoplasms (except for the initially identified acute myelogenous leukemia).

    - The first identified acute myeloblastic leukemia in patients younger than 55 years and / or in the presence of favorable cytogenetic prognostic signs (translocation l(8;21), t(l5;17), inv(16)).

    - Simultaneous use with cytotoxic chemotherapy.

    Carefully:

    - Pre-tumor lesions of myeloid bone marrow germ (see section "Special instructions"),

    - Splenomegaly (increased risk of rupture of the spleen, see section "Special instructions").

    - The recently transferred infiltrative lesion of the lungs or pneumonia (increased risk of developing respiratory distress syndrome, see the sections "Side effects", "Special instructions").

    Pregnancy and lactation:

    Safety of lenograstim in pregnant women is not established. Care should be taken to evaluate the possible risk of lenograstim influence on the fetus relative to the expected therapeutic benefit. In studies conducted on rats and rabbits, there is no evidence that lenograstim has teratogenic properties. An increase in the incidence of miscarriages in rabbits was noted, but no developmental abnormalities were observed.

    It is not known whether the blood is excreted lenograstim in breast milk.It is not recommended to use the preparation Granocyte ® 34 during breastfeeding.

    Dosing and Administration:

    Subcutaneously or intravenously drip for 30 minutes.

    Granocyte ® 34 in this dosage (363 μg) is used in patients with a body surface area of ​​up to 1.8 m2.

    After bone marrow transplantation

    The recommended dose of Granocyte® 34 is 150 μg (19.2 million) ME) / m2 body surface / day, which is equivalent to 5 μg (0.64 million IU) / kg body weight / day. The preparation is started the day after bone marrow transplantation. The drug is injected daily subcutaneously or in the form of a 30-minute intravenous infusion until the white blood cell count is restored to the normal value, upon which the drug can be withdrawn. The maximum duration of daily administration of the drug is 28 days. It should be borne in mind that with an increase in the number of leukocytes to 50.0 x 109cells / l or more, discontinue the administration of the drug.

    After standard cytotoxic chemotherapy

    The recommended dose of Granocyte® 34 is 150 μg (19.2 million) ME) / m2 body surface / day, which is equivalent to 5 μg (0.64 million IU) / kg body weight / day.The administration of the drug is started the day after the end of chemotherapy. The drug is injected daily subcutaneously until after the expected decrease in the level of leukocytes, their number is not restored to normal, when the drug can be canceled. The maximum duration of daily administration of the drug is 28 days. It should be borne in mind that with an increase in the number of leukocytes to 50.0 x 109cell / l or more dose should be discontinued.

    Mobilization of progenitor cells of hemopoiesis in peripheral blood after cytotoxic chemotherapy

    The recommended dose is 150 μg (19.2 million IU) / kg body weight / day, equivalent to 5 μg (0.64 million IU) / kg body weight / day. The preparation is started on the day after the end chemotherapy. The drug is injected daily subcutaneously until after the expected decrease in the level of leukocytes, their number is not restored to the required level. Leukapheresis should be performed after recovery of the number of white blood cells or after determination in the blood Cd34+ cells using conventional techniques. The drug is canceled after the completion of the procedure of leukapheresis. In patients who did not receive previous massive chemotherapy, it is often sufficient to perform a single leukapheresis to obtain the minimum required number of cells (≥ 2.0 x 106 Cd34+ cells / kg body weight). It should be borne in mind that with an increase in the number of white blood cells to 70 x 109 cells / L administration of the drug should be discontinued.

    Mobilization of hematopoietic progenitor cells in peripheral blood with lenograstim only

    The recommended dose of the drug is 10 μg (1.28 million IU) / kg body weight / day, daily subcutaneously for 4-6 days. Leukapheresis should be conducted between the 5th and 7th days. In patients who did not receive previous massive chemotherapy, it is often sufficient to perform a single leukapheresis to obtain the minimum required number of cells (≥ 2.0 x 106 Cd34+ cells / kg body weight).

