Enoxaparin-Bienergia, 10,000 anti-ha me/ml 0.4 ml 10 pcs

• prevention of venous thrombosis and embolism in surgical interventions, especially in orthopedic and general surgical procedures;
• prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic diseases (acute heart failure, chronic heart failure in the upper and lower extremities).prophylaxis of venous thromboses and thromboembolisms in bed-ridden patients due to acute therapeutic diseases (acute heart failure, chronic decompensated heart failure III or IV functional class according to NYHA classification, acute respiratory failure, severe acute infection, acute rheumatic diseases combined with a risk factor for venous thrombosis);
• treatment of deep vein thrombosis with or without pulmonary embolism;
• treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid;
• prevention of thrombosis in the extracorporeal circulation system during hemodialysis (usually with a session duration of less than 4 hours).

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Active ingredient

Enoxaparin sodium

Composition

1 syringe or ampoule (1.0 ml) contains:

the active ingredient:

enoxaparin sodium 10000 anti-Ha ME (100 mg*);

component:water for injection – up to 1.0 ml.

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

How to take, the dosage

Except in special cases, enoxaparin sodium is injected deep subcutaneously. Injections should preferably be performed in the supine position. When using 20 mg and 40 mg pre-filled syringes, 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 should not be released until the injection is complete. The injection site should not be massaged after the injection.
The pre-filled disposable syringe is ready for use.

The drug must not be injected intramuscularly!

Prevention of venous thrombosis and embolism in surgical procedures, especially in orthopedic and general surgical procedures.

Patients at moderate risk of 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,

The drug is recommended in a dose of 40 mg once a day subcutaneously, with the first dose given 12 hours before surgical intervention, or in a dose of 30 mg twice a day starting 12-24 hours after surgery.

The duration of treatment with Enoxaparin sodium 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 orthopedic surgeries, it may be appropriate to continue treatment after initial therapy by dosing 40 mg once daily for 3 weeks.

Peculiarities of using the drug in spinal/epidural anesthesia as well as in coronary revascularization procedures.

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

The recommended dose of enoxaparin sodium is 40 mg once daily subcutaneously for at least 6 days. Therapy should be continued until the patient is fully ambulatory (maximum of 14 days).

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. In patients with complicated thromboembolic disorders it is recommended to use the drug in a dose of 1 mg/kg twice a day. The duration of treatment is on average 10 days.

The therapy with indirect anticoagulants should be started immediately while treatment with enoxaparin sodium must be continued until therapeutic anticoagulant effect is achieved (INR value should be 2.0-3.0).

Prevention of thrombosis in the extracorporeal circulation system during hemodialysis

The recommended dose of enoxaparin sodium 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. One dose is usually sufficient for a four-hour session; however, if fibrin rings are detected during longer hemodialysis, additional drug may be administered at a rate of 0.5-1 mg/kg body weight.

Treatment of unstable angina and myocardial infarction without Q-wave

Enoxaparin sodium is administered at a rate of 1 mg/kg body weight every 12 hours, subcutaneously, with concomitant use of acetylsalicylic acid at a dose of 100-325 mg once daily.

The average duration of therapy is at least 2 days and continues until the patient’s clinical condition stabilizes. Usually the drug is administered for 2 to 8 days.

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 body weight. Then the drug is administered subcutaneously in 1 mg/kg of body weight every 12 hours (maximum 100 mg of enoxaparin sodium for each of the first two subcutaneous injections, then 1 mg/kg of body weight for the remaining subcutaneous doses, i.e. in case of body weight over 100 kg a single dose may exceed 100 mg).

In patients 75 years of age and older, the 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, meaning that if the body weight is over 100 kg the single dose may exceed 75 mg).

When combined with thrombolytics (fibrin-specific and fibrin-unspecific), enoxaparin sodium should be administered between 15 minutes before and 30 minutes after thrombolytic therapy. As soon as possible after detection of acute ST-segment elevation myocardial infarction, patients should be simultaneously prescribed acetylsalicylic acid 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 enoxaparin sodium is 8 days or until the patient is discharged from the hospital (if the hospitalization period is less than 8 days).

