Enixum 8000 anti-Ha IU/0.8 ml, 10 pcs.

Enoxaparin sodium is a low molecular weight heparin. The average molecular weight is about 4500 Da: less than 2000 Da – <20%, 2000 to 8000 Da – >68%, more than 8000 Da – <18%. Enoxaparin sodium is obtained by alkaline hydrolysis of heparin benzyl ether isolated from pig small intestinal mucosa. Its structure is characterized by a nonreducible fragment of 2-O-sulfo-4-enpyrazinosuronic acid and a reducible fragment of 2-N,6-O-disulfo-D-glucopyranoside. The structure of enoxaparin sodium contains about 20% (in the range of 15 to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain.

In vitro, enoxaparin sodium has high activity against factor Xa clotting (anti-Xa activity of approximately 100 IU/ml) and low activity against factor IIa clotting (anti-IIa or antithrombin activity of approximately 28 IU/ml). This anticoagulant activity is mediated by antithrombin III. 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, which include AT-III-dependent inhibition of other clotting factors such as factor VIIa, activation of tissue factor pathway inhibitor release, and reduction of Willebrand factor release from the vascular endothelium into the bloodstream. These factors provide the anticoagulant effect of enoxaparin sodium in general.

When used in prophylactic doses, enoxaparin sodium slightly changes the PTC and has almost no effect on platelet aggregation and the degree of binding of fibrinogen to platelet receptors.

The anti-IIa activity in plasma is about 10 times lower than the anti-Xa activity. Mean maximal anti-IIa activity is observed approximately 3-4 h after p/q administration and reaches 0.13 and 0.19 IU/ml after repeated administration of 1 mg/kg with double administration and 1.5 mg/kg with single administration, respectively.

The mean maximum plasma anti-Xa activity is observed 3-5 h after a p/k injection of the drug and is approximately 0.2; 0.4; 1 and 1.3 anti-Xa IU/ml after a p/k injection of 20, 40 mg and 1 and 1.5 mg/kg, respectively.

Indications

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

prophylaxis of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic conditions, including acute heart failure and decompensation of chronic heart failure (NYHA class III or IV), acute respiratory failure; acute infectious diseases; acute stage of rheumatic diseases combined with a risk factor for venous thrombosis (see “Special Indications. “Special Indications);

The treatment of deep vein thrombosis with or without pulmonary embolism;

Prevention of thrombosis in the extracorporeal circulation system during hemodialysis (usually with a session duration of 4 hours or less);

The treatment of unstable angina and myocardial infarction without the Q-wave in combination with acetylsalicylic acid;

The treatment of acute ST-segment elevation myocardial infarction in patients undergoing medication-assisted or subsequent percutaneous coronary intervention.

Active ingredient

How to take, the dosage

(deeply), except in special cases (see Treatment of ST-segment elevation myocardial infarction, drug or percutaneous coronary intervention – IV bolus injection and Prevention of thrombosis in extracorporeal circulation system during hemodialysis – in the arterial shunt area at the beginning of the hemodialysis session).

The drug should not be administered by injection.

Injections should preferably be given in the supine position. Injections should alternate on the left or right anterolateral or posterolateral surface of the abdomen. The needle should be inserted vertically (not laterally) into the full length skin fold, gathered and held 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.

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

For patients with a moderate risk of thrombosis and embolism (e.g., abdominal surgery), the recommended dose is 20 mg once daily by injection. The first injection is given 2 hours before the surgical intervention.

. For patients with high risk of thrombosis and embolism (e.g., orthopedic surgeries, oncologic surgeries, additional risk factors not associated with surgery, such as congenital or acquired thrombophilia, malignant neoplasm, bed rest for more than 3 days, obesity, history of venous thrombosis, varicose veins in lower limbs, pregnancy) the drug is recommended in a dose of 40 mg 1 time daily by oral; With the 1st dose 12 hours before surgery or 30 mg 2 times a day starting 12-24 hours after surgery.

The duration of treatment 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, after initial therapy, to continue treatment with a dose of 40 mg/day for 3 weeks.

The peculiarities of using the drug in spinal/epidural anesthesia as well as in coronary revascularization procedures – see “Special information. See “Special Precautions.”

Prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic conditions

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

The treatment of deep vein thrombosis with or without VTE

Enixum® is administered p/k, at a rate of 1.5 mg/kg/day or at a dose of 1 mg/kg 2 times daily. In patients with complicated thromboembolic disorders the drug is recommended at a dose of 1 mg/kg 2 times daily.

