Immunost - instructions for use, doses, side effects, contraindications

Excipients: D-sorbitol 50.0 mg, polysorbate-80 0.04 mg, sodium acetate trihydrate 0.204 mg, acetic acid ice 0.480 μl, water for injection up to 1.0 ml.

Description:

Transparent colorless liquid.

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 a strain Escherichia coli, the genome of which was introduced into the genome by the gene of granulocyte human colony-stimulating factor (G-CSF), a glycoprotein that regulates the formation of functionally active neutrophils and their release into the blood from the bone marrow. Filgrastim, containing recombinant G-CSF, significantly increases the number of neutrophils in peripheral blood as early as the first 24 hours after administration, with a slight increase in the number of monocytes. In patients with severe chronic neutropenia filgrastim can cause a slight increase in the number of circulating eosinophils and basophils.

Filgrastim dose-dependently increases the number of neutrophils with normal or increased functional activity.After the end of treatment, the number of neutrophils in the peripheral blood is reduced by 50% within 1-2 days and returns to normal within the next 1-7 days. The duration of action with intravenous administration may be shortened. The clinical significance of this phenomenon with repeated administration of the drug is unclear.

Application filgrastima both independently and after chemotherapy, mobilizes the yield of hematopoietic stem cells in the peripheral bloodstream. Autologous or allogeneic transplantation of 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 PSKK, mobilized with filgrastim, accelerates the restoration of hematopoiesis, reduces the severity and duration of thrombocytopenia, the risk of hemorrhagic complications and the need for transfusion of platelet mass after myelosuppressive or myeloablative therapy.

The efficacy and safety of filgrastim in adults and children receiving cytotoxic chemotherapy are the same.

In children and adults with severe chronic neutropenia (severe congenital, periodic, idiopathic neutropenia) filgrastim Stably increases the number of neutrophils in peripheral blood, reduces the incidence of infectious complications. The appointment of filgrastim to patients with HIV infection allows maintaining normal neutrophil levels and following recommended doses of antiretroviral and / or other myelosuppressive therapy. There are no signs of an increase in HIV replication with filgrastim.

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

Pharmacokinetics:

With intravenous and subcutaneous filgrastim administration, a positive linear relationship between the administered dose and serum concentration is observed. After subcutaneous administration of therapeutic doses, its plasma concentration exceeds 10 ng / ml for 8-16 hours. The volume of distribution is 150 ml / kg.

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. Long-term administration of filgrastim up to 28 days after autologous bone marrow transplantation does not result in cumulation and an increase in the half-life.

In patients with terminal stage of renal failure, an increase in the maximum concentration (C_m_Oh) and the area under the curve (AUC), and a decrease in the volume of distribution and clearance compared to healthy volunteers and patients with moderate-level renal failure.

Indications:

Neutropenia, febrile neutropenia in patients receiving intensive myelosuppressive cytotoxic chemotherapy for malignant neoplasms (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.

- Mobilization of peripheral blood stem cells, including after myelosuppressive therapy.

- Severe congenital, periodic or idiopathic neutropenia (absolute number of neutrophils less than or equal to 0.5 × 10⁹/ l) in children and adults with severe or recurrent infections in the history.

- Persistent neutropenia (absolute number of neutrophils, less than or equal to 1.0х10⁹/ l) in patients with advanced stage of HIV infection to reduce the risk of bacterial infections when ineffective or impossible to use other methods of treatment.

Contraindications:

- Hypersensitivity to filgrastimu or other components of the drug.

- Severe congenital neutropenia (Kostmann's syndrome) with cytogenetic disorders.

- Use of the drug to increase the doses of cytotoxic chemotherapeutic drugs above recommended.

- Simultaneous administration with cytotoxic chemo- and radiotherapy.

- Terminal stage of chronic renal failure.

- Myelodysplastic syndrome (MDS) and chronic myeloid leukemia (no data on efficacy and safety)

- Lactation.

- Newborn age (up to 28 days of life).

Carefully:

In pregnancy, malignant neoplasms and premalignant diseases of a myeloid nature, (including acute myelogenous leukemia), sickle cell anemia; in combination with high-dose chemotherapy.

Pregnancy and lactation:

Safety filgrastim for pregnant women is not established. It is possible to pass Immugast® through the placental barrier in women. When prescribing the drug, pregnant women should match the expected therapeutic effect to the mother with a possible risk to the fetus. In animal studies filgrastim did not have a teratogenic effect. There was an increased incidence of miscarriages, but no abnormalities of fetal development were noted.

