Novoparin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOVOPARIN® (NOVOPARIN)

Composition:

Active substance: enoxaparin sodium;

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

1 vial contains enoxaparin sodium with anti-factor Xa activity of 50,000 IU, equivalent to 500 mg of enoxaparin sodium in 5.0 ml of water for injections;

or

1 vial contains enoxaparin sodium with anti-factor Xa activity of 30,000 IU, equivalent to 300 mg of enoxaparin sodium in 3.0 ml of water for injections;

* Enoxaparin sodium is a biological substance obtained by alkaline depolymerization of the benzyl ether of heparin derived from the intestinal mucosa of pigs.

Excipients: benzyl alcohol, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: 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 no significant effect on activated partial thromboplastin time (aPTT). When used for treatment, aPTT may be prolonged by 1.5–2.2 times compared to the control value at peak drug activity.

Clinical Efficacy and Safety

Prophylaxis of venous thromboembolic complications associated with surgical procedures

Long-term prophylaxis of venous thromboembolism (VTE) following orthopedic surgery. In a double-blind study on long-term prophylaxis after hip replacement surgery, 179 patients without any prior venous thromboembolic complications, who had initially received enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) during hospitalization, were randomized after hospital discharge to either continue 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 who had undergone hip replacement surgery and who 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 events (enoxaparin sodium – 21 [16%] versus placebo – 45 [34.4%]; p = 0.001) and proximal deep vein thrombosis (DVT) (enoxaparin sodium – 8 [6.1%] versus placebo – 28 [21.4%]; p = <0.001). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT following surgery for cancer.

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 planned abdominal or pelvic surgery for cancer. Patients received enoxaparin sodium (4000 IU [40 mg] subcutaneously) daily for 6–10 days, after which they were randomized to receive either enoxaparin sodium or placebo for an additional 21 days. 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 cancer surgery significantly reduced the incidence of venographically confirmed thrombosis compared to a 1-week prophylaxis regimen. The incidence of VTE at the end of the double-blind phase was 12.0% (n = 20) in the placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference was maintained over 3 months [13.8% vs. 5.5% (n = 23 vs. 9), p = 0.01]. No differences were observed between groups in terms of bleeding or other complications during the double-blind period or the follow-up period.

Prevention of venous thromboembolic complications in medically ill patients with acute conditions 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 the prevention of DVT in medically ill patients with severely limited mobility (defined as walking distance < 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, or acute infection, or acute rheumatic disease, provided they had at least one risk factor for VTE (age ≥ 75 years, cancer, prior VTE, obesity, varicose veins, hormonal therapy, chronic heart or respiratory failure).

Overall, 1102 patients were enrolled in the study, and 1073 patients received the investigational treatment. Treatment lasted 6–14 days (median duration was 7 days). Enoxaparin sodium administered at 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 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 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 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 inpatient treatment with either 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 (to achieve an aPTT of 55 to 85 seconds). Overall, 900 patients were randomized in the study, and all received the study treatment. All patients also received sodium warfarin (dose adjusted according to prothrombin time to achieve an INR 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 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 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, in combination with acetylsalicylic acid (100–325 mg once daily), either sodium enoxaparin 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 up to 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 combined incidence of angina, myocardial infarction, and death from 19.8% to 16.6% (relative risk reduction of 16.2%) by day 14. This reduction in combined incidence was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).

There were no statistically significant differences in the incidence of major bleeding, although injection site hemorrhages 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 subcutaneous administration of 100 IU/kg (1 mg/kg) and subsequent dosing of 100 IU/kg (1 mg/kg) subcutaneously 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 elderly patients (≥75 years). Subcutaneous injections of sodium enoxaparin were continued until hospital discharge or for a maximum of 8 days (whichever occurred earlier).

Percutaneous coronary intervention (PCI) was performed in 4716 patients, with antithrombotic support maintained using the study drugs in a blinded manner. Thus, patients receiving sodium enoxaparin underwent PCI while continuing sodium enoxaparin (without switching to the comparator drug), following a regimen studied in previous trials: no additional enoxaparin was administered if the last subcutaneous dose had been given less than 8 hours before balloon inflation; an intravenous bolus of sodium enoxaparin 30 IU/kg (0.3 mg/kg) was administered if the last subcutaneous dose had been 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 vs. 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 at 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 compared to UFH were observed in patients who underwent PCI within 30 days after randomization (23% relative risk reduction) and in those managed with medical therapy alone (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 overall clinical benefit), at 30 days was statistically 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 statistically 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 positive impact of sodium enoxaparin treatment on the primary endpoint observed during the first 30 days was sustained throughout the 12-month follow-up period.

