Clexane

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLEKSAN® (CLEXANE®)

Composition:

Active substance: enoxaparin;

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

1 pre-filled syringe contains 2000 anti-Xa IU, equivalent to 20 mg of sodium enoxaparin*, or 4000 anti-Xa IU, equivalent to 40 mg of sodium enoxaparin*, or 10,000 anti-Xa IU, equivalent to 100 mg of sodium enoxaparin*;

Excipient: water for injections.

*Sodium enoxaparin is a biological substance obtained by alkaline depolymerization of the benzyl ester of heparin derived from porcine intestinal mucosa.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colorless or pale yellow clear solution.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01AB05.

Pharmacological properties.

Pharmacodynamics.

Enoxaparin is a low molecular weight heparin (LMWH) with an average molecular weight of approximately 4500 daltons, in which the antithrombotic and anticoagulant activities of standard heparin are dissociated. 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 during 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 has no significant effect on activated partial thromboplastin time (aPTT). When used for treatment, aPTT may be prolonged 1.5–2.2 times compared to baseline values at peak drug activity.

Clinical efficacy and safety.

Prevention of venous thromboembolic complications associated with surgical procedures.

Extended prophylaxis of venous thromboembolism (VTE) following orthopedic surgery. In a double-blind study of extended prophylaxis after 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 were observed.

Efficacy data are presented in Table 1.

Table 1

In another double-blind study, 262 patients without any history of venous thromboembolism who underwent hip replacement surgery and initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously during hospitalization were randomized to receive, after hospital discharge, either enoxaparin sodium 4000 IU (40 mg) (n = 131) once daily subcutaneously or placebo (n = 131) 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 (enoxaparin sodium − 21 [16%] vs. placebo − 45 [34.4%]; p = 0.001) and proximal deep vein thrombosis (DVT) (enoxaparin sodium − 8 [6.1%] vs. placebo − 28 [21.4%]; p < 0.001). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Long-term prevention of DVT after surgery for malignancy. In a double-blind, multicenter study, the safety and efficacy of a 4-week versus a 1-week regimen of prophylactic enoxaparin sodium were compared in 332 patients undergoing elective abdominal or pelvic surgery for malignancy. 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 day 25 and day 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 surgery for malignancy significantly reduced the frequency of venographically confirmed thrombosis compared to a 1-week prophylactic 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 the follow-up period.

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

In a double-blind, multicenter, parallel-group study, enoxaparin sodium at a dose of 2000 IU (20 mg) or 4000 IU (40 mg) once daily subcutaneously was compared with placebo for the prevention of DVT in medical patients with markedly reduced 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 failure or complicated chronic respiratory insufficiency, acute infection, or acute rheumatic disease, provided they had at least one risk factor for VTE (age ≥ 75 years, malignancy, prior VTE, obesity, varicose veins, hormonal therapy, or chronic heart or respiratory failure).

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

Table 2

After approximately 3 months of patient enrollment 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 frequency of bleeding events and the frequency of major bleeding were 8.6% and 1.1%, respectively, in the placebo group; 11.7% and 0.3% in the group receiving enoxaparin sodium at a dose of 2000 IU (20 mg); and 12.6% and 1.7% in the group receiving enoxaparin sodium at a dose of 4000 IU (40 mg).

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 inpatient treatment either with enoxaparin sodium at a dose of 150 IU/kg (1.5 mg/kg) once daily subcutaneously; or enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours subcutaneously; or heparin as an intravenous bolus (5000 IU) followed by continuous intravenous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 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 INR of 2.0 to 3.0), which was initiated within 72 hours after the start of 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 therapy. 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

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.

Long-term treatment of deep vein thrombosis and pulmonary embolism, as well as prevention of their recurrence in patients with active cancer

In clinical studies with a limited number of patients, the recurrence rate of VTE in patients receiving enoxaparin once daily or twice daily for 3–6 months was comparable to that in patients receiving warfarin. Effectiveness under real-world conditions was evaluated in a cohort of 4,451 patients with symptomatic VTE and active cancer from the multinational RIETE registry of patients with VTE and other thrombotic conditions. Of these, 3,526 patients received subcutaneous enoxaparin for 6 months and 925 patients received subcutaneous tinzaparin or dalteparin. Among the 3,526 patients treated with enoxaparin, 891 received 1.5 mg/kg once daily as both initial and long-term treatment up to 6 months (once daily), 1,854 received 1.0 mg/kg twice daily as both initial and long-term treatment up to 6 months (twice daily), and 687 received 1.0 mg/kg twice daily as initial treatment followed by 1.5 mg/kg once daily (twice daily, then once daily) as long-term treatment up to 6 months. The mean and median durations of treatment before dose regimen change were 17 days and 8 days, respectively. There was no significant difference in the rate of VTE recurrence between the two treatment groups (see Table 4), with enoxaparin meeting the pre-specified non-inferiority criterion of 1.5 (adjusted HR 0.817, 95% CI 0.499–1.336). There was no statistically significant difference between the two treatment groups in the relative risk of major bleeding (fatal or non-fatal) or death from any cause (see Table 5).

