Quadraparin-SOLofarm, 10000 anti-ha me/ml 0.4 ml syringes 10 pcs

Pharmacotherapeutic group

A direct acting anticoagulant.

ATC code: B01AB05

Pharmacological properties

Enoxaparin sodium is a low molecular weight heparin with an average molecular weight of about 4500 daltons: less than 2000 daltons, < 20%, 2000 to 8000 daltons, > 68%, more than 8000 daltons, < 18%. Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester isolated from pig small intestine mucosa. Its structure is characterized by a nonreducible fragment of 2-O-sulfo-4-enpyrazino-suronic acid and a reducible fragment of 2-N,6-O-disulfo-D-gluco-pyranoside. 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 human and animal models. These include AT-III dependent inhibition of other clotting factors such as 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.

The use of the drug in prophylactic doses slightly changes the activated partial thromboplastin time (APT), has almost no effect on platelet aggregation and on the degree of binding of fibrinogen to platelet receptors.

Pharmacokinetics

Bioavailability and absorption

The absolute bioavailability of enoxaparin sodium with subcutaneous (p/k) administration, estimated on the basis of anti-Xa activity, is close to 100%.

The mean maximal plasma anti-Xa activity is observed 3-5 h after b/c administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU/ml after b/c administration of 20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg.

Intravenous bolus administration of 30 mg followed by immediate subcutaneous administration of 1 mg/kg every 12 h provides an initial maximum anti-Xa activity of 1.16 IU/ml (n=16), with mean blood exposure of approximately 88% of the equilibrium state reached by the second day of therapy.

The pharmacokinetics of enoxaparin sodium in the indicated dosing regimens is linear. The variability within and between patient groups is low. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once daily and subcutaneous administration of 1.5 mg/kg body weight once daily in healthy volunteers the equilibrium concentration is reached by the second day, 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 a day the equilibrium concentration is reached after 3-4 days, the area under the curve (AUC) is on average 65 % higher than after a single injection, and average values of maximum concentrations are 1.2 ME/ml and 0.52 ME/ml respectively.

The anti-IIa activity in plasma is about 10 times lower than the anti-Xa activity. Mean 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.

Distribution

The volume of distribution of the anti-Xa activity of enoxaparin sodium is approximately 4.3 L and approximates the volume of circulating blood.

Elimination

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 anti-Xa plasma clearance is 0.74 L/hour.

The excretion of the drug is monophasic with a half-life (T_1/2) of about 5 hours (after single subcutaneous 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. Excretion through the kidneys of active drug fragments is approximately 10% of the administered dose, and total excretion of active and inactive fragments is approximately 40% of the administered dose.

Particular patient groups

Patients in the elderly (over 75 years): The pharmacokinetic profile of enoxaparin sodium does not differ in elderly patients and younger patients with normal renal function. However, as a result of decreased renal function with age, slower excretion of enoxaparin sodium may be observed in elderly patients.

Liver dysfunction: In a study involving patients with advanced liver cirrhosis who received enoxaparin sodium at a dose of 4000 IU (40 mg) once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of liver function impairment (as assessed by the Child-Pugh score). This decrease was mainly due to a decrease in AT-III levels secondary to a decrease in AT-III synthesis in patients with impaired liver function.

With impaired renal function: decreased clearance of enoxaparin sodium has been noted in patients with impaired renal function. After repeated subcutaneous administration of 40 mg of enoxaparin sodium once a day there is increase of anti-Xa activity represented by area under pharmacokinetic curve (AUC) in patients with mild (creatinine clearance ≥50 and <80 ml/min) and moderate renal dysfunction (creatinine clearance ≥30 and <50 ml/min). In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the AUC at equilibrium is on average 65% higher with repeated subcutaneous administration of 40 mg of the drug once daily.

Hemodialysis: The pharmacokinetics of enoxaparin sodium were comparable to those in the control population after single intravenous doses of 25 IU, 50 IU or 100 IU/kg (0.25, 0.50 or 1.0 mg/kg), but the AUC was twice as high as in the control population.