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

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

Various doses, dosage forms, and administration regimens can 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 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 by immediate subcutaneous dosing 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 the mean exposure corresponded to 88% of steady-state levels. Steady state was achieved by day 2 of treatment.

After multiple subcutaneous administration using 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 using the regimen of 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 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 using regimens of 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, resulting in 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 of 150 IU/kg (1.5 mg/kg).

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

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 not impaired.

However, since renal function may decrease 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, a reduction in 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 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. Exposure to anti-Xa activity, expressed as AUC (area under the concentration-time curve), increased markedly at steady state in patients with mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–50 mL/min) renal impairment 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 for use").

Hemodialysis. The pharmacokinetics of sodium enoxaparin during hemodialysis were similar to those in the control group after single intravenous administration 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 of 150 IU/kg (1.5 mg/kg) once daily, mean steady-state anti-Xa AUC was slightly higher in healthy volunteers with obesity (BMI 30–48 kg/m²) compared to the control group without obesity, whereas peak plasma anti-Xa activity did not increase. In obese individuals, subcutaneous administration resulted in lower clearance after correction for body weight.

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

Pharmacokinetic interactions. No pharmacokinetic interactions were 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 primates.

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 administration of enoxaparin 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 when administered subcutaneously at doses up to 20 mg/kg/day.

Clinical characteristics.

Indications.

The drug is indicated for use in adults for:

• Prophylaxis of venous thromboembolic complications in surgical patients with moderate and high risk, especially in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases.
• Prophylaxis of venous thromboembolic complications in medical patients with acute 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.
• 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 medical treatment or subsequent percutaneous coronary intervention (PCI).

Contraindications.

Sodium enoxaparin is contraindicated in patients with the following conditions:

• Hypersensitivity to sodium enoxaparin, heparin or its derivatives, including other low-molecular-weight heparins, or to any of the excipients 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 instructions").
• 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 abnormalities of intraspinal or intracerebral vessels.
• Spinal or epidural anesthesia or locoregional anesthesia if sodium enoxaparin has been administered for treatment within the previous 24 hours (see section "Special instructions").
• Due to the presence of benzyl alcohol, the multidose vial formulation should not be administered to neonates or premature infants.

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 instructions"). Some agents affecting hemostasis should be discontinued prior to initiating enoxaparin sodium treatment, except when such agents are absolutely indicated. If such combination is necessary, enoxaparin sodium should be administered 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 "Dosage and administration").

Medicinal products requiring cautious concomitant use.

• Other medicinal products affecting hemostasis, such as:
  • platelet aggregation inhibitors, including acetylsalicylic acid used at antiplatelet dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome, due to the risk of bleeding;
  • dextran 40;
  • systemic glucocorticoids.
• Medicinal products that increase serum potassium levels may be administered concomitantly with sodium enoxaparin with careful clinical and laboratory monitoring (see sections "Special instructions" and "Side effects").

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., antithrombotic activity, interaction with platelets).

Therefore, particular attention must be paid to the instructions for medical use specific to each proprietary medicinal product, and these must be strictly followed.

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

The use of enoxaparin sodium in patients with a history of immune-mediated HIT within the past 100 days in the presence of circulating antibodies is contraindicated (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 only be made after careful assessment of the benefit-risk ratio and after considering the possibility of using alternative non-heparin anticoagulant agents (e.g., danaparoid sodium or lepirudin).

Platelet monitoring.

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

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

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

If clinical symptoms suggestive of HIT occur (any new episode of arterial and/or venous thromboembolism, any painful skin 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 immediately to their physician.

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 at any site may occur. 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 development of diabetic retinopathy;
• surgery on the nervous system or eyes;
• concomitant use of medicinal products affecting hemostasis (see section "Interaction with other medicinal products and other forms of interaction").

Laboratory tests.

Enoxaparin sodium, when used at doses recommended for prevention 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. 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 to monitor enoxaparin sodium activity.

Use during spinal/epidural anesthesia or lumbar puncture.

Spinal/epidural anesthesia or lumbar puncture should 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 anesthesia or spinal puncture, leading to long-term or permanent paralysis. These events are rare when enoxaparin sodium is used at a regimen of 4000 IU (40 mg) once daily or at lower doses. The risk of such events is higher when postoperative continuous epidural catheters are used, with concomitant use of other medicinal products affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs), following traumatic or repeated epidural or spinal procedures, or in patients with a history of spinal surgery or spinal deformities.