Table 4

Efficacy and safety outcomes in the RIETECAT study

Below is a brief summary of the results for each treatment regimen used in the RIETECAT study in patients who received treatment for 6 months.

Table 5

Results after 6 months of treatment in patients receiving different treatment regimens

* All data with 95% CI.

Treatment of unstable angina and non-ST-segment elevation myocardial infarction.

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 in combination with acetylsalicylic acid (100−325 mg once daily) at a dose of 100 IU/kg (1 mg/kg) every 12 hours, or unfractionated heparin (UFH) intravenously with dose adjustment based on aPTT levels. Patients received inpatient treatment for a minimum of 2 days and a maximum of 8 days until clinical stabilization, revascularization procedures, or hospital discharge. Patients were followed up for 30 days. Compared with heparin, sodium enoxaparin significantly reduced the composite incidence of angina, myocardial infarction, and death from 19.8% to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the composite incidence was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).

No statistically significant differences were observed in the incidence of major bleeding, although injection site bleeding occurred more frequently.

Treatment of acute ST-segment elevation myocardial infarction (STEMI).

In a large multicenter study, 20,479 patients with STEMI eligible for fibrinolytic therapy were randomized to receive either sodium enoxaparin as a single intravenous bolus of 3000 IU (30 mg) followed by a subcutaneous dose of 100 IU/kg (1 mg/kg) and subsequent administration of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or intravenous UFH for 48 hours with dose adjustment based on aPTT levels. All patients also received acetylsalicylic acid for at least 30 days. The dosing regimen of sodium enoxaparin was adjusted for patients with severe renal impairment and elderly patients (≥75 years). Subcutaneous injections of sodium enoxaparin were continued until hospital discharge or for a maximum of 8 days (whichever came first).

Percutaneous coronary intervention (PCI) with blinded antithrombotic support using the study drugs was performed in 4716 patients. Thus, patients receiving sodium enoxaparin underwent PCI while continuing sodium enoxaparin (without switching to the comparator drug) using a regimen studied in previous trials: no additional enoxaparin was administered if the last subcutaneous dose was given less than 8 hours before balloon inflation; an intravenous bolus of sodium enoxaparin at 30 IU/kg (0.3 mg/kg) was administered if the last subcutaneous dose was given more than 8 hours before balloon inflation.

Compared with UFH, sodium enoxaparin significantly reduced the rate of the primary endpoint, a composite of all-cause mortality and recurrent myocardial infarction, during the first 30 days after randomization [9.9% in the sodium enoxaparin group vs. 12.0% in the UFH group], with a relative risk reduction of 17% (p < 0.001).

The benefits of sodium enoxaparin treatment, evident across multiple efficacy measures, were apparent within 48 hours, when a relative risk reduction of 35% in recurrent myocardial infarction was observed compared to UFH treatment (p < 0.001).

The positive effect of sodium enoxaparin treatment on the primary endpoint was consistent across all key subgroups, including subgroups defined by age, sex, infarct location, history of diabetes mellitus, history of prior myocardial infarction, type of fibrinolytic agent used, and time to initiation of study treatment.

Statistically significant advantages of sodium enoxaparin treatment over UFH were observed in patients who underwent PCI within 30 days after randomization (relative risk reduction of 23%) and in those managed medically (relative risk reduction of 15%, p = 0.27 for interaction).

The rate of the composite endpoint including death, recurrent myocardial infarction, or intracranial hemorrhage (a measure of net clinical benefit) at 30 days was significantly lower (p < 0.0001) in the sodium enoxaparin group (10.1%) compared to the UFH group (12.2%), corresponding to a 17% relative risk reduction in favor of sodium enoxaparin treatment.

The incidence of major bleeding at 30 days was significantly higher (p < 0.0001) in the sodium enoxaparin group (2.1%) compared to the heparin group (1.4%). The rate of gastrointestinal bleeding was higher in the sodium enoxaparin group (0.5%) compared to the heparin group (0.1%), while the incidence of intracranial hemorrhage was similar in both groups (0.8% with sodium enoxaparin vs. 0.7% with heparin).

The beneficial effect of sodium enoxaparin treatment on the primary endpoint observed during the first 30 days was maintained throughout the 12-month follow-up period.

