Enoxaparin-pharmex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENOXAPARIN-PHARMEX

Composition:

Active substance: enoxaparin;

1 ml of solution contains 10,000 anti-Xa IU, equivalent to 100 mg of sodium enoxaparin;

Excipients: benzyl alcohol, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless or slightly yellow solution.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01A B05.

Pharmacological properties.

Pharmacodynamics.

Enoxaparin is a low molecular weight heparin in which the antithrombotic and anticoagulant effects are dissociated from those of standard heparin. The active substance is presented as the sodium salt.

In a purified in vitro system, enoxaparin sodium exhibits high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa (or antithrombin) activity (approximately 28 IU/mg), resulting in a ratio of 3.6. These anticoagulant activities are mediated through antithrombin III (ATIII), which underlies the antithrombotic effects in humans.

In addition to anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy volunteers and patients, as well as in experimental models within preclinical studies. These include ATIII-dependent inhibition of other coagulation factors, such as factor VIIa, induction of endogenous release of tissue factor pathway inhibitor (TFPI), and reduction of von Willebrand factor (vWF) release from vascular endothelium into the circulation. These mechanisms contribute to the overall antithrombotic effect of enoxaparin sodium.

When used for prophylaxis, enoxaparin sodium does not substantially affect activated partial thromboplastin time (aPTT). When used for treatment, aPTT may be prolonged by 1.5–2.2 times compared to the control value at peak drug activity.

Clinical efficacy and safety.

Prevention of venous thromboembolic complications associated with surgical procedures.

Extended prevention of venous thromboembolism (VTE) following orthopedic surgery.

In a double-blind study on extended prophylaxis after elective hip replacement surgery, 179 patients without any venous thromboembolic complications who initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospitalization were randomized after hospital discharge to receive either enoxaparin sodium 4000 IU (40 mg) (n = 90) once daily s.c. or placebo (n = 89) for 3 weeks. The incidence of deep vein thrombosis (DVT) during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to the placebo group; no cases of pulmonary embolism (PE) were recorded. No major bleeding events occurred.

Efficacy data are presented in Table 1.

Table 1.

Parameter	Enoxaparin sodium 4000 IU (40 mg) once daily s.c., n (%)	Placebo once daily s.c., n (%)
All patients who received study treatment for long-term prophylaxis	90 (100)	89 (100)
Total number of VTE events (%)	6 (6.6)	18 (20.2)
Total number of DVT events (%)	6 (6.6)*	18 (20.2)
Number of proximal DVT events (%)	5 (5.6)#	7 (8.8)
* p-value compared to placebo is 0.008. # p-value compared to placebo is 0.537.

In another double-blind study, 262 patients without any venous thromboembolic events, who underwent hip replacement surgery and initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously during hospitalization, were randomized to receive either enoxaparin sodium 4000 IU (40 mg) (n = 131) once daily subcutaneously or placebo (n = 131) after hospital discharge for 3 weeks. Similar to the results of the first study, the incidence of VTE during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to placebo, both in terms of total VTE events (enoxaparin sodium – 21 [16%] versus placebo – 45 [34.4%]; p = 0.001) and proximal deep vein thrombosis (DVT) (enoxaparin sodium – 8 [6.1%] versus placebo – 28 [21.4%]; p < 0.001). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT after surgery for cancer.

In a double-blind, multicenter study, safety and efficacy of 4-week versus 1-week prophylactic regimens of enoxaparin sodium were compared in 332 patients undergoing planned abdominal or pelvic surgery for cancer. Patients received enoxaparin sodium (4000 IU [40 mg] subcutaneously) daily for 6–10 days, after which they were randomized to receive either enoxaparin sodium or placebo for an additional 21 days. Bilateral venography was performed between days 25 and 31, or earlier if symptoms of VTE occurred. Patients were followed for 3 months. Prophylactic use of enoxaparin sodium for 4 weeks after abdominal or pelvic cancer surgery significantly reduced the incidence of venographically confirmed thrombosis compared to a 1-week prophylaxis regimen. The incidence of VTE at the end of the double-blind phase was 12.0% (n = 20) in the placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference persisted over 3 months [13.8% vs. 5.5% (n = 23 vs. 9), p = 0.01]. No differences were observed between groups in the frequency of bleeding or other complications during the double-blind period or follow-up period.

Prophylaxis of venous thromboembolic complications in medical patients with acute illnesses expected to cause limited mobility.

In a double-blind, multicenter, parallel-group study, the efficacy of enoxaparin sodium 2000 IU (20 mg) or 4000 IU (40 mg) once daily subcutaneously was compared to placebo for prevention of VTE in medical patients with severely limited mobility (defined as walking less than 10 meters within ≤ 3 days) due to an acute illness. The study included patients with heart failure (NYHA functional class III or IV), acute respiratory insufficiency or complicated chronic respiratory insufficiency, acute infection, or acute rheumatic disease, provided they had at least one VTE risk factor (age ≥ 75 years, cancer, prior VTE, obesity, varicose veins, hormonal therapy, chronic heart or respiratory failure).

Overall, 1102 patients were enrolled in the study, and 1073 patients received the investigational treatment. Treatment duration was 6–14 days (median duration was 7 days). Enoxaparin sodium administered at a dose of 4000 IU (40 mg) once daily subcutaneously significantly reduced the incidence of VTE compared to placebo. Efficacy data are presented in Table 2.

Table 2.

Parameter	Enoxaparin sodium 2000 IU (20 mg) once daily s.c., n (%)	Enoxaparin sodium 4000 IU (40 mg) once daily s.c., n (%)	Placebo n (%)
All treated patients who received investigational prophylactic treatment during acute illness	287 (100)	291 (100)	288 (100)
Total number of VTE (%)	43 (15.0)	16 (5.5)*	43 (14.9)
Total number of DVT (%)	43 (15.0)	16 (5.5)	40 (13.9)
Number of proximal DVT (%)	13 (4.5)	5 (1.7)	14 (4.9)
VTE – venous thromboembolic events, including cases of DVT, PE, and deaths considered to be due to thromboembolic events. * p-value compared to placebo is 0.0002.

After approximately 3 months of patient inclusion in the study, the incidence of VTE in the group receiving enoxaparin sodium at a dose of 4000 IU (40 mg) remained statistically significantly lower compared to the placebo group.

The overall incidence of bleeding and the incidence of major bleeding were 8.6% and 1.1%, respectively, in the placebo group, 11.7% and 0.3% in the enoxaparin sodium 2000 IU (20 mg) group, and 12.6% and 1.7% in the enoxaparin sodium 4000 IU (40 mg) group.

Treatment of deep vein thrombosis, with or without pulmonary embolism.

