Neupogen - instructions for use, dose, side effects, contraindications

Excipients: Acetic Acid Ice 0.3 mg, 1 N sodium hydroxide solution - q.s. up to pH 4, sorbitol 25.0 mg, polysorbate-80 0.02 mg, water for injection up to 0.5 ml.

Description:

Transparent colorless or slightly yellowish liquid, odorless or with a faint odor.

Pharmacotherapeutic group:leukopoiesis stimulant

ATX: & nbsp

L.03.A.A.02 Filgrastim

Pharmacodynamics:

Filgrastim is a highly purified, non-glycosylated protein, consisting of 175 amino acids. It is produced by strain K12 Escherichia coli, the genome of which by genetic engineering methods introduced gene granulotsitarnogo colony-stimulating factor (G-CSF) rights.

Human G-CSF is a glycoprotein that regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow. Neupogen® containing recombinant human G-CSF (filgrastim), significantly increases the number of neutrophils in peripheral blood in the first 24 hours after administration with a small increase in the number of monocytes. In patients with severe chronic neutropenia (TCN), Neupogen® can cause a slight increase in the number of circulatingeosinophils and basophils. Some of these patients may experience eosinophilia or basophilia before starting therapy.

Neupogen ® dose-dependently increases the number of neutrophils with normal or increased functional activity, which was detected by determining the chemotactic and phagocytic activity of neutrophils. After the end of treatment, the number of neutrophils in peripheral blood is reduced by 50% within 1-2 days and returns to normal level during the next 1-7 days.

Neupogen ® significantly reduces the frequency, severity and duration of neutropenia and febrile neutropenia, reducing the need and duration of inpatient treatment in patients receiving chemotherapy with cytostatics or myeloablative therapy followed by bone marrow transplantation.

Patients receiving Neupogen® and cytotoxic chemotherapy require smaller doses of antibiotics compared to patients receiving only cytotoxic chemotherapy.

Treatment with Neupogen ® significantly reduces the duration of febrile neutropenia, the need for antibiotic therapy and hospitalization after induction chemotherapy for acute myelogenous infection, without affecting the incidence of fever and infectious complications.

The use of Neupogen ® both alone and after chemotherapy, mobilizes the release of hematopoietic stem cells into the peripheral bloodstream. Transplantation of autologous peripheral blood stem cells (PSKK) is performed after therapy with large doses of cytostatics, or instead of bone marrow transplantation, or in addition to it. Transplantation of PSKK can also be administered after (high-dose) myelosuppressive cytotoxic therapy. The use of PSKC, mobilized with Neupogen ®, accelerates the recovery of hematopoiesis, reduces the risk of hemorrhagic complications and the need for transfusion of platelet mass. In children and adults with TCN (severe congenital, periodic, idiopathic neutropenia), Neupogen® stably increases the number of neutrophils in peripheral blood, reduces the incidence of infectious complications.

The administration of Neupogen ® to patients with HIV infection allows maintaining a normal level of neutrophils and following recommended doses of antiviral and / or other myelosuppressive therapy. There were no signs of an increase in HIV replication with Neupogen ®.

Like other hematopoietic growth factors, G-CSF stimulates human endothelial cells in vitro.

Preclinical safety data

The carcinogenic properties of filgrastim have not been studied. Filgrastim did not cause mutations in the genome of bacteria, regardless of the presence of the enzyme system necessary for the metabolism of the drug.

It was found that some malignant cells have on their surface receptors for G-CSF. The probability that filgrastim can serve as a growth factor for various types of tumors, can not be ruled out.

In studies on rats of both sexes, no effect was found on fertility and pregnancy with filgrastim at doses up to 500 μg / kg.

In studies on rats and rabbits filgrastim did not have a teratogenic effect. Rabbits had an increased incidence of miscarriages, but there was no abnormality of fetal development.

Pharmacokinetics:

Suction

After subcutaneous (SC) administration filgrastim quickly absorbed and after 2-8 hours reaches its maximum concentration in serum. The half-life after intravenous (IV) or SC administration is usually from 2 to 4 hours. The clearance and half-life period depend on the dose of the drug and the number of neutrophils.Considering the dependence of the clearance on the number of neutrophils, its saturation with increasing filgrastim concentration and a decrease in neutropenia, we can speak of the prevalence of the linear nature of clearance and the linear nature of the pharmacokinetics. Absolute bioavailability after SC administration is 62% at a dose of 375 μg and 72% at a dose of 750 μg. After the termination of the administration of filgrastim, its concentration is reduced to endogenous values within 24 hours.

In healthy volunteers and patients with oncological diseases, a reduction in the plasma concentration of filgrastim after repeated administration was shown before chemotherapy. The increase in clearance of filgrastim in this case is dose-dependent, and the degree of this increase, possibly, depends on the degree of neutrophilia in the recipients, which agrees with the data on the increase in neutrophil-dependent clearance with increasing neutrophil pool. In patients receiving filgrastim after the chemotherapy, the concentration of the drug in the plasma remained at the same level until the beginning of the restoration of hemopoiesis.