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

Pharmacokinetics.

General characteristics.

The pharmacokinetic parameters of sodium enoxaparin were primarily evaluated based on plasma anti-Xa activity, as well as anti-IIa activity, within the recommended dose range after single and multiple subcutaneous administrations and after single intravenous administration. Quantitative determination of pharmacokinetic anti-Xa and anti-IIa activities was performed using validated amidolytic methods.

Absorption. Absolute bioavailability of sodium enoxaparin after subcutaneous injection, assessed by anti-Xa activity, approaches 100%.

Various doses, dosage forms, and administration regimens may be used.

The mean peak plasma anti-Xa activity occurs within 3−5 hours after subcutaneous injection and reaches approximately 0.2, 0.4, 1.0, and 1.3 IU/mL of anti-Xa activity after single subcutaneous doses of 2000 IU, 4000 IU, 100 IU/kg, and 150 IU/kg (20 mg, 40 mg, 1 mg/kg, and 1.5 mg/kg), respectively.

After administration of 3000 IU (30 mg) as an intravenous bolus followed immediately by 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, the initial peak plasma anti-Xa activity was 1.16 IU/mL (n = 16), and average exposure corresponded to 88% of steady-state levels. Steady state was achieved by day 2 of treatment.

After multiple subcutaneous administration at regimens of 4000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily in healthy volunteers, steady state was achieved by day 2, with mean exposure approximately 15% higher than after single-dose administration. After multiple subcutaneous administration at 100 IU/kg (1 mg/kg) twice daily, steady state was achieved between days 3 and 4, with mean exposure approximately 65% higher than after single-dose administration, and mean peak and trough anti-Xa activity levels of approximately 1.2 and 0.52 IU/mL, respectively.

Injection volume and dose concentration within the range of 100−200 mg/mL did not affect pharmacokinetic parameters in healthy volunteers.

Within the recommended dose range, the pharmacokinetics of sodium enoxaparin are linear.

Intra- and inter-individual variability is low. No accumulation occurs after multiple subcutaneous administrations.

Anti-IIa activity in plasma after subcutaneous administration is approximately 10-fold lower than anti-Xa activity. The mean peak anti-IIa activity occurs approximately 3−4 hours after subcutaneous injection, reaching 0.13 IU/mL and 0.19 IU/mL after multiple administration at 100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.

Distribution. The volume of distribution of anti-Xa activity of sodium enoxaparin is approximately 4.3 liters, close to the volume of circulating blood.

Biotransformation. Sodium enoxaparin is primarily metabolized in the liver via desulfation and/or depolymerization, forming compounds with lower molecular weight and significantly reduced biological activity.

Elimination. Sodium enoxaparin is a drug with low clearance, with a mean plasma anti-Xa clearance of 0.74 L/h after a 6-hour infusion at 150 IU/kg (1.5 mg/kg).

Elimination is monophasic, with a half-life ranging from approximately 5 hours after single subcutaneous administration to about 7 hours after multiple administrations.

Renal clearance of active fragments accounts for approximately 10% of the administered dose, and total renal excretion of active and inactive fragments accounts for 40% of the dose.

Special patient groups.

Elderly patients. Population pharmacokinetic analysis indicates that the pharmacokinetic profile of sodium enoxaparin in elderly patients does not differ from that in younger patients if renal function is normal.

However, since renal function may decline with age, lower elimination rates of sodium enoxaparin may be observed in elderly patients (see sections "Special precautions for use" and "Dosage and administration").

Hepatic impairment. In a study involving patients with severe liver cirrhosis receiving sodium enoxaparin at 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 ATIII levels, secondary to reduced ATIII synthesis in patients with hepatic impairment.

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

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 was twice as high compared to the control group.

Body weight. After multiple subcutaneous administration at 150 IU/kg (1.5 mg/kg) once daily, mean steady-state AUC of anti-Xa activity was 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, lower clearance was observed after subcutaneous administration when corrected for body weight.

When administered without dose adjustment for body weight, after a single subcutaneous dose of 4000 IU (40 mg), anti-Xa exposure 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 for use").

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

Preclinical safety data. Apart from the anticoagulant effects of sodium enoxaparin, no signs of adverse effects were observed when the drug was administered at 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 with subcutaneous enoxaparin administration at doses up to 30 mg/kg/day revealed 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 after subcutaneous administration at doses up to 20 mg/kg/day.

Clinical characteristics.

Indications.