In a multicenter, parallel-group study, 900 patients with acute DVT of the lower limbs, with or without PE, were randomized to receive in-hospital treatment either with enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily subcutaneously, or enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours subcutaneously, or heparin as an intravenous bolus (5000 IU) followed by continuous intravenous infusion (to achieve an aPTT of 55 to 85 seconds). Overall, 900 patients were randomized in the study, all of whom received the investigational treatment. All patients also received sodium warfarin (dose adjusted according to prothrombin time with the aim of achieving an international normalized ratio (INR) between 2.0 and 3.0), which was initiated within 72 hours after starting enoxaparin sodium or standard heparin therapy and continued for 90 days. Enoxaparin sodium or standard heparin therapy was administered for at least 5 days and until the target INR was achieved on warfarin sodium. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolic events (DVT and/or PE). Efficacy data are presented in Table 3.

Table 3.

Parameter	Enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily s.c., n (%)	Enoxaparin sodium 100 IU/kg (1 mg/kg) twice daily s.c., n (%)	Heparin i.v. infusion with dose adjustment based on aPTT levels, n (%)
All patients with DVT with or without PE who received study treatment	298 (100)	312 (100)	290 (100)
Total incidence of VTE (%)	13 (4.4)*	9 (2.9)*	12 (4.1)
Incidence of DVT only (%)	11 (3.7)	7 (2.2)	8 (2.8)
Incidence of proximal DVT (%)	9 (3.0)	6 (1.9)	7 (2.4)
Incidence of PE (%)	2 (0.7)	2 (0.6)	4 (1.4)
VTE – venous thromboembolism (DVT and/or PE). * 95% confidence intervals for the difference between treatment groups in overall VTE rate were: enoxaparin sodium once daily vs. heparin: from –3.0 to 3.5; enoxaparin sodium every 12 hours vs. heparin: from –4.2 to 1.7.

The frequency of major bleeding was 1.7% in the group receiving sodium enoxaparin 150 IU/kg (1.5 mg/kg) once daily, 1.3% in the group receiving sodium enoxaparin 100 IU/kg (1 mg/kg) twice daily, and 2.1% in the heparin group.

Unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) treatment.

In a large multicenter study, 3171 patients enrolled during the acute phase of unstable angina and non-Q-wave myocardial infarction were randomized to receive either sodium enoxaparin 100 IU/kg (1 mg/kg) every 12 hours or unfractionated heparin (UFH) intravenously with dose adjustment based on aPTT levels, all in combination with acetylsalicylic acid (100–325 mg once daily). Patients received in-hospital treatment for a minimum of 2 days and up to 8 days until clinical stabilization, revascularization procedures, or hospital discharge. Patients were followed for up to 30 days. Compared with heparin, sodium enoxaparin significantly reduced the composite incidence of angina, myocardial infarction, and death from 19.8% to 16.6% at day 14 (relative risk reduction of 16.2%). This reduction in the composite endpoint was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%). There were no statistically significant differences in the frequency of major bleeding, although injection site hemorrhages occurred more frequently.

Treatment of acute ST-segment elevation myocardial infarction (STEMI) in combination with thrombolytic therapy in patients eligible for subsequent coronary angioplasty.

In a large multicenter clinical trial involving 20,479 patients with acute ST-segment elevation myocardial infarction, after receiving fibrinolytic therapy, patients were randomized to receive either enoxaparin as an intravenous bolus of 3000 anti-Xa IU followed by immediate subcutaneous administration of 100 anti-Xa IU/kg, then subcutaneous doses of 100 anti-Xa IU/kg every 12 hours, or intravenous unfractionated heparin as a bolus of 60 IU/kg (maximum 4000 IU) followed by continuous infusion adjusted according to activated partial thromboplastin time (aPTT). Subcutaneous enoxaparin injections were continued until hospital discharge or for no more than 8 days (in 75% of cases, at least 6 days). Half of the patients receiving heparin were treated for at least 48 hours (in 89.5% of cases, ≥36 hours). All patients also received aspirin for at least 30 days. The enoxaparin dose was adjusted for patients aged ≥75 years: 75 anti-Xa IU/kg subcutaneously every 12 hours without an initial intravenous bolus.

During the study, 4716 (23%) patients underwent coronary angioplasty while on masked study treatment. Patients did not receive additional doses if less than 8 hours had elapsed between the last subcutaneous enoxaparin injection and balloon inflation, or they received an intravenous bolus of enoxaparin 30 anti-Xa IU/kg if more than 8 hours had elapsed between the last subcutaneous enoxaparin injection and balloon inflation.

Enoxaparin significantly reduced the rate of primary outcome events (a composite endpoint including recurrent myocardial infarction and all-cause mortality occurring within the 30-day period after enrollment: 9.9% in the enoxaparin group compared to 12% in the unfractionated heparin group (relative risk reduction of 17%, p < 0.001)). The rate of recurrent myocardial infarction was significantly lower in the enoxaparin group (3.4% vs. 5%, p < 0.001, relative risk reduction of 31%). Mortality was lower in the enoxaparin group, with a statistically significant difference between groups (6.9% vs. 7.5%, p = 0.11).

The advantage of enoxaparin regarding the primary endpoint was consistent across all subgroups: age, sex, location of myocardial infarction, diabetes or history of myocardial infarction, type of thrombolytic agent used, and time interval between first symptoms and initiation of treatment.

Enoxaparin demonstrated significant superiority over unfractionated heparin in terms of the primary efficacy endpoint both in patients who underwent coronary angioplasty within the 30-day period after enrollment (10.8% vs. 13.9%, 23% relative risk reduction) and in those who did not undergo angioplasty (9.7% vs. 11.4%, 15% relative risk reduction).

The frequency of major bleeding by day 30 was significantly higher in the enoxaparin group (2.1%) compared to the heparin group (1.4%). The rate of gastrointestinal bleeding was higher in the enoxaparin group (0.5%) than in the heparin group (0.1%), while the rate of intracranial hemorrhage was similar in both groups (0.8% for enoxaparin vs. 0.7% for heparin).

An analysis of composite clinical benefit criteria showed a statistically significant advantage (p < 0.0001) of enoxaparin over unfractionated heparin: a 14% relative risk reduction in favor of enoxaparin (11% vs. 12.8%) for the composite endpoint of mortality, recurrence, myocardial infarction, and major bleeding (TIMI criteria) by day 30, and a 17% reduction (10.1% vs. 12.2%) for the composite endpoint of mortality, recurrent myocardial infarction, and intracranial hemorrhage by day 30.

Hepatic impairment. According to scientific literature, administration of sodium enoxaparin 4000 IU (40 mg) in patients with liver cirrhosis (Child-Pugh class B–C) is safe and effective for prevention of portal vein thrombosis. However, it should be noted that the studies described in the literature may have certain limitations. Caution should be exercised in patients with hepatic impairment, as they are more prone to bleeding (see section "Special precautions"), and no formal dose-finding studies have been conducted in patients with cirrhosis (Child-Pugh class A, B, or C).

Pharmacokinetics.

The pharmacokinetic parameters of enoxaparin were assessed based on the duration of plasma anti-Xa and anti-IIa activity at recommended doses (validated amidolytic methods) after single and repeated subcutaneous administrations and after single intravenous injection.

