Enixum 2000 anti-Ha IU/0.2 ml 0.2 ml syringes, 10 pcs.

Pharmacotherapeutic group: direct acting anticoagulant.

ATC code: B01AB05

Pharmacological properties

Characteristics
Enoxaparin sodium is a low molecular weight heparin. The average molecular weight is about 4500 daltons: less than 2000 daltons – < 20%, 2000 to 8000 daltons – > 68%, more than 8000 daltons – < 18%. Enoxaparin sodium is obtained by alkaline hydrolysis of heparin benzyl ether isolated from mucous membrane of pig small intestine. Its structure is characterized by a nonreducible fragment of 2-O-sulfo-4-enpyrazinosuronic acid and a reducible fragment of 2-N,6-O-disulfo-D-glucopyranoside. The structure of enoxaparin sodium contains about 20% (ranging from 15% to 25%) of the 1,6-anhydro derivative in the reducing fragment of the polysaccharide chain. Pharmacodynamics
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 (AT-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 vascular endothelium into the bloodstream. These factors provide anticoagulant effect of enoxaparin sodium in general.
When used in prophylactic doses enoxaparin sodium slightly changes activated partial thromboplastin time (APT), has almost no effect on platelet aggregation and on the degree of binding of fibrinogen to platelet receptors.
Anti-IIa activity in plasma is about 10 times lower than anti-Xa activity. The average maximum anti-IIa activity is observed approximately 3-4 hours after subcutaneous
administration and reaches 0.13 IU/ml and 0.19 IU/ml after repeated administration of 1 mg/kg body weight – when administered twice and 1.5 mg/kg body weight – when administered once, respectively.
Mean maximum plasma anti-Xa activity is observed 3-5 hours after subcutaneous administration of the drug and is approximately 0.2; 0.4; 1.0 and 1.3 anti-Xa IU/ml after
subcutaneous administration of 20 mg, 40 mg and 1 mg/kg and 1.5 mg/kg, respectively.

Pharmacokinetics

The pharmacokinetics of enoxaparin sodium at therapeutic doses are linear. Variability within and between patient groups is low. After a single subcutaneous administration of Enixum® at the 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/hour. According to literature data, after repeated subcutaneous administration of enoxaparin sodium at a dose of 40 mg once daily
and subcutaneous administration of enoxaparin sodium at a dose of 1.5 mg/kg once daily, the equilibrium concentration is reached by day 2, and the area under the pharmacokinetic curve is on average 15% higher than after a single injection. After repeated subcutaneous injections of enoxaparin sodium at a daily dose of 1 mg/kg twice a day the equilibrium concentration is reached after 3-4 days, and the area under the pharmacokinetic curve is on average 65 % higher than after a single injection. The bioavailability of enoxaparin sodium when administered subcutaneously, estimated on the basis of anti-Xa activity, is close
to 100%.

The volume of distribution of anti-Xa activity of sodium enoxaparin is approximately 5 liters and approximates the blood volume.
Sodium enoxaparin is a drug with low clearance. After IV administration for 6 h at a dose of 1.5 mg/kg body weight, the average anti-Xa plasma clearance was
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. Excretion through the kidneys of active fragments of the drug is about 10% of the administered dose and total excretion of active and inactive fragments is about 40% of the administered dose.

Patients in the elderly
Excretion is delayed because of the physiological decrease in renal function. This change does not affect the dosing and administration regimen for prophylactic therapy if the
renal function of such patients remains within acceptable limits, i.e., is mildly impaired.

Patients with impaired renal function
The clearance of enoxaparin sodium is decreased in patients with reduced renal function.
Decreased clearance of enoxaparin sodium has been noted in renal failure. After repeated subcutaneous administration of 40 mg of Enoxaparin sodium once a day there is an increase of anti-Xa activity represented by the area under the pharmacokinetic curve in mild (creatinine clearance (CK) 50-80 ml/min) and moderate (CK 30-50 ml/min) renal insufficiency. In patients with severe renal insufficiency (CKR less than 30 ml/min) the area under pharmacokinetic curve at equilibrium is, on average, 65% higher with repeated subcutaneous administration of 40 mg of the drug once daily.

