Clexane® (Clexane®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceSodium EnoxaparinSodium Enoxaparin
Similar drugsTo uncover
  • Anfiber
    solution for injections 
    VEROPHARM SA     Russia
  • Hemapaksan
    solution PC 
    Italfarmaco SpA     Italy
  • Clexane®
    solution for injections 
    Sanofi-Aventis France     France
  • Flenox® NEO
    solution for injections 
    FARMAK, JSC     Ukraine
  • Eniksum®
    solution for injections 
    FarmSirma Soteks, ZAO     Russia
  • Sodium Enoxaparin
    solution for injections 
    BIOCAD, CJSC     Russia
    • Dosage form: & nbspinjection
    Composition:

    Composition per syringe

    Dosage 2000 ant and-Ha IU / 0.2 ml (equivalent to 20 mg / 0.2 ml).

    Active substance: Enoxaparin sodium (Hef.F., ND firm)

    20 mg *

    Solvent:

    Water for Injection (Hebrews F.)

    up to 0.2 ml

    Dosage 4000 ant and I-IU IU / 0.4 mL (equivalent to 40 mg / 0.4 mL).

    Active substance: Enoxaparin sodium (Hef.F., ND firm)

    40 mg *

    Solvent:

    Water for Injection (Hebrews F.)

    up to 0.4 ml

    The dosage is 6000 ant and-Ha IU / 0.6 mL (equivalent to 60 mg / 0.6 mL).

    Active substance: Enoxaparin sodium (Hef.F., ND firm)

    60 mg *

    Solvent:

    Water for Injection (Hebrews F.)

    up to 0,6 ml

    Dosage of 8000 ant I and Xa IU / 0.8 ml (equivalent to 80 mg / 0.8 ml).

    Active substance: Enoxaparin sodium (Hef.F., ND firm)

    80 mg *

    Solvent:

    Water for Injection (Hebrews F.)

    up to 0.8 ml

    Dosage 10,000 ant and-Xa / 1 mL (equivalent to 100 mg / 1 mL).

    Active substance: Enoxaparin sodium (Hef.F., ND firm)

    100 mg *

    Solvent:

    Water for Injection (Hebrews F.)

    up to 1.0 ml

    * - the mass is calculated on the basis of the content of the used enoxaparin sodium (theoretical activity of 100 anti-Xa IU / mg).

    Description:Transparent, from a colorless to pale yellow solution.
    Pharmacotherapeutic group:Anticoagulant means of direct action
    ATX: & nbsp

    B.01.A.B.05   Enoxaparin

    Pharmacodynamics:

    Characteristic

    Enoxaparin sodium is a low molecular weight heparin with an average molecular weight of about 4500 dalton: less than 2000 daltons - <20%, from 2000 to 8000 daltons -> 68%, more than 8000 daltons - <18%. Sodium Enoxaparin are obtained by alkaline hydrolysis of benzyl ester of heparin isolated from the mucosa of the small intestine of a pig. Its structure is characterized by a reducing fragment of 2-O-sulfo-4-enapyrazinosuronic acid and a reducing fragment 2-N,6- O-disulfo-B-glucopyranoside. The structure of sodium enoxaparin contains about 20% (ranging from 15% to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

    Pharmacodynamics

    In the purified system in vitro enoxaparin sodium has a high anti-Xa activity (about 100 IU / ml) and low anti-IIa or antithrombin activity (about 28 IU / ml).This anticoagulant activity acts through antithrombin III (AT-TTT), providing anticoagulant activity in humans. In addition to anti-Xa /IIand activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have been revealed both in healthy people and patients, and in animal models. This includes AT-TTT dependent inhibition of other clotting factors as a factor VIIa, activation of the release of the tissue factor pathway inhibitor (PTF), as well as a reduction in the release of von Willebrand factor from the vascular endothelium into the bloodstream. These factors provide an anticoagulant effect of sodium enoxaparin as a whole.

    When used in prophylactic doses, it slightly changes the activated partial thromboplastin time (APTT), has virtually no effect on platelet aggregation and the degree of binding of fibrinogen to platelet receptors.

    Anti-IIand plasma activity is about 10 times lower than anti-Xa activity. The average maximum anti-IIand the activity is observed approximately 3-4 hours after subcutaneous administration and reaches 0.13 IU / ml and 0.19 IU / ml after repeated administration of 1 mg / kg of body weight with double administration and 1.5 mg / kg of body weight with a single administration, respectively.

    The average maximum anti-Xa plasma activity is observed 3-5 hours after subcutaneous administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU / ml after subcutaneous administration of 20, 40 mg, and 1 mg / kg and 1.5 mg / kg, respectively.

    Pharmacokinetics:

    The pharmacokinetics of enoxaparin in these dosage regimens is linear. The variability within and between groups of patients is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once a day and subcutaneous administration of enoxaparin sodium at a dose of 1.5 mg / kg body weight once a day in healthy volunteers, the equilibrium concentration is reached by day 2, the area under the pharmacokinetic curve on average 15 % higher than after a single injection. After repeated subcutaneous injections of sodium enoxaparin in a daily dose of 1 mg / kg body weight, twice a day, the equilibrium concentration is achieved after 3-4 days, the area under the pharmacokinetic curve is 65% higher on average than after a single injection and the average maximum concentrations are respectively 1.2 IU / ml and 0.52 IU / ml.