    It should be borne in mind that with an increase in the number of white blood cells to 70 x 109 cells / L administration of the drug should be discontinued.

    Mobilization of progenitor cells of hemopoiesis in peripheral blood in healthy dopors

    Administration of the preparation subcutaneously for 5-6 days at a dose of 10 μg (1.28 million IU) / kg of body weight made it possible to obtain ≥3 x 106 Cd34+ cells / kg body weight as a result of a single leukapheresis in 83% of cases and as a result of two leukapheresis in 97% of cases.

    It should be borne in mind that with an increase in the number of white blood cells to 70 x 109 cells / L administration of the drug should be discontinued.

    Individual patient groups

    Elderly patients

    Special studies in elderly patients were not conducted. In this regard, no special recommendations for doses in elderly patients are not given.

    Children

    The safety and efficacy of granovit® 34 in bone marrow transplantation in children older than 2 years has been established. Doses for children older than 2 years are the same as for adults with Granocyt ® 34 to reduce the duration of neutropenia after myelosuppressive therapy followed by bone marrow transplantation or after standard cytotoxic chemotherapy.

    The safety and efficacy of granovit® 34 during bone marrow transplantation in children under 2 years of age is not established.

    Patients with hepatic impairment

    In patients with severe impairment of liver function, the safety and efficacy of the drug have not been established (seesection "Special instructions").

    Patients with impaired renal function

    In patients with severe impaired renal function, the safety and efficacy of the drug have not been established (see section "Special instructions").

    Instructions for preparing a solution for subcutaneous and intravenous administration

    When preparing the solution for subcutaneous administration, the contents of the vial are dissolved in 1 ml of the supplied solvent, gently stirring (not strongly shaking) for about 5 seconds.

    For intravenous administration, the resulting solution should be further diluted with 0.9% sodium chloride solution or 5% dextrose solution to a concentration of not less than 0.32 million IU / ml (2.5 μg / ml), but not more than 100 ml of the above solutions. The prepared solution should be used as soon as possible. The reconstituted solution should be stored at a temperature of 2 ° C to 8 ° C for a maximum of 24 hours.

    Side effects:

    When using the Granocyte ® 34 preparation healthy donors the most common side effects were bone pain, back pain, asthenia, headache, fever, nausea, increased activity of aspartate aminotransferase (ACT), alanine aminotransferase (ALT), alkaline phosphatase (APF) and lactate dehydrogenase (LDH). The risk of pain was higher in patients with an elevated white blood cell count, especially if the number of leukocytes exceeded 50 x 109 cells / l. Leukocytosis ≥50 x 109 cells / l was observed in 24% of donors, and associated with apheresis of thrombocytopenia (the number of platelets less than 100 x 109 cells / l) was observed in 42% of donors.

    When bone marrow transplantation there were adverse reactions that were more likely to be associated with conditioning regimens than with Granocyte® 34. The most frequently reported development of infectious inflammatory lesions of the oral cavity, fever, diarrhea, rash, abdominal pain, nausea, vomiting, alopecia , sepsis, headache. The effect of Granocyte ® 34 on the incidence and severity of acute and chronic "graft versus host" reactions is not reliably determined.

    Particular attention in bone marrow transplantation should be given to the control of the number of platelets in the peripheral blood, since their amount can be lower in the application of the drug than usual. When using Granocyte® 34 with neutropenia caused by chemotherapy, there are usually side effects that are typical for the use of cytostatics. Somewhat more often, pain in the bones and reactions at the injection site (redness, swelling) were noted. Seldom reported on the occurrence of infiltrates in the lungs, which in several cases led to the development of pulmonary insufficiency or respiratory distress syndrome in adults. If symptoms such as cough, fever, or dyspnea occur in combination with radiologic changes and respiratory disorders, appropriate therapy should be prescribed and consider discontinuing Granocyte® 34.

    In very rare cases, various allergic reactions were noted extremely rarely with the development of anaphylactic shock. Very rarely there were cases of vasculitis, nodal erythema, pyoderma, Lyell's syndrome.

