Neypogen

General characteristics. Structure:

Active ingredient: 300,0 mkg (30 million. Piece) a filgrastima in 1 ml of solution in a bottle.

300,0 mkg (30 million. Piece) or 480,0 mkg (48 million. Piece) a filgrastina in 0,5 ml of solution in an unit-dose syringe.

Excipients: ice acetic acid, 1 N hydroxide sodium solution, sorbitol, polysorbate-80, water for injections. 

Drug which works in marrow where new blood cells are made. It stimulates growth of the white blood cells called granulocytes of neutrophils or neutrophils.

Pharmacological properties:

Pharmacodynamics. Filgrastim - the high cleaning neglikozilirovanny protein consisting of 175 amino acids. It is developed by a strain of K12 Escherichia coli into which genome methods of genetic engineering entered a gene of a granulotsitarny colony stimulating factor (G-KSF) of the person.

Human G-KSF - the glycoprotein regulating formation of functionally active neutrophils and their exit in blood from marrow. Нейпоген®, the containing recombinant human G-KSF (filgrasty), considerably increases number of neutrophils in peripheral blood already in the first 24 h after introduction with small increase in number of monocytes. With the heavy chronic neutropenia (HCN) of Neypogen® can cause insignificant increase in number of the circulating eosinophils and basophiles in patients. At some of these patients even prior to therapy the eosinophilia or a basophilia can come to light.

Нейпоген® дозозависимо increases number of neutrophils with the normal or increased functional activity that was revealed by means of definition of the hemotaksichesky and englobing activity of neutrophils. After the end of treatment the number of neutrophils in peripheral blood decreases by 50% within 1-2 days and is returned to normal level during the next 1-7 days.

Нейпоген® considerably reduces the frequency, weight and duration of a neutropenia and febrile neutropenia, reducing need and duration of hospitalization at the patients receiving chemotherapy cytostatics or miyeloablativny therapy with the subsequent transplantation of marrow.

The patients receiving Neypogen® and cytotoxic chemotherapy demand smaller doses of antibiotics in comparison with the patients receiving only cytotoxic chemotherapy.

Treatment by the drug Neypogen® considerably reduces duration of a febrile neutropenia, the need for an antibioticotherapia and hospitalization after induction chemotherapy at an acute myeloleukemia, without influencing the frequency of fever and infectious complications.

Drug Neypogen® use as independently, and after chemotherapy, will mobilize an exit of haematopoietic stem cells in a peripheral blood stream. Transplantation of the autologous peripheral stem cells of blood (PSCB) is carried out after therapy by high doses of tsitostatik, or instead of transplantation of marrow, or in addition to it. Transplantation of PSKK can be also appointed after (high-dose) myelosuppressive cytotoxic therapy. Use of PSKK mobilized by means of the drug Neypogen® accelerates hemopoiesis recovery, reduces danger of hemorrhagic complications and the need for transfusion of a platelet concentrate. At children and adults with THN (a heavy inborn, periodic, idiopathic neutropenia) Neypogen® steadily increases number of neutrophils in peripheral blood, reduces the frequency of infectious complications.

Purpose of the drug Neypogen® to patients with HIV infection allows to support the normal level of neutrophils and to follow the recommended doses of anti-virus and/or other myelosuppressive therapy. Signs of increase in replication of HIV at use of the drug Neypogen® are noted.

As well as other hemopoietic growth factors, G-KSF stimulates human endothelial cells of in vitro.

Preclinical data on safety. Cancerogenic properties of a filgrastim were not studied. Filgrastim did not cause mutations in a genome of bacteria regardless of existence of the fermental system necessary for drug metabolism.

It was revealed that some malignant cells have on the surface receptors to G-KSF. The probability that filgrasty can serve as a growth factor for various type of tumors cannot be excluded.

In researches on rats of both sexes any influence on fertility and course of pregnancy at use of a filgrastim in doses to 500 mkg/kg was not revealed.

In researches on rats and rabbits filgrasty had no teratogenic effect. At rabbits the increased frequency of abortions was observed, however anomalies of fetation were not noted.

Pharmacokinetics. Absorption. After hypodermic (п / to) introductions by filgrasty it is quickly soaked up and in 2-8 h reaches the maximum concentration in blood serum. The elimination half-life after intravenous (in/in) or п / to introduction usually makes from 2 to 4 h. The clearance and an elimination half-life depend on a dose of drug and number of neutrophils. Considering dependence of clearance on number of neutrophils, its saturation at increase in concentration of a filgrastim and decrease at a neutropenia, it is possible to speak about dominance of linear nature of clearance and linear character of pharmacokinetics. Absolute bioavailability after п / to introduction makes 62% at a dose of 375 mkg and 72% at a dose of 750 mkg. After the termination of introduction of a filgrastim its concentration decreases to values of endogenous sizes during 24 h.

At healthy volunteers and patients with oncological diseases before carrying out chemotherapy reduction of plasma concentration of a filgrastim at its repeated introduction was shown. Increase in clearance of a filgrastim in this case is dozozavisimy, and extent of this increase perhaps depends on neutrophilia degree at recipients that will be coordinated with data on increase in neytrofilzavisimy clearance at increase in a pool of neutrophils. At the patients receiving filgrasty after carrying out chemotherapy, concentration of drug in plasma remained at one level up to the beginning of recovery of a hemogenesis.

