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

Excipients: acetic acid ice 0.60 mg / ml, sorbitol 50.0 mg / ml, polysorbate-80 0.055 mg, sodium hydroxide to pH 4.20, water for injection up to 1.00 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, in the genome of which gene genetically engineered gene granulotsitarnogo colony-stimulating factor of man.

Human granulocyte colony-stimulating factor (G-CSF) is 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 peripheral blood is reduced by 50% within 1-2 days and returns to normal level during the next 1-7 days. The duration of action with intravenous administration may be shortened. Filgrastim significantly reduces the frequency, severity and duration of neutropenia and febrile neutropenia, reducing the need for and duration of inpatient treatment in patients receiving chemotherapy with cytostatics or myeloablative therapy followed by bone marrow transplantation.

Patients receiving filgrastim and cytotoxic chemotherapy, require lower doses of antibiotics compared to patients receiving only cytotoxic chemotherapy.

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

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 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_mOh) and the area under the curve (AUG), and a decrease in the volume of distribution and clearance in comparison with healthy volunteers and patients with moderate-level renal failure.

Indications:

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.

Mobilization of peripheral blood stem cells, incl. after mielosupressivnoy therapy.

Severe congenital, periodic or idiopathic neutropenia (absolute neutrophil count (ACN) 0.5 × 10⁹/ l and less) in children and adults with severe or recurrent infections in the history. Persistent neutropenia (ACN 1.0х10⁹/ l and less) in patients with developed stage of HIV infection to reduce the risk of bacterial infections when other methods of treatment are not possible.

Contraindications:

Hypersensitivity to the active substance (filgrastim) or other components of the drug; severe congenital neutropenia (Costman's syndrome) with cytogenetic disorders; use of the drug for the purpose of increasing doses of cytotoxic chemotherapeutic drugs above recommended; simultaneous appointment with cytotoxic chemo- and radiotherapy; terminal stage of chronic renal failure; the period of breastfeeding; newborn age (up to 28 days of life).

Carefully:

In pregnancy, malignant and premalignant diseases, incl. with acute myelogenous leukemia (insufficient data on efficacy and safety), sickle-cell anemia, bone disease (including osteoporosis), in combination with high-dose chemotherapy, with hereditary intolerance to fructose (the drug contains sorbitol).

Pregnancy and lactation:

Safety filgrastim for pregnant women is not established. Perhaps the passage of filgrastim through the placental barrier in women. When prescribing filgrastim, pregnant women should correlate the expected therapeutic effect with the possible risk to the fetus.

There is no data on the penetration of filgrastim into breast milk. Use filgrastim in the period of breastfeeding is not recommended.

Dosing and Administration:

Daily subcutaneously (SC) or in the form of short intravenous (IV) infusions (30 minutes) in a 5% dextrose solution (see "Instructions for breeding") until the amount of neutrophils passes the expected minimum (nadir) and will not return to the normal range. The choice of route of administration depends on the specific clinical situation. Preferably after the route of administration.

If necessary, in / in the introduction of the required amount of the drug is injected from the syringe into a vial or plastic container with 5% dextrose, then a 30-minute infusion of the diluted drug is made. Syringes with Tevagrastim are intended for single use only.

Breeding instructions

The drug Tevagrastim is diluted only with 5% dextrose solution, it is impossible to dilute with 0.9% sodium chloride solution. The diluted drug can be adsorbed by glass and plastics. 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, the total dose of Tevagrastim is less than 300 μg (less than 30 million) ME) should be administered with the addition of 0.2 ml of a 20% solution of human albumin. Tevagrastim can not be diluted to a final concentration of less than 2 μg / ml (less than 0.2 million IU / ml).

The ready-made solution of the drug Tevagrastim should be stored at a temperature of 2 to 8 ° C for no more than a day.