    Common but mostly asymptomatic cases of spleen enlargement and very rare cases of spleen rupture were noted in healthy donors or in patients after G-CSF administration.

    Post-marketing data

    Classification of undesirable adverse reactions by frequency of development,according to the recommendations of the World Health Organization: very often (≥10%); often (≥1% and <10%); infrequently (≥0.1% and <1%); rarely (≥0.01% and <0.1%); very rarely (<0.01%); the frequency is unknown (based on the available data it is impossible to estimate the incidence of side effects).

    Disturbances from the respiratory system, organs of the chest and mediastinum

    Rarely: pulmonary infiltrates, impairment of lung function (including symptoms of interstitial lung diseases, acute respiratory distress syndrome, pulmonary edema, dyspnea, hypoxemia, cough, fever), sometimes with the development of respiratory failure, up to a lethal outcome.

    Disturbances from the skin and subcutaneous tissues

    Infrequent: skin rash.

    Very rarely: acute febrile neutrophilic dermatosis, nodal erythema, pyoderma, toxic epidermal necrolysis (Lyell's syndrome), cutaneous vasculitis.

    Violations of the blood and lymphatic system

    Very often: thrombocytopenia, leukocytosis.

    Often: splenomegaly.

    Very rarely: rupture of the spleen.

    Disturbances from musculoskeletal and connective tissue

    Very often: pain in the bones, pain in the back.

    Disturbances from the liver and bile ducts

    Highly often: impaired liver function, increased activity alanine aminotransferase (ALT), an increase in activity aspartate aminotransferase (ACT), an increase in the activity of alkaline phosphatase (ALP), an increase in lactate dehydrogenase (LDH) activity.

    Immune system disorders

    Highly rarely: anaphylactic shock, increased reactions sensitivity.

    Violation of the nervous system

    Very often: headache.

    General disorders and disorders at the site of administration

    Often: pyrexia (fever), reactions at the injection site.

    Infrequently: malaise.

    Vascular disorders

    Infrequently: the development of a syndrome of increased capillary permeability (which can be life-threatening if not treated properly) has been reported after the administration of G-CSF, in most cases in patients undergoing chemotherapy. The syndrome of increased permeability of capillaries is characterized by the following symptoms: hypotension, hypoalbuminemia, edema and hemoconcentration (see section "Special instructions").

    Overdose:

    Effects arising from an overdose of Granotitis ® 34 are not established.

    Interaction:

    Possible interactions with other factors that stimulate hematopoiesis and cytokines to date have not been studied in clinical studies.

    Due to the increased sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, the use of Granotitis® 34 is not recommended later than 24 hours before and no earlier than 24 hours after the end of chemotherapy (see "Contraindications", "Special instructions" ).

    Special instructions:

    Treatment with Granotz® 34 should be performed under the supervision of a physician with experience in the use of cytostatic therapy.

    Growth of malignant cells

    Granulocyte colony-stimulating factor (G-CSF) is able to enhance the growth of myeloid cells in vitro, the same action in vitro can also be manifested in some non-myeloid cells. In connection with the possibility of tumor growth, caution should be exercised when using lenograstim in patients with myeloid leukemia with insufficient reduction of blast cells in the bone marrow or in which blast cells are present in the peripheral blood, since the number of blast cells may increase.

    Myelodysplastic syndrome, secondary acute myeloblastic leukemia, chronic myeloid leukemia

    The efficacy and safety of Granocyt ® 34 in the myelodysplastic syndrome, secondary acute myeloblastic leukemia, or chronic myeloid leukemia has not been established. Therefore, patients with the above pathology drug should not be prescribed. Particular attention is required in the diagnosis of acute myelogenous leukemia. This diagnosis should be precisely differentiated from the blast crisis of chronic myeloid leukemia.

    The effect of Granocyte® 34 on the progression of the myelodysplastic syndrome and its transformation into acute myeloid leukemia was not established. Granocyte® 34 should be used with extreme caution in all premalignant lesions of the myeloid bone marrow. Since some tumors can, as an exception, carry a G-CSF receptor, caution should be exercised with regard to unexpected tumor recurrence during G-CSF treatment.

