Angioks® (Angiox®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceBivalirudinBivalirudin
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  • Angioks®
    lyophilizate in / in 
    Medicinz Company YuK Ltd.     United Kingdom
    • Dosage form: & nbsplyophilizate for the preparation of a solution for intravenous administration
    Composition:

    1 bottle contains:

    active substance: bivalirudin trifluoroacetate (in terms of bivalirudin) 250.0 mg;

    Excipients: Mannitol 125.0 mg, 0.5 M sodium hydroxide solution to pH 5.10-5.50

    Description:

    Lyophilizate: porous mass from white to almost white.

    Reconstituted solution: transparent or slightly opalescent colorless or pale yellow solution.

    Pharmacotherapeutic group:thrombin inhibitor direct
    ATX: & nbsp

    B.01.A.E.06   Bivalirudin

    Pharmacodynamics:

    Characteristics of the preparation

    Bivalirudin is a single-chain polypeptide with a molecular weight of 2180.19, consisting of 20 amino acids and having a core structure of hirudin. As a direct inhibitor of thrombin, bivalirudin inhibits all catalyzed and thrombin-induced reactions, including fibrin formation, activation of clotting factors V, VIII and XIII, activation of protein C, and platelet aggregation. Bivalirudin has a high selectivity to thrombin with an inhibition constant (K)) of 2.3 nM, and does not require the presence of co-factors.

    Pharmacodynamics

    The preparation of Angioks® contains bivalirudin a selective, reversible and direct thrombin inhibitor that binds to the catalytic site of thrombin, as well as to the anion-binding site of both free and fibrin linked thrombin.

    Thrombin plays a central role in the thrombogenesis process, cleaving fibrinogen to form fibrin monomers and activating the clotting factor XIII to form an active coagulation factor XIIIa, which promotes the formation of covalent cross-links between molecules of fibrin, which leads to the formation of a stable thrombus. Thrombin also activates clotting factors V and VIII, promoting the further formation of thrombin, and activates platelets, stimulating their aggregation and release of granules. Bivalirudin inhibits each of these thrombin effects.

    The binding of bivalirudin to thrombin, and, consequently, suppression of the latter's activity, is reversible, since thrombin slowly splits bivalirudin, Arg3-Pro4 bond, which leads to the restoration of the function of the active site of thrombin. Therefore, initially bivalirudin acts as a complete noncompetitive thrombin inhibitor, but over time becomes a competitive inhibitor capable of initially inhibiting the interaction of thrombin molecules with other clot substrates and, if necessary, inhibiting the coagulation process.

    Bivalirudin increases activated partial thromboplastin time (aCTT), thrombin time (TB), and prothrombin time (PT) of normal human plasma in vitro depending on the concentration. Bivalirudin does not cause platelet aggregation unlike serum obtained from a patient with a history of heparin-induced thrombocytopenia / thrombosis syndrome.

    In healthy volunteers and patients bivalirudin shows anticoagulant activity, depending on the dose and concentration, which is confirmed by an increase in activated clotting time (ABC), aTTV, PV / international normalization ratio (MNO) and TV. Intravenous administration of bivalirudin causes a measurable anticoagulant effect in just a few minutes.

    Bivalirudin has an antithrombotic effect during percutaneous transluminal coronary intervention (CTT) and stenting.

    The pharmacodynamic effects of bivalirudin can be evaluated by measuring the anti-shake action, including ABC. The magnitude of ABC is positively correlated with the dose and concentration of bivalirudin in plasma. ABC remains unchanged when treated in combination with a glycoprotein inhibitor GPIIb/IIIa.

    The available data indicate the safety and feasibility of using bivalirudin in patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia with thrombotic syndrome, but information is limited.

    Pharmacokinetics:

    Pharmacokinetic parameters are linear.

    Suction: Bioavailability of bivalirudin for intravenous administration is complete and immediate. The average equilibrium concentration of bivalirudin after a constant intravenous infusion at a rate of 2.5 mg / kg / h is 12.4 μg / ml.

