Indications for the use of Clexane, clinical effectiveness, instructions for use and contraindications. Clexane: instructions for use, analogues and reviews, prices in Russian pharmacies
*registered by the Ministry of Health of the Russian Federation (according to grls.rosminzdrav.ru)
INSTRUCTIONS
on the use of the drug
for medical use Clexane ®
Registration number:
P No. 014462/01.Tradename:
Clexane ® .International nonproprietary name:
enoxaparin sodium.Dosage form:
injection.Composition per syringe
Dosage 2000 anti-Xa IU/0.2 ml (equivalent to 20 mg/0.2 ml)Dosage 4000 anti-Xa IU/0.4 ml (equivalent to 40 mg/0.4 ml )
Dosage 6000 anti-Xa IU/0.6 ml (equivalent to 60 mg/0.6 ml)
Dosage 8000 anti-Xa IU/0.8 ml (equivalent to 80 mg/0.8 ml)
Dosage 10,000 anti-Xa/1 ml (equivalent to 100 mg/1 ml)
* - weight calculated based on the content of sodium enoxaparin used (theoretical activity 100 anti-Xa IU/mg).
Description: transparent, colorless to pale yellow solution.
Pharmacotherapeutic group:
direct acting anticoagulant.ATX code- В01АВ05.
Pharmacological properties
CharacteristicEnoxaparin sodium - low molecular weight heparin with an average molecular weight of about 4,500 daltons: less than 2000 daltons -<20%, от 2000 до 8000 дальтон - >68%, more than 8000 daltons -<18%. Эноксапарин натрия получают щелочным гидролизом бензилового эфира гепарина, выделенного из слизистой оболочки тонкой кишки свиньи. Его структура характеризуется невосстанавливающимся фрагментом 2-О-сульфо-4-енпиразиносуроновой кислоты и восстанавливающимся фрагментом 2-N,6-О-дисульфо-D-глюкопиранозида. Структура эноксапарина натрия содержит около 20% (в пределах от 15% до 25%) 1,6-ангидропроизводного в восстанавливающемся фрагменте полисахаридной цепи.
Pharmacodynamics
In a clean system in vitro Enoxaparin sodium has high anti-Xa activity (approximately 100 IU/ml) and low anti-IIa or antithrombin activity (approximately 28 IU/ml). This anticoagulant activity acts through antithrombin III (AT-III) to provide anticoagulant activity in humans. In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified both in healthy humans and patients, and in animal models. This includes AT-III dependent inhibition of other coagulation factors such as factor VIIa, activation of tissue factor pathway inhibitor (TFP) release, and decreased release of von Willebrand factor from the vascular endothelium into the bloodstream. These factors provide the anticoagulant effect of enoxaparin sodium in general. When used in prophylactic doses, it slightly changes the activated partial thromboplastin time (aPTT) and has virtually no effect on platelet aggregation and the degree of fibrinogen binding to platelet receptors. Anti-IIa activity in plasma is approximately 10 times lower than anti-Xa activity. The average maximum anti-IIa 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 body weight when administered twice and 1.5 mg/kg body weight with a single injection, respectively. The average maximum anti-Xa activity of plasma 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 the indicated dosage regimens is linear. Variability within and between patient groups is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once daily and subcutaneous administration of enoxaparin sodium at a dose of 1.5 mg/kg body weight once daily in healthy volunteers, equilibrium concentrations are achieved by day 2, with an area under the pharmacokinetic curve of an average of 15 % higher than after a single injection. After repeated subcutaneous administrations of enoxaparin sodium at a daily dose of 1 mg/kg body weight twice a day, the equilibrium concentration is achieved after 3-4 days, and the area under the pharmacokinetic curve is on average 65% higher than after a single dose, and the average values of maximum concentrations are 1.2 IU/ml and 0.52 IU/ml, respectively. The bioavailability of enoxaparin sodium when administered subcutaneously, assessed on the basis of anti-Xa activity, is close to 100%. The volume of distribution of the anti-Xa activity of enoxaparin sodium is approximately 5 liters and approaches the volume of blood. Enoxaparin sodium is a drug with low clearance. After intravenous administration for 6 hours at a dose of 1.5 mg/kg body weight, the average clearance of anti-Xa in plasma is 0.74 l/hour.