Biological availability. Subcutaneously administered enoxaparin is rapidly and almost completely absorbed (approximately 100%). Peak plasma activity occurs 3–4 hours after administration. This peak activity (expressed in anti-Xa IU) is 0.18 ± 0.04 (after 2000 anti-Xa IU), 0.43 ± 0.11 (after 4000 anti-Xa IU) for prophylactic treatment, and 1.01 ± 0.14 (after 10,000 anti-Xa IU) for therapeutic treatment.

An intravenous bolus of 3000 anti-Xa IU followed by subcutaneous injections of 100 anti-Xa IU/kg every 12 hours achieved a maximum anti-factor Xa concentration of 1.16 IU/mL (n = 16) and a mean exposure corresponding to 88% of steady-state levels. Steady-state levels are reached by day 2 of treatment.

Within the recommended dose range, the pharmacokinetics of enoxaparin are linear. Intra- and inter-subject variability is low. After repeated subcutaneous administration of 4000 anti-Xa IU once daily to healthy volunteers, steady-state is achieved by day 2, with mean enoxaparin activity approximately 15% higher than after a single dose. The steady-state enoxaparin activity is well predicted by the pharmacokinetics of a single dose. After multiple subcutaneous doses of 100 anti-Xa IU/kg twice daily, steady-state is reached by days 3–4, with mean exposure approximately 65% higher than after a single dose, and peak and trough anti-Xa activity levels of 1.2 and 0.52 anti-Xa IU/mL, respectively. Based on the pharmacokinetics of sodium enoxaparin, this difference at steady-state is predictable and remains within the therapeutic range. Plasma anti-IIa activity after subcutaneous administration is approximately 10 times lower than anti-Xa activity. Mean peak anti-IIa activity occurs approximately 3–4 hours after subcutaneous injection and reaches 0.13 anti-IIa IU/mL with repeated administration of 100 anti-Xa IU/kg twice daily.

No pharmacokinetic interaction between enoxaparin and thrombolytic agents was observed when administered concomitantly.

Distribution. The volume of distribution of anti-Xa activity of enoxaparin is approximately 5 L, close to blood volume.

Metabolism. Enoxaparin is primarily metabolized in the liver (desulfation, depolymerization).

Elimination. After subcutaneous administration, the elimination half-life of anti-Xa activity of low-molecular-weight heparins is longer than that of unfractionated heparins.

Enoxaparin exhibits monophasic elimination with a half-life of approximately 4 hours after a single subcutaneous dose and about 7 hours after repeated administration.

In low-molecular-weight heparin, the decline in plasma anti-IIa activity occurs faster than anti-Xa activity.

Enoxaparin and its metabolites are eliminated via the kidneys (non-saturable mechanism) and bile.

Renal clearance of fragments with anti-Xa activity is approximately 10% of the administered dose, and total renal excretion of active and inactive substances is 40% of the dose.

High-risk groups.

Elderly patients. Elimination is slowed due to physiologically reduced renal function in this group. This change does not affect dosing and administration regimen for prophylactic therapy if renal function remains within acceptable limits, i.e., only slightly reduced.

Before initiating low-molecular-weight heparin (LMWH) therapy, patients over 75 years of age should undergo systematic renal function assessment.

Hepatic impairment. In a study involving patients with severe liver cirrhosis receiving sodium enoxaparin 4000 IU (40 mg) once daily, reduced peak anti-Xa activity was associated with increasing severity of hepatic dysfunction (assessed by Child-Pugh classification). This reduction was primarily explained by decreased antithrombin III (AT III) levels, secondary to reduced AT III synthesis in patients with hepatic impairment.

Renal impairment. A linear relationship was observed between plasma clearance of anti-Xa activity and creatinine clearance at steady-state, indicating reduced clearance of sodium enoxaparin in patients with renal impairment. Exposure to anti-Xa activity, expressed as AUC (area under the concentration-time curve), increased markedly in patients with mild renal impairment (creatinine clearance 50–80 mL/min) and moderate renal impairment (creatinine clearance 30–50 mL/min) after multiple subcutaneous administrations of 4000 IU (40 mg) once daily. In patients with severe renal impairment (creatinine clearance < 30 mL/min), steady-state AUC levels significantly increased by an average of 65% after multiple subcutaneous administrations of 4000 IU (40 mg) once daily (see sections "Dosage and administration" and "Special precautions").

Hemodialysis. The pharmacokinetics of sodium enoxaparin during hemodialysis were similar to those in the control group after single intravenous doses of 25 IU, 50 IU, or 100 IU/kg (0.25, 0.50, or 1.0 mg/kg), but AUC levels were twice as high compared to the control group.

Body weight. After multiple subcutaneous administrations of 150 IU/kg (1.5 mg/kg) once daily, mean steady-state AUC levels of anti-Xa activity were marginally higher in healthy obese volunteers (BMI 30–48 kg/m²) compared to non-obese controls, while peak plasma anti-Xa activity did not increase. In obese individuals, subcutaneous administration resulted in lower clearance after correction for body weight.

When administered without dose adjustment for body weight, after a single subcutaneous dose of 4000 IU (40 mg), exposure to anti-Xa activity was 52% higher in women with low body weight (<45 kg) and 27% higher in men with low body weight (<57 kg) compared to controls with normal body weight (see section "Special precautions").

Pharmacokinetic interactions. No pharmacokinetic interaction was observed between sodium enoxaparin and thrombolytic agents when administered concomitantly.

Preclinical safety data. Apart from the anticoagulant effects of sodium enoxaparin, no signs of adverse effects were observed when administered at doses of 15 mg/kg/day in 13-week toxicity studies after subcutaneous administration in rats and dogs, and at 10 mg/kg/day in 26-week toxicity studies after subcutaneous and intravenous administration in rats and monkeys.

Sodium enoxaparin showed no mutagenic activity in in vitro studies, including the Ames test, mouse lymphoma cell direct mutation assay, and no clastogenic activity in in vitro human lymphocyte chromosome aberration analysis and in vivo rat bone marrow chromosome aberration analysis.

Studies in pregnant rats and rabbits receiving subcutaneous enoxaparin up to 30 mg/kg/day showed no evidence of teratogenic effects or fetotoxicity. Sodium enoxaparin was shown to have no effect on fertility or reproductive function in male and female rats when administered subcutaneously at doses up to 20 mg/kg/day.

Clinical characteristics.

Indications

The drug is indicated for use in adults for:

• Prophylaxis of venous thromboembolic complications in surgical patients with moderate and high risk, especially in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases.
  • Prophylaxis of venous thromboembolic complications in medical patients with acute conditions (such as acute heart failure, respiratory failure, severe infections, or rheumatic diseases) and reduced mobility who are at increased risk of venous thromboembolism.
• Prophylaxis of thrombus formation in extracorporeal circulation during hemodialysis.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required;
• In acute coronary syndrome:
• for treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid;
• for treatment of ST-segment elevation myocardial infarction (STEMI), including in patients planned for medical treatment or subsequent percutaneous coronary intervention (PCI).