Distribution

With iv and n / k administration of filgrastim there is a positive linear dependence between the administered dose and serum concentration. After sc administration of therapeutic doses, its concentration exceeds 10 ng / ml for 8-16 hours. The volume of distribution is 150 ml / kg.

Excretion

Long-term administration of filgrastim (up to 28 days) after autologous bone marrow transplantation does not lead to cumulation and a change in the half-life.

Regardless of the mode of administration, the elimination of filgrastim proceeds according to the rules of kinetics of the first order. The half-life is 3.5 hours, the clearance is 0.6 ml / min / kg.

Pharmacokinetics in special patient groups

Children After the chemotherapy the pharmacokinetics of filgrastim is similar to that in adult patients receiving the same doses taking into account the mass of the body, which makes it possible to conclude that the pharmacokinetics of filgrastim are independent of age.

Pharmacokinetic data in patients older than 65 years are absent.

In studies on the use of filgrastim, it was shown that pharmacodynamics and pharmacokinetics in patients with severe renal or hepatic impairment are similar to those of healthy subjects. Therefore, in these cases, there is no need for dose adjustment.

In patients with terminal stage of renal failure There was a tendency to increase the systemic exposure of filgrastim compared with healthy volunteers and patients with creatinine clearance of 30-60 ml / min.

Indications:

Adults and children

Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant diseases (with the exception of chronic myelogenous leukemia and myelodysplastic syndrome), as well as neutropenia and its clinical consequences in patients receiving myeloablative therapy followed by allogeneic or autologous bone marrow transplantation with increased risk of developing prolonged and severe neutropenia.

Mobilization of autologous peripheral blood stem cells (autologous PSKK), including after myelosuppressive therapy, as well as mobilization of peripheral blood stem cells in healthy donors (allogeneic PSKK).

Severe congenital, periodic or idiopathic neutropenia (absolute number of neutrophils (ACH) less than or equal to 0.5 × 10⁹/ l) in children and adults with severe or recurrent infections in history to increase the number of neutrophils, as well as to reduce the frequency and duration of infectious complications.

Persistent neutropenia (ACH less than or equal to 1.0 × 10⁹/ l) in patients with developed stage of HIV infection to reduce the risk of bacterial infections when other methods of treatment are not possible.

Neutropenia in patients with acute myelogenous leukemia receiving induction or consolidation chemotherapy, to reduce its duration and clinical consequences.

Contraindications:

Hypersensitivity to the drug or its components in anamnesis.

Severe congenital neutropenia (Kostmann's syndrome) with cytogenetic disorders (see section "Precautions").

Neupogen® should not be used to increase the doses of cytotoxic chemotherapeutic drugs above those recommended.

Simultaneous administration with cytotoxic chemo- and radiotherapy.

Carefully:

Patients with sickle-cell anemia, bone pathology (including those with osteoporosis), hereditary fructose intolerance (the drug contains sorbitol), with secondary acute myelogenous leukemia (due to limited safety and efficacy data), in the treatment of patients receiving high-dose chemotherapy.

Pregnancy and lactation:

The drug category C.

The safety of Neupogen ® for pregnant women is not established. It is possible to pass the drug Neupogen® through the placental barrier in women. In animal studies, reproductive toxicity was identified. When prescribing Neupogen®, pregnant women should correlate the expected therapeutic effect with the possible risk to the fetus.

In studies on rats of both sexes, no effect was found on fertility and course of pregnancy with filgrastim at doses up to 500 μg / kg.

In studies on rats and rabbits, Neupogen® did not have a teratogenic effect. Rabbits had an increased incidence of miscarriages, but there was no abnormality of fetal development.

It is not known whether Neipogen ® penetrates into breast milk. It is not recommended to use Neupogen® in nursing mothers.

Dosing and Administration:

Adults and children

Daily sc or in the form of short intravenous infusions (30-minute) on 5% glucose solution (cm.See "Dilution guidelines" in "Dosage and administration" section) pores until the number of neutrophils passes the expected minimum (nadir) and returns to range of normal values. Preferential way of introduction!

Standard schemes of cytotoxic chemotherapy

For 0.5 million units (5 μg) / kg 1 time per day daily or in the form of short intravenous infusions (30 minutes) in a 5% solution of glucose. In most cases, the route of administration is preferred. There is evidence that with IV injection of the drug, the duration of the effect is shortened. However, the clinical relevance of these data remains unclear. The choice of route of administration should depend on the individual characteristics of the patient and the clinical picture of the disease. The first dose of Neupogen ® is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy: Daily administration of Neupogen ® should be continued until the number of neutrophils exceeds the expected minimum and reaches normal values. After the chemotherapy (standard regimens) for the treatment of solid tumors, lymphomas and lymphoid leukemia duration of therapy to achieve the desired effect usually up to 14 days.After induction and consolidation therapy of acute myelogenous leukemia, the duration of application of Neupogen ® can be increased up to 38 days depending on the type, dosage and the used scheme of cytotoxic chemotherapy.