    Distribution: Bivalirudin is rapidly distributed between plasma and extracellular fluid. The equilibrium volume of distribution is 0.1 l / kg. Bivalirudin does not bind to blood plasma proteins (with the exception of thrombin) or with erythrocytes.

    Biotransformation: It is assumed that bivalirudin, as a peptide, undergoes catabolism to the amino acids that make up its composition, followed by the utilization of amino acids in the body. Bivalirudin metabolized by proteases, including thrombin. The main metabolite formed as a result of the splitting of the Arg3-Pro4 bond N-end sequence by thrombin, is not active due to loss of affinity for the catalytic active site of thrombin. About 20% of bivalirudin is excreted unchanged in urine.

    Excretion: The dependence of concentration on time for intravenous administration is well described by a two-chamber model. Excretion is a first-order process with a terminal half-life of 25 ± 12 minutes in patients with normal renal function. The corresponding clearance is 3.4 ± 0.5 ml / min / kg. Half-life (t1/2) is 35-40 minutes.

    Liver failureь: The pharmacokinetics of bivalirudin in patients with impaired liver function has not been studied, but it is assumed that it does not change because bivalirudin It is not metabolized by the involvement of liver enzymes, for example, cytochrome P450 isoenzymes.

    Renal insufficiency: Systemic clearance of bivalirudin decreases depending on the rate of glomerular filtration (GFR). The clearance of bivalirudin in patients with normal renal function and in patients with slightly impaired renal function is the same. The clearance decreases by approximately 20% in patients with moderate or severe renal failure, and by 80% in patients on dialysis (Table 1).

    Table 1. Pharmacokinetic parameters of bivalirudin in patients with normal and impaired renal function

    Renal Function (GFR)

    Clearance (ml / min / kg)

    Period half-life (minutes)

    Normal renal function (> 90 mL / min)

    3,4

    25

    Slightly expressed renal failure (60-89 ml / min)

    3,4

    22

    Moderate renal failure (30-59 ml / min)

    2,7

    34

    Severe renal insufficiency (10-29 ml / min)

    2,8

    57

    Patients on dialysis (without dialysis)

    1,0

    3,5 hours

    In patients with renal insufficiency, when treating with the preparation of Angioks®, it is necessary to monitor coagulation parameters, for example, ABC.

    Elderly: The pharmacokinetics of bivalirudin in elderly patients was evaluated as part of a pharmacokinetics study depending on renal function.For this age group of patients, dose adjustment should be performed depending on the renal function.

    Body mass: The dose of bivalirudin is selected depending on the body weight in mg / kg. Dependence of the pharmacokinetics of bivalirudin on sex and race was not studied.

    Indications:

    As an anticoagulant:

    - in adult patients with percutaneous transluminal coronary intervention (PTCA), including in the performance of primary PTCA in patients with acute myocardial infarction (AMI) with segment elevation ST on the ECG;

    - in adults with unstable angina or MI without segment enhancement ST, which shows an urgent or early PTCA.

    Contraindications:

    - Hypersensitivity to bivalirudin or other components of the drug, and also to hirudin (to leeches);

    - active bleeding or an increased risk of bleeding due to congenital or acquired hemostasis disorders;

    - severe uncontrolled hypertension;

    - subacute bacterial endocarditis;

    - severe renal failure (GFR <30 ml / min), including, in patients, who are on dialysis;

    - children under 18 years of age (lack of data on effectiveness and safety).

    Carefully:

    The drug Angioks® should be used with caution in the conduct of beta brachio, taking into account the cases of thrombosis during gamma-brachytherapy.

    Pregnancy and lactation:

    There were no controlled studies of the drug during pregnancy. The potential risk to humans is not defined.

    It is not established whether the bivalirudin in breast milk.

    The drug AngioX® should not be used during pregnancy and during breastfeeding, except when the benefit to the mother exceeds the possible risk to the fetus and baby.

    Dosing and Administration:

    For intravenous administration.

    When carrying out percutaneous transluminal coronary intervention (PTCA) the preparation of Angioks® is injected intravenously in a dose of 0.75 mg / kg of body weight followed by immediate continuation of the infusion at a rate of 1.75 mg / kg / h until the end of the procedure. If necessary, the administration of the drug in the same dose can continue for another 4 hours after the end of PTCA, and then in the next 4-12 hours at a dose of 0.25 mg / kg / h.