Standard schemes of cytotoxic chemotherapy

In a dose of 5 μg (0.5 million IU) / kg once a day, daily SC or IV in the form of short infusions (30-minute) in a 5% solution of dextrose. The first dose of the drug is administered no earlier than 24 hours after the end of the course of cytotoxic chemotherapy. 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 the drug Tevagrastim may increase 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 Tevagrastim.To achieve a stable therapeutic effect, it is necessary to continue therapy with Tevagrastim until the amount of neutrophils passes the expected minimum and reaches normal values.

It is not recommended to cancel the drug Tevagrastim prematurely, before the transition of the number of neutrophils through the expected minimum. Treatment should be stopped if ACN after nadir reached 1,0x10⁹/ l.

After myeloablative chemotherapy followed by bone marrow transplantation

P / to or iv in the form of infusion in 20 ml of a 5% solution of dextrose. The initial dose of 10 μg (1.0 million IU) / kg IV drip for 30 minutes or 24 hours or by continuous infusion for 24 hours. The first dose of Tevagrastim should be administered no earlier than 24 h after cytotoxic chemotherapy, and with bone marrow transplantation - no later than 24 hours after bone marrow infusion. The duration of therapy is not more than 28 days. After the maximum reduction in the number of neutrophils (nadir), the daily dose is adjusted depending on the dynamics of their number. If the number of neutrophils in peripheral blood exceeds 1.0x10⁹/ l for three consecutive days, the dose of Tevagrastim is reduced to 5.0 μg (0.5 million IU) / kg; Then, if the DCA exceeds 1.0x10⁹/ l for three consecutive days, the drug Tevagrastim is canceled. If during the treatment period, ACN decreases less than 1.0 × 10⁹/ l, the dose of Tevagrastim 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

In a dose of 10 μg (1.0 million IU) / kg by injection once a day or a continuous 24-hour infusion for 6 consecutive days, usually two leukapheresis procedures are usually sufficient for the 5th , 6th days. In some cases, additional leukapheresis is possible. The use of Tevagrastim 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 SC injection, 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 DCA 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

In a dose of 10 mcg (1.0 million units) / kg / day p / c, 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 at least 4 x 10⁶cells / kg body weight of the recipient. The efficacy and safety of the drug Tevagrastim in healthy donors under the age of 16 and older than 60 years have not been investigated.

Severe chronic neutropenia (THC)

Daily c / o, about a bottom or divided into several introductions. In congenital neutropenia, the initial dose of 12 μg (1.2 million IU) / kg / day, with idiopathic or intermittent neutropenia, is 5 μg (0.5 million IU) / kg / 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 amount 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 97% of patients who responded positively to treatment, a full therapeutic effect is observed when filgrastim doses are administered up to 24 μg / kg / day. The daily dose of Tevagrastim should not exceed 24 mcg / kg / day.

Neutropenia in HIV infection

The initial dose of 1-4 μg (0.1-0.4 million IU) / kg / day, once, until the normalization of the number of neutrophils (at least 2 × 10⁹/ l). Normalization of neutrophil counts usually occurs after 2 days. After reaching the therapeutic effect, a maintenance dose of 300 mcg per day 2-3 times a week according to the alternating schedule (every other day). In the future, individual dose adjustment and long-term therapy with Tevagrastim may be required to maintain a neutrophil count of more than 2.0 × 10⁹/ l.

Special instructions for dosing

For elderly patients Special recommendations for dosing are not available.

Childhood: in children with THC and oncological diseases the safety profile of filgrastim did not differ from that in adults.Recommendations for dosing for children 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.

Side effects:

Adverse effects are distributed according to the frequency classification: very often (≥ 1/10); often (≥ 1/100, but <1/10); infrequently (≥ 1/1000, but <1/100); rarely (≥ 1/10000, but <1/100); very rarely (<1/10000); unknown frequency (can not be determined based on available data).

Patients with oncological diseases

The most common undesirable effects associated with the use of filgrastim at the recommended dose were mild to moderate musculoskeletal pain (in 10% of patients) and severe musculoskeletal pain (in 3% of patients). Musculoskeletal pains were usually eliminated with standard analgesics. Less frequent adverse effects were micturition disorders (mainly dysuria of mild and moderate severity).