Distribution. At in/in and п / to introduction of a filgrastim positive linear dependence between the entered dose and concentration in blood serum is observed. After п / to introduction of therapeutic doses its concentration exceeds 10 ng/ml during 8-16 h. The volume of distribution makes 150 ml/kg.

Removal. Long purpose of a filgrastim (up to 28 days) after autologous transplantation of marrow does not lead to cumulation and change of an elimination half-life.

Irrespective of a way of introduction, elimination of a filgrastim proceeds by rules of kinetics of the 1st order. The elimination half-life - 3.5 h, clearance is equal to 0.6 ml/min.

Pharmacokinetics in special groups of patients. At children after carrying out chemotherapy the pharmacokinetics of a filgrastim is similar to that at the adult patients receiving the same doses of drug taking into account body weight that allows to draw a conclusion on independence of pharmacokinetics of a filgrastim of age.

Pharmacokinetic data at patients are more senior than 65 years are absent.

In researches on use of a filgrastim it was shown that the pharmacodynamics and pharmacokinetics at patients with heavy disturbances of renal or hepatic functions are similar to that at healthy investigated. Therefore in these cases need for dose adjustment is absent.

At patients with an end-stage of a renal failure the tendency to increase in system exposure of a filgrastim in comparison with healthy volunteers and patients with clearance of creatinine of 30-60 ml/min. was noted.

Indications to use:

Adults and children. A neutropenia, a febrile neutropenia at the patients receiving intensive myelosuppressive cytotoxic chemotherapy concerning malignant diseases (except for a myelosis and a miyelodisplastichesky syndrome), and also a neutropenia and its clinical effects at the patients receiving miyeloablativny therapy with the subsequent allogenic or autologous transplantation of marrow, with the increased risk of development of a long and heavy neutropenia.

Mobilization of autologous peripheral stem cells of blood (autologous PSKK), including after myelosuppressive therapy, and also mobilization of peripheral stem cells of blood at healthy donors (allogenic PSKK).

Heavy inborn, periodic or idiopathic neutropenia (the absolute number of neutrophils (ANN) less or equal 0.5 x 109/l) at children and adults with heavy or recurrent infections in the anamnesis for increase in number of neutrophils, and also for reduction of frequency and duration of infectious complications.

Resistant neutropenia (AChN less or equal 1.0 x 109/l) at patients with the developed HIV infection stage for decrease in risk of bacterial infections at impossibility of use of other ways of treatment.

Neutropenia at the patients with an acute myeloleukemia receiving the induction or consolidating chemotherapy for reduction of its duration and clinical effects.

Route of administration and doses:

Adults and children. Daily п / to or in the form of short in/in infusions (30-minute) for 5% glucose solution (see the subsection "Instructions on Cultivation" of the section "Route of Administration and Doses") until the number of neutrophils does not pass the expected minimum (nadir) and will not return to the range of normal values. It is preferable п / to a way of introduction.

Standard schemes of cytotoxic chemotherapy. On 0.5 mln units (5 mkg) / kg of 1 times a day daily п / to or in the form of short in/in infusions (30-minute) for 5% glucose solution. It is in most cases preferable п / to a way of introduction. There are data that at in administration of drug there is a shortening of duration of effect. However there is not clear a clinical importance of these data. The choice of a way of introduction has to depend on specific features of the patient and a clinical picture of a disease. The first dose of the drug Neypogen® is entered not earlier than in 24 h after the termination of a course of cytotoxic chemotherapy. Daily administration of the drug Neypogen® needs to be continued until the number of neutrophils does not exceed the expected minimum and will not reach normal values. After carrying out a course of chemotherapy (standard schemes) for treatment of solid tumors, lymphoma and lymphoid leukemia therapy duration for achievement of necessary effect usually makes up to 14 days. After the induction and consolidating therapy of an acute myeloleukemia duration of use of the drug Neypogen® can increase up to 38 days depending on type, doses and the used scheme of cytotoxic chemotherapy.

Passing increase in number of neutrophils is observed usually in 1-2 days after an initiation of treatment by the drug Neypogen®. For achievement of stable therapeutic effect it is necessary to continue therapy by the drug Neypogen® until the number of neutrophils does not exceed the expected minimum and will not reach normal values. It is not recommended to cancel Neypogen® prematurely, before transition of number of neutrophils through the expected minimum.

Use for children - see the section "Features of Use of Drug by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases".

After miyeloablativny therapy with the subsequent transplantation of marrow. Daily п / to or in/in in the form of infusion in 20 ml of 5% of solution of glucose (see the subsection "Instructions on Cultivation" of the section "Route of Administration and Doses"). An initial dose - 1.0 mln units (10 mkg) / kg a day in/in kapelno within 30 min. or 24 h or by a continuous p / to infusion during 24 h. It is necessary to enter the first dose of the drug Neypogen® not earlier than in 24 h after cytotoxic chemotherapy, and at transplantation of marrow - not later than in 24 h after infusion of marrow. Therapy duration no more than 28 days (efficiency and safety of therapy lasting more than 28 days are not established).          