    Leukocytosis

    When Granocyte ® was administered, 34 adverse reactions directly associated with leukocytosis were not observed.In connection with the potential risk associated with the development of severe leukocytosis, during treatment with Granotzit® 34, the number of leukocytes in the blood should be monitored regularly and the drug should be discontinued in a timely manner (see the section on "Method of administration and dose").

    Disturbances from the respiratory system

    The appearance of symptoms such as cough, fever or shortness of breath, combined with radiologic changes in the form of pulmonary infiltrates, as well as respiratory failure, may indicate the development of acute respiratory distress syndrome. It is necessary to stop the administration of Granocyte® 34 and to prescribe appropriate therapy.

    Risks, associated with an increase in the dose of chemotherapy

    Granocyte® 34 should not be used to increase the doses of cytotoxic drugs (not prescribed by the prescribed dosing regimen), since the drug may reduce myelotoxicity, but not the overall toxicity of cytotoxic drugs.

    Standard cytotoxic chemotherapy

    Granocyte® 34 is not recommended later than 24 hours before and no earlier than 24 hours after the end of chemotherapy.

    The safety of the use of lenograstm in combination with antitumor agents with cumulative bone marrow toxicity or the prevalent platelet toxicity (nitrosoureas derivatives, mitomycin) not installed. The administration of lenograstim may increase the toxicity of these drugs, in particular, with respect to platelets.

    Thrombocytopenia

    Because severe thrombocytopenia can develop after apheresis in peripheral blood stem cell dopors, it is necessary to monitor all changes in hematologic tests.

    The choice of the method of mobilization of progenitor cells

    Mobilization of peripheral blood stem cells using Granocyte® 34 after chemotherapy is higher than using only Granocyte® 34. However, the choice between both methods of mobilization should be carried out individually for each patient, taking into account all treatment goals.

    Patients, who underwent massive myelosuppressive therapy and / or radiation therapy

    In patients who underwent massive myelosuppressive therapy and / or radiation therapy,mobilization of progenitor cells of hemopoiesis in peripheral blood may not be sufficient to obtain the minimum required number of cells (≥ 2.0 x 106 Cd34+ cells / kg of body weight) and, consequently, hematopoiesis recovery may be inadequate.

    In patients with a significant reduction in the number of stem cells in the bone marrow (due to previous intensive radiation or chemotherapy), the neutrophil response can sometimes be reduced, the effectiveness of Granotitis® 34 in such cases is not established.

    The program of transplantation of hematopoietic progenitor cells should be planned in the early stages of treatment of patients. Particular attention should be paid to the number of mobilized peripheral blood stem cells before using high-dose chemotherapy. If the number of cells obtained is small, transplantation of peripheral blood stem cells should be replaced by other methods treatment.

    Evaluation of the quantitative determination of the precursor cells obtained

    Particular attention should be paid to methods for quantifying the obtained progenitor cells.On the basis of the published data, for the adequate and faster recovery of hematopoiesis (including platelets), it is recommended that the minimum required amount of ≥2.0 x 106 FROMD34+ cells / kg body weight. With fewer cells, hemopoiesis recovery is slower.

    Healthy donors

    Since mobilization of cells in peripheral blood does not directly benefit healthy donors, this procedure should be carried out in accordance with the rules of bone marrow transplantation established by law. The efficacy and safety of Granotz® 34 in a group of donors under the age of 18 and over 60 years of age has not been evaluated. In this regard, in these age groups of donors, a drug for the collection of hematopoietic progenitor cells is not recommended.

    The procedure for mobilization of hematopoietic progenitor cells should be performed only in donors, which, according to the results of clinical and laboratory studies, are suitable for bone marrow donation. Leukapheresis should not be given to donors who take anticoagulants or have hemostasis disorders.If more than one leukapheresis is required, special attention should be given to donors who have a platelet count <100 x 10 before carrying out leukapheresis9/ l; in general, leukapheresis should not be performed with a platelet count of <75 x 109/ l.