Filgrastim did not increase the incidence of adverse reactions associated with cytotoxic chemotherapy.Unwanted effects were observed with the same frequency in patients with filgrastim / chemotherapy and placebo / chemotherapy, including nausea and vomiting, alopecia, diarrhea, fatigue, lack of appetite, mucositis, headache, cough, skin rash, chest pain , general weakness, sore throat, constipation and nonspecific pain.

A reversible, dose-dependent and usually mild to moderate increase in lactate dehydrogenase (LDH) activity, alkaline phosphatase (UF), uric acid concentration and gamma-glutamyl transferase (GGT) activity in plasma was observed with filgrastim at recommended doses of approximately 50%, 35 %, 25% and 10% of patients, respectively.

Occasionally there was a transient decrease in blood pressure (BP), not requiring therapeutic intervention.

The "graft versus host" reaction was reported and the death of patients receiving G-CSF after allogeneic bone marrow transplantation.

Sometimes, patients receiving high-dose chemotherapy followed by autologous bone marrow transplantation, noted vascular disorders, including veno-occlusive disease and disorders associated with water metabolism in the body.Causal connection with filgrastim in these cases is not established.

Very rare cases of cutaneous vasculitis have been reported in patients who received filgrastim. The mechanism of development of vasculitis in patients receiving filgrastim not installed.

There are rare reports of the development of the Sweet syndrome (acute fibrillar dermatosis). Since a significant proportion of these patients suffered from leukemia, which is known to be associated with Sweet's syndrome, a causal relationship with filgrastim has not been established.

In some cases, exacerbation of rheumatoid arthritis was observed.

It was reported on the development of pseudogout in patients with oncological diseases who received filgrastim.

Rare adverse effects from the lungs have been reported, including interstitial pneumonia, pulmonary edema and pulmonary infiltrates, in isolated cases with an unfavorable outcome in the form of respiratory failure or adult respiratory distress syndrome (ARDS), including fatalities.

Single cases of the appearance of symptoms indicating allergic reactions, including anaphylaxis, skin rash,urticaria, Quincke's edema, dyspnoea, a decrease in blood pressure, developing with the administration of the first dose or the subsequent application of filgrastim, were recorded in patients receiving filgrastim. There were more such reactions after intravenous application. In some cases, the symptoms recurred after repeated application of filgrastim, which indicates a causal relationship. The use of filgrastim should be discontinued in patients who developed severe allergic reactions.

Single cases of sickle cell crises have been reported in patients with sickle cell anemia.

From the immune system: very rarely - allergic reactions.

From the side of metabolism and nutrition: very often - an increase in the activity of LDH, AP, an increase in the concentration of uric acid in the plasma.

From the nervous system: often a headache.

From the side of the vessels: infrequently - a syndrome of increased capillary permeability; rarely - vascular disorders, angiopathy.

From the respiratory system: often - cough, sore throat; very rarely - infiltrates in the lungs.

From the gastrointestinal tract: very often - nausea, vomiting; often - constipation, diarrhea, anorexia, mucositis.

From the liver and biliary tract: very often - an increase in GGT activity.

From the skin and subcutaneous fat: often - alopecia, skin rash; very rarely - Svita syndrome, cutaneous vasculitis.

From the musculoskeletal system: often - chest pain, musculoskeletal pain; very rarely - exacerbation of rheumatoid arthritis.

From the urinary system: very rarely - a violation of urination.

Other: often fatigue, general weakness; infrequently, nonspecific pain.

Healthy donors in the mobilization of ISPS

Very often transient weak or moderate osteomuscular pain was observed.

Leukocytosis (more than 50х10⁹/ l) was observed in 41% of healthy donors and transient thrombocytopenia (less than 100x10⁹/ ll) after application of filgrastim and leukophoresis was observed in 35% of healthy donors.