After the maximum decrease in number of neutrophils (nadir) a daily dose is korrigirut depending on dynamics of maintenance of neutrophils. If the quantity of neutrophils exceeds 1.0 x 109/l within three days in a row, the dose of the drug Neypogen® is reduced to 0.5 million PIECES/kg a day; then, if AChN exceeds 1.0 x 109/l within three days in a row, Neypogen® cancel. If during treatment of AChN decreases less than 1.0 x 109/l, the dose of the drug Neypogen® needs to be increased again, according to above the provided scheme.

Mobilization of the peripheral stem cells of blood (PSCB) at the patients receiving myelosuppressive or miyeloablativny therapy with the subsequent autologous transfusion of PSKK with (or without) transplantation of marrow. For mobilization of PSKK - on 1.0 mln units (10 mkg) / kg a day by п / to an injection of 1 times a day or continuous 24-hour п / to infusion (in 20 ml of 5% of solution of glucose (see the subsection "Instructions on Cultivation" of the section "Route of Administration and Doses")) within 5-7 days in a row, at the same time there are usually enough one-two procedures of a leukopheresis in a row for the 5th, 6th days. Carrying out an additional leukopheresis is in some cases possible. Purpose of the drug Neypogen® needs to be continued to the last leukopheresis.

For mobilization of PSKK after myelosuppressive chemotherapy - on 0.5 mln units (5 mkg) / the kg a day by daily p / to injections, since first day after end of chemotherapy and until the quantity of neutrophils does not pass through the expected minimum and will not reach normal values. Leykaferez it is necessary to carry out during the period when AChN rises with less than 0.5 x 109/l to more than 5.0 x 109/l. Enough one leukopheresis happens the patient who was not receiving intensive chemotherapy. It is in some cases recommended to carry out additional leykafereza.

Mobilization of PSKK at healthy donors for allogenic transplantation. On 1 mln units (10 mkg) / kg a day п / to within 4-5 days. Leykaferez carry out from 5 in the afternoon and if necessary till 6 in the afternoon with the purpose to receive CD34+ ≥ 4 x 106 cells/kg of body weight of the recipient. Efficiency and safety of use of the drug Neypogen® for mobilization of PSKK at healthy donors are younger 16 and 60 years are more senior it was not investigated.

Heavy Chronic Neutropenia (HCN). Daily, п / to, once or having divided into several introductions. At an inborn neutropenia: an initial dose - on 1.2 mln units (12 mkg) / kg a day; at an idiopathic or periodic neutropenia: on 0.5 mln units (5 mkg) / kg a day before stable exceeding of number of neutrophils 1.5 x 109/l. After achievement of therapeutic effect it is necessary to define a minimal effective dose for maintenance of this level. Maintenance of the necessary number of neutrophils requires long daily administration of drug. In 1-2 weeks of treatment, depending on reaction of the patient to therapy, an initial dose it is possible to double or to reduce half. Afterwards each 1-2 weeks it is possible to make individual dose adjustment for maintenance of number of neutrophils in the range of 1.5-10 x 109/l. At patients with heavy infections it is possible to apply the scheme with more bystry increase in a dose. At 97% of the patients who positively reacted to treatment, the full therapeutic effect is observed at purpose of doses to 24 mkg/kg a day. Safety of long administration of the drug Neypogen® in doses over 24 mkg/kg a day at patients with THN is not established.

Use for children - see the section "Features of Use of Drug by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases".

Neutropenia at HIV infection. An initial dose of 0.1-0.4 mln units (1-4 mkg) / kg a day once п / to before achievement and for maintenance of normal number of neutrophils (more than 2.0 x 109/l). At more than 90% of the patients who positively reacted to treatment normalization of number of neutrophils usually occurs in 2 days. A small amount of patients (less than 10%) for achievement of normal number of neutrophils needed introduction of doses of drug to 1.0 mln units (10 mkg) / to kg a day (the maximum daily dose no more than 10 mkg/kg). After achievement of therapeutic effect introduction of a minimal effective dose is necessary for maintenance of normal number of neutrophils. The recommended maintenance dose of 300 mkg a day п / to on average 3 once a week according to the alternating scheme (every other day). Afterwards individual dose adjustment and long purpose of drug for maintenance of average of neutrophils> 2.0 x 109/l can be required.

Special instructions on dosing. Recommendations about dosing at special groups of patients are specified in the section "Features of Use of Drug by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases".

Instructions on cultivation. Нейпоген® part only 5% with glucose solution. At the same time cultivation of 0.9% is not allowed by chloride sodium solution. It is impossible to dissolve drug to final concentration less than 5 mkg in 1 ml.

If Neypogen® gets divorced to concentration less than 1.5 mln units (15 mkg) in 1 ml, then it is necessary to add a seralbumin of the person in quantity that final concentration of albumine made 2 mg/ml to solution. For example, at the final volume of solution of 20 ml, total doses of a filgrastim less than 30 mln units (300 mkg) it is necessary to enter 0.2 ml of 20% of solution of albumine with addition.

Divorced Neypogen® can be adsorbed by glass and plastic. However, Neypogen® at cultivation of 5% solution of glucose is compatible to glass and a number of plastic, including polyvinylchloride, polyolefin (copolymer of polypropylene and polyethylene) and polypropylene.

Ready solution of the drug Neypogen® is stored at a temperature from 2 to 8 °C no more days.