Body weight: After repeated subcutaneous doses of 1.5 mg/kg once daily, mean AUC of anti-Xa activity at equilibrium was slightly higher in overweight patients (BMI 30-48 kg/m²) compared with patients with normal average body weight, whereas maximum plasma anti-Xa activity was not increased. In overweight patients with subcutaneous administration of the drug, the clearance is slightly lower. If no dose adjustment is made for patient weight, after a single subcutaneous injection of 40 mg of sodium enoxaparin, anti-Xa activity will be 52% 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

– Prevention of venous thrombosis and embolism in surgical interventions in moderate- and high-risk patients, especially in orthopedic and general surgical interventions, including oncology;

– Prevention of venous thrombosis and embolism in bedridden patients due to acute therapeutic conditions, including acute heart failure and decompensation of chronic heart failure (NYHA class III or IV), respiratory failure, and in severe infections and rheumatic diseases at increased risk of venous thrombosis (see

– Treatment of deep vein thrombosis with or without pulmonary embolism, except in cases of pulmonary embolism requiring thromboembolic therapy or surgery;

– Prevention of thrombosis in the extracorporeal circulation system during hemodialysis;

– Acute coronary syndrome:

– Treatment of unstable angina and myocardial infarction without ST-segment elevation in combination with oral administration of acetylsalicylic acid;

– Treatment of acute myocardial infarction with ST-segment elevation in patients undergoing medication-assisted treatment or subsequent percutaneous coronary intervention (PCI).

Active ingredient

Enoxaparin sodium

Composition

1 syringe or ampoule (0.4 ml) contains:

the active ingredient: enoxaparin sodium 4000 anti-Ha IU (40 mg)

excipient: water for injection – up to 0.4 ml.

How to take, the dosage

Subcutaneously, except in special cases (see subsections “Prevention of thrombosis in extracorporeal circulation during hemodialysis” and “Treatment of acute ST-segment elevation myocardial infarction, medication-assisted or percutaneous coronary intervention” below).

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

Patients at moderate risk for thrombosis and embolism (e.g., abdominal surgeries) have a recommended dose of 20 mg once daily subcutaneously. The first injection should be given 2 hours before surgery.

. In patients at high risk of thrombosis and embolism (e.g., orthopedic surgery, oncologic surgery, patients with additional risk factors unrelated to surgery, such as congenital or acquired thrombophilia malignant neoplasm, bed rest for more than three days, obesity, venous thrombosis in anamnesis, varicose veins of lower limbs, pregnancy) the drug is recommended in a dose of 40 mg once a day subcutaneously, with the first dose administered 12 hours before the surgical intervention. If earlier preoperative prophylaxis is necessary (e.g., 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 the drug is on average 7-10 days. If necessary, therapy may be continued as long as the risk of thrombosis and embolism persists and as long as the patient remains ambulatory.

In major orthopedic surgeries, it may be appropriate to continue treatment after initial therapy with a dose of 40 mg once daily for five weeks.

In 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 therapy with a dose of 40 mg once daily for four weeks.

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

The recommended dose of the drug is 40 mg once daily, subcutaneously, for at least 6-14 days. Therapy should be continued until the patient is fully transitioned to an outpatient regimen (for a maximum of 14 days).

The treatment of deep vein thrombosis with or without pulmonary embolism

The drug is administered subcutaneously at a 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 a physician based on the assessment of the risk of thromboembolism and the risk of bleeding. In patients without thromboembolic complications and at low risk of venous thromboembolism, the drug is recommended to be administered subcutaneously at a 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 at a dose of 1 mg/kg twice daily.

The duration of treatment is on average 10 days. Therapy with indirect anticoagulants should be started immediately, and treatment with the drug should be continued until therapeutic anticoagulant effect is achieved (INR [International Normalized Ratio] values should be 2.0-3.0).

Prevention of thrombosis in the extracorporeal circulation system during hemodialysis

The recommended dose of the drug is on average 1 mg/kg body weight. If the risk of bleeding is high, the dose should be reduced to 0.5 mg/kg body weight for dual vascular access or 0.75 mg for single vascular access.

In hemodialysis, enoxaparin sodium should be injected into the arterial shunt site at the beginning of the hemodialysis session. A single dose is usually sufficient for a four-hour session; however, if fibrin rings are detected during longer hemodialysis, an additional dose of 0.5-1 mg/kg body weight may be administered.

There are no data available for patients using enoxaparin sodium for prophylaxis or treatment and during hemodialysis sessions.

The treatment of unstable angina and myocardial infarction without ST-segment elevation

The drug is administered at a rate of 1 mg/kg body weight every 12 hours, subcutaneously, with concomitant use of antiplatelet therapy. The average duration of therapy is at least 2 days and continues until the patient’s clinical condition stabilizes. Usually the drug administration lasts 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.