The transient increase in the number of neutrophils is usually observed 1-2 days after the beginning of treatment with Neupogen ®. To achieve a stable therapeutic effect, it is necessary to continue therapy with Neupogen ® until the number of neutrophils exceeds the expected minimum and reaches normal values. It is not recommended to abolish Neupogen® prematurely, until the number of neutrophils passes through the expected minimum.

Use in children - see the section "Features of the use of the drug by pregnant women, women during breastfeeding, children and adults with chronic diseases."

After myeloablative therapy followed by bone marrow transplantation

Daily sc or IV in the form of infusion in 20 ml of a 5% solution of glucose (see subsection "Dilution instructions" of the section "Method of administration and dose"). The initial dose is 1.0 million units (10 μg) / kg / day drip for 30 minutes or 24 hours, or by continuous infusion for 24 hours.The first dose of Neupogen ® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and with bone marrow transplantation - no later than 24 hours after the infusion of the bone marrow. The duration of therapy is not more than 28 days (efficacy and safety of therapy lasting more than 28 days are not established).

After the maximum reduction in the number of neutrophils (nadir), the daily dose is corrected depending on the dynamics of the neutrophil content. If the number of neutrophils exceeds 1.0 × 10⁹/ l for three consecutive days, the dose of Neupogen ® is reduced to 0.5 million units / kg per day; Then, if the ACCH exceeds 1.0х10⁹/ l for three consecutive days, Neupogen® is canceled. If during the period of treatment ASC decreases less than 1.0х10⁹/ l, the dose of Neupogen ® should be increased again, in accordance with the above scheme.

Mobilization of peripheral blood stem cells (SBSC) in patients receiving myelosuppressive or myeloablative therapy followed by autologous transfusion of PSKK with or without bone marrow transplantation

For the mobilization of PSKK, 1.0 million units (10 μg) / kg per day by way of a SC injection once a day or a continuous 24 hour infusion (in 20 ml of a 5% solution of glucose (see.See "Dilution Directions" in the section "Dosing and Administration") for 5-7 consecutive days, usually one or two leukapheresis procedures in a row on the 5th, 6th days. In some cases, additional leukapheresis is possible. The appointment of Neupogen ® should be continued until the last leukapheresis.

To mobilize PSKC after mielosupressivnoy chemotherapy - 0.5 million units (5 mcg) / kg per day by daily injections, starting from the first day after completion of chemotherapy and until the amount of neutrophils passes through the expected minimum and not will reach normal values. Leukapheresis should be carried out within period, when ACN rises from less than 0.5 × 10⁹/ l to more than 5.0х10⁹/ l. Patients who did not receive intensive chemotherapy, it is enough to have one leukapheresis. In some cases, additional leukapheresis is recommended.

Mobilization of PSKC in healthy donors for allogeneic transplantation

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

Severe chronic neutropenia (THC)

Daily, c / o, once or divided into several introductions. With congenital neutropenia: the initial dose is 1.2 million units (12 μg) / kg per day; with idiopathic or intermittent neutropenia: 0.5 million units (5 μg) / kg per day to a stable excess number of neutrophils 1.5х10⁹/ l. After achieving a therapeutic effect, the minimum effective dose should be determined to maintain this level. To maintain the required number of neutrophils requires a long daily administration of the drug.

After 1-2 weeks of treatment, depending on the response of the patient to therapy, the initial dose can be doubled or halved. Subsequently, every 1-2 weeks, individual dose adjustment can be performed to maintain the number of neutrophils in the range of 1.5-10 × 10⁹/ l. Patients with severe infections can be treated with a regimen, with a faster increase in dose. In 97% of patients who responded positively to treatment; the full therapeutic effect is observed when doses are prescribed up to 24 mcg / kg per day.The safety of prolonged administration of Neupogen ® in doses exceeding 24 μg / kg per day in patients with THC is not established.

Use in children - see the section "Features of the use of the drug by pregnant women, women during breastfeeding, children and adults with chronic diseases."

Neutropenia in HIV infection

The initial dose of 0.1-0.4 million units (1-4 μg) / kg per day once p / to achieve and to maintain a normal number of neutrophils (more than 2.0 × 10⁹/ l). In more than 90% of patients who responded positively to treatment, the normalization of the number of neutrophils usually occurs in 2 days. A small number of patients (less than 10%) to achieve a normal neutrophil count required doses of up to 1.0 million units (10 μg) / kg per day (the maximum daily dose is not more than 10 μg / kg). After achieving the therapeutic effect, it is necessary to administer the minimum effective dose to maintain a normal number of neutrophils. The recommended maintenance dose of 300 mcg per day is p / k an average of 3 times a week according to the alternating schedule (every other day). Subsequently, individual dose adjustment and long-term administration of the drug may be required to maintain the average number of neutrophils> 2.0 × 10⁹/ l.

