Clexane, 4000 anti-ha me/0.4 ml 0.04 ml syringes 9 pcs

Pharmacotherapeutic group: direct acting anticoagulant.

ATX code – B01AB05.

Pharmacological properties Characteristics
Enoxaparin sodium is a low molecular weight heparin with an average molecular weight of about 4,500 daltons: less than 2000 daltons – <20%, 2000 to 8000 daltons – >68%, more than 8000 daltons -<18%. Enoxaparin sodium is obtained by alkaline hydrolysis of heparin benzyl ether isolated from the mucous membrane of pig small intestine. Its structure is characterized by a nonreducible fragment of 2-O-sulfo-4-enpyrazinosuronic acid and a reducible fragment of 2-N,6-O-disulfo-D-glucopyranoside. The structure of enoxaparin sodium contains about 20% (between 15% and 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

Pharmacodynamics

In a purified in vitro system, sodium enoxaparin 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), providing anticoagulant activity in humans. In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have also been identified in both healthy subjects and patients and in animal models. These include AT-III dependent inhibition of other clotting factors like factor VIIa, activation of tissue factor pathway inhibitor (TFP) release, and reduction of Willebrand factor release from the vascular endothelium into the bloodstream. These factors provide the anticoagulant effect of enoxaparin sodium in general.

When used in prophylactic doses, it has little effect on partial thromboplastin time (PTP), virtually no effect on platelet aggregation and on the degree of fibrinogen binding to platelet receptors. Anti-IIa activity in plasma is about 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 when administered once, respectively. Mean maximum plasma anti-Xa 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 the indicated dosing regimens are 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 the equilibrium concentration is reached by day 2, with the area under the pharmacokinetic curve being on average 15% higher than after a single injection.

After repeated subcutaneous injections of enoxaparin sodium at a daily dose of 1 mg/kg body weight twice daily, the equilibrium concentration is reached after 3-4 days with the area under the pharmacokinetic curve being on average 65% higher than after a single injection and the mean values of maximum concentrations being respectively 1.2 IU/mL and 0.52 IU/mL.

The bioavailability of enoxaparin sodium by subcutaneous administration, estimated on the basis of anti-Xa activity, is close to 100%. The volume of distribution of the anti-Xa activity of sodium enoxaparin is approximately 5 liters and approximates the blood volume. Enoxaparin sodium is a low clearance drug.

After intravenous administration for 6 hours at a dose of 1.5 mg/kg body weight, the average plasma clearance of anti-Xa is 0.74 L/hour.

The elimination of the drug is monophasic with half-lives of 4 hours (after single subcutaneous administration) and 7 hours (after multiple administration of the drug).

Enoxaparin sodium is mainly metabolized in the liver by desulfation and/or depolymerization to form low molecular weight substances with very low biological activity.

The excretion through the kidneys 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. Delayed excretion of enoxaparin sodium in elderly patients as a result of decreased renal function with age is possible. Decrease of clearance of enoxaparin sodium in patients with decreased renal function has been noted.

After repeated subcutaneous administration of 40 mg of sodium enoxaparin once daily there is an increase in anti-Xa activity represented by the area under the pharmacokinetic curve in patients with mild (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) area under pharmacokinetic curve in equilibrium condition is in average 65% higher while repeated subcutaneous administration of 40 mg of preparation once a day. In people with excessive body weight when the drug is administered subcutaneously, clearance is slightly lower.

If no dose adjustment is made for patient weight, after a single subcutaneous injection of 40 mg of Enoxaparin sodium anti-Xa activity will be 50% higher in women with a body weight less than 45 kg and 27% higher in men with a body weight less than 57 kg compared with patients of normal average body weight.

Indications

Active ingredient

Enoxaparin sodium

Composition

1 ml contains:

Active ingredients:

enoxaparin sodium 100 mg.

Solvent:

Injection water up to 0.4 ml

How to take, the dosage

Except in special cases (see “Treatment of ST-segment elevation myocardial infarction, drug or percutaneous coronary intervention” and “Prevention of thrombosis in extracorporeal circulation during hemodialysis” below), enoxaparin sodium is injected deep subcutaneously. Injections should preferably be performed in the “supine” position of the patient. When using pre-filled 20 mg and 40 mg syringes, air bubbles should not be removed from the syringe before injection to avoid loss of product. Injections should be given alternately on the left or right anterolateral or posterolateral surface of the abdomen. The needle should be inserted vertically (not laterally) into the full length skin fold, gathered and held until the injection is complete between the thumb and forefinger. The skin fold is only released when the injection is complete. The injection site should not be massaged after the injection of the drug.

Pre-filled disposable syringe is ready for use. The drug must not be injected intramuscularly! Prevention of venous thromboses and embolias in surgical interventions, especially in orthopedic and general surgeries.