The treatment of acute ST-segment elevation myocardial infarction, drug or percutaneous coronary intervention

The treatment begins with a single intravenous bolus injection of Enoxaparin sodium at a dose of 30 mg. Immediately thereafter, enoxaparin sodium is administered subcutaneously at a dose of 1 mg/kg of body weight. The drug is then administered subcutaneously at 1 mg/kg of body weight every 12 hours (maximum 100 mg of sodium enoxaparin for each of the first two subcutaneous injections, then 1 mg/kg of body weight for the remaining subcutaneous doses, that is, if the body weight exceeds 100 kg, the single dose may not exceed 100 mg). As soon as possible after detection of acute myocardial infarction with ST-segment elevation, patients should be simultaneously prescribed acetylsalicylic acid and, if there are no contraindications, administration of acetylsalicylic acid (in doses of 75-325 mg) should be continued daily for at least 30 days.

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

When combined with thrombolytics (fibrin-specific and fibrin-unspecific), enoxaparin sodium must be administered between 15 minutes before and 30 minutes after thrombolytic therapy.

In patients aged 75 years and older, an initial intravenous bolus injection 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, that is, if body weight exceeds 100 kg, the single dose cannot exceed 75 mg).

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

Pretentions for administration

The prefilled disposable syringe is ready for use.

The drug must not be administered intramuscularly!

The subcutaneous administration

Injections should preferably be performed in the supine position of the patient. If pre-filled syringes are used, air bubbles should not be removed from the syringe prior to 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 full length vertically (not laterally) into the skin fold, gathered and held between the thumb and forefinger until the injection is complete. The skin fold is not released until the injection is complete.

The injection site should not be massaged after the injection.

Intravenous bolus injection

Intravenous bolus injection of sodium enoxaparin should be performed through a venous catheter. Enoxaparin sodium should not be mixed or administered together with other medications. In order to avoid the presence of traces of other drugs in the infusion system and their interaction with sodium enoxaparin, the venous catheter should be flushed with sufficient amounts of 0.9% sodium chloride solution or 5% dextrose solution 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.

In order to perform a 30 mg bolus infusion of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the excess amount is removed from the larger glass syringes so that only 30 mg (0.3 ml) remains. The 30 mg dose can be directly administered intravenously.

Pre-filled 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg and 100 mg hypodermic syringes may be used for intravenous bolus injection of enoxaparin sodium via a venous catheter. We recommend the use of 30 mg, 40 mg, 50 mg, and 60 mg syringes because it reduces the amount of drug removed from the syringe. The 20 mg syringe is not used because it does not contain enough product to bolus 30 mg of enoxaparin sodium.

In order to increase the accuracy of additional small volume intravenous bolus injections into a venous catheter during percutaneous coronary interventions, it is recommended that the drug be diluted to a concentration of 3 mg/ml. Dilution of the solution is recommended immediately prior to administration.

To obtain enoxaparin sodium solution at a concentration of 3 mg/ml using a pre-filled 60 mg syringe, it is recommended to use a 50 ml infusion solution container (i.e. 0.9% sodium chloride solution or 5% dextrose solution). From the container with the infusion solution using a normal syringe, 30 ml of the solution is extracted and removed. Enoxaparin sodium (the contents of the 60 mg hypodermic syringe) 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 mixed gently. The necessary volume of diluted enoxaparin sodium solution is extracted for injection using a syringe, which is calculated according to 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

/p>

Switching between enoxaparin sodium and oral anticoagulants

Switching between sodium enoxaparin and vitamin K antagonists (VKAs)

To monitor the effect of VKAs, physician supervision and laboratory tests [prothrombin time, presented as INR] are necessary.

Since it takes time to develop maximum AVC effect, therapy with enoxaparin sodium should be continued at a constant dose as long as necessary to maintain INR values (based on two consecutive determinations) in the desired therapeutic range depending on the indication.

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

Switching between sodium enoxaparin and direct-acting oral anticoagulants (DAAs)

Cancellation of sodium enoxaparin and administration of DAAs should be performed 0-2 h before the next scheduled administration of sodium enoxaparin according to the oral anticoagulants guidelines.

For patients receiving POACs, administration of the first dose of enoxaparin sodium and withdrawal of direct-acting oral anticoagulants should occur at the time corresponding to the next scheduled POAC administration.

The use during spinal/epidural anesthesia or lumbar puncture

If anticoagulant therapy is used during epidural or spinal anesthesia/analgesia or lumbar puncture, neurologic monitoring should be performed due to the risk of neuroaxial hematomas (see section “Special Considerations”).