Elimination 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 primarily metabolized in the liver by desulfation and/or depolymerization to form low molecular weight substances with very low biological activity. Renal 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. There may be a delay in the elimination of enoxaparin sodium in elderly patients as a result of decreased renal function with age. A decrease in the clearance of enoxaparin sodium was noted in patients with reduced renal function. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once daily, there is an increase in anti-Xa activity, represented by the area under the pharmacokinetic curve in patients with minor (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 at equilibrium is on average 65% higher with repeated subcutaneous administration of 40 mg of the drug once daily. In people with excess body weight, when the drug is administered subcutaneously, the clearance is slightly less. If you do not adjust the dose taking into account the patient's body weight, then after a single subcutaneous injection 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 to patients with normal average body weight.
Indications for use
Contraindications
Carefully use for the following conditions:
The company does not have data on the clinical use of the drug Clexan ® for the following diseases: active tuberculosis, radiation therapy (recently undergone)
Pregnancy and breastfeeding period
There is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy in humans. There is no relevant information regarding the first and third trimesters of pregnancy. Since there are no adequate and well-controlled studies in pregnant women, and animal studies do not always predict the response to enoxaparin sodium during pregnancy in humans, it should be used during pregnancy only when there is an urgent need for its use, as determined by a physician. .It is unknown whether unchanged enoxaparin sodium is excreted into breast milk in humans. Breastfeeding should be stopped while the mother is being treated with Clexane ® .
Directions for use and doses
Except in special cases (see below) “Treatment of myocardial infarction with ST-segment elevation, medication or using percutaneous coronary intervention” and “Prevention of thrombus formation in the extracorporeal circulatory system during hemodialysis”), enoxaparin sodium is injected deep subcutaneously. It is advisable to carry out injections with the patient lying down. When using pre-filled 20 mg and 40 mg syringes, do not remove air bubbles from the syringe before injection to avoid loss of the drug. Injections should be performed alternately into the left or right anterolateral or posterolateral surface of the abdomen. The needle must be inserted vertically (not from the side) into the skin fold for its entire length, collected and held until the injection is completed between the thumb and forefinger. The skin fold is released only after the injection is completed. Do not massage the injection site after administering the drug.The pre-filled disposable syringe is ready for use. The drug cannot be administered intramuscularly! Prevention of venous thrombosis and embolism during surgical interventions, especially during orthopedic and general surgical operations
For patients with a moderate risk of developing thrombosis and embolism (general surgery), the recommended dose of Clexane ® is 20 mg once a day subcutaneously. The first injection is given 2 hours before surgery. For patients with a high risk of developing thrombosis and embolism (general surgical and orthopedic operations), the drug is recommended at a dose of 40 mg once a day subcutaneously, the first dose is administered 12 hours before surgery, or 30 mg twice a day with the start of administration after 12-24 hours after surgery.
The duration of treatment with Clexane ® is on average 7-10 days. If necessary, therapy can be continued as long as the risk of thrombosis and embolism remains (for example, in orthopedics, Clexane ® is prescribed at a dose of 40 mg once a day for 5 weeks).
Features of the administration of Clexane ® during spinal/epidural anesthesia, as well as during coronary revascularization procedures, are described in the “Special Instructions” section.
Prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases
The recommended dose of Clexane ® is 40 mg once daily subcutaneously for 6-14 days.
Treatment of deep vein thrombosis with or without pulmonary embolism
The drug is administered subcutaneously at a dose of 1.5 mg/kg body weight once a day or at a dose of 1 mg/kg body weight twice a day. In patients with complicated thromboembolic disorders, the drug is recommended to be used at a dose of 1 mg/kg twice a day.
The average duration of treatment is 10 days. It is advisable to immediately begin therapy with indirect anticoagulants, while therapy with Clexane ® must be continued until a sufficient anticoagulant effect is achieved, i.e. the international normalized ratio (INR) should be 2.0-3.0.
Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis
The dose of Clexane ® is on average 1 mg/kg body weight. If there is a high risk of bleeding, the dose should be reduced to 0.5 mg/kg body weight with double vascular access or 0.75 mg with single vascular access. During hemodialysis, the drug should be injected into the arterial site of the shunt at the beginning of the hemodialysis session. One dose is usually sufficient for a four-hour session, however, if fibrin rings are detected during longer hemodialysis, you can additionally administer the drug at the rate of 0.5-1 mg/kg body weight.
Treatment of unstable angina and non-Q wave myocardial infarction
Clexane ® is administered at a rate of 1 mg/kg body weight every 12 hours subcutaneously, with simultaneous use of acetylsalicylic acid at a dose of 100-325 mg once a day.
The average duration of therapy is 2-8 days (until the patient’s clinical condition stabilizes).