Patients with moderate risk of thromboses and embolias (general surgeries) are recommended to take a dose of Klexan® 20 mg once a day subcutaneously.

The first injection is given two hours before surgical intervention. For patients with high risk of thrombosis and embolism development (general surgery and orthopedic surgery) the drug is recommended in dose 40 mg once a day subcutaneously, the first dose is administered 12 hours before surgical intervention, or 30 mg twice a day with the beginning of injection 12-24 hours after surgery.

Duration of Clexane® treatment is 7-10 days at average. If necessary the therapy may be continued until the risk of thrombosis and embolism persists (e.g. in orthopedics Clexane® is administered in a dose of 40 mg once a day for 5 weeks).

The specifics of Clexane® administration during spinal and epidural anesthesia as well as during coronary revascularization procedures are described in section “Cautions”.

Prevention of venous thrombosis and embolism in bedridden patients due to acute therapeutic diseases.

The recommended dose of Clexane® is 40 mg once a day subcutaneously for 6-14 days.

Treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered subcutaneously at the rate 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 in a dose of 1 mg/kg twice a day.

The duration of treatment is on average 10 days. It is advisable to start therapy with indirect anticoagulants right away, while therapy with Klexan® 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 thrombosis in extracorporeal circulation during hemodialysis

Dose of Clexane® averages 1 mg/kg body weight. At high risk of bleeding the dose should be reduced to 0.5 mg/kg of body weight during double vascular access or 0.75 mg during single vascular access. In hemodialysis, the drug should be injected into the arterial shunt site at the beginning of the hemodialysis session. One dose is usually sufficient for a four-hour session, but if fibrin rings are detected during a longer hemodialysis, the drug may be administered additionally at a rate of 0.5-1 mg/kg body weight.

Treatment of unstable angina and myocardial infarction without Q-wave

Clexane® is administered at a rate of 1 mg/kg of body weight every 12 hours subcutaneously while concomitant use of acetylsalicylic acid at a dose of 100-325 mg once daily.

The average therapy duration is 2-8 days (until the patient’s clinical condition stabilizes).

Treatment of ST-segment elevation myocardial infarction, drug or percutaneous coronary intervention

Treatment begins with an intravenous bolus injection of 30 mg of enoxaparin sodium and is immediately followed (within 15 minutes) by a subcutaneous injection of 1 mg/kg of enoxaparin sodium (and the first two subcutaneous injections may be 100 mg of enoxaparin sodium maximum). Thereafter, all subsequent subcutaneous doses are administered every 12 hours at a rate of 1 mg/kg body weight (i.e., for body weights greater than 100 kg, the dose may exceed 100 mg).

In persons 75 years and older, an initial intravenous bolus injection is not used. Enoxaparin sodium is administered subcutaneously at a dose of 0.75 mg/kg every 12 hours (with a maximum of 75 mg of enoxaparin sodium being administered for the first two subcutaneous injections). Then all subsequent subcutaneous doses are administered every 12 hours at a rate of 0.75 mg/kg body weight (i.e., if the weight exceeds 100 kg, the dose may exceed 75 mg).

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

The recommended duration of drug treatment is 8 days or until discharge from hospital, if the hospitalization period is less than 8 days. Bolus injection of sodium enoxaparin should be done through a venous catheter and sodium enoxaparin should not be mixed or administered with other medications. In order to avoid the presence of traces of other drugs in the system and their interaction with sodium enoxaparin, the venous catheter should be flushed with sufficient amounts of 0.9% sodium chloride solution or dextrose before and after intravenous bolus injection of sodium enoxaparin. Enoxaparin sodium can be administered safely with 0.9% sodium chloride solution and 5% dextrose solution.

For 30 mg bolus injection of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the 60 mg, 80 mg and 100 mg glass syringes are discarded so that only 30 mg (0.3 ml) remains. The 30 mg dose may be directly administered intravenously.

For intravenous bolus injection of enoxaparin sodium through a venous catheter, pre-filled 60 mg, 80 mg and 100 mg hypodermic syringes may be used. The 60 mg syringe is recommended because it reduces the amount of drug removed from the syringe. The 20 mg syringe is not used because it does not contain enough preparation for a 30 mg bolus of enoxaparin sodium. The 40 mg syringes are not used because they have no divisions and therefore it is impossible to accurately measure the 30 mg.

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of sodium enoxaparin was given less than 8 hours before the balloon catheter inserted into the coronary artery narrowing, additional injection of sodium enoxaparin is not required. If the last subcutaneous injection of sodium enoxaparin was made more than 8 hours before the balloon catheter was inflated, an intravenous additional bolus injection of sodium enoxaparin should be made at a dose of 0.3 mg/kg.