Contraindications

Sodium enoxaparin is contraindicated in patients with the following conditions:

• Hypersensitivity to sodium enoxaparin, heparin or its derivatives, including other low molecular weight heparins, or to any of the excipients (see section "Composition").
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or presence of circulating antibodies (see also section "Special precautions").
• Active clinically significant bleeding and conditions with high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of malignant tumor with high bleeding risk, recent surgery on the brain, spinal cord or eyes, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or serious congenital defects of intraspinal or intracerebral vessels.
• Spinal or epidural anesthesia or locoregional anesthesia if sodium enoxaparin has been used for treatment within the previous 24 hours (see section "Special precautions").
• Hypersensitivity to benzyl alcohol.
• Due to the presence of benzyl alcohol (see section "Composition"), sodium enoxaparin in multidose vials should not be administered to newborns and premature infants (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

Concomitant use with the following medications is not recommended.

Medicinal products affecting hemostasis (see section "Special precautions"). Some agents affecting hemostasis should be discontinued prior to initiating enoxaparin sodium treatment, unless absolutely indicated. If such combination is indicated, enoxaparin sodium should be used with careful clinical and laboratory monitoring.

These include:

• systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and nonsteroidal anti-inflammatory drugs (NSAIDs), including ketorolac;
• other thrombolytics (e.g., alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants (see section "Method of administration and dosage").

Medicinal products that should be used concomitantly with caution

Other medicinal products affecting hemostasis, such as:

• platelet aggregation inhibitors, including acetylsalicylic acid used at antiplatelet dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome – due to the risk of bleeding;
• dextran 40;
• systemic glucocorticoids.

Medicinal products that increase potassium levels. Medicinal products that increase serum potassium levels may be prescribed concomitantly with sodium enoxaparin with careful clinical and laboratory monitoring (see sections "Special precautions" and "Adverse reactions").

Special precautions for use.

General warnings.

Enoxaparin sodium must not be used interchangeably (unit for unit) with other low-molecular-weight heparins (LMWHs). These medicinal products differ in their manufacturing processes, molecular weights, specific anti-Xa and anti-IIa activities, units of activity, dosing regimens, and clinical efficacy and safety. These differences result in variations in pharmacokinetics and biological activity (e.g., antithrombin activity, platelet interactions).

Therefore, the instructions for medical use specific to each brand-name product must be carefully reviewed and strictly followed.

History of heparin-induced thrombocytopenia (HIT) (>100 days).

Administration of enoxaparin sodium is contraindicated in patients with a history of immune-mediated HIT within the past 100 days or in patients with circulating antibodies (see section "Contraindications"). Circulating antibodies may persist for several years.

Enoxaparin sodium should be used with extreme caution in patients with a history of immune-mediated HIT (>100 days) in the absence of circulating antibodies. The decision to use enoxaparin sodium in such cases should be made only after careful benefit-risk assessment and after considering the possibility of using alternative non-heparin treatments (e.g., danaparoid sodium or lepirudin).

Platelet monitoring.

There is a risk of antibody-mediated HIT during treatment with LMWHs, which typically develops between the 5th and 21st day after initiation of enoxaparin sodium therapy.

The risk of HIT is higher in patients who have undergone surgery, particularly cardiac surgery, and in patients with malignancies.

Therefore, platelet counts should be determined before starting enoxaparin sodium therapy and regularly monitored during treatment.

If clinical symptoms suggestive of HIT occur (any new episode of arterial and/or venous thromboembolism, any painful skin lesions at injection sites, or any allergic or anaphylactoid reactions during treatment), platelet counts must be determined. Patients should be informed about these potential symptoms and advised to report them to their physician immediately.

In clinical practice, if a confirmed significant decrease in platelet count (30−50% from baseline) occurs, enoxaparin sodium must be discontinued immediately and the patient should be switched to an alternative non-heparin anticoagulant therapy.

Bleeding events.

As with other anticoagulants, bleeding or hemorrhage may occur at any site. In case of bleeding, the source should be investigated and appropriate treatment initiated.

Enoxaparin sodium, like any other anticoagulant, should be used with caution in conditions that increase the risk of bleeding, such as:

• coagulation disorders;
• history of peptic ulcer;
• recent ischemic stroke;
• severe arterial hypertension;
• recent onset of diabetic retinopathy;
• surgery on the nervous system or eyes;
• concomitant use of medicinal products affecting hemostasis (see section "Interaction with other medicinal products and other forms of interaction").

Laboratory tests.

At doses used for prevention of venous thromboembolism, enoxaparin sodium has no significant effect on bleeding time, general coagulation parameters, platelet aggregation, or fibrinogen binding to platelets.

When higher doses are used, activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may increase. However, since there is no linear correlation between the increase in aPTT and ACT and the antithrombotic activity of enoxaparin sodium, these parameters are unreliable and should not be used to monitor enoxaparin sodium activity.

Use during spinal/epidural anesthesia or lumbar puncture.

Spinal/epidural anesthesia or lumbar puncture must not be performed within 24 hours after administration of therapeutic doses of enoxaparin sodium (see also section "Contraindications").

Cases of neuraxial hematomas have been reported with concomitant use of enoxaparin sodium and spinal/epidural anesthesia or spinal puncture, leading to long-term or irreversible paralysis. These events are rare when enoxaparin sodium is used at a dose of 4000 IU (40 mg) once daily or at lower doses. The risk of such complications is higher with postoperative continuous epidural catheters, concomitant use of other agents affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs), traumatic or repeated epidural or spinal procedures, and in patients with a history of spinal surgery or spinal deformity.

To minimize the potential risk of bleeding associated with concomitant use of enoxaparin sodium and spinal/epidural anesthesia/analgesia or lumbar puncture, the pharmacokinetic profile of enoxaparin sodium should be considered (see section "Pharmacokinetics"). Insertion or removal of an epidural catheter or performance of lumbar puncture should ideally occur when the anticoagulant effect of enoxaparin sodium is low, although the exact time to achieve sufficiently low anticoagulant effect in individual patients is unknown. It should also be noted that elimination of enoxaparin sodium is prolonged in patients with creatinine clearance of 15−30 ml/min (see section "Dosage and administration").

If the physician decides to use anticoagulant therapy during spinal/epidural anesthesia/analgesia or lumbar puncture, careful monitoring for neurological symptoms such as midline back pain, sensory or motor disturbances (numbness or weakness in lower limbs), or bowel and/or bladder dysfunction is required. Patients should be instructed to immediately report any of these symptoms. If spinal hematoma is suspected, appropriate diagnostic and therapeutic measures should be initiated immediately, including consideration of spinal cord decompression, even though such treatment may not prevent adverse neurological outcomes.