Precautionary measures. Treatment by the drug Neypogen® has to be carried out only under control of the oncologist or hematologist, having experience of use of G-KSF, in the presence of necessary diagnostic opportunities. Procedures of mobilization and an aferez of cells have to be held in the oncological or hematologic center having experience in this area and a possibility of adequate monitoring of progenitors of a hemogenesis.

Infrequent cases of emergence of a rupture of a spleen, in some cases - with a lethal outcome, against the background of reception of G-KSF (filgrastim) are described. Considering these data, careful observation of the spleen sizes by means of clinical inspection (palpation) and tool methods is recommended (for example, ultrasonography). It is necessary to carry out aim diagnosis at suspicion on a rupture of a spleen or a splenomegaly in case of complaints of patients or healthy donors to pain in an upper left quadrant of a stomach or upper humeral area.

According to literary data, existence of a sickemia and high number of leukocytes is an adverse predictive factor. At such patients it is regularly necessary to perform blood test and to consider a possibility of development of a splenomegaly and thrombosis of vessels. Cases of drepanocytic crises against the background of reception of a filgrastim, some – with a lethal outcome are described. It is necessary to be careful at patients with a sickemia at purpose of the drug Neypogen® (filgrastim), having carefully estimated advantage and possible risks.

Due to the frequent cases of development of thrombocytopenia in the patients receiving filgrasty careful observation of quantity of thrombocytes is recommended.
Including with the osteoporosis receiving continuous treatment by the drug Neypogen® within more than 6 months control of density of bone substance is shown to patients with pathology of a bone tissue.

Effect of the drug Neypogen® at patients with much reduced quantity of myeloid progenitors is not known. Нейпоген® increases number of neutrophils by impact, first of all, by progenitors of neutrophils therefore at patients with the lowered maintenance of progenitors (for example, the undergone intensive radiation therapy or chemotherapy) extent of increase in quantity of neutrophils can be lower.

Effect of the drug Neypogen® on reaction "A transplant against the owner" is not established.

Нейпоген® contains sorbitol in concentration of 50 mg/ml. It is improbable that owing to monotherapy by the drug Neypogen® enough sorbitol for development of toxic reaction will come to an organism, however patients should be careful with hereditary intolerance of fructose.

At emergence of symptoms, such as cough, temperature increase and диспноэ, in combination with radiological data in the form of availability of infiltrates in lungs and deterioration in function of lungs, it is possible to assume development respiratory a distress syndrome of adults. In this case therapy drug it is necessary to cancel and appoint the corresponding treatment.

a) Growth of malignant cells. Safety and efficiency of use of the drug Neypogen® for patients with a miyelodisplastichesky syndrome and a myelosis are not established therefore at these diseases it is not shown. Special attention should be paid on the differential diagnosis between an acute myeloleukemia and blast crisis of a myelosis.

G-KSF of the person can stimulate growth of myeloid cells of in vitro. Similar effects can be observed by in vitro and concerning some not myeloid cells.

It is necessary to apply with care Neypogen® at patients with a secondary acute myeloleukemia, in view of limited data on safety and efficiency in this case.

Safety and efficiency of use of the drug Neypogen® for patients with an acute myeloleukemia of de novo are younger than 55 years in cases predictively of advantage cytogenetic factors (t translocations (8; 21), t (15; 17), inv (16)) are not established.

b) The patients receiving cytotoxic chemotherapy. Leukocytosis: less than at 5% of the patients receiving Neypogen® in doses more than 0.3 mln units (3 mkg/kg a day), the number of leukocytes increased to 100 x 109/l and more. Any by-effects which are directly connected with such leukocytosis are not described. However, considering the possible risk connected with a high leukocytosis during treatment by the drug Neypogen® follows regularly (for example, 2-3 times a week) to define number of leukocytes. If after passing of the expected minimum the number of leukocytes exceeds 50 x 109/l, Neypogen® should be cancelled immediately. If Neypogen® is applied to mobilization of PSKK, its dose should be lowered or to cancel completely in that case when the number of leukocytes exceeds 70 x 109/l.

The risk connected with high-dose chemotherapy: extra care should be shown at treatment of the patients receiving high-dose chemotherapy as improvement of an outcome of a malignant new growth is noted while the raised doses of himiopreparat have more expressed toxicity, including skin reactions and side effects from cardiovascular, nervous and respiratory systems (see instructions to use of specific himiopreparat).

Monotherapy by the drug Neypogen® does not prevent the thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Because of a possibility of use of higher doses of himiopreparat (for example, full doses according to schemes), the patient can be exposed to bigger risk of thrombocytopenia and anemia. It is regularly recommended to carry out blood test and to define number of thrombocytes and a hematocrit. Extra care should be shown at use of the one-component or combined chemotherapeutic schemes capable to cause heavy thrombocytopenia.

It was shown that use of the drug Neypogen® for mobilization of PSKK leads to reduction of degree and duration of the thrombocytopenia which developed owing to myelosuppressive or miyeloablativny chemotherapy.

c) Patients with THN. Transformation in a leukosis or a preleukosis (a miyelodisplastichesky syndrome): extra care should be shown at diagnosis of THN and to differentiate it from other hematologic diseases, such as aplastic anemia, a myelodisplasia and a myeloleukemia. Prior to treatment it is necessary to carry out the developed blood test with definition of a leukocytic formula and quantity of thrombocytes, and also to investigate a morphological picture of marrow and a karyotype.