To improve accuracy of additional bolus injection of small volumes into venous catheter during percutaneous coronary interventions it is recommended to dilute the drug to concentration 3 mg/ml. Dilution of the solution is recommended immediately prior to use. To obtain Enoxaparin sodium solution with a concentration of 3 mg/ml using a 60 mg pre-filled syringe, it is recommended to use a container with 50 ml infusion solution (i.e. 0.9% sodium chloride solution or 5% dextrose solution).

Enoxaparin sodium (the contents of the syringe for subcutaneous injection of 60 mg) is injected into the remaining 20 ml of the infusion solution in the container. The contents of the container with the diluted sodium enoxaparin solution are stirred gently. The required volume of the diluted sodium enoxaparin solution is extracted for injection using a syringe, which is calculated according to 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

Elderly patients
Except for treatment of ST-segment elevation myocardial infarction (see above) for all other indications, no reduction in doses of enoxaparin sodium in elderly patients if they do not have renal impairment is necessary.
Patients with renal impairment

The dose of sodium enoxaparin is reduced according to the tables below because the drug is accumulating in these patients.
The following dosing regimen adjustments are recommended when using the drug for therapeutic purposes:

The following dosing regimen adjustment is recommended when using the drug for prophylactic purposes

table>

The recommended dosing regimen adjustment is not applicable for hemodialysis.

Dose adjustment is not required, but laboratory monitoring of therapy should be conducted more carefully.

Patients with hepatic impairment

Due to the lack of clinical studies, caution should be exercised when prescribing enoxaparin sodium to patients with hepatic impairment.

Interaction

Clexane® must not be mixed with other medications! Enoxaparin sodium and other low molecular weight heparins should not be used interchangeably, since they differ in production method, molecular weight, specific anti-Xa activity, units and dosage. And, as a consequence, the drugs have different pharmacokinetics and biological activity (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 agents (including glycoprotein IIb/IIIa antagonists) – increased risk of bleeding (see “Special Precautions. “Special indications”).

Special Instructions

When the drug is prescribed for prophylactic purposes, no tendency to increased bleeding has been found. When prescribing the drug for therapeutic purposes, there is a risk of bleeding in elderly patients (especially in those over 80 years). Close monitoring of the patient’s condition is recommended.

Before starting therapy with this drug, it is recommended to cancel other drugs affecting hemostasis system because of the risk of bleeding: salicylates, including acetylsalicylic acid, NSAIDs (including ketorolac); dextran 40, ticlopidine, clopidogrel; GCS, thrombolytics, anticoagulants, antiaggregants (including glycoprotein receptor antagonists IIb/IIIa), except when their use is necessary. If it is necessary to combine the use of Clexane with these drugs, special care must be taken (close monitoring of the patient’s condition and the corresponding laboratory blood values).

In patients with impaired renal function, there is a risk of bleeding as a result of increased anti-Xa activity. Since this increase is significantly greater in patients with significant renal dysfunction (CKD less than 30 ml/min), it is recommended to perform dose adjustment in both prophylactic and therapeutic administration of the drug. Although no dose adjustment is required in patients with mild to moderate renal dysfunction (CKD greater than 30 ml/min), close monitoring of these patients is recommended.

The increased anti-Xa activity of enoxaparin when prophylactically administered in women with a body weight less than 45 kg and in men with a body weight less than 57 kg may lead to an increased risk of bleeding.

The risk of heparin-induced immune thrombocytopenia also exists with low molecular weight heparins. If thrombocytopenia develops, it is usually detected between days 5 and 21 after initiation of therapy with enoxaparin sodium. Therefore, it is recommended that platelet counts be monitored regularly before and during treatment with Enoxaparin sodium.

If a significant decrease in platelet count is confirmed (30-50% compared to baseline), sodium enoxaparin should be stopped immediately and the patient transferred to another therapy.

Contraindications

Cautiously use with the following conditions:

.

Side effects

Side effects of enoxaparin sodium were studied in more than 15000 patients who participated in clinical trials, including 1776 patients – in the prevention of venous thrombosis and embolism in general surgery and orthopedic surgeries; 1169 patients – in the prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic diseases; in 559 patients – in treatment of deep vein thrombosis with or without pulmonary embolism; in 1578 patients – in treatment of unstable angina and myocardial infarction without Q wave; in 10176 patients – in treatment of myocardial infarction with ST-segment elevation. The mode of enoxaparin sodium administration differed depending on the indication. In prophylaxis of venous thromboses and embolisms during general and orthopedic surgeries or in patients on bed rest we administered 40 mg subcutaneously once a day. In the treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium at a rate of 1 mg/kg body weight subcutaneously every 12 hours or 1.5 mg/kg body weight subcutaneously once daily. During treatment of unstable angina and myocardial infarction without Q-wave, enoxaparin sodium dose was 1 mg/kg of body weight subcutaneously every 12 hours, and in case of myocardial infarction with ST-segment elevation we used intravenous bolus injection of 30 mg, followed by subcutaneous injection of 1 mg/kg of body weight 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 frequency unknown (the incidence of the adverse reaction could not be estimated from available data). Adverse reactions observed after the drug was placed on the market were classified as “frequency unknown”. Vascular disorders

Bleeding

In clinical trials, 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 by 2 g/l or more, required transfusion of 2 or more doses of blood components; and if it was retroperitoneal or intracranial). Some of these cases have been fatal.