The duration of treatment is on average 10 days. Therapy with oral anticoagulants should be started immediately, while therapy with enoxaparin sodium should be continued until therapeutic anticoagulant effect is achieved (INR value should be 2-3). If necessary, control of anticoagulant effect should be assessed by anti-Xa activity.

The treatment of unstable angina and myocardial infarction without Q-wave in combination with acetylsalicylic acid

Enixum.® is administered at a rate of 1 mg/kg every 12 h by mouth, with concomitant administration of oral acetylsalicylic acid at a dose of 100-325 mg once daily.

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

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

. Treatment begins with an IV bolus injection of enoxaparin sodium at a dose of 30 mg and immediately thereafter (within 15 minutes) administered p/c at a dose of 1 mg/kg (with a maximum of 100 mg of enoxaparin sodium in the first two p/c injections). Thereafter, all subsequent doses are given every 12 hours b/c at a rate of 1 mg/kg (i.e., if the body weight exceeds 100 kg, the dose may exceed 100 mg).

In persons 75 years of age and older, the initial IV bolus infusion is not used.

Enoxaparin sodium is administered by p/k at a dose of 0.75 mg/kg every 12 hours (with a maximum of 75 mg of enoxaparin sodium being administered in the first two p/k injections). Thereafter, all subsequent p/k doses are administered every 12 hours at a rate of 0.75 mg/kg (i.e., the dose may exceed 75 mg if the weight is greater than 100 kg).

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

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

The B/V bolus infusion of sodium enoxaparin should be administered via a venous catheter, and sodium enoxaparin should not be mixed or administered with other medications. In order to avoid the presence of traces of other drugs in the system and their interaction with sodium enoxaparin, the venous catheter should be flushed with an adequate amount of 0.9% sodium chloride solution or 5% dextrose solution before and after the IV 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 60, 80 and 100 mg glass syringes are discarded so that only 30 mg (0.3 ml) remains. The 30 mg dose can be directly administered intravenously.

Pre-filled 60 mg, 80 mg and 100 mg IV syringes can be used to perform an IV 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 a 30 mg bolus of Enoxaparin sodium. The 40 mg syringe is not used because it has no graduations and therefore the 30 mg cannot be accurately measured.

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

In order to improve the accuracy of additional bolus injection of small volumes into the venous catheter during percutaneous coronary interventions, it is recommended to dilute the drug with infusion solution to a concentration of 3 mg/ml. Dilution of the solution is recommended immediately prior to injection.

To obtain a 3 mg/ml solution of Enoxaparin sodium using a pre-filled syringe, it is recommended to use a container with infusion solution from which a portion of the solution is extracted to the desired volume using a normal syringe. Enoxaparin sodium (the contents of the IV syringe) is injected into the remaining infusion solution in the reservoir (see Table 1).

Table 1

The contents of the container of diluted enoxaparin sodium solution are mixed gently. The required volume of the 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 Table 2.

Table 2

Volumes to be administered by IV after dilution

Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis (usually with a session duration of no more than 4 h)

The dose of enoxaparin sodium is 1 mg/kg. For patients at high risk of bleeding, the dose should be reduced to 0.5 mg/kg for dual vascular access or 0.75 mg/kg for single vascular access.

In hemodialysis, Enixum® should be injected into the arterial shunt site at the beginning of the hemodialysis session. A single dose is usually sufficient for a 4-hour session; however, if fibrin rings are detected during longer hemodialysis, Enixum® may be administered additionally at a dose of 0.5-1 mg/kg.

Patient special groups

Elderly age. With the exception of treatment of ST-segment elevation myocardial infarction (see above) for all other indications, dose reduction of enoxaparin sodium in elderly patients if they have no renal impairment is not necessary.

Renal insufficiency. In severe renal impairment (Cl endogenous creatinine less than 30 ml/min), the dose of enoxaparin sodium is reduced according to the tables below, since in these patients there is an increase in systemic exposure (duration of action) of the drug.

Table 3

Recommendations for dosing adjustment when using the drug for therapeutic purposes

Treatment of acute ST-segment elevation myocardial infarction in patients 75 years and older

Table 4

Preventive dosing recommendations when using the drug for prophylactic purposes

/p> Conventional dosing regimen Dosing regimen for severe renal failure 40 mg p/k once daily 20 mg p/k once daily 20 mg p/k once daily 20 mg p/k once daily

The recommended dosing regimen correction is not applicable for hemodialysis.