The use of prophylactic doses of enoxaparin sodium

The insertion or removal of a catheter must be performed at least 12 hours after the last prophylactic dose of enoxaparin sodium was injected.

If a continuous technique is used, at least a 12 h interval before catheter removal must be observed.

In patients with creatinine clearance ≥15 and <30 mL/min, consider doubling the time to puncture or catheter insertion/removal to at least 24 h.

Preoperative administration of enoxaparin sodium 2 h before intervention at a dose of 20 mg is incompatible with neuroaxial anesthesia.

Therapeutic doses of enoxaparin sodium must be inserted or removed at least 24 hours after the last therapeutic dose of enoxaparin sodium was injected (see section “Contraindications”).

If a continuous technique is used, at least a 24 h interval before catheter removal must be observed.

In patients with creatinine clearance ≥15 and <30 mL/min, consider doubling the time to puncture or catheter insertion/removal to at least 48 h.

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 insertion or replacement. Similarly, consideration should be given to delaying the next dose of drug for at least 4 h based on a benefit/risk assessment (risk of thrombosis and bleeding during the procedure based on patients’ risk factors). At these time points, anti-Xa activity of the drug is still detectable, and time delays are no guarantee that neuroaxial hematoma development will be avoided.

The dosing regimen in special patient groups

Children under 18 years of age

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

Patients in the elderly (over 75 years)

Except for treatment of ST-segment elevation myocardial infarction for all other indications, dosage reduction of enoxaparin sodium in elderly patients in the absence of renal dysfunction is not required.

Patients with impaired renal function

Severe renal impairment (creatinine clearance ≥15 and <30 ml/min)

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

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

The following dosing regimen adjustments are recommended when using the drug in therapeutic doses:

When using the drug for prophylactic purposes, a dosing regimen adjustment as shown in the table below is recommended:

The recommended dosing regimen adjustment is not applicable in hemodialysis.

Mild (creatinine clearance ≥50 and <80 ml/min) and moderate (creatinine clearance ≥30 and <50 ml/min) renal dysfunction

Dose adjustment is not required, but patients should be under close medical supervision.

Patients with hepatic impairment

In the absence of clinical studies, the drug should be used with caution in patients with hepatic impairment.

Instructions for self-injection of enoxaparin sodium

1. Wash your hands and the area of skin (injection site) where you will inject with soap and water. Dry them.

2. take a comfortable sitting or lying position and relax. Make sure that you can clearly see the place where you are going to inject the medication. It is optimal to use a lounge chair, a lounge chair, or a bed covered with pillows for support.

3. Choose a place to inject on the right or left side of your abdomen. This location should be at least 5 cm from your belly button or around any existing scarring or bruising. Alternate injection sites on the right and left side of the abdomen, depending on where you injected the previous time.

4. wipe the injection site with an alcohol swab.

5. Carefully remove the cap from the syringe needle with the medication. Set the cap aside. The syringe is pre-filled and ready to use. Do not squeeze the plunger to dislodge air bubbles before inserting the needle into the injection site. Doing so can cause loss of product. After removing the cap, do not allow the needle to touch any objects. This is to keep the needle sterile.

Please note: If you have a needle safety label – follow the Instructions for Use of the Needle Safety Label below.

6. Hold the syringe in one hand as you would hold a pencil, and with the other hand gently squeeze the alcohol-soaked injection site between your thumb and forefinger to form a skin fold. Hold the skin fold the entire time you are injecting.

7. Hold the syringe so that the needle points downwards (vertically at an angle of 90⁰). Insert the needle all the way into the skin fold.

8. Press the plunger with your finger. This will ensure that the drug is injected into the subcutaneous fatty tissue of the abdomen. Hold the skin fold the entire time you are injecting.

9. Remove the needle by pulling it back without tilting it. You can now stop holding the skin fold.

Please note: if you have a safety device, follow the Safety Device Instructions for Use below.

10. To prevent bruising, do not rub the injection site after injection.

11. Dispose of used disposable syringes in a waste container.

When using the drug, strictly follow the recommendations given in these instructions and the instructions of your physician or pharmacist. Talk to your doctor or pharmacist if you have any questions.

Instructions for use of the needle protection label (if available)

Without opening the package, check that the syringe is intact and that there is no liquid in the carton pack. If you have any doubts about the integrity of the syringe or its tightness, take another pack.

Open the carton pack.

Check the contents of the syringe.

