Гранокрин®

General characteristics. Structure:

Active ingredient: 75 mkg or 150 mkg рекомбинантног a granulotsitarny colony stimulating factor of the person (rchg-KSF) in 1 bottle.

Excipients: sodium - the acetate buffer, Mannitolum, polysorbate 80, water for injections.

Pharmacological properties:

Pharmacodynamics. Active agent of drug is the recombinant granulotsitarny colony stimulating factor of the person (rchg-KSF) received from a strain of a bacterium of Escherichia coli into which genome methods of genetic engineering entered a gene of human G-KSF. Unlike natural molecule G-KSF which is exposed to the O-glycosylation in situation Tr-133 rchg-KSF does not contain the carbohydrate rest. On the amino-acid sequence and conformational structure rchg-KSF it is identical to natural and has biological activity, identical with it, in the conditions of in vitro and in vivo.

G-KSF is one of the main factors controlling processes of a granulocytopoiesis in marrow. G-KSF selectively affects cells - predecessors of granulocytes, stimulates their growth, a differentiation, and also regulates processes of maturing in marrow of active neutrophils and their exit in blood.

Use of G-KSF reduces the frequency, weight and duration of the neutropenia which arose as a result of chemotherapy cytostatics or miyeloablativny therapy with the subsequent bone marrow transplantation. After introduction of tsitostatik decrease in levels of neutrophils and leukocytes which depth depends on the used scheme of cytotoxic chemotherapy is observed. Growth of levels of neutrophils and leukocytes (hemopoiesis recovery) happens after passing of the maximum level of decrease in leukocytes and neutrophils (nadir).

Use of G-KSF strengthens mobilization of progenitors of a hemogenesis from marrow in peripheral blood.

At the patients receiving cytostatic chemotherapy, introduction of G-KSF led to the reliable growth of the CD level of 34+ cells in comparison with the group receiving only chemotherapy.

The patients receiving G-KSF need hospitalization less often, demand less long treatment in a hospital, and also smaller doses of antibiotics in comparison with the patients receiving only chemotherapy.

Pharmacokinetics. Increase in a dose of drug leads to the proportional growth of concentration of G-KSF in a blood plasma. G-KSF elimination half-life at hypodermic introduction makes 3.5 hours of blood serum. Prolonged use of G-KSF during the period up to 28 days is not followed by signs of cumulation and increase in an elimination half-life.

Speed of clearance makes 0.5 - 0.65 ml/min. Concentration of G-KSF of blood serum exceeds the level of 10 ng/ml within 8-16 hours after hypodermic introduction of therapeutic doses of drug. There is a direct dependence between concentration of G-KSF in plasma and growth of level of neutrophils in peripheral blood.

Indications to use:

The prevention of development and treatment of the neutropenia caused by cytotoxic chemotherapy of tumors. Granokrin appoint after use by oncological patients of the cytotoxic drugs inhibiting functional activity of marrow, especially when carrying out high-dose chemotherapy.

Mobilization of progenitors of a hemogenesis. Granokrin's use independently or after chemotherapy activates cells - predecessors of a hemogenesis in peripheral blood which can be taken away from the patient and to enter to it after use of tsitostatik, instead of bone marrow transplantation or in addition to it. Introduction of progenitors of a hemogenesis accelerates hemopoiesis recovery, reduces the need for transfusion of a platelet concentrate.

Route of administration and doses:

Treatment of the neutropenia caused by cytotoxic chemotherapy of tumors. The drug is administered once a day subcutaneously in 24-28 h after the termination of a course of chemotherapy.

The dosage of drug depends on type, doses and the used scheme of cytotoxic chemotherapy.

The dose of drug depends also on extent of decrease in level of neutrophils. If the level of neutrophils is lower 1.0Õ109/l, then a necessary initial dose of drug of 5 mkg/kg/days. Use of drug can be stopped if for the 7th day of use the level of neutrophils reaches 5.0Õ109/l, and number of leukocytes of 10.0х109/l. If the maintenance of neutrophils and leukocytes for 7-14 day of use of drug does not reach the specified values, then it is necessary to keep a dose of 5 mkg/kg/days before achievement of level of neutrophils 5.0Õ109/l. It is necessary to control the level of neutrophils and number of leukocytes 2-3 times a week throughout all course of therapy by Granokrin.

If prior to treatment at the patient the level of neutrophils is higher 1.0 x 109/l, then the necessary dose makes 2.5 mkg/kg/days. Use of drug can be stopped if the level of neutrophils for the 7th or later day of use reaches 5.0 x 109/l, and number of leukocytes 10.0 x 109/l. If indicators of neutrophils and leukocytes for 7-14 day of use of drug do not reach the specified values, it is necessary to keep a dose of 2.5 mkg/kg/days before achievement of level of neutrophils 5.0 x 109/l.

If the chemotherapy dose low and the level of inhibition of cells of marrow small, can be used a dose of 1.25 mkg/kg/days for maintenance of level of neutrophils. Use of drug can be stopped if the level of neutrophils for the 7th or later day of use reaches 5.0 h109/l, and number of leukocytes 10.0 x 109/l. If indicators of neutrophils and leukocytes for 7-14 day of use of drug do not reach the specified values, it is necessary to keep a dose of 1.25 mkg/kg/days before achievement of level of neutrophils 5.0 h109/l.