Transient insignificant increase in activity of alkaline phosphatase, LDH, aspartate aminotransferase (ACT) and the concentration of uric acid in the blood plasma were recorded in healthy donors receiving filgrastim (without clinical consequences).

Occasionally reported on exacerbation of arthritis.

Occasionally, there were reports of symptoms indicating severe allergic reactions.

Headache is believed to be associated with the use of filgrastim, was registered in healthy donors when mobilizing PSKK in studies.

Frequent, mostly asymptomatic cases of splenomegaly and very rare cases of rupture of the spleen were recorded in healthy donors and patients after the administration of G-CSF.

In healthy donors, undesirable phenomena on the part of the respiratory organs (hemoptysis, pulmonary hemorrhage, pulmonary infiltrates, dyspnea and hypoxia) were very rare with filgrastim in the postgistrictional period.

During the post-registration period cases of the syndrome of increased capillary permeability were observed in the application of G-CSF. They, as a rule, were observed in patients with progressive malignant disease, sepsis, taking simultaneously several drugs for chemotherapy or passing apheresis. The syndrome of increased permeability of capillaries can be life threatening if the treatment is delayed. Infrequently (> 1/1000 to <1/100) this syndrome was observed in healthy donors in the mobilization of PSKK after the administration of G-CSF.

On the part of the blood and lymphatic system: very often - leukocytosis, thrombocytopenia; infrequently - violations from the side of the spleen.

From the immune system: infrequently - severe allergic reactions.

From the side of metabolism and nutrition: often - increased activity of alkaline phosphatase, LDH; infrequently - increased activity ACT.

From the nervous system: very often - a headache.

From the side of the vessels: infrequently - a syndrome of increased permeability of capillaries.

From the musculoskeletal system: very often - musculoskeletal pain; infrequent - exacerbation of rheumatoid arthritis.

Patients from THC

The incidence of undesirable effects associated with the use of filgrastim in patients with TCN tends to decrease over time.

The most common undesirable effects associated with the use of filgrastim were pain in the bones and muscles.

There was also an increase in the spleen, progressing in some cases, and thrombocytopenia.

Headache and diarrhea were usually observed soon after initiation of filgrastim treatment in less than 10% of patients.

Anemia and nasal bleeding were also reported.

There was a transient increase in the concentration of uric acid, LDH activity, AP in the blood plasma without clinical consequences.There was also a transient moderate decrease in glucose in the blood after eating.

The undesirable effects possibly associated with the use of filgrastim and, as a rule, observed in less than 2% of patients with THC, were reactions at the injection site, headache, enlargement of the liver, joint pain, alopecia, osteoporosis, and skin rash.

During the long-term use of filgrastim, the development of cutaneous vasculitis in 2% of patients with THC was reported, as well as very rare cases of proteinuria / hematuria.

From the side of the blood and lymphatic system: very often - anemia, splenomegaly; often - thrombocytopenia; infrequently - violations from the side of the spleen.

From the side of metabolism and nutrition: very often - a decrease in the concentration of glucose in the blood, an increase in AP, LDH, hyperuricemia.

From the nervous system: often - headache.

From the respiratory system: very often - nosebleeds.

From the digestive system: often - diarrhea, hepatomegaly.

From the skin and subcutaneous tissues: often - alopecia, skin rash, skin vasculitis, pain at the injection site.

From the musculoskeletal system: very often - pain in the bones and muscles; Often - osteoporosis.

From the side of the kidneys and urinary tract: infrequently - hematuria, proteinuria.

Patients with HIV infection

Weak and moderate musculoskeletal pain and myalgia associated with filgrastim were constantly observed. The incidence of pain is similar to that in patients with cancer.

Enlargement of the spleen, associated with the use of filgrastim, was observed in less than 3% of patients. In all cases, a physical examination showed splenomegaly of mild to moderate severity with a favorable clinical course; there was not a single case of hypersplenism and splenectomy. Splenomegaly is quite common in patients with HIV infection, and is also present in varying degrees in most patients with AIDS. In these cases, the association of splenomegaly with filgrastim remains unclear.

