Enoxaparin-lekhim

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENOXAPARIN-LEKCHIM (ENOXAPARIN-LEKCHIM)

Composition:

Active substance: enoxaparin;

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

1 pre-filled syringe contains 2000 anti-Xa IU/0.2 ml, equivalent to 20 mg sodium enoxaparin*, or 4000 anti-Xa IU/0.4 ml, equivalent to 40 mg sodium enoxaparin*, or 6000 anti-Xa IU/0.6 ml, equivalent to 60 mg sodium enoxaparin*, or 8000 anti-Xa IU/0.8 ml, equivalent to 80 mg sodium enoxaparin*, or 10,000 anti-Xa IU/1 ml, equivalent to 100 mg sodium enoxaparin*;

Excipient: water for injections.

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

Pharmaceutical form. Solution for injection.

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

Pharmacotherapeutic group. Antithrombotic agents. Heparin group.

ATC code B01AB05.

Pharmacological properties.

Pharmacodynamics.

Enoxaparin is a low molecular weight heparin (LMWH) with an average molecular weight of approximately 4,500 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-factor Xa activity (approximately 100 IU/mg) and low anti-factor IIa or antithrombin activity (approximately 28 IU/mg), with 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 factor activity, additional antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy volunteers, patients, and in preclinical models. These include ATIII-dependent inhibition of other coagulation factors such as factor VIIa, induction of release of endogenous tissue factor pathway inhibitor (TFPI), and reduction of von Willebrand factor (vWF) release from vascular endothelium into circulation. These factors are known to 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 purposes, aPTT may be prolonged 1.5 to 2.2 times longer than the control value at peak activity.

Clinical efficacy and safety

Prevention of venous thromboembolism associated with surgical intervention

Long-term prevention of venous thromboembolism (VTE) following orthopedic surgery. In a double-blind study of long-term prophylaxis after hip replacement surgery, 179 patients without venous thromboembolism who had received initial in-hospital treatment with enoxaparin sodium 4000 IU (40 mg) subcutaneously (s.c.) were randomly assigned after 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 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. There were no major bleeding events observed.

Efficacy data are presented in Table 1.

Table 1

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

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

Extended DVT prophylaxis after oncological surgery

In a double-blind, multicenter study, the safety and efficacy of 4-week versus 1-week enoxaparin sodium prophylaxis were compared in 332 patients who underwent elective surgery for abdominal or pelvic cancer. Patients received enoxaparin sodium (4000 IU (40 mg) s.c.) once daily for 6–10 days, then were randomly assigned to continue either enoxaparin sodium or placebo for an additional 21 days. Bilateral venography was performed on days 25 to 31, or earlier if VTE symptoms occurred. Patients were followed for 3 months. Four weeks of postoperative prophylaxis with enoxaparin sodium after abdominal or pelvic cancer surgery significantly reduced the frequency of venographically confirmed thromboses compared to 1-week prophylaxis with enoxaparin sodium. The VTE rates at the end of the double-blind phase were 12.0% (n = 20) in the placebo group and 4.8% (n = 8) in the enoxaparin sodium group; p = 0.02. This difference persisted at 3 months [13.8% vs. 5.5% (n = 23 vs. 9), p = 0.01]. No differences in bleeding rates or other complications were observed during the double-blind or follow-up phases.

Prophylaxis of VTE in medically ill patients with acute conditions expected to cause limited mobility

In a double-blind, multicenter, parallel-group study, enoxaparin sodium 2000 IU (20 mg) or 4000 IU (40 mg) once daily s.c. was compared to placebo for DVT prophylaxis in medically ill patients with severe mobility limitation during an acute illness (defined as walking distance <10 meters for ≤3 days). Patients with heart failure (NYHA functional class III or IV), acute respiratory failure or complicated chronic respiratory insufficiency, acute infection, or acute rheumatic disease were included, provided they had at least one VTE risk factor (age ≥75 years, active cancer, prior VTE, obesity, varicose veins, hormonal therapy, chronic heart or respiratory failure).

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

Table 2

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

Approximately 3 months after 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 incidence of major and clinically significant bleeding was 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 deep vein thrombosis of the lower limbs, with or without pulmonary embolism, were randomly assigned to receive inpatient (hospital) treatment with either (i) 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 injection (5000 IU) followed by continuous infusion (to achieve an aPTT of 55 to 85 seconds). Overall, 900 patients participated in the study, and all patients received treatment. All patients also received sodium warfarin (dose adjusted according to prothrombin time to achieve an international normalized ratio (INR) of 2.0 to 3.0), initiated within 72 hours after starting enoxaparin sodium or standard heparin therapy, with a total treatment duration of 90 days. Enoxaparin sodium or standard heparin therapy was administered for at least 5 days and until the target INR was achieved on warfarin sodium. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolic events (DVT and/or PE). Efficacy data are presented in Table 3.