At a small number (3%) of the patients with a heavy inborn neutropenia (Kostmann's syndrome) receiving Neypogen® the miyelodisplastichesky syndrome and a leukosis was observed. The Miyelodisplastichesky syndrome and a leukosis - natural complications of this disease. Their communication with treatment by the drug Neypogen® 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 by the drug Neypogen®. At development of a miyelodisplastichesky syndrome or a leukosis of Neypogen® it is necessary to cancel. For the present it is not clear whether prolonged treatment with the drug Neypogen® of patients with a heavy inborn neutropenia (Kostmann's syndrome) contributes to development of cytogenetic anomalies, a miyelodisplastichesky syndrome and a leukosis. With Kostmann's syndrome it is regularly recommended to patients (approximately each 12 months) to conduct morphological and cytogenetic researches of marrow.

Cytogenetic disturbances, leukosis and osteoporosis were found at prolonged use of the drug Neypogen® (> 5 years) in patients (9.1%) with THN. Communication of these phenomena using drug is not found out.

Blood count: it is necessary to control carefully number of thrombocytes, especially within the first several weeks of treatment by the drug Neypogen®. At THN within the first weeks of initial therapy clinical blood test and number of thrombocytes define 2 times a week, at a stable condition of the patient - once a month. If the patient has a thrombocytopenia (the number of thrombocytes is stable lower than 100 x 109/l), it is necessary to consider a question of temporary drug withdrawal or reduction of a dose. Are observed as well other changes of a blood count demanding its careful control including anemia and passing increase in quantity of myeloid progenitors.

Other: it is necessary to exclude such reasons of a passing neutropenia as viral infections. Increase in a spleen is a direct consequence of treatment by the drug Neypogen®. During clinical trials the splenomegaly was found in 31% of patients with THN at a palpation. At a X-ray analysis increase in volume comes to light soon after an initiation of treatment and tends to stabilization. Reduction of a dose slows down or stops increase in the size of a spleen; the splenectomy can be required at 3% of patients. The sizes of a spleen need to be controlled regularly by a palpation.

At a small number of patients the hamaturia and a proteinuria were observed. For control of these indicators it is necessary to do the analysis of urine regularly.

Safety and efficiency of use of drug for newborns and patients with an autoimmune neutropenia are not established (see the section "Features of Use of Drug by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases").

d) The patients undergoing mobilization of PSKK. After transplantation of marrow carry out blood test and 3 times a week define quantity of thrombocytes.

Mobilization: comparison of two recommended mobilization methods (only filgrasty or with myelosuppressive chemotherapy) on the same contingent of patients was not carried out to combinations. Direct comparison of results of various researches is complicated owing to individual distinctions between patients, and also owing to distinctions between the CD34+ values received by means of laboratory analyses. Therefore it is rather difficult to recommend any optimum method of mobilization. The choice of a method of mobilization should be carried out depending on overall objectives of treatment of this patient.

The previous treatment by cytotoxic means: at patients to whom in the past active myelosuppressive therapy was carried out can not occur sufficient increase in PSKK up to the recommended minimum level (³2.0 x 106 CD34+/kg) or accelerations of normalization of quantity of thrombocytes.

Some cytostatics have special toxicity in relation to progenitors of a hemogenesis and can negatively influence their mobilization. Use of such drugs as Melphalanum, кармустин and карбоплатин throughout the long period prior to mobilization can reduce degree of its expressiveness. However, use of Melphalanum, karboplatin or karmustin together with the drug Neypogen® effectively at activation of PSKK. If transplantation of PSKK is planned, it is recommended to plan their mobilization at an early stage of a course of treatment. Special attention should be paid on number of the progenitors activated at such patients to high-dose chemotherapy. If results of mobilization according to the above-stated criteria are insufficient, it is necessary to consider the alternative types of treatment which are not demanding use of progenitors.

Assessment of quantity ("harvest") of peripheral stem cells of blood: estimating number of PSKK mobilized at patients by means of the drug Neypogen® it is necessary to pay special attention to a method of quantitative definition. Results of the flowing cytometric analysis of number of CD34+ cells differ depending on specific methodology, and it is necessary to treat with care the recommendations about their number based on the researches conducted in other laboratories.

There is a difficult, but stable statistical dependence between number entered into reinfusion by CD34+ cells and speed of normalization of quantity of thrombocytes after high-dose chemotherapy.

The minimum quantity of PSKK equal or the exceeding 2.0 x 106 CD34+-kletok/kg, leads to sufficient recovery of hematologic indicators. The quantity surpassing this value, apparently, is followed by more bystry normalization, quantity less specified - slower normalization of a picture of blood.

e) Mobilization of PSKK at healthy donors. The procedure of mobilization of PSKK does not bear direct advantage for healthy donors and has to be held only for allogenic transplantation.

Procedures of mobilization and aferez of cells have to be held in the medical center having experience in this area. Mobilization of PSKK is possible only on condition of compliance of laboratory parameters of, especially, hematologic indicators of the donor, to criteria of the choice, also special attention should be paid on existence of infectious diseases (see the section "Features of Use of Drug by Pregnant Women, Women during Breastfeeding, the Children and Adults Having Chronic Diseases").

