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 10000 IU, equivalent to 100 mg of enoxaparin sodium;

2000 anti-factor Xa IU / 0.2 ml, equivalent to 20 mg of enoxaparin sodium;

4000 anti-factor Xa IU / 0.4 ml, equivalent to 40 mg of enoxaparin sodium;

6000 anti-factor Xa IU / 0.6 ml, equivalent to 60 mg of enoxaparin sodium;

8000 anti-factor Xa IU / 0.8 ml, equivalent to 80 mg of enoxaparin sodium;

10000 anti-factor Xa IU / 1.0 ml, equivalent to 100 mg of enoxaparin sodium;

Excipient: 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 during preclinical studies. These include ATIII-dependent inhibition of other coagulation factors such as factor VIIa, induction of endogenous release of tissue factor pathway inhibitor (TFPI), and reduction of von Willebrand factor (vWF) release from vascular endothelium into the circulation. These mechanisms contribute to the overall antithrombotic effect of enoxaparin sodium.

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

Clinical efficacy and safety.

Prevention of venous thromboembolic complications associated with surgical procedures.

Extended prophylaxis of venous thromboembolism (VTE) following orthopedic surgery. In a double-blind study on extended prophylaxis after 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 hospital discharge to receive either enoxaparin sodium 4000 IU (40 mg) (n = 90) once daily s.c. or placebo (n = 89) for 3 weeks. The incidence of deep vein thrombosis (DVT) during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to the placebo group; no cases of pulmonary embolism (PE) were recorded. No major bleeding events occurred.

Efficacy data are presented in Table 1.

Table 1

In another double-blind study, 262 patients without any history of venous thromboembolism undergoing elective hip replacement surgery and initially receiving enoxaparin sodium 4000 IU (40 mg) subcutaneously once daily during hospitalization were randomized after hospital discharge to receive either enoxaparin sodium 4000 IU (40 mg) (n = 131) subcutaneously once daily or placebo (n = 131) for

3 weeks. Similar to the results of the first study, the incidence of VTE with extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared to placebo, both in terms of total VTE (enoxaparin sodium – 21 [16%] vs. placebo – 45 [34.4%]; p = 0.001) and proximal deep vein thrombosis (DVT) (enoxaparin sodium – 8 [6.1%] vs. placebo – 28 [21.4%]; p < 0.001). There were no differences in the frequency of major bleeding between the enoxaparin sodium and placebo groups.

Extended prophylaxis of DVT following surgery for oncological diseases.

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

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

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

Overall, 1102 patients were enrolled in the study, and 1073 patients received the study treatment. The duration of treatment ranged from 6 to 14 days (median duration was 7 days). Enoxaparin sodium administered at a dose of 4000 IU (40 mg) subcutaneously once daily 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 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 receive either in-hospital treatment with enoxaparin sodium at a dose of 150 IU/kg (1.5 mg/kg) once daily subcutaneously; or enoxaparin sodium at a dose of 100 IU/kg (1 mg/kg) every 12 hours subcutaneously; or heparin as an intravenous bolus (5000 IU) followed by continuous intravenous infusion (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 with the aim of achieving 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 with sodium warfarin. 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 frequency of major bleeding was 1.7% in the group receiving sodium enoxaparin 150 IU/kg (1.5 mg/kg) once daily, 1.3% in the group receiving sodium enoxaparin 100 IU/kg (1 mg/kg) twice daily, and 2.1% in the heparin group.

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 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 the combined endpoint was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).

There were no statistically significant differences in the frequency of major bleeding, although injection site hemorrhages occurred more frequently.

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

In 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 first.

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

Compared with UFH, sodium enoxaparin significantly reduced the rate of the primary endpoint—a composite of all-cause mortality and recurrent myocardial infarction—during the first 30 days after randomization [9.9% in the sodium enoxaparin group vs. 12.0% in the UFH group], 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 rate of the composite endpoint of 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.