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

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

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

Procedures of percutaneous coronary intervention. To minimize the risk of bleeding following invasive vascular procedures in the treatment of unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), and acute ST-segment elevation myocardial infarction (STEMI), recommended intervals between doses of enoxaparin sodium 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 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 be administered no earlier than 6−8 hours after removal of the introducer. The catheter insertion site should be monitored for early detection of signs of bleeding or hematoma formation.

Acute infective endocarditis. The use of heparin 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 heart valve thrombosis have been reported in patients receiving enoxaparin sodium for thromboprophylaxis. The presence of contributing risk factors, including underlying disease and limited clinical data, limits the assessment of these cases. In some of these cases observed in pregnant women, thrombosis resulted in fatal outcomes for both mother and fetus.

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 study where pregnant women with mechanical heart valves received enoxaparin sodium (100 IU/kg [1 mg/kg] twice daily) to reduce the risk of thromboembolic events, two out of eight women developed blood clots leading to valve obstruction and fatal outcomes for both mother and fetus. Post-marketing reports have included isolated cases of valve thrombosis in pregnant women with mechanical heart valves receiving enoxaparin sodium for thromboprophylaxis. Pregnant women with mechanical heart valves may have an increased risk of thromboembolic events.

Elderly patients. When used in the prophylactic dose range, no increased bleeding tendency has been observed in elderly patients. However, in elderly patients (especially those aged 80 years and older), the risk of hemorrhagic complications may be increased when the drug is used at therapeutic doses. For patients aged 75 years and older receiving treatment for ST-segment 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 use in patients with end-stage renal disease (creatinine clearance <15 mL/min) due to lack of adequate data in this population, except for prevention of clot formation in the extracorporeal circuit during hemodialysis.

For patients with severe renal impairment (creatinine clearance 15−30 mL/min), dose adjustment of enoxaparin sodium is recommended for both therapeutic and prophylactic use due to significantly increased 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 an increased risk of bleeding. Dose adjustment based on anti-Xa activity monitoring is unreliable in patients with liver cirrhosis and is not recommended (see section "Pharmacokinetics").

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

Obese patients. Obese patients have an increased risk of thromboembolic events. The safety and efficacy of prophylactic doses of enoxaparin sodium in obese patients (BMI >30 kg/m²) have not been sufficiently studied, and there is currently no consensus on whether dose adjustment is necessary in this patient group. These patients should be closely monitored for possible signs and symptoms of thromboembolism.

Hyperkalemia. Heparins may suppress aldosterone secretion in the adrenal glands, leading to hyperkalemia (see section "Side effects"), particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, or those receiving medicinal products 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.

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

Intravenous administration of benzyl alcohol has been associated with serious adverse reactions and fatal outcomes in neonates ("Gasping syndrome") (see section "Contraindications"). The minimal 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 an increased risk of accumulation.

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

Sodium

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

Acute generalized exanthematous pustulosis (AGEP)

Acute generalized exanthematous pustulosis (AGEP) has been reported with unknown frequency during enoxaparin therapy. When prescribing this medicinal product, patients should be informed about the signs and symptoms, and skin reactions should be closely monitored. If signs or symptoms suggestive of such reactions occur, enoxaparin should be discontinued immediately and alternative treatment considered (if necessary).

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

Use during pregnancy or breastfeeding

Pregnancy. There is no evidence in humans 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 signs of fetotoxicity or teratogenicity. Experimental data in animals indicate minimal placental transfer of enoxaparin.

Enoxaparin sodium should be administered to pregnant women 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 should be informed about the risk of hemorrhagic events. Overall, available data suggest no evidence of increased risk of bleeding, thrombocytopenia, or osteoporosis in such patients 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, it is recommended to discontinue enoxaparin sodium therapy prior to the procedure (see section "Special precautions for use").

Since benzyl alcohol can cross the placenta, it is recommended to use NOVOPARIN® in pre-filled syringes that do not contain this excipient.

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 during 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 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.

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 (score).

• For patients with moderate risk of thromboembolic events, the recommended dose of sodium enoxaparin is 2000 IU (20 mg) once daily administered by subcutaneous (SC) 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 surgical procedures associated with moderate risk.

In patients at moderate risk, prophylactic treatment with sodium enoxaparin should be continued 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 events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered by subcutaneous (SC) injection 12 hours before surgery. If prophylactic use of sodium enoxaparin needs to be initiated more than 12 hours before surgery (e.g., 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, prolonged thromboprophylaxis is recommended—up to 5 weeks.
• For patients at high risk of venous thromboembolism (VTE) undergoing abdominal or pelvic surgery for oncological diseases, prolonged 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 SC 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 been established.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Sodium enoxaparin should be administered SC as an injection of 150 IU/kg (1.5 mg/kg) once daily or as injections 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 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 thrombosis of proximal veins (iliac vein).

