Active substanceDrotrekogin alfa (activated)Drotrekogin alfa (activated)
Similar drugsTo uncover
  • Sigris®
    lyophilizate d / infusion 
  • Dosage form: & nbsplyophilizate for solution for infusion
    Composition:1 bottle contains:

    For a dosage of 5 mg:

    Active substance: drotrekogina alpha (activated) 5 mg;

    Excipients: sodium chloride 38 mg, sodium citrate (equivalent citrate ion) 7.56 mg, sucrose 30 mg.

    For the dosage of 20 mg:

    Active substance: drotrekogina alpha (activated) 20 mg;

    Excipients: sodium chloride 152 mg, sodium citrate (equivalent citrate ion) 30.2 mg, sucrose 120 mg.

    Description:Lyophilizate from white to almost white.
    Pharmacotherapeutic group:Anticoagulant
    ATX: & nbsp

    B.01.A.D.10   Drotrekalin alpha (activated)

    Pharmacodynamics:

    Activated protein C has an antithrombotic effect by inhibiting the Va and VIIIa coagulation factors. Data obtained under in vitro conditions indicate that the activated protein C has an indirect profibrinolytic effect due to its ability to inhibit the inhibitor of the plasminogen-1 activator (IAP-1) and to limit the production of an activated thrombin-activated fibrinolysis inhibitor. In addition, experimental data in vitro indicate that the activated protein C has an anti-inflammatory effect due to suppression of tumor necrosis factor, synthesized by monocytes, blocking of adhesion of leukocytes to selectins, and also restriction of thrombin-induced inflammatory response in the vascular endothelium microcirculatory bed.

    Pharmacodynamics

    The mechanism by which drotrekogin alfa reduces the mortality of patients with severe sepsis is not fully understood. In patients with severe sepsis, the infusion of drtrekogin alpha for 48 or 96 hours resulted in a dose-dependent decrease in the level of D-dimer and interleukin-6 (IL-6). Compared to patients receiving placebo, patients receiving drotrecoquine alpha, there was a more rapid decrease in the level of D-dimer, IAP-1, thrombin-antithrombin level, prothrombin F1.2, IL-6, faster increase in protein C and antithrombin, and normalization of plasminogen levels. Based on the duration of the infusion, it was found that the maximum pharmacodynamic effect of drotrecohin alpha on the D-dimer level was observed at the end of the 96th hour of infusion at a dose of 24 μg / kg / h.

    Pharmacokinetics:

    Drotrekogin alfa and endogenous human activated protein C is inactivated by endogenous plasma protease inhibitors. The concentration of activated protein C in plasma in healthy subjects and in patients with severe sepsis is usually below the level of the minimum detectable concentration.

    In patients with severe sepsis, the infusion of drtrekogin alpha at a dose of 12 μg / kg / h to 30 μg / kg / h rapidly creates an equilibrium concentration (Css), which is proportional to the intensity of the infusion. The average clearance of drtrekogin alfa is 40 l / h (27 to 52 l / h). Average Css, equal to 45 ng / ml (35 to 62 ng / ml), was achieved within 2 hours from the beginning of the infusion. In most patients, the concentration of drtrekogin alpha in plasma dropped below the quantification limit of 10 ng / ml within 2 hours of the end of the infusion. The plasma clearance of drotrecoagin alpha in patients with severe sepsis was approximately 50% higher than in healthy subjects.

    Special patient groups

    In the treatment of adult patients with severe sepsis, there was no clinically significant difference in the plasma clearance of drotrecohin alpha, depending on age, sex, liver function and kidney function,or the parallel administration of small doses of heparin, which implies that dose adjustments based on these criteria are not required.

    Terminal stage of renal failure. In patients who did not suffer from severe sepsis and who were on hemodialysis, the average plasma clearance of drtrekogin alpha when the drug was administered not on the days of hemodialysis was 30 ± 8 l / h. In patients who did not suffer from severe sepsis who underwent peritoneal dialysis, the plasma clearance of drtrekogin alpha was 23 ± 4 l / hr. Such parameters of plasma clearance practically did not differ from those observed in healthy subjects - (28 ± 9 l / h) (n = 190).

    In the drotrekogin alpha (activated) group, there was a greater number of bleeding to the central nervous system (CNS), compared with the placebo group.

    Cases of fatal hemorrhages in the central nervous system, severe bleeding (during infusions and the 28-day study period), serious adverse events, as well as amputations occurred in the groups of drotrekogin alpha (activated) and placebo at the same frequency.

    Indications:

    Sepsis, accompanied by acute polyorganic insufficiency and / or high risk of death ( 25 points on the scale APACHE).