    Bioavailability of sodium enoxaparin for subcutaneous administration, estimated on the basis of anti-Xa activity, is close to 100%.

    The volume of distribution of anti-Xa activity of enoxaparin sodium is approximately 5 liters and approaches the blood volume.

    Enoxaparin sodium is a preparation with low clearance. After intravenous administration for 6 hours at a dose of 1.5 mg / kg body weight, the average value of anti-Xa clearance in plasma is 0.74 l / h.

    Excretion of the drug is monophasic with half-lives of 4 hours (after a single subcutaneous injection) and 7 hours (after repeated administration of the drug).

    Enoxaparin sodium is mainly metabolized in the liver by desulfating and / or depolymerizing to form low molecular weight substances with very low biological activity. Kidney excretion of active fragments of the drug is approximately 10% of the administered dose, and the total excretion of active and inactive fragments is approximately 40% of the administered dose. It is possible to delay the excretion of sodium enoxaparin in elderly patients as a result of a decrease in renal function with age.

    A decrease in the clearance of enoxaparin sodium in patients with decreased renal function was noted. After repeated subcutaneous administration of 40 mg of enoxaparin sodium, an increase in anti-Xa activity occurs once a day,represented by the area under the pharmacokinetic curve in patients with insignificant (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-50 ml / min) impaired renal function. In patients with severe renal impairment (creatinine clearance less than 30 ml / min), the area under the pharmacokinetic curve in equilibrium is an average 65% higher with repeated subcutaneous administration of 40 mg of the drug once a day.

    In people with overweight with subcutaneous injection of the drug, the clearance is slightly less. If the dose is not adjusted to take into account the patient's body weight, then after a single subcutaneous administration of 40 mg of enoxaparin sodium, anti-Xa activity will be 50% higher in women weighing less than 45 kg and 27% higher in men weighing less than 57 kg compared with patients with normal average body weight.

    Indications:

    - Prevention of venous thrombosis and embolism in surgical interventions, especially with orthopedic and general surgical operations.

    - Prevention of venous thrombosis and embolism in patients on bed rest, due to acute therapeutic illnesses, including acute heart failure and decompensation of chronic heart failure (grade III or IV NYHA), acute respiratory failure, as well as severe acute infections and acute rheumatic diseases in combination with one of the risk factors for venous thrombosis (see "Special instructions").

    - Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary arterial thromboembolism.

    - Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis (usually with a session duration of no more than 4 hours).

    - Treatment of unstable angina and myocardial infarction without a tooth Q in combination with acetylsalicylic acid.

    - Treatment of acute myocardial infarction with segment elevation ST in patients who are subject to drug treatment or subsequent percutaneous coronary intervention.

    Contraindications:

    - Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins.

    - Active large bleeding, as well as conditions and diseases in which there is a high risk of bleeding: threatening abortion, an aneurysm of the cerebral vessels or exfoliating aortic aneurysm (with the exception of cases of surgical intervention forthis), a recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia in combination with a positive test under conditions in vitro on antiplatelet antibodies in the presence of enoxaparin sodium.

    - It is not recommended to use the drug Clexane® for the purpose of preventing thrombosis in pregnant women with mechanical heart valves (lack of clinical experience).

    - Age to 18 years (effectiveness and safety not established).

    Carefully:

    Conditions in which there is a potential risk of bleeding:

    - hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease, etc.), severe vasculitis;

    - peptic ulcer of the stomach or duodenum or other erosive-ulcerative lesions of the gastrointestinal tract in the anamnesis;

    - recent ischemic stroke;

    - uncontrolled severe arterial hypertension;

    - diabetic or hemorrhagic retinopathy;

    - severe diabetes mellitus;

    - recent or alleged neurologic or ophthalmic surgery;

    - spinal or epidural anesthesia (potential risk of hematoma), spinal puncture (recently transferred);

    - recent childbirth;

    - endocarditis bacterial (acute or subacute);

    - pericarditis or pericardial effusion;

    - renal and / or liver failure;

    - intrauterine contraception (IUD);

    - severe trauma (especially the central nervous system), open wounds on large surfaces;

    - simultaneous reception of drugs that affect the hemostasis system;

    - heparin-induced thrombocytopenia (in the anamnesis) in combination with or without thrombosis.

    The company does not have data on the clinical use of Clexan® in the following diseases: active tuberculosis, radiation therapy (recently transferred).

    Pregnancy and lactation:

    Information about the fact that sodium enoxaparin penetrates the placental barrier during the second trimester of pregnancy in humans, no. There is no relevant information regarding the first and third trimester of pregnancy. Since there are no adequate and well-controlled studies in pregnant women,and animal studies do not always predict a reaction to the administration of sodium enoxaparin during pregnancy in humans, it should be used during pregnancy only when there is an urgent need for its use, as established by the doctor. It is not known whether the unchanged sodium enoxaparin in human milk. Breastfeeding should be discontinued during the treatment of the mother with Clexane®.

