Clexane^® (Solution) Instructions for Use

Marketing Authorization Holder

Sanofi-Aventis France (France)

Manufactured By

Sanofi Winthrop Industrie (France)

Or

Pharmstandard-UfaVITA OJSC (Russia)

Packaging and Quality Control Release

SANOFI WINTHROP INDUSTRIE (France)

Or

SANOFI-AVENTIS EAST, CJSC (Russia)

Or

PHARMSTANDARD-UfaVITA, OJSC (Russia)

Or

SANOFI EAST, JSC (Russia)

Contact Information

SANOFI

ATC Code

B01AB05 (Enoxaparin)

Active Substance

Enoxaparin sodium (Rec.INN registered by WHO)

Dosage Forms

	Clexane®	Solution for injection 2000 anti-Xa IU/0.2 ml: syringes 2, 9 or 10 pcs. with or without needle protection system
		Solution for injection 4000 anti-Xa IU/0.4 ml: syringes 2, 9 or 10 pcs. with or without needle protection system
		Solution for injection 6000 anti-Xa IU/0.6 ml: syringes 2, 9 or 10 pcs. with or without needle protection system
		Solution for injection 8000 anti-Xa IU/0.8 ml: syringes 2, 9 or 10 pcs. with or without needle protection system
		Solution for injection 10000 anti-Xa IU/1 ml: syringes 2 or 10 pcs. with or without needle protection system

Dosage Form, Packaging, and Composition

Solution for injection clear, from colorless to pale yellow.

Solvent water for injections – up to 0.2 ml.

0.2 ml – glass syringes (type I) (2) – blisters (1, 5) – cardboard packs.
0.2 ml – glass syringes (type I) (3) – blisters (3) – cardboard packs.
0.2 ml – glass syringes (type I) with needle protection system (2) – blisters (1, 5) – cardboard packs.

Solution for injection clear, from colorless to pale yellow.

Solvent water for injections – up to 0.4 ml.

0.4 ml – glass syringes (type I) (2) – blisters (1, 5) – cardboard packs.
0.4 ml – glass syringes (type I) (3) – blisters (3) – cardboard packs.
0.4 ml – glass syringes (type I) with needle protection system (2) – blisters (1, 5) – cardboard packs.

Solution for injection clear, from colorless to pale yellow.

Solvent water for injections – up to 0.6 ml.

0.6 ml – glass syringes (type I) (2) – blisters (1, 5) – cardboard packs.
0.6 ml – glass syringes (type I) (3) – blisters (3) – cardboard packs.
0.6 ml – glass syringes (type I) with needle protection system (2) – blisters (1, 5) – cardboard packs.

Solution for injection clear, from colorless to pale yellow.

Solvent water for injections – up to 0.8 ml.

0.8 ml – glass syringes (type I) (2) – blisters (1, 5) – cardboard packs.
0.8 ml – glass syringes (type I) (3) – blisters (3) – cardboard packs.
0.8 ml – glass syringes (type I) with needle protection system (2) – blisters (1, 5) – cardboard packs.

Solution for injection clear, from colorless to pale yellow.

Solvent water for injections – up to 1 ml.

1 ml – glass syringes (type I) (2) – blisters (1, 5) – cardboard packs.
1 ml – glass syringes (type I) with needle protection system (2) – blisters (1, 5) – cardboard packs.

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

Clinical-Pharmacological Group

Direct-acting anticoagulant – low molecular weight heparin

Pharmacotherapeutic Group

Direct-acting anticoagulant agent

Pharmacological Action

Enoxaparin sodium is a low molecular weight heparin with an average molecular weight of about 4500 daltons: less than 2000 daltons – <20%, from 2000 to 8000 daltons – >68%, more than 8000 daltons – <18%. Enoxaparin sodium is obtained by alkaline hydrolysis of the benzyl ester of heparin isolated from the porcine intestinal mucosa. Its structure is characterized by a non-reducing end 2-O-sulfo-4-enpyrazinosuronic acid and a reducing end 2-N,6-O-disulfo-D-glucopyranoside. The structure of enoxaparin contains about 20% (ranging from 15% to 25%) of a 1,6-anhydro derivative at the reducing end of the polysaccharide chain.

In a purified in vitro system, 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), providing anticoagulant activity in humans. In addition to anti-Xa/IIa activity, additional anticoagulant and anti-inflammatory properties of enoxaparin sodium have been identified in healthy individuals and patients, as well as in animal models. This includes AT-III-dependent inhibition of other coagulation factors such as factor VIIa, activation of tissue factor pathway inhibitor (TFPI) release, and reduction of von Willebrand factor release from the vascular endothelium into the bloodstream. These factors provide the overall anticoagulant effect of enoxaparin sodium.

When the drug is used in prophylactic doses, it slightly changes aPTT, has practically no effect on platelet aggregation and the level of fibrinogen binding to platelet receptors.

Pharmacokinetics

Absorption

The absolute bioavailability of enoxaparin sodium after subcutaneous (s.c.) administration, assessed based on anti-Xa activity, is close to 100%.

The mean maximum anti-Xa activity in plasma is observed 3-5 hours after s.c. administration and reaches approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/ml after a single s.c. administration of the drug at doses of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg. An intravenous bolus injection of the drug at a dose of 30 mg, followed immediately by s.c. administration of the drug at a dose of 1 mg/kg every 12 hours, provides an initial maximum anti-Xa activity of 1.16 IU/ml (n=16), the mean drug exposure in the blood is approximately 88% of the steady state, which is achieved on the 2nd day of therapy.

The pharmacokinetics of enoxaparin sodium in the specified dosing regimens is linear.

Variability within and between patient groups is low.

After repeated s.c. administration of 40 mg enoxaparin sodium once daily and s.c. administration of enoxaparin sodium at a dose of 1.5 mg/kg body weight once daily in healthy volunteers, C_ss is reached by day 2, with AUC on average 15% higher than after a single administration.

After repeated s.c. administrations of enoxaparin sodium at a daily dose of 1 mg/kg body weight twice daily, C_ss is reached after 3-4 days, with AUC on average 65% higher than after a single administration, and the mean C_max values are 1.2 IU/ml and 0.52 IU/ml, respectively.

