Extremia® (Extimia)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEmpagfilgrastimEmpagfilgrastim
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  • Extremia®
    solution PC 
    BIOCAD, CJSC     Russia
    • Dosage form: & nbspSolution for subcutaneous administration.
    Composition:

    The 1 syringe contains:

    active substance: pegylated recombinant granulocyte human colony-stimulating factor (empagfilgrastim) 7.5 mg;

    Excipients: sodium acetate trihydrate 0.23 mg, acetic acid ice to pH 4.0, polysorbate 20 0.04 mg, mannitol 50.0 mg, water for injection up to 1.0 ml.

    Description:

    A clear, colorless solution.

    Pharmacotherapeutic group:Leukopoiesis stimulant
    ATX: & nbsp

    L.03.A.A   Colony-stimulating factors

    Pharmacodynamics:

    Empagfilgrastim is a covalent filgrastim conjugate (recombinant human granulocyte colony-stimulating factor, rhGHSF) with one molecule of polyethylene glycol (PEG) with a molecular mass of 30 kD, with a prolonged effect as a result of decreased renal clearance.

    Empagfilgrastim binds to the G-CSF receptor like filgrastim and pegfilgrastim. Similarly filgrastimu, empagfilgrastim regulates the formation and release of neutrophils from the bone marrow, markedly increases the number of neutrophils with normal or increased functional activity (chemotaxis and phagocytosis) in the peripheral blood for 24 hours and causes a slight increase in the number of monocytes and / or lymphocytes.

    According to clinical studies, it has been established that a single subcutaneous injection of empegilgrastim after each cycle of myelosuppressive cytotoxic therapy reduces the duration of grade 4 neutropenia by approximately 2-fold, compared with the daily administration of filgrastim. The incidence of febrile neutropenia was comparable to the frequency in the group of patients receiving daily filgrastim. The overall frequency of neutropenia after chemotherapy with a single administration of empegilgrastim and the daily administration of filgrastim was comparable at the first cycle, and in subsequent cycles there was a clear tendency to decrease the overall frequency of neutropenia in the empagilgrastim group with each cycle, compared with the filgrastim group.

    Pharmacokinetics:

    Suction

    In healthy volunteers, after a single subcutaneous injection of various doses of empagilgrastim (3 mg - 9 mg) the maximum concentration (FROMmOh) empagfilgrastima in the blood was achieved on average 36-48 hours. In patients with breast cancer receiving chemotherapy with a combination of docetaxel and doxorubicin, during the first cycle of chemotherapy after a single subcutaneous injection of empagglilgrastim in a dose 7,5 mg FROMmOh, average 192143,6 pg / ml, was achieved in the blood on average 61 hours, and the half-life (T1/2) was 78 hours.

    Distribution

    The concentration of empagglilgrastim in the blood serum is maintained during the neutropenia period after myelosuppressive chemotherapy. Average system exposure AUQ(0-∞) empegfilgrastima after a single subcutaneous injection at a dose of 7.5 mg was 27,718,704 (pg / ml) * h.

    Excretion

    Empagfilgrastima excretion is nonlinear, dose-dependent, saturable. Clearance is mainly carried out by neutrophils. In accordance with the self-regulating clearance mechanism, the concentration of empagglilgrastim in the serum slowly decreases during the transient reduction in the number of neutrophils associated with chemotherapy, and quickly - after the start of recovery of the number of neutrophils. In patients with breast cancer receiving chemotherapy with a combination of docetaxel and doxorubicin, during the first cycle of chemotherapy after a single subcutaneous injection of empagglilgrastim at a dose of 7.5 mg, the median clearance was 368.8 ml / (h * kg), and the median elimination constant was 0, 0087 h-1.

    Pharmacokinetics in special patient groups

    Pharmacokinetics of empegilgrastima in special groups of patients (patients with renal and hepatic insufficiency,children and elderly patients) has not been studied to date.

    Patients with impaired hepatic and renal function

    Since the mechanism of excretion of empagglilgrastima is not associated with the kidneys or liver (excretion is carried out mainly by neutrophils), changes in its properties are not expected in patients with impaired function of these organs.

    Children and patients of advanced age

    Data on the use of empagfilgrastim in children or elderly patients (over 65 years) are not available.