The intravenous bolus infusion of sodium enoxaparin should be given via 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 injection of enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the excess amount of drug is removed from 60 mg, 80 mg or 100 mg glass syringes so that only 30 mg (0.3 ml) remains. The 30 mg dose can be given directly intravenously.

Pre-filled 60 mg, 80 mg or 100 mg hypodermic syringes may be used for intravenous bolus injection of enoxaparin sodium via a venous catheter. The 60 mg syringe is recommended because it reduces the amount of drug removed from the syringe. The 20 mg syringe is not used because it does not contain enough product for an intravenous bolus of 30 mg of enoxaparin sodium. The 40 mg syringes are not used because they have no graduations and therefore cannot be accurately measured 30 mg.

In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection was given less than 8 hours before the balloon catheter introduced into the coronary artery narrowing, 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.

In order to improve the accuracy of additional intravenous bolus injection of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug to a concentration of 3 mg/ml. It is recommended to dilute the solution just before injection.

To obtain Enoxaparin sodium solution with 3 mg/ml concentration using 60 mg pre-filled syringe it is recommended to use a container with 50 ml infusion solution (i.e. with 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 the diluted sodium enoxaparin solution is extracted using a syringe and calculated according to the formula:
Volume of diluted solution = Patient’s body weight (kg) x 0.1;
or with the help of the table below.

Table 1. Volumes to be administered intravenously after dilution

Dosing regimen in special patient groups

Elderly patients

. With the exception of treatment of ST-segment elevation myocardial infarction (see above) for all other indications, no dose reduction of enoxaparin sodium is required in elderly patients if they have no renal impairment.

Patients with impaired renal function

.Severe renal impairment (creatinine clearance less than 30 mL/min)

. The dose of enoxaparin sodium is reduced according to the tables below because these patients have increased systemic exposure (duration of action) to the drug.

The following dosing regimen adjustments are recommended when using the drug for therapeutic purposes:

The recommended dosing regimen adjustment is not applicable in hemodialysis.

Mild (creatinine clearance 50-80 ml/min) and moderate (creatinine clearance 50-50 ml/min) renal dysfunction do not require dose adjustment, but patients should be under close medical supervision.

Patients with hepatic impairment

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

Instruction 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. Place yourself in a comfortable sitting or lying position and relax. Make sure that you can clearly see the place where you are going to inject the drug. It is optimal to use a lounge chair, a chaise lounge, or a bed covered with pillows for support.
3. Select the place for the injection on the right or left side of the abdomen. This location should be at least 5 centimeters from the navel toward the sides. Do not self-inject within 5 centimeters of the belly button or around any existing scars or bruises. Alternate injection sites on the right and left side of the abdomen, depending on where you last injected.
4. Wipe the injection site with an alcohol swab.
5. Carefully remove the cap from the needle of the syringe containing the drug. 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 maintain the sterility of the needle.
6. Hold the syringe in the hand you are writing with as you hold a pencil, and with the other hand gently squeeze the alcohol rubbed injection site between your thumb and forefinger so that a skin fold is formed. Hold the skin fold the entire time you are injecting.
7. Hold the syringe with the needle pointing downwards (vertically at a 90° angle). Insert the full length of the needle into the skin fold.
8. Push 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 whole time you are injecting.
9. Eject the needle by pulling it back without tilting it. If there is a safety mechanism, it will automatically close the needle. You can now stop holding the skin fold. The safety system, which triggers the safety mechanism, is only activated when the full contents of the syringe have been injected by pressing down on the piston the full length of its stroke.
10. To prevent bruising, do not rub the injection site after the injection.
11. Place used syringe, with or without safety mechanism, in the sharps container. Keep the container tightly closed with the lid and out of the reach of children.

When using the product, follow the directions in these instructions and the directions given by your physician or pharmacist. Ask your physician or pharmacist if you have any questions.

Interaction

Enoxaparin sodium must not be mixed with other drugs!

. When concomitant use with drugs that affect hemostasis (salicylates of systemic action, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (including ketorolac), dextran with a molecular weight of 40 kDa, ticlopidine and clopidogrel, systemic glucocorticosteroids, thrombolytics or anticoagulants, other antiplatelet agents (including glycoprotein IIb/IIIa antagonists), the risk of bleeding increases.