    After the PTCA, patients should be under constant monitoring to detect symptoms of myocardial ischemia in a timely manner.

    For patients with unstable angina or AMI without an increase STsegment the initial dose of the preparation of Angioks®, which is administered intravenously, is 0.1 mg / kg body weight, followed by immediate infusion of the drug at a dose of 0.25 mg / kg / h for no more than 72 hours.

    If a patient is scheduled to receive a CTHQ, the procedure is additionally injected bivalirudin in a dose of 0.5 mg / kg of body weight, followed by infusion of the drug at a dose of 1.75 mg / kg / h until the end of the procedure. After the end of PTCA, the administration of the drug may continue for a further 4-12 hours at a dose of 0.25 mg / kg / h.

    In patients who have aorto-coronary bypass surgery (CABG) in the working heart, Infusion of the drug is carried out before the beginning of the surgical procedure. Immediately in front of the CABG bivalirudin injected intravenously in a dose of 0.5 mg / kg body weight, followed by infusion of the drug at a dose of 1.75 mg / kg / h until the end of the CABG.

    If the CABG is planned to be performed in conditions of artificial circulation, Intravenous bivalirudin should be discontinued 1 hour before surgery, after which it is recommended to begin treatment with unfractionated heparin (NG).

    Indicators of activated clotting time (ABC) can be used to assess the activity of bivalirudin.

    The ABC value after 5 minutes after the jet infusion of bivalirudin should be 365 ± 100 seconds.If this figure 5 minutes after the administration of the drug does not exceed 225 seconds, you need to re-inject bivalirudin in a dose of 0.3 mg / kg.

    At ABC values ​​greater than 225 seconds, further monitoring of this indicator is not required when maintaining the dose of the drug in the range of 1.75 mg / kg / h.

    In order to reduce the risk of obtaining low ABC values, the prepared concentrate and the diluted solution of the drug must be thoroughly mixed before administration and the initial dose is administered rapidly.

    The arterial catheter can be removed 2 hours after the termination of the infusion of bivalirudin without subsequent control of the ABC.

    Peculiarities of application in separate groups of patients

    Children and teens

    The safety and efficacy of bivalirudin in patients under the age of 18 years have not been studied.

    Elderly patients

    In elderly patients, caution should be exercised because of the possible age-related reduction in renal function.

    Use in patients with impaired renal function

    In severe renal failure (GFR <30 ml / min), including in patients on dialysis, the preparation of Angioks® is contraindicated.

    If the renal function is impaired, the dose / speed of the infusion should be adjusted. In patients with moderate renal failure (glomerular filtration rate 30-59 ml / min), which are subject to PTCA and regardless of whether they received bivalirudin with regard to ACS or not, the infusion rate should be reduced to 1.4 mg / kg / h. The initial dose of 0.75 mg / kg, which is injected intranasally, does not change.

    In patients with ACS and impaired renal function of mild to moderate severity, the recommended dose of the preparation AngioX® (0.1 mg / kg jet / 0.25 mg / kg / h as infusion) should not be changed.

    In patients with impaired renal function, it is recommended that the coagulation time be monitored, for example, during PCI. ABC.

    The value of ABC should be checked 5 minutes after the initial dose is sprayed. If the value of ABC is less than 225 seconds, it is necessary to re-inject the drug in a dose of 0.3 mg / kg and again check the ABC 5 minutes after the introduction of a second dose.

    Use in patients with impaired liver function

    Correction of the dose is not required. Pharmacokinetic studies show that,that the metabolism of bivalirudin in the liver is limited, so the safety and efficacy of bivalirudin in patients with liver failure have not been specifically studied.

    Simultaneous appointment with other anticoagulants

    In patients with MI with segment elevation ST, which is planned for PTCA, standard prehospital therapy should include clopidogrel and, in some cases, unfractionated heparin (NG).

    Patients can be administered the preparation of Angioks® 30 minutes after the end of intravenous infusion of NG or 8 hours after subcutaneous injection of low molecular weight heparin (LMWH).