    Indications:

    To reduce the duration of neutropenia, the incidence of febrile neutropenia and infections manifested by febrile neutropenia, with cytostatic therapy for malignant neoplasms.

    Contraindications:

    - Neutropenia in chronic myelogenous leukemia and myelodysplastic syndromes;

    - acute leukemia;

    - to increase the doses of cytotoxic chemotherapy higher than those established in dosing regimens;

    - simultaneous appointment with cytotoxic chemo- and radiotherapy;

    - pregnancy and the period of breastfeeding;

    - age to 18 years;

    - hypersensitivity to proteins obtained using E. coli, filgrastim, empagfilgrastimu, pegfilgrastimu, pegylated proteins, excipients of the drug.

    Carefully:

    - Malignant and premalignant diseases of myeloid nature (including acute myelogenous leukemia de novo and secondary);

    - in combination with high-dosage chemotherapy;

    - sickle-cell anemia.

    Pregnancy and lactation:

    Pregnancy

    Studies in pregnant women have not been conducted. The potential risk associated with influencing an embryo or human fetus is unknown.

    Breastfeeding period

    Studies in lactating women have not been carried out, so do not use the drug during breastfeeding.

    Dosing and Administration:

    Adults (≥ 18 years): once, subcutaneously, at a dose of 7.5 mg (one syringe), not less than 24 hours after the end of the administration of chemotherapy. The drug is administered subcutaneously, to the area of ​​the shoulder, anterior abdominal wall or thigh.

    Correction of the dosing regimen

    Do not use Eximmia® less than 14 days before, during, and less than 24 hours after the administration of cytotoxic chemotherapeutic agents. It is necessary to cancel the planned introduction of the drug Ecstimia® with an increase in the total number of leukocytes above 50 x 109/ l.

    Use in special patient groups

    Children: recommendations for the use of the drug Ecstimia ® in children and adolescents under the age of 18 years are not (not enough data).

    Patients with renal / hepatic insufficiency: correction of the dose is not required.

    Information for the patient on the technique of conducting a sc injection

    Before the injection, it is necessary to undergo special training from the attending physician or nurse.

    Self-administration of the drug:

    1. Remove from the refrigerator one blister with a syringe. In order to make the injection more comfortable, you should hold the syringe at room temperature for 30 minutes or warm it in your hand. Do not heat the drug in other ways.

    2. Check the expiration date on the label. Do not use the drug after the expiration date.

    3. Wash your hands thoroughly.

    4. Prepare everything you need for an injection (a tissue moistened with alcohol, a sterile gauze swab).

    5. Remove the syringe with the drug

    6. Check the appearance of the solution. It should be clear, colorless and without visible solids. Do not use the drug if the solution is cloudy or contains visible particles.

    7. Caution, do not rotate, pulling in a straight line, without touching the needle, remove the protective cap from the needle.

    8. If you have small air bubbles in the syringe, gently tap the syringe with your finger, holding it with the needle up, so that the air bubbles gather at the top of the syringe, and slowly, with gentle pressure on the piston, remove all air from the syringe. The syringe with the drug should not be shaken.

    9. The most optimal areas for subcutaneous administration are the anterolateral hip surface and abdomen, except for the area around the navel (Figure 1). You can also inject into the outer surface of the shoulder.

    10. Disinfect the skin at the injection site with an alcohol-soaked wipe. Collect the skin into the fold with the thumb and index finger without pressing.

    11. Fully insert the needle into the base of the skin fold at an angle of at least 45 degrees (Figure 2).

    12. Gently pull the plunger of the syringe to make sure that there is no puncture of the vessel. If blood appears in the syringe, remove the needle and enter it into another place.

    13. After inserting the needle, start injecting the solution under the skin, slowly and evenly pressing the syringe onto the piston, continuing to hold the skin in the fold.

    14. Continue pressing the plunger until the entire solution is introduced.After the entire dose is administered, remove the needle from the injection site and put a protective cap on the needle.

    15. For a few seconds, attach a sterile gauze swab to the injection site.

    16. Use each syringe for only one injection. Do not reinsert the solution remaining in the syringe.

    If you have any problems, ask your doctor or nurse for help.