Special instructions for dosing

Recommendations for dosing in special groups of patients are indicated in the section "Features of the drug use by pregnant women, women during breastfeeding, children and adults with chronic diseases."

Breeding instructions

Neupogen® is diluted with only 5% glucose solution. It is not allowed to dilute 0,9% solution of sodium chloride. Do not dilute the drug to a final concentration of less than 5 μg per ml.

If Neupogen® is diluted to a concentration of less than 1.5 million units (15 μg) in 1 ml, serum human albumin in an amount such that the final concentration of albumin is 2 mg / ml. For example, with a final solution volume of 20 ml, total doses of filgrastim less than 30 million units (300 μg) should be administered with the addition of 0.2 ml of a 20% albumin solution.

Diluted Neupogen® can be adsorbed by glass and plastics. However, Neupogen® when diluted with a 5% solution of glucose is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (polypropylene-polyethylene) and polypropylene.

The finished solution of Neupogen ® is stored at a temperature of 2 to 8 ° C, not more than days.

Side effects:

Clinical Trials Data

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

Patients with oncological diseases

Neupogen® does not increase the incidence of adverse reactions to cytotoxic chemotherapy. Adverse events with the same frequency were observed in patients receiving Neupogen® / chemotherapy and placebo / chemotherapy.

Organism as a whole: often - fatigue, general weakness, inflammation of the mucous membranes (mucositis), anorexia; infrequently - nonspecific pain; rarely - exacerbation of rheumatoid arthritis.

Musculoskeletal system: often pain in the chest, pain in the bones (especially in bones with active blood formation) and muscles (weak or moderate (10%), sometimes strong (3%), which in most cases are stopped by usual analgesics).

Gastrointestinal tract: very often - nausea, vomiting; often - constipation, diarrhea.

The cardiovascular system: in isolated cases - transient arterial hypotension, which does not require medical correction, vascular disorders (venoclusive disease, disorders associated with changes in body fluid content, in patients receiving high doses of chemotherapy followed by autologous bone marrow transplantation, communication with Neupogen® is not installed).

Respiratory system: often - cough, sore throat; rarely infiltrates in the lungs, interstitial pneumonia, pulmonary edema, in isolated cases with an unfavorable outcome in the form of respiratory failure or adult respiratory distress syndrome (can be fatal). Skin and subcutaneous fat: often - alopecia, skin rash; rarely - Sweet syndrome (febrile acute dermatosis), cutaneous vasculitis (the mechanism of development in patients receiving Neupogen ® is not known).

Nervous system: often a headache.

The immune system: rarely allergic reactions. About half of allergic reactions are associated with the administration of the first dose, more often after intravenous administration of the drug. Sometimes the resumption treatment is accompanied by a relapse of symptoms.

Genitourinary system: rarely - a violation of urination (mainly dysuria of mild to moderate degree).

Laboratory indicators: very often - increased activity of lactate dehydrogenase, alkaline phosphatase, γ-glutamyltransferase, increased serum uric acid concentration (reversible dose-dependent changes, usually mild or moderate).

Patients with HIV infection

Musculoskeletal system: very often - pain in the bones and muscles (myalgia), mostly weak or moderate (the frequency is similar to that in patients with cancer).

Blood and lymphatic system: often with splenomegaly (association with taking the drug in less than 3% of cases, in all cases with physical examination there was a small or moderate degree of splenomegaly with a favorable clinical course, no cases of hypersplenism, no splenectomy in any case). Splenomegaly is quite common in patients with HIV infection, as well as in varying degrees of severity in most patients with AIDS; in such cases, the association with the use of Neupogen ® is not established.

Healthy donors (mobilization of allogeneic PSKK)

Organism as a whole: rarely - exacerbation of rheumatoid arthritis.

Musculoskeletal system: very often - pain in the bones and muscles, mostly weak or moderate.

Respiratory system: rarely hemoptysis, infiltrates in the lungs.

Nervous system: very often - a headache.

The immune system: infrequently - severe allergic reactions.

Blood and lymphatic system: very often - leukocytosis (more than 50x10⁹/ l) was observed in 41% of healthy donors, transient thrombocytopenia (less than 100x10⁹/ l) was observed in 35% of healthy donors; often - splenomegaly (without clinical manifestations); infrequently - disorders of the spleen function.

Laboratory indicators: often - a transient slight increase in lactate dehydrogenase activity, alkaline phosphatase; infrequent - a slight increase in activity of aspartate aminotransferase (ACT) (without clinical consequences), hyperuricemia.

Patients with THC

The incidence of adverse events with the use of Neupogen® with patients with TCN decreases with time.