As with the use of other anticoagulants when using enoxaparin sodium bleeding may occur, especially in the presence of risk factors contributing to bleeding, during invasive procedures or the use of drugs that disrupt hemostasis (see

In the description of bleeding below the sign “*” denotes the following types of bleeding: hematoma, ecchymoses (except developed in the injection site), wound hematomas, hematuria, nasal bleeding, 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 bed rest patients and in the treatment of unstable angina, myocardial infarction without Q-wave and myocardial infarction with ST-segment elevation.

Infrequent

Transperitoneal bleeding and intracranial hemorrhage in patients treated for deep vein thrombosis with or without pulmonary thromboembolism and for treatment of ST-segment elevation myocardial infarction.

Rare

Subperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina and myocardial infarction without Q-wave.

Thrombocytopenia and thrombocytosis

Very frequent

Thrombocytosis (peripheral blood platelet count greater than 400×109/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 ST-segment elevation myocardial infarction.

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

Infrequent

Thrombocytopenia in the prevention of venous thrombosis in bed rest patients and in the treatment of unstable angina and myocardial infarction without the Q-wave.

Very rare

Immune-allergic thrombocytopenia in the treatment of patients with acute ST-segment elevation myocardial infarction. Other clinically significant adverse reactions regardless of the indication – these adverse reactions, presented below, are grouped by systemic organ class, are given with the frequency of occurrence defined above and in decreasing order of severity.

Immune System Disorders

Frequent: Allergic reactions.

Rare: Anaphylactic and anaphylactoid reactions (see also below subsection “Data obtained after the drug was placed on the market”).

Disorders of the liver and biliary tract
Very common: Increased activity of “liver” enzymes, mainly increased transaminase activity, more than three times the upper limit of normal).

Skin and subcutaneous tissue disorders

Frequent: Urticaria, pruritus, erythema.

Infrequent: bullous dermatitis.

General disorders and disorders at the injection site:

Frequent: Hematoma at the injection site, pain at the injection site, swelling at the injection site, bleeding, hypersensitivity reactions, inflammation,seal formation at the injection site.

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

Laboratory and instrumental data

Rare

Hyperkalemia. Post-marketing data

The following adverse reactions have been reported during the post-marketing use of Clexane®. These adverse reactions were spontaneously reported and their frequency was defined as “frequency unknown” (cannot be determined based on 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 neuroaxial hematoma) were observed. These reactions have led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis (see section “Cautions”).

Disorders of the blood or lymphatic system

Hemorrhagic anemia.

Cases of immune-allergic thrombocytopenia with thrombosis; in some cases thrombosis was complicated by the development of organ infarction or limb ischemia (see.

Eosinophilia.

Skin and subcutaneous tissue disorders

Skin vasculitis, 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. Solid inflammatory nodules- infiltrates may form at the injection site which disappear after several days and are not reasons for discontinuation of the drug.

Alopecia.

Disorders of the liver and biliary tract

Hepatocellular liver.
Cholestatic liver.

Disorders of the skeletal-muscular and connective tissue: Osteoporosis in long-term therapy (more than three months).

Overdose

Accidental overdose of Klexan® with intravenous, extracorporeal or subcutaneous administration may lead to hemorrhagic complications. When administered orally, even large doses are unlikely to be absorbed. The anticoagulant effects can mainly be neutralized by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of Klexan® administered.

One mg (1 mg) of protamine sulfate will neutralize the anticoagulant effect of one mg (1 mg) of Clexane® (see information on the use of protamine salts) if enoxaparin sodium was administered no more than 8 hours before protamine administration. 0.5 mg of protamine will neutralize the anticoagulant effect of 1 mg of Klexan® if more than 8 hours have elapsed since the latter was administered or if a second dose of protamine must be administered.

If, however, 12 hours or more have elapsed since the administration of enoxaparin sodium, the administration of protamine is not required. However, even when large doses of protamine sulfate are administered, the anti-Xa activity of Klexan® is not completely neutralized (maximum 60%).

Pregnancy use

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. Because adequate and well-controlled studies in pregnant women are lacking, and animal studies do not always predict the response to enoxaparin sodium administration during pregnancy in humans, it should only be used during pregnancy if there is an urgent medical need for it.

It is unknown whether unchanged enoxaparin sodium is excreted into human breast milk. Breast-feeding should be stopped during treatment of the mother with Clexane®.

Similarities

Enixum