    Side effects:

    Classification according to WHO recommendations was used to assess the incidence of adverse events: very often (≥ 10%), often (≥ 1% and <10%), infrequently (≥ 0.1% and <1%), rarely (≥ 0.01% and <0.1%), very rarely (<0.01%).

    Below is a list of adverse events reported in patients who received Eximmia® after cytotoxic chemotherapy, and in healthy volunteers as part of a clinical trial. The vast majority of adverse events were due to a major malignant disease or cytotoxic chemotherapy and were not associated with the use of the drug Ecstimia®.

    Infectious and parasitic diseases

    Often: acute respiratory viral infection.

    Violations of the blood and lymphatic system

    Very often: anemia, thrombocytopenia, leukocytosis, neutrophilia, lymphocytosis, leukopenia, neutropenia and lymphopenia.

    Often: febrile neutropenia.

    Leukopenia, neutropenia, lymphopenia, and febrile neutropenia are probably related to the chemotherapy drugs used. A healthy case of spleen enlargement was recorded in healthy volunteers.

    Disturbances from the nervous system

    Often: headache, dizziness, paresthesia, sensory neuropathy.

    Disturbances on the part of the organ of sight

    Often: lacrimation.

    Heart Disease

    Often: tachycardia, arrhythmia.

    Vascular disorders

    Often: arterial hypo - and hypertension, phlebitis.

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: cough, dryness of the nasal mucosa.

    Disorders from the gastrointestinal tract

    Very often: nausea, diarrhea.

    Often: stomatitis, vomiting, abdominal pain, indigestion, constipation, hemorrhoids, belching, itching of the gums, loss of appetite.

    Disturbances from the liver and bile ducts

    Very often: an increase in total bilirubin, an increase in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase,lactate dehydrogenase.

    Often: increased gamma-glutamyl transpeptidase, pain in the right upper quadrant, hepatotoxicity.

    Disturbances from the skin and subcutaneous tissues

    Very often: alopecia.

    Often: dry skin of the face, hyperemia of the skin of the face, itching of the skin, change of nails.

    Disturbances from musculoskeletal and connective tissue

    Very often: arthralgia, ossalgia.

    Often: myalgia, back pain, pain in the extremities.

    Ossalgia and arthralgia are undesirable reactions for G-CSF preparations. As a rule, they are weak or moderate and stop themselves.

    Disorders from the kidneys and urinary tract

    Very often: hypercreatininaemia.

    Often - increased levels of urea, proteinuria, bacteriuria, leukocyturia.

    Violations of the genitals and mammary gland

    Often: pain in the area of ​​the breast, uterine bleeding.

    General disorders and disorders at the site of administration

    Very often: fever, weakness, fatigue.

    Often: local reactions (skin hyperemia at the injection site), edema, asthenia, influenza-like syndrome, lymphostasis.

    Laboratory and instrumental data

    Very often: hyperglycemia, hyperalbuminaemia, hyperkalemia, hyperchloremia.

    Often: hypernatremia, hyperuricemia.

    Overdose:

    The maximum dosage of the drug Ecstimia®, studied in humans, is 9 mg once. When using the drug Ecstymia ® at a dose of 9 mg in healthy volunteers, headache, myalgia, back pain, thrombocytopenia, hyperbilirubinemia, hyperuricemia, hyperglycemia, increased ACT, Alkaline phosphatase, hyponatremia, hypochloraemia. All the undesirable events passed without consequences, alone or after the application of symptomatic therapy (headache, myalgia, arthralgia, bone pains were stopped using NSAIDs). Thus, undesirable phenomena in an overdose do not differ from the phenomena when the drug is administered in the recommended doses.

    The safety of the drug Ecstymia® in a dose of more than 9 mg has not been studied. With the introduction of higher doses of the drug Ecstymia, one can expect an increase in the described undesirable phenomena, hyperleukocytosis and the development of ricochet neutropenia.

    Interaction:

    Studies devoted to specific interactions or metabolism have not been conducted.

    Because the empagfilgrastim is excreted mainly by neutrophils, i.e. with the help of a specific mechanism that does not overlap with the ways of metabolism of most drugs, the probability of drug interactions appears to be minimal.