The frequency 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%). Gastrointestinal bleeding occurred more frequently in the sodium enoxaparin group (0.5%) than in the heparin group (0.1%), while the rates of intracranial hemorrhage were 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 the 12-month follow-up period.

Hepatic impairment. According to literature data, 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 is advised in patients with hepatic impairment, as they are more prone to bleeding (see section "Special precautions"), and no formal dose-finding studies have been conducted in patients with 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 its effect on 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 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 intravenous bolus administration of 3000 IU (30 mg) 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 dosing 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 dosing at 100 IU/kg (1 mg/kg) twice daily, steady state was achieved between days 3 and 4, with mean exposure approximately 65% higher than after single-dose administration, and mean peak and trough anti-Xa activity levels of approximately 1.2 and 0.52 IU/mL, respectively.

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

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

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

Plasma anti-IIa activity after subcutaneous administration is approximately 10 times lower than anti-Xa activity. Mean peak anti-IIa activity occurs approximately 3–4 hours after subcutaneous injection, reaching 0.13 IU/mL and 0.19 IU/mL after multiple dosing 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 mean plasma anti-Xa clearance of 0.74 L/h after a 6-hour infusion at 150 IU/kg (1.5 mg/kg).

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

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

Special patient groups.

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

However, since renal function may decline with age, lower elimination rates of sodium enoxaparin may be observed in elderly patients (see 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 dysfunction (assessed by Child-Pugh classification). This reduction was primarily explained by decreased ATIII levels, secondary to reduced ATIII synthesis in patients with hepatic impairment.

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

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

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

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

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 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 chromosomal aberration tests in human lymphocytes and in vivo chromosomal aberration tests in rat bone marrow.

Studies in pregnant rats and rabbits receiving subcutaneous enoxaparin at doses up to 30 mg/kg/day showed no evidence of teratogenic or fetotoxic effects. 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:

• 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.
• Prevention 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 clot 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 therapy 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.
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 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 ulceration, presence of malignant tumors with a high risk of bleeding, 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 used for treatment within the previous 24 hours (see section "Special precautions").

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 therapy, except when such agents are absolutely indicated. If such combination is indicated, enoxaparin sodium should be administered with careful clinical and laboratory monitoring.

These include:

• Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and 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 that should be used concomitantly with caution.

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

Special precautions.

General warnings.

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

Therefore, it is essential to pay close attention to the instructions for medical use specific to each brand-name product and to strictly follow them.

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

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

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

Platelet monitoring.

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

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

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

If clinical symptoms suggestive of HIT occur (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, or any allergic or anaphylactoid reactions during treatment), platelet counts must be measured. Patients should be informed about these potential 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) occurs, sodium enoxaparin must be discontinued immediately and the patient switched to an alternative non-heparin anticoagulant therapy.

Bleeding events.

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

Sodium enoxaparin, like any other anticoagulant, should be used with caution in conditions associated with an increased risk of bleeding, such as:

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

Laboratory tests.

Sodium enoxaparin, when used at doses 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. However, since there is no linear correlation between the increase in aPTT and ACT and the antithrombotic activity of sodium enoxaparin, these parameters are unreliable and should not be used for monitoring the activity of sodium enoxaparin.

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 sodium enoxaparin (see also section "Contraindications").

Cases of neuroaxial hematomas have been reported with concomitant use of sodium enoxaparin and spinal/epidural anesthesia or spinal puncture, leading to long-term or irreversible paralysis. These events are rare when sodium enoxaparin is used at a dose 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), with traumatic or repeated epidural or spinal procedures, or in patients with a history of spinal surgery or spinal deformities.

To minimize the potential risk of bleeding associated with concomitant use of sodium enoxaparin and spinal/epidural anesthesia/analgesia or lumbar puncture, the pharmacokinetic profile of sodium enoxaparin 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 sodium enoxaparin is low. However, the exact time to achieve a sufficiently low anticoagulant effect in individual patients is unknown. It should also be noted that elimination of sodium enoxaparin is prolonged in patients with creatinine clearance of 15−30 mL/min (see section "Method of administration and dosage").