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

Indications

– prevention of venous thrombosis and embolism during surgical interventions,
especially during orthopedic and general surgery;
– prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic
diseases (including acute heart failure and decompensation of chronic heart failure (III or IV class NYHA), acute respiratory
failure; acute infectious diseases; acute stages of rheumatic diseases in combination with one of the risk factors of venous thrombosis
(see “Special Indications”);
– prevention of venous thrombosis and embolism in patients under bed rest due to acute therapeutic
diseases. “Special indications);
– treatment of deep vein thrombosis, which is accompanied or not accompanied by 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, when the session lasts no more than 4 hours);
– Treatment of acute myocardial infarction with ST-segment elevation in patients undergoing drug treatment or subsequent percutaneous coronary
intervention.

Active ingredient

Composition

Position per 1 syringe or 1 ampoule:
Active ingredient: enoxaparin sodium 2000 anti Xa ME (20 mg);
excipients: water for injection – up to 0.2 ml

How to take, the dosage

Except in special cases (see “Treatment of ST-segment elevation myocardial infarction, drug or percutaneous coronary intervention” and “Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis” below), enoxaparin sodium is injected deep subcutaneously. Injections should preferably be performed in the “supine” position of the patient. Injections should be given alternately on the left or right anterolateral or posterolateral surface of the abdomen. The needle should be inserted vertically (not laterally) into the full length skin fold, gathered and held until the injection is completed between the thumb and forefinger. The skin fold, release only after the completion of the injection. 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 during surgical procedures, especially orthopedic and general surgical procedures. In patients at moderate risk of thrombosis and embolism (e.g., abdominal
surgery), the recommended dose is 20 mg once daily subcutaneously. The first injection should be given 2 hours before surgery.

Patients at high risk for thrombosis and embolism (e.g., orthopedic surgery, oncology surgery, patients with additional
non-operative risk factors such as congenital or acquired thrombophilia, malignancy, bed rest for more than three days,
obesity, venous thrombosis, and thrombophiliabr> obesity, venous thrombosis in anamnesis, varicose veins of lower limbs, pregnancy) the preparation is recommended in a dose of 40 mg once a day subcutaneously, with the first dose administered 12 hours before the operation, or in a dose of 30 mg twice a day, starting 12-24 hours after the operation.
The duration of drug therapy is 7-10 days on average. If necessary the therapy can be continued until the risk of thrombosis and embolism is preserved and until the patient switches to an outpatient regimen.
After the initial therapy it may be reasonable to continue treatment by dosing the drug 40 mg once daily for
3 weeks in orthopedic surgeries. The peculiarities of the drug administration during spinal/epidural anesthesia as well as during coronary revascularization procedures are described under “Special Precautions”.
Prevention of venous thrombosis and embolism in bed-ridden patients due to acute therapeutic diseases.