Preventive safety device instructions

/p>

Without opening the package, check the integrity of the syringe and that there is no liquid in the contour cell pack. If you have any doubts about the integrity of the syringe or its tightness, take another pack.

Open the carton pack.

Check the contents of the drug in the syringe.

Interaction

Enoxaparin sodium must not be mixed with other drugs!

Preferred combinations

Drugs that affect hemostasis (systemic salicylates, acetylsalicylic acid in anti-inflammatory doses, non-steroidal anti-inflammatory drugs including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) are recommended to be stopped before starting therapy with Enoxaparin Sodium. If concomitant use with enoxaparin sodium is necessary, caution should be exercised and close clinical observation and monitoring of relevant laboratory parameters should be performed.

Combinations requiring caution

– Other drugs affecting hemostasis, such as:

– Platelet aggregation inhibitors, including acetylsalicylic acid at doses with antiaggregant effects (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa receptor antagonists indicated for acute coronary syndrome because of the increased risk of bleeding;

– dextran with a molecular weight of 40 kDa;

– systemic glucocorticosteroids.

– Drugs that increase potassium content

Clinical and laboratory monitoring should be performed when concomitant use with drugs that increase potassium content in the blood serum.

Special Instructions

General

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

Bleeding

As with other anticoagulants, bleeding of any localization is possible when administering the drug (see section “Side effects”). If bleeding develops, it is necessary to find its source and prescribe the appropriate treatment.

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

– hemostasis disorders;

– history of peptic ulcer disease;

– recent ischemic stroke;

– severe arterial hypertension;

– diabetic retinopathy;

– neurosurgical or ophthalmic surgery;

– concurrent use of drugs that affect hemostasis (see

– concomitant use of drugs affecting hemostasis (see section “Interaction with other medicinal products”).

Bleeding in elderly patients

There is no increased risk of bleeding when using the drug in prophylactic doses in elderly patients.

There is an increased risk of bleeding when using the drug in therapeutic doses in elderly patients (especially those aged 80 years and older). Close monitoring of these patients is recommended (see section “Pharmacokinetics” and section “Administration and doses”, subsection “Elderly patients”).

The concomitant use of other drugs affecting hemostasis

The use of drugs that affect hemostasis (systemic salicylates, including acetylsalicylic acid in doses with anti-inflammatory effects, nonsteroidal anti-inflammatory drugs including ketorolac, other thrombolytics (alteplase, reteplase, streptokinase, tenecteplase, urokinase)) is recommended to be stopped before treatment with Enoxaparin sodium unless their use is necessary. If combinations of enoxaparin sodium with these drugs are indicated, close clinical observation and monitoring of relevant laboratory parameters should be performed.

Renal failure

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

In patients with severe renal impairment (creatinine clearance ≥15 and <30 ml/min) there is a significant increase of sodium enoxaparin exposure, therefore it is recommended to perform dose adjustment during both prophylactic and therapeutic use of the drug. Although no dose adjustment is required in patients with mild to moderate renal dysfunction (creatinine clearance 30 – 50 ml/min or 50 – 80 ml/min), close monitoring of such patients is recommended, and biological monitoring with measurement of anti-Xa activity may be considered (see sections “Pharmacokinetics” and “Dosage and administration”, subsection “Patients with renal dysfunction”).

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

Low body weight

There has been increased exposure to enoxaparin sodium when prophylactically used in women with a body weight less than 45 kg and in men with a body weight less than 57 kg, which may lead to an increased risk of bleeding. Close monitoring of such patients is recommended.

Patients with obesity

Patients with obesity have an increased risk of thrombosis and embolism. The safety and efficacy of enoxaparin sodium at prophylactic doses in obese patients (BMI greater than 30 kg/m²) is not fully defined and there is no general consensus on dose adjustment. These patients should be closely monitored for signs and symptoms of thrombosis and embolism.

Peripheral blood platelet count monitoring

The risk of antibody-mediated heparin-induced thrombocytopenia also exists with the use of low molecular weight heparins, with a higher risk in patients who have undergone heart surgery and patients with cancer. If thrombocytopenia develops, it is usually detected between days 5 and 21 after the start of therapy with enoxaparin sodium. Therefore, it is recommended to monitor the platelet count in the peripheral blood regularly before and during treatment with the drug. Blood platelet count should be determined in the presence of symptoms indicating GIT (new episode of arterial and/or venous thromboembolic complications, painful skin lesions at the injection site, allergic or anaphylactic reactions during treatment). In case of the occurrence of these symptoms, the attending physician should be informed.