Anti-IIa activity in plasma is approximately 10 times lower than anti-Xa activity. The mean maximum anti-IIa activity is observed approximately 3-4 hours after s.c. administration and reaches 0.13 IU/ml and 0.19 IU/ml after repeated administration of 1 mg/kg body weight with twice-daily administration and 1.5 mg/kg body weight with once-daily administration, respectively.

Distribution

The V_d of anti-Xa activity of enoxaparin sodium is approximately 4.3 L and is close to the blood volume.

Metabolism and Excretion

Enoxaparin sodium is a drug with low clearance. After intravenous administration over 6 hours at a dose of 1.5 mg/kg body weight, the mean value of anti-Xa plasma clearance is 0.74 L/h.

Drug elimination is monophasic with a T_1/2 of about 5 hours (after a single s.c. administration) and about 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. Renal excretion of active metabolites of the drug is approximately 10% of the administered dose, and total excretion of active and inactive metabolites is approximately 40% of the administered dose.

Special Patient Groups

Elderly patients (over 75 years old) the pharmacokinetic profile of enoxaparin sodium does not differ in elderly patients and younger patients with normal renal function. However, due to the decrease in renal function with age, a slowdown in the elimination of enoxaparin sodium may be observed in elderly patients.

Liver function impairment in a study involving patients with late stages of liver cirrhosis receiving Enoxaparin sodium at a dosage of 4000 IU (40 mg) once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of liver dysfunction (assessed by Child-Pugh score). This decrease was mainly due to a decrease in AT-III levels, secondary to decreased AT-III synthesis in patients with impaired liver function.

Renal function impairment a decrease in the clearance of enoxaparin sodium was noted in patients with renal impairment. After repeated s.c. administration of 40 mg enoxaparin sodium once daily, an increase in anti-Xa activity, represented by AUC, occurs in patients with mild (CrCl ≥50 and < 80 ml/min) and moderate (CrCl ≥30 and <50 ml/min) renal impairment. In patients with severe renal impairment (CrCl < 30 ml/min), the steady-state AUC is on average 65% higher with repeated subcutaneous administration of 40 mg of the drug once daily.

Hemodialysis the pharmacokinetics of enoxaparin sodium are comparable to those in the control population after single intravenous administrations of doses of 25 IU, 50 IU or 100 IU/kg (0.25, 0.50 or 1.0 mg/kg), however the AUC was 2 times higher than in the control population.

Body weight after repeated s.c. administrations at a dose of 1.5 mg/kg once daily, the mean steady-state AUC of anti-Xa activity is slightly higher in overweight patients (BMI 30-48 kg/m²) compared to patients with normal average body weight, while the maximum anti-Xa plasma activity does not increase. In overweight patients, clearance after s.c. administration of the drug is somewhat lower. If the dose is not adjusted for the patient’s body weight, then after a single s.c. administration of 40 mg enoxaparin sodium, anti-Xa activity will be 52% 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

• Prevention of venous thrombosis and embolism during surgical interventions, especially orthopedic and general surgical operations, including oncological ones;
• Prevention of venous thrombosis and thromboembolism in patients on bed rest due to acute therapeutic diseases, including acute heart failure, chronic heart failure in the stage of decompensation (III or IV functional class according to NYHA classification), respiratory failure, severe infection and rheumatic diseases with an increased risk of venous thrombosis);
• Treatment of deep vein thrombosis with or without pulmonary embolism, in all cases of pulmonary embolism requiring thrombolytic therapy or surgical intervention;
• Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis (usually for sessions lasting no more than 4 hours);
• Acute coronary syndrome:
  • Treatment of unstable angina and myocardial infarction without ST-segment elevation in combination with oral acetylsalicylic acid;
  • Treatment of acute ST-segment elevation myocardial infarction in patients eligible for medical treatment or subsequent percutaneous coronary intervention (PCI).

ICD codes

Dosage Regimen

S.C., except in special cases (see below subsections “Treatment of ST-segment elevation myocardial infarction, medical or with percutaneous coronary intervention” and “Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis”).

Prevention of venous thrombosis and embolism during surgical interventions in patients with moderate and high risk

For patients with moderate risk of thrombosis and embolism (e.g., abdominal surgery) the recommended dose of Clexane^® is 20 mg once daily s.c. The first injection should be given 2 hours before surgery.

For patients with high risk of thrombosis and embolism (e.g., during orthopedic surgery, oncological surgery, patients with additional risk factors not related to surgery, such as congenital or acquired thrombophilia, malignant neoplasm, bed rest for more than three days, obesity, history of venous thrombosis, varicose veins of the lower extremities, pregnancy) the drug is recommended at a dose of 40 mg once daily s.c., with the first dose administered 12 hours before surgery. If earlier preoperative prophylaxis is necessary (for example, in patients at high risk of thrombosis and thromboembolism awaiting delayed orthopedic surgery) the last injection should be given 12 hours before surgery and 12 hours after surgery

The duration of treatment with Clexane^® averages 7-10 days. If necessary, therapy can be continued as long as the risk of thrombosis and embolism persists, and until the patient becomes ambulatory.

For major orthopedic surgery it may be appropriate after initial therapy to continue treatment by administering Clexane^® at a dose of 40 mg once daily for 5 weeks.

For patients at high risk of venous thromboembolism who have undergone surgery, abdominal and pelvic surgery due to cancer , it may be appropriate to increase the duration of administration of Clexane^® at a dose of 40 mg once daily for 4 weeks.

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 s.c., for 6-14 days. Therapy should be continued until the patient is fully ambulatory (maximum for 14 days).

Treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered s.c. at the rate of 1.5 mg/kg body weight once daily or 1 mg/kg body weight twice daily. The dosing regimen should be chosen by the doctor based on an assessment of the risk of thromboembolism and the risk of bleeding. In patients without thromboembolic complications and with a low risk of venous thromboembolism the drug is recommended to be administered s.c. at the rate of 1.5 mg/kg body weight once daily. In all other patients, including patients with obesity, symptomatic pulmonary embolism, cancer, recurrent venous thromboembolism and proximal thrombosis (in the iliac vein) the drug is recommended to be used at a dose of 1 mg/kg twice daily.