If the physician decides to use anticoagulant therapy during spinal/epidural anesthesia/analgesia or lumbar puncture, frequent monitoring is required to detect any symptoms of neurological disorders, such as midline back pain, sensory or motor disturbances (numbness or weakness in the lower limbs), or bowel and/or bladder dysfunction. Patients should be instructed to immediately report any of these symptoms to their physician. If a spinal hematoma is suspected, immediate 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.

Procedures of percutaneous coronary revascularization. To minimize the risk of bleeding after invasive vascular procedures in the treatment of unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and acute ST-elevation myocardial infarction (STEMI), recommended intervals between doses of sodium enoxaparin 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 injection of sodium enoxaparin. If sodium enoxaparin treatment is to be continued, the next scheduled dose should be administered no earlier than 6−8 hours after removal of the introducer. The puncture site should be monitored for early detection 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 a careful individual benefit-risk assessment.

Mechanical heart valves. The use of sodium enoxaparin 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 sodium enoxaparin for thromboprophylaxis. The presence of factors that may contribute to additional risk, including underlying disease and insufficient clinical data, limits the evaluation of these cases. In some of these cases observed in pregnant women, valve thrombosis led to maternal and fetal death.

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

Elderly patients. When used at prophylactic dose ranges, no increased tendency to bleeding 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 over 75 years of age receiving treatment with the drug for ST-elevation myocardial infarction (STEMI), careful clinical monitoring is recommended, and dose reduction may be considered (see sections "Method of administration and dosage" and "Pharmacokinetics").

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

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

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

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

Low body weight. Increased exposure to sodium enoxaparin administered at prophylactic doses (without body weight adjustment) has been observed in women with low body weight (< 45 kg) and men with low body weight (< 57 kg), 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 the drug in obese patients (BMI > 30 kg/m²) have not been sufficiently studied, and there is currently no consensus on the need for dose adjustment in this patient group. These patients should be closely monitored for possible 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, existing metabolic acidosis, and in patients 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.

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

Acute generalized exanthematous pustulosis (AGEP).

Cases of acute generalized exanthematous pustulosis (AGEP) of unknown frequency have been reported during treatment with enoxaparin. When prescribing this medicinal product to patients, signs and symptoms should be communicated and skin reactions should be closely monitored. If signs and symptoms suggestive of these reactions appear, enoxaparin should be discontinued immediately and alternative treatment considered (if necessary).

Use during pregnancy or breastfeeding

Pregnancy. In humans, there is no evidence 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. Data from animal experiments indicate that placental transfer of enoxaparin is minimal.

Sodium enoxaparin should be administered to pregnant women only if a clear medical need has been established by the physician.

Pregnant women receiving sodium enoxaparin 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 indicate 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").

If epidural anesthesia is planned, it is recommended to discontinue sodium enoxaparin treatment prior to the procedure (see section "Special precautions").

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

Oral absorption of sodium enoxaparin is unlikely; therefore, it may be used during breastfeeding.

Fertility. Clinical data on the effect of sodium enoxaparin on fertility are currently lacking. Animal studies have not demonstrated any effect of the drug on fertility.

Ability to affect reaction speed when driving vehicles or operating machinery.

The effect of sodium enoxaparin on the ability to drive vehicles 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 (scale).

• For patients at moderate risk of thromboembolic events, the recommended dose of sodium enoxaparin is 2000 IU (20 mg) once daily administered by subcutaneous (s.c.) injection. Preoperative 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 continue for a period of at least 7–10 days, regardless of recovery status (e.g., mobility). Prophylaxis should be continued until the patient no longer exhibits significantly reduced mobility.