The medicinal product is indicated for use in adults for:

• Prophylaxis of venous thromboembolic complications in surgical patients at moderate or high risk, particularly in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases.
• Prophylaxis of venous thromboembolic complications in medical patients with acute illnesses (such as acute heart failure, respiratory failure, severe infections, or rheumatic diseases) and reduced mobility who are at increased risk of venous thromboembolism.
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required.
• Long-term treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as prevention of their recurrence in patients with active cancer.
• Prevention of thrombus formation in the extracorporeal circulation during hemodialysis.
• 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 acute ST-segment elevation myocardial infarction (STEMI), including in patients planned for pharmacological 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 or conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm 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 abnormalities of intraspinal or intracerebral vessels.
• Spinal or epidural anesthesia or regional block anesthesia when sodium enoxaparin has been used for treatment within the previous 24 hours (see section "Special precautions").

Interaction with other medicinal products and other forms of interaction.

Concomitant use with the following medicinal products is not recommended.

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

These include:

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

Medicinal products requiring cautious concomitant use.

The following medicinal products may be used concomitantly with enoxaparin sodium with caution.

• Other medicinal products affecting hemostasis, such as:
• platelet aggregation inhibitors, including acetylsalicylic acid used at antiplatelet (cardioprotective) doses, 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 elevate serum potassium levels may be prescribed concomitantly with enoxaparin sodium under 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, particular attention must be paid to the instructions for medical use specific to each proprietary medicinal product, and these instructions must be strictly followed.

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

The use of enoxaparin sodium is contraindicated in patients with a history of immune-mediated HIT within the past 100 days or in those 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 anticoagulant agents (e.g., danaparoid sodium or lepirudin).

Platelet monitoring.

In cancer patients with platelet counts below 80 × 10⁹/L, anticoagulant therapy should be initiated only after careful individual assessment, and close monitoring is recommended.

There is also a risk of antibody-mediated HIT occurring during treatment with LMWHs, which typically develops between days 5 and 21 after starting enoxaparin sodium therapy.

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

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

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

In clinical practice, confirmed significant reduction in platelet count (30–50% of baseline value) requires immediate discontinuation of enoxaparin sodium and initiation of an alternative non-heparin anticoagulant therapy.

Bleeding events.

As with other anticoagulants, bleeding 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 associated with an increased risk of bleeding, such as:

• coagulation disorders;
• history of peptic ulcer;
• recent ischemic stroke;
• severe arterial hypertension;
• recent onset of diabetic retinopathy;
• recent 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 increases in aPTT and ACT and enhanced antithrombotic activity of enoxaparin sodium, these parameters are unreliable and should not be used for monitoring enoxaparin sodium activity.

Use during spinal/epidural anaesthesia or lumbar puncture.

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

Cases of neuroaxial hematomas have been reported with concomitant use of enoxaparin sodium and procedures involving spinal/epidural anaesthesia or spinal puncture, resulting in long-term or permanent 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 is higher with postoperative continuous epidural catheters, concomitant use of other drugs affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs), traumatic or repeated epidural or spinal punctures, or in patients with a history of spinal surgery or spinal deformity.

To reduce the potential risk of bleeding associated with concomitant use of enoxaparin sodium and spinal/epidural anaesthesia/analgesia or lumbar puncture, the pharmacokinetic profile of enoxaparin sodium should be considered (see section "Pharmacokinetics"). Placement or removal of an epidural catheter or performance of lumbar puncture should ideally occur when the anticoagulant effect of enoxaparin sodium is low. However, the exact time at which sufficiently low anticoagulant effect is achieved 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 "Posology and method of administration").

If the physician decides to use anticoagulant therapy during spinal/epidural anaesthesia/analgesia or lumbar puncture, frequent 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, prompt diagnostic and therapeutic measures should be initiated, 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.

Percutaneous coronary interventions. To minimize the risk of bleeding after interventional vascular procedures in the treatment of unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI), recommended intervals between enoxaparin sodium doses must be strictly followed. 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 should be removed at least 6 hours after the last intravenous or subcutaneous dose 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 early signs of bleeding or hematoma formation.

Acute infective endocarditis. Heparin use in 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 heart valves has not been adequately studied. Isolated cases of mechanical valve thrombosis have been reported in patients receiving enoxaparin sodium for thromboprophylaxis. The presence of contributing risk factors, including underlying disease and insufficient clinical data, limits 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 heart valves has not been adequately studied. In a clinical trial where pregnant women with mechanical heart valves received enoxaparin sodium (100 IU/kg [1 mg/kg] twice daily) to reduce thromboembolic risk, two out of eight women developed clots leading to valve obstruction and maternal and fetal death. Post-marketing reports have also described 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 at prophylactic dose ranges, no increased bleeding tendency has been observed in elderly patients. However, elderly patients (especially those aged 80 years and older) may have an increased risk of hemorrhagic complications when enoxaparin sodium is used at therapeutic doses. For patients over 75 years receiving treatment for ST-elevation myocardial infarction (STEMI), careful clinical monitoring is recommended, and dose reduction may be considered (see sections "Posology and method of administration" and "Pharmacokinetics").