The duration of treatment averages 10 days. Therapy with indirect anticoagulants should be started immediately, and treatment with Clexane^® should be continued until a therapeutic anticoagulant effect is achieved (INR values should be 2.0-3.0).

Prevention of thrombus formation in the extracorporeal circulation system during hemodialysis

The recommended 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 for dual vascular access or to 0.75 mg/kg for single vascular access.

During hemodialysis, Clexane^® should be injected into the arterial part of the shunt at the beginning of the hemodialysis session. One dose is usually sufficient for a 4-hour session, but if fibrin rings are detected during longer hemodialysis, an additional dose of the drug can be administered at the rate of 0.5-1 mg/kg body weight.

There is no data regarding patients receiving Enoxaparin sodium for prophylaxis or treatment and during hemodialysis sessions.

Treatment of unstable angina and myocardial infarction without ST-segment elevation

Clexane^® is administered at the rate of 1 mg/kg body weight every 12 hours, s.c., with simultaneous use of antiplatelet therapy. The average duration of therapy is at least 2 days and continues until the patient’s clinical condition stabilizes. Usually, drug administration continues from 2 to 8 days.

Acetylsalicylic acid is recommended for all patients without contraindications, with an initial dose of 150-300 mg orally followed by a maintenance dose of 75-325 mg once daily.

Treatment of acute ST-segment elevation myocardial infarction, medical or with percutaneous coronary intervention

Treatment begins with a single intravenous bolus injection of enoxaparin sodium at a dose of 30 mg. Immediately after it, Enoxaparin sodium is administered s.c. at a dose of 1 mg/kg body weight. Then the drug is used s.c. at 1 mg/kg body weight every 12 hours (maximum 100 mg of enoxaparin sodium for each of the first two subcutaneous injections, then – 1 mg/kg body weight for the remaining subcutaneous doses, i.e., with a body weight of more than 100 kg, a single dose cannot exceed 100 mg). As soon as possible after detection of acute ST-segment elevation myocardial infarction, patients should be prescribed acetylsalicylic acid simultaneously and, if there are no contraindications, acetylsalicylic acid (in doses of 75-325 mg) should be continued daily for at least 30 days.

The recommended duration of treatment with Clexane^® is 8 days or until the patient is discharged from the hospital (if the hospitalization period is less than 8 days).

When combined with thrombolytics (fibrin-specific and fibrin-nonspecific), Enoxaparin sodium should be administered within the interval from 15 minutes before the start of thrombolytic therapy to 30 minutes after it.

In patients aged 75 years and older, the initial IV bolus administration is not used. The drug is administered subcutaneously at a dose of 0.75 mg/kg every 12 hours (maximum 75 mg of enoxaparin sodium for each of the first two subcutaneous injections, then 0.75 mg/kg body weight for the remaining subcutaneous doses, i.e., for body weight over 100 kg, a single dose cannot exceed 75 mg).

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of enoxaparin sodium was administered less than 8 hours before balloon catheter inflation at the site of coronary artery stenosis, no additional administration of enoxaparin sodium is required. If the last subcutaneous injection of enoxaparin sodium was administered more than 8 hours before balloon catheter inflation, an additional IV bolus of enoxaparin sodium at a dose of 0.3 mg/kg should be administered.

Features of drug administration

The pre-filled disposable syringe is ready for use.

The drug must not be administered intramuscularly!

Subcutaneous administration

Enoxaparin sodium is administered via deep subcutaneous injection.

Injections are preferably performed with the patient in a “lying down” position.

Air bubbles should not be expelled from the syringe before injection to avoid loss of the medicinal product when using pre-filled syringes. If the amount of drug to be administered needs to be adjusted based on the patient’s body weight, pre-filled graduated syringes should be used, removing excess solution before injection to achieve the required volume. It should be taken into account that in some cases it is impossible to obtain an exact dose due to the graduation marks on the syringe; in this case, the volume should be rounded to the nearest mark.

Injections should be performed alternately in the left or right side of the anterior abdominal wall.

The needle must be inserted to its full length, vertically (not from the side), into a skin fold held between the thumb and forefinger until the injection is complete. The skin fold should be released only after the injection is complete.

The injection site should not be massaged after administration of the drug.

Intravenous bolus administration

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

For bolus administration of 30 mg of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, excess drug is removed from the 60 mg, 80 mg, and 100 mg glass syringes so that only 30 mg (0.3 ml) remains. The 30 mg dose can be administered directly IV.

Pre-filled syringes for subcutaneous administration of 60 mg, 80 mg, and 100 mg can be used for IV bolus administration of enoxaparin sodium through a venous catheter. The use of 60 mg syringes is recommended, as this reduces the amount of drug to be removed from the syringe. The 20 mg syringes are not used because they do not contain enough drug for a 30 mg enoxaparin sodium bolus. The 40 mg syringes are not used because they lack graduation marks and thus it is impossible to accurately measure the 30 mg amount.

To improve the accuracy of additional IV bolus administration of small volumes into a 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 with a concentration of 3 mg/ml using a pre-filled 60 mg syringe, it is recommended to use a container with 50 ml of infusion solution (i.e., 0.9% sodium chloride solution or 5% dextrose solution). Using a regular syringe, 30 ml of solution is withdrawn from the infusion solution container and discarded. Enoxaparin sodium (the contents of the 60 mg subcutaneous injection syringe) is injected into the remaining 20 ml of infusion solution in the container. The contents of the container with the diluted enoxaparin sodium solution are gently mixed. The required volume of the diluted enoxaparin sodium solution is withdrawn using a syringe for administration; it is calculated using the formula:

Volume of diluted solution = patient body weight (kg) × 0.1 or using the table below.

Volumes to be administered intravenously after dilution to a concentration of 3 mg/ml

Switching between enoxaparin sodium and oral anticoagulants

Switching between enoxaparin sodium and vitamin K antagonists (VKAs)

Monitoring of the VKA effect requires medical supervision and laboratory tests (prothrombin time, presented as INR).

Since it takes time for the maximum effect of VKAs to develop, therapy with enoxaparin sodium should continue at a constant dose for as long as necessary to maintain INR values (based on two consecutive determinations) within the desired therapeutic range depending on the indications.