• For patients at high risk of thromboembolic events, the recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily, preferably administered 12 hours before surgery by subcutaneous (s.c.) injection. 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 conditions, 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 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 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 hemorrhagic risk. The once-daily regimen of 150 IU/kg (1.5 mg/kg) is recommended for uncomplicated patients at low risk of recurrent VTE. The twice-daily regimen of 100 IU/kg (1 mg/kg) should be prescribed for all other patients, including those with obesity, symptomatic PE, cancer, recurrent VTE, or proximal venous thrombosis (iliac vein).

Sodium enoxaparin is typically administered for an average of 10 days. If necessary, oral anticoagulants should be initiated (see "Transition from sodium enoxaparin to oral anticoagulants and vice versa" 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 hemorrhagic events, the dose should be reduced to 50 IU/kg (0.5 mg/kg) with dual vascular access or to 75 IU/kg (0.75 mg/kg) with single vascular access.

During hemodialysis, sodium enoxaparin should be administered into the arterial limb of the circuit at the beginning of the dialysis session. This dose is generally sufficient for a 4-hour dialysis session. However, if fibrin rings occur, for example, during 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 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.
• All uncomplicated patients should receive oral acetylsalicylic acid with an initial loading dose of 150–300 mg (for patients not already on acetylsalicylic acid) and a maintenance dose of 75–325 mg/day long-term, regardless of treatment strategy.
• For treatment of acute STEMI, the recommended dose of sodium enoxaparin is a single intravenous (i.v.) bolus of 3000 IU (30 mg) plus a s.c. dose of 100 IU/kg (1 mg/kg), followed by s.c. administration of 100 IU/kg (1 mg/kg) every 12 hours (maximum 10000 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 start of fibrinolytic therapy.
• Dosage specifics for patients aged ≥75 years are provided below ("Elderly patients").
• For patients undergoing PCI, if the last s.c. dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional dose is required. If the last s.c. dose was given more than 8 hours before balloon inflation, an i.v. bolus of 30 IU/kg (0.3 mg/kg) of sodium enoxaparin should be administered.

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

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

For treatment of STEMI, elderly patients (≥75 years) should not receive the initial i.v. bolus. 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 s.c. administration of 75 IU/kg (0.75 mg/kg) for subsequent doses. Dosage specifics for elderly patients with renal impairment are provided below in the subsection "Ren/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 circulation during hemodialysis.

Table 1.

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

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

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

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

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

Technique for subcutaneous injection.

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

To avoid loss of medication when using pre-filled syringes, air bubbles should not be expelled from the syringe before injection. If dose adjustment according to patient's body weight is required, graduated pre-filled syringes should be used, allowing the required volume to be obtained by removing the excess before injection. Note that in some cases it may not be possible to achieve 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 vertically along its full length into a skin fold gently held between the thumb and index finger. The skin fold must be held throughout the injection until completion. The injection site should not be massaged after administration.

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

If the patient is self-administering the drug, he or she should be advised to follow the instructions for self-administration of Novoparin® from a pre-filled syringe.

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 (i.v.) bolus injection, followed immediately by subcutaneous (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 drugs, the selected i.v. access must 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 medicinal products. 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 must be expelled from the syringe so that only 3000 IU (30 mg) remains. The 3000 IU (30 mg) dose 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) is required if the last s.c. dose was administered more than 8 hours before balloon inflation.

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

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

After dilution, the volume to be administered can be calculated using the following formula: [Volume of diluted solution (mL) = Patient's body weight (kg) × 0.1] or by using Table 2. Dilution should be performed immediately before drug administration.

Table 2.

Volume to be administered through the 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 clot formation in the extracorporeal blood circuit 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 period required for VKAs to reach their maximum effect, administration of sodium enoxaparin at a constant dose should be continued for as long as necessary to maintain the INR within the target therapeutic range for the corresponding indication, based on results of two consecutive tests.

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 next scheduled dose of sodium enoxaparin is due.

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

Use of the drug in spinal/epidural anesthesia or lumbar puncture. If the physician decides that anticoagulants are necessary for 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 without any puncture procedures should be maintained between the last injection of prophylactic-dose 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 removal of the catheter.

