Nardin® multidose

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NARDIN® MULTIDOSE

Composition:

Active substance: enoxaparin;

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

Excipients: benzyl alcohol, water for injections.

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

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: colorless or slightly yellow clear solution.

Pharmacotherapeutic group. Antithrombotic agents. Heparin group. Enoxaparin. 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 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 factors contribute to the overall antithrombotic effect of enoxaparin sodium.

When used for prophylaxis, enoxaparin sodium has little effect on the 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 the time of maximum drug activity.

Clinical efficacy and safety

Prevention of venous thromboembolic complications associated with surgical procedures

Long-term prevention of venous thromboembolism (VTE) after orthopedic surgery. In a double-blind study on long-term prophylaxis following hip replacement surgery, 179 patients without any venous thromboembolic complications who had initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospitalization were randomized after discharge to 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 long-term 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

In another double-blind study, 262 patients without any venous thromboembolic events, undergoing elective hip replacement surgery, who initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously once daily 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%), versus placebo — 45 (34.4%); p = 0.001] and proximal 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 oncological surgery. In a double-blind, multicenter study, the safety and efficacy of 4-week versus 1-week prophylactic regimens of enoxaparin sodium were compared in 332 patients undergoing elective 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. Between days 25 and 31, or earlier if symptoms of VTE occurred, bilateral venography was performed. Patients were followed for 3 months. Prophylactic use of enoxaparin sodium for 4 weeks after abdominal or pelvic oncological surgery significantly reduced the incidence 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 between groups were observed in terms of bleeding or other complications during the double-blind phase or the follow-up period.

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

In a double-blind, multicenter, parallel-group study, enoxaparin sodium at doses of 2000 IU (20 mg) or 4000 IU (40 mg) once daily subcutaneously was compared with placebo for VTE prophylaxis in medical patients with severely limited mobility (defined as walking distance < 10 meters within ≤ 3 days) due to acute illness. The study included patients with heart failure (NYHA functional class III or IV), acute respiratory insufficiency or complicated chronic respiratory insufficiency, or acute infection or acute rheumatic disease, provided at least one VTE risk factor was present (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 study treatment. Treatment duration ranged from 6 to 14 days (median duration was 7 days). Enoxaparin sodium 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

After approximately 3 months from patient enrollment in the study, the incidence rate 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 with either enoxaparin sodium at a dose of 150 IU/kg (1.5 mg/kg) once daily subcutaneously (s.c.); or enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours s.c.; or heparin as an intravenous (i.v.) bolus (5000 IU) followed by continuous i.v. infusion (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 to achieve an INR [international normalized ratio] of 2.0 to 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 therapeutic INR was achieved on warfarin sodium. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). Efficacy data are presented in Table 3.

Table 3

The incidence 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.

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 100 IU/kg (1 mg/kg) every 12 hours or unfractionated heparin (UFH) intravenously with dose adjustment based on aPTT levels, both in combination with acetylsalicylic acid (100–325 mg once daily). Patients received inpatient 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 combined incidence of angina, myocardial infarction, and death from 19.8% to 16.6% (a 16.2% relative risk reduction) by day 14. This reduction in the combined endpoint was maintained at 30 days (from 23.3% to 19.8%; a 15% relative risk reduction).

There were no statistically significant differences 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 STEMI patients eligible for fibrinolytic therapy were randomized to receive either sodium enoxaparin as a single intravenous bolus of 3000 IU (30 mg), followed by 100 IU/kg (1 mg/kg) subcutaneously and subsequent subcutaneous administration every 12 hours, or 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 for elderly patients (≥75 years). Subcutaneous injections of sodium enoxaparin were continued until hospital discharge or for a maximum of 8 days (whichever occurred earlier).

4716 patients underwent percutaneous coronary intervention (PCI) with blinded antithrombotic support using the study medications. 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 sodium 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 incidence 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 versus 12.0% in the UFH group), representing a 17% relative risk reduction (p < 0.001).

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

The positive effect of sodium enoxaparin on the primary endpoint was consistent across all key subgroups, including age, sex, infarct location, history of diabetes, 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 (23% relative risk reduction) and in those managed medically (15% relative risk reduction, p = 0.27 for interaction).