Treatment of ST-segment elevation myocardial infarction, medical or percutaneous coronary intervention
Treatment begins with an intravenous bolus injection of enoxaparin sodium at a dose of 30 mg and immediately after it (within 15 minutes) subcutaneous administration of enoxaparin sodium at a dose of 1 mg/kg is carried out (and during the first two subcutaneous injections, a maximum of 100 mg of enoxaparin sodium can be administered ). Then all subsequent subcutaneous doses are administered every 12 hours at a rate of 1 mg/kg body weight (that is, for body weight more than 100 kg, the dose may exceed 100 mg). In persons 75 years of age and older, the initial intravenous bolus is not used. Enoxaparin sodium is administered subcutaneously at a dose of 0.75 mg/kg every 12 hours (and during the first two subcutaneous injections, a maximum of 75 mg of enoxaparin sodium can be administered). Then all subsequent subcutaneous doses are administered every 12 hours at a rate of 0.75 mg/kg body weight (i.e., for people weighing more than 100 kg, the dose may exceed 75 mg).
When combined with thrombolytics (fibrin-specific and fibrin-nonspecific), enoxaparin sodium should be administered within 15 minutes. before the start of thrombolytic therapy up to 30 minutes. after her. As soon as possible after detection of acute ST-segment elevation myocardial infarction, acetylsalicylic acid should be started simultaneously and, unless contraindicated, should be continued for at least 30 days at doses of 75 to 325 mg daily. The recommended duration of treatment with the drug is 8 days or until the patient is discharged from the hospital if the period of hospitalization is less than 8 days. Bolus administration of enoxaparin sodium should be administered through a venous catheter and enoxaparin sodium should not be mixed or administered with other drugs. In order to avoid the presence of traces of other drugs in the system and their interaction with enoxaparin sodium, the venous catheter should be flushed with a sufficient amount of 0.9% sodium chloride solution or dextrose before and after an intravenous bolus of enoxaparin sodium. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution and 5% dextrose solution.
To administer a 30 mg bolus of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, excess drug is removed from 60 mg, 80 mg and 100 mg glass syringes so that only 30 mg (0.3 ml) remains. A dose of 30 mg can be administered directly intravenously.
For intravenous bolus administration of enoxaparin sodium through a venous catheter, pre-filled syringes for subcutaneous administration of the drug 60 mg, 80 mg and 100 mg can be used. It is recommended to use 60 mg syringes as this reduces the amount of drug removed from the syringe. 20 mg syringes are not used because they do not contain enough drug to administer a 30 mg bolus of enoxaparin sodium. 40 mg syringes are not used because they do not have graduations and therefore it is impossible to accurately measure the amount of 30 mg.
In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of enoxaparin sodium was given less than 8 hours before inflating the balloon catheter inserted into the site of narrowing of the coronary artery, additional administration of enoxaparin sodium is not required. If the last subcutaneous injection of enoxaparin sodium was carried out more than 8 hours before inflating the balloon catheter, an additional intravenous bolus of enoxaparin sodium should be administered at a dose of 0.3 mg/kg.
To improve the accuracy of additional bolus administration 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. It is recommended to dilute the solution immediately before use. To obtain a 3 mg/mL enoxaparin sodium solution using a 60 mg prefilled syringe, it is recommended to use a 50 mL infusion solution container (i.e., 0.9% sodium chloride solution or 5% dextrose solution). 30 ml of solution is removed and removed from the container with the infusion solution using a regular syringe. Enoxaparin sodium (contents of the syringe for subcutaneous administration is 60 mg) is injected into the remaining 20 ml of infusion solution in the container. The contents of the container with a diluted solution of enoxaparin sodium are carefully mixed. For administration, the required volume of diluted enoxaparin sodium solution is extracted using a syringe, which is calculated using the formula: Volume of diluted solution = Patient’s body weight (kg) x 0.1 or using the table below.
Volumes to be administered intravenously after dilution
| Patient's body weight [kg] | Required dose (0.3 mg/kg) [mg] | The volume of solution required for administration, diluted to a concentration of 3 mg/ml [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 |
With the exception of the treatment of ST-segment elevation myocardial infarction (see above), for all other indications, dose reduction of enoxaparin sodium is not required in elderly patients unless they have impaired renal function.
Patients with kidney failure
The dose of enoxaparin sodium is reduced according to the tables below as drug accumulation occurs in these patients.
