ÂÓá¡«µ¿Ô® 34

General characteristics. Structure:

Active agent: lenograsty 33,6 million ME (263 mkg);
excipients: Mannitolum (D-Mannitolum) — 25 mg; polysorbate of 20 — 0,1 mg; arginine (L-arginine) — 10 mg; phenylalanine (L-phenylalanine) — 10 mg; methionine (L-methionine) — 1 mg; Acidum hydrochloricum — to pH 6,5. Composition of the enclosed solvent: water for injections.

Description. Lyophilisate of white color.

Pharmacological properties:

Pharmacodynamics. Granotsit 34 (a recombinant human granulotsitarny colony stimulating factor, G-KSF) treats group of cytokines, biologically active proteins regulating a differentiation and proliferation of cells.
G-KSF is the factor stimulating progenitors of a neutrophylic sprout of marrow. Granotsit 34 causes noticeable increase in quantity of neutrophils in peripheral blood which is in the range of doses 1k10 mkg/kg/days dozozavisimy. Repeated administrations of drug in the recommended doses cause additional increase in maintenance of neutrophils in blood. The neutrophils produced in response to Granotsit's 34 introduction have normal hemotaksichesky properties and phagocytal activity. G-KSF is capable to stimulate proliferation of endothelial cells of the person. Granotsit's use 34 both after chemotherapy, and irrespective of it, leads to mobilization (exit) in peripheral blood of progenitors of a hemogenesis which can be allocated from blood and are entered intravenously sick after high-dose chemotherapy for the purpose of recovery of the damaged hemopoiesis instead of transplantation of marrow or in addition to it.
 
It is shown that introduction to the patient of the autologous progenitors of a hemogenesis from peripheral blood received by means of stimulation by Granotsit 34 promotes more bystry recovery of a hemopoiesis in comparison with autotransplantation of marrow that also significantly reduces thrombocytopenia duration.

Pharmacokinetics. Granotsit's pharmacokinetics 34 depends on a dose of drug and duration of its introduction.
At repeated introduction (intravenously or subcutaneously) the maximum concentration of drug in a blood plasma is proportional to the entered dose; cumulation of drug is not revealed. In the recommended doses absolute bioavailability of Granotsit 34 makes 30%. The average time of stay in an organism at hypodermic introduction of 7 hours.
The elimination half-life of Granotsit 34 at hypodermic introduction makes about 3-4 hours, at intravenous repeated - 1-1,5 hours.
Granotsit 34 generally it is metabolized to peptides and only in insignificant degree it is removed with urine in not changed look (less than 1% of the entered dose). There is a direct dependence between a dose and plasma concentration of Granotsit 34 and between the neutrophylic answer and Granotsit's concentration 34 in plasma.

Indications to use:

Granotsit 34 it is applied for:
• reductions of the period of a neutropenia and the related complications (at patients with not myeloproliferative new growths) which carried out myelosuppressive chemotherapy with the subsequent transplantation of marrow (TM) and being in group of the increased risk of development of the long expressed neutropenia;
• reduction of duration of the expressed neutropenia and the related complications after standard myelosuppressive chemotherapy;
• mobilization of peripheral progenitors of a hemogenesis in peripheral blood.

Route of administration and doses:

Subcutaneously or intravenously kapelno within 30 minutes.
At bone marrow transplantation, at standard chemotherapy cytotoxic means and for mobilization of progenitors of a hemogenesis in peripheral blood after use of tsitostatik the recommended Granotsit's dose 34 makes 150 mkg (19,2 million ME) on 1 sq.m of a body surface a day that is equivalent to 5 mkg (0,64 million ME) on 1 kg of weight a day. Administration of drug is begun next day after transplantation of marrow or the termination of chemotherapy. The drug is administered daily subcutaneously (at transplantation of marrow it can be entered in the form of 30-minute intravenous infusion) until, after approach of the expected decrease in level of leukocytes, their quantity is not recovered to a normal indicator at which achievement drug can be cancelled. The maximum duration of daily administration of drug makes 28 days. For carrying out mobilization of progenitors of a hemogenesis in peripheral blood without use of tsitostatik the recommended dose of drug makes 10 mkg (1,28 million ME) on weight kg a day, daily subcutaneously within 4-6 days. Leykaferez it is necessary to carry out after recovery of quantity of leukocytes or after definition to CD34+ blood of cells by means of the standard techniques. Patients who did not receive earlier massive chemotherapy have often enough carrying out one leukopheresis for obtaining minimum necessary quantity of cells (> 2,0 x 106 CD34+ of cells on body weight kg).
At healthy donors drug use subcutaneously within 5-6 days in a dose of 10 mkg (1,28 million ME) on kg of body weight allowed to receive> 3,0 x 106 CD34+ of cells on body weight kg as a result of one leukopheresis in 83% of cases and as a result of two leykaferez in 97% of cases. Elderly patients
Special researches at elderly persons were not conducted. In this regard any
special recommendations about doses at elderly patients are not made.
Children
Safety and efficiency of use of Granotsit 34 is established at bone marrow transplantation at children 2 years are more senior.

Instruction for solution preparation

For preparation of solution for hypodermic introduction contents of a bottle are dissolved in 1 ml of the enclosed solvent, carefully mixing (not to stir up strongly) about 5 seconds.
For intravenous use the received solution should be diluted in addition with 0,9% solution of sodium of chloride or 5% dextrose solution up to concentration not less, than 0,32 million ME/ml (2,5mkg/ml), but no more, than in 100 ml of above-mentioned solutions.
To store the recovered solution at a temperature from 2 of 0C up to 8 0C within 24 hours.
The prepared solution should be used as soon as possible.

Features of use:

• Treatment by Granotsit 34 has to be carried out under observation of the doctor having experience of use of cytostatic therapy.
• The Granulotsitarny colony stimulating factor is capable to strengthen growth of myeloid cells of in vitro, similar action of in vitro can be shown also on some cells of not myeloid row.
• Efficiency and Granotsit's safety 34 is not established at a miyelodisplastichesky syndrome, a secondary acute miyeloblastny leukosis or a myelosis. Therefore patients with above-mentioned pathology should not appoint drug. The special attention is required when diagnosing an acute miyeloblastny leukosis. This diagnosis has to be accurately differentiated from blast crisis of a myelosis.
• Granotsit's influence 34 on progressing of a miyelodisplastichesky syndrome and its transformation in an acute myeloleukemia was not established. Granotsit 34 it has to be applied with extra care at all pretumor defeats of a myeloid sprout of marrow. As some tumors can as an exception to bear G-KSF a receptor, it is necessary to be careful concerning an unexpected recurrent tumor during treatment by human G-KSF.
• At administration of drug in a dose of 5 mkg/kg/days (0,64 million МЕ/кг/сутки) at transplantation of marrow, in one case the quantity of leukocytes did not exceed 50 h109/l. Less, than in 5% of cases at Granotsit's use 34 in a dose of 5 mkg/kg/days (0,64 million МЕ/кг/сутки) and cytotoxic chemotherapy the number of leukocytes was equal or exceeded 70 h109/l. At the same time no by-effects which are directly connected with a leukocytosis were observed.
• Due to the potential risk connected with emergence of the expressed leukocytosis during treatment by Granotsit 34 it is regularly necessary to control quantity of leukocytes in blood. If the quantity of leukocytes reaches 50 h109/l, use of drug has to be immediately stopped.
• During Granotsit's use 34 for mobilization of progenitors of a hemogenesis in peripheral blood, the drug should not be administered in case of increase in quantity of leukocytes over 70 x 109/l.
• Granotsit 34 it should not be used for the purpose of reduction of the established intervals between courses of chemotherapy and/or for the purpose of increase in doses of himiopreparat as drug reduces only a miyelotoksichnost and does not influence other side effects of tsitostatik.
• Due to the hypersensitivity of quickly sharing myeloid cells to cytotoxic chemotherapy, Granotsit's use 34 is not recommended later, than in 24 hours prior to and not earlier than in 24 hours after the termination of chemotherapy.
• Mobilization of progenitors of a hemogenesis in peripheral blood when using Granotsit's 34 after chemotherapy is higher in comparison with only one Granotsit's use 34. However the choice between both methods of mobilization has to be carried out individually for each patient taking into account all purposes of treatment.
• Patients to whom massive myelosuppressive therapy and/or radiation therapy was carried out in peripheral blood can have an insufficient for obtaining minimum necessary quantity of cells mobilization of progenitors of a hemogenesis and, therefore, recovery of a hemopoiesis can be inadequate.
• Patients with considerable decrease have quantities of stem cells in marrow (owing to previous intensive beam or chemotherapy), the neutrophylic answer can be sometimes reduced, safety of use of Granotsit 34 in such cases is not established.
• The program of transplantation of progenitors of a hemogenesis has to be planned at early stages of treatment of patients, and special attention should be paid on quantity of the mobilized hemogenesis progenitors in peripheral blood before use of chemotherapy in high doses. If the quantity of the received cells is small, transplantation of progenitors of a hemogenesis has to be replaced with other methods of treatment.
• As results of analyses on determination of quantity of CD34+ of cells, method of a flowing tsitometriya, in various laboratories differ, special attention should be paid to methods of quantitative definition of the received progenitors.
• On the basis of the published data, for adequate recovery of a hemopoiesis achievement of minimum necessary number of CD of 34+ cells> 2,0kh 106 on body weight kg is recommended.
• As mobilization of cells in peripheral blood does not bear a sure gain to healthy donors, this procedure has to be carried out according to the rules of transplantation of marrow established by the legislation. Efficiency and Granotsit's safety 34 in group of donors are more senior than 60 years was not estimated. In this regard at this age group of donors it is not recommended to use drug for a fence of progenitors of a hemogenesis. Also you should not carry out the procedure of mobilization of progenitors of a hemogenesis at persons under 18.
• The procedure of mobilization of progenitors of a hemogenesis should be carried out only at donors who by results of clinical and laboratory trials are suitable for donorship of marrow.
• Leykaferez donors who accept anticoagulants should not see off or have disturbances of a hemostasis. If carrying out more than one leukopheresis is required, then special attention should be paid to donors who before carrying out a leukopheresis had a number of thrombocytes <100 x 109/l.
• In general the leukopheresis should not be carried out at an indicator of number of thrombocytes <75 x 109/l. Whenever possible it is necessary to avoid installation of the central venous catheter.
• According to observation of donors (duration up to 6 years) any serious complications were not revealed. However, despite it, the risk of stimulation of malignant clones of myeloid cells is possible. In this regard it is recommended to conduct systematic observation of donors with maintaining the corresponding documentation in the centers for carrying out a leukopheresis.
• Transplantation of the allogenic progenitors of a hemogenesis mobilized by Granotsit 34 to patients can be followed by the increased risk of development of chronic reaction "a transplant against the owner". Data of long observation of functioning of a transplant are not numerous.
• So far efficiency and safety of use of Granotsit 34 at patients with heavy abnormal liver functions and kidneys is not studied.
• At people use of drug in a dose to 40 mkg/kg/days was not followed by emergence of toxic side effects, except for muscle and bones pains. The termination of treatment by Granotsit 34 usually conducts to 50% to decrease in neutrophils in peripheral blood within 1-2 days, then this indicator is returned to norm within 1-7 days. Increase in quantity of leukocytes for the fifth day of treatment approximately to 50 h109/l is observed at every third patient receiving Granotsit 34 in the maximum dose of 40 mkg/kg/days (5,12 million МЕ/кг/сутки).
• After introduction of granulotsitarny colony stimulating factors (G-KSF) to healthy donors or patients cases of increase, generally asymptomatic, spleens and extremely seldom cases of its gap in this connection it is recommended to control carefully the spleen sizes (physical survey, ultrasonography) were noted. At emergence of pains in an upper left half of an abdominal cavity and under a shovel it is necessary to exclude a possibility of a rupture of a spleen.