Special Instructions

General

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

Bleeding

As with the use of other anticoagulants, the administration of enoxaparin sodium may cause bleeding of any localization. If bleeding develops, the source of bleeding must be found and appropriate treatment administered.

Bleeding in elderly patients

When using enoxaparin sodium in prophylactic doses in elderly patients no increased risk of bleeding has been noted.

When using the drug in therapeutic doses in elderly patients (especially those aged 80 years and older) there is an increased risk of bleeding. Close monitoring of these patients is recommended.

Simultaneous use of other drugs affecting hemostasis

. It is recommended that the use of drugs that affect hemostasis (salicylates, including acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, including ketorolac; dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel; glucocorticosteroid drugs, thrombolytics, anticoagulants, antiaggregants, including glycoprotein IIb/IIIa receptor antagonists) were stopped before treatment with Enoxaparin sodium, except when 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 less than 30 ml/min) a significant increase in sodium enoxaparin exposure is noted, therefore it is recommended to perform dose adjustment during both prophylactic and therapeutic use of the drug. Although dose adjustment is not 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.

Low body weight

. Increased exposure to enoxaparin sodium has been noted with prophylactic use in women with a body weight less than 45 kg and in men with a body weight less than 57 kg, which may result in 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 (body mass index (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.

Control of peripheral blood platelet count

The risk of antibody-mediated heparin-induced thrombocytopenia also exists with low molecular weight heparins. If thrombocytopenia develops, it is usually detected between days 5 and 21 after initiation of therapy with enoxaparin sodium. Therefore, it is recommended to monitor the peripheral blood platelet count regularly before and during treatment with Enoxaparin sodium. If a significant decrease in platelet count is confirmed (by 30-50% compared to the initial count), Enoxaparin sodium should be stopped immediately and the patient should be transferred to another therapy.

Spinal/epidural anesthesia

. There have been reports of neuroaxial hematomas when sodium enoxaparin has been used concomitantly with spinal/epidural anesthesia with the development of long-standing 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 Enoxaparin sodium, as well as when using permanent catheters after surgery, or when concomitant use of additional drugs affecting hemostasis, such as nonsteroidal anti-inflammatory drugs. The risk also increases 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.

The insertion or removal of a catheter is best performed when the anticoagulant effect of sodium enoxaparin is low, but the exact time to achieve sufficient reduction of anticoagulant effect in different patients is unknown.

. Catheter insertion or removal should be performed at least 12 hours after administration of lower doses of enoxaparin sodium (20 mg once daily, 30 mg once or twice daily, 40 mg once daily) and at least 24 hours after administration of higher doses of enoxaparin sodium (0.75 mg/kg body weight twice daily, 1 mg/kg body weight twice daily, 1.5 mg/kg body weight once daily).

The drug’s anti-Xa activity is still detectable at these time points, and time delays are no guarantee that neuroaxial hematoma development will be avoided. Patients receiving enoxaparin sodium at doses of 0.75 mg/kg body weight twice daily or 1 mg/kg body weight twice daily on this (twice daily) dosing regimen should not be given a second dose in order to extend the interval before inserting or changing a catheter.

In the same way, consideration should be given to delaying the next dose of drug by at least 4 hours, based on a benefit/risk assessment (risk of thrombosis and bleeding during the procedure, taking into account patients’ risk factors). However, it is not possible to give a clear recommendation on the timing of the next dose of sodium enoxaparin after catheter removal. Note that in patients with a creatinine clearance of less than 30 ml/min, excretion of sodium enoxaparin slows down. Therefore, in this category of patients, consideration should be given to doubling the time from catheter removal: at least 24 hours for lower doses of sodium enoxaparin (30 mg once daily) and at least 48 hours for higher doses (1 mg/kg body weight daily).

If anticoagulant therapy is prescribed by a physician during epidural/spinal anesthesia or lumbar puncture, the patient should be monitored continuously for any neurologic symptoms such as back pain, sensory and motor impairment (numbness or weakness in lower extremities), 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

. Enoxaparin sodium should be used with particular caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis. The risk of heparin-induced thrombocytopenia may persist for several years. If heparin-induced thrombocytopenia is suspected anamnesthetically, in vitro platelet aggregation tests are of limited value in predicting the risk of its development. The decision to use enoxaparin sodium in this case can only be made after consultation with an appropriate specialist.