From the blood of the lymphatic system: often - a violation of the spleen.

From the musculoskeletal system: very often - musculoskeletal pain.

Overdose:

Filgrastim overdose cases are not noted. 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 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.

Fluorouracil increases the severity of neutropenia with concomitant administration with filgrastim. Possible interaction with other hematopoietic growth factors and cytokines is not known.

Given that lithium stimulates the release of neutrophils, it is possible to intensify the action of filgrastim with a combined appointment, but such studies have not been 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 Tevagrastim should only be carried out under the supervision of an oncologist or hematologist with experience in the use of 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.

The syringe in which the solution is located can be equipped with or without an additional needle safety device. An additional safety device is designed to prevent injuries and pricks with already used syringes (needles) and does not require any special precautions. To inject the solution, slowly and evenly push the syringe onto the piston. The pressure on the piston is maintained until the recommended dose is administered and the syringe is removed from the injection site. Dispose of used syringes in accordance with the instructions of the medical institution or doctor. Syringes without a safety device before disposal are placed in a container of durablematerial.

Precautions for patients with acute myeloid leukemia

Growth of malignant cells

Human G-CSF can stimulate the growth of myeloid cells in vitro. Similar effects can be observed in vitro and for some non-myeloid cells.

With myelodysplastic syndrome (MDS) and chronic myeloid leukemia, the efficacy and safety of filgrastim have not been established. Patients with the abovementioned diseases, as well as with pre-tumor lesions of the myeloid germ of hematopoiesis, filgrastim is not indicated. Particular attention should be paid to a differential diagnosis between the blast crisis of chronic myelogenous leukemia and acute myelogenous leukemia.

Caution should be exercised when using Tevagrastim in patients with secondary myelocytic leukemia (AML) because safety and efficacy data are limited.

The safety and efficacy of Tevagrastim, first used in patients with AML at the age of 55 years without cytogenetic abnormalities [t(8; 21), t(15; 17) and inv(16)] have not been established.

Other Precautions

Patients with osteoporosis, developed due to bone disease, with prolonged (more than 6 months) use of the drug Tevagrastim is recommended to regularly monitor bone density.

There are rare reports of unwanted adverse reactions from the respiratory system when G-CSF is used, in particular, interstitial pneumonia. Patients who have recently had infiltrative lung disease or pneumonia may have a high risk. The appearance of symptoms such as coughing, fever and shortness of breath on the background of pulmonary infiltrates detected during X-ray examination, and signs of worsening lung function may be the first signs of ARDS. In case of development of ARDS, the use of Tevagrastim is stopped and appropriate therapy is administered

There was reported the development of a syndrome of increased capillary permeability in the use of G-CSF, which is accompanied by a decrease in blood pressure, hypoalbuminemia, edema and haemoconcentration. It is necessary to monitor the condition of patients who develop a syndrome of increased capillary permeability, conduct symptomatic treatment and resuscitation,if necessary.

Precautions for patients with cancer

Leukocytosis

A small number of patients (less than 5%) who received filgrastim in doses above 3 μg (0.3 million IU) / kg per day, leukocytosis was observed (the number of leukocytes was 100 × 10⁹/ l and more). Adverse events directly associated with filgrastim induced leukocytosis are not described. However, given the possible risk associated with leukocytosis, during treatment with filgrastim, the number of leukocytes should be determined regularly. If after passing the expected minimum, it will exceed 50х10⁹/ l, filgrastim should be immediately canceled. In the case of filgrastim for the mobilization of hematopoietic stem cells, the drug should be discarded when the number of leukocytes exceeds 70x10⁹/ l.

The risk associated with high-dose chemotherapy

Particular care should be taken in the treatment of patients receiving high-dose chemotherapy, as higher doses of chemotherapy have more pronounced toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems.instructions for the use of specific chemotherapy drugs).