If a significant decrease in platelet count is confirmed
(by 30-50% compared to baseline), enoxaparin sodium should be stopped immediately and the patient transferred to another anticoagulant therapy without the use of heparin.

Spinal/epidural anesthesia

There have been described cases of neuroaxial hematomas when using the drug simultaneously with spinal/epidural anesthesia with the development of long-lasting or irreversible paralysis. The risk of these phenomena is reduced when using the drug at a dose of 40 mg or lower. The risk increases when using higher doses of the drug, as well as when using permanent catheters after surgery, or when concomitant use of additional drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs (see section “Interaction with other medicinal products”). There is also an increased risk with traumatic or repeated spinal tap 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 should be considered (see section “Pharmacokinetics”). Catheter placement or removal is better performed when the anticoagulant effect of enoxaparin sodium is low, but the exact time to achieve sufficient reduction of anticoagulant effect in different patients is unknown. Additionally, it should be taken into account that in patients with a creatinine clearance of 15-30 ml/min, excretion of enoxaparin sodium is delayed.

If anticoagulant therapy is prescribed by a physician during epidural/spinal anesthesia or lumbar puncture, the patient should be continuously monitored for any neurological symptoms such as back pain, sensory and motor disturbances (numbness or weakness in the lower extremities), impaired bowel and/or bladder function. The patient should be instructed to inform the physician immediately if the above symptoms occur. If symptoms characteristic of a spinal cord hematoma are suspected, prompt diagnosis and treatment, including spinal cord decompression if necessary, are necessary.

Heparin-induced thrombocytopenia

The use of enoxaparin sodium in patients with a history of heparin-induced thrombocytopenia within the past 100 days or in the presence of circulating antibodies is contraindicated (see section “Contraindications”). 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 a benefit/risk assessment and in the absence of heparin-free alternative therapy.

Prescope coronary angioplasty

In order to minimize the risk of bleeding associated with invasive vascular instrumentation in the treatment of unstable angina and myocardial infarction without Q-wave and acute myocardial infarction with ST-segment elevation, these procedures should be performed in intervals between drug administrations. This is necessary in order to achieve hemostasis at the catheter insertion site after percutaneous coronary intervention. If a closure device is used, the femoral artery intraductor can be removed immediately. If manual compression is used, the femoral artery intromedullary tube should be removed 6 h after the last intravenous or subcutaneous injection of sodium enoxaparin. If treatment with sodium enoxaparin is continued, the next dose should not be administered before 6-8 h after removal of the femoral artery intraductor. The site of insertion of the intraductor should be monitored to detect timely signs of bleeding and hematoma formation.

Patients with mechanical artificial heart valves

The use of the drug to prevent thrombosis in patients with mechanical artificial heart valves has not been well studied. There have been isolated reports of thrombosis of heart valves in patients with mechanical artificial heart valves on therapy with Enoxaparin sodium for prophylaxis of thrombosis. Because of insufficient clinical data and ambiguous factors, including underlying disease, it is difficult to evaluate such reports.

Pregnant women with mechanical artificial heart valves

The use of the drug for prophylaxis of thrombosis in pregnant women with mechanical artificial heart valves has not been well studied. In a clinical study of pregnant women with mechanical heart valves, when enoxaparin sodium was used at a dose of 1 mg/kg body weight twice daily to reduce the risk of thrombosis and embolism, 2 of 8 women developed thrombi that resulted in heart valve block and death to mother and fetus.

There have been anecdotal postmarketing reports of heart valve thrombosis in pregnant women with mechanical artificial heart valves treated with enoxaparin to prevent thrombosis.

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

Skin necrosis/skin vasculitis

The development of skin necrosis and skin vasculitis has been reported with the use of low molecular weight heparins. If skin necrosis/skin vasculitis develops, the use of the drug should be discontinued.

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 careful individual evaluation of the benefit-risk ratio.

Laboratory tests

In doses used for prevention of thromboembolic complications, the drug does not significantly affect bleeding time and clotting parameters, as well as platelet aggregation or their binding to fibrinogen.

In case of increasing the dose, the ACTV and activated clotting time may be prolonged. Increase of ACTV and activated clotting time are not in direct linear relation to increase of anticoagulant activity of the drug, so there is no need to monitor them.