When using the drug for therapeutic purposes, the following dosage adjustment is recommended:
| Usual dosage regimen | Dosage regimen for severe renal failure |
| 1 mg/kg subcutaneously 2 times a day | 1 mg/kg subcutaneously once daily |
| 1.5 mg subcutaneously once daily | 1 mg/kg subcutaneously once daily |
| Treatment of acute myocardial infarction with ST segment elevation in patients<75 лет | |
| Single dose: bolus intravenous administration of 30 mg plus 1 mg/kg subcutaneously; followed by subcutaneous administration at a dose of 1 mg/kg twice daily (maximum 100 mg for each of the first two subcutaneous injections) | Single dose: bolus intravenous administration of 30 mg plus 1 mg/kg subcutaneously; followed by subcutaneous administration at a dose of 1 mg/kg once daily (maximum 100 mg for the first subcutaneous injection) |
| Treatment of acute ST-segment elevation myocardial infarction in patients ≥75 years of age | |
| 0.75 mg/kg subcutaneously twice daily without initial bolus (maximum 75 mg for each of the first two subcutaneous injections) | 1 mg/kg subcutaneously once daily without initial bolus (maximum 100 mg for first subcutaneous injection) |
When using the drug for prophylactic purposes, the following dosage adjustment is recommended:
No dose adjustment is required, but laboratory monitoring of therapy should be carried out more carefully.
Patients with liver failure
Due to the lack of clinical studies, caution should be exercised when prescribing enoxaparin sodium to patients with impaired liver function.
Side effect
The study of the side effects of enoxaparin sodium was carried out in more than 15,000 patients participating in clinical studies, of which 1,776 patients - in the prevention of venous thrombosis and embolism during general surgery and orthopedic operations; in 1169 patients - for the prevention of venous thrombosis and embolism in patients on bed rest due to acute therapeutic diseases; in 559 patients - in the treatment of deep vein thrombosis with pulmonary embolism or without pulmonary embolism; in 1578 patients - in the treatment of unstable angina and myocardial infarction without a Q wave; in 10,176 patients - in the treatment of myocardial infarction with ST segment elevation. The mode of administration of enoxaparin sodium differed depending on the indication. For the prevention of venous thrombosis and embolism during general surgical and orthopedic operations or in patients on bed rest, 40 mg was administered subcutaneously once a day. For the treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium at a dose of 1 mg/kg body weight subcutaneously every 12 hours or 1.5 mg/kg body weight subcutaneously once daily. In the treatment of unstable angina and non-Q wave myocardial infarction, the dose of enoxaparin sodium was 1 mg/kg body weight subcutaneously every 12 hours, and in the case of ST-segment elevation myocardial infarction, an intravenous bolus of 30 mg was administered followed by 1 mg/kg body weight subcutaneously every 12 hoursAdverse reactions were classified by frequency of occurrence in the following way: very common (≥1/10), frequent (≥1/100-<1/10), нечастые (≥1/1000-<1/100), редкие (≥1/10000-<1/1000), очень редкие (<1/10000), или частота неизвестна (по имеющимся данным частоту встречаемости нежелательной реакции оценить не представляется возможным). Нежелательные реакции, наблюдавшиеся после выхода препарата на рынок, были отнесены к частоте «частота неизвестна». Vascular disorders
Bleeding
In clinical studies, bleeding was the most common adverse reaction. These included major bleeding, observed in 4.2% of patients (bleeding was considered major if it was accompanied by a decrease in hemoglobin levels by 2 g/l or more, required transfusion of 2 or more units of blood components, and also if it was retroperitoneal or intracranial ). Some of these cases were fatal.
As with the use of other anticoagulants, bleeding may occur when using enoxaparin sodium, especially in the presence of risk factors that contribute to the development of bleeding, during invasive procedures or the use of drugs that impair hemostasis (see sections "Special instructions" and "Interaction with other drugs" ).
When describing bleeding below, the sign “*” means an indication of the following types of bleeding: hematoma, ecchymoses (except those developed at the injection site), wound hematomas, hematuria, nosebleeds, 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, non-Q wave myocardial infarction and ST-segment elevation myocardial infarction.
Infrequent
Retroperitoneal bleeding and intracranial hemorrhage in patients treated for deep vein thrombosis with or without pulmonary embolism, as well as in the treatment of ST-segment elevation myocardial infarction.
Rare
Retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina and myocardial infarction without a Q wave.
Thrombocytopenia and thrombocytosis
Very frequent
Thrombocytosis (platelet count in peripheral blood more than 400x10 9 /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 ST segment elevation.
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 in acute ST-segment elevation myocardial infarction.
Infrequent
Thrombocytopenia in the prevention of venous thrombosis in patients on bed rest and in the treatment of unstable angina and non-Q wave myocardial infarction.
Very rare
Immune-allergic thrombocytopenia in the treatment of patients with acute myocardial infarction with ST segment elevation. Other clinically significant adverse reactions, regardless of indication - these undesirable reactions, presented below, are grouped by system-organ classes, given with an indication of the frequency of their occurrence determined above and in decreasing order of their severity.