    Dosing and Administration:

    With the exception of special cases (see below, subsections "Treatment of myocardial infarction with segment elevation ST, medicamentous or by means of percutaneous coronary intervention "and" Prevention of thrombus formation in the system of extracorporeal circulation during hemodialysis "), sodium enoxaparin is deeply subcutaneously. Injections should preferably be performed in the patient's "lying" position. When using pre-filled syringes for 20 mg and 40 mg to avoid loss of the drug before the injection, do not remove air bubbles from the syringe. Injections should be performed alternately in the left or right anterolateral or posterolateral surface of the abdomen.

    The needle must be inserted the entire length vertically (not laterally) into the skin fold, collected and held until the injection is completed between the thumb and forefinger. Skin fold is released only after the injection is completed.

    Do not massage the injection site after injection. The pre-filled disposable syringe is ready for use. The drug can not be administered intramuscularly!

    Prevention of venous thrombosis and embolism during surgical interventions, especially in orthopedic and general surgical operations

    Patients with a moderate risk of developing thrombosis and embolism (eg, abdominal surgery) the recommended dose of Clexan® is 20 mg or 40 mg once daily subcutaneously. The first injection should be done 2 hours before surgery.

    Patients with a high risk of developing thrombosis and embolism (for example, in orthopedic operations) the drug is recommended at a dose of 40 mg once a day subcutaneously, with the administration of the first dose 12 hours before surgery, or at a dose of 30 mg twice a day with the onset of administration 12-24 hours after the operation.

    The duration of treatment with Clexan® is on average 7-10 days.If necessary, therapy can be continued as long as there is a risk of developing thrombosis and embolism, and until the patient goes into an outpatient setting.

    In orthopedic operations, it may be advisable after the initial therapy to continue treatment by administering Clexan® at a dose of 40 mg once daily for 3 weeks.

    Features of the use of Clexane® spinal / epidural anesthesia, as well as in coronary revascularization procedures, are described in the section "Special instructions".

    Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases The recommended dose of Clexan® is 40 mg once a day, subcutaneously, for at least 6 days. Therapy should be continued until the patient fully switches to an outpatient schedule (maximum for 14 days).

    Treatment of deep vein thrombosis with pulmonary embolism or without pulmonary arterial thromboembolism

    The drug is administered subcutaneously at a rate of 1.5 mg / kg body weight once a day or 1 mg / kg body weight twice a day.In patients with complicated thromboembolic disorders, the drug is recommended to be applied at a dose of 1 mg / kg twice a day.

    The average duration of treatment is 10 days. Immediately begin therapy with indirect anticoagulants, while treatment with Clexane® It is necessary to continue until therapeutic anticoagulant effect (values ​​of INR [International Normalized Relations] should be 2.03.0).

    Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis

    The recommended dose of Clexane® averages 1 mg / kg body weight. If there is a high risk of bleeding, the dose should be reduce to 0.5 mg / kg body weight with dual vascular access or up to 0.75 mg with single vascular access.

    In hemodialysis, Klexan® should be injected into the arterial region of the shunt at the beginning of the hemodialysis session. A single dose, as a rule, is sufficient for a four-hour session, however, if the fibrin rings are detected with a longer hemodialysis, the drug can be additionally administered at a dose of 0.5-1 mg / kg body weight.

    Treatment of unstable angina and myocardial infarction without a tooth Q

    The drug Clexan® is administered at a dose of 1 mg / kg body weight every 12 hours, subcutaneously, with simultaneous use of acetylsalicylic acid in a dose of 100-325 mg once a day.

    The average duration of therapy is at least 2 days and continues until the patient's clinical condition is stabilized. Usually, the drug is administered from 2 to 8 days.

    Treatment of acute myocardial infarction with segment elevation ST, medication or by percutaneous coronary intervention

    Treatment begins with a single intravenous bolus administration of enoxaparin sodium at a dose of 30 mg. Immediately after it, subcutaneously injected sodium enoxaparin in a dose of 1 mg / kg body weight. Next, the drug is administered subcutaneously at 1 mg / kg body weight every 12 hours (maximum 100 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 1 mg / kg of body weight for the remaining subcutaneous doses, i.e., with a body weight of more than 100 kg, single dose may exceed 100 mg).

    Patients 75 years of age or older do not have an initial intravenous bolus injection. The drug is administered subcutaneously at a dose of 0.75 mg / kg every 12 hours (maximum 75 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 0.75 mg / kg of body weight for the remaining subcutaneous doses, that is, with a body weight of more than 100 kg, a single dose may exceed 75 mg).