Renal impairment. In patients with impaired renal function, exposure to enoxaparin sodium is increased, which raises the risk of bleeding. Careful clinical monitoring is recommended for such patients, and biological monitoring via anti-Xa activity measurement may be considered (see sections "Posology and method of administration" and "Pharmacokinetics").

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

For patients with severe renal impairment (creatinine clearance 15–30 mL/min), dose adjustment is recommended for both therapeutic and prophylactic use due to significantly increased enoxaparin sodium exposure (see section "Posology and method of 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 increased bleeding risk. 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), potentially increasing bleeding risk. Therefore, careful clinical monitoring is recommended for these 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 (BMI > 30 kg/m²) have not been sufficiently studied, and there is currently no consensus on dose adjustment for this patient group. Close monitoring for possible signs of thromboembolism is required.

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 drugs known to 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 of hyperkalemia.

Traceability. Low molecular weight heparins are biological medicinal products. To improve traceability, healthcare professionals are advised to record the trade name and batch number of the administered product in the patient's medical records.

Sodium-sensitive patients

Patients receiving doses exceeding 210 mg/day should be aware that one dose of this medicinal product contains more than 24 mg of sodium, equivalent to 1.2% of the WHO recommended maximum daily intake of sodium (2 g for an adult).

Acute generalized exanthematous pustulosis (AGEP)

Acute generalized exanthematous pustulosis (AGEP) has been reported with "unknown" frequency in association with enoxaparin treatment. Patients should be informed about AGEP symptoms and closely monitored for skin reactions. If symptoms suggestive of these reactions occur, enoxaparin should be discontinued immediately, and alternative therapy should be considered if necessary.

Use during pregnancy or breastfeeding

Pregnancy. There are no data in humans indicating that enoxaparin crosses the placental barrier during the second and third trimesters of pregnancy. Information regarding the first trimester is currently lacking.

Animal studies have shown no evidence of fetotoxicity or teratogenicity (see section "Preclinical safety data"). Data from experimental animals indicate minimal placental transfer of enoxaparin.

Enoxaparin sodium should be administered during pregnancy only if clearly needed, as determined by the physician.

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

If epidural anesthesia is planned, discontinuation of enoxaparin sodium therapy is recommended prior to the procedure (see section "Special precautions for use").

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

Oral absorption of enoxaparin sodium is unlikely; therefore, 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 (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration.

Dosage.

Prophylaxis of venous thromboembolic complications in surgical patients with moderate and high risk. Individual thromboembolic risk in patients can be assessed using a validated risk stratification model (scale).

• 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 initial administration (2 hours before surgery) of sodium enoxaparin at a dose of 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 by subcutaneous (s.c.) injection 12 hours before surgery. If prophylactic use of sodium enoxaparin must 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 diseases, 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 at least 6–14 days, regardless of 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) every 12 hours.

The dosing regimen should be selected by the physician based on individual assessment, including evaluation of thromboembolic and bleeding risks. 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 prescribed for all other patients, including 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).

For long-term treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of their recurrence in patients with active cancer, the physician must carefully assess the risks of thromboembolism and bleeding.

The recommended dose is 100 IU/kg (1 mg/kg) twice daily administered by s.c. injection for 5–10 days, followed by 150 IU/kg (1.5 mg/kg) once daily by s.c. injection for 6 months. The benefits of continuous anticoagulant therapy should be re-evaluated after 6 months of treatment.

Prophylaxis 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, 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 prophylaxis 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 every 12 hours by s.c. injection, 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 2–8 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 s.c. dose of 100 IU/kg (1 mg/kg), followed by s.c. administration of 100 IU/kg (1 mg/kg) every 12 hours (maximum 10,000 IU [100 mg] for each of the first two s.c. doses). Appropriate antiplatelet therapy, e.g., oral acetylsalicylic acid (75–325 mg once daily), should be administered concomitantly, in the absence of contraindications. 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 up to 30 minutes after initiation of fibrinolytic therapy.
• Dosage specifics for patients aged ≥75 years are provided below ("Elderly Patients").
• For patients undergoing PCI, if the last s.c. dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional doses are required. If the last s.c. dose was administered 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 Warnings and Precautions for Use").