    The preparation of Angioks® can be administered simultaneously with glycoprotein inhibitors GPIIb/IIIa.

    Recommendations for solution preparation and infusion

    In the bottle with the preparation of Angioks® add 5 ml of water for injection and gently shake the bottle until complete dissolution and a clear solution. Using a sterile syringe with a needle, 5 ml of the resulting solution are taken from the vial, which is then diluted with a solution of 5% dextrose (glucose) or 0.9% sodium chloride solution to a total volume of 50 ml to obtain a final bivalirudin concentration of 5 mg / ml.

    The prepared reconstituted solution and diluted solution should be clear or slightly opalescent, from colorless to light yellow.

    If the solution has a different color or is determined in it visible inclusions, its use is not allowed.

    The reconstituted solution Store at a temperature of 2 to 8 ° C for no more than 24 hours.

    The diluted solution Store at 25 ° C for no more than 24 hours.

    Side effects:

    The summary of adverse reactions noted during clinical trials in patients who received bivalirudin, according to the frequency of occurrence: "very often" (≥1 / 10); "often" (≥1 / 100, <1/10); "infrequently" (≥1 / 1000, <1/100), "rarely" (≥1 / 10000, <1/1000) and "unknown" (it is impossible to estimate from available data).

    Violations of the blood and lymphatic system:

    Often - decrease in hemoglobin concentration;

    Infrequently - Thrombocytopenia, anemia;

    Rarely - increase INR.

    Immune system disorders:

    Infrequently - Hypersensitivity reactions (including anaphylactic reactions and shock, including cases with fatal outcome).

    Impaired nervous system:

    Infrequently - headache;

    Rarely - intracranial bleeding.

    Hearing disorders and labyrinthine disorders:

    Rarely bleeding from the ear.

    Disturbances on the part of the organ of sight:

    Rarely - intraocular bleeding.

    Heart Disease:

    Rarely - Myocardial infarction, cardiac tamponade, pericardial hemorrhage, coronary artery thrombosis, angina, bradycardia, ventricular tachycardia, chest pain.

    Vascular disorders:

    Often - minor bleeding of different locations;

    Often - significant bleeding of various locations (including fatal cases);

    Infrequently - hematoma, lowering blood pressure;

    Rarely - thrombosis of the stent of the coronary artery (including cases with fatal outcome)from, thrombosis (including fatal cases), arteriovenous fistula, catheter thrombosis, vascular pseudoaneurysm;

    Rarely - syndrome of "compression" a,b;

    Unknown hemorrhagic shock.

    Disorders from the gastrointestinal tract:

    Infrequently - gastrointestinal bleeding (including vomiting of blood, melena, esophageal hemorrhage, anal bleeding), retroperitoneal bleeding, bleeding gums, nausea;

    Rarely - intraperitoneal bleeding, retroperitoneal hematoma, vomiting.

    Disturbances from the respiratory system and chest organs:

    Infrequently - pharyngeal bleeding, hemoptysis, nosebleeds;

    Rarely - pulmonary hemorrhage, dyspneaa.

    Disturbances from the skin and subcutaneous tissues:

    Often - a bruise;

    Rarely - hives, rash.

    Disorders from the kidneys and urinary tract:

    Infrequently - Hematuria.

    Disturbances from musculoskeletal and connective tissue:

    Rarely - pain in the back, pain in the groin.

    General disorders and disorders at the site of administration:

    Often - bleeding at the site of the vascular puncture, hematoma at the puncture site with a diameter> 5 cm, a hematoma at the site of the vascular puncture (diameter <5 cm);

    Rarely - reactions at the injection site (discomfort and pain at the injection site).

    Trauma, intoxication and complications of procedures:

    Rarely - reperfusion injury (delayed reperfusion blood flow or its absence), concussion.

    a - AEs registered in the postmarketing period of drug use;

    b - "compression" syndrome was registered in the postmarketing period as a complication of the forearm hematoma, which developed as a result of the introduction of bivalirudin during access through the radial artery;

    from - details of monitoring of acute stent thrombosis are indicated in the section below.