The incidence 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 sodium enoxaparin group had a higher incidence of gastrointestinal bleeding (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 on the primary endpoint observed during the first 30 days was maintained throughout a 12-month follow-up period.

Hepatic impairment. Published data indicate that 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 studies described in the scientific 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 pharmacokinetic studies have been conducted on dosing in patients with liver cirrhosis (Child-Pugh class 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 is observed within 3–5 hours after subcutaneous injection and reaches approximately 0.2, 0.4, 1.0, and 1.3 IU/mL 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 by immediate subcutaneous administration of 100 IU/kg (1 mg/kg) every 12 hours, the initial peak plasma anti-Xa activity was 1.16 IU/mL (n = 16), and mean 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 reached 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-subject variability is low. No accumulation was observed after multiple subcutaneous administrations.

Plasma anti-IIa activity after subcutaneous administration is approximately 10 times 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 clearance of anti-Xa activity 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 of approximately 5 hours after single subcutaneous administration and 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

According to population pharmacokinetic analysis, 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 section "Dosage and administration").

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 impairment (assessed by Child-Pugh classification). This reduction was primarily explained by decreased ATIII levels, secondary to reduced ATIII synthesis in patients with hepatic dysfunction.

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. Exposure to anti-Xa activity, 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 significantly increased by an average of 65% after multiple subcutaneous administration 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), although AUC was twice as high compared to the control group.

Body weight

After multiple subcutaneous administration of 150 IU/kg (1.5 mg/kg) once daily, mean steady-state AUC of anti-Xa activity was marginally higher in healthy volunteers with obesity (BMI 30–48 kg/m²) compared to the non-obese control group, while peak plasma anti-Xa activity did not increase. In obese individuals, subcutaneous administration resulted in lower clearance adjusted for body weight.

When administered at fixed doses without body weight adjustment, after single subcutaneous administration 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 control subjects 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 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 receiving subcutaneous enoxaparin 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 up to 20 mg/kg/day.

Clinical Characteristics

Indications. The medicinal product is indicated for use in adults:

• for the prevention of venous thromboembolic complications in surgical patients with moderate and high risk, particularly in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases;
• for the prevention 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;
• for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required;
• for the prevention of thrombus formation in the extracorporeal circulation during hemodialysis;
• in acute coronary syndrome:
  • for the treatment of unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid;
  • for the 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 their derivatives, including other low-molecular-weight heparins, or to any of the excipients contained in the medicinal product;
• history of immune-mediated heparin-induced thrombocytopenia (HIT) within the last 100 days in the presence of circulating antibodies (see also section "Special precautions");
• active clinically significant bleeding and conditions with a 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 was used for treatment within the previous 24 hours (see section "Special precautions");
• hypersensitivity to benzyl alcohol.

Due to the presence of benzyl alcohol, the medicinal product in multidose vials should not be administered to neonates, particularly premature infants.

Interaction with other medicinal products and other types of interactions

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 treatment, unless such agents are 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 requiring caution when used concomitantly

• Other medicinal products affecting hemostasis, such as:
  • platelet aggregation inhibitors, including acetylsalicylic acid used at antiplatelet doses (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 serum potassium levels may be administered concomitantly with sodium enoxaparin provided that careful clinical and laboratory monitoring is performed (see sections "Special precautions" and "Adverse reactions").

Special Warnings and Precautions for Use

General Warnings

Enoxaparin sodium must not be used as a direct (unit-for-unit) substitute for 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., antithrombotic activity, platelet interactions).

Therefore, the instructions for use of these medicinal products must be carefully studied and strictly followed.

History of Heparin-Induced Thrombocytopenia (HIT) (> 100 days)

Enoxaparin sodium is contraindicated in patients with a history of immune-mediated HIT within the past 100 days if circulating antibodies are present (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 (within the past 100 days) in the absence of circulating antibodies. The decision to use enoxaparin sodium in such cases should be made only after a careful benefit-risk assessment and after considering the use of alternative non-heparin anticoagulant agents (e.g., danaparoid sodium or lepirudin).

Platelet Monitoring

There is a risk of antibody-mediated HIT when using LMWHs, which typically develops between the 5th and 21st day after starting enoxaparin sodium treatment.