Immune system disorders
Frequent
Allergic reactions.
Rare
Anaphylactic and anaphylactoid reactions (see also subsection “Data obtained after marketing the drug” below).
Disorders of the liver and biliary tract
Very frequent
Increased activity of liver enzymes, mainly increased activity of transaminases, more than three times the upper limit of normal).
Skin and subcutaneous tissue disorders
Frequent
Urticaria, itching, erythema.
Infrequent
Bullous dermatitis.
General and injection site disorders
Frequent
Hematoma at the injection site, pain at the injection site, swelling at the injection site, bleeding, hypersensitivity reactions, inflammation, formation of lumps 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 drug entered the market
The following adverse reactions were observed during post-marketing use of the drug Clexane ®. These adverse reactions have been spontaneously reported and their frequency has been defined as “frequency unknown” (cannot be determined from available data).
Immune system disorders
Anaphylactic/anaphylactoid reactions, including shock.
Nervous system disorders
Headache.
Vascular disorders
When using enoxaparin sodium against the background of spinal/epidural anesthesia or spinal puncture, cases of spinal hematoma (or neuraxial hematoma) have been reported. These reactions led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis (see section "Special Instructions").
Blood or lymphatic system disorders
Hemorrhagic anemia.
Cases of development of immune-allergic thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of organ infarction or limb ischemia (see section “Special instructions”, subsection “Monitoring the number of platelets in peripheral blood”.
Eosinophilia.
Skin and subcutaneous tissue disorders
Cutaneous vasculitis and skin necrosis may develop at the injection site, which is usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful). In these cases, therapy with Clexane ® should be discontinued. The formation of hard inflammatory nodules-infiltrates at the injection site of the drug is possible, which disappear after a few days and are not grounds for discontinuation of the drug.
Alopecia.
Disorders of the liver and biliary tract
Hepatocellular liver damage.
Cholestatic liver damage.
Musculoskeletal and connective tissue disorders
Osteoporosis with long-term therapy (more than three months).
Overdose
Accidental overdose of Clexane ® during intravenous, extracorporeal or subcutaneous use can lead to hemorrhagic complications. When taken orally, even large doses, absorption of the drug is unlikely. Anticoagulant effects can generally be counteracted by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of Clexane ® administered. One mg (1 mg) of protamine sulfate counteracts the anticoagulant effect of one mg (1 mg) of Clexane ® ( see information on using protamine salts), if enoxaparin sodium was administered no more than 8 hours before the administration of protamine. 0.5 mg of protamine neutralizes the anticoagulant effect of 1 mg of Clexane ® if more than 8 hours have passed since the latter was administered or if a second dose of protamine is necessary. If 12 or more hours have passed since the administration of enoxaparin sodium, administration of protamine is not required. However, even with the introduction of large doses of protamine sulfate, the anti-Xa activity of Clexane ® is not completely neutralized (maximum 60%). Interaction with other drugsClexane ® must not be mixed with other drugs! You should not alternate the use of enoxaparin sodium and other low molecular weight heparins, since they differ from each other in the method of production, molecular weight, specific anti-Xa activity, units of measurement and dosage. And, as a consequence of this, the drugs have different pharmacokinetics and biological activities (anti-IIa activity, interaction with platelets).
With systemic salicylates, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids, thrombolytics or anticoagulants, other antiplatelet drugs (including glycoprotein IIb/IIIa antagonists) - increased risk of bleeding (See “Special Instructions”).
special instructions
Are commonLow molecular weight heparins are not interchangeable, as they differ in the manufacturing process, molecular weight, specific anti-Xa activity, dosage units and dosage regimen, which are associated with differences in their pharmacokinetics and biological activity (antithrombin activity and interaction with platelets). Therefore, it is necessary 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, when using the drug Clexan ®, bleeding of any location may develop (see section “Side effects”). If bleeding develops, it is necessary to find its source and carry out appropriate treatment.
Bleeding in elderly patients
When using the drug Clexane ® in prophylactic doses in elderly patients, there was no tendency to increase bleeding.
When using the drug in therapeutic doses in elderly patients (especially those aged ≥80 years), there is an increased risk of bleeding. It is recommended to carefully monitor the condition of such patients (see section “Pharmacokinetics” and section “Dosage and Administration”, subsection “Elderly Patients”).