Sodium enoxaparin should be 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).

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 injected 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 longer-than-usual 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 SC 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.

• All uncomplicated patients should receive oral acetylsalicylic acid 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 treatment of acute STEMI, the recommended dose of sodium enoxaparin is a single intravenous (IV) bolus of 3000 IU (30 mg) plus a dose of 100 IU/kg (1 mg/kg) SC, followed by 100 IU/kg (1 mg/kg) SC every 12 hours (maximum 10,000 IU [100 mg] for each of the first two SC doses). Appropriate antiplatelet therapy, such as 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 with thrombolytic therapy (fibrin-specific or non-fibrin-specific), sodium enoxaparin should be administered between 15 minutes before and 30 minutes after the start of fibrinolytic therapy.

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

• For patients undergoing PCI, if the last dose of sodium enoxaparin was administered SC less than 8 hours before balloon inflation, no additional doses are required. If the last SC dose was administered more than 8 hours before balloon inflation, an IV bolus of 30 IU/kg (0.3 mg/kg) of sodium enoxaparin should be administered.

Pediatric patients. 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 in elderly patients is not required, except in cases of renal impairment (see below "Renal impairment" and section "Special precautions").

For treatment of STEMI in elderly patients (≥75 years), the initial IV bolus should not be administered. Treatment should begin with a dose of 75 IU/kg (0.75 mg/kg) SC every 12 hours (maximum 7500 IU [75 mg] for each of the first two SC doses), followed by continued administration at 75 IU/kg (0.75 mg/kg) SC for subsequent doses. Dosage specifics for elderly patients with renal impairment are provided below in the subsection "Renal impairment" and 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.

Dosage for patients with severe renal impairment (creatinine clearance 15–30 mL/min)

Table 1

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

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

Route of administration. Novoparin® must not be administered intramuscularly.

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

• For the treatment of acute STEMI, administration of the drug should begin with a single intravenous 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.

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

Technique of subcutaneous injection.

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

To avoid loss of drug when using prefilled syringes, air bubbles should not be expelled from the syringe before injection. If it is necessary to adjust the amount of drug to be administered according to the patient’s body weight, graduated prefilled syringes should be used, which allow the required volume to be obtained by removing the excess before injection. It should be noted that in some cases it may not be possible to obtain the exact dose due to the nature of the syringe graduations, and in such cases the volume should be rounded to the nearest graduation mark.

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

The needle should be inserted fully in a vertical direction into a skin fold gently held between the thumb and index finger. The skin fold should be maintained until the injection is completed. The injection site should not be massaged after administration.

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 intravenous bolus injection followed immediately by subcutaneous administration.

For intravenous injection, either a multidose vial or a prefilled syringe may be used.

Sodium enoxaparin should be administered through an intravenous infusion system. It must not be mixed or co-administered with other medicinal products. To avoid possible mixing of sodium enoxaparin with other medicinal products, the selected intravenous access must be flushed with an adequate amount of 0.9% sodium chloride solution or glucose solution before and after administration of the sodium enoxaparin bolus 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 prefilled syringe, the excess volume should be removed from the syringe so that only 3000 IU (30 mg) remains in the syringe. The dose of 3000 IU (30 mg) can then be administered directly intravenously.

Additional bolus For patients undergoing PCI, an additional intravenous bolus of 30 IU/kg (0.3 mg/kg) should be administered if the last subcutaneous dose of the drug 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 into the intravenous infusion system.

To prepare a solution of 300 IU/ml (3 mg/ml) using a 6000 IU (60 mg) prefilled syringe of sodium enoxaparin, it is recommended to use a 50 ml infusion bag (i.e., 0.9% sodium chloride solution (9 mg/ml) 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) prefilled syringe of sodium enoxaparin should be added to the bag containing the remaining 20 ml. The contents of the bag should be gently mixed. Then the required volume of the diluted solution should be drawn into a syringe for administration into the intravenous 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 2. Dilution should be performed immediately before administration of the drug.

Volume to be administered through the intravenous infusion system after dilution of the drug to a concentration of 300 IU (3 mg)/ml.

Table 2

Administration into the arterial part of the dialysis circuit. The drug should be 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 and laboratory monitoring [prothrombin time expressed as international normalized ratio (INR)] should be intensified to monitor the effect of VKAs.

Since there is a certain period required for VKAs to reach their maximum effect, administration of sodium enoxaparin at a constant dose should be continued as long as necessary to maintain the INR within the target therapeutic range for the corresponding indication, 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 instructions for medical use of each DOAC) before the time of the next scheduled dose of sodium enoxaparin.