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

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

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 count must be measured. Patients should be informed about the possibility of such symptoms and instructed to report them to their physician immediately.

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

Bleeding Events

As with other anticoagulants, bleeding or hemorrhage may occur at any site. In the event 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 central 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

Enoxaparin sodium, when used at doses for prophylaxis of venous thromboembolism, 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 or 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 should 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 when enoxaparin sodium was used concomitantly with 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 of such complications is higher when postoperative indwelling epidural catheters are used, when other drugs affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs) are administered concomitantly, when traumatic or repeated epidural or spinal procedures are performed, or when patients have a history of spinal surgery or spinal deformity.

To minimize the potential risk of bleeding associated with concomitant use of enoxaparin sodium and neuraxial procedures (epidural/spinal anaesthesia/analgesia or lumbar puncture), the pharmacokinetic profile of enoxaparin sodium should be considered (see section "Pharmacokinetics"). Placement or removal of epidural catheters or performance of lumbar puncture should ideally be performed when the anticoagulant effect of enoxaparin sodium is low. However, 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 a physician decides to use anticoagulant therapy during epidural/spinal anaesthesia/analgesia or lumbar puncture, careful monitoring for signs of neurological impairment (e.g., midline back pain, sensory or motor disturbances such as numbness or weakness in the lower limbs, bowel or bladder dysfunction) is required. Patients should be instructed to immediately report any of these symptoms. If a 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 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 enoxaparin sodium doses 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 should be removed 6 hours after the last intravenous or subcutaneous dose of enoxaparin sodium. If enoxaparin sodium therapy 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

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 a 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 contributing risk factors, underlying disease, and limited clinical data make evaluation of these cases difficult. In some reported cases in pregnant women, valve thrombosis led to maternal and fetal death.

Pregnant Women with Mechanical Prosthetic 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 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 thrombi leading to valve obstruction and maternal and fetal death. Post-marketing reports have 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 or older) may have an increased risk of hemorrhagic complications when therapeutic doses are used. For patients over 75 years receiving enoxaparin sodium for ST-elevation myocardial infarction (STEMI), careful clinical monitoring is recommended and dose reduction may be considered (see sections "Dosage and Administration" and "Pharmacokinetics").

Renal Impairment

In patients with renal impairment, 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 "Dosage and 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 "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 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

Patients with obesity 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 no consensus on dose adjustment for this patient group. These patients should be closely monitored for possible signs of thromboembolism.

Hyperkalemia

Heparins may suppress aldosterone secretion in the adrenal glands, leading to hyperkalemia (see section "Adverse Reactions"), particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, or those receiving drugs that may 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 high risk of hyperkalemia.

Traceability

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

Benzyl Alcohol

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse reactions and death in neonates ("gasping syndrome") (see section "Contraindications"). The minimum amount of benzyl alcohol that may cause toxicity is unknown. Benzyl alcohol may also cause toxic reactions in infants and children under 3 years of age due to increased risk of accumulation.

Large volumes of medicinal products containing benzyl alcohol should be used cautiously and only when necessary in patients with hepatic or renal impairment and in pregnant women due to the risk of accumulation and toxicity (metabolic acidosis).

Acute Generalized Exanthematous Pustulosis (AGEP)

Cases of acute generalized exanthematous pustulosis (AGEP) have been reported in association with enoxaparin treatment (frequency unknown). When prescribing enoxaparin, patients should be informed about the signs and symptoms of AGEP and closely monitored for skin reactions. If symptoms suggestive of AGEP occur, enoxaparin should be discontinued immediately and alternative treatment considered (if necessary).

Sodium

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

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. Data for the first trimester are currently unavailable.

Preclinical studies in animals have shown no signs of fetotoxicity or teratogenicity (see section "Preclinical Safety Data"). Animal studies indicate minimal placental transfer of enoxaparin.

Enoxaparin sodium should be administered to pregnant women only if clearly needed.

Pregnant women receiving enoxaparin sodium should be closely monitored for signs of bleeding or excessive anticoagulant effect, and should be informed 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 prosthetic heart valves (see section "Special Warnings and Precautions for Use").