    Bleeding

    Data on bleeding were assessed separately from other adverse events (Table 2).

    Table 2. Frequency of bleeding depending on their location (bivalirudin in comparison with heparin + glycoprotein inhibitor IIb(IIIa)

    Localization bleeding

    Bivalirudin

    (n=2994) %

    Heparin + glycoprotein inhibitor IIb/IIIa (n=3008)%

    Value

    R

    Location of the vascular catheter

    0,8

    2,5

    0,001

    Other site of a vascular puncture

    0,2

    0,2

    1,000

    Zabrjushinnoe

    0,2

    0,5

    0,062

    Gastrointestinal

    0,1

    0,6

    0,003

    Ear, nose or throat

    0,1

    0,3

    0,085

    Urogenital

    <0,1

    0,2

    0,125

    Intracranial

    <0,1

    0,1

    1,000

    Cardiopulmonary

    0,1

    0,3

    0,035

    Other

    0,4

    0,5

    0,556

    Table 3 shows the frequency of significant bleeding in the main clinical trials of bivalirudin.

    Table 3. Frequency of significant bleeding during clinical trials of bivalirudin

    Type of therapy

    Bivalirudin

    Bivalirudin +

    inhibitor

    glycoprotein IIb/IIIa

    NG / enoxaparin * + inhibitor

    glycoprotein IIb /IIIa

    room research

    1

    2

    3

    2

    1

    2

    3

    amount patients

    2994

    4612

    1800

    4604

    3008

    4603

    1802

    Significant bleeding according to the protocol and study population criteria,%

    2,4

    3,0

    5,1

    5,3

    4,1

    5,7

    8,8

    Bleeding as a result thrombolysis in myocardial ischemia (not associated with CABG),%

    0,4

    0,9

    1,8

    1,8

    0,8

    1,9

    3,2

    * Enoxaparin was used as a comparator in only one of the studies.

    Generally, minor hemorrhages were observed very often (≥ 1/10), and significant - often (≥ 1/100 and <1/10).

    Both minor and significant hemorrhages were significantly less frequent in the group receiving bivalirudin relative to the comparison group receiving heparin and a glycoprotein inhibitor IIb/IIIa. Significant bleeding occurred most often at the site of insertion of the catheter (see Table 3). Other, more rare localizations of hemorrhagic complications (frequency ≥1 / 1000 and <1/100) were alternative sites of puncture, retroperitoneal space, gastrointestinal tract, ear, nose and pharynx.

    Additional Information

    Adverse events were observed more often in women and patients older than 65 years.

    Overdose:

    The excess of the recommended doses of the preparation of Angioks® was recorded more than 10 times. There was also an excess of the initial dose injected with jet (more than 7.5 mg / kg). At some patients on a background of an overdose of a preparation hemorrhages were marked.

    In cases of overdose, treatment with bivalirudin should be stopped immediately, and the patient should be monitored for the timely detection of bleeding symptoms.

    The antidote for bivalirudin is unknown, but bivalirudin undergoes hemodialysis.

    Interaction:

    Pharmaceutical

    Investigations of drug interaction with platelet aggregation inhibitors, including acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, eptifibatide and tirofiban. The results obtained indicate a lack of pharmacodynamic interaction with these drugs.

    Given the mechanism of action of these drugs, it can be assumed that the use of bivalirudin together with anticoagulants (heparin, warfarin), thrombolytic or antiaggregants is accompanied by an increased risk of bleeding.

    Special instructions:

    The drug Angioks® is recommended to be prescribed simultaneously with acetylsalicylic acid and clopidogrel.

    The drug Angioks® should be administered only by a physician with experience in the intensive care unit or interventional cardiology.

    Do not administer intramuscularly!

    The preparation of Angioks® should be administered using the system for intravenous administration.

    It is not allowed to use the system for intravenous administration of bivalirudin for the administration of the following drugs,because they cause cloudiness of the solution, the formation of microparticles or intense precipitation: alteplase, amiodarone hydrochloride, amphotericin B, chlorpromazine hydrochloride, diazepam, prochlorperazine edisylate, reteplase, streptokinase and vancomycin hydrochloride.