For treatment of acute STEMI in elderly patients (≥75 years), the initial i.v. bolus should not be administered. Treatment should begin with a s.c. dose of 75 IU/kg (0.75 mg/kg) every 12 hours (maximum 7500 IU [75 mg] for each of the first two s.c. doses), followed by continued administration of 75 IU/kg (0.75 mg/kg) s.c. for subsequent doses. Dosage specifics for elderly patients with renal impairment are described below in the subsection "Renal Impairment" and in the section "Special Warnings and Precautions for Use."

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 Warnings and Precautions for Use").

Renal impairment (see sections "Special Warnings and Precautions for Use" 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 prophylaxis of thrombus formation in the extracorporeal circuit during hemodialysis.

Table 6

Dosing for patients with severe renal impairment

(creatinine clearance 15–30 mL/min)

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) or moderate (creatinine clearance 30–50 mL/min) renal impairment, careful clinical monitoring of such patients is required.

Route of administration. The drug CLEXANE® must not be administered intramuscularly.

For the prevention of venous thromboembolic complications after surgery, treatment of DVT and PE, long-term treatment of DVT and PE in patients with active cancer, and treatment of unstable angina and NSTEMI, enoxaparin sodium should be administered by subcutaneous injection.

• For the treatment of acute STEMI, the drug should be initiated with a single intravenous (IV) bolus injection followed immediately by subcutaneous administration.
• For the prevention of clot formation in the extracorporeal circulation during hemodialysis, the drug is administered into the arterial line of the dialysis circuit.

Single-use pre-filled syringe, ready for use

Technique for subcutaneous injection.

Administration of the drug should preferably be performed while the patient is lying down. Enoxaparin sodium is administered by deep subcutaneous injection.

To avoid loss of the drug when using a pre-filled syringe, the air bubble should not be expelled before injection. If it is necessary to adjust the amount of drug to be administered according to the patient’s body weight, graduated syringes should be used, allowing the required volume to be obtained by removing the excess before injection. Please note that in some cases it may not be possible to obtain the exact dose due to the nature of the syringe graduations, and the volume should then be rounded to the nearest graduation mark.

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

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

The safety system of the pre-filled syringe with a needle protection system is activated at the end of the injection.

If the patient is self-administering the drug, they should be advised to follow the instructions for self-administration of Clexane® using the pre-filled syringe with a needle protection system.

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 intravenous (IV) bolus injection, followed immediately by subcutaneous administration.

For IV injection, the drug from another packaging may be used: a multidose vial or a pre-filled syringe.

Enoxaparin sodium should be administered via an IV infusion system. It must not be mixed or co-administered with other medicinal products. To avoid potential mixing of enoxaparin sodium with other drugs, the selected IV access should be flushed with an adequate amount of 0.9% sodium chloride solution or dextrose (glucose) solution before and after the IV bolus administration 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% aqueous dextrose (glucose) solution.

Initial bolus 3,000 IU (30 mg). To administer the initial bolus of 3,000 IU (30 mg) using a pre-filled syringe, the excess volume should be removed from the syringe so that only 3,000 IU (30 mg) remains. The 3,000 IU (30 mg) dose can then be administered directly into the IV infusion system.

Additional bolus in the case of PCI when the last subcutaneous dose was administered more than 8 hours before balloon inflation. For patients undergoing PCI, an additional IV bolus of 30 IU/kg (0.3 mg/kg) should be administered if the last subcutaneous dose was given 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).

To prepare a solution of 300 IU/mL (3 mg/mL), it is recommended to use a pre-filled syringe containing 6,000 IU (60 mg) of enoxaparin sodium and a 50 mL infusion bag (i.e., normal saline 0.9% or 5% dextrose solution) as follows: withdraw 30 mL from the infusion bag and discard the withdrawn fluid. Inject the entire contents of the pre-filled syringe containing 6,000 IU (60 mg) of enoxaparin sodium into the remaining 20 mL in the infusion bag. Gently mix the contents of the bag.

Withdraw the required volume of the diluted solution using a syringe for administration into the IV 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 7. Dilution should be performed immediately before drug administration.

Table 7

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

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

Transition from sodium enoxaparin to oral anticoagulants.

Transition between sodium enoxaparin and vitamin K antagonists (VKAs) and vice versa. Close clinical and laboratory monitoring [prothrombin time expressed as the international normalized ratio (INR)] should be maintained to monitor the effect of VKAs.

Since there is a time lag until VKAs reach their maximum effect, administration of sodium enoxaparin should be continued at a constant dose for as long as necessary to maintain the INR within the target therapeutic range for the respective indication, based on two consecutive test results.

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

Transition between sodium enoxaparin and direct oral anticoagulants (DOACs) and vice versa. In patients currently receiving sodium enoxaparin, sodium enoxaparin should be discontinued and DOAC treatment should be initiated 0–2 hours (see the instructions for medical use of the specific DOAC) before the time the next scheduled dose of sodium enoxaparin would have been administered.