The passing leukocytosis (leukocytes more than 50 x 109/l) is noted at 41% of healthy donors. Passing thrombocytopenia (quantity of thrombocytes less than 100 x 109/l) after purpose of a filgrastim and carrying out a leukopheresis is observed at 35% of donors. Besides, 2 cases of thrombocytopenia less than 50 x 109/l after holding a procedure of a leukopheresis are noted.

If carrying out more than one leukopheresis is required, it is necessary to control quantity of thrombocytes before each procedure of an aferez, especially, if number of thrombocytes less than 100 x 109/l. Carrying out a leukopheresis is not recommended if number of thrombocytes less than 75 x 109/l, at purpose of anticoagulants or the known disturbances of a hemostasis.

Нейпоген® it has to be cancelled or its dose has to be lowered if quantity of leukocytes more than 70 x 109/l.

At healthy donors it is regularly necessary to control all indicators of blood test before their normalization.

Considering isolated cases of a rupture of a spleen after purpose of G-KSF to healthy donors, it is recommended to control its sizes (a palpation, ultrasonography).

It is impossible to exclude risk of emergence of a clone of malignant tumor cells. In the center of an aferez it is recommended to carry out systematic monitoring of the remote safety of use of drug for healthy donors.

Assessment of safety and efficiency of the drug Neypogen® at healthy donors is younger 16 and 60 years are more senior it was not carried out.

Special instructions for recipients of the allogenic PSKK received by means of the drug Neypogen®. Use of an allogenic transplant of PSKK can be associated with increase in risk of development of acute or chronic reaction "A transplant against the owner" in comparison with transplantation of marrow.

e) A neutropenia at HIV patients. At very prompt affirmative answer on therapy perhaps significant increase in quantity of neutrophils after introduction of initial doses of the drug Neypogen®.

At treatment it is necessary to carry out by the drug Neypogen® regularly developed blood test (AChN, number of erythrocytes, thrombocytes, etc.) daily during the first 2-3 days, then 2 times a week within the first 2 weeks and every week or in a week during a maintenance therapy. When carrying out a maintenance therapy of 300 mkg a day according to the alternating scheme considerable fluctuations of quantity of neutrophils are possible. Taking into account AChN value fluctuations, for definition of true maximum decrease in AChN (nadir) blood sampling needs to be carried out before purpose of the following dose of drug.

Monotherapy by the drug Neypogen® does not prevent the thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Because of a possibility of use of higher doses of himiopreparat (for example, full doses according to schemes) or their bigger quantity as a part of a combination therapy, the patient can be exposed to bigger risk of thrombocytopenia and anemia. It is regularly recommended to carry out blood test and to define number of thrombocytes and a hematocrit.

At patients with infectious diseases and infiltration of marrow with infectious activators (for example, the Mycobacterium avium complex) or with tumoral damage of marrow (lymphoma) therapy filgrastimy is carried out along with the therapy directed against these states. Efficiency of the drug Neypogen® at treatment of the neutropenia caused by infiltration of marrow infectious activators (osteomyelitis) or tumoral defeat is not established.

To the application instruction, address and destruction. It is necessary to avoid vigorous stirring. Before introduction solution of the drug Neypogen® should be examined on presence of foreign visible particles. Administration of solution only without existence of foreign visible particles is allowed.

Bottles and the syringe tubes with the drug Neypogen® are intended only for disposable. Hit of medicines to the environment has to be minimized. Utilization of the drug Neypogen® by means of sewage or together with household waste is not allowed. It is whenever possible necessary to use special systems for utilization of medicines.

Features of use:

Pregnancy and period of feeding by a breast. Category C drug. Safety of the drug Neypogen® for pregnant women is not established. Passing of the drug Neypogen® through a placental barrier at women is possible. In researches on animals reproductive toxicity was revealed. At purpose of the drug Neypogen® pregnant women should correlate the expected therapeutic effect to possible risk for a fruit.

In researches on rats of both sexes any influence on fertility and the course of pregnancy at use of a filgrastim in doses to 500 mkg/kg was not revealed.

In researches on rats and rabbits of Neypogen® had no teratogenic effect. At rabbits the increased frequency of abortions was observed, however anomalies of fetation were not noted. 

It is unknown whether Neypogen® gets into breast milk. It is not recommended to apply Neypogen® at nursing mothers.

Advanced age. A small amount of elderly patients participated in researches, special researches of this group of patients were not conducted. Special recommendations for patients of senile age are absent.

Assessment of safety and efficiency of the drug Neypogen® at healthy donors is more senior than 60 years was not carried out.

Children. Standard schemes of cytotoxic chemotherapy: profiles of safety and efficiency of the drug Neypogen® at the children receiving cytotoxic chemotherapy did not differ from those at adults.

Patients after myelosuppressive or miyeloablativny therapy with the subsequent autologous transfusion of PSKK: assessment of safety and efficiency of the drug Neypogen® at healthy donors is younger than 16 years was not carried out.

Patients with THN and oncological diseases: efficiency and safety of use of the drug Neypogen® for the newborns suffering from THN are not established.