Monotherapy with filgrastim does not prevent the development of 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 a greater risk of developing thrombocytopenia and anemia. It is recommended to perform regular blood tests twice a week, to determine the number of platelets and hematocrit during the filgrastim application after chemotherapy. Particular caution should be exercised when using single-component or combined chemotherapeutic regimens capable of causing severe thrombocytopenia.

When filgrastim was used to mobilize PSKK, a decrease in the severity and duration of thrombocytopenia due to myelosuppressive or myeloblastic chemotherapy was observed.

Other Precautions

The effect of filgrastim in patients with a significantly reduced number of myeloid progenitor cells is not known. Filgrastim increases the number of neutrophils by primarily affecting the neutrophil precursor cells.Therefore, in patients with a low 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.

There have been reports of "graft versus host" reactions and deaths in patients who received G-CSF after allogeneic bone marrow transplantation.

When radiography of bone tissue in the dynamics of increased hematopoietic activity of the bone marrow in response to therapy with human G-CSF. These data should be taken into account when analyzing the results of radiography of bones.

Precautions for Patients Undergoing Mobilization of PMSC

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

Mobilization

Comparison of the two recommended mobilization methods (only filgrastim or in combination with myelosuppressive chemotherapy) on the same contingent of patients was not performed. The degree of difference in the results of laboratory determination of the amount of CD34 + cells means that direct comparison of various studies is difficult. Therefore, it is difficult to recommend the best method.The choice of method of mobilization should be made depending on the overall goals of the treatment of this patient.

Prior treatment with cytotoxic agents

In patients who in the past been actively pursued myelosuppressive therapy is sufficient to increase the PSCC recommended minimum may not occur (at least 2,0h10⁶ FROMD34 + cells / kg) or increasing the speed normalization platelet count.

Some cytotoxic agents have a particular toxicity to the precursor cells of hemopoiesis and can adversely affect their mobilization. Long-term use of such drugs as melphalin, carboplatin or carmustine before mobilization of progenitor cells can lead to deterioration of the results. However, simultaneous application menfalana, karboplatna and carmustine with filgrastim effective in mobilizing PSCC. If you plan to PBSC transplantation, it is recommended to plan their mobilization in the early stages of the course of treating a patient. Particular attention should be paid to the number of progenitor cells activated in such patients before the application of high-dose chemotherapy.If, as a result of the mobilization, it was not possible to obtain a sufficient amount of PSMC, then alternative therapies that do not require the use of progenitor cells should be considered.

Estimate of the amount of CPPS

Estimating the number of PSMCs mobilized in patients with Tevagrastim, special attention should be given to the quantification method. The results of flow-cytometric analysis of the amount Cd34 + cells differ depending on the chosen method, and therefore it is necessary to interpret with care the results obtained during the research in different laboratories.

There is a complex but stable statistical relationship between the number of C injected into reinfusionD34 + cells and the rate of recovery of platelet count after high-dose chemotherapy.

The minimum amount of PSKK, equal to or greater than 2x10⁶ FROMD34 + cells / kg, leads to a sufficient recovery of hematological parameters and is recommended on the basis of published data. Number of CD34 + cells, which exceeds this value, appears to be accompanied by faster normalization, if the number of cells is less than the indicated value, recovery of blood indices is slower.

Precautions for healthy donors in the mobilization of PMSCs

Procedures for mobilization and apheresis of cells should be conducted in a center with experience in this field.

Mobilization of PSKC does not have a direct clinical result when used in healthy donors and can be performed solely for the purpose of allogeneic stem cell transplantation. Mobilization of PMSC can be carried out only in donors that meet the standard clinical and laboratory criteria for stem cell donation. Particular attention should be paid to hematological indicators and the presence of infectious diseases.

The safety and efficacy of the drug Tevagrastim in healthy donors under the age of 16 and older than 60 years has not been studied.

Transient leukocytosis (leukocytes more than 50х10⁹/ l) was observed in 41% of patients. Transient thrombocytopenia (number of platelets less than 100x10⁹/ l) after applying filgrastim and carrying out 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,especially carefully monitor the number of platelets before each apheresis procedure, especially if the number of platelets is less than 100x10⁹/ l. Conduction of leukapheresis is not recommended if the number of platelets is less than 75x10⁹/ l, with the use of anticoagulants or there are violations of hemostasis.