The recommended dose of enoxaparin sodium is 40 mg once daily subcutaneously for at least 6 days. The therapy should be continued until the patient is fully ambulatory (maximum 14 days).
Treatment of deep vein thrombosis accompanied or not accompanied by pulmonary embolism.
Enixum® is administered subcutaneously at the rate of 1.5 mg/kg body weight once daily or at the rate of 1 mg/kg body weight twice daily. In patients with complicated thromboembolic disorders the drug is recommended in 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, while therapy with enoxaparin sodium should be continued until therapeutic anticoagulant effect is achieved (INR [International Normalized Ratio] values should be 2.0-3.0). If necessary, the anticoagulant effect should be assessed by anti-Xa activity.
Treatment of unstable angina and myocardial infarction without Q wave in combination with acetylsalicylic acid
Enixum® is administered at the rate of 1 mg/kg body weight every 12 hours, subcutaneously, with simultaneous administration of oral acetylsalicylic acid 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 is administered for 2 to 8 days.
Treatment of ST-segment elevation myocardial infarction, medication or by percutaneous coronary intervention.
Treatment begins with an intravenous bolus injection of sodium enoxaparin at a dose of 30 mg and immediately thereafter (within 15 minutes) administered subcutaneously at a dose of 1 mg/kg body weight
(with a maximum of 100 mg of sodium enoxaparin administered during the first two subcutaneous injections). Thereafter, all subsequent subcutaneous doses are administered every
12 hours at a rate of 1 mg/kg body weight (i.e., for body weights greater than 100 kg, the dose may exceed 100 mg).
In patients 75 years and older, the initial intravenous bolus injection is not used. Enoxaparin sodium is administered subcutaneously at a dose of 0.75 mg/kg every 12 hours (with a maximum of 75 mg of enoxaparin sodium administered for the first two subcutaneous injections). Then all subsequent subcutaneous doses are administered every 12 hours at a rate of 0.75 mg/kg body weight (i.e. if body weight exceeds 100 kg, the dose may exceed 75 mg).
When combined with thrombolytics (fibrin-specific and fibrin-unspecific) sodium enoxaparin should be administered between 15 minutes before thrombolytic
therapy and 30 minutes after it. After detection of acute ST-segment elevation myocardial infarction, acetylsalicylic
acid should be started as soon as possible 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 hospitalization period is less than 8 days.
Intravenous bolus injection of sodium enoxaparin should be performed through a venous catheter and sodium enoxaparin should not be mixed or injected with other
medications. In order to avoid traces of other medications 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 intravenous bolus injection of sodium enoxaparin. Enoxaparin sodium is compatible with 0.9% sodium chloride solution and 5% dextrose solution.
To perform 30 mg bolus injection of Enoxaparin sodium in the treatment of acute ST-segment elevation myocardial infarction, the 60 mg, 80 mg and 100 mg glass syringes are removed so that only 30 mg (0.3 ml) remains.
The 30 mg dose may be directly administered intravenously.
Prefilled 60 mg, 80 mg and 100 mg hypodermic syringes may be used for intravenous bolus injection of enoxaparin sodium through a venous catheter. The 60 mg syringe is recommended because it reduces the amount of product 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. 40 mg syringes are not used because they have no divisions and therefore it is impossible to accurately measure the 30 mg.
In patients undergoing percutaneous coronary intervention, if the last subcutaneous injection of sodium enoxaparin was given less than 8 hours before
inflating the balloon catheter introduced into the coronary artery narrowing, no additional injection of sodium enoxaparin is required. If the last subcutaneous
injection of sodium enoxaparin was administered more than 8 hours before balloon catheter inflation, an intravenous additional bolus injection of sodium enoxaparin
at a dose of 0.3 mg/kg should be given.
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 a concentration of 3 mg/ml using a pre-filled syringe, it is recommended to use a container with infusion
solution, from which a part of the solution is extracted to the required volume using a regular syringe. Enoxaparin sodium (the contents of the hypodermic syringe)
is injected into the remaining infusion solution in the container.

The volume of the pre-filled
syringe

The amount of infusion solution left in the reservoir
./p>

0.3 ml 10 ml
0.6 ml 20 ml

The contents of the diluted Enoxaparin Sodium Solution container are gently stirred. A syringe is used to extract the desired volume of the diluted
sodium enoxaparin solution, which is calculated according to the formula: Volume of diluted solution = Patient body weight (kg) x 0.1 or using the table below.
Volumes to be administered intravenously after dilution.

Patient weight [kg] Dose required
(0.3 mg/kg) [mg] Volume of solution diluted to 3 mg/ml needed to administer
br> 45 13,5 4,5
50 15 5
55 16,5,5
60 18 6
65 19,5 6,5
70 21 7
75 22,5 7,5
80 24 8
85 25,5 8,5
90 27 9
95 28.5 9.5
100 30 10

Prevention of thrombosis in the extracorporeal circulatory system during hemodialysis (usually with a session duration of 4 hours or less)
The dose of Enoxaparin sodium averages 1 mg/kg body weight. For patients at high risk of bleeding, the dose should be reduced to 0.5 mg/kg body weight for double
vascular access or 0.75 mg for single vascular access.
In hemodialysis, Enixum® 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, an additional drug at the rate of 0.5-1 mg/kg body weight may be administered.

Interaction

Enixum® must not be mixed with other drugs in the same syringe.
When used simultaneously with other drugs affecting hemostasis (salicylates, including acetylacetic acid, acetylacetic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac. acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), including ketorolac, dextran with a molecular weight of 40 kDa, ticlopidine, clopidogrel, systemic glucocorticosteroids (GCS), thrombolytics or anticoagulants, other antiplatelet drugs, including glycoprotein IIb/IIIa receptor antagonists), there is an increased risk of bleeding (see “Special
Instructions. “Special
instructions”).

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, the use of Enixum® may cause bleeding of any localization (see “Adverse 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 increased risk of bleeding has been noted.
When using enoxaparin sodium 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 (see section “Pharmacokinetics” and section “Administration and doses”, subsection “Elderly patients”).