Side effects:

At Granotsit's use 34 at healthy faces the most often arising side effects were a headache at 30%, an ostealgia at 23%, a dorsodynia at 17,5%, an adynamy at 11% and an abdominal pain at 6% of persons. The risk of developing of pains was higher at the persons having the increased quantity of leukocytes in blood, especially if the number of leukocytes exceeded 50 h109/l. The leukocytosis> 50 h109/l was noted at 24% of donors, and the thrombocytopenia connected with aferezy (quantity of thrombocytes less than 100 x 109/l) was observed at 42% of donors.
Passing increase in level of nuclear heating plant and/or ALT was observed at 12%, and passing increase in level of an alkaline phosphatase - at 16% of donors.
At transplantation of marrow the observed by-effects, such as infectious and inflammatory damages of an oral cavity, fever, diarrhea, rash, abdominal pains, vomiting, alopecia, sepsis and infections, were connected with the conditioning modes, but not with Granotsit's reception 34.
Granotsit's influence 34 on the frequency of emergence and expressiveness of acute and chronic reaction "a transplant against the owner" is authentically not defined. Special attention at transplantation of marrow has to be paid to control of quantity of thrombocytes  in peripheral blood  as their level at use of drug can be lower, than usually.
At Granotsit's use 34 at the neutropenia caused by chemotherapy the side effects characteristic of reception of tsitostatik usually are observed. Ostealgias and reactions in the place of injections (reddening, a swelling) were slightly more often noted. It was occasionally reported about emergence of infiltrates in lungs which in several cases led to development of pulmonary insufficiency or respiratory a syndrome distress at adults. At emergence of such symptoms as cough, fever or short wind in combination with radiological changes and disturbances of respiratory function it is necessary to appoint the corresponding therapy and to consider a question of the termination of introduction of Granotsit 34.
Various allergic reactions extremely seldom with development of an acute anaphylaxis were seldom or never noted. Cases of a vasculitis, a nodal erythema, a pyoderma, a Lyell's disease were extremely seldom noted.
The general, but generally asymptomatic cases of increase in a spleen and very exceptional cases of a rupture of a spleen were noted at healthy donors or at patients after introduction of granulotsitarny colony stimulating factors is (G-KSF).

Interaction with other medicines:

Possible interactions with other factors stimulating a hemopoiesis, and cytokines in clinical trials were not studied so far.

Contraindications:

•  hypersensitivity to a lenograstim  or other components of drug;
• pregnancy and period of a lactation;
• myeloid new growths (except for initially revealed acute miyeloblastny leukosis);
• for the first time the revealed acute miyeloblastny leukosis at patients is younger than 55 years in the presence of favorable cytogenetic predictive signs.

Overdose:

The effects arising at Granotsit's 34 overdose are not studied.

Storage conditions:

At a temperature from 2 °C to 25 °C. Not to freeze. List B. To store in the place, unavailable to children. Period of validity 2 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous and hypodermic administration on 33,6 million ME (263 mkg) in the bottle of colourless glass (type I) corked by a rubber bung with the aluminum cap (on an aluminum cap is repeatedly put 34) which from above is latched a plastic lid of white color (on a lid it is put stylized by G and 34).
Solvent on 1 ml in ampoules of colourless neutral glass. On an ampoule the point or the line of a break and an additional white ring are put.
On 5 bottles with drug and 5 ampoules with solvent place in plastic planimetric packaging without covering (pallet). On 1 pallet together with the application instruction in a cardboard pack.