    When combined with thrombolytics (fibrin-specific and fibrin-nonspecific) sodium enoxaparin should be administered in the range from 15 minutes before the start of thrombolytic therapy and up to 30 minutes after it. As soon as possible after the detection of acute myocardial infarction with segment elevation ST, patients should be assigned simultaneously acetylsalicylic acid and, if there are no contraindications, taking acetylsalicylic acid (in doses of 75-325 mg) should be continued daily for at least 30 days.

    The recommended duration of treatment with Clexan® is 8 days or before discharge from the hospital (if the hospitalization period is less than 8 days).

    Intravenous bolus administration of sodium enoxaparin should be performed through a venous catheter. Sodium Enoxaparin should not be mixed or administered together with other medicinal products. In order to avoid the presence in the infusion system traces of other drugs and their interaction with enoxaparin sodium venous catheter should be flushed with a sufficient amount of 0.9% sodium chloride solution or 5% dextrose solution before and after an intravenous bolus of enoxaparin sodium. Sodium Enoxaparin can be safely administered with 0.9% sodium chloride solution and 5% dextrose solution.

    For the bolus administration of 30 mg of sodium enoxaparin in the treatment of acute myocardial infarction with segment elevation ST from glass syringes 60 mg, 80 mg and 100 mg remove the excess amount of the drug so that they remain only 30 mg (0.3 ml). A dose of 30 mg can be directly administered intravenously.

    Pre-filled syringes for subcutaneous administration of 60 mg, 80 mg and 100 mg can be used to perform an intravenous bolus injection of enoxaparin sodium through a venous catheter. It is recommended to use 60 mg syringes, as this reduces the amount of drug removed from the syringe. Syringes of 20 mg are not used, since they are not sufficient for bolus administration of 30 mg of enoxaparin sodium. 40 mg syringes are not used, as there are no fissions on them and it is therefore impossible to accurately measure the amount of 30 mg.

    In patients undergoing percutaneous coronary intervention, in the event that the last subcutaneous injection of enoxaparin sodium was performed less than 8 hours before the balloon catheter inserted into the narrowing of the coronary artery is inflated, no additional sodium enoxaparin is required.If the last subcutaneous injection of sodium enoxaparin was carried out more than 8 hours before the balloon catheter was inflated, an additional intravenous bolus injection of sodium enoxaparin at a dose of 0.3 mg / kg should be performed.

    To increase the accuracy of the additional intravenous bolus injection of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg / ml. Dilution of the solution is recommended immediately before administration.

    To obtain a solution of enoxaparin sodium at a concentration of 3 mg / ml with a prefilled syringe of 60 mg, it is recommended to use a container with an infusion solution of 50 ml (ie with 0.9% sodium chloride solution or 5% dextrose solution). 30 ml of the solution is removed from the container with the infusion solution using a conventional syringe. Sodium Enoxaparin (the contents of the syringe for subcutaneous administration of 60 mg) is introduced into the remaining 20 ml infusion solution. The contents of the container with diluted sodium enoxaparin solution are gently mixed. For administration by means of a syringe, the required volume of the diluted solution of sodium enoxaparin is extracted, which is calculated by the formula:

    Volume of reconstituted solution = Body weight of the patient (kg) x 0.1 or using the table below.

    Volumes to be administered intravenously after reconstitution

    Body weight of the patient [kg]

    The required dose (0.3 mg / kg) [mg]

    The volume of the solution diluted to a concentration of 3 mg / ml

    45

    13,5

    4,5

    50

    15

    5

    55

    16,5

    5,5

    60

    18

    6

    65

    19,5

    6,5

    70

    21

    7

    75

    22,5

    7,5

    80

    24

    8

    85

    25,5

    8,5

    90

    27

    9

    95

    28,5

    9,5

    100

    30

    10

    Dosage regimen for specific patient groups

    Elderly patients

    Except for the treatment of myocardial infarction with segment elevation ST (see above) for all other indications of reduced doses of enoxaparin sodium in elderly patients, if they have no renal dysfunction, is not required.

    Patients with impaired renal function

    Severe renal impairment (creatinine clearance less than 30 mL / min) The dose of sodium enoxaparin is reduced in accordance with the tables presented below, since these patients have an increase in the system exposure (duration of action) of the drug.

    When using the drug with a therapeutic purpose, the following correction of the dosing regimen is recommended:

    The usual dosing regimen

    Dosing regimen for severe renal failure

    1 mg / kg body weight subcutaneously twice a day

    1 mg / kg body weight subcutaneously once a day

    1.5 mg / kg body weight subcutaneously once a day

    1 mg / kg body weight subcutaneously once a day

    Treatment of acute myocardial infarction with segment elevation ST in patients younger than 75 years

    A single intravenous bolus injection of 30 mg plus 1 mg / kg body weight subcutaneously; followed by subcutaneous administration at a dose of 1 mg / kg body weight twice a day (maximum 100 mg for each of the first two subcutaneous injections)

    A single intravenous bolus

    administration of 30 mg plus 1 mg / kg body weight

    body subcutaneously; followed by

    subcutaneous administration at a dose of 1 mg / kg

    body weight once a day

    (max. 100 mg only for

    first subcutaneous injection)

    Treatment of acute myocardial infarction with ST-segment elevation in patients 75 years and older

    0.75 mg / kg body weight subcutaneously

    twice a day without an initial

    intravenous bolus

    administration (maximum 75 mg

    for each of the first two

    subcutaneous injections)

    1 mg / kg body weight subcutaneously once

    per day without an initial intravenous

    bolus administration (maximally

    100 mg only for the first subcutaneous

    injections)

    When using the drug for prophylactic purposes, in patients with a moderate risk of thromboembolic complications, correction of the dosing regimen is recommended,presented in the table below.