Escopic 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 injections of enoxaparin sodium. This is necessary in order to achieve hemostasis after percutaneous coronary intervention.

When a femoral artery intromedullary device is used, it can be removed immediately. When manual (manual) compression is used, the femoral intromedullary tube should be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin sodium. If treatment with sodium enoxaparin is continued, the next dose should not be administered earlier than 6-8 hours after removal of the femoral artery intraductor. The insertion site of the introducer should be monitored to detect timely signs of bleeding and hematoma formation.

Patients with mechanical artificial heart valves

The use of enoxaparin sodium for thrombus prophylaxis in patients with mechanical artificial heart valves has not been well studied. There are isolated reports of the development of heart valve thrombosis in patients with mechanical artificial heart valves on therapy with enoxaparin sodium for prophylaxis of thrombosis. The evaluation of these reports is limited because of competing factors contributing to the development of artificial heart valve thrombosis, including underlying disease, and because of insufficient clinical data.

Pregnant women with mechanical artificial heart valves

The use of enoxaparin sodium for the prevention of thrombosis in pregnant women with mechanical artificial heart valves has not been well studied. In a clinical study of pregnant women with mechanical artificial 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 the mother and fetus.

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

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

Laboratory tests

. At doses used for the prevention of thromboembolic complications, enoxaparin sodium has no significant effect on bleeding time and clotting parameters, or on platelet aggregation or binding to fibrinogen.

Added dose may lengthen ACTV and activated clotting time. The increase of ACTV and activated clotting time are not in direct linear relation to the increase in anticoagulant activity of the drug, so there is no need to monitor them.

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

. In the case of acute infection, acute rheumatic conditions, prophylactic use of enoxaparin sodium is justified 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.

Pediatric use

The safety and effectiveness of enoxaparin sodium in children under the age of 18 years has not been established.

Impact on ability to drive vehicles, mechanisms

Enoxaparin sodium has no effect on the ability to drive vehicles and mechanisms.

Synopsis

Transparent, colorless to pale yellow solution.

Contraindications

• high sensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins;
• active major bleeding, and conditions and diseases with a high risk of bleeding: Threatened abortion, cerebral vascular aneurysm or dissecting aortic aneurysm (unless surgical intervention is performed for this purpose), recent hemorrhagic stroke, uncontrolled bleeding, thrombocytopenia combined with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin sodium;
• age less than 18 years (efficacy and safety not established).

Cautions

Conditions in which there is a potential risk of bleeding:

• disorders of hemostasis (including hemophilia, thrombocytopenia, hypocoagulation, Willebrand disease, etc.
• gastric or duodenal ulcer disease, other erosive-ulcerative lesions of the gastrointestinal tract (GIT) in the anamnesis;
• A recent ischemic stroke;
• uncontrolled severe arterial hypertension; diabetic or hemorrhagic retinopathy; severe diabetes mellitus;
• Last seen or suspected neurologic or ophthalmic surgery;
• Having spinal or epidural anesthesia (potential risk of hematoma), spinal tap (recently seen);
• followed childbirth;
• bacterial endocarditis (acute or subacute);
• pericarditis or pericardial effusion;
• renal and/or hepatic insufficiency;
• intrauterine contraception (IUI);
• severe trauma (especially central nervous system), open wounds on large surfaces;
• concurrent administration of drugs that affect the hemostatic system; heparin-induced thrombocytopenia (history) in combination with or without thrombosis.

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 the treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium at a rate of 1 mg/kg body weight subcutaneously every 12 hours or 1.5 mg/kg body weight subcutaneously once daily.

In the treatment of unstable angina and myocardial infarction without Q-wave, the dose of enoxaparin sodium was 1 mg/kg body weight subcutaneously every 12 hours, and in cases of ST-segment elevation myocardial infarction, an intravenous bolus of 30 mg followed by 1 mg/kg body weight subcutaneously every 12 hours was administered.

The adverse reactions were classified according to frequency of occurrence as follows: Very frequent (≥1/10), frequent (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10000 to < 1/1000), very rare (< 1/10000), or frequency unknown (the incidence of the adverse reaction could not be estimated 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 “Special Precautions” and “Interactions with other medicinal products”).