Skin necrosis / cutaneous vasculitis. Cases of skin necrosis and cutaneous vasculitis have been reported during treatment with low-molecular-weight heparins; in such cases, the drug must be discontinued immediately.

Acute generalized exanthematous pustulosis. Cases of acute generalized exanthematous pustulosis (AGEP) have been reported.

Procedures of percutaneous coronary revascularization. To minimize the risk of bleeding after invasive vascular procedures in the treatment of unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and acute ST-elevation myocardial infarction (STEMI), recommended intervals between doses of enoxaparin sodium must be strictly observed. Achieving hemostasis at the puncture site after percutaneous coronary intervention (PCI) is essential. If a vascular closure device is used, the introducer can be removed immediately after the procedure. If manual compression is used, the introducer must be removed 6 hours after the last intravenous or subcutaneous injection of enoxaparin sodium. If enoxaparin sodium treatment is to be continued, the next scheduled dose should not be administered earlier than 6−8 hours after removal of the introducer. The puncture site should be monitored for signs of bleeding or hematoma formation.

Acute infective endocarditis. Administration of heparin to patients with acute infective endocarditis is generally not recommended due to the risk of cerebral hemorrhage. If such use is considered absolutely necessary, the decision should be made only after careful individual benefit-risk assessment.

Mechanical heart valves. The use of enoxaparin sodium for thromboprophylaxis in patients with mechanical prosthetic heart valves has not been adequately studied. Isolated cases of prosthetic valve thrombosis have been reported in patients with mechanical heart valves receiving enoxaparin sodium for thromboprophylaxis. The presence of risk factors, underlying disease, and limited clinical data complicate the evaluation of these cases. Some of these cases occurred in pregnant women, resulting in maternal and fetal death.

Pregnant women with mechanical heart valves. The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study where pregnant women with mechanical heart valves received enoxaparin sodium (100 IU/kg [1 mg/kg] twice daily) to reduce the risk of thromboembolism, two out of eight women developed blood clots leading to valve obstruction and maternal and fetal death. Post-marketing reports have included isolated cases of valve thrombosis in pregnant women with mechanical heart valves receiving enoxaparin sodium for thromboprophylaxis. Pregnant women with mechanical heart valves may have an increased risk of thromboembolic events.

Elderly patients. When used in the prophylactic dose range, no increased bleeding tendency has been observed in elderly patients. However, elderly patients (especially those aged 80 years and older) have an increased risk of hemorrhagic complications when the drug is used at therapeutic doses. For patients over 75 years of age receiving treatment for ST-elevation myocardial infarction (STEMI), careful clinical monitoring is recommended and dose reduction may be appropriate (see sections "Dosage and administration" and "Pharmacokinetics").

Renal impairment. In patients with renal impairment, exposure to enoxaparin sodium is increased, leading to a higher risk of bleeding. Careful clinical monitoring is recommended for such patients, and biological monitoring via anti-Xa activity measurement may be appropriate (see sections "Dosage and administration" and "Pharmacokinetics").

Enoxaparin sodium is not recommended for use in patients with end-stage renal disease (creatinine clearance < 15 ml/min) due to lack of adequate data in this population, except for prevention of thrombus formation in the extracorporeal circuit during hemodialysis.

For patients with severe renal impairment (creatinine clearance 15−30 ml/min), due to significantly increased exposure to enoxaparin sodium, dose adjustment is recommended for both therapeutic and prophylactic use (see section "Dosage and administration").

Dose adjustment is not recommended for patients with moderate (creatinine clearance 30−50 ml/min) or mild (creatinine clearance 50−80 ml/min) renal impairment.

Hepatic impairment. Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased risk of bleeding. Dose adjustment based on anti-Xa activity monitoring is unreliable in patients with liver cirrhosis and is not recommended (see section "Pharmacokinetics").

Low body weight. Increased exposure to enoxaparin sodium has been observed in women with low body weight (< 45 kg) and men with low body weight (< 57 kg) receiving prophylactic doses (without weight adjustment), increasing the risk of bleeding. Therefore, careful clinical monitoring is recommended for such patients (see section "Pharmacokinetics").

Obese patients. Obese patients have an increased risk of thromboembolic events. The safety and efficacy of prophylactic doses of enoxaparin sodium in obese patients (body mass index [BMI] > 30 kg/m²) have not been sufficiently studied, and there is currently no consensus on dose adjustment for this patient group. These patients require careful monitoring for possible symptoms of thromboembolism.

Hyperkalemia. Heparins may suppress aldosterone secretion in the adrenal glands, leading to hyperkalemia (see section "Undesirable effects"), particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, or those receiving medications that can increase potassium levels (see section "Interaction with other medicinal products and other forms of interaction"). Plasma potassium levels should be monitored periodically, especially in patients at increased risk.

Traceability. Low-molecular-weight heparins are biological medicinal products. To improve traceability, it is recommended that healthcare professionals record the brand name and batch number of the administered product in the patient's medical records.

Use during pregnancy or breastfeeding

Pregnancy.

There is no evidence that enoxaparin crosses the placental barrier in humans during the second and third trimesters of pregnancy. Information regarding the first trimester is currently unavailable.

Animal studies have shown no signs of fetotoxicity or teratogenicity (see section "Preclinical safety data"). Animal experiments indicate minimal placental transfer of enoxaparin.

Enoxaparin sodium should be administered to pregnant women only if clearly indicated by the physician.

Pregnant women receiving enoxaparin sodium should be carefully monitored for signs of bleeding or excessive anticoagulant effect, and should be warned about the risk of hemorrhagic events. Overall, available data suggest no evidence of increased risk of bleeding, thrombocytopenia, or osteoporosis in these patients compared to non-pregnant women, except for the risk observed in pregnant women with prosthetic heart valves (see section "Special precautions for use").

If epidural anesthesia is planned, enoxaparin sodium therapy should be discontinued prior to the procedure (see section "Special precautions for use").

Breastfeeding.

It is unknown whether enoxaparin is excreted in human breast milk. In lactating rats, transfer of enoxaparin or its metabolites into milk is very low.

Since oral absorption of enoxaparin sodium is unlikely, it may be used during breastfeeding.

Fertility. Clinical data on the effect of enoxaparin sodium on fertility are currently lacking. Animal studies have shown no effect of the drug on fertility.

Effects on ability to drive and use machines

The effect of enoxaparin sodium on the ability to drive or operate machinery is absent or negligible.

Method of Administration and Dosage.

Route of administration – subcutaneous (except for patients with ST-segment elevation myocardial infarction who require intravenous bolus administration).

Recommended for use in adults.

The drug should not be administered intramuscularly.

1 ml of injection solution is equivalent to approximately 10000 anti-Xa IU of enoxaparin.

Dosing.

Prophylaxis of venous thromboembolic complications in surgical patients at moderate and high risk.

Individual thromboembolic risk in patients may be assessed using a validated risk stratification model (score).