    If possible, the central venous catheter should be avoided.

    According to the observation of donors (duration of up to 6 years), there were no serious complications. However, despite this, there is a risk of stimulation of malignant clones of myeloid cells. The development of transient cytogenetic modifications in healthy donors with the use of G-CSF has been reported. However, the significance of these changes is unknown. In this regard, it is recommended to conduct systematic monitoring of donors with the maintenance of appropriate documentation in the centers for the conduct of apheresis.

    Transplantation of allogeneic hematopoietic progenitor cells

    Transplantation of allogenic peripheral blood stem cells mobilized with Granotitis ® 34 can be accompanied by an increased risk of developing a chronic "graft versus host" reaction.The data of long-term follow-up of the functioning of the transplant are few.

    Enlargement and rupture of the spleen

    After Granocyte® was administered to 34 healthy donors or patients, spleen enlargement cases and, rarely, cases of rupture of the spleen were noted, and therefore it is recommended to carefully monitor the hematological parameters and dimensions of the spleen (for example, physical examination, ultrasound). When pain occurs in the upper left half of the abdominal cavity and under the scapula, the possibility of rupture of the spleen should be ruled out. With an increase in the size of the spleen during therapy with lenograstim, appropriate therapeutic measures should be taken, including the abolition of the drug.

    Syndrome of increased permeability

    The development of a syndrome of increased capillary permeability after the administration of G-CSF was reported, with characteristic symptoms being hypotension, hypoalbuminemia, edema and hemoconcentration. If suspicion of developing a capillary permeability syndrome is indicated, treatment with lenograstim should be discontinued and appropriate symptomatic therapy should be prescribed, which, if necessary, may include intensive care.

    Other special instructions

    To date, the effectiveness and safety of Granotz® 34 in patients with severe disorders of the liver, kidneys, heart and lungs.

    The use of the drug in a dose of up to 40 μg / kg of body weight / day does not accompanied by the appearance of toxic side effects, with the exception of pain in the muscles and bones. Discontinuation of treatment with Granotitis® 34 usually leads to a 50% reduction in neutrophils in peripheral blood for 1-2 days, then this indicator returns to normal within 1-7 days. Increasing the number leukocytes on the fifth day of treatment to about 50 x 109 cells / l was observed in every third patient who received Granocyte ® 34 at a maximum dose of 40 μg / kg body weight / day (5.12 million IU / body weight / day).

    There is an experience of Granocyt ® 34 in children with neutropenia after standard cytotoxic therapy at the same doses as in adults.

    Granotzit® 34 contains phenylalanine, which is harmful for patients with phenylketonuria.

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

    Studies on the effect of Granotzit® 34 on the ability to drive vehicles and engage in other potentially hazardous activities have not been conducted.

    Form release / dosage:Liofilizate for the preparation of a solution for intravenous and subcutaneous injection of 33.6 million. ME (263 μg).
    Packaging:

    ATabout a vial of colorless glass (type I), sealed with a rubber stopper with an aluminum cap (34 times on an aluminum cap), on top with a plastic latch of a white color (stitched on the lid G and 34).

    Solvent 1 ml into ampoules of colorless neutral glass. The ampoule contains a dot or a fault line and an additional white ring.

    Five vials of the preparation and 5 ampoules of the solvent are placed in a plastic outline package without coating (pallet).

    1 pallet together with instructions for use in a cardboard bundle.

    Storage conditions:

    Store at temperatures between 2 ° C and 25 ° C.

    Do not freeze.

    Keep out of the reach of children.

    Shelf life:

    2.5 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:П N013473 / 01
    Date of registration:24.12.2007 / 11.03.2016
    Expiration Date:Unlimited
    The owner of the registration certificate: Shugai Sanofi Aventis Shugai Sanofi Aventis France
    Manufacturer: & nbsp
    Representation: & nbspSanofi Aventis GroupSanofi Aventis Group
    Information update date: & nbsp09.05.2017
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