For patients receiving VKAs, discontinuation of the VKA and administration of the first dose of enoxaparin sodium should be performed after the INR has fallen below the lower limit of the therapeutic range.

Switching between enoxaparin sodium and direct oral anticoagulants (DOACs)

Discontinuation of enoxaparin sodium and prescription of a DOAC should be performed 0-2 hours before the time of the next scheduled administration of enoxaparin sodium, in accordance with the instructions for use of the oral anticoagulants.

For patients receiving DOACs, administration of the first dose of enoxaparin sodium and discontinuation of the direct oral anticoagulants should be performed at the time corresponding to the next scheduled use of the DOAC.

Use during spinal/epidural anesthesia or lumbar puncture

In case of anticoagulant therapy use during epidural or spinal anesthesia/analgesia or lumbar puncture, neurological monitoring is necessary due to the risk of neuroaxial hematomas (see section “Special Instructions”).

Use of enoxaparin sodium in prophylactic doses

Catheter placement or removal should be performed at least 12 hours after the last injection of the prophylactic dose of enoxaparin sodium.

When using continuous techniques, an interval of at least 12 hours must be observed before catheter removal.

In patients with CrCl ≥15 and <30 ml/min, consideration should be given to doubling the time to puncture or catheter insertion/removal to at least 24 hours.

Preoperative administration of enoxaparin sodium 2 hours before the intervention at a dosage of 20 mg is incompatible with neuroaxial anesthesia.

Use of enoxaparin sodium in therapeutic doses

Catheter placement or removal should be performed at least 24 hours after the last injection of the therapeutic dose of enoxaparin sodium (see section “Contraindications”).

When using continuous techniques, an interval of at least 24 hours must be observed before catheter removal.

In patients with CrCl ≥15 and <30 ml/min, consideration should be given to doubling the time to puncture or catheter insertion/removal to at least 48 hours.

Patients receiving Enoxaparin sodium at doses of 0.75 mg/kg or 1 mg/kg body weight twice daily should not be given a second dose of the drug to increase the interval before catheter placement or replacement. Similarly, consideration should be given to the possibility of delaying the next dose of the drug by at least 4 hours, based on a benefit/risk assessment (the risk of thrombosis and bleeding during the procedure, taking into account the patient’s risk factors). At these time points, anti-Xa activity of the drug is still detectable, and time delays are not a guarantee that the development of a neuroaxial hematoma can be avoided.

Dosage regimen in special patient groups

Children under 18 years of age

The safety and efficacy of enoxaparin sodium in children have not been established.

Elderly patients (over 75 years of age)

Except for the treatment of ST-segment elevation myocardial infarction, for all other indications, dose reduction of enoxaparin sodium in elderly patients without renal impairment is not required.

Patients with renal impairment

• Severe renal impairment (CrCl >15 and <30 ml/min)

The use of enoxaparin sodium is not recommended for patients with end-stage chronic kidney disease (CrCl <15 ml/min) due to lack of data, except for cases of prevention of thrombosis in the extracorporeal circulation system during hemodialysis.

In patients with severe renal impairment (CrCl ≥15 and <30 ml/min), the dose of enoxaparin sodium is reduced according to the tables below, as these patients have increased systemic exposure (duration of action) of the drug.

When using the drug in therapeutic doses, the following dosage regimen adjustment is recommended:

When using the drug for prophylactic purposes, the following dosage regimen adjustment is recommended:

The recommended dosage adjustment does not apply during hemodialysis.

• Mild (CrCl ≥50 and <80 ml/min) and moderate (CrCl≥30 and <50 ml/min) renal impairment

No dose adjustment is required, but patients should be under close medical supervision.

Patients with hepatic impairment

Due to the lack of clinical studies, Clexane^® should be used with caution in patients with hepatic impairment.

Instructions for self-administration of Clexane^®® injection

Pre-filled syringe without needle safety system

Preparing the injection site

1) Choose an area on the right or left side of the anterior abdominal wall. It should be at least 5 cm away from the navel and on the lateral side.

• Do not inject closer than 5 cm from the navel or around existing scars or bruises.
• Alternate injection sites between the left and right sides of the abdomen, depending on the area where you last injected the drug.

2) Wash your hands. Clean (but do not rub) the injection site with an alcohol swab or with water and soap.

3) Assume a comfortable “sitting” or “lying” position and relax. Make sure you can see the site chosen for the injection. A recliner, armchair, or bed is ideal for giving the injection.

Selecting the required dose

1) Carefully remove the needle cap from the syringe. Discard the cap.

• Do not press the plunger before starting the injection to get rid of air bubbles in the syringe. This may lead to loss of the medicinal product.
• After removing the cap, do not allow the needle to touch anything. This is necessary to maintain the cleanliness (sterility) of the needle.

2) If the amount of medicinal product in the syringe already corresponds to your prescribed dose, there is no need to adjust it. You are now ready to administer the drug.

3) If the dose is determined based on body weight, you may need to adjust the dose contained in the syringe to match the prescribed one. In this case, you can get rid of the excess amount of medicinal product by holding the syringe pointing downwards (so that an air bubble remains in the syringe) and expelling the excess amount of solution into a container.

4) A drop may appear at the tip of the needle. In this case, remove the drop before injection by tapping the syringe held needle downwards. You are now ready to administer the drug.

Injection

1) Hold the syringe in your writing hand (like a pencil). With the index finger and thumb of your other hand, gently pinch the disinfected area of the abdomen to form a skin fold.

• Make sure you hold the skin fold during the injection.

2) Hold the syringe so that the needle is pointing straight down (vertically at a 90° angle). Insert the needle into the skin fold for its entire length.

3) Press the syringe plunger with your thumb. This will deliver the medicinal product into the subcutaneous adipose tissue of the abdomen. Complete the injection by administering the entire volume of the medicinal product in the syringe.

4) Remove the needle from the injection site by pulling the syringe straight up. Point the needle away from yourself and others. You can now release the skin fold.

After completing the injection

1) To avoid bruising, do not rub the injection site after performing this procedure.

2) Discard the used syringe in a sharps container. Close the container lid tightly and keep it out of the reach of children. After the container is full, dispose of it according to your doctor’s or pharmacist’s instructions.