Table 3

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

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

Long-term treatment of DVT and PE and prevention of their recurrence in patients with active cancer

In clinical studies involving a limited number of patients, the rate of VTE recurrence in patients receiving enoxaparin once or twice daily for 3–6 months was comparable to that with warfarin.

Effectiveness under real-world conditions was evaluated in a cohort including 4451 patients with symptomatic VTE and active cancer from the multinational RIETE registry of patients with VTE and other thrombotic conditions. Of these, 3526 patients received subcutaneous enoxaparin for 6 months, while 925 patients received subcutaneous tinzaparin or dalteparin.

Among the 3526 patients treated with enoxaparin, 891 patients received initial therapy at a dose of 1.5 mg/kg once daily as initial treatment and continued long-term treatment up to 6 months (once daily only), while 1854 patients initially received 1.0 mg/kg twice daily, followed by 1.5 mg/kg once daily (twice daily – transitioned to once daily) as long-term treatment up to 6 months. The median duration of treatment before regimen change was 17 days and 8 days, respectively. There were no significant differences in the rate of VTE recurrence between the two groups (see Table), and enoxaparin met the predefined criterion for non-inferiority of 1.5 (adjusted hazard ratio, adjusted for relevant covariates, 0.817, 95% CI: 0.499–1.336). There were no statistically significant differences between the two groups in the relative risks of major (fatal or non-fatal) bleeding or all-cause mortality (see Table).

Table 4

Outcome	Enoxaparin sodium n=3526 (%)	Other LMWH n=925 (%)	Adjusted risk ratios enoxaparin / other LMWH [95% confidence interval] (%)
Recurrent VTE	70 (2.0)	23 (2.5)	0.817 [0.499–1.336]
Major bleeding	111 (3.1)	18 (1.9)	1.522 [0.899–2.577]
Minor bleeding	87 (2.5)	24 (2.6)	0.881 [0.550–1.410]
Total mortality	666 (18.9)	157 (17.0)	0.974 [0.813–1.165]

An overview of results according to the treatment regimen used in the RIETECAT study for volunteers who completed the 6-month course is presented below:

Table 5

Outcome N (%) (95% CI)	Enoxaparin sodium all regimens	Enoxaparin sodium all regimens					EU-registered LMWHs
		Enoxaparin sodium once daily	Enoxaparin sodium twice daily	Enoxaparin sodium twice daily – once daily	Enoxaparin sodium once daily – twice daily	Enoxaparin sodium with more than one switch
	N=1432	N=444	N=529	N=406	N=14	N=39	N=428
Recurrent VTE	70 (4.9) (3.8–6.0)	33 (7.4) (5.0–9.9)	22 (4.2) (2.5–5.9)	10 (2.5) (0.9–4.0)	1 (7.1) (0–22.6)	4 (10.3) (0.3–20.2)	23 (5.4) (3.2–7.5)
Major bleeding (fatal and non-fatal)	111 (7.8) (6.4–9.1)	31 (7.0) (4.6–9.4)	52 (9.8) (7.3–12.4)	21 (5.2) (3.0–7.3)	1 (7.1) (0–22.6)	6 (15.4) (3.5–27.2)	18 (4.2) (2.3–6.1)
Clinically relevant non-major bleeding	87 (6.1) (4.8–7.3)	26 (5.9) (3.7–8.0)	33 (6.2) (4.2–8.3)	23 (5.7) (3.4–7.9)	1 (7.1) (0–22.6)	4 (10.3) (0.3–20.2)	24 (5.6) (3.4–7.8)
Death from any cause	666 (46.5) (43.9–49.1)	175 (39.4) (34.9–44.0)	323 (61.1) (56.9–65.2)	146 (36.0) (31.3–40.6)	6 (42.9) (13.2–72.5)	16 (41.0) (24.9–57.2)	157 (36.7) (32.1–41.3)
Death related to fatal PE or fatal bleeding	48 (3.4) (2.4–4.3)	7 (1.6) (0.4–2.7)	35 (6.6) (4.5–8.7)	5 (1.2) (0.2–2.3)	0	1 (2.6) (0–7.8)	11 (2.6) (1.1–4.1)
*All data with 95% CI

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

In a large multicenter study involving 3171 patients during the acute phase of unstable angina and non-Q-wave myocardial infarction, patients were randomly assigned to receive either sodium enoxaparin at a dose of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours or intravenous unfractionated heparin adjusted according to aPTT, in combination with acetylsalicylic acid (100–325 mg once daily). Patients were hospitalized for at least 2 days and up to 8 days until clinical stabilization, revascularization procedures, or hospital discharge. Patient follow-up was planned for up to 30 days. Compared with heparin, sodium enoxaparin significantly reduced the composite incidence of angina, myocardial infarction, and death from 19.8% to 16.6% (relative risk reduction of 16.2%) by day 14. This reduction in the composite endpoint was maintained at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).