• For patients at moderate risk of thromboembolic events, the recommended dose of sodium enoxaparin is 2000 IU (20 mg) once daily administered by subcutaneous (s.c.) injection. Preoperative initiation (2 hours before surgery) of sodium enoxaparin 2000 IU (20 mg) has been shown to be effective and safe in surgical procedures associated with moderate risk.

In patients at moderate risk, prophylactic treatment with sodium enoxaparin should continue for a period of at least 7–10 days, regardless of recovery status (e.g., mobility). Prophylaxis should be continued until the patient no longer exhibits significantly reduced mobility.

• For patients at high risk of thromboembolic events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered 12 hours before surgery via subcutaneous (s.c.) injection. If prophylactic administration of sodium enoxaparin needs to be initiated more than 12 hours before surgery (e.g., a high-risk patient awaiting delayed orthopedic surgery), the last injection should be given no later than 12 hours before surgery, and prophylactic dosing should be resumed 12 hours after surgery.
• For patients undergoing major orthopedic surgery, extended thromboprophylaxis is recommended – up to 5 weeks.
• For patients at high risk of venous thromboembolism (VTE) undergoing abdominal or pelvic surgery for oncological conditions, extended thromboprophylaxis is recommended – up to 4 weeks.

Prophylaxis of venous thromboembolism in medical patients.

The recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily administered by s.c. injection.

Prophylactic treatment with sodium enoxaparin should be continued for a period of at least 6–14 days, depending on recovery status (e.g., mobility). The benefit of treatment beyond 14 days has not yet been established.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Sodium enoxaparin should be administered s.c. as a single daily injection of 150 IU/kg (1.5 mg/kg) or as two daily injections of 100 IU/kg (1 mg/kg).

The dosing regimen should be selected by the physician based on individual assessment, including evaluation of thromboembolic risk and bleeding risk. The regimen of 150 IU/kg (1.5 mg/kg) once daily is recommended for uncomplicated patients at low risk of recurrent VTE. The regimen of 100 IU/kg (1 mg/kg) twice daily should be used for all other patients, such as those with obesity, symptomatic PE, cancer, recurrent VTE, or proximal venous thrombosis (iliac vein).

Sodium enoxaparin is typically administered for an average of 10 days. If necessary, oral anticoagulants should be initiated (see "Switching between sodium enoxaparin and oral anticoagulants" at the end of this section).

Prevention of thrombus formation during hemodialysis.

The recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg). For patients at high risk of bleeding complications, the dose should be reduced to 50 IU/kg (0.5 mg/kg) with dual vascular access or to 75 IU/kg (0.75 mg/kg) with single vascular access.

During hemodialysis, sodium enoxaparin should be administered into the arterial limb of the circuit at the beginning of the dialysis session. This dose is generally sufficient for a 4-hour dialysis session. However, if fibrin rings occur, for example during prolonged sessions, an additional dose of 50–100 IU/kg (0.5–1 mg/kg) may be administered.

There are no data on the use of sodium enoxaparin in patients for prevention or treatment during hemodialysis sessions.

Acute coronary syndrome: treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), and acute ST-segment elevation myocardial infarction (STEMI).

• For treatment of unstable angina and NSTEMI, the recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg) administered subcutaneously every 12 hours, in combination with antiplatelet therapy. Treatment should be initiated for at least 2 days and continued until clinical stabilization of the patient. The usual duration of treatment is 2 to 8 days.
• All uncomplicated patients should receive oral acetylsalicylic acid, with an initial loading dose of 150–300 mg (for patients not previously on acetylsalicylic acid) and a maintenance dose of 75–325 mg/day long-term, regardless of treatment strategy.
• For treatment of acute STEMI, the recommended dose of sodium enoxaparin is a single intravenous (i.v.) bolus of 3000 IU (30 mg) plus a subcutaneous dose of 100 IU/kg (1 mg/kg), followed by subcutaneous administration of 100 IU/kg (1 mg/kg) every 12 hours (maximum 10000 IU [100 mg] for each of the first two subcutaneous doses). Concomitant antiplatelet therapy, such as oral acetylsalicylic acid (75–325 mg once daily), should be administered, unless contraindicated. The recommended duration of treatment is 8 days or until hospital discharge, whichever occurs earlier. When used in combination with thrombolytic therapy (fibrin-specific or non-fibrin-specific), sodium enoxaparin should be administered between 15 minutes before and 30 minutes after the start of fibrinolytic therapy.
• Dose adjustments for patients aged ≥75 years are described below ("Elderly patients").
• For patients undergoing PCI, if the last subcutaneous dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional dose is required. If the last subcutaneous dose was given more than 8 hours before balloon inflation, an i.v. bolus of 30 IU/kg (0.3 mg/kg) of sodium enoxaparin should be administered.

Pediatric patients. The safety and efficacy of sodium enoxaparin in pediatric patients have not been established.

Elderly patients. For all indications except ST-segment elevation myocardial infarction (STEMI), dose reduction is not required in elderly patients, except in cases of renal impairment (see below "Renal impairment" and section "Special instructions").

For treatment of STEMI, elderly patients (≥75 years) should not receive the initial i.v. bolus. Treatment should be initiated with a subcutaneous dose of 75 IU/kg (0.75 mg/kg) every 12 hours (maximum 7500 IU [75 mg] for each of the first two subcutaneous doses), followed by continued administration of 75 IU/kg (0.75 mg/kg) s.c. for subsequent doses. Dose adjustments for elderly patients with renal impairment are described below in the section "Ren/renal impairment" and section "Special instructions".

Hepatic impairment. Limited data are currently available on the use of the drug in patients with hepatic impairment (see sections "Pharmacodynamics" and "Pharmacokinetics"); therefore, caution should be exercised in this patient population (see section "Special instructions").

Renal impairment (see sections "Special instructions" and "Pharmacokinetics").

Severe renal impairment. Sodium enoxaparin is not recommended for use in patients with end-stage renal disease (creatinine clearance <15 ml/min) due to lack of adequate data in this population, except for prevention of thrombus formation in the extracorporeal circuit during hemodialysis.

Table 4.

Dosing in patients with severe renal impairment

(creatinine clearance 15–30 ml/min)

Indications	Dosing regimen
Prophylaxis of venous thromboembolic complications	2000 IU (20 mg) s.c. once daily
Treatment of VTE and PE	100 IU/kg (1 mg/kg) body weight s.c. once daily
Treatment of unstable angina and NSTEMI	100 IU/kg (1 mg/kg) body weight s.c. once daily
Treatment of acute STEMI (in patients under 75 years of age) Treatment of acute STEMI (in patients over 75 years of age)	1 x 3000 IU (30 mg) i.v. bolus plus 100 IU/kg (1 mg/kg) body weight s.c. followed by 100 IU/kg (1 mg/kg) body weight s.c. every 24 hours Without initial i.v. bolus: 100 IU/kg (1 mg/kg) body weight s.c. followed by 100 IU/kg (1 mg/kg) body weight s.c. every 24 hours

The recommended dose adjustment does not apply to the use of the drug for hemodialysis.