All unused medicinal product or waste should be disposed of in accordance with local requirements.

Pre-filled syringe with ERIS needle safety system

Preparing the injection site

1) Choose an area on the right or left side of the anterior abdominal wall. It should be at least 5 cm away from the navel and on the lateral side.

• Do not inject closer than 5 cm from the navel or around existing scars or bruises.
• Alternate injection sites between the left and right sides of the abdomen, depending on the area where you last injected the drug.

2) Wash your hands. Clean (but do not rub) the injection site with an alcohol swab or with water and soap.

3) Assume a comfortable “sitting” or “lying” position and relax. Make sure you can see the site chosen for the injection. A recliner, armchair, or bed is ideal for giving the injection.

Selecting the required dose

1) Carefully remove the needle cap from the syringe. Discard the cap.

• Do not press the plunger before starting the injection to get rid of air bubbles in the syringe. This may lead to loss of the medicinal product.
• After removing the cap, do not allow the needle to touch anything. This is necessary to maintain the cleanliness (sterility) of the needle.

2) If the amount of medicinal product in the syringe already corresponds to your prescribed dose, there is no need to adjust it. You are now ready to administer the drug.

3) If the dose is determined based on body weight, you may need to adjust the dose contained in the syringe to match the prescribed one. In this case, you can get rid of the excess amount of medicinal product by holding the syringe pointing downwards (so that an air bubble remains in the syringe) and expelling the excess amount of solution into a container.

4) A drop may appear at the tip of the needle. In this case, remove the drop before injection by tapping the syringe held needle downwards. You are now ready to administer the drug.

Injection

1) Hold the syringe in your writing hand (like a pencil). With the index finger and thumb of your other hand, gently pinch the disinfected area of the abdomen to form a skin fold.

• Make sure you hold the skin fold during the injection.

2) Hold the syringe so that the needle is pointing straight down (vertically at a 90° angle). Insert the needle into the skin fold for its entire length.

3) Press the syringe plunger with your thumb. This will deliver the medicinal product into the subcutaneous adipose tissue of the abdomen. Complete the injection by administering the entire volume of the medicinal product in the syringe.

4) Remove the needle from the injection site by pulling the syringe straight up. The protective mechanism will automatically cover the needle. You can now release the skin fold. The safety system ensuring the activation of the needle protective mechanism is triggered only after the entire contents of the syringe have been administered by pressing the plunger through its full stroke.

After completing the injection

1) To avoid bruising, do not rub the injection site after performing this procedure.

2) Dispose of the used syringe in a sharps container. Close the container tightly with the lid and keep it out of the reach of children. After the container is full, dispose of it according to the instructions of your doctor or pharmacist.

All unused medicinal product or waste should be disposed of in accordance with local requirements.

When using the drug, strictly adhere to the recommendations presented above, as well as the instructions of your doctor or pharmacist. If you have any questions, consult your doctor or pharmacist.

PREVENTIS needle safety system prefilled syringe

Preparing the injection site

1) Select an area on the right or left side of the anterior abdominal wall. It should be at least 5 cm away from the navel and on the lateral side.

• Do not inject closer than 5 cm from the navel or around existing scars or bruises.
• Alternate injection sites between the left and right sides of the abdomen, depending on the area where you last administered the drug.

2) Wash your hands. Clean (but do not rub) the injection site with an alcohol swab or with soap and water.

3) Assume a comfortable sitting or lying position and relax. Make sure you can see the chosen injection site. A recliner, armchair, or bed is ideal for administering the injection.

Selecting the required dose

1) Carefully remove the needle cap from the syringe. Discard the cap.

• Do not press the plunger before the injection to get rid of air bubbles in the syringe. This may lead to loss of the medicinal product.
• After removing the cap, do not allow the needle to touch any objects. This is necessary to maintain the cleanliness (sterility) of the needle.

2) If the amount of medicinal product in the syringe already corresponds to your prescribed dose, there is no need to adjust it. You are now ready to administer the drug.

3) If the dose is determined based on body weight, you may need to adjust the dose contained in the syringe to match the prescribed dose. In this case, you can get rid of the excess amount of medicinal product by holding the syringe pointing downward (so that an air bubble remains in the syringe) and expelling the excess solution into a container.

4) A drop may appear at the tip of the needle. In this case, remove the drop before the injection by tapping the syringe with the needle pointing downward. You are now ready to administer the drug.

Injection

1) Hold the syringe in your writing hand (like a pencil). With the index finger and thumb of your other hand, gently pinch the disinfected area of the abdomen to form a skin fold.

• Make sure you hold the skin fold during the injection.

2) Hold the syringe so that the needle is pointing straight down (vertically at a 90° angle). Insert the needle fully into the skin fold.

3) Press the syringe plunger with your thumb. This will deliver the medicinal product into the subcutaneous adipose tissue of the abdomen. Complete the injection by administering the entire volume of the medicinal product in the syringe.

4) Remove the needle from the injection site by pulling the syringe straight up, keeping your finger on the plunger. Point the needle away from yourself and others and press the plunger firmly to activate the safety system. The protective mechanism will automatically cover the needle. You will hear a “click” confirming the activation of the protective mechanism. You can now release the skin fold.

FIGURE

After completing the injection

1) To avoid bruising, do not rub the injection site after performing this procedure.

2) Dispose of the used syringe in a sharps container. Close the container tightly with the lid and keep it out of the reach of children. After the container is full, dispose of it according to the instructions of your doctor or pharmacist.

All unused medicinal product or waste should be disposed of in accordance with local requirements.

When using the drug, strictly adhere to the recommendations presented above, as well as the instructions of your doctor or pharmacist. If you have any questions, consult your doctor or pharmacist.

Adverse Reactions

The study of adverse effects of enoxaparin sodium was conducted in more than 15,000 patients participating in clinical trials, of which 1,776 patients were for the prevention of venous thrombosis and embolism in general surgical and orthopedic operations, 1,169 patients were for the prevention of venous thrombosis and embolism in bedridden patients due to acute therapeutic diseases, 559 patients were for the treatment of deep vein thrombosis with or without pulmonary embolism, 1,578 patients were for the treatment of unstable angina and non-Q-wave myocardial infarction, and 10,176 patients were for the treatment of ST-segment elevation myocardial infarction.