    The usual dosing regimen

    Dosing regimen for severe renal failure

    40 mg subcutaneously once daily

    20 mg subcutaneously once daily

    20 mg subcutaneously once daily

    20 mg subcutaneously once daily

    The recommended dosage adjustment is not used for hemodialysis.

    With a mild (creatinine clearance 50-80 ml / min) and moderate (creatinine clearance 30-50 ml / min), renal dysfunction

    Dose adjustments are not required, but patients should be under close medical supervision.

    Patients with hepatic impairment

    Due to the lack of clinical studies, Clexan® should be used with caution in patients with impaired hepatic function.

    Side effects:

    A study of the side effects of sodium enoxaparin was conducted in more than 15,000 patients who participated in clinical trials, of which 1776 patients had venous thrombosis and embolism prophylaxis for general surgical and orthopedic operations; in 1169 patients prevention of venous thrombosis and embolism in patients on bed rest, due to acute therapeutic diseases; 559patients - in the treatment of deep vein thrombosis with pulmonary embolism or pulmonary embolism; in 1578 patients - in the treatment of unstable angina and myocardial infarction without a tooth Q; in 10176 patients - in the treatment of myocardial infarction with segment elevation ST. The mode of administration of sodium enoxaparin differed depending on the indications. In the prophylaxis of venous thrombosis and embolisms with general surgery and orthopedic surgery, or in patients on bedrest, was injected 40 mg subcutaneously once per day. In the treatment of deep vein thrombosis with or without pulmonary embolism, patients received sodium enoxaparin at the rate of 1 mg / kg body weight subcutaneously every 12 hours or 1.5 mg / kg body weight subcutaneously once a day. In the treatment of unstable angina and myocardial infarction without a tooth Q the dose of enoxaparin sodium was 1 mg / kg body weight subcutaneously every 12 hours, and in the case of myocardial infarction with segment elevation ST an intravenous bolus injection of 30 mg was administered followed by 1 mg / kg body weight subcutaneously every 12 hours.

    Adverse reactions were classified according to frequency of occurrence as follows: very frequent (≥1 / 10), frequent (≥1 / 100 - <1/10), infrequent (≥1 / 1000 - <1/100)rare (≥1 / 10000 - <1/1000), very rare (<1/10000), or the frequency is unknown (according to available data, the frequency of occurrence of an undesirable reaction can not be estimated). The undesirable reactions observed after the release of the drug on the market were assigned to the frequency of "frequency unknown."

    Vascular disorders

    Bleeding

    In clinical studies, bleeding was the most common adverse reaction. These included large bleeding observed in 4.2% of patients (bleeding was considered large if accompanied by a decrease in hemoglobin content of 2 g / l or more, requiring transfusion of 2 or more doses of blood components, and also if it was retroperitoneal or intracranial ). Some of these cases were lethal.

    As with the use of other anticoagulants with sodium enoxaparin, bleeding may occur, especially in the presence of risk factors that contribute to the development of bleeding, during invasive procedures or the use of drugs that disrupt hemostasis (see the sections on "Specific guidance" and "Interaction with other drugs" ).

    In describing bleeding below the sign "*" means a reference to the following types of haemorrhage: hematoma, ecchymosis (except perhaps at the injection site), wound hematoma, hematuria, epistaxis, gastrointestinal bleeding.

    Very Frequent

    Bleeding * in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism.

    Frequent

    Bleeding * in the prevention of venous thrombosis in patients on bed rest, and in the treatment of unstable angina, myocardial infarction without a tooth Q and myocardial infarction with segment elevation ST.

    Infrequent

    Retrosternal bleeding and intracranial hemorrhage in patients with deep vein thrombosis with thromboembolic pulmonary disease arteries or without it, as well as in the treatment of myocardial infarction with segment elevation ST.

    Rare

    Retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina and myocardial infarction without a tooth Q.

    Thrombocytopenia and thrombocytosis

    Very Frequent

    Thrombocytosis (the number of platelets in the peripheral blood is more than 400x109/ l) in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism.

    Frequent

    Thrombocytosis in the treatment of patients with acute myocardial infarction with segment elevation ST.

    Thrombocytopenia in the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with or without pulmonary embolism, as well as with acute myocardial infarction with segment elevation ST.

    Infrequent

    Thrombocytopenia in the prevention of venous thrombosis in patients on bed, and in the treatment of unstable angina and myocardial infarction without a tooth Q.