• Mild and moderate renal impairment. Although dose adjustment is not recommended for patients with mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–50 mL/min) renal impairment, careful clinical monitoring of such patients is required.

Route of administration. Enoxaparin-Farmex must not be administered intramuscularly.

For the prevention of venous thromboembolic complications following surgery, treatment of DVT and PE, and treatment of unstable angina and NSTEMI, enoxaparin sodium should be administered by subcutaneous (s.c.) injection.

• For the treatment of acute STEMI, administration of the drug should begin with a single intravenous (i.v.) bolus injection, followed immediately by s.c. administration.
• For the prevention of clot formation in the extracorporeal blood circuit during hemodialysis, the drug is administered into the arterial line of the dialysis circuit.

Technique for subcutaneous injection.

Administration of the drug is best performed with the patient lying down. Enoxaparin sodium is administered by deep subcutaneous injection.

When using multidose vials, it is recommended to use syringes that allow withdrawal of the exact amount of drug required for administration, calculated according to the patient's body weight. Please note that in some cases it may be impossible to obtain the precise dose due to the syringe's calibration markings; in such cases, the volume should be rounded to the nearest calibration mark.

The drug should be administered alternately into the left and right anterolateral or posterolateral abdominal walls.

The needle should be inserted fully and vertically into a skin fold gently held between the thumb and index finger. The skin fold must be held throughout the injection until completion. The injection site should not be massaged after administration.

If the patient is self-administering the drug, they must follow the instructions for medical use provided with the medicinal product.

Intravenous (bolus) injection [only when the drug is used for the indication acute ST-segment elevation myocardial infarction (STEMI)].

For the treatment of acute STEMI, administration of the drug should begin with a single i.v. bolus injection, followed immediately by s.c. administration.

For i.v. injection, either a multidose vial or a pre-filled syringe may be used.

Enoxaparin sodium should be administered via an i.v. infusion system. It must not be mixed or co-administered simultaneously with other medicinal products. To avoid potential mixing of enoxaparin sodium with other drugs, the selected i.v. access must be flushed adequately with physiological saline (0.9% sodium chloride) or glucose solution before and after administration of the i.v. bolus of enoxaparin sodium to clear the administration port of other drugs. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution or 5% glucose solution.

Initial bolus 3000 IU (30 mg). To administer the initial bolus of 3000 IU (30 mg) using a graduated pre-filled syringe, the excess volume must be expelled so that only 3000 IU (30 mg) remains in the syringe. The 3000 IU (30 mg) dose can then be administered directly i.v.

Additional bolus in case of PCI when the last s.c. dose was administered more than 8 hours before balloon inflation. For patients undergoing PCI, an additional i.v. bolus of 30 IU/kg (0.3 mg/kg) is required if the last s.c. dose was administered more than 8 hours before balloon inflation.

To ensure accurate administration of such a small volume, it is recommended to dilute the drug to a concentration of 300 IU/mL (3 mg/mL).

Withdraw the required volume of the diluted solution into a syringe for administration via the i.v. infusion system.

After dilution, the volume to be administered can be calculated using the following formula: [Volume of diluted solution (mL) = patient's body weight (kg) × 0.1] or by using Table 5. Dilution should be performed immediately before drug administration.

Table 5.

Volume to be administered via the i.v. infusion system after dilution of the drug to a concentration of 300 IU (3 mg)/mL.

Body weight	Required dose 30 IU/kg (0.3 mg/kg)	Volume to be administered after dilution of the medicinal product to a final concentration of 300 IU (3 mg)/ml
kg	IU	mg	ml
45	1350	13.5	4.5
50	1500	15	5
55	1650	16.5	5.5
60	1800	18	6
65	1950	19.5	6.5
70	2100	21	7
75	2250	22.5	7.5
80	2400	24	8
85	2550	25.5	8.5
90	2700	27	9
95	2850	28.5	9.5
100	3000	30	10
105	3150	31.5	10.5
110	3300	33	11
115	3450	34.5	11.5
120	3600	36	12
125	3750	37.5	12.5
130	3900	39	13
135	4050	40.5	13.5
140	4200	42	14
145	4350	43.5	14.5
150	4500	45	15

Administration into the arterial portion of the dialysis circuit. The drug is administered into the arterial line of the dialysis circuit to prevent clot formation in the extracorporeal blood circuit during hemodialysis.

Transition from enoxaparin sodium to oral anticoagulants.

Transition from enoxaparin sodium to vitamin K antagonists (VKAs). Clinical monitoring and laboratory parameters [prothrombin time expressed as international normalized ratio (INR)] should be intensified to monitor the effect of VKAs.

Since there is a certain period required for VKAs to reach their maximum effect, enoxaparin sodium should be continued at a constant dose until the INR remains within the target therapeutic range for the specific indication, as confirmed by two consecutive measurements.

For patients currently receiving VKAs, VKAs should be discontinued and the first dose of enoxaparin sodium should be administered when the INR decreases to below the therapeutic range.

Transition from enoxaparin sodium to direct oral anticoagulants (DOACs) and vice versa. For patients currently receiving enoxaparin sodium, enoxaparin sodium should be discontinued and DOAC therapy should be initiated 0–2 hours (depending on the medical instructions for each DOAC) before the next scheduled dose of enoxaparin sodium.

For patients currently receiving DOACs, the first dose of enoxap inflamm sodium should be administered at the time when the next DOAC dose was due.

Use of the drug during spinal/epidural anesthesia or lumbar puncture. If the physician decides that anticoagulant use is necessary during spinal/epidural anesthesia or lumbar puncture, careful neurological monitoring is recommended due to the risk of neuraxial hematoma (see section "Special precautions").

Use of prophylactic doses. A minimum interval of at least 12 hours should be maintained between the last injection of prophylactic-dose enoxaparin sodium and the insertion of a needle or catheter.

For procedures involving prolonged access, a similar interval of at least 12 hours should be maintained before catheter removal.

For patients with creatinine clearance of 15–30 mL/min, consideration should be given to doubling the time interval before performing puncture/catheter insertion or removal to at least 24 hours.

Initial administration of enoxaparin sodium 2000 IU (20 mg) two hours before surgery is not applicable when neuraxial anesthesia is performed.

Use of therapeutic doses. A minimum interval of at least 24 hours should be maintained between the last injection of therapeutic-dose enoxaparin sodium and the insertion of a needle or catheter (see also section "Contraindications").

For procedures involving prolonged access, a similar interval of at least 24 hours should be maintained before catheter removal.

For patients with creatinine clearance of 15–30 mL/min, consideration should be given to doubling the time interval before performing puncture/catheter insertion or removal to at least 48 hours.

Patients receiving the drug according to a twice-daily regimen (i.e., 75 IU/kg (0.75 mg/kg) twice daily or 100 IU/kg (1 mg/kg) twice daily) should skip the second dose of enoxaparin sodium to ensure an adequate time interval before catheter insertion or removal.