Organism as a whole: often - reactions (including pain) at the injection site (less than 2% of patients), arthralgia (less than 2% of patients).

Musculoskeletal system: very often - pain in the bones and muscles; Often - osteoporosis (less than 2% of patients).

Gastrointestinal tract: often diarrhea (usually after initiation of therapy), hepatomegaly (less than 2% of patients).

Skin and subcutaneous fatty tissue: often - alopecia (less than 2% of patients), rash (less than 2% of patients), cutaneous vasculitis (in 2% of patients).

Nervous system: often - headache (less than 2% of patients, usually after initiation of therapy).

Blood and lymphatic system: very often - anemia, splenomegaly (in some cases may progress); often - thrombocytopenia; infrequently - disorders of the spleen function. There were also cases of epistaxis.

Genitourinary system: infrequently - hematuria, proteinuria.

Laboratory indicators: very often - a transient increase in lactate dehydrogenase activity, alkaline phosphatase without clinical manifestations, transient moderate hypoglycemia after eating, hyperuricemia.

Post-marketing application of the drug

The immune system: in rare cases, allergic reactions, including anaphylaxis, skin rash, urticaria, which can develop at the beginning of therapy or with subsequent treatment with filgrastim.

In some cases, the resumption of treatment was accompanied by a relapse of symptoms, suggesting a relationship between the drug and the undesirable phenomenon.

With the development of serious allergic reactions, therapy with filgrastim should be stopped.

Blood and lymphatic system: Separate cases of sickle-cell crises are described on the background of filgrastim administration, some - with a fatal outcome (see section "Precautions"),

In patients who received filgrastim, cases of development of splenomegaly (> 1% and <10%) were often observed.

Against the background of G-CSF (filgrastim), infrequent (> 0.1% and <1%) cases of spleen rupture in healthy donors and patients with oncological diseases are described (see section "Precautions").

Skin and subcutaneous fatty tissue: rare cases (> 0.01% and <0.1%) of the Sweet syndrome (febrile acute dermatosis) are described. Patients with oncological diseases with filgrastim described very rare cases (approximately 1 case per 100,000 patients (0.001%)) of cutaneous vasculitis (estimated frequency of reports is 0.001%).

Musculoskeletal system: In patients with oncological diseases against the background filgrastim described very rare (approximately 0.03 cases per 100,000 patients (0.00003%)) cases of pseudogout development (chondrocalcinosis).

Pediatric patients with TCN receiving long-term treatment with filgrastim described frequent cases of bone density reduction and development of osteoporosis (> 1% and <10%).

Laboratory indicators: in patients receiving filgrastim after cytotoxic chemotherapy, there was a reversible increase in the concentration of uric acid in the serum,activity of alkaline phosphatase and lactate dehydrogenase without clinical manifestations (usually mild or moderate).

Overdose:

Cases of overdose are not marked. In studies on bone marrow transplantation

patients Neupogen® was administered at doses up to 138 μg / kg per day without the development of toxic effects. 1-2 days after discontinuation of the drug, the number of circulating neutrophils usually decreases by 50% and returns to normal levels after 1-7 days.

Interaction:

The safety and efficacy of Neupogen in the same day as myelosuppressive cytotoxic chemotherapeutic agents have not been established. In view of the sensitivity of the rapidly dividing myeloid cells to myelosuppressive cytotoxic chemotherapy, it is not recommended to designate Neupogen® within 24 hours before or after the administration of these drugs. With the simultaneous administration of Neupogen ® and fluorouracil, the severity of neutropenia may increase. Possible interaction with other hematopoietic growth factors and cytokines is not known.

Given that lithium stimulates the release of neutrophils, it is possible to enhance the effect of Neupogen ® in a combined prescription, but such studies have not been conducted.

The increased hematopoietic activity of the bone marrow in response to therapy with growth factors leads to transient positive changes in the visualization of the bones, which should be taken into account when interpreting the results.

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

Special instructions:

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

We describe infrequent cases of splenic rupture, in some cases - with a fatal outcome, against the background of G-CSF (filgrastim). Given these data, careful monitoring of the size of the spleen is recommended by clinical examination (palpation) and instrumental methods (eg, ultrasound). It is necessary to conduct an on-site diagnosis if there is a suspected rupture of the spleen orsplenomegaly in case of patient complaints or healthy donors for pain in the upper left quadrant of the abdomen or upper humeral region.

According to the literature, the presence of sickle-cell anemia and a high number of leukocytes is an unfavorable prognostic factor. Such patients should regularly perform a blood test and take into account the possibility of developing splenomegaly and thrombosis of blood vessels.

Cases of sickle cell crises are described against filgrastim, some with fatal outcome. Care should be taken in patients with sickle cell anemia when prescribing Neupogen® (filgrastim), carefully evaluating the benefits and possible risks.