    Table 4 indicates preparations in which the incompatibility with bivalirudine depends on their concentration in the solution.

    Table 4. Preparations, the compatibility of which with bivalirudin depends on their concentration

    Name of the drug

    Compatible

    concentration

    Incompatible

    concentration

    Dobutamine hydrochloride

    4.0 mg / ml

    12.5 mg / ml

    Famotidine

    2.0 mg / ml

    10.0 mg / ml

    Haloperidol lactate

    0.2 mg / ml

    5.0 mg / ml

    Labetolol hydrochloride

    2.0 mg / ml

    5.0 mg / ml

    Lorazepam

    0.5 mg / ml

    2.0 mg / ml

    Promethazine hydrochloride

    2.0 mg / ml

    25.0 mg / ml

    The efficacy and safety of the exclusively jet infusion of the dose of the preparation of Angioks has not been studied and therefore is not recommended even for short-term procedures of the PTCA.

    Bleeding: During treatment, patients should be under close medical supervision for the timely detection of symptoms and signs of bleeding.Although most of the bleeding associated with bivalirudin occurs in patients undergoing PTCA at the artery puncture site, bleeding during therapy can be of any localization. An unexplained decrease in hematocrit, hemoglobin, or blood pressure may be a sign of latent bleeding. When bleeding symptoms appear, bivalirudin should be discontinued. There is no known antidote for bivalirudin, but its effect quickly disappears (t1/2 is 35-40 minutes).

    Simultaneous use with antiplatelet agents or oral anticoagulants

    The combined use of bivalirudin with antiplatelet agents may be accompanied by an increased risk of hemorrhagic complications.

    Therefore, it is necessary to regularly monitor the clinical and biological parameters of hemostasis with the combined use of bivalirudin with platelet aggregation inhibitors or anticoagulants.

    In patients receiving warfarin, which was administered bivalirudin, control of INR after discontinuing the administration of bivalirudin should be carried out until the moment it returns to the initial value.

    Hypersensitivity

    In clinical studies, reactions of hypersensitivity of the allergic type were rarely observed. Nevertheless, appropriate precautions should be taken. Patients should be informed of early signs of hypersensitivity reactions that include urticaria, generalized rash, a feeling of heaviness in the chest, shortness of breath, lowering of blood pressure and anaphylaxis. In the case of shock, standard anti-shock therapy should be performed. The development of anaphylaxis, including anaphylactic shock with a fatal outcome, was recorded in isolated cases (<1/10 000).

    Immediate appearance of antibodies to bivalirudin is rare and is not associated with the development of a clinical picture of allergic or anaphylactic reactions. Caution should be exercised in patients who have previously been treated with lepiridin and who have developed antibodies to lepirudin.

    Acute stent thrombosis

    Acute stent thrombosis (<24 h), diagnosed in patients with MI with segment elevation ST, who underwent primary PCI, required the implementation of targeted vascular revascularization.After the primary CHTC, patients should remain in the intensive care unit for at least 24 hours to promptly detect symptoms of myocardial ischemia and promptly provide appropriate care.

    The remaining unused product must be disposed of immediately. Do not reuse syringe or needles. Any unused or consumable material must be disposed of in accordance with local requirements.

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

    Studies to study the impact on the ability to drive vehicles and the use of mechanisms were not carried out.

    Form release / dosage:

    Lyophilizate for the preparation of a solution for intravenous administration, 250 mg.

    Packaging:

    250 mg of the active ingredient in a neutral glass type I bottle (Hebrew F.) with a capacity of 10 ml, sealed with a rubber stopper, sealed with an aluminum cap with a detachable plastic lid of the "Flip-off".

    For 10 vials with instructions for use in a cardboard pack with the control of the first autopsy.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:4 years.
    Do not use after the expiry date indicated on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-008510/10
    Date of registration:20.08.2010
    The owner of the registration certificate:Medicinz Company YuK Ltd.Medicinz Company YuK Ltd. United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspRAYFARM, LLCRAYFARM, LLC
    Information update date: & nbsp20.11.2015
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