There is no data on the penetration of filgrastim into breast milk. It is not recommended to use Immugrast® in nursing mothers.

Dosing and Administration:

Daily subcutaneously (sc) or in the form of short intravenous (IV) infusions (30-minute). Also, the preparation can be administered in the form; 24 hour, intravenous or subcutaneous infusions.

The choice of route of administration depends on the specific clinical situation. Preferably a subcutaneous route of administration.

Standard schemes of cytotoxic chemotherapy

In a dose of 5 mcg (0.5 million IU) / kg once a day daily sc, or in the form of short intravenous infusions. The first dose of the drug is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy.A transient increase in the number of neutrophils is usually observed 1-2 days after the beginning of treatment with Immu- grast®. To achieve a stable therapeutic effect, it is necessary to continue therapy with Immu- grast® until the number of neutrophils passes the expected minimum and reaches normal values. If necessary, the duration of the course of therapy can be up to 14 days, depending on the severity of the disease and the severity of neutropenia. After induction and consolidation therapy of acute myelogenous leukemia, the duration of therapy with Immugrast® can increase up to 38 days, depending on the type, dosage and mode of administration of the cytotoxic drugs used.

It is not recommended to cancel Immugrast® prematurely, before the expected minimum of neutrophil count.

After myeloablative chemotherapy followed by bone marrow transplantation

The recommended initial dose is 10 μg (1.0 million IU) / kg diluted in 20 ml of a 5% dextrose solution as a 30-minute or 24-hour intravenous infusion or by continuous subcutaneous infusion for 24 hours.The first dose of Immugast® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and for bone marrow transplantation - no later than 24 hours after the infusion of the bone marrow. The duration of therapy is no more than 28 days. After the maximum reduction in the number of neutrophils, the daily dose is adjusted depending on the dynamics of their number. If the neutrophil count in peripheral blood exceeds 1.0x10⁹/ l for three consecutive days, the dose of Immugast® is reduced to 5.0 μg (0.5 million IU) / kg; if at this dose the absolute number of neutrophils exceeds 1.0x10⁹/ l for another three consecutive days, Immugrast® is canceled. If during the treatment period the absolute number of neutrophils decreases less than 1.0х10⁹/ l, the dose of Immugast® is increased again, in accordance with the above scheme.

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

At a dose of 10 μg (1.0 million IU) / kg by subcutaneous injection once a day or continuous 24-hour subcutaneous infusion for 6 consecutive days, with two leukapheresis procedures in a row at the 5th,6th days. In some cases, additional leukapheresis is possible. The appointment of Immugast® should be continued until the last leukapheresis.

Mobilization of PSKC after myelosuppressive therapy

At a dose of 5 μg (0.5 million IU) / kg by daily subcutaneous injections, starting from the first day after completion of chemotherapy and until the amount of neutrophils passes through the expected minimum and reaches normal values. Leukapheresis should be performed during the period when the absolute number of neutrophils rises from less than 0.5 x 10⁹/ l to more than 5.0 х10⁹/ l. Patients who did not receive intensive chemotherapy, it happens - just one leukapheresis. In some cases, additional leukapheresis is recommended.

Mobilization of PSKC in healthy donors for allogeneic transplantation

In a dose of 10 mcg (1.0 million units) / kg per day subcutaneously, for 4-5 days. Leukapheresis is carried out from the 5th day and, if necessary, until the 6th day in order to obtain CD34 + cells in an amount of ≥4x10⁶ cells / kg body weight of the recipient. The effectiveness and safety of Immugast® in healthy donors under the age of 16 and older than 60 years have not been investigated.

Severe chronic neutropenia (THC)

Daily subcutaneously, once or divided into several administrations. The initial dose for congenital neutropenia is 12 μg (1.2 million IU) / kg per day, with idiopathic or intermittent neutropenia - 5 μg (0.5 million IU) / kg per day, to a stable excess of neutrophil counts 1, 5x10⁹/ l. After achieving the therapeutic effect, the minimum effective dose should be determined to maintain this content of neutrophils. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient's response to therapy. Subsequently, every 1-2 weeks, you can make a dose adjustment to maintain the number of neutrophils in the range of 1.5-10 × 10⁹/ l.