The concomitant use of other drugs that affect hemostasis
It is recommended that the use of drugs that affect hemostasis (salicylates, including Salicylic acid, NSAIDs including ketorolac, 40 kDa dextran, ticlopidine, clopidogrel, GCS, thrombolytics, anticoagulants, antiaggregants including glycoprotein IIb/IIIa receptor antagonists) should 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 sodium enoxaparin.
In patients with severe renal impairment (creatinine clearance less than 30 ml/min) a significant increase of sodium enoxaparin exposure is noted, therefore
it is recommended to perform dose adjustment both during 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), it is recommended to closely monitor these patients (see sections “Pharmacokinetics” and “Dosage and administration”, subsection “Patients with renal impairment”).

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 lead to an increased risk of bleeding. Close monitoring of these patients is recommended.

Patients with obesity
Patients with obesity have an increased risk of thrombosis and embolism. The safety and efficacy of prophylactic doses of enoxaparin sodium in
obese patients (body mass index 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 counts
The risk of antibody-mediated heparin-induced thrombocytopenia also exists with the use of low molecular weight heparins. If thrombocytopenia develops, it is usually detected between day 5 and 21 after the start 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 platelet count (by 30-50 % compared to the initial value) it is necessary to stop Enoxaparin sodium immediately and put the patient on another therapy.

Spinal/epidural anesthesia
There have been cases of neuroaxial hematomas when using enoxaparin sodium concomitantly with spinal/epidural anesthesia with development of long-lasting 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 when using higher doses of enoxaparin sodium as well as when using permanent catheters after surgery or when using additional drugs that affect hemostasis, such as NSAIDs (see “Interaction with other medicinal products”). 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 insertion or removal is best performed when the anticoagulant effect of enoxaparin sodium is low, but the exact time to achieve sufficient reduction in anticoagulant effect in different patients is unknown.
Catheter placement or removal 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 h after administering higher doses of Enixum® (0.75 mg/kg body weight twice daily, 1 mg/kg body weight
twice daily, 1.5 mg/kg body weight once daily). Enoxaparin sodium anti-Xa activity is still detectable at these time points, and time delays are not
a 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 administer a second dose in order to increase the interval before inserting or replacing the catheter. Similarly, consideration should be given to delaying the next dose of enoxaparin sodium by 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 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 h for lower doses of sodium enoxaparin (30 mg once per
day) and at least 48 h for higher doses (1 mg/kg body weight per day).
If anticoagulant therapy is prescribed by a physician during epidural/spinal anesthesia or lumbar puncture, constant
monitoring of the patient is required to detect any neurological symptoms such as back pain, sensory and motor disturbances (numbness or weakness in the lower
limbs), abnormal bowel and/or bladder function. The patient should be instructed to inform the physician immediately if the symptoms described above 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
With special caution Enixum® should be used in patients with a history of heparin-induced thrombocytopenia in combination with
thrombosis or without it.
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 Enixum® in such a
case should be made only after consultation with an appropriate specialist.

Prescope coronary angioplasty
In order to minimize the risk of bleeding associated with invasive vascular instrumental manipulation in the treatment of unstable angina and myocardial infarction
br> without Q-wave and acute myocardial infarction with ST-segment elevation, these procedures should be performed in intervals between Enixum® administration. This is necessary in order to achieve hemostasis after percutaneous coronary intervention.
If a femoral artery intromedullary device is used, the femoral artery intromedullary device can be removed immediately. If manual compression is used, the femoral artery intromedullary tube must 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 h after removal of the femoral artery introducer. The site of introducer insertion should be monitored to detect timely signs of bleeding and hematoma formation.
Patients with mechanical artificial heart valves

The use of sodium enoxaparin 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,
leading to heart valve blockage and maternal and fetal death.
There are 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
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 their binding to fibrinogen.
At increasing the dose the ACTV and activated clotting time may be prolonged.
The increase of ACTV and activated clotting time do not directly linearly depend on 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;
– chronic respiratory failure.

Pediatric use
Safety and effectiveness of enoxaparin sodium in children under 18 years of age has not been established.

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

Synopsis

Contraindications

– hypersensitivity to enoxaparin sodium, heparin or its derivatives,
including other low molecular weight heparins;
– active major bleeding, as well as conditions and diseases in which
there is a high risk of bleeding: threatened abortion, cerebral vascular aneurysm or dissecting aortic aneurysm (unless there is
surgical intervention for this reason), 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, since the effectiveness and safety in this category of
patients has not been established (see section “Indications.
– children under 18 years of age.)