The heavy inborn, periodic or idiopathic neutropenia (AChN less or equal 0.5 x 109/l) is the indication to prolonged use of the drug Neypogen® at children with heavy or recurrent infections in the anamnesis for increase in number of neutrophils, and also for reduction of frequency and duration of the complications connected with an infection (see the section "Indications").
In clinical trials efficiency of the drug Neypogen® at patients aged up to 18 years with THN and oncological diseases was proved. The profile of safety of drug at children at treatment of THN did not differ from that at adults.

Recommendations about dosing for patients of children's age same, as for the adults receiving myelosuppressive cytotoxic chemotherapy.

Patients with a renal or liver failure. Dose adjustment is not required from patients with a heavy renal or liver failure as their pharmacokinetic and pharmakodinamichesky indicators were similar to those at healthy volunteers.
 
Influence on ability to driving of vehicles and work with cars and mechanisms. It is noted influences of the drug Neypogen® on ability to driving of the car or work with mechanisms.

Side effects:

Data of clinical trials. Very frequent (more than 10%), frequent (1-10%), infrequent (less than 1%) and rare (less than 0.01%) side effects.

Patients with oncological diseases. Нейпоген® does not increase the frequency of side reactions by cytotoxic chemotherapy. The undesirable phenomena with an identical frequency were noted at the patients receiving Neypogen®/himioterapiyu and placebo/chemotherapy.

Organism in general: often – fatigue, the general weakness, an inflammation of mucous membranes (mukozit), anorexia; infrequently – nonspecific pains; seldom – a pseudorheumatism aggravation.

Musculoskeletal system: often – a stethalgia, ostealgias (especially, in bones with an active hemopoiesis) and muscles (weak or moderate (10%), sometimes strong (3%) which are in most cases stopped by usual analgetics).

Digestive tract: very often – nausea, vomiting; often – a lock, diarrhea.
Cardiovascular system: in isolated cases – the passing arterial hypotension which is not demanding medicamentous correction, vascular disorders (the venookklyuzionny disease, disturbances connected with change of content of liquid in an organism at the patients receiving high doses of chemotherapy with the subsequent autologous bone marrow transplantation; connection using the drug Neypogen® is not established).

Respiratory organs: often – cough, a pharyngalgia; seldom – infiltrates in lungs, intersticial pneumonia, a fluid lungs, in isolated cases from the failure in the form of respiratory insufficiency or respiratory a distress syndrome of adults (can have a lethal outcome).

Skin and hypodermic fatty tissue: often – an alopecia, skin rash; seldom – a syndrome It is twisted (a febrile acute dermatosis), a skin vasculitis (the mechanism of development in the patients receiving Neypogen® is not known).

Nervous system: often – a headache.

Immune system: seldom – allergic reactions. About a half of allergic reactions are connected with introduction of the first dose, a thicket – later in/in drug uses. Sometimes resuming of treatment is followed by a recurrence of symptoms.

Urinogenital system: seldom – disturbance of an urination (generally a dysuria of easy and moderate degree).

Laboratory indicators: very often – increase in activity of a lactate dehydrogenase, alkaline phosphatase, g-glutamiltransferazy, increase in concentration of uric acid in blood serum (reversible dozozavisimy changes, usually weak or moderate).

Patients with HIV infection. Musculoskeletal system: very often – an ostealgia and muscles (mialgiya), generally weak or moderate (frequency is similar to that at patients with oncological diseases).

Blood and lymphatic system: often – a splenomegaly (communication with administration of drug less than 3% of cases; in all cases at physical inspection small or moderate degree of a splenomegaly with a favorable clinical current was observed; hypersplenism cases were not noted, the splenectomy was not carried out in one case). The splenomegaly quite often occurs at the patients having HIV infection and also in various degree of manifestation occurs at most of patients about AIDS; in such cases connection with administration of drug of Neypogen® is not established.

Healthy donors (mobilization of allogenic PSKK). Organism in general: seldom – a pseudorheumatism aggravation.

Musculoskeletal system: very often – an ostealgia and muscles, generally weak or moderate.

Respiratory organs: seldom – a pneumorrhagia, infiltrates in lungs.

Nervous system: very often – a headache.

Immune system: infrequently – heavy allergic reactions.

Blood and lymphatic system: very often – the leukocytosis (more than 50 x 109/l) was observed at 41% of healthy donors, passing thrombocytopenia (less than 100 x 109/l) was observed at 35% of healthy donors; often – a splenomegaly (without clinical manifestations); infrequently – disorders of function of a spleen.

Laboratory indicators: often – passing slight increase of activity of a lactate dehydrogenase, alkaline phosphatase; infrequently – slight increase of activity of aspartate aminotransferase (nuclear heating plant) (without clinical effects), a hyperuricemia.

Patients with THN. Frequency of the undesirable phenomena at administration of drug of Neypogen® by patients with THN decreases over time.

Organism in general: often – reactions (including pain) in the place of an injection (less than at 2% of patients), arthralgias (less than at 2% of patients).

Musculoskeletal system: very often – an ostealgia and muscles; often – osteoporosis (less than at 2% of patients).

Digestive tract: often – diarrhea (usually after the beginning of therapy), a hepatomegalia (less than at 2% of patients).

Skin and hypodermic fatty tissue: often – an alopecia (less than at 2% of patients), rash (less than at 2% of patients), a skin vasculitis (at 2% of patients).