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

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

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

Percutaneous coronary intervention (PCI) was performed in 4716 patients with blinded antithrombotic support using the study drugs. Thus, PCI was performed in patients receiving sodium enoxaparin while continuing the same drug, according to the regimen established in previous studies: without additional doses of sodium enoxaparin if the last subcutaneous dose was administered less than 8 hours before balloon inflation, or with an intravenous bolus of sodium enoxaparin at 30 IU/kg (0.3 mg/kg) if more than 8 hours had elapsed since the last subcutaneous dose before balloon inflation.

Compared with unfractionated heparin (UFH), sodium enoxaparin significantly reduced the rate of the primary composite endpoint of all-cause mortality or recurrent myocardial infarction within 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 several efficacy outcomes, were apparent within 48 hours, with a 35% relative reduction in the risk of recurrent myocardial infarction compared to UFH treatment (p<0.001).

The favorable 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 study drug administration.

A significant advantage of sodium enoxaparin treatment over UFH was 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 30-day rate of the composite endpoint of death, recurrent myocardial infarction, or intracranial hemorrhage (a measure of net clinical benefit) was significantly lower (p<0.0001) in the sodium enoxaparin group (10.1%) compared to the heparin group (12.2%), representing a 17% relative risk reduction in favor of sodium enoxaparin treatment.

The rate 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%). Gastrointestinal bleeding occurred more frequently in the sodium enoxaparin group (0.5%) compared to the heparin group (0.1%), while the rate of intracranial hemorrhage was similar in both groups (0.8% in the sodium enoxaparin group vs. 0.7% in the heparin group).

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

Pharmacokinetics.

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

Absorption. The absolute bioavailability of sodium enoxaparin after subcutaneous injection, based on anti-Xa factor activity, is close to 100%.

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

The mean peak plasma anti-Xa factor 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.

An intravenous bolus dose of 3000 IU (30 mg), followed by 100 IU/kg (1 mg/kg) subcutaneously every 12 hours, resulted in an initial peak anti-Xa factor activity of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of steady-state levels. Steady state is achieved by day 2 of treatment.

After repeated subcutaneous administration at regimens of 4000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily in healthy volunteers, steady state was reached by day 2, with mean exposure approximately 15% higher than that observed after a single dose. After repeated subcutaneous administration at 100 IU/kg (1 mg/kg) twice daily, steady state was achieved by days 3–4, with mean exposure approximately 65% higher than after a single dose, and mean peak and trough anti-Xa factor activities 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-patient variability is low. No accumulation occurs after repeated subcutaneous administration.

The plasma anti-IIa factor activity after subcutaneous administration is approximately 10 times lower than anti-Xa factor activity. The mean peak anti-IIa factor activity occurs approximately 3–4 hours after subcutaneous injection, reaching 0.13 IU/mL and 0.19 IU/mL after multiple dosing 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 factor activity of sodium enoxaparin is approximately 4.3 liters, approaching the volume of circulating blood.

Biotransformation. Sodium enoxaparin is primarily metabolized in the liver via desulfation and/or depolymerization into low-molecular-weight species with significantly reduced biological activity.

Elimination. Sodium enoxaparin is a drug with low clearance, with a mean plasma anti-Xa activity 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 of approximately 5 hours after a single subcutaneous dose and increasing to about 7 hours after repeated doses.

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 populations

Elderly patients. According to population pharmacokinetic analysis, the pharmacokinetic profile of sodium enoxaparin in elderly patients does not differ from that in younger patients if renal function is not impaired. However, since renal function declines with age, reduced elimination of sodium enoxaparin may occur in elderly patients (see section "Dosage and administration").

Hepatic impairment. In a study involving patients with progressive cirrhosis receiving sodium enoxaparin 4000 IU (40 mg) once daily, reduced peak anti-Xa factor activity was associated with increasing severity of hepatic impairment (assessed by Child-Pugh categories). This reduction was primarily attributed to decreased ATIII levels in patients with hepatic impairment.

Renal impairment. A linear relationship was observed between plasma anti-Xa factor activity clearance and creatinine clearance at steady state, indicating reduced clearance of sodium enoxaparin in patients with renal impairment. Exposure to anti-Xa factor activity, expressed as AUC, is slightly increased in mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30–50 mL/min) renal impairment after repeated subcutaneous doses of 4000 IU (40 mg) once daily. In patients with severe renal impairment