Hyperkalemia

Heparins may inhibit aldosterone secretion by the adrenal glands, resulting in the development of hyperkalemia, especially in patients with diabetes, chronic renal failure, prior metabolic acidosis, taking drugs that increase potassium content (see section “Interaction with other medicinal products”). Plasma potassium content should be monitored regularly, especially in patients in the risk group.

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

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

– age greater than 75 years;

– malignant neoplasms;

– history of thrombosis and embolism;

– obesity;

– hormone therapy;

– heart failure;

– chronic respiratory failure.

Hepatic impairment

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

Impact on driving and operating ability

Enoxaparin sodium has no effect on driving and operating ability.

Synopsis

Transparent colorless or yellowish, or brownish-yellowish liquid.

Contraindications

– hypersensitivity to enoxaparin sodium, heparin or 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 recent hemorrhagic stroke, acute gastrointestinal (GI) ulcer, and the presence of a malignancy with a high risk of bleeding, Recent brain and spinal cord surgery, ophthalmologic surgery, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, spinal cord and brain vascular anomalies;

– spinal or epidural anesthesia or locoregional anesthesia when sodium enoxaparin has been used for treatment in the previous 24 hours;

– immune-mediated heparin-induced thrombocytopenia (history) within the last 100 days or the presence of circulating antiplatelet antibodies in the blood;

– childhood age less than 18 years, since efficacy and safety in this patient population has not been established (see

– children under 18 years of age.)

With caution

Conditions with potential risk of bleeding:

– hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, Willebrand’s disease, etc.

– gastric or duodenal ulcer or other erosive-ulcerative lesions of the gastrointestinal tract in the anamnesis;

– recent ischemic stroke;

– uncontrolled severe arterial hypertension;

– diabetic or hemorrhagic retinopathy;

– severe diabetes mellitus;

– recent or suspected neurologic or ophthalmic surgery;

– performing spinal or epidural anesthesia (potential risk of hematoma), spinal tap (recent);

– recent childbirth;

– bacterial endocarditis (acute or subacute);

– pericarditis or pericardial effusion;

– renal and/or hepatic insufficiency;

– intrauterine contraception (IUI);

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

– concomitant administration of drugs affecting the hemostasis system;

– heparin-induced thrombocytopenia without a history of circulating antibodies (more than 100 days).

There are no data on clinical use of enoxaparin sodium in the following diseases: active tuberculosis, radiation therapy (recent).

Side effects

The side effects of enoxaparin sodium have been studied in more than 15,000 patients who participated in clinical trials, including 1,776 patients in the prevention of venous thrombosis and embolism in general surgery and orthopedic surgery; 1,169 patients in the prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic conditions; in 559 patients, in the treatment of deep vein thrombosis with or without pulmonary embolism; in 1578 patients, in the treatment of unstable angina and myocardial infarction without a Q wave; in 10176 patients, in the treatment of ST-segment elevation myocardial infarction.

The mode of administration of enoxaparin sodium differed depending on the indication. In the prevention of venous thrombosis and embolism during general surgery and orthopedic surgery or in patients on bed rest, 40 mg was administered subcutaneously once daily. In 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. For treatment of unstable angina and myocardial infarction without Q-wave, the dose of enoxaparin sodium was 1 mg/kg of body weight subcutaneously every 12 hours, and in case of myocardial infarction with ST-segment elevation, an intravenous bolus injection of 30 mg followed by 1 mg/kg of body weight subcutaneously every 12 hours was administered.

The incidence of adverse reactions was determined according to the WHO classification: Very common (≥1/10); common (≥1/100 and <1/10); infrequent (≥1/1000 and <1/100); rare (≥1/10 000 and <1/1000); very rare (<1/10 000), frequency unknown (cannot be calculated from available data).

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 of 2 g/L or more, required a transfusion of 2 or more doses of blood components, and if it was retroperitoneal or intracranial). Some of these cases were fatal.

As with other anticoagulants, bleeding is possible with the use of enoxaparin sodium, especially in the presence of risk factors contributing to bleeding, during invasive procedures or when using drugs that disrupt hemostasis (see sections “Interaction with other medicinal products” and “Cautions”).

In the description of bleeding below the sign “*” means to indicate the following types of bleeding: hematoma, ecchymosis (except developed at the injection site), wound hematoma, hematuria, nasal bleeding, gastrointestinal bleeding.

Very common – bleeding* during prophylaxis of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without thromboembolism.

Often – bleeding* in prophylaxis of venous thrombosis in bed-ridden patients and in treatment of unstable angina, myocardial infarction without Q-wave, and ST-segment elevation myocardial infarction.