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

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

Use of therapeutic doses. An interval of at least 24 hours without any puncture procedures should be maintained between the last injection of therapeutic-dose 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 removal of the catheter.

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

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

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

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

Instructions for self-administration of Novoparin® in pre-filled syringes

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

1. Change the injection site by alternating between the right and left sides of the abdomen, depending on where the previous injection was administered. Clean the injection site with an alcohol swab.

1. Carefully remove the needle cap from the syringe pre-filled with Novoparin®. Discard this cap. The syringe is pre-filled and ready for use. DO NOT press the plunger before administering the injection to expel air bubbles. This may result in loss of medication. After removing the cap, avoid contact of the needle with any surface to ensure sterility.

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

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

1. Press the syringe plunger with your finger. Maintain the skin fold throughout the injection.
2. Remove the needle by pulling it straight back. You may now release the skin fold. Immediately discard the syringe into the nearest sharps container.

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

Children.

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

Overdose.

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

Treatment. The anticoagulant effects of the drug can be largely neutralized by slow intravenous administration of protamine. The dose of protamine depends on the 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.
• Infusion of protamine 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 previously, or if a second dose of protamine is required.
• Administration of protamine more than 12 hours after sodium enoxaparin may not be necessary.

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. Enoxaparin sodium has been studied in more than 15,000 patients who received enoxaparin sodium in clinical trials. Among them, there were 1,776 cases of drug use for the prevention of deep vein thrombosis after orthopedic or abdominal surgery in patients at increased risk of thromboembolic complications, 1,169 cases of drug use for the prevention of deep vein thrombosis in patients with acute medical conditions and severely limited mobility, 559 cases of drug use for the treatment of deep vein thrombosis with or without pulmonary embolism, 1,578 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.

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 severely 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 at a dose of 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, and 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 initial 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 section "Special 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 was defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data). Within each "System-Organ-Class" category, adverse reactions are listed in order of decreasing severity.

Disorders of the blood and lymphatic system.

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

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

Uncommon: hepatocellular liver injury*.

Rare: cholestatic liver injury*.

Skin and subcutaneous tissue disorders.

Common: urticaria, pruritus, erythema.

Uncommon: bullous dermatitis.

Rare: alopecia*, skin vasculitis*, skin necrosis*, which usually occurs at the injection site (these events are typically preceded by purpura or erythematous, infiltrated, and painful plaques). Nodules at the injection site* (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 prolonged therapy (more than 3 months).

General disorders and administration site conditions.

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

Uncommon: local irritation, skin necrosis at injection site.

Investigations.

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

Description of selected adverse reactions.

Hemorrhagic events. Serious hemorrhagic events were observed and reported in no more than 4.2% of patients (surgical patients). Some of these cases were fatal. In surgical patients, hemorrhagic complications were considered serious if the hemorrhagic event caused a significant clinical event or 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 potential risk of bleeding, invasive procedures, or concomitant use of medicinal products affecting hemostasis (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Table 3.

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

Table 4.

Thrombocytopenia and thrombocytosis

β Increase in platelet count > 400 G/L.

Pediatric population. The safety and efficacy of sodium enoxaparin in children have not yet been established (see section “Dosage and administration”).

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

Shelf life. 3 years.

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

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C, in a place inaccessible to children. Do not freeze.

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

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

Packaging.

Injection solution 100 mg/mL: 20 mg/0.2 mL; or 40 mg/0.4 mL; or 60 mg/0.6 mL; or 80 mg/0.8 mL; or 100 mg/1.0 mL in pre-filled syringes, pack of 2 in blister within a cardboard box; or 20 mg/0.2 mL; or 40 mg/0.4 mL; or 60 mg/0.6 mL; or 80 mg/0.8 mL in pre-filled syringes, pack of 10, 2 syringes per blister, 5 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Shenzhen Techdow Pharmaceutical Co. Ltd.

Address of manufacturer and location of its operations.

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