    Contraindications:
    • Continuing internal bleeding
    • Recently transferred (within 3 previous months) hemorrhagic stroke
    • Recently transferred (within 2 previous months) intracranial or intraspinal surgical intervention or severe craniocerebral injury that required hospitalization
    • Trauma, accompanied by a high risk of life-threatening bleeding
    • Patients with epidural catheterization
    • Intracranial tumors / neoplasms or signs of cerebral hernia
    • Hypersensitivity to drotrecohin alpha or other substances in the formulation
    Carefully:

    In some conditions, there is an increased risk of bleeding during Sigris® treatment. In this regard, special care should be taken when appointing Sigris® patients with severe sepsis, with one or more of the following conditions:

    • Treatment with heparin (≥ 15 U / kg / h)
    • The number of platelets <30000 x 106/ l, even if the platelet count increased after transfusion
    • Prothrombin time> 3 min
    • Recently suffered (within 6 weeks) gastrointestinal bleeding
    • Thrombolytic therapy in the anamnesis (for 3 previous days)
    • Reception of oral anticoagulants or glycoprotein IIb / IIIa inhibitors (for 7 previous days)
    • Admission (within 7 previous days) of acetylsalicylic acid at a dose of> 650 mg per day or other platelet inhibitors
    • Ischemic stroke in history (within 3 preceding months)
    • Intracranial arteriovenous disease or aneurysm
    • The presence of hemorrhagic diathesis, except for cases of acute coagulopathy, related to sepsis
    • Severe chronic liver disease
    • Any other conditions in which there is a high risk of bleeding or difficulty stopping bleeding due to its localization.

    Pregnancy and lactation:

    There are no data on the possible damaging effect of Sigris® on fetus Women and the effect of the drug on reproductive function. Assigning Sigris® Pregnant women should only be used if the potential benefit to the patient is significantly greater than the potential risk to the fetus.

    There are no data on the possibility of breeding Sigris® from milk of the mother or systemic absorption after ingestion of the drug into the gastrointestinal tract. In connection with the fact that many drugs are excreted with the mother's milk, as well as with the probability of side effects reactions from A child who is breastfed should to accept decision about discontinuation of the breast feeding or application drug, given the importance of continuing treatment with this drug for the mother.

    Dosing and Administration:

    Sigris® should be administered intravenously at a rate of 24 μg / kg / h, with a total infusion duration of 96 hours.

    After the interruption of the infusion, the administration of Sigris® should be resumed at a rate of 24 μg / kg / h. Increasing the dose or bolus of Sigris ® is not recommended.

    Instructions for preparation and introduction:

    1. Observe proper asepsis rules when preparing Sigris® for intravenous administration.

    2. Calculate the dose and the required number of Sigris® vials. Each Sigris® vial contains 5 mg or 20 mg of the drug.

    3. Before administration, the contents of the 5 mg vial should be diluted with 2.5 ml of sterile water for injection; the contents of the 20 mg bottle should be diluted with 10 ml of sterile water for injection.The concentration of the preparation in the solution thus obtained is approximately 2 mg / ml. Slowly add sterile water for injection to the contents of the vial, without flipping or shaking it. Carefully shake each bottle until the lyophilizate contained in it is completely dissolved.

    4. The Sigris® solution must be further diluted with sterile 0.9% sodium chloride solution for intravenous administration to a concentration of 100 μg / ml to 200 μg / ml. Slowly draw the appropriate amount of Sigris® solution from the vial and add Zigris® solution to the dropper container containing 0.9% sterile sodium chloride solution. When adding Zigris®, direct the spray of solution to the wall of the dropper container so as to reduce the shaking of the solution. Carefully flip over container, that homogenize solution. Not transport container with a dropper using mechanical systems delivery.

    5. Due to the fact that antibacterial preservatives are not included in Sigris®, the solution for intravenous administration should be prepared immediately after diluting Sigris® in the vial (s).If bottles with dilute Zigrisom® not used immediately, they can be stored at room temperature of from 15 ° to 30 ° C, however, these vials must be used during the next 3 hours.

    6. Before use, preparations for parenteral administration should be carefully inspected for visible suspended particles and discoloration of the solution.

    7. When using a pump for intravenous administration Zigrisa® solution is typically diluted in sterile sodium chloride solution 0.9 for intravenous administration to a concentration of 100 .mu.g / ml to 200 mcg / ml. After preparation, the solution for intravenous administration should be used at room temperature (15 - 30 ° C) for 12 hours. If the intravenous solution has not been used immediately, it should be stored in the refrigerator (2 - 8 ° C) for 12 hours. If the prepared solution was stored in the refrigerator before use, the maximum time during which it is possible to use it, including preparation, storage in the refrigerator and the introduction is 24 hours.

    8. When using a syringe pump for administering the drug, the solution of Sigris® is diluted with a sterile 0.9 % solution of sodium chloride for injection to a concentration of 100 μg / ml to 200 μg / ml.In the case when Sigris® is administered at a low rate (less than 5 ml / h), the infusion rate in the first 15 minutes should be about 5 ml / h. After preparation in a syringe solution for intravenous administration should be used at room temperature (15 - 30 ° C) for 12 hours. The maximum time to use the solution, including preparation and administration, is 24 hours.

    9. Sigris® should be injected through a separate intravenous port or through an isolated lumen of a multi-lumen central catheter. Via the same port, you can enter only 0.9% solution of sodium chloride for injection, Ringer's injection, dextrose or a mixture of dextrose and 0.9% sodium chloride solution.