Concomitant use of other drugs that affect hemostasis
It is recommended that the use of drugs that can disrupt hemostasis (salicylates, including acetylsalicylic acid, non-steroidal anti-inflammatory drugs, including ketorolac; dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel; glucocorticosteroid drugs, thrombolytics, anticoagulants, antiplatelet agents, including glycoprotein IIb receptor antagonists /IIIa) was discontinued before starting treatment with enoxaparin sodium, unless their use is strictly indicated. If combinations of enoxaparin sodium with these drugs are indicated, careful clinical observation and monitoring of relevant laboratory parameters should be carried out.
Kidney failure In patients with impaired renal function, there is a risk of bleeding as a result of increased systemic exposure to enoxaparin sodium.
In patients with severe renal impairment (creatinine clearance less than 30 ml/min), dose adjustment is recommended for both prophylactic and therapeutic use of the drug. Although no dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance 30-50 ml/min or 50-80 ml/min), close monitoring of such patients is recommended (see sections "Pharmacokinetics" and " Method of administration and dosage", subsection "Patients with renal failure").
Low body weight
An increase in the anti-Xa activity of enoxaparin sodium when used prophylactically in women weighing less than 45 kg and in men weighing less than 57 kg may lead to an increased risk of bleeding). Close monitoring of the condition of such patients is recommended.
Obese patients
Obese patients have an increased risk of developing thrombosis and embolism. The safety and effectiveness of enoxaparin in prophylactic doses in obese patients (BMI more than 30 kg/m2) has not been fully determined 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.
Monitoring the number of platelets in peripheral blood
The risk of developing antibody-mediated heparin-induced thrombocytopenia also exists with the use of low molecular weight heparins. If thrombocytopenia occurs, it usually develops between 5 and 21 days after initiation of enoxaparin sodium therapy. In this regard, it is recommended to regularly monitor the number of platelets in the peripheral blood before starting treatment with Clexane ® and during its use. If there is a confirmed significant decrease in platelet count (by 30-50% compared to the initial value), it is necessary to immediately discontinue enoxaparin sodium and transfer the patient to another therapy.
Spinal/epidural anesthesia
As with the use of other anticoagulants, cases of neuraxial hematomas have been described when using the drug Clexane ® during simultaneous spinal/epidural anesthesia with the development of persistent or irreversible paralysis. The risk of these events is reduced when using the drug at 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 indwelling catheters after surgery, or with the simultaneous use of additional drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (see section "Interaction with other drugs"). The risk also increases with traumatic or repeated spinal puncture or in patients with a history of spinal surgery or spinal deformity.
To reduce the possible risk of bleeding associated with the use of enoxaparin sodium and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug must be taken into account (see section "Pharmacokinetics"). It is best to install or remove a catheter when the anticoagulant effect of enoxaparin sodium is low.
Installation or removal of the catheter should be carried out 10-12 hours after the use of prophylactic doses of the drug Clexane ® for the prevention of deep vein thrombosis. In cases where patients are receiving higher doses of enoxaparin sodium (1 mg/kg twice daily or 1.5 mg/kg once daily), these procedures should be delayed for a longer period of time (24 hours). Subsequent administration of the drug should be carried out no earlier than 2 hours after removal of the catheter.
If, as prescribed by a physician, anticoagulant therapy is used during epidural/spinal anesthesia, particularly careful continuous monitoring of the patient is necessary to identify any neurological symptoms, such as: back pain, impaired sensory and motor functions (numbness or weakness in the lower extremities), impaired bowel and/or bladder functions. The patient should be instructed to immediately inform the doctor if the above symptoms occur. If symptoms consistent with a spinal cord hematoma are suspected, prompt diagnosis and treatment are necessary, including, if necessary, spinal cord decompression.
Heparin-induced thrombocytopenia
Clexane ® should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis.
The risk of heparin-induced thrombocytopenia may persist for several years. If the history suggests heparin-induced thrombocytopenia, then platelet aggregation tests in vitro have limited value in predicting the risk of its development. The decision to use Clexane ® in this case can only be made after consultation with an appropriate specialist.
Percutaneous coronary angioplasty
To minimize the risk of bleeding associated with invasive vascular instrumentation in the treatment of unstable angina and non-Q wave myocardial infarction and acute ST-segment elevation myocardial infarction, these instrumentation procedures should be strictly followed by the recommended intervals between the administration of Clexane ® and these procedures. This is necessary in order to achieve hemostasis after percutaneous coronary intervention. If a closure device is used, the femoral artery sheath can be removed immediately. If manual compression is used, the femoral artery sheath should be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin sodium. If treatment with enoxaparin sodium is continued, the next dose should be administered no earlier than 6-8 hours after removal of the femoral artery sheath. It is necessary to monitor the insertion site of the introducer to promptly identify signs of bleeding and hematoma formation.