Infrequent – retroperitoneal bleeding and intracranial hemorrhage in patients treated for deep vein thrombosis with or without pulmonary embolism and ST-segment elevation myocardial infarction.

Rarely, retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of angina pectoris, myocardial infarction without the Q wave.

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.

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

Infrequent – thrombocytopenia in prophylaxis of venous thrombosis in patients on bed rest and during treatment of unstable angina, myocardial infarction without Q-wave.

Very rarely, 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 presented below are grouped by systemic organ class, given by the frequency of occurrence defined above and in decreasing order of severity.

Disorders of the blood and lymphatic system

Often – bleeding, thrombocytopenia, thrombocytosis.

Rarely – 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”, subsection “Peripheral blood platelet count control”).

Immune system disorders

Often – allergic reactions.

Liver and biliary tract disorders

very often – increased activity of “liver” enzymes, mainly increased activity of transaminases, more than three times higher than the upper limit of normal.

Skin and subcutaneous tissue disorders

Often – urticaria, pruritus, erythema.

Infrequent – bullous dermatitis.

General disorders and disorders at the injection site

Often – 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; necrosis of the skin at the injection site.

Data obtained in the post-registration period

The following adverse reactions were noted during post-marketing use of the drug. There have been spontaneous reports of these adverse reactions.

Immune system disorders

Rarely, anaphylactic/anaphylactoid reactions, including shock.

Nervous system disorders

Often – headache.

Vascular disorders

Rarely, cases of spinal hematoma (or neuroaxial hematoma) have been reported with the use of enoxaparin sodium against a background of spinal/epidural anesthesia or spinal tap. These reactions have led to the development of neurological disorders of varying severity, including persistent or irreversible paralysis
(see section “Special Precautions”).

Disorders of the blood or lymphatic system

Often – hemorrhagic anemia.

Rarely – eosinophilia.

Skin and subcutaneous tissue disorders

Rarely, alopecia; cutaneous vasculitis, skin necrosis may develop at the injection site, which are usually preceded by the appearance of purpura or erythematous papules (infiltrated and painful). In these cases, therapy with the drug should be discontinued.

There may be hard inflammatory nodules/infiltrates at the injection site, which disappear after a few days and are not a reason to discontinue the drug.

Hepatic and biliary tract disorders

Infrequent – hepatocellular liver disease.

Rarely – cholestatic liver damage.

Muscular and connective tissue disorders

Rarely – osteoporosis in long-term therapy (more than three months).

Laboratory and instrumental findings

Rarely – hyperkalemia.

Overdose

Accidental overdose of the drug during intravenous, extracorporeal or subcutaneous administration may lead to hemorrhagic complications. When administered orally, even in high doses, absorption of the drug is unlikely.

The anticoagulant effects can mainly be neutralized by slow intravenous administration of protamine sulfate, the dose of which depends on the dose of the drug administered. One mg (1 mg) of protamine sulfate will neutralize the anticoagulant effects of one mg (1 mg) of the drug if enoxaparin sodium was administered no more than 8 h before protamine administration. 0.5 mg of protamine will neutralize the anticoagulant effect of 1 mg of the drug if more than 8 hours have elapsed since the last injection or if a second dose of protamine must be administered. If, however, 12 hours or more have elapsed since the administration of enoxaparin sodium, no protamine administration is required. However, even when large doses of protamine sulfate are administered, the anti-Xa activity of the drug is not completely neutralized (maximum 60%).

Pregnancy use

Pregnancy

There is no evidence that enoxaparin sodium crosses the placental barrier during pregnancy. Because there are no adequate and well-controlled studies involving pregnant women, and animal studies do not always predict response to enoxaparin sodium administration during pregnancy in humans, it should only be used during pregnancy in exceptional cases where there is an urgent physician-assessed need for its use.

Patients should be monitored for signs of bleeding or excessive anticoagulation, and patients should be advised of the risk of bleeding.

There is no evidence of an increased risk of bleeding, thrombocytopenia, or osteoporosis in pregnant women, except as noted in patients with artificial heart valves (see section “Special Precautions”).

If epidural anesthesia is planned, it is recommended that enoxaparin sodium be withdrawn before it is performed (see section “Special Precautions”).

Breastfeeding period

It is not known whether unchanged enoxaparin sodium is excreted into the breast milk. Absorption of enoxaparin sodium in the gastrointestinal tract in the newborn is unlikely. The drug may be used during breastfeeding.

Similarities

Clexane, Enixum