In mild (creatinine Cl 50-80 ml/min) and moderate (creatinine Cl 30-50 ml/min) renal failure, dosage adjustment is not required, but patients should be under close medical supervision.

Hepatic failure. Because of the lack of clinical studies, caution should be exercised when using enoxaparin sodium in patients with hepatic impairment.

Interaction

Enixum® must not be mixed with other drugs in the same syringe.

When used simultaneously with other drugs affecting hemostasis (salicylates, incl.acetylsalicylic acid, NSAIDs including ketorolac, 40 kDa dextran, ticlopidine, clopidogrel, systemic GCS, thrombolytics or anticoagulants, other antiplatelet agents including glycoprotein IIb/IIIa receptor antagonists) increase the risk of bleeding.

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 the use of each drug belonging to the class of low molecular weight heparins.

Bleeding

As with other anticoagulants, the use of Enixum® may cause bleeding of any localization (see “Side effects”). In case of bleeding it is necessary to find its source and prescribe an appropriate treatment.

Bleeding in elderly patients

When using enoxaparin sodium in prophylactic doses in elderly patients no tendency to increase bleeding has been found. There is an increased risk of bleeding when using enoxaparin sodium in therapeutic doses in elderly patients (especially those aged 80 years and older). Close monitoring of such patients is recommended (see “Pharmacokinetics” and “Dosage and administration”, Elderly age).

The concomitant use of other drugs affecting hemostasis

It is recommended that the use of drugs affecting hemostasis (salicylates, incl.acetylsalicylic acid, NSAIDs including ketorolac, 40 kDa dextran, ticlopidine, clopidogrel, GCS, thrombolytics, anticoagulants, antiaggregants including glycoprotein IIb/IIIa receptor antagonists) should be stopped before starting enoxaparin sodium treatment 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 Cl less than 30 mL/min), there is a significant increase in sodium enoxaparin exposure, so dose adjustment is recommended for both prophylactic and therapeutic use of the drug. Although no dose adjustment is required in patients with mild to moderate renal dysfunction (creatinine Cl 30-50 or 50-80 ml/min), close monitoring of such patients is recommended (see “Pharmacokinetics” and “Dosage and administration”, Renal failure).

Low body weight

Enoxaparin sodium exposure has been observed to increase with prophylactic administration 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 symptoms and signs of thrombosis and embolism.

Peripheral blood platelet count monitoring

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 Enixum®. In case of confirmed significant decrease of platelets amount (by 30-50% compared to the initial value) it is necessary to cancel Enoxaparin sodium immediately and put the patient on another therapy.

Spinal/epidural anesthesia

There have been reports of neuroaxial hematomas when using enoxaparin sodium concomitantly with spinal/epidural anesthesia with the development of long-standing or irreversible paralysis. The risk of these phenomena is reduced when using enoxaparin sodium at a dose of 40 mg or lower.

The risk increases with higher doses of enoxaparin sodium and with the use of permanent catheters after surgery or with the simultaneous use of additional drugs that affect hemostasis, such as NSAIDs (see “Interactions”). 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 (see “Pharmacokinetics”). Catheter placement or removal is best 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.

The insertion or removal of a catheter should be performed at least 12 h after lower doses of Enixum® (20 mg once daily, 30 mg once or twice daily, 40 mg once daily) and at least 24 hours after administering higher doses of Enixum® (0.75 mg/kg 2 times daily, 1 mg/kg 2 times daily, 1.5 mg/kg/day). Enoxaparin sodium 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 2 times daily or 1 mg/kg 2 times daily should not be given a second dose in this dosing regimen (twice daily) in order to extend the interval before inserting or changing a catheter. Similarly, consideration should be given to delaying the next dose of enoxaparin sodium for at least 4 h 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 Cl 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 h for lower doses of sodium enoxaparin (30 mg/day) and at least 48 h for higher doses (1 mg/kg/day).

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

Enixum® 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 a history of heparin-induced thrombocytopenia is suspected, in vitro platelet aggregation tests are of limited value in predicting risk. The decision to use Enixum® in such a case should only be made after consultation with an appropriate specialist.