In patients currently receiving DOACs, the first dose of sodium enoxaparin should be administered at the time when the next dose of DOAC was 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 neuraxial hematoma (see section "Special precautions").

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

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

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

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

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

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

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

Patients receiving the drug according to a regimen of twice-daily dosing (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 levels of the drug are still detectable, and adherence to these 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 an individual benefit-risk assessment, taking into account both the risk of thrombosis and the risk of bleeding associated with the procedure and the patient-specific risk factors.

Children.

The safety and efficacy of sodium enoxaparin in pediatric patients have not been established. The medicinal product contains benzyl alcohol and should not be used in neonates and preterm infants (see section "Contraindications").

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 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 prior to protamine administration or if a second dose of protamine is required.

• Administration of protamine may not be necessary 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 approximately 60%) (see Instructions for medical use of protamine salts).

Adverse Reactions

General description of the drug safety profile. More than 15,000 patients received enoxaparin sodium in clinical trials. Among them were 1,776 cases of enoxaparin sodium use for prophylaxis of deep vein thrombosis following orthopedic or abdominal surgery in patients at high risk of thromboembolic complications; 1,169 cases of enoxaparin sodium use for prophylaxis of deep vein thrombosis in patients with acute medical conditions and severely limited mobility; 559 cases of enoxaparin sodium use for treatment of deep vein thrombosis with or without pulmonary embolism; 1,578 cases of enoxaparin sodium use for treatment of unstable angina and non-Q-wave myocardial infarction; and 10,176 cases of enoxaparin sodium use for treatment of acute ST-segment elevation myocardial infarction.

Dosing regimens of enoxaparin sodium in these clinical trials varied depending on the indication. The dose of enoxaparin sodium for prophylaxis of deep vein thrombosis following surgery or in patients with acute medical conditions and severely limited mobility was 4000 IU (40 mg) subcutaneously once daily. For 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 evaluating enoxaparin sodium for treatment of unstable angina and non-Q-wave myocardial infarction, the dose was 100 IU/kg (1 mg/kg) subcutaneously every 12 hours. In the clinical trial evaluating enoxaparin sodium for treatment of acute ST-segment elevation myocardial infarction, the regimen included an initial intravenous bolus of 3000 IU (30 mg), followed by subcutaneous administration of enoxaparin sodium 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 Warnings and Precautions for Use" and "Description of Selected Adverse Reactions" below).

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 categories are 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" category, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders.

Common: hemorrhagic events, hemorrhagic anemia*, thrombocytopenia, thrombocytosis.
Rare: cases of immune-mediated heparin-induced thrombocytopenia with thrombosis; in some of these cases, thrombosis was complicated by organ infarction or limb ischemia (see section "Special Warnings and Precautions for Use").
Rare: eosinophilia*.

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 Warnings and 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*, typically occurring at the injection site (these events are usually preceded by purpura or erythematous, infiltrated, and painful plaques). Injection site nodules* (inflammatory nodules representing non-cystic "pockets" of enoxaparin), which resolve within several days and do not require discontinuation of the drug.
Frequency not known: acute generalized exanthematous pustulosis (AGEP).

Musculoskeletal, connective tissue and bone disorders.

Rare: osteoporosis* after prolonged therapy (longer 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, pain, or other reactions).
Uncommon: local irritation, skin necrosis at injection site.

Investigations.

Rare: hyperkalemia* (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interactions").

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 clinically significant event, or if it was associated with a hemoglobin decrease ≥ 2 g/dL or required transfusion of two 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 potential for bleeding, invasive procedures, or concomitant use of medicinal products affecting hemostasis (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interactions").

Table 3

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

Thrombocytopenia and thrombocytosis

Table 4

β Increase in platelet count > 400 G/L.

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

Intravenous administration of benzyl alcohol is associated with serious adverse reactions and fatal outcomes in neonates ("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 of adverse reactions after marketing authorization is of significant importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

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

Recommended shelf life after first opening of the vial. Chemical and physical in-use stability 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. Any other storage period and conditions are the responsibility of the user.

Recommended shelf life after dilution. After dilution with 0.9 % sodium chloride solution or 5 % glucose solution. Chemical and physical in-use stability 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 diluted solution should be used immediately after preparation. If the solution is not used immediately, any other storage period and conditions are the responsibility of the user.

Storage conditions.

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

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

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

Packaging.

1 or 5 multidose vials of 3 mL or 5 mL in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shenzhen Techdow Pharmaceutical Co. Ltd.

Manufacturer's address and location of its operations.

No. 19 Gaoxinzhongyi Road, Nanshan District, Shenzhen, 518057, China.