Patients with mechanical artificial heart valves
The use of Clexane ® for the prevention of thrombus formation in patients with mechanical artificial heart valves has not been sufficiently studied. There are isolated reports of the development of heart valve thrombosis in patients with mechanical artificial heart valves during therapy with enoxaparin sodium to prevent thrombosis. The evaluation of these reports is limited by the presence of competing factors that contribute to the development of thrombosis of prosthetic heart valves, including the underlying disease, and by the paucity of clinical data.
Pregnant women with mechanical artificial heart valves
The use of Clexane ® for the prevention of thrombus formation in pregnant women with mechanical artificial heart valves has not been sufficiently studied. In a clinical study of pregnant women with mechanical prosthetic heart valves using enoxaparin sodium at a dose of 1 mg/kg body weight twice daily to reduce the risk of thrombosis and embolism, 2 out of 8 women developed a blood clot, leading to blockage of the heart valves and death of the mother and fruit.
There are isolated post-marketing reports of valvular thrombosis in pregnant women with mechanical prosthetic heart valves treated with enoxaparin for thrombotic prophylaxis.
Pregnant women with mechanical artificial heart valves are at high risk of developing thrombosis and embolism.
Laboratory tests
At doses used for the prevention of thromboembolic complications, Clexane ® does not significantly affect bleeding time and blood coagulation parameters, as well as platelet aggregation or their binding to fibrinogen.
As the dose increases, the aPTT and activated clotting time may prolong. The increase in aPTT and activated clotting time are not in a direct linear relationship with the increase in the 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 on bed rest
In the event of the development of an acute infection or acute rheumatic conditions, the prophylactic use of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombus formation:
Impact on the ability to drive vehicles and engage in other potentially hazardous activities
The drug Clexane ® does not affect the ability to drive vehicles and machines.
Release forms
Solution for injection 2000 anti-Xa IU/0.2 ml; 4000 anti-Xa IU/0.4 ml; 6000 anti-Xa IU/0.6 ml; 8000 anti-Xa IU/0.8 ml; 10,000 anti-Xa IU/1 ml.1 type of packaging
0.2 ml or 0.4 ml or 0.6 ml or 0.8 ml or 1.0 ml of the drug solution in a glass syringe (type I), respectively. 2 syringes per blister. 1 or 5 blisters along with instructions for use in a cardboard box.
2 types of packaging
0.2 ml or 0.4 ml or 0.6 ml or 0.8 ml or 1.0 ml of the drug solution in a glass syringe (type I) with a needle protection system, respectively. 2 syringes per blister. 1 or 5 blisters along with instructions for use in a cardboard box.
Storage conditions
At a temperature not higher than +25°C. Keep out of the reach of children!Best before date
3 years.After the expiration date, the drug cannot be used.
Vacation conditions
On prescription.Registration Certificate Holder
SANOFI-AVENTIS FRANCE, France.
Manufacturer
1) Sanofi Winthrop Industry, France.Manufacturer's address: 180, rue Jean Jaurès, 94702 Maisons Elfort Cedex, France.
2) Sanofi Winthrop Industry, France.
Manufacturer's address: Boulevard Industrial, Zone Industrial, 76580 Le Tray, France.
Consumer complaints should be sent to:
125009, Moscow, st. Tverskaya, 22.
The syringe contains 20, 40, 60, 80 or 100 mg of Clexane (enoxaparin), respectively, in 0.2; 0.4; 0.6; 0.8 or 1.0 ml of aqueous solution. 1 mg of Clexane contains 100 anti-Xa units.
PHARMACOLOGICAL PROPERTIES
Clexane is a low molecular weight heparin with high activity against coagulation factor Xa (thrombokinase) and low activity against factor IIa (thrombin). At doses used for the prevention of venous thrombosis, it has virtually no effect on bleeding time, clotting time, aPTT, and platelet aggregation.
When administered subcutaneously, it is quickly and almost completely absorbed. The peak of anti-Xa activity in plasma is reached after 3-5 hours. Clexane is excreted mainly in the urine. The half-life is about 4 hours. Anti-Xa activity in the blood plasma is determined within 24 hours after a single injection. In case of renal failure in the elderly, the half-life may increase to 5-7 hours, but no dose adjustment is required. During hemodialysis, the elimination of enoxaparin does not change.
INDICATIONS FOR USE
- Prevention of venous thrombosis and thromboembolism, especially during orthopedic and general surgical operations and in cancer patients.
- Treatment of deep vein thrombosis with or without pulmonary embolism.
- Treatment of unstable angina and non-Q wave myocardial infarction (in combination with aspirin).