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

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

Frequent – Bleeding* in the prevention of venous thrombosis in bed-ridden patients and in the 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 for treatment of ST-segment elevation myocardial infarction.

Rare – retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in unstable angina and myocardial infarction without Q-wave.

Thrombocytopenia and thrombocytosis

Very common – thrombocytosis (peripheral blood platelet count 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.

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

Infrequent – thrombocytopenia in the prevention of venous thrombosis in bed-ridden patients and in the treatment of unstable angina and myocardial infarction without Q-wave.

Very rare – immunoallergic 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 with the frequency of occurrence defined above and in decreasing order of severity.

• Immune system disorders
• Frequent:allergic reactions.
• rare:anaphylactic and anaphylactoid reactions.

Hepatic and biliary tract disorders

• Very frequent:increased activity of “liver” enzymes, mainly, increased activity of transaminases, more than three times the upper limit of normal.

Skin and subcutaneous tissue disorders

• Frequent: urticaria, pruritus, erythema.
• infrequent: bullous dermatitis.

General disorders and disorders at the injection site

• Frequent:Hematoma at the injection site, pain at the injection site, swelling at the injection site, bleeding, hypersensitivity reactions, inflammation, formation of lumps at the injection site.
• Infrequent:irritation at the injection site, skin necrosis at the injection site.

Laboratory and instrumental findings: Rare:hyperkalemia.

Data obtained during the post-registration period

The following adverse reactions were noted during the post-marketing use of enoxaparin sodium. These adverse reactions have been spontaneously reported and their frequency has been defined as “frequency unknown” (cannot be determined from available data).

Immune system disorders: Anaphylactic/anaphylactoid reactions, including shock.

Nervous system disorders: Headache.

Vascular disorders: When using enoxaparin sodium against the background of spinal/epidural anesthesia or spinal tap there have been cases of development of spinal hematoma (or neuroaxial hematoma). 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 and lymphatic system: Hemorrhagic anemia. Cases of the development of immune-allergic thrombocytopenia with thrombosis; in some cases thrombosis was complicated by the development of organ infarction or limb ischemia (see section “Special Indications”, subsection “Control of platelet count in peripheral blood”).

Eosinophilia.

Skin and subcutaneous tissue disorders: Skin 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 Enoxaparin sodium should be discontinued. Solid inflammatory nodules-infiltrates may form at the injection site of the drug, which disappear after a few days and are not a reason for discontinuation of the drug.

Alopecia.

Hepatic and biliary tract disorders: Hepatocellular liver damage. Cholestatic liver damage.

Muscular and connective tissue disorders: Osteoporosis with prolonged therapy (more than three months).

Overdose

Symptoms: accidental overdose by intravenous, extracorporeal or subcutaneous administration may lead to hemorrhagic complications. Absorption is unlikely when administered orally, even in high doses.

Treatment: slow intravenous administration of protamine sulfate is indicated as a neutralizing agent, the dose of which depends on the dose of enoxaparin sodium administered. It should be taken into account that 1 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if the drug was administered no more than 8 hours before the administration of protamine sulfate. 0.5 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of sodium enoxaparin if more than 8 hours have passed since the last injection or if a second dose of protamine sulfate is required. If 12 hours or more have elapsed since the administration of enoxaparin sodium, the administration of protamine sulfate is not required. However, even when large doses of protamine sulfate are administered. the anti-Xa activity of sodium enoxaparin is not completely neutralized (maximum 60%).

Pregnancy use

Pregnancy

There is no evidence that enoxaparin sodium crosses the placental barrier during the second trimester of pregnancy in humans. There is no relevant information for the first and third trimesters of pregnancy.

Because there are no adequate and well-controlled studies in 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 when there is an urgent need for use established by a physician.

Breastfeeding

It is not known whether unchanged enoxaparin sodium is excreted into human breast milk. Absorption of enoxaparin sodium in the gastrointestinal tract in the newborn is unlikely. However, as a precautionary measure, breastfeeding women treated with enoxaparin sodium should be advised to interrupt breastfeeding.

Similarities

Clexane, Enixum