The administration regimen of enoxaparin sodium differed depending on the indication. For the prevention of venous thrombosis and embolism in general surgical and orthopedic operations or in bedridden patients, 40 mg was administered subcutaneously once daily. 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. For 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, a bolus injection of 30 mg was administered followed by a dose of 1 mg/kg body weight subcutaneously every 12 hours. The frequency of adverse reactions was determined in accordance with the WHO classification: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Vascular disorders

Bleeding

In clinical trials, bleeding was the most frequently reported 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 of 2 g/L or more, required transfusion of 2 or more units of blood components, or if it was retroperitoneal or intracranial). Some of these cases were fatal.

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

In the description of bleeding below, the “*” sign indicates the following types of bleeding: hematoma, ecchymosis (other than those developing at the injection site), wound hematoma, hematuria, epistaxis, gastrointestinal bleeding.

Very common – bleeding* in the prevention of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without pulmonary embolism.

Common – bleeding* in the prevention of venous thrombosis in bedridden patients and in the treatment of unstable angina, non-Q-wave myocardial infarction, and ST-segment elevation myocardial infarction.

Uncommon – retroperitoneal bleeding and intracranial hemorrhage in patients during treatment of deep vein thrombosis with or without pulmonary embolism, as well as in ST-segment elevation myocardial infarction.

Rare – retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of unstable angina, non-Q-wave myocardial infarction.

Thrombocytopenia and thrombocytosis

Very common – thrombocytosis (platelet count in peripheral blood greater than 400×10⁹/L) in the prevention of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without pulmonary embolism.

Common – thrombocytosis in the treatment of patients with acute ST-segment elevation myocardial infarction; thrombocytopenia in the prevention of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without pulmonary embolism, as well as in ST-segment elevation myocardial infarction.

Uncommon – thrombocytopenia in the prevention of venous thrombosis in bedridden patients and in the treatment of unstable angina, non-Q-wave myocardial infarction.

Very rare – autoimmune thrombocytopenia in the treatment of patients with acute ST-segment elevation myocardial infarction.

Other clinically significant adverse reactions regardless of indication

The adverse reactions listed below are grouped by system-organ class, with the frequency of occurrence specified above, and in order of decreasing severity.

Blood and lymphatic system disorders common – bleeding, thrombocytopenia, thrombocytosis; rare – cases of autoimmune thrombocytopenia with thrombosis; in some cases, thrombosis was complicated by the development of organ infarction or limb ischemia (see section “Special Precautions”).

Immune system disorders common – allergic reactions; rare – anaphylactic and anaphylactoid reactions.

Hepatobiliary disorders very common – increased activity of liver enzymes, mainly an increase in transaminase activity more than 3 times the upper limit of normal.

Skin and subcutaneous tissue disorders common – urticaria, pruritus, erythema; uncommon – bullous dermatitis.

General disorders and administration site conditions common – hematoma, pain, swelling at the injection site, bleeding, hypersensitivity reactions, inflammation, induration at the injection site; uncommon – irritation at the injection site, skin necrosis at the injection site.

Data from post-marketing experience

The following adverse reactions have been reported during the post-marketing use of Clexane^®. These side effects have been reported spontaneously.

Immune system disorders rare – anaphylactic/anaphylactoid reactions, including shock.

Nervous system disorders rare – headache.

Vascular disorders: rare – when enoxaparin sodium was used in the context of spinal/epidural anesthesia or spinal puncture, cases of spinal hematoma (or neuroaxial hematoma) have been reported. These reactions led to neurological impairments of varying severity, including persistent or irreversible paralysis.

Blood and lymphatic system disorders: common – hemorrhagic anemia; rare – eosinophilia.

Skin and subcutaneous tissue disorders rare – alopecia; cutaneous vasculitis, skin necrosis may develop at the injection site, usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful), in these cases therapy with Clexane^® should be discontinued; formation of hard inflammatory nodules-infiltrates at the injection sites of the drug is possible, which disappear after a few days and are not a reason for drug discontinuation.

Hepatobiliary disorders uncommon – hepatocellular liver damage; rare – cholestatic liver damage.

Musculoskeletal and connective tissue disorders rare – osteoporosis with long-term therapy (more than 3 months).

Investigations rare – hyperkalemia.

Contraindications

• Hypersensitivity to enoxaparin, heparin and its derivatives, including other low molecular weight heparins;
• Active clinically significant bleeding, as well as conditions and diseases with a high risk of bleeding, including recently suffered hemorrhagic stroke, acute gastrointestinal ulcer, presence of a malignant neoplasm with a high risk of bleeding, recent operations on the brain and spinal cord, ophthalmic operations, known or suspected presence of esophageal varices, arteriovenous malformations, vascular aneurysms, vascular anomalies of the spinal cord and brain;
• Spinal or epidural anesthesia or locoregional anesthesia when Enoxaparin sodium was used for treatment in the previous 24 hours;
• Immune-mediated heparin-induced thrombocytopenia (in history) within the last 100 days or presence of circulating antiplatelet antibodies in the blood;
• Age under 18 years (efficacy and safety not established).

With caution

Conditions with a potential risk of bleeding:

• Hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, von Willebrand disease), severe vasculitis;
• History of gastric and duodenal ulcer or other erosive-ulcerative lesions of the gastrointestinal tract;
• Recently suffered ischemic stroke;
• Uncontrolled severe arterial hypertension;
• Diabetic or hemorrhagic retinopathy;
• Severe diabetes mellitus;
• Recent or anticipated neurological or ophthalmic surgery;
• Performance of spinal or epidural anesthesia (potential risk of hematoma), lumbar puncture (recently performed);
• Recent childbirth;
• Bacterial endocarditis (acute or subacute);
• Pericarditis or pericardial effusion;
• Renal and/or hepatic impairment;
• Intrauterine contraceptive device (IUD);
• Severe trauma (especially CNS), open wounds with a large wound surface;
• Concomitant use of drugs affecting the hemostasis system;
• History of heparin-induced thrombocytopenia without circulating antibodies (more than 100 days ago).