In patients with severe infections, a scheme with a faster increase in dose can be used. In 91% of patients who responded positively to the treatment, the full therapeutic effect is observed with the appointment of filgrastim doses up to 24 mcg / kg / day. The daily dose of Immugast® should not exceed 24 mcg / kg.

Neutropenia in HIV infection

The initial dose of 1-4 μg (0.1-0.4 million IU) / kg per day once subcutaneously to normalize the amount of neutrophils (≥2 × 10⁹/ l). Normalization of neutrophil counts usually occurs after 2 days.After reaching the therapeutic effect, a maintenance dose of 300 μg per day every other day. In the future, individual dose adjustment and prolonged therapy with Immugast® may be required to maintain neutrophil counts in excess of 2.0 × 10⁹/ l.

Special instructions for dosing

Elderly age: special recommendations for elderly patients are absent.

Children: when applied in pediatric practice in patients with severe chronic neutropenia and oncological diseases, the safety profile of filgrastim did not differ from that in adults. Recommendations for dosing for children of the same age are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.

Correction of filgrastim dose is not required in patients with severe renal or hepatic insufficiency, since their pharmacokinetic and pharmacodynamic parameters are similar to those of healthy volunteers.

Recommendations for the preparation of a solution for intravenous administration

If you need intravenous Immugast®, the required amount of the drug is injected from the syringe into a vial or plastic container with a 5% dextrose solution.

Immugrast® can not be diluted with 0.9% sodium chloride solution.

If the drug is diluted to a concentration of less than 15 μg / ml (less than 1.5 million IU / ml), serum human albumin, so that the final concentration of albumin is 2 mg / ml. For example, with a final solution volume of 20 ml, a total dose of Immugast® preparation of less than 300 μg (less than 30 million ME) should be administered with the addition of 0.2 ml of a 20% human albumin solution. Do not dilute Immougrast® to a final concentration of less than 2 μg / ml (less than 0.2 million IU / mL).

Immugast®, when diluted with 5% dextrose or 5% dextrose and albumin, is compatible with glass and a number of plastics, including polyvinyl chloride, polyolefin (polypropylene-polyethylene) and polypropylene.

Syringes with the preparation Immigrast® are intended for single use only.

A ready-made solution of Immugast® is stored at a temperature of 2 to 8 ° C for no more than a day.

Side effects:

Adverse reactions are listed according to the following gradation: very often (> 10%); often (> 1% - <10%); infrequently (> 0.1% - <1%); rarely (> 0.01% to <0.1%); very rarely (<0.01%).

From the hematopoiesis: very often - neutrophilia and leukocytosis (as a consequence of the pharmacological action of filgrastim), with prolonged use - anemia,splenomegaly; often - thrombocytopenia; very rarely - rupture of the spleen.

On the part of the respiratory system: often - cough; very rarely - infiltrates in - the lungs, adult respiratory distress syndrome.

From the musculoskeletal system: often - pain in the bones, muscles, joints; Often - osteoporosis; very rarely - exacerbation of rheumatoid arthritis, pseudogout (pyrophosphate arthropathy).

From the cardiovascular system: very rarely - a decrease or increase in blood pressure, skin vasculitis (with prolonged therapy in patients with TCN).

On the part of the digestive system: often - diarrhea, hepatomegaly.

From the genitourinary system: rarely - hematuria, proteinuria; very rarely, dysuria.

From the skin and its appendages: often - skin rash, with long-term use - alopecia; rarely - Sweet syndrome (acute febrile neutrophilic dermatosis, connection with filgrastim is not established).

Allergic reactions: very rarely - skin rash, hives, face swelling, wheezing, shortness of breath, lowering of blood pressure, tachycardia.

From the laboratory indicators: very often - reversible,a weak and moderate increase in the activity of gamma-glutamyltransferase, alkaline phosphatase, lactate dehydrogenase, increased serum uric acid concentration, transient hypoglycemia; rarely - increased activity of aspartate aminotransferase.

Other: often - headache, fatigue, general weakness, reactions at the injection site (less than 2% of patients with TCN).

Overdose:

Filgrastim overdose cases are not noted. 1-2 days after drug withdrawal, the number of circulating neutrophils usually decreases by 50% and returns to the normal value after 1-7 days.