If epidural anesthesia is planned, it is recommended to discontinue enoxaparin sodium prior to the procedure (see section "Special Warnings and Precautions for Use").

Since benzyl alcohol can cross the placenta, NARDIN® MULTIDOSE in pre-filled syringes, which does not contain this excipient, is recommended.

Breastfeeding

It is unknown whether 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 in women who are breastfeeding.

Fertility

Clinical data on the effect of enoxaparin sodium on fertility are currently lacking. Animal studies did not demonstrate any effect of the drug on fertility.

Ability to Drive and Operate Machinery
The effect of enoxaparin sodium on the ability to drive or operate machinery is negligible or none.

Method of Administration and Dosage

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 with moderate risk of thromboembolic complications, 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 at a dose of 2000 IU (20 mg) has been shown to be effective and safe in surgeries 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 with high risk of thromboembolic complications, 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 dose should be administered no later than 12 hours before surgery, and prophylactic dosing should be resumed 12 hours after surgery.

• For patients undergoing major orthopedic surgery, prolonged thromboprophylaxis is recommended — up to 5 weeks.

• For high-risk patients undergoing abdominal or pelvic surgery for oncological diseases, prolonged thromboprophylaxis is recommended — up to 4 weeks.

Prophylaxis of venous thromboembolism (VTE) 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 an injection of 150 IU/kg (1.5 mg/kg) once daily or as an injection of 100 IU/kg (1 mg/kg) twice daily.

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, 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 "Transition from sodium enoxaparin to oral anticoagulants" at the end of this section).

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 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 injected into the arterial portion 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 the 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 to 8 days.

• For all uncomplicated patients, oral acetylsalicylic acid is recommended with an initial loading dose of 150–300 mg (for patients not previously receiving acetylsalicylic acid) and a maintenance dose of 75–325 mg/day long-term, regardless of treatment strategy.

• For the treatment of acute STEMI, the recommended dose of sodium enoxaparin is a single intravenous (i.v.) bolus of 3000 IU (30 mg), followed by a s.c. dose of 100 IU/kg (1 mg/kg), then subsequent s.c. doses 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]. 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 initiation of fibrinolytic therapy.

• Dosage specifics for patients aged ≥ 75 years are described below ("Elderly patients").

• For patients undergoing percutaneous coronary intervention (PCI), if the last s.c. dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional dose is 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 precautions").

For the treatment of 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 s.c. dosing of 75 IU/kg (0.75 mg/kg)]. Dosage specifics for elderly patients with renal impairment are described below in the subsection "Renal impairment" and in the section "Special precautions."

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 precautions").

Renal impairment (see sections "Special precautions" 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 4

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 medicinal product 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.

Administration method

The medicinal product NARDIN® MULTIDOSE must not be administered intramuscularly.

• For the prevention of venous thromboembolic complications following surgery, treatment of VTE and PE, and treatment of unstable angina and NSTEMI, sodium enoxaparin should be administered by subcutaneous (s.c.) injection;
• for the treatment of acute STEMI, the drug should be initiated with a single intravenous (i.v.) bolus injection followed immediately by s.c. administration;
• for the prevention of clot formation in the extracorporeal circulation during hemodialysis, the drug should be administered into the arterial line of the dialysis circuit.

It is recommended to use a tuberculin syringe or equivalent syringe of appropriate volume for administering the medicinal product from multidose vials.

Technique for subcutaneous injection

Administration of the drug is preferably performed with the patient lying down. Sodium enoxaparin is administered by deep subcutaneous injection.

To avoid loss of the drug when using pre-filled syringes, air bubbles should not be expelled from the syringe before injection. If the dose needs to be adjusted according to the patient's body weight, graduated pre-filled syringes should be used, allowing the required volume to be obtained by removing the excess prior to injection. It should be noted that in some cases it may not be possible to obtain the exact dose due to the syringe's graduation marks, and in such cases the volume should be rounded to the nearest graduation mark.

The injection should be alternated between the left and right anterolateral or posterolateral abdominal walls.

The needle should be inserted fully, perpendicularly, 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 NARDIN® MULTIDOSE in a pre-filled syringe with a needle protection system.

Intravenous (bolus) injection [only when the drug is used for the indication of 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.