If necessary duration of a course of therapy can make up to 14 days, depending on disease severity and expressiveness of a neutropenia.

Prevention of a neutropenia. Drug is appointed in 24-28 h after the termination of chemotherapy. In the preventive purposes for maintenance of safe level of neutrophils the drug is administered subcutaneously in a dose of 1.25 mkg/kg/days within 7-14 days. It is necessary to control the level of neutrophils and number of leukocytes 2-3 times a week throughout all course of therapy by Granokrin.

Use of drug can be stopped if the level of neutrophils for the 7th or later day of use reaches 5.0 x 109/l, and number of leukocytes 10.0 x 109/l.

Mobilization of progenitors of a hemogenesis. For activation of progenitors of a hemogenesis in peripheral blood the drug is administered subcutaneously in a dose of 5 mkg/kg/days within 7 days. In case of carrying out cytotoxic chemotherapy drug is appointed in 24-28 h after the termination of chemotherapy. Procedures of a leukopheresis should be carried out in case of increase in number of leukocytes of peripheral blood to 5.0 x 109/l. To patients who did not receive intensive chemotherapy there is enough one procedure of a leukopheresis. In other cases it is recommended to carry out additional leykafereza.

Repeated appointment of drug according to the above-stated schemes is allowed if necessary by results of the analysis of hematologic indicators.

Instructions on use. At emergence of need of cultivation of drug it is recommended to use only 5% dextrose solution. Cultivation of drug of 0.9% solution of sodium chloride is not allowed.

Features of use:

1. Drug is appointed in 24-28 h after the termination of a course of chemotherapy. It is not recommended to use drug before carrying out chemotherapy or during it.

2. Safety of use of drug at pregnancy and feeding are not established by a breast. In preclinical trials on animals data on teratogenecity of drug were not obtained, however at purpose of drug pregnant women should correlate the expected result to possible risk for a fruit. It is not recommended to use drug feeding.

3. During use of drug it is necessary to control 2-3 times a week key parameters of blood, especially level of neutrophils (see the ROUTE OF ADMINISTRATION AND DOSES).

4. Safety of use of drug for patients with a miyelodisplastichesky syndrome and a myelosis is not established therefore at these diseases it is not recommended to appoint drug. It is necessary to use with care drug at an acute myeloleukemia. Special attention needs to be paid on the differential diagnosis between imperious crisis of a myelosis and an acute myeloleukemia.

5. It is necessary to be careful at appointment to patients with hereditary intolerance of fructose as drug contains Mannitolum.

To apply only under control of the doctor.

Influence of G-KSF on ability to driving of vehicles or work with mechanisms it is not established.

Side effects:

The most often side effects are shown by ostealgias and the generalized muscle pains (10%) which sometimes were more expressed 3-4 degrees (1-2%). These phenomena are not long and are successfully stopped by reception of non-steroidal anti-inflammatory drugs.

Sometimes (less than 1%) skin rash, temperature increase, cold, a fever, weakness, a grippopodobny syndrome develops. These manifestations are usually poorly expressed and take place without additional intervention after the end of use of drug.

Observations on long-term safety rchg-KSF cannot be considered finished. Separate cases of increase in a spleen were registered. When using drug Granokrin® such cases are noted. However, when using similar foreign drugs, according to the statistical analysis, the probability of development of such complications makes 1/4000. Exceptional cases of emergence of the symptoms indicating reactions of allergic types are described, at the same time lowering of blood pressure, a cardiopalmus, the complicated breath, edematization of the person, a small tortoiseshell, skin rash is observed. Similar cases are noted when using Granokrin®.

According to the statistical analysis the specified side effects most often can develop at introduction of the first dose within the first 30 min. after introduction rchg-KSF. At the same time it is recommended to administer the antihistaminic drugs, adrenokortikosteroida, bronchial spasmolytic drugs or drugs containing hormones of epinephral gland then the specified symptoms have to be stopped. At development of similar side effects use of drug should be stopped.

Interaction with other medicines:

Expediency and safety of administration of drug per day or on the same day, as cytotoxic chemotherapy, are not established.

As chemotherapeutic drugs actively influence cells of the hemopoietic system, it is recommended to appoint drug in 24 hours after the termination of chemotherapy.

Contraindications:

- hypersensitivity to rchg-KSF, to the excipients which are a part of drug;

- a heavy inborn neutropenia (Kostmann's syndrome) with cytogenetic disturbances;

- disease end-stage;

- chronic renal failure;

- lactation.

Overdose:

Action of Granokrin® at overdose is not established. After drug withdrawal the number of the circulating neutrophils usually at first decreases and then is returned to norm.

Storage conditions:

To store at a temperature from 2 to 8 °C in the place, unavailable to children. Not to freeze. To transport all types of the covered transport at a temperature from 2 to 8 °C. Not to freeze. A period of validity - 2 years. Drug is not subject to expired use.

Issue conditions:

According to the recipe

Packaging:

Solution for hypodermic introduction of 75 mkg / 0,75 ml, 150 mkg / 0,75 ml, glass bottles of 0,75 ml. On 1 glass bottle together with the instruction on a medical use in a cardboard pack.