Interaction:

The efficacy and safety of filgrastim administration in one day with cytotoxic chemotherapeutic agents have not been established. Due to the high sensitivity of actively proliferating myeloid cells to antitumor cytotoxic drugs, filgrastim 24 hours before or after the administration of these drugs is not recommended. There are some reports of increased severity of neutropenia with the simultaneous use of filgrastim and fluorouracil. Data on the possible interaction with other hematopoietic growth factors and cytokines are currently not available.

Given that lithium stimulates the release of neutrophils, it is possible to increase the action of filgrastim in a combined application. Studies on the interaction of lithium and filgrastim were not conducted.

Filgrastim is not pharmaceutically compatible with 0.9% sodium chloride solution.

When filgrastim is used to mobilize hematopoietic stem cells after chemotherapy, it should be borne in mind that when cytostatics are prescribed for a long time melphalan, carmustine and carboplatin, mobilization efficiency can be reduced.

Special instructions:

Treatment with Immugast® should be performed under the supervision of a doctor who has experience with colony-stimulating factors, provided that the necessary diagnostic capabilities are available. Procedures for mobilization and apheresis of cells should be carried out in specialized medical institutions.

With myelodysplastic syndrome (MDS) and chronic myeloid leukemia, the efficacy and safety of filgrastim have not been established. Patients with the above diseases, filgrastim not shown.Particular attention should be paid to a differential diagnosis between the blast crisis of chronic myelogenous leukemia and acute myelogenous leukemia.

Particular care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematologic diseases, such as aplastic anemia, myelodysplasia and myeloid leukemia.

A small number (3%) of patients with severe congenital neutropenia (Costman's syndrome) who received filgrastim, MDS and leukemia were observed. MDS and leukemia are natural complications of this disease; their connection with treatment with filgrastim is unclear. Approximately 12% of patients with initially normal cytogenetics were found to have anomalies during repeated examination, including monosomy. If a patient with Costman's syndrome develops cytogenetic disorders, as well as with the development of MDS or leukemia filgrastim should be canceled. It is not yet clear whether long-term treatment with filgrastim predisposes patients with Kostmann's syndrome. to the development of cytogenetic abnormalities, MDS and leukemia. Patients with Costman's syndrome are recommended to perform morphological and cytogenetic studies of the bone marrow at regular intervals (approximately every 12 months).

Cytogenetic disorders, leukemia and osteoporosis were detected with long-term use - filgrastim (> 5 years) in 9.1% of patients with severe chronic neutropenia. Their connection with the drug is not clear.

Treatment with filgrastim should be carried out under regular control of a general blood test with counting of the leukocyte formula and the number of platelets (before the start of therapy and then twice a week with standard chemotherapy and at least 3 times per week in mobilizing PSKK with or without a subsequent bone marrow transplantation). With an increase in the number of leukocytes more than 50x10⁹l, filgrastim should be immediately canceled. If filgrastim It is used to mobilize hematopoietic stem cells, it must be discarded, if the number of leukocytes exceeds 70x10⁹/ l.

Filgrastim does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. It is recommended to perform regular blood tests twice a week and determine the number of platelets and hematocrit in the filgrastim application after chemotherapy.

It is necessary to carefully monitor the number of platelets, especially during the first few weeks of treatment with filgrastim.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 patient - 1 time per month. If a patient has thrombocytopenia (the number of platelets stably below 100x10⁹/ l), should consider the temporary cancellation of the drug or a decrease in dose. There are also other changes in the blood formula, which require its careful monitoring, incl. anemia and a transient increase in the number of myeloid progenitor cells.

It is necessary to exclude such causes of transient neutropenia as viral infections.

During treatment with filgrastim, urine analysis should be performed regularly (to exclude hematuria and proteinuria) and control the size of the spleen.

The safety and efficacy of filgrastim in newborns and patients with autoimmune neutropenia have not been established.

After bone marrow transplantation, a blood test is performed and the platelet count is determined 3 times a week.

In patients who have undergone active myelosuppressive therapy in the past, there may not be a sufficient increase in PMSC to the recommended minimum level, (≥2.0 x10⁶ CD34 + / kg). In this regard, such patients, when it is necessary to carry out transplantation of PSKK, are advised to schedule their mobilization at an early stage of treatment, and if as a result of mobilization before the introduction of high-dose chemotherapy failed to obtain a sufficient amount of PSKK, alternative treatments that do not require the use of cells predecessors.