    Cytotoxic chemotherapy

    Because of the possible sensitivity of rapidly dividing myeloid cells to cytotoxic therapy, the drug Ecstimia® should be administered 24 hours after administration of cytotoxic chemotherapeutic agents.

    Interaction with other hematopoietic growth factors and cytostatics is unknown.

    It is known that lithium enhances the release of neutrophils. Although pharmacodynamic interaction with lithium has not been proven either for filgrastim or for pegfilgrastim, its feasibility should be considered when using the drug Ecstimia®.

    An evaluation of the safety and efficacy of Ecstymia® in patients receiving chemotherapeutic drugs whose use is associated with delayed myelosuppression (eg, nitrosourea derivatives) has not been evaluated.

    Signs of interaction of the drug Ecstimia® with other drugs have not been fixed to date.

    Special instructions:

    Treatment with Ecstimia® should only be carried out under the supervision of a physician with expertise in the use of G-CSF, provided that the necessary diagnostic capabilities are available.

    G-CSF stimulates endothelial cells and can accelerate the growth of myeloid cells, including malignant cells, and some non-myeloid cells in vitro.

    The drug Ecstymia® should not be used in myelodysplastic syndromes, chronic myelogenous leukemia, secondary acute myelogenous leukemia, since the safety and effectiveness of the drug in these patient groups were not evaluated.

    Especially careful differential diagnosis between blasttransformation in chronic myelogenous leukemia and acute myeloid leukemia.

    The safety and efficacy of Ecstymia® in patients with acute myelogenous leukemia have not been studied.

    The safety and efficacy of the drug Ecstimia® in patients receiving high-dose chemotherapy have not been studied.

    Cough, fever and shortness of breath, combined with radiographic infiltrative changes, impaired lung function, and an increase in the number of neutrophils may serve as signs of respiratory distress syndrome in adults.In this case, at the discretion of the doctor, the drug Ecstimia® should be discontinued and appropriate treatment should be prescribed.

    Very rare cases of rupture of the spleen after application of pegylated filgrastim preparations, some with a fatal outcome have been recorded, therefore, it is necessary to carefully monitor the size of the spleen with the help of instrumental examination (ultrasound). Should anticipatedthird the possibility of splenomegaly or rupture of the spleen in patients with complaints of pain in the upper left part of the abdomen and / or in the upper part of the left shoulder.

    Monotherapy with the drug Ecstymia® does not exclude the development of thrombocytopenia and anemia with the continuation of myelosuppressive chemotherapy in a full dose. It is recommended to regularly determine the number of platelets and hematocrit.

    The drug Ecstimia® should not be used to increase the doses of cytotoxic chemotherapy above those established in the dosing regimens.

    The development of sickle cell crises was associated with therapy with pegylated filgrastim in patients with sickle cell anemia. Therapy with Ecstymia® in patients with sickle cell anemia should be done with caution only aftercareful identification of potential risks and benefits. There were isolated cases of leukocytosis 100 x 109/ l or more in patients receiving the drug Eximmia®. This phenomenon was temporary and usually observed 24-48 hours after the administration of the drug in accordance with its pharmacodynamic effects. There are no side effects directly associated with such leukocytosis, not described.

    The safety and effectiveness of the drug Ecstimia® in the mobilization of peripheral blood stem cells in patients were not appropriately evaluated.

    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.

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

    Given the possible side effects of the drug Eksstimia, during the treatment patients should be careful when driving vehicles and performing work that requires increased concentration.

    Form release / dosage:RA mortar for subcutaneous administration, 7.5 mg / ml.
    Packaging:

    By 1.0 ml of empagfilgrastim solution into sterile syringes of the type BD Hypak from a colorless neutral glass I hydrolytic class. For each syringe stick the label self-adhesive.

    1 syringe per contour mesh box made of PVC film.

    1 contour pack with instructions for use in a pack of cardboard.

    Storage conditions:

    At a temperature of 2 to 8 ° C, in a dark place. Do not freeze.

    Keep out of the reach of children.

    Shelf life:

    3 years.

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

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003566
    Date of registration:13.04.2016
    Expiration Date:13.04.2021
    The owner of the registration certificate:BIOCAD, CJSC BIOCAD, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspBIOCAD CJSC BIOCAD CJSC Russia
    Information update date: & nbsp28.06.2016
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