It is necessary to cancel or reduce the applied dose of Tevagrastim, if the number of white blood cells is more than 70x10⁹/ l.

In healthy donors who receive G-CSF to mobilize PSKK, it is necessary to regularly monitor all indicators of the clinical blood test prior to their normalization. Monitoring the safety of the drug Tevagrastim in healthy donors continues. At present, the risk of myeloid malignant clone development in donors can not be ruled out. Medical centers conducting apheresis procedures are advised to systematically monitor the status of stem cell donors for a minimum of 10 years to monitor the safety of the drug Tevagrastim in the long-term.

There is information about particular, mostly asymptomatic cases of splenomegaly,and also about very rare cases of rupture of the spleen in healthy donors and patients after the administration of G-CSF. Some cases of rupture of the spleen resulted in a fatal outcome. In this regard, it is necessary to carefully monitor the size of the spleen (with clinical examination (palpation) and ultrasound examination). The risk of rupture of the spleen in donors and patients should be taken into account when they have pain in the upper left part of the abdominal cavity or the upper part of the left shoulder.

During the post-registration period in healthy donors, very rare cases of adverse effects of G-CSF on respiratory organs (hemoptysis, pulmonary hemorrhage, pulmonary infiltrates, dyspnea and hypoxia) are noted. If you suspect a presence of these symptoms, you should consider the advisability of further use of the drug and the need for appropriate treatment.

Precautions for recipients allogeneic PSKK, obtained with filgrastim

With allogeneic transplantation of PSKK, the risk of developing an acute or chronic "graft versus host" reaction is higher than with allogeneic bone marrow transplantation.

Precautions for patients with THC

Number of blood cells

It is necessary to carefully monitor the number of platelets, especially during the first few weeks of treatment with the drug. If the patient develops thrombocytopenia (the number of platelets for a long time is less than 100x10⁹/ l), should consider the temporary withdrawal of the drug or a decrease in its dose.

There are other possible changes in the blood formula that require careful monitoring, including anemia and transient increase in the number of myeloid progenitor cells.

Development of acute leukemia or MDS

It is necessary to perform timely diagnosis of TCN and differentiate this diagnosis from other disorders of the hematopoietic system, such as aplastic anemia, MDS and myeloid leukemia. Before the start of therapy, a general blood test should be performed to determine the leukocyte formula and the number of platelets, and also determine the bone marrow and karyotype morphology.

During clinical trials, a small number (approximately 3%) of patients with TCN who received filgrastim, MDS and leukemia were observed. These results were obtained only when observing patients with congenital neutropenia (Costman's syndrome).MDS and leukemia are the most frequent complications of TCN; and their connection with treatment with filgrastim is not defined. Approximately 12% of patients with initially normal cytogenetics were found to have anomalies during a second examination, including monosomy 7. If a patient with TCN exhibits cytogenetic disorders, it is necessary to carefully evaluate the relationship between the expected benefit and the possible risk of continuing therapy with Tevagrastim. The drug should be withdrawn in the case of development of MDS or leukemia. Currently, it is unclear whether the long-term use of the drug Tevagrastim provokes the development of cytogenetic disorders, MDS or leukemia in patients with THC. It is recommended to carry out morphological and cytogenetic studies of the bone marrow regularly (approximately 12 months).

With long-term (more than 5 years) application of filgrastim, cytogenetic disorders, leukemia and osteoporosis were found in 9.1% of patients with THC. Communication with filgrastim is not established.

Other Precautions

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

Enlargement of the spleen is a probable effect associated with the treatment with filgrastim.During clinical trials, 31% of patients showed palpation with splenomegaly. In radiography, an increase in the size of the spleen is detected soon after the initiation of treatment with filgrastim and tends to stabilize. It was noted that a decrease in the dose of the drug slows or stops the increase in the size of the spleen; 3% of patients may need splenectomy. It is necessary to regularly monitor the size of the spleen during clinical examination.