With caution

Regenerative states with a potential risk of bleeding:
– hemostasis disorders (including hemophilia, thrombocytopenia, hypocoagulation, Willebrand’s disease and others.), severe vasculitis;
– 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;
– recent or suspected neurological or ophthalmologic
surgery;
– 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 liver failure;
– intrauterine contraception (IUD);
– severe trauma (especially central nervous system (CNS), open wounds on
large surfaces;
– simultaneous use of drugs that affect the hemostatic system;
– heparin-induced thrombocytopenia (in anamnesis) in combination with thrombosis or
without it.
There are no data on the clinical use of enoxaparin sodium in the following
diseases: active tuberculosis, radiation therapy (recent).

Side effects

Side effects were classified according to frequency as follows: very frequent
(≥1/10), frequent (≥1/100 – < 1/10), infrequent (≥1/1000 – < 1/100), rare (≥1/10000 – < 1/1000),
very rare (< 1/10000).

Bleeding
Bleeding is possible, especially in the presence of associated risk factors: organic changes with a tendency to bleeding, age, renal insufficiency, low body weight and some combinations of drugs (see “Interactions with other drugs”). In case of bleeding it is necessary to cancel the drug administration, determine the cause of bleeding and initiate appropriate therapy.
Very common – bleeding during prophylaxis of venous thrombosis, in surgical patients and treatment of deep vein thrombosis with or without thromboembolism.
Frequent – bleeding in the prevention of venous thrombosis in patients on bed rest and in the treatment of angina, myocardial infarction without Q-wave and ST-segment elevation myocardial infarction.
Infrequent – retroperitoneal bleeding and intracranial bleeding in patients treated for deep vein thrombosis with or without thromboembolism and ST-segment elevation myocardial infarction.
Rare – retroperitoneal bleeding in the prevention of venous thrombosis in surgical patients and in the treatment of angina, myocardial infarction without Q-wave.
When using enoxaparin sodium against the background of spinal/epidural anesthesia and postoperative use of penetrating catheters rare cases have been described
of neuroaxial hematomas resulting in neurological disorders of varying severity, including long-term persistent or irreversible
paralysis (see “Special indications”).

Thrombocytopenia and thrombocytosis
Very frequent – thrombocytosis in the prophylaxis of venous thrombosis in surgical patients and treatment of deep vein thrombosis with or without thromboembolism.
Frequent – thrombocytopenia. In the prevention of venous thrombosis in surgical patients and the treatment of deep vein thrombosis with thromboembolism or without it, as well as myocardial infarction with ST-segment elevation.
Infrequent – thrombocytopenia in the prevention of venous thrombosis in patients on bed rest and in the treatment of angina, myocardial infarction without Q wave.
Very rare are autoimmune thrombocytopenia in ST-segment elevation myocardial infarction.
In rare cases, the development of autoimmune thrombocytopenia in combination with thrombosis has been reported. In some of them, thrombosis has been complicated by organ infarction or limb ischemia (see section “Special Indications”).

Other
Very common – increased activity of “hepatic” transaminases.
Often – allergic reactions, urticaria, itching, redness of the skin, hematoma and pain at the injection site.
Infrequent – skin (bullous rashes), inflammatory reaction in the injection site, skin necrosis in the injection site.
Rarely – anaphylactic and anaphylactoid reactions, hyperkalemia. Necrosis of the skin 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 of accidental overdose during subcutaneous injection of enoxaparin sodium. In case of accidental ingestion even large doses absorption of the drug is unlikely.
Treatment: neutralize the effect of Enoxaparin sodium by slow intravenous (IV) administration of protamine sulfate. 1 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of sodium enoxaparin if the drug was administered no more than 8 hours before protamine sulfate administration.
0.5 mg of protamine sulfate will neutralize the anticoagulant effect of 1 mg of sodium enoxaparin if it was administered more than 8 hours ago or if a second dose of sodium protamine sulfate is needed.
If 12 hours or more have passed since administration of sodium enoxaparin, 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 are currently insufficient clinical data to determine the possible teratogenic or fetotoxic effects of enoxaparin sodium when administered prophylactically during pregnancy. Enixum® should not be used during pregnancy unless the potential benefit to the mother outweighs the possible risk to the fetus.

A spinal or epidural anesthesia should not be performed during treatment with the drug.
If epidural anesthesia is planned, preventive treatment with Enoxaparin sodium should be discontinued if possible at least 12 h prior to anesthesia.
Enoxaparin sodium is not recommended in pregnant women with prosthetic heart valves.

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