    Very rare

    Immuno-allergic thrombocytopenia in the treatment of patients with acute myocardial infarction with segment elevation ST.

    Other clinically relevant adverse reactions, regardless of the indications - These undesirable reactions, presented below, are grouped according to the system-organ classes, are given with an indication defined above the frequency of their occurrence and in order of decreasing their severity.

    Immune system disorders

    Frequent

    Allergic reactions.

    Rare

    Anaphylactic and anaphylactoid reactions (see also below "Data obtained after the release of the drug on the market").

    Disturbances from the liver and bile ducts

    Very Frequent

    Increased activity of "liver" enzymes, mainly, an increase in the activity of transaminases, more than three times the upper limit of the norm).

    Disturbances from the skin and subcutaneous tissues

    Frequent

    Hives, itching, erythema.

    Infrequent

    Bullous dermatitis.

    General disorders and disorders at the injection site

    Frequent

    Hematoma at the injection site, pain at the injection site, edema at the injection site, bleeding, hypersensitivity reactions, inflammation, the formation of seals at the injection site.

    Infrequent

    Irritation at the injection site, skin necrosis at the injection site.

    Laboratory and instrumental data

    Rare

    Hyperkalemia.

    Data obtained after the release of the drug on the market

    The following undesirable reactions were noted during the post-marketing application of the Clexan® preparation. There were spontaneous reports of these adverse reactions, and their frequency was defined as "the frequency is unknown" (it can not be established from the available data).

    Immune system disorders

    Anaphylactic / anaphylactoid reactions, including shock.

    Disturbances from the nervous system

    Headache.

    Vascular disorders

    When sodium enoxaparin was applied against the background of spinal / epidural anesthesia or spinal puncture, there were cases of development of spinal hematoma (or neuraxial hematoma). These reactions lead to the development of neurological disorders of varying severity, including permanent or irreversible paralysis (see. The "Special instructions").

    Violations from the blood or lymphatic system

    Hemorrhagic anemia.

    Cases of development of immune-allergic thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of an infarction of organs or ischemia of the extremities (see section "Special instructions", subsection "Control of the number of platelets in peripheral blood".

    Eosinophilia.

    Disturbances from the skin and subcutaneous tissues

    At the injection site, skin vasculitis, skin necrosis, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful) can develop. In these cases, therapy with Clexane® should be discontinued.

    Possible formation of solid inflammatory nodules-infiltrates at the injection site of the drug, which disappear after a few days and are not grounds for drug withdrawal.

    Alopecia.

    Disturbances from the liver and bile ducts

    Hepatocellular liver damage.

    Cholestatic liver damage.

    Disturbances from musculoskeletal and connective tissue

    Osteoporosis with long-term therapy (more than three months).

    Overdose:

    Accidental overdose of Kleksan with intravenous, extracorporeal or subcutaneous application can lead to hemorrhagic complications. When ingested, even large doses of absorption of the drug is unlikely.

    Anticoagulant effects can generally be neutralized by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of Kleksan administered. One mg (1 mg) of protamine sulfate neutralizes the anticoagulant effect of one mg (1 mg) of Kleksan (see information on the use of protamine salts), if sodium enoxaparin was administered no more than 8 hours before the introduction of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of Kleksan,if more than 8 hours have elapsed since the introduction of the latter, or if a second dose of protamine is needed. If after the introduction sodium enoxaparin passed 12 or more hours, the introduction of protamine is not required. However, even with the administration of large doses of protamine sulfate, anti-Xa activity of Kleksana is not completely neutralized (by up to 60%).
    Interaction:

    The drug Clexane ® can not be mixed with other drugs!

    While the use of drugs affecting hemostasis (salicylates systemic action of acetylsalicylic acid, nonsteroidal antiinflammatory drugs [including ketorolac], dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids, thrombolytic or anticoagulant and other antiplatelet drugs [including glycoprotein antagonists IIb/IIIa]), the risk of bleeding increases (see "Special instructions").

    Special instructions:

    Are common

    Low molecular weight heparins are not interchangeable, since they differ in the production process, molecular weight, specific anti-Xa activity, dosage units and dosage regimen,with which differences in their pharmacokinetics and biological activity are associated (antithrombin activity and interaction with platelets). Therefore, it is required to strictly follow the recommendations for use for each drug belonging to the class of low molecular weight heparins.

    Bleeding

    As with the use of other anticoagulants, with the introduction of the drug Kleksan ® possible development of bleeding of any location (see section "Side effect"). With the development of bleeding it is necessary to find its source and prescribe the appropriate treatment.

    Bleeding in elderly patients

    When using the drug Clexane® in prophylactic doses in elderly patients there was no increased risk of bleeding.

    When using the drug in therapeutic doses in elderly patients (especially at the age of 80 years and older) there is an increased

    risk of bleeding. It is recommended that careful monitoring of the condition of such patients is made (see the section "Pharmacokinetics" and the section "Dosing and Administration", subsection "Patients of advanced age").