In connection with the frequent cases of thrombocytopenia in patients who received filgrastim, careful monitoring of the number of platelets is recommended. Patients with bone pathology, including those with osteoporosis receiving continuous treatment with Neupogen® for more than 6 months, are shown to control bone density.

The effect of Neupogen ® in patients with a significantly reduced number of myeloid progenitor cells is not known.Neupogen ® increases the number of neutrophils by primarily affecting the neutrophil precursor cells, therefore, in patients with a reduced content of progenitor cells (for example, those subjected to intensive radiation therapy or chemotherapy), the degree of increase in the number of neutrophils may be lower.

The effect of the Neupogen ® preparation on the "Graft versus host" reaction has not been established.

Neupogen® contains sorbitol in a concentration of 50 mg / ml. It is unlikely that due to monotherapy with Neupogen ®, sufficient amounts of sorbitol will be supplied to the body to develop a toxic reaction, but patients with hereditary intolerance to fructose should be careful.

If symptoms such as coughing, fever and dyspnea occur, combined with radiological data in the form of lung infiltrates and impaired lung function, it can be assumed that adult respiratory distress syndrome develops. In this case, therapy with the drug should be canceled and appropriate treatment should be prescribed.

a) Growth of malignant cells

The safety and efficacy of Neupogen ® in patients with myelodysplastic syndrome and chronic myelogenous leukemia have not been established, therefore, it is not indicated in these diseases. Particular attention should be paid to the differential diagnosis between acute myelogenous leukemia and blast crisis of chronic myelogenous leukemia.

Human G-CSF can stimulate the growth of myeloid cells in vitro. Similar effects can be observed in vitro and in some nonmyeloid cells. It is necessary to use with caution Neipogen in patients with secondary acute myeloid leukemia, due to limited safety and efficacy data in this case.

The safety and efficacy of Neupogen® in patients with acute myeloid leukemia de novo under 55 years of age in cases of prognostically favorable cytogenetic factors (translocation t (8; 21), t (15; 17), inv (16)) have not been established.

b) Patients receiving cytotoxic chemotherapy

Leukocytosis: less than 5% of patients who received Neupogen ® at doses greater than 0.3 million units (3 μg / kg / day), the number of leukocytes increased to 100 × 10⁹/ l and more. There are no side effects directly associated with such leukocytosis, not described.However, considering the possible risk associated with high leukocytosis, during treatment with Neupogen ® it is necessary to determine the number of leukocytes regularly (for example, 2-3 times a week). If after passing the expected minimum, the number of leukocytes exceeds 50x10⁹/ l, Neupogen® should be immediately discontinued.

If Neupogen® is used to mobilize PSKK, its dose should be reduced or completely eliminated if the number of leukocytes exceeds 70x10⁹/ l.

The risk associated with high-dosage chemotherapy: special caution should be exercised in the treatment of patients receiving high-dose chemotherapy, since no improvement in the outcome of malignant neoplasm has been observed, while increased doses of chemotherapeutic agents have more pronounced toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems (cm instructions for the use of specific chemotherapeutic agents).

Monotherapy with Neupogen® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Because of the possibility of using higher doses of chemotherapy (eg, full doses according to the regimens), the patient may be at greater risk of thrombocytopenia and anemia.It is recommended to conduct regular blood tests and determine the number of platelets and hematocrit. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens capable of causing severe thrombocytopenia.

It has been shown that the use of Neupogen ® for the mobilization of PSKC leads to a decrease in the degree and duration of thrombocytopenia that has developed as a result of myelosuppressive or myeloablative chemotherapy.

c) Patients with THC

Transformation into leukemia or preleukemia (myelodysplastic syndrome): special caution should be exercised when diagnosing TCN, and differentiate it from other hematological diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia. Prior to treatment should be carried out with the full blood count and determination of leukocyte platelet counts, as well as explore morphologic picture of bone marrow and karyotype.

A small number (3%) of patients with severe congenital neutropenia (Costman's syndrome) who received Neupogen® had myelodysplastic syndrome and leukemia.Myelodysplastic syndrome and leukemia are natural complications of this disease. Their association with treatment with Neupogen ® is unclear. Approximately 12% of patients with initially normal cytogenetics showed abnormalities in a second examination, including monosomy 7. If a patient with Costman's syndrome develops cytogenetic disorders, the benefits and risks of continuing Neupogen® therapy should be carefully evaluated. With the development of myelodysplastic syndrome or leukemia Neupogen ® should be discarded. It is not yet clear whether the long-term treatment with Neupogen® predisposes patients with severe congenital neutropenia (Costman's syndrome) to the development of cytogenetic abnormalities, myelodysplastic syndrome and leukemia. Patients with Costman's syndrome are recommended to conduct regular (approximately every 12 months) morphological and cytogenetic studies of the bone marrow.

Cytogenetic disorders, leukemia and osteoporosis were detected with prolonged use of Neupogen® (> 5 years) in patients (9.1%) with THC. The association of these phenomena with the use of the drug has not been clarified.