Sodium enoxaparin should be administered through an i.v. infusion system. It must not be mixed or co-administered with other medicinal products. To avoid potential mixing of sodium enoxaparin with other medicinal products, the selected i.v. access should be flushed with an adequate amount of 0.9% sodium chloride solution or glucose solution before and after the i.v. bolus administration of sodium enoxaparin to clear the administration port of other drugs. Sodium enoxaparin 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 should be expelled from the syringe so that only 3000 IU (30 mg) remains. The dose of 3000 IU (30 mg) can then be administered directly i.v.

Additional bolus for patients undergoing PCI. An additional i.v. bolus of 30 IU/kg (0.3 mg/kg) should be administered if the last s.c. 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).

The required volume of the diluted solution should be drawn into a syringe for administration via an i.v. infusion system.

To prepare a solution of 300 IU/mL (3 mg/mL) using a 6000 IU (60 mg) pre-filled syringe of sodium enoxaparin, it is recommended to use a 50 mL infusion bag [i.e., 0.9% sodium chloride solution for infusion or 5% glucose solution in water for injection]: 30 mL of the solution should be withdrawn from the infusion bag using a syringe and discarded. The contents of the 6000 IU (60 mg) pre-filled syringe of sodium enoxaparin should be added to the bag containing the remaining 20 mL. The contents of the bag should be gently mixed. The required volume of the diluted solution should then be drawn into a syringe for administration via an 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 preferably be performed immediately before administration.

Table 5

Volume to be administered via an i.v. 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 thrombus formation in the extracorporeal circulation during hemodialysis.

Transition from sodium enoxaparin to oral anticoagulants

Transition from sodium enoxaparin to vitamin K antagonists (VKAs)

Clinical monitoring and laboratory testing [prothrombin time expressed as international normalized ratio (INR)] should be intensified to monitor the effect of VKAs.

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

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

Transition from sodium enoxaparin to direct oral anticoagulants (DOACs) and vice versa

In patients currently receiving sodium enoxaparin, sodium enoxaparin 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 sodium enoxaparin.

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 medicinal product in spinal/epidural anesthesia or lumbar puncture

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

Use of prophylactic doses

A minimum interval of at least 12 hours should elapse between the last prophylactic dose of sodium enoxaparin and 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.

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

Initial administration of sodium enoxaparin 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 elapse between the last therapeutic dose of sodium enoxaparin and 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.

In patients with creatinine clearance of 15–30 mL/min, consideration should be given to doubling the time interval before performing a puncture or inserting/removing a catheter 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 omit 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 may still be present, and adherence to the specified time intervals does not guarantee prevention of neuraxial 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 a benefit-risk assessment that considers both thrombosis and bleeding risks associated with the procedure, taking into account patient-specific risk factors.

Children

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

The medicinal product NARDIN® MULTIDOSE contains benzyl alcohol and must not be used in neonates, particularly premature neonates (see section "Contraindications").

Overdose

Symptoms

Unintentional overdose of sodium enoxaparin due to intravenous, extracorporeal, or subcutaneous administration may lead to hemorrhagic complications. Following 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 administered dose of sodium enoxaparin:

• 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 earlier or if a second dose of protamine is required;
• protamine administration may not be necessary more than 12 hours after sodium enoxaparin administration.

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

Adverse Reactions

General description of the drug safety profile

The effect of enoxaparin sodium was studied in clinical trials involving more than 15,000 patients. Specifically, 1776 cases of drug use for the prevention of deep vein thrombosis after orthopedic or abdominal surgery in patients at increased risk of thromboembolic complications, 1169 cases of drug use for the prevention of deep vein thrombosis in patients with acute medical conditions and very limited mobility, 559 cases of drug use for the treatment of deep vein thrombosis with or without pulmonary embolism, 1578 cases of drug use for the treatment of unstable angina and non-Q-wave myocardial infarction, and 10,176 cases of drug use for the treatment of acute ST-segment elevation myocardial infarction (STEMI) were evaluated.