A small number of patients had hematuria / proteinuria. To exclude these manifestations, a general urine test should be monitored regularly.

Safety and efficacy of the drug in newborns and patients with autoimmune neutropenia have not been established.

Precautions for patients with HIV infection

Number of blood cells

It is necessary to strictly control ACN, especially during the first weeks of therapy with Tevagrastim. Some patients may have a very rapid and significant increase in DCC with an initial dose of Tevagrastim. During the first 2-3 days of the drug, it is recommended to measure ACN daily.Subsequently, ACN should be tested at least 2 times a week for the first 2 weeks and then every week or one week throughout the course of maintenance therapy. At a break in the use of the drug Tevagrastim in a dose of 30 million IU / day (300 μg / day) in the patient during treatment, there may be significant fluctuations in ACE. In order to determine the minimum ACN (nadir), it is recommended that a general blood test be performed before each administration of Tevagrastim.

The risk caused by the use of high doses of myelosuppressive drugs (MSLP)

Monotherapy with Tevagrastim is not used to prevent the development of thrombocytopenia and anemia when using MSLP. In the case of higher doses, or at the same time several MSLP combined with therapy with Tevagrastim, the risk of thrombocytopenia and anemia increases. Regular monitoring of a detailed blood test is recommended.

Development of myelosuppression due to infections or neoplastic tumors

Neutropenia may be due to bone marrow damage in opportunistic infections that are caused by pathogens such as Mycobacterium avium complex, or malignant neoplasms, for example, lymphoma. When infiltrative lesions of the bone marrow of an inflammatory lesion or malignant neoplasm are detected, simultaneously with the use of the drug Tevagrastim for the treatment of neutropenia, appropriate therapy of diagnosed diseases is necessary. The effectiveness of the drug Tevagrastim in the treatment of neutropenia due to infection of the bone marrow of infectious genesis or tumor neoplasms has not been established.

Precautions for Patients with Sickle Cell Anemia

In patients with sickle-cell anemia, cases of hemolytic crisis (an increase in the number of altered cells), sometimes with a fatal outcome, were noted. Patients with sickle-cell disease should use Tevagrastim only if the expected benefit exceeds the possible risk with the use of Tevagrastim.

Effect of excipients

Contained in the preparation of Tevagrastim sorbitol in the amount of 50 mg / ml should not have a negative effect on patients with hereditary intolerance to fructose.However, the use of Tevagrastim in these patients should be carried out with caution.

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

The effect of filgrastim on the ability to drive vehicles and work with mechanisms has not been noted.

Form release / dosage:

Solution for intravenous and dermal administration, 60 million IU / ml.

Packaging:

For 0.5 ml (30 ppm) ME, which corresponds to 300 μg filgrastim) or 0.8 ml (48 million. ME, which corresponds to 480 μg filgrastim) in a glass graduated syringe of one-time use (glass type according to Hept. F.), graduated to 1 ml (0.1 ml scale division) with a fixed injection needle covered with a protective cap with a rubber insert, with a piston seal of elastomer type I (according to Hept. F.).

The syringe can be additionally equipped with a needle safety device or be without it. 1, 5, 10 syringes with a preparation (with or without a needle safety device) are placed in a cardboard holder or a plastic contour mesh package, or 10 syringes (with or without a needle safety device) are placed on 5 in 2 cardboard holders or 2 plastic contour packagings .All types of syringes can be sealed in a transparent blister, which is used only for automatic packaging.

Syringes are put together with instructions for medical use in a cardboard box.

Storage conditions:

At a temperature of 2 ° C to 8 ° C in a dark place.

Keep out of the reach of children.

Shelf life:

2.5 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-008796/10

Date of registration:26.08.2010

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp23.09.2015

Illustrated instructions

Instructions

Tevagrastim (Tevagrastim)