    Simultaneous use of other drugs, influencing hemostasis

    It is recommended that the use of drugs that affect hemostasis (salicylates, including acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including ketorolac; dextran with a molecular mass of 40 kD, ticlopidine, clopidogrel; glucocorticosteroid preparations, thrombolytic agents, anticoagulants, antiplatelet agents, including glycoprotein receptor antagonists IIb/IIIa), was discontinued before treatment with enoxaparin sodium, except when their use is necessary. If combinations of sodium enoxaparin with these drugs are shown, careful clinical observation and monitoring of relevant laboratory parameters should be carried out.

    Renal insufficiency

    In patients with impaired renal function, there is a risk of bleeding as a result of an increase in the systemic exposure of enoxaparin sodium.

    In patients with severe renal dysfunction (creatinine clearance less than 30 ml / min), there is a significant increase in exposure to sodium enoxaparin, so it is recommended to dose adjustments for both prophylactic and therapeutic use of the drug.Although dose adjustment is not required in patients with mild or moderate renal impairment (creatinine clearance 30-50 ml / min or 50-80 ml / min), careful monitoring of the condition of such patients is recommended (see Sections "Pharmacokinetics" and "Method of administration and dose", subsection "Patients with renal insufficiency").

    Low body weight

    An increase in the exposure of sodium enoxaparin was noted for its preventive use in women weighing less than 45 kg and for men weighing less than 57 kg, which may lead to an increased risk of bleeding. It is recommended that careful monitoring of the condition of such patients is made.

    Patients with obesity

    Patients with obesity have an increased risk of developing thrombosis and embolism. The safety and effectiveness of the use of enoxaparin sodium in prophylactic doses in obese patients (BMI more than 30 kg / m) is not fully defined and there is no general consensus on dose adjustment. These patients should be closely monitored for the development of symptoms and signs of thrombosis and embolism.

    Control of the number of platelets in the peripheral blood

    The risk of developing antibody-mediated heparin-induced thrombocytopenia exists even when low molecular weight heparins are used. If thrombocytopenia develops, it is usually detected between the 5th and 21st days after initiation of sodium enoxaparin therapy. In this regard, it is recommended that the number of platelets in the peripheral blood be monitored regularly before treatment with Clexan® and during its use. In the presence of a confirmed significant decrease in the number of platelets (by 30-50% compared with the initial index), it is necessary to immediately cancel sodium enoxaparin and transfer the patient to another therapy.

    Spinal / epidural anesthesia

    The cases of occurrence of neuroaxial hematomas with the use of Clexan® while carrying out spinal / epidural anesthesia with the development of long-lasting or irreversible paralysis. The risk of occurrence of these phenomena decreases with the use of the drug in a dose of 40 mg or lower. The risk increases with the use of higher doses of Clexane®, as well as with the use of permanent catheters after surgery,or with the simultaneous use of additional drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (see "Interactions with Other Drugs"). The risk also increases with a traumatically performed or repeated spinal puncture or in patients who have a history of referring to the transferred operations in the spine or deformity of the spine.

    To reduce the possible risk of bleeding associated with the use of sodium enoxaparin and epidural or spinal anesthesia / analgesia, it is necessary to take into account the pharmacokinetic profile of the drug (see the section "Pharmacokinetics"). It is better to install or remove a catheter with a low anticoagulant effect of enoxaparin sodium, but the exact time to achieve a sufficient reduction in the anticoagulant effect in different patients is unknown. The installation or removal of the catheter should be performed at least 12 hours after the administration of lower doses of Clexan® (20 mg once daily, 30 mg once or twice daily, 40 mg once daily) and, at a minimum,24 hours after the administration of higher doses of Clexan® (0.75 mg / kg body weight twice a day, 1 mg / kg body weight twice a day, 1.5 mg / kg body weight once a day). At these time points, the anti-Xa activity of the drug still continues to be detected, and the time delays are not a guarantee that the development of the neuroaxial hematoma will be avoided. Patients receiving sodium enoxaparin in doses of 0.75 mg / kg body weight twice in day or 1 mg / kg of body weight twice a day, with this (twice-daily) dosing regimen, do not enter the second dose, in order to increase the interval before installing or replacing the catheter. Similarly, consideration should be given to the possibility of delaying the introduction of the next dose of the drug for at least 4 hours, based on an assessment of the benefit / risk ratio (risk of thrombosis and bleeding during the procedure, taking into account the presence of risk factors in patients). However, it is not possible to give clear recommendations on the timing of the next dose of enoxaparin sodium after removal of the catheter. It should be noted that in patients with creatinine clearance less than 30 ml / min, the excretion of sodium enoxaparin is slowed.Therefore, this category of patients should consider doubling the time from catheter removal: at least 24 hours for lower doses of enoxaparin sodium (30 mg once daily) and at least 48 hours for higher doses (1 mg / kg of body weight per day).

    If anticoagulant therapy is used as prescribed by the doctor during epidural / spinal anesthesia or lumbar puncture, constant monitoring of the patient is necessary to detect any neurological symptoms such as back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), violation function of the intestine and / or bladder. The patient should be instructed about the need to inform the doctor immediately if any of the above symptoms occur. When suspected of the symptoms characteristic of the hematoma of the spinal cord, urgent diagnosis and treatment is needed, including, if necessary, decompression of the spinal cord.