Nervous system: often – a headache (less than at 2% of patients, usually after the beginning of therapy).

Blood and lymphatic system: very often – anemia, a splenomegaly (in certain cases can progress); often – thrombocytopenia; infrequently – disorders of function of a spleen. Also cases of nasal bleeding came to light.

Urinogenital system: infrequently – a hamaturia, a proteinuria.

Laboratory indicators: very often – passing increase in activity of a lactate dehydrogenase, alkaline phosphatase without clinical manifestations, a passing moderate hypoglycemia after food, a hyperuricemia.

Post-registration use of drug. Immune system: in rare instances the allergic reactions including an anaphylaxis, skin rash, a small tortoiseshell which can develop at the beginning of therapy or at the subsequent treatment filgrastimy. In some cases resuming of treatment was followed by a recurrence of symptoms that assumes existence of interrelation between drug and the undesirable phenomenon.

At development of serious allergic reactions therapy filgrastimy needs to be stopped.

Blood and lymphatic system: against the background of reception of a filgrastim separate cases of drepanocytic crises, some – with a lethal outcome are described (see the section "Precautionary measures").

At the patients receiving filgrasty cases of development of a splenomegaly were often observed (≥1% and <10%).

Against the background of reception of G-KSF (filgrastim) are described infrequent (≥0.1% and <1%) cases of a rupture of a spleen at healthy donors and patients with oncological diseases (see the section "Precautionary measures").

Skin and hypodermic fatty tissue: exceptional cases are described (≥0.01% and <0.1%) a syndrome It is twisted (a febrile acute dermatosis). At patients with oncological diseases at use of a filgrastim are described very rare (about 1 case on 100000 patients (0.001%)) cases of a skin vasculitis (settlement frequency of messages of 0.001%).

Musculoskeletal system: at patients with oncological diseases against the background of reception of a filgrastim are described very rare (about 0.03 cases on 100000 patients (0.00003%)) cases of development of a pseudogout (chondrocalcinosis).

At patients of children's age from THN receiving prolonged treatment filgrastimy are described frequent (≥1% and <10%) cases of reduction of density of a bone tissue and development of osteoporosis.

Laboratory indicators: at the patients receiving filgrasty after cytotoxic chemotherapy reversible increase in concentration of uric acid in blood serum, activities of an alkaline phosphatase and a lactate dehydrogenase without clinical manifestations was observed (usually weak or moderate).

Interaction with other medicines:

Safety and efficiency of administration of the drug Neypogen® on the same day, as myelosuppressive cytotoxic himiopreparat, are not established. In view of sensitivity of quickly sharing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to appoint Neypogen® in an interval for 24 h to or after administration of these drugs. At drug Neypogen® co-administration also ftoruratsit weight of a neutropenia can amplify. Possible interaction with other hemopoietic growth factors and cytokines is unknown.

Considering that lithium stimulates release of neutrophils, strengthening of effect of the drug Neypogen® at the combined appointment is possible, but such researches were not conducted.

The increased hemopoietic activity of marrow in response to therapy by growth factors leads to tranzitorny positive changes at visualization of bones that it is necessary to take into account at interpretation of results.

Owing to pharmaceutical incompatibility it is impossible to mix 0.9% with chloride sodium solution.

Contraindications:

Hypersensitivity to drug or its components in the anamnesis.

Heavy inborn neutropenia (Kostmann's syndrome) with cytogenetic disturbances (see the section "Precautionary measures").

Нейпоген® it should not be used for the purpose of increase in doses of cytotoxic chemotherapeutic drugs above recommended.

Co-administration with a cytotoxic himio-and radiation therapy.

With care. Patients with a sickemia, pathology of a bone tissue (including with osteoporosis), hereditary intolerance of fructose (drug contains sorbitol), with a secondary acute myeloleukemia (in view of limitation of data on safety and efficiency), at treatment of the patients receiving high-dose chemotherapy.

Overdose:

Cases of overdose are noted. In researches on transplantation of marrow to patients of Neypogen® it was entered in doses to 138 mkg/kg a day without development of toxic effects. In 1-2 days after drug withdrawal the number of the circulating neutrophils usually decreases by 50% and is returned to normal level in 1-7 days.

Storage conditions:

Period of validity 2 years. Not to use after the period of validity specified on packaging.

At a temperature of 2-8 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Solution for intravenous and hypodermic administration of 30 million PIECES/ml. On 30 mln units (1 ml) in a bottle from glass of hydrolytic type 1 on the EF corked by the stopper from the butyl rubber laminated by a ftorpolimer which is pressed out by an aluminum cap and closed by a plastic cover.

5 bottles with the application instruction place in a cardboard pack.

Solution for hypodermic introduction of 30 mln units / 0.5 ml, 48 mln units / 0.5 ml. On 30 million PIECES / 0.5 ml and 48 million PIECES / 0.5 ml in the syringe tubes which case is manufactured of glass of hydrolytic type 1 on EF, the piston - from plastic, with a stopper from the butyl rubber laminated by a ftorpolimer. On the other hand the unit-dose syringe is corked by a tip from the butyl rubber laminated by a ftorpolimer.

1 unit-dose syringe together with 1 sterile injection cannula which is hermetically packed and the application instruction is placed in a cardboard pack.