In patients currently receiving DOACs, the first dose of sodium enoxaparin should be administered at the time the next DOAC dose would have been due.

Use of the drug in 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 neuroaxial hematoma (see section "Special precautions").

Use of prophylactic doses. A minimum interval of at least 12 hours without procedures should be maintained between the last injection of prophylactic-dose sodium enoxaparin and the insertion of a needle or catheter.

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

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

Initial administration of sodium enoxaparin 2,000 IU (20 mg) two hours before surgery is not applicable when neuroaxial anesthesia is performed.

Use of therapeutic doses. A minimum interval of at least 24 hours without procedures should be maintained between the last injection of therapeutic-dose sodium enoxaparin and the insertion of a needle or catheter (see also section "Contraindications").

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

In patients with creatinine clearance of 15–30 mL/min, consideration should be given to doubling the time to 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 sodium enoxaparin to ensure an adequate time interval before catheter insertion or removal.

At these time points, anti-Xa activity of the drug is still detectable, and adherence to these time intervals does not guarantee prevention of neuroaxial hematoma.

Therefore, sodium enoxaparin should not be administered for at least 4 hours after spinal/epidural puncture or after catheter removal. This time interval should be based on an individual benefit-risk assessment, taking into account both thrombosis and bleeding risks associated with the procedure and the patient's individual risk factors.

Instructions for self-administration of Clexane® pre-filled syringe with needle safety system ERIS or PREVENTIS

The automatic needle safety system helps reduce the risk of pain and bruising at the injection site.

CLEXANEâ is a solution for injection in pre-filled syringes with a needle safety system to prevent accidental needlestick injury after injection.

1. Wash hands with soap and water. Dry them thoroughly.
2. Select an area on the right or left side of the abdomen. This area should be at least 5 centimeters away (laterally) from the navel.

1. Rotate injection sites, alternating between the right and left sides of the abdomen, depending on the side used for the previous injection. Clean the injection site with an alcohol swab.

1. Carefully remove the needle cap from the syringe containing CLEXANE®. Discard this cap. The syringe is pre-filled and ready for use. DO NOT press the plunger to expel air bubbles before injection. This may result in loss of medication. After removing the cap, avoid letting the needle touch anything to maintain sterility.

1. Hold the syringe like a pencil. With the other hand, gently pinch the cleaned area of the abdomen between the index and thumb to form a skin fold. It is essential to maintain the skin fold throughout the entire injection.

1. Hold the syringe so that the needle is pointing downward (vertically at a 90° angle). Insert the needle fully into the skin fold.

1. Press the syringe plunger with the thumb. Maintain the skin fold throughout the injection.
2. Withdraw the needle straight back and release the skin fold.
3. When using CLEXANE® pre-filled syringe with the ERIS needle safety system, the needle will automatically be covered by a protective sheath.
4. When using CLEXANE® pre-filled syringe with the PREVENTIS needle safety system, after removing the needle from the injection site, keep your finger on the plunger. Direct the needle downward and away from yourself and others, then press the plunger fully to activate the safety mechanism. The protective sheath will automatically cover the needle, and a clicking sound will confirm activation of the safety feature.
5. Immediately dispose of the syringe in an appropriate sharps container.
6. Note: The ERIS or PREVENTIS needle safety systems can only be activated when the syringe is fully emptied.

To avoid bruising, do not rub the injection site after administering the drug.

Children.

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

Overdose.

Symptoms. Accidental overdose of sodium enoxaparin due to intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. After oral intake, even of relatively high doses, absorption of sodium enoxaparin 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 amount of sodium enoxaparin administered:

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

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

Adverse reactions.

General description of the drug safety profile. Sodium enoxaparin has been studied in more than 15,000 patients who received sodium enoxaparin in clinical trials: 1,776 cases of drug use for prophylaxis of deep vein thrombosis after orthopedic surgery or abdominal surgery in patients at increased risk of thromboembolic complications, 1,169 cases of drug use for prophylaxis of deep vein thrombosis in patients with acute medical conditions and very limited mobility, 559 cases of drug use for treatment of deep vein thrombosis with or without pulmonary embolism, 1,578 cases of drug use for treatment of unstable angina and non-Q-wave myocardial infarction, and 10,176 cases of drug use for treatment of acute ST-segment elevation myocardial infarction.