    Heparin-induced thrombocytopenia

    With extreme caution, Cexan® should be used in patients who have a history of heparin-induced thrombocytopenia in combination with or without thrombosis.The risk of developing heparin-induced thrombocytopenia can persist for several years. If anamnesis is presumed to have heparin-induced thrombocytopenia, then platelet aggregation assays in vitro are of limited importance in forecasting the risk of its development. The decision on the use of Clexane ® in this case can be taken only after consultation with the appropriate specialist.

    Percutaneous coronary angioplasty

    In order to minimize the risk of bleeding associated with invasive vascular instrumental manipulation in the treatment of unstable angina and myocardial infarction without a tooth Q and acute myocardial infarction with segment elevation ST, these procedures should be performed in the intervals between the administration of Clexane®. This is necessary in order to achieve hemostasis after percutaneous coronary intervention. When using a closure device, the introducer of the femoral artery can be removed immediately. When manual (manual) compression is used, the femoral artery introducer should be removed 6 hours after the last intravenous or subcutaneous injection of sodium enoxaparin.If sodium enoxaparin treatment is continued, the next dose should be administered no earlier than 6-8 hours after removal of the femoral artery introducer. It is necessary to monitor the place of introduction of the introducer, in order to detect signs of bleeding and formation of a hematoma in time.

    Patients with mechanical heart valves

    The use of the drug Clexan® for the prevention of thrombosis in patients with mechanical heart valves has been studied insufficiently. There are separate reports on the development of thrombosis of heart valves in patients with mechanical heart valves on the background of therapy with enoxaparin sodium for the prevention of thrombosis. Assessment of these reports is limited due to the presence of competing factors contributing to the development of thrombosis of artificial heart valves, including the underlying disease, and because of the lack of clinical data.

    Pregnant women with mechanical artificial heart valves

    The use of the drug Clexane for the prevention of thrombosis in pregnant women with mechanical artificial heart valves has been studied insufficiently.In a clinical study of pregnant women with mechanical heart valves using sodium enoxaparin at a dose of 1 mg / kg body weight twice a day to reduce the risk of thrombosis and embolism, 2 of 8 women developed thrombi that led to the blocking of the heart valves and to the death of the mother and the fetus.

    There are separate post-marketing reports on thrombosis of heart valves in pregnant women with mechanical heart valves treated with enoxaparin for the prevention of thrombosis.

    Pregnant women with mechanical artificial heart valves have a high risk of developing thrombosis and embolism.

    Laboratory Tests

    In doses used to prevent thromboembolic complications, the drug Clexane® does not significantly affect the time bleeding and blood coagulation, as well as platelet aggregation or binding to fibrinogen.

    When the dose is raised, the APTT and the activated clotting time can be prolonged. The increase in APTT and the activated clotting time are not in a direct linear relationship with the increase in anticoagulant activity of the drug, so there is no need to monitor them.

    Prevention of venous thrombosis and embolism in patients with acute therapeutic diseases, who are in bed

    In the case of acute infection, acute rheumatic conditions, the prophylactic use of sodium enoxaparin is justified only if the above conditions are combined with one of the following risk factors for venous thrombus formation:

    - age over 75 years;

    - malignant neoplasms;

    - thrombosis and embolism in the anamnesis;

    - obesity;

    - hormonal therapy;

    - heart failure;

    - chronic respiratory failure.

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

    The drug Clexane® does not affect the ability to drive vehicles and mechanisms.

    Form release / dosage:Solution for Injection 2000 anti-Ha IU / 0.2 ml; 4000 anti-Ha IU / 0.4 mL; 6000 anti-Ha IU / 0.6 mL; 8000 anti-Ha IU / 0.8 ml; 10,000 anti-Ha IU / 1 ml.
    Packaging:

    1 kind of packing

    For 0.2 ml or 0.4 ml or 0.6 ml or 0.8 ml or 1.0 ml solution of the drug in a glass syringe (type I) respectively. 2 syringes per blister. For 1 or 5 blisters together with instructions for use in a cardboard box.

    2 type of packaging

    For 0.2 ml or 0.4 ml or 0.6 ml or 0.8 ml or 1.0 ml solution of the drug in a glass syringe (type I) with a protective needle system, respectively. 2 syringes per blister. For 1 or 5 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature not higher than + 25 ° С.

    Keep out of the reach of children!

    Shelf life:3 of the year. After the expiration date, the drug should not be used.
    Terms of leave from pharmacies:On prescription
    Registration number:П N014462 / 01
    Date of registration:18.09.2008 / 08.12.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:Sanofi-Aventis FranceSanofi-Aventis France France
    Manufacturer: & nbsp
    Representation: & nbspSanofi Aventis GroupSanofi Aventis Group
    Information update date: & nbsp17.09.2016
    Illustrated instructions
    Instructions
    Up