Blood formula: The number of platelets should be carefully monitored, especially during the first few weeks of treatment with Neupogen®. At TCHN during the first weeks of initial therapy, a clinical blood test and the number of platelets are determined 2 times a week, with a stable condition of the patient - once a month. If a patient has thrombocytopenia (the number of platelets stably below 100 x 10⁹/ l), consideration should be given to the temporary withdrawal of the drug or a reduction in the dose. There are also other changes in the blood formula that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.

Other: should exclude such causes of transient neutropenia, as viral infections. The enlargement of the spleen is a direct consequence of the treatment with Neupogen®. During clinical trials, 31% of patients with THC showed palpation with splenomegaly. In radiography, the increase in volume is detected soon after the start of treatment and tends to stabilize. Reducing the dose slows or stops the increase in the size of the spleen; splenectomy may be required in 3% of patients.The size of the spleen should be monitored regularly by palpation.

A small number of patients had hematuria and proteinuria. To monitor these indicators, urine tests should be done regularly.

The safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established (see "Features of the use of the drug by pregnant women, women during breastfeeding, children and adults with chronic diseases").

d) Patients undergoing the mobilization of PSKK

After bone marrow transplantation, a blood test is performed and the platelet count is determined 3 times a week. Mobilization: a comparison of the two recommended mobilization methods (only filgrastim or in combination with myelosuppressive chemotherapy) were not performed on the same contingent of patients. Direct comparison of the results of different studies is difficult due to individual differences between patients, and also because of differences between CD34 + values obtained by laboratory tests. Therefore, it is difficult to recommend any optimal method of mobilization.The choice of the mobilization method should be carried out depending on the overall goals of the treatment of the patient.

Prior treatment with cytotoxic agents: in patients who have undergone active myelosuppressive therapy in the past, there may not be a sufficient increase in PSMC up to the recommended minimum level (> 2.0 x 10⁶ CD34 + / kg) or the acceleration of the normalization of the number of platelets.

Some cytostatics have a particular toxicity to the precursor cells of hemopoiesis and can adversely affect their mobilization. The use of such drugs as melphalan, carmustine and carboplatin for a long period before mobilization may reduce its severity. However, the use of melphalan, carboplatin or carmustine together with the Neupogen® preparation is effective in the activation of PSKK. If it is planned to transplant PSKK, it is recommended to schedule their mobilization at an early stage of treatment. Particular attention should be paid to the number of progenitor cells activated in such patients before high-dose chemotherapy. If the results of mobilization in accordance with the above criteria are insufficient,Alternative treatments that do not require the use of progenitor cells should be considered.

Assessment of the number ("yield") of peripheral blood stem cells: When evaluating the number of PSMCs that have been mobilized in patients with Neupogen®, special attention should be given to the quantification method. The results of a flow cytometric analysis of the number CD34 + cells differ depending on the specific methodology, and one should be cautious about recommendations on their number, based on studies conducted in other laboratories. There is a complex but stable statistical relationship between the number of C injected into reinfusionD34 + cells and the rate of normalization of platelet count after high-dose chemotherapy. The minimum amount of PSKK, equal to or exceeding 2.0х10⁶ CD34 + cells / kg, leads to a sufficient recovery of hematological parameters. The amount exceeding this value seems to be accompanied by a faster normalization, the amount less than that indicated by a slower normalization of the blood picture.

e) Mobilization of PSKC in healthy donors

The mobilization procedure for PSMC does not directly benefit healthy donors and should only be carried out for the purpose of allogeneic transplantation.

Procedures for mobilization and apheresis of cells should be conducted in a medical center with experience in this field. Mobilization of PSKK is possible only if the laboratory parameters, especially the hematological parameters of the donor, match the criteria for selection, and special attention should be paid to the presence of infectious diseases (see the section "Features of the drug use by pregnant women, women during breastfeeding, children and adults with chronic diseases ").

Transient leukocytosis (leukocytes more than 50х10⁹/ l) is observed in 41% of healthy donors. Transient thrombocytopenia (number of platelets less than 100x10⁹/ l) after the appointment of filgrastim and the conduct of leukapheresis is observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50x10⁹/ l after the procedure of leukapheresis.

If more than one leukapheresis is required, the number of platelets must be monitored before each apheresis procedure, especially if the platelet count is less than 100x10⁹/ l. Conduction of leukapheresis is not recommended if the number of platelets is less than 75x10⁹/ l, with the appointment of anticoagulants or known violations of hemostasis.

Neupogen® should be withdrawn or its dose should be reduced if the number of leukocytes is more than 70x10⁹/ l.

In healthy donors, it is necessary to regularly monitor all blood test parameters prior to their normalization.

Given single cases of rupture of the spleen after the appointment of G-CSF to healthy donors, it is recommended to control its size (palpation, ultrasound).