    10. Sigris® solution should be protected from exposure to high temperatures and / or direct sunlight. It was not revealed incompatibility between Zigris® and glass droppers, as well as droppers and syringes made of polyvinyl chloride, polyethylene, polypropylene or polyolefin.

    Side effects:

    The most frequently reported side effect with Sigris® is bleeding (3.5% of patients), most commonly developing during infusion.Serious bleeding (any intracranial, life-threatening or bleeding that required transfusions 3 packages of erythrocyte mass per day for 2 days) were met with a frequency of 2.4%.

    Other adverse reactions

    In patients receiving Sigris® for the treatment of severe sepsis, many reactions are noted that may be due to severe sepsis and may or may not be related to treatment with Sigris®. In the course of clinical studies of other adverse reactions caused by the use of Sigrisom®, except for those exhibiting bleeding, it was not revealed.

    Overdose:

    There have been reports of drug overdose. In most cases (patients received a dose 60 times higher than the recommended dose), no side effects were noted reactions. In other cases bleeding associated with sepsis was observed.

    The antigots of Zygris® are unknown. If an overdose should immediately stop the infusion of the drug, establish a thorough control for possible bleeding and conduct symptomatic treatment.

    Interaction:

    In patients with severe sepsis, a study Sigris® interaction with other drugs is not was conducted.Should take care when use of Sigris ® in combination with other medicines, affecting the hemostasis. The concomitant use of low doses of unfractionated heparin (<15,000 U / day) and nizomolecular heparin for prophylactic purposes (2850 U / day) did not adversely affect the efficacy of Sigris®, and did not increase the risk of severe bleeding, including bleeding in the central nervous system. When small doses of heparin were used, the frequency of non-life-threatening bleeding increased as compared with placebo during the study period during the first 6 days. Heparin in small doses can be used in parallel with drotrecohin alpha to prevent venous thrombosis.

    Preventive use of heparin should not be interrupted until it is deemed necessary for medical reasons.

    Special instructions:

    The most frequent of the serious side effects noted in the treatment of Sigris®, is bleeding. Each patient to whom the appointment of Sigris®, should be carefully examined, and the expected effect of treatment should be compared with the possible risk of usepreparation.

    If clinically significant bleeding occurs, Sigris® infusion should be discontinued immediately. Continue the use of other drugs that affect the blood clotting system, taking special care. When the achievement of adequate hemostatic parameters may be considered the issue of continued use of Sigris ®. Treatment with Zygris® should be discontinued 2 hours before surgery or other procedures associated with an increased risk of bleeding. When adequate hemostasis is achieved, Sigrisom® treatment can be started 12 hours after extensive invasive procedures and surgeries, or resumed immediately after uncomplicated, less invasive interventions.

    If the results of successive hemostasis studies indicate the presence of uncontrolled or worsening coagulopathy, which significantly increases the risk of bleeding, it is necessary to assess the benefits of continued infusion and the potentially increased risk of bleeding in the patient.

    Laboratory Tests

    Most patients with severe sepsis have coagulopathy,which is usually associated with an increase in activated partial thromboplastin time (APTT) and prothrombin time (PT). Sigris® can increase the APTT to varying degrees. In this regard, the importance of APTT can not be used to assess the severity of coagulopathy during the infusion of Zygris®. The value of PV Zigris® has minimal effect, so the value of PV can be used to assess the severity of coagulopathy in this category of patients.

    Immunogenicity

    As with the use of other protein preparations, there is a potential for immunogenicity in the application of Sigris®. The incidence of antibodies in patients receiving Sigris® was not reliably determined because the sensitivity of the assay methods was not high enough to detect all cases of antibody production.

    Sigris® was not re-administered to patients with severe sepsis.

    Use in children

    The effectiveness of Drotekogin alpha (activated) in children has not been established. Consequently, recommendations on dosage can not be given.

    Use in geriatric practice

    In general, there was no difference in the efficacy and safety of the drug between these patients and younger patients.

    Form release / dosage:Liofilizate for the preparation of a solution for infusions of 5 mg and 20 mg.
    Packaging:

    In a vial of transparent glass type I, sealed with a rubber stopper under aluminum with a polypropylene detachable top. One bottle with instructions for use in a pack of cardboard.

    Storage conditions:

    List B.

    Store in the refrigerator at a temperature of 2 ° to 8 ° C. Do not freeze. Store in a dark place in a cardboard box until use.

    Keep out of the reach of children.

    Shelf life:

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

    Terms of leave from pharmacies:On prescription
    Registration number:П N014540 / 01
    Date of registration:09.02.2009
    Expiration Date:Unlimited
    Date of cancellation:2012-03-19
    The owner of the registration certificate:Lilly Pharma Fertigung und Distribution GmbH & Co. KGLilly Pharma Fertigung und Distribution GmbH & Co. KG Germany
    Manufacturer: & nbsp
    Representation: & nbspELI LILLY EAST SA ELI LILLY EAST SA Switzerland
    Information update date: & nbsp12.10.2017
    Illustrated instructions
      Instructions
      Up