Dosing regimens of sodium enoxaparin in these clinical trials varied depending on the indication. The dose of sodium enoxaparin for prophylaxis of deep vein thrombosis after surgery or in patients with acute medical conditions and very limited mobility was 4,000 IU (40 mg) subcutaneously once daily. For treatment of deep vein thrombosis with or without pulmonary embolism, patients received sodium enoxaparin either at a dose of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or at a dose of 150 IU/kg (1.5 mg/kg) subcutaneously once daily. In clinical trials where the drug was used for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, and in the clinical trial where the drug was used for treatment of acute ST-segment elevation myocardial infarction, the dosing regimen of sodium enoxaparin included an intravenous bolus of 3,000 IU (30 mg) followed by subcutaneous administration of the drug at a dose of 100 IU/kg (1 mg/kg) every 12 hours.

In clinical trials, the most frequently reported adverse reactions were hemorrhagic events, thrombocytopenia, and thrombocytosis (see section "Special precautions for use" and "Description of selected adverse reactions" below).

Acute generalized exanthematous pustulosis (AGEP) has been reported during treatment with enoxaparin (see section "Special precautions for use").

The safety profile of enoxaparin for long-term treatment of DVT and PE in patients with active cancer is similar to its safety profile for treatment of DVT and PE.

Tabulated list of adverse reactions. Other adverse reactions observed in clinical trials and reported during the post-marketing period (* indicates adverse reactions reported during the post-marketing period) are described in detail below.

Frequency was defined 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 available data). Within each "System-Organ-Class," adverse reactions are listed in order of decreasing severity.

Disorders of the blood and lymphatic system.

Common: hemorrhagic events, hemorrhagic anemia*, thrombocytopenia, thrombocytosis.

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

Disorders of the immune system.

Common: allergic reaction.

Rare: anaphylactic/anaphylactoid reactions, including shock*.

Disorders of the nervous system.

Common: headache*.

Vascular disorders.

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

Hepatobiliary disorders.

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

Uncommon: hepatocellular liver injury*.

Rare: cholestatic liver injury*.

Disorders of the skin and subcutaneous tissue.

Common: urticaria, pruritus, erythema.

Uncommon: bullous dermatitis.

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

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

Musculoskeletal and connective tissue disorders, bone disorders.

Rare: osteoporosis* after prolonged therapy (longer than 3 months).

General disorders and administration site reactions.

Common: hematoma at injection site, pain at injection site, other injection site reactions (e.g., swelling, bruising, hypersensitivity, inflammation, mass, pain, or other reactions).

Uncommon: local irritation, skin necrosis at injection site.

Investigations.

Rare: hyperkalemia* (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Description of selected adverse reactions.

Hemorrhagic events. Serious hemorrhagic events were observed and reported in no more than 4.2% of patients (surgical patients). Some of these cases were fatal. In surgical patients, hemorrhagic complications were considered serious if the hemorrhagic event caused a significant clinical event, or if it was associated with a hemoglobin decrease ≥ 2 g/dL or required transfusion of 2 or more standard units of blood products. Retroperitoneal and intracranial hemorrhages were always considered serious.

As with other anticoagulants, hemorrhagic 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 hemostasis (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Table 8

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

b Frequency based on a retrospective study from a registry including 3526 patients (see section "Pharmacodynamics").

Table 9

Thrombocytopenia and thrombocytosis (see section "Special precautions for use". Platelet count monitoring)

c Increase in platelet count > 400 × 10⁹/L.

Paediatric population. The safety and efficacy of enoxaparin sodium in children have not been established to date (see section "Paediatric use").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Keep out of reach and sight of children. Store at a temperature not exceeding 25°C. Do not freeze.

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

Intravenous (bolus) injection (exclusively for treatment of acute ST-segment elevation myocardial infarction). Enoxaparin sodium should not be mixed with other medicinal products except as specified in section "Dosage and method of administration".

Packaging. No. 10 (2×5):

0.2 ml in a pre-filled syringe with needle protection system ERIS; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

0.2 ml in a pre-filled syringe with needle protection system PREVENTIS; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

0.2 ml in a pre-filled syringe without needle protection system; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

0.4 ml in a pre-filled syringe with needle protection system ERIS; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

0.4 ml in a pre-filled syringe with needle protection system PREVENTIS; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

0.4 ml in a pre-filled syringe without needle protection system; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

1 ml in a pre-filled syringe with needle protection system ERIS; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

1 ml in a pre-filled syringe with needle protection system PREVENTIS; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box;

1 ml in a pre-filled syringe without needle protection system; 2 pre-filled syringes in a blister; 5 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI WINTHROP INDUSTRIE.

Manufacturer's address.

180, rue Jean Jaurès, 94700 MAISONS-ALFORT, France.

or

1051, Boulevard Industriel, 76580 LE TREPORT, France.

Marketing Authorization Holder. LLC "Sanofi-Aventis Ukraine".