With the use of mobilized filgrastim PSKK there is a decrease in the severity and duration of thrombocytopenia caused by myelosuppressive or myeloablative chemotherapy.

There is a complex but stable statistical relationship between the number of CD34 + cells and the normalization rate of platelet count after high-dose chemotherapy.

The minimum amount of UCSW equal to or greater than 2.0x10⁶ FROMD34 + cells / kg, leads to a sufficient recovery of hematological parameters.

The mobilization of PSKK can only be considered for those healthy donors whose clinical and laboratory parameters, especially hematological parameters, meet the criteria for selecting donors for mobilizing PSKK.

Transient leukocytosis (leukocytes more than 50х10⁹/ l) is observed in 41% of healthy donors, more than 75x10⁹/ l - in 2% 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 50 x 10⁹/ l after the procedure of leukapheresis.

If more than one leukapheresis is required, special care should be taken when the donor's platelet count is less than 100x10 before the leukapheresis⁹/ l. Conduction of leukapheresis is not recommended if the number of platelets is less than 75x10⁹/ l, as well as in donors, with a violation of hemostasis or receiving anticoagulants.

Filgrastim should be withdrawn or its dose should be reduced if the number of leukocytes exceeds 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 a granulocyte colony-stimulating factor to healthy donors, it is recommended to control its size (palpation, ultrasound).

With long-term monitoring of the safety of filgrastim in healthy donors up to 4 years after application of filgrastim, no cases of hemopoiesis were detected. However, it is impossible to exclude the risk of stimulation of a clone of malignant myeloid cells, and therefore it is recommended that in the centers of apheresis, it is recommended to follow the healthy donors of stem cells systematically for a minimum of 10 years.

Specific guidance for recipients of allogeneic PSKK, obtained with filgrastim: 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.

When treating filgrastim with HIV-infected patients with neutropenia, a thorough blood test (absolute number of neutrophils (ASC), platelet erythrocytes, etc.) should be performed on a daily basis for the first few days, then 2 times a week for the first 2 weeks and each a week or a week during maintenance therapy. 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.

In patients with infectious diseases and infiltration of bone marrow by infectious agents (for example, a complex Mycobacterium avium) or with a bone marrow (lymphoma) tumor, filgrastim therapy is administered concomitantly with therapy directed against these conditions.

Patients with sickle-cell anemia should regularly perform a blood test and take into account the possibility of developing splenomegaly and thrombosis of blood vessels.

Patients with bone pathology and osteoporosis receiving continuous treatment with filgrastim for more than 6 months are shown to control bone density.

The effect of filgrastim in patients with significantly reduced number of myeloid progenitor cells is not known. Filgrastim increases the number of neutrophils by first 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.

Presence in the anamnesis of a pneumonia or infiltrates in lungs can be the risk factors of occurrence of an intersticial disease of lungs against therapy filgrastimom.The appearance of cough, fever and shortness of breath associated with the appearance of infiltrates in the lungs may be the first signs of the development of adult respiratory distress syndrome. When these signs appear filgrastim should be canceled and appropriate treatment prescribed.

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

It is not noted the influence of filgrastim on the ability to drive vehicles and work with mechanisms.

Form release / dosage:

Solution for intravenous and subcutaneous injection, 30 million IU / ml.

Packaging:

1 ml in bottles of colorless glass class I (USP), Sealed with rubber stopper and aluminum cap with safety plastic the lid.

For 1 bottle in a pack of cardboard with instructions for use.

1 ml in syringes of colorless glass class I (USP) with a needle for subcutaneous injection.

1 syringe per blister. 1 blister in a pack of cardboard with instruction on application.

Storage conditions:

At a temperature of 2 to 8 ° C. Do not freeze.

Keep out of the reach of children.

Transportation conditions

At a temperature of 2 to 8 ° C in thermal containers.

Do not freeze.

Shelf life:

2 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-000368

Date of registration:24.02.2011 / 10.06.2013

Expiration Date:24.02.2016

The owner of the registration certificate:Dr. Reddy's Laboratories Ltd.Dr. Reddy's Laboratories Ltd. India

Manufacturer: & nbsp

DR. REDDY`S LABORATORIES, LTD. India

Representation: & nbspDR REDDY'S LABORATORIS LTD. DR REDDY'S LABORATORIS LTD. India

Information update date: & nbsp24.10.2017

Illustrated instructions

Instructions

Immugrast® (Immugrast®)