Prescapular 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 the administration of Enixum®. This is necessary in order to achieve hemostasis after percutaneous coronary intervention. If a femoral artery intraductor 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 IV or p/c injection of enoxaparin sodium. If treatment with sodium enoxaparin is continued, the next dose should not be administered before 6-8 h after removal of the femoral artery intromedullary tube. The site of insertion 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 prophylaxis of thrombosis in patients with mechanical artificial heart valves has not been well studied. There are isolated reports about the development of heart valve thrombosis in patients with mechanical artificial heart valves on the background of administration of 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 been poorly studied. In a clinical study in pregnant women with mechanical artificial heart valves, when enoxaparin sodium was used at a dose of 1 mg/kg 2 times daily to reduce the risk of thrombosis and embolism, 2 of 8 women developed thrombus, resulting in heart valve block and maternal and fetal death. There have been anecdotal post-marketing 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

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

Additional doses may lengthen the ACTV and activated clotting time. The increase of ACTV and activated clotting time is not in direct linear relation to the increase of 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 case of acute infection, acute rheumatic conditions, prophylactic use of enoxaparin sodium is justified 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; and chronic respiratory failure.

Pediatric use

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

Impact on performance of potentially hazardous activities requiring special attention and quick reactions. There are no data indicating an adverse effect of enoxaparin sodium on the ability to drive vehicles and engage in other potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.

Features

The pharmacokinetics of enoxaparin sodium at therapeutic doses is linear. Variability within and between patient groups is low. After a single oral injection of Enixum® at a dose of 1 mg/kg Cmax is (0.49±0.07) IU/mL, Tmax is (3.19+1.08) h, AUC0-24=(4.44+0.91) IU-mL/h. According to the literature, after repeated p/c administration of enoxaparin sodium at a dose of 40 mg once daily and p/c administration of enoxaparin sodium at a dose of 1.5 mg/kg once daily, Css is achieved by day 2, with an average AUC 15% higher than after a single administration. After repeated p/c injections of enoxaparin sodium at a daily dose of 1 mg/kg 2 times daily, Css is reached after 3-4 days, with an AUC on average 65% higher than after a single injection. The bioavailability of enoxaparin sodium when administered by injection, estimated on the basis of anti-Xa activity, is close to 100%.

The Vd of the anti-Kha activity of enoxaparin sodium is approximately 5 liters and approximates the blood volume.

Enoxaparin sodium is a low clearance drug. After IV administration for 6 h at a dose of 1.5 mg/kg, the average anti-Xa plasma clearance is 0.74 L/h.

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

The excretion of the drug is monophasic with T1/2 – 4 h (after single infusion of the drug) and 7 h (after multiple infusions of the drug).

The excretion through the kidneys of active fragments of the drug is approximately 10% of the administered dose, and the total excretion of active and inactive fragments is approximately 40% of the administered dose.

Patients in the elderly. Excretion is delayed due to physiological decreases in renal function. This change does not affect the dosing and mode of administration in prophylactic therapy if the renal function of such patients remains within acceptable limits, i.e., decreased slightly.

Disordered renal function. Clearance of enoxaparin sodium is decreased in patients with decreased renal function. Decreased clearance of enoxaparin sodium has been noted in renal failure. After repeated p/c administration of 40 mg of enoxaparin sodium once a day there is an increase of anti-Xa activity represented by AUC in mild (creatinine Cl 50-80 ml/min) and moderate (creatinine Cl 30-50 ml/min) renal insufficiency. In patients with severe renal insufficiency (creatinine Cl less than 30 ml/min) AUC at equilibrium is on the average 65% higher when repeated p/c injection of 40 mg of preparation once daily.

Patients with excess body weight. In overweight people, the clearance is slightly lower when the drug is administered b/c. If no dose adjustment is made for patient weight, after a single unit of 40 mg of Enoxaparin sodium administered by injection, the anti-Xa activity will be 50% higher in women with a body mass less than 45 kg and 27% higher in men with a body mass less than 57 kg compared to patients of normal average body mass.

Contraindications

Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins;

An active major bleeding and conditions and diseases with a high risk of bleeding – threatened abortion, cerebral aneurysm or dissecting aortic aneurysm (unless surgical intervention for this purpose is performed);

A recent hemorrhagic stroke;

Uncontrolled bleeding;

thrombocytopenia in combination with a positive in vitro test for antiplatelet antibodies in the presence of enoxaparin sodium;

children under 18 years of age (efficacy and safety not established) (see “Special Indications. “Special Indications”).