It is impossible to exclude the risk of a clone of malignant tumor cells. In the center of apheresis, it is recommended to systematically monitor the remote safety of the drug in healthy donors.

An evaluation of the safety and efficacy of Neupogen ® in healthy donors under the age of 16 and older than 60 years was not carried out.

Specific guidance for recipients of allogeneic PSKK, obtained with Neupogen ®

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

f) Neutropenia in HIV patients

With a very fast positive response to therapy, a significant increase in the number of neutrophils after the administration of the initial doses of Neupogen ® is possible. When treating with Neupogen ®, a thorough blood test (ACH, number of erythrocytes, platelets, etc.) should be performed on a daily basis for the first 2-3 days, then 2 times a week for the first 2 weeks and every week or one week in time of maintenance therapy. When carrying out maintenance therapy 300 mcg per day, according to the alternating scheme, significant fluctuations in the amount of neutrophils are possible.

Taking into account fluctuations in the value of AChN, in order to determine the true maximum decrease in AFN (nadir), blood sampling should be performed before the next dose of the drug is prescribed.

Monotherapy with Neupogen® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Because of the possibility of using higher doses of chemotherapy (eg, full doses according to the regimens) or more of them in combination therapy, the patient may be at greater risk of thrombocytopenia and anemia.It is recommended to conduct regular blood tests and determine the number of platelets and hematocrit.

In patients with infectious diseases and infiltration of the bone marrow by infectious agents (for example, the complex Mycobacterium avium) or with a bone marrow (lymphoma) tumor, filgrastim therapy is administered concomitantly with therapy directed against these conditions. The effectiveness of Neupogen ® in the treatment of neutropenia due to infiltration of the bone marrow by infectious agents (osteomyelitis) or tumor damage has not been established.

Features of the drug use by children and adults with chronic diseases

Elderly age

A small number of elderly patients participated in the studies, no special studies of this group of patients were performed.

Special recommendations for patients of senile age are absent.

An evaluation of the safety and efficacy of Neupogen ® in healthy donors over the age of 60 years has not been carried out.

Children

Standard cytotoxic chemotherapy regimens: the safety and efficacy profiles of Neupogen ® in children receiving cytotoxic chemotherapy did not differ from those in adults.

Patients after myelosuppressive or myeloablative therapy followed by autologous transfusion of PSKK: the safety and efficacy of Neupogen ® in healthy donors under 16 years of age have not been evaluated.

Patients with TCN and oncological diseases: efficacy and safety of Neupogen in newborns suffering from TCN are not established. Severe congenital, periodic or idiopathic neutropenia (AFN less than or equal to 0.5 × 10⁹/ l) is an indication for a prolonged use of Neupogen ® in children with severe or recurrent infections in history to increase the number of neutrophils, and to reduce the frequency and duration of complications associated with infection (see Indication section).

In clinical trials, the effectiveness of Neupogen ® in patients under 18 years of age with TCN and oncological diseases was proved. The profile of drug safety in children in the treatment of TCN did not differ from that in adults.

Recommendations for dosing for children of the same age are the same as for adults receiving myelosuppressive cytotoxic chemotherapy.

Patients with renal or hepatic insufficiency

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

Instructions for use, handling and destruction

Avoid vigorous shaking.

Before administration, the Neupogen® solution should be examined for the presence of foreign visible particles. Allowed to introduce a solution only without the presence of foreign visible particles.

Vials and syringe tubes of drug Neypogen® intended for single use only.

The presence of drugs in the environment should be minimized. Do not dispose of the drug Neypogen® via wastewater or with household waste. If possible, it is necessary to use special systems for the disposal of medicinal products.

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

No effect of Neupogen ® on the ability to drive a car or work with mechanisms.

Form release / dosage:A solution for subcutaneous administration, 30 million units / 0.5 ml, 48 million units / 0.5 ml.

Packaging:

For 30 million units / 0.5 ml and 48 million units / 0.5 ml in syringe tubes, the body of which is made of glass of hydrolytic type 1 to EP, piston from plastic, with plug of butyl rubber laminated with fluoropolymer. On the other hand, the syringe tube is capped with a tip of butyl rubber laminated with fluoropolymer.

1 syringe tube together with 1 sterile injection needle, hermetically sealed, and Instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of 2-8 ° C.

Keep out of the reach of children.

Transportation

At a temperature of 2-8 ° C.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:П N011221 / 02

Date of registration:09.06.2010

The owner of the registration certificate:Hoffmann-La Roche Ltd.Hoffmann-La Roche Ltd. Switzerland

Manufacturer: & nbsp

F.Hoffmann-La Roche, Ltd. Switzerland

Representation: & nbspF.Hoffmann-La Roche Ltd. F.Hoffmann-La Roche Ltd. Switzerland

Information update date: & nbsp24.09.2015

Illustrated instructions

Instructions

Neupogen® (Neupogen® )