The company lacks data on the clinical use of Clexane^® in the following conditions: active tuberculosis, radiotherapy (recently undergone).

Use in Pregnancy and Lactation

Pregnancy

There is no information that Enoxaparin sodium crosses the placental barrier in the second trimester, and there is no corresponding 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 administration during human pregnancy, Clexane^® should be used during pregnancy only in exceptional cases when there is an urgent need for its use, as determined by a physician.

Monitoring of patients for signs of bleeding or excessive anticoagulation is recommended; patients should be warned about the risk of bleeding.

There are no data on an increased risk of bleeding, thrombocytopenia, or osteoporosis in pregnant women, except for cases noted in patients with prosthetic heart valves (see section “Special Precautions”).

When planning epidural anesthesia, it is recommended to discontinue Enoxaparin sodium before its performance (see section “Special Precautions”).

Breastfeeding period

It is not known whether unchanged Enoxaparin sodium is excreted in breast milk. Absorption of enoxaparin sodium from the gastrointestinal tract in a newborn is unlikely. The drug Clexane^® can be used during breastfeeding.

Use in Hepatic Impairment

Use with caution in hepatic impairment.

Use in Renal Impairment

Use with caution in renal impairment.

Pediatric Use

Contraindication: age under 18 years (efficacy and safety not established).

Geriatric Use

In patients aged 75 years and older, initial intravenous bolus administration is not used. Enoxaparin sodium is administered subcutaneously at a dose of 0.75 mg/kg every 12 hours (moreover, during the first two subcutaneous injections, a maximum of 75 mg of Enoxaparin sodium can be administered each). Then all subsequent subcutaneous doses are administered every 12 hours at a dose of 0.75 mg/kg body weight (i.e., with a body weight over 100 kg, the dose may exceed 75 mg).

Special Precautions

General

Low molecular weight heparins are not interchangeable because they differ in the manufacturing process, molecular weight, specific anti-Xa activity, dosing units, and dosing regimen, which is 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, bleeding of any location may develop with the use of Clexane^®. If bleeding occurs, it is necessary to identify its source and provide appropriate treatment.

Enoxaparin sodium, like other anticoagulants, should be used with caution in conditions with an increased risk of bleeding, such as

• Hemostasis disorders;
• History of peptic ulcer;
• Recently suffered ischemic stroke;
• Severe arterial hypertension;
• Diabetic retinopathy;
• Neurosurgical or ophthalmic surgical intervention;
• Concomitant use of drugs affecting hemostasis (see section “Drug Interactions”).

Bleeding in elderly patients

When using enoxaparin sodium in prophylactic doses in elderly patients, no risk of bleeding was noted.

When using the drug in therapeutic doses in elderly patients (especially those aged ≥80 years), there is an increased risk of bleeding. Thorough monitoring of such patients is recommended.

Concomitant use of other drugs affecting hemostasis

The use of drugs affecting hemostasis (systemic salicylates, including acetylsalicylic acid in doses that have an anti-inflammatory effect, NSAIDs, including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) is recommended to be discontinued before starting treatment with enoxaparin sodium, except in cases where their use is necessary. If their concomitant use with enoxaparin sodium is indicated, then careful clinical monitoring and monitoring of relevant laboratory parameters should be carried out.

Renal impairment

In patients with impaired renal function, there is an increased risk of bleeding due to increased systemic exposure to enoxaparin sodium.

In patients with severe renal impairment (CrCl ≥15 and <30 ml/min), a significant increase in exposure to enoxaparin sodium is observed, so dose adjustment is recommended for both prophylactic and therapeutic use of the drug. Although no dose adjustment is required in patients with mild (CrCl ≥30 and <50 ml/min) and moderate (CrCl ≥50 and <80 ml/min) renal impairment, careful monitoring of such patients is recommended, and biological monitoring with measurement of anti-Xa activity may be considered. The use of enoxaparin sodium is not recommended in patients with end-stage chronic kidney disease (CrCl <15 ml/min) due to lack of data, except for cases of prevention of thrombosis in the extracorporeal circulation system during hemodialysis.

Low body weight

Increased exposure to enoxaparin sodium was observed during its prophylactic use in women with a body weight of less than 45 kg and in men with a body weight of less than 57 kg, which may lead to an increased risk of bleeding. Close monitoring of such patients is recommended.

Obese patients

Obese patients have an increased risk of thrombosis and embolism. The safety and efficacy of enoxaparin in prophylactic doses in obese patients (BMI >30 kg/m²) have not been fully established, and there is no general consensus on dose adjustment. Such patients should be closely monitored for the development of symptoms and signs of thrombosis and embolism.

Monitoring of platelet count in peripheral blood

The risk of antibody-mediated heparin-induced thrombocytopenia (HIT) exists even with the use of low molecular weight heparins, and this risk is higher in patients who have undergone cardiac surgery and in patients with cancer. If thrombocytopenia develops, it is usually detected between the 5th and 21st days after the start of enoxaparin sodium therapy. In this regard, it is recommended to regularly monitor the platelet count in peripheral blood before starting treatment with enoxaparin sodium and during its use. The platelet count should be determined in the presence of symptoms indicating HIT (a new episode of arterial and/or venous thromboembolic complications, painful skin lesion at the injection site, allergic or anaphylactic reaction during treatment). If these symptoms occur, the attending physician should be informed.

If a confirmed significant decrease in platelet count (by 30-50% compared to the baseline) is present, it is necessary to immediately discontinue Enoxaparin sodium and switch the patient to another anticoagulant therapy without the use of heparins.

Spinal/epidural anesthesia

Cases of neuraxial hematomas have been described with the use of the drug Clexane^® during simultaneous spinal/epidural anesthesia, resulting in persistent or permanent paralysis. The risk of these events is reduced when the drug is used at a dose of 40 mg or lower. The risk increases with the use of the drug Clexane^® in higher doses, as well as with the use of indwelling catheters postoperatively, or with the simultaneous use of additional drugs affecting hemostasis, such as NSAIDs. The risk also increases with traumatically performed 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 the performance of epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug must be taken into account. Placement or removal of the catheter is best performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact time to achieve a sufficient reduction in the anticoagulant effect varies among patients. It should be additionally considered that in patients with CrCl 15-30 ml/min, the elimination of enoxaparin sodium is slowed.