Dosing regimens of enoxaparin sodium in these clinical trials varied depending on the indication. The dose of enoxaparin sodium for the prevention of deep vein thrombosis after surgery or in patients with acute medical conditions and very limited mobility was 4000 IU (40 mg) subcutaneously once daily. For the treatment of deep vein thrombosis with or without pulmonary embolism, patients received enoxaparin sodium either at a dose of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, or 150 IU/kg (1.5 mg/kg) subcutaneously once daily. In clinical trials where the drug was used for the treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) subcutaneously every 12 hours. In the clinical trial where the drug was used for the treatment of acute ST-segment elevation myocardial infarction, the enoxaparin sodium regimen included an intravenous bolus of 3000 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 sections "Special precautions for use" and "Description of selected adverse reactions" below).

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 is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data). Within each organ system, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders

Common: hemorrhagic events, hemorrhagic anemia*, 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 ischemia (see section "Special precautions for use").

Immune system disorders

Common: allergic reaction.

Rare: anaphylactic/anaphylactoid reactions, including shock*.

Nervous system disorders

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: elevated liver enzymes (primarily 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*, 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

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

General disorders and administration site conditions

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

Blood and lymphatic system disorders

Prophylaxis in surgical patients

Very common: hemorrhagic eventsα.

Rare: retroperitoneal hemorrhage.

Prophylaxis in medical patients

Common: hemorrhagic eventsα.

Treatment in patients with DVT, with or without PE

Very common: hemorrhagic eventsα.

Uncommon: intracranial hemorrhage, retroperitoneal hemorrhage.

Treatment in patients with unstable angina and non-Q-wave myocardial infarction

Common: hemorrhagic eventsα.

Rare: retroperitoneal hemorrhage.

Treatment in patients with acute STEMI

Common: hemorrhagic eventsα.

Uncommon: intracranial hemorrhage, retroperitoneal hemorrhage.

α Such as hematoma, ecchymosis (excluding those at the injection site), wound hematoma, hematuria, epistaxis, and gastrointestinal bleeding.

Thrombocytopenia and thrombocytosis

Blood and lymphatic system disorders

Prophylaxis in surgical patients

Very common: thrombocytosisβ.

Common: thrombocytopenia.

Prophylaxis in medical patients

Uncommon: thrombocytopenia.

Treatment in patients with DVT, with or without PE

Very common: thrombocytosisβ.

Common: thrombocytopenia.

Treatment in patients with unstable angina and non-Q-wave myocardial infarction

Uncommon: thrombocytopenia.

Treatment in patients with acute STEMI

Common: thrombocytosisβ, thrombocytopenia.

Very rare: immune-mediated thrombocytopenia.

β Platelet count increase > 400 x 10⁹/L.

Pediatric patients

The safety and efficacy of enoxaparin sodium in children have not been established (see section "Dosage and administration").

Intravenous administration of benzyl alcohol is associated with serious adverse reactions and neonatal death ("gasping syndrome") (see section "Contraindications").

Benzyl alcohol may also cause toxic reactions in infants and children under 3 years of age due to an increased risk of accumulation (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years (from the date of manufacture of the in bulk form).

Do not use the medicinal product after the expiry date stated on the packaging.

Proposed shelf life after first opening of the vial. Chemical and physical stability during use has been demonstrated for 28 days at 25 °C. From a microbiological standpoint, after opening the vial, the medicinal product may be stored for up to 28 days at a temperature not exceeding 25 °C. Under other storage conditions, responsibility lies with the user.

Proposed shelf life after dilution (with 0.9% sodium chloride solution or 5% glucose solution). Chemical and physical stability during use has been demonstrated for 8 hours at 25 °C. From a microbiological standpoint, if the dilution method does not exclude the risk of microbial contamination, the prepared solution should be used immediately after preparation. If the solution is not used immediately, storage responsibility lies with the user.

Storage conditions. Store out of reach of children at a temperature not exceeding 25 °C in the original packaging. Do not freeze.

Incompatibility

Subcutaneous injection. Do not mix with other medicinal products.

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

Packaging. 1 multidose vial of 3 ml or 5 ml in a cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Yuria-Pharm" (packaging of the in bulk form produced by Shenzhen Techdow Pharmaceutical Co. Ltd, China).

Manufacturer's address and location of business activity. 108, Kobzarska Street, Cherkasy, Cherkasy Oblast, Ukraine.

Tel.: (044) 281-01-01.