At these time points, anti-Xa activity of the drug may still be present, and adherence to these time intervals does not guarantee prevention of neuraxial hematoma.

Therefore, enoxaparin sodium should not be administered for at least 4 hours after spinal/epidural puncture or after catheter removal. The time interval should be determined based on a benefit-risk assessment considering both thrombosis risk and bleeding risk associated with the procedure, taking into account patient-specific risk factors.

Children.

Due to lack of appropriate data, low molecular weight heparins (LMWH) are not recommended for use in pediatric practice.

The medicinal product contains benzyl alcohol and should not be used in neonates and preterm newborns (see section "Contraindications").

Overdose.

Symptoms. Accidental overdose of enoxaparin sodium via intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. After oral intake, even of relatively high doses, absorption of enoxaparin sodium is unlikely.

Treatment. The anticoagulant effects of the drug can be largely neutralized by slow intravenous administration of protamine. The dose of protamine depends on the administered dose of enoxaparin sodium:

• 1 mg of protamine neutralizes the anticoagulant effect of 100 IU (1 mg) of enoxaparin sodium if enoxaparin sodium was administered within the preceding 8 hours.
• An infusion dose of 0.5 mg protamine per 100 IU (1 mg) enoxaparin sodium may be used if enoxaparin sodium was administered more than 8 hours prior to protamine administration or if a second dose of protamine is required.
• Administration of protamine may not be necessary more than 12 hours after enoxaparin sodium injection.

However, even with high doses of protamine, the anti-Xa activity of enoxaparin sodium is never completely neutralized (maximum approximately 60%) (see medical instructions for protamine sulfate).

Adverse reactions.

Frequency was determined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are listed in order of decreasing seriousness.

Disorders of the blood and lymphatic system.

Common: haemorrhagic events, haemorrhagic anaemia, thrombocytopenia, thrombocytosis.

Rare: eosinophilia.

Rare: cases of immune-mediated thrombocytopenia with thrombosis; in some of these cases, thrombosis was complicated by organ infarction or limb ischaemia (see section "Special precautions").

Immune system disorders.

Common: allergic reaction.

Rare: anaphylactic/anaphylactoid reactions, including shock.

Nervous system disorders.

Common: headache.

Vascular disorders.

Rare: spinal haematoma (or neuraxial haematoma). These reactions have led to neurological disorders of varying severity, including permanent or irreversible paralysis (see section "Special precautions").

Hepatobiliary disorders.

Very common: increased levels of liver enzymes (mainly transaminases more than 3 times the upper limit of normal).

Uncommon: hepatocellular liver injury.

Rare: cholestatic liver injury.

Skin and subcutaneous tissue disorders.

Common: urticaria, pruritus, erythema.

Uncommon: bullous dermatitis.

Rare: alopecia, cutaneous vasculitis, skin necrosis, which usually occurs at the injection site (these events are usually preceded by purpura or erythematous plaques that are infiltrated and painful). Injection site nodules (inflammatory nodules representing non-cystic "pockets" of enoxaparin). These nodules resolve within several days and do not require discontinuation of the drug.

Frequency not known: acute generalised exanthematous pustulosis (AGEP).

Musculoskeletal and connective tissue disorders, bone disorders.

Rare: osteoporosis after long-term therapy (longer than 3 months).

General disorders and administration site conditions.

Common: haematoma at injection site, pain at injection site, other reaction at injection site (e.g. swelling, bruising, hyperaesthesia, inflammation, mass, pain or other reactions).

Uncommon: local irritation, skin necrosis at injection site.

Investigations.

Rare: hyperkalaemia (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Description of selected adverse reactions.

Haemorrhagic events. Significant haemorrhagic complications have been reported, some of which were fatal. In surgical patients, haemorrhagic complications were considered serious if the haemorrhagic event caused a significant clinical event, or if it was associated with a haemoglobin decrease ≥ 2 g/dL or required transfusion of 2 or more standard units of blood products. Retroperitoneal and intracranial haemorrhages were always considered serious.

As with other anticoagulants, haemorrhagic events may occur in the presence of concomitant risk factors such as: organic lesions with a risk of bleeding, invasive procedures, or concomitant use of medicinal products affecting haemostasis (see sections "Special precautions" and "Interaction with other medicinal products and other forms of interaction").

Table 6.

System organs	Prophylaxis in surgical patients	Prophylaxis in medical patients	Treatment in patients with DVT with or without PE	Treatment in patients with unstable angina and myocardial infarction (MI) without Q wave	Treatment in patients with acute STEMI
Blood and lymphatic system	Very common: hemorrhagic manifestations* Rare: retroperitoneal hemorrhage	Common: hemorrhagic manifestations*	Very common: hemorrhagic manifestations* Uncommon: intracranial hemorrhage, retroperitoneal hemorrhage	Common: hemorrhagic manifestations* Rare: retroperitoneal hemorrhage	Common: hemorrhagic manifestations* Uncommon: intracranial hemorrhage, retroperitoneal hemorrhage

• Such as hematoma, ecchymosis (except at the injection site), wound hematoma, hematuria, epistaxis, and gastrointestinal hemorrhage.

Thrombocytopenia and thrombocytosis. Table 7.

Organ system	Prophylaxis in surgical patients	Prophylaxis in medical patients	Treatment in patients with DVT with or without PE	Treatment in patients with unstable angina and NSTEMI	Treatment in patients with acute STEMI
Blood and lymphatic system	Very common: thrombocytosis** Common: thrombocytopenia	Uncommon: thrombocytopenia	Very common: thrombocytosis** Common: thrombocytopenia	Uncommon: thrombocytopenia	Common: thrombocytosis** thrombocytopenia Very rare: immune-mediated thrombocytopenia

** Platelet count increase > 400 G/L.

Pediatric population. Safety and efficacy of sodium enoxaparin in children have not been established (see section "Dosage and administration").

Shelf life. 2 years.

Shelf life after opening the vial – no more than 28 days.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Do not freeze.

Keep out of reach of children.

Incompatibility.

Subcutaneous injection. Do not mix with other medicinal products.

Intravenous (bolus) injection (exclusively for treatment of acute ST-segment elevation myocardial infarction). Sodium enoxaparin can be safely administered with 0.9% sodium chloride solution or 5% glucose solution (see section "Dosage and administration").

Packaging.

3 mL in a multidose vial, 1 multidose vial in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

LLC "FARMEKS GROUP".

Manufacturer's address and place of business.

100, Shevchenka Street, Boryspil, Kyiv Oblast, Ukraine, 08301.

All cases of adverse reactions should be reported to the manufacturer:

LLC "Farmeks Group", Ukraine, 08301, Kyiv Oblast, Boryspil, Shevchenka Street, 100, tel.: +38(044)391-19-19, fax: +38(044)391-19-18, or via the form at the website: http://www.pharmex.com.ua/kontakty/forma-137-o/