- Prevention of thrombus formation in the extracorporeal bloodstream during hemodialysis.
CONTRAINDICATIONS
Allergic reactions to Clexane (enoxaparin), heparin and other low molecular weight heparins. High risk of bleeding, including acute gastric and duodenal ulcers.
PRECAUTIONARY MEASURES
Do not inject IM! Follow the instructions strictly. If there is a history of thrombocytopenia caused by heparin, Clexane is used only in exceptional cases, after consultation with a specialist. Before and during treatment, the platelet count should be regularly checked, and if it decreases by 30-50%, enoxaparin administration should be stopped immediately.
Clexane is prescribed with caution in case of risk of bleeding: hypocoagulation, history of peptic ulcer, recurrent ischemic strokes, severe arterial hypertension, diabetic retinopathy, repeated neurological or ophthalmological operations, severe liver diseases. Rare cases of spinal cord hematoma have been described when using Clexanan against the background of spinal and epidural anesthesia with the development of persistent or irreversible paralysis. During pregnancy, the drug is prescribed only for strict indications.
SIDE EVENTS
When recommended dosages are observed, hemorrhagic manifestations are extremely rare. In the first days of treatment, moderate asymptomatic thrombocytopenia may appear. An asymptomatic, reversible increase in platelet count is possible, and, rarely, immune thrombocytopenia. A reversible increase in liver enzyme levels is possible. There may be moderate redness and hematoma at the injection site; occasionally, dense inflammatory nodes appear, which resolve after a few days, without the need to stop treatment. Necrosis at the injection site occurs extremely rarely. In such cases, you should immediately stop administering the drug. Skin or systemic allergic reactions to the drug have been reported rarely.
SPECIAL MARKS
In case of overdose, hemorrhagic complications are possible. In case of overdose, slow intravenous administration of protamine is indicated. 1 mg of protamine neutralizes the anticoagulant activity caused by 1 mg of Clexane. However, even high doses of protamine do not completely neutralize the anti-Xa activity of Clexane (maximum - 60%).
Before prescribing Clexan, drugs that affect hemostasis, such as aspirin, non-steroidal anti-inflammatory drugs, dextran, ticlopidine, glucocorticoids, thrombolytics and anticoagulants, should be discontinued. If this is not possible, Clexane should be used under close clinical and laboratory supervision. DO NOT MIX WITH OTHER DRUGS IN THE SAME SYRINGE!
APPLICATION AND DOSAGE
Mode of application
Clexane is administered subcutaneously in the supine position, into the antero- or posterolateral region of the abdominal wall at waist level. The needle is inserted vertically over its entire length into the thickness of the skin, sandwiched in a fold; the skin fold is not straightened until the end of the injection. After the injection, the injection site should not be rubbed. When performing hemodialysis, Clexane should be injected into the arterial line.
Prevention of venous thrombosis and thromboembolism
At moderately high risk Clexane is prescribed 20 mg (0.2 ml) subcutaneously once a day. The drug is started to be administered 2 hours before surgery and continued as long as there is a risk of thromboembolic complications (usually 7 days). At very high risk Clexane is prescribed 40 mg (0.4 ml) subcutaneously once a day, with the first dose administered 12 hours before surgery and continued as long as there is a risk of thromboembolic complications (usually for 10 days).
Treatment of deep vein thrombosis
1 mg/kg subcutaneously every 12 hours for 10 days. In this case, treatment with oral anticoagulants is started, and the administration of Clexane is continued until the effect is achieved (INR from 2 to 3).
Treatment of unstable angina and non-Q wave myocardial infarction
The recommended dose of Clexane is 1 mg/kg every 12 hours subcutaneously, while aspirin is used (100-325 mg once a day). Clexane is prescribed for at least 2 days and treatment is continued until the condition stabilizes. The usual duration of treatment is 2-8 days.
Prevention of coagulation in the extracorporeal circulation system during hemodialysis
Clexane is injected into the arterial line at the beginning of hemodialysis at a dose of 1 mg/kg over a 4-hour procedure. If the risk of bleeding is high, the dose is reduced to 0.5 mg/kg with double access to the vessels or to 0.75 mg/kg with single access. But if fibrin rings are deposited, an additional 0.5-1 mg/kg can be administered.
Release form
Ready-to-use syringes: 20 mg/0.2 ml, 40 mg/0.4 ml, 60 mg/0.6 ml, 80 mg/0.8 ml, 100 mg/1.0 ml, 2 syringes per pack .
Storage
Shelf life 24 months. Store at a temperature not exceeding 25°C. Do not freeze.
Sanofi-Aventis, France
Glaxo Wellcome Production, France