With caution: conditions with potential risk of bleeding – hemostasis disorders (including Hemophilia, thrombocytopenia, hypocoagulation, Willebrand disease), severe vasculitis; peptic ulcer disease or other gastrointestinal erosive and ulcerative lesions in anamnesis; recent ischemic stroke; uncontrolled severe arterial hypertension; diabetic or hemorrhagic retinopathy; severe diabetes mellitus; recent or suspected neurologic or ophthalmic surgery; spinal or epidural anesthesia (potential risk of hematoma), spinal tap (recent); recent labor; bacterial endocarditis (acute or subacute); pericarditis or pericardial effusion; renal and/or liver failure; intrauterine contraception; severe trauma (especially CNS), open wounds on large surfaces; simultaneous use of drugs that affect the hemostasis system; heparin-induced thrombocytopenia (history) in combination with or without thrombosis.

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

Side effects

Side effects were classified according to frequency as follows: very common – ≥1/10; common – ≥1/100-< 1/10; infrequent – ≥1/1000-< 1/100; rare – ≥1/10000-< 1/1000; very rare – < 1/10000.

Bleeding: bleeding is possible, especially in the presence of associated risk factors – organic changes with a tendency to bleeding, age, renal failure, low body weight and some combinations of drugs (see “Interaction”). If bleeding develops, it is necessary to cancel the drug administration, determine the cause of bleeding and start an appropriate therapy. Very often – bleeding during prophylaxis of venous thrombosis during surgical interventions and treatment of deep vein thrombosis with or without thromboembolism; often – bleeding during prophylaxis of venous thrombosis in patients on bed rest due to acute therapeutic diseases and during treatment of angina and myocardial infarction without Q wave and myocardial infarction with ST-segment elevation; infrequent – retroperitoneal bleeding and intracranial bleeding in patients during treatment of deep vein thrombosis with or without thromboembolism, as well as myocardial infarction with ST-segment elevation; rarely – retroperitoneal bleeding during prophylaxis of venous thrombosis in surgical patients and during treatment of angina and myocardial infarction without Q wave. When using enoxaparin sodium against the background of spinal/epidural anesthesia and postoperative use of penetrating catheters rare cases of neuroaxial hematomas have been described, leading to neurological disorders of varying severity, including long-term persistent or irreversible paralysis (see “Special indications”).

Thrombocytopenia and thrombocytosis: During the first days after the start of therapy, mildly pronounced transient asymptomatic thrombocytopenia may develop. Very often – thrombocytosis during prophylaxis of venous thrombosis during surgical interventions and treatment of deep vein thrombosis with or without thromboembolism; often – thrombocytopenia. In the prevention of venous thrombosis during surgical interventions and treatment of deep vein thrombosis with or without thromboembolism, as well as in myocardial infarction with ST-segment elevation; infrequent – thrombocytopenia during prophylaxis of venous thrombosis in patients on bed rest and during treatment of angina pectoris, myocardial infarction without Q wave; very rare – autoimmune thrombocytopenia during myocardial infarction with ST-segment elevation. In rare cases, the development of autoimmune thrombocytopenia combined with thrombosis has been reported. In some of them, thrombosis has been complicated by organ infarction or limb ischemia (see “Special Precautions”).

Other: very common – increased liver transaminase activity; common – allergic reactions, urticaria, itching, redness of the skin, hematoma and pain at the injection site; infrequent – skin (bullous rashes), inflammatory reaction at the injection site, necrosis of the skin at the injection site; rare – anaphylactic and anaphylactoid reactions, hyperkalemia. Skin necrosis may develop at the injection site, preceded by purpura or erythematous painful papules. In these cases the drug therapy 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.

Overdose

Symptoms: hemorrhagic complications in case of accidental overdose by injection of Enoxaparin sodium. Absorption of the drug is unlikely when administered orally, even in large doses.

Treatment: neutralize the effect of enoxaparin sodium by slow IV administration of protamine sulfate (or hydrochloride). Before using protamine sulfate, due to the possibility of side effects (particularly anaphylactic shock), the benefit/risk ratio should be carefully weighed.

1 mg of protamine sulfate neutralizes the anticoagulant effect of 1 mg of enoxaparin sodium if the drug was administered no more than 8 hours before administration of protamine sulfate.

The 0.5 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of enoxaparin sodium if administered more than 8 hours previously or if a second dose of protamine sulfate is necessary.

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

Similarities