If anticoagulant therapy is used as prescribed by a physician during epidural/spinal anesthesia, constant monitoring of the patient is necessary to detect any neurological symptoms, such as: back pain, sensory and motor dysfunction (numbness or weakness in the lower limbs), bowel and/or bladder dysfunction. The patient should be instructed to immediately inform the doctor if the above symptoms occur. If symptoms characteristic of a spinal hematoma are suspected, urgent diagnosis and treatment, including spinal cord decompression if necessary, are required.

Heparin-induced thrombocytopenia

The use of enoxaparin sodium in patients with a history of heparin-induced thrombocytopenia within the last 100 days or in the presence of circulating antibodies is contraindicated. Circulating antibodies can persist for several years.

Enoxaparin sodium should be used with extreme caution in patients with a history (more than 100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in this situation should be made only after assessing the benefit/risk ratio and in the absence of a heparin-free (non-heparin) alternative therapy.

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 procedures should be performed in the intervals between administrations of the drug Clexane^®. This is necessary to achieve hemostasis after percutaneous coronary intervention. When using a closure device, the femoral artery introducer can be removed immediately. With manual compression, the femoral artery introducer should be removed 6 hours after the last IV or SC injection of enoxaparin sodium. If treatment with enoxaparin sodium continues, the next dose should be administered no earlier than 6-8 hours after the removal of the femoral artery introducer. The introducer site should be monitored to promptly detect signs of bleeding and hematoma formation.

Patients with mechanical prosthetic heart valves

The use of the drug Clexane^® for the prevention of thrombosis in patients with mechanical prosthetic heart valves has not been sufficiently studied. There are isolated reports of heart valve thrombosis in patients with mechanical prosthetic heart valves during therapy with enoxaparin sodium for thrombosis prophylaxis. Due to insufficient clinical data and the presence of ambiguous factors, including the underlying disease, the assessment of such reports is difficult.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin sodium for the prevention of thrombosis in pregnant women with mechanical prosthetic heart valves has not been sufficiently studied.

In a clinical study involving 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 thrombi that led to heart valve blockage and the death of the mother and fetus.

There are isolated post-marketing reports of heart valve thrombosis in pregnant women with mechanical prosthetic heart valves receiving treatment with enoxaparin sodium for thrombosis prophylaxis.

Pregnant women with mechanical prosthetic heart valves may have an increased risk of thrombosis and embolism.

Skin necrosis/cutaneous vasculitis

Cases of skin necrosis and cutaneous vasculitis have been reported with the use of low molecular weight heparins. In case of development of skin necrosis/cutaneous vasculitis, the use of the drug should be discontinued.

Acute infective endocarditis

The use of heparin is not recommended in patients with acute infective endocarditis due to the risk of hemorrhagic stroke. If the use of the drug is considered absolutely necessary, the decision should be made only after a thorough individual assessment of the benefit-risk ratio.

Laboratory tests

At doses used for the prevention of thromboembolic complications, the drug Clexane^® does not significantly affect bleeding time and blood coagulation parameters, nor platelet aggregation or their binding to fibrinogen.

With an increase in dose, aPTT and activated clotting time may be prolonged. The increase in aPTT and activated clotting time is not in a direct linear relationship with the increase in the anticoagulant activity of the drug, so there is no need to monitor them.

Hyperkalemia

Heparins can suppress aldosterone secretion by the adrenal glands, leading to the development of hyperkalemia, especially in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking medications that increase potassium levels (see the “Drug Interactions” section). Plasma potassium levels should be monitored regularly, especially in at-risk patients.

Prevention of venous thrombosis and embolism in patients with acute medical conditions on bed rest

In case of development of acute infection, acute rheumatic conditions, prophylactic administration of enoxaparin sodium is justified only if the above conditions are combined with one of the following risk factors for venous thrombosis: age over 75 years, malignant neoplasms, history of thrombosis and embolism, obesity, hormonal therapy, heart failure, chronic respiratory failure.

Liver dysfunction

Enoxaparin sodium should be used with caution in patients with liver dysfunction due to an increased risk of bleeding. Dose adjustment based on monitoring of anti-Xa activity in patients with liver cirrhosis is unreliable and is not recommended.

Effect on ability to drive vehicles and mechanisms

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

Overdose

Symptoms accidental overdose with IV, extracorporeal or SC administration may lead to hemorrhagic complications. When taken orally, even in large doses, absorption of the drug is unlikely.

Treatment anticoagulant effects can be largely neutralized by slow IV injection of protamine sulfate, the dose of which depends on the dose of the administered drug; as a neutralizing agent, slow IV injection of protamine sulfate is indicated, the dose of which depends on the dose of the administered drug. It must be taken into account that 1 mg of protamine neutralizes the anticoagulant effect of 1 mg of enoxaparin if Clexane^® 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 the drug if it was administered more than 8 hours ago or if a second dose of protamine is required. If more than 12 hours have passed after the administration of enoxaparin sodium, then the administration of protamine is not required. However, even with the administration of protamine sulfate in high doses, the anti-Xa activity of the drug Clexane^® is not completely neutralized (maximum by 60%).

Drug Interactions

Clexane^® must not be mixed with other drugs!

Not recommended combinations

Drugs affecting hemostasis (systemic salicylates, acetylsalicylic acid in doses exerting an anti-inflammatory effect, NSAIDs, including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) are recommended to be discontinued before starting therapy with enoxaparin sodium. If simultaneous use with enoxaparin sodium is necessary, caution should be exercised and careful clinical monitoring and monitoring of relevant laboratory parameters should be carried out.

Combinations requiring caution

Other medicinal products affecting hemostasis, such as

• Platelet aggregation inhibitors, including acetylsalicylic acid in doses exerting an antiplatelet effect (cardioprotection), clopidogrel, ticlopidine and glycoprotein IIb/IIIa receptor antagonists, indicated for acute coronary syndrome, due to an increased risk of bleeding;
• Dextran with a molecular weight of 40 kDa;
• Systemic corticosteroids.

Medicinal products that increase potassium levels: when used concomitantly with medicinal products that increase serum potassium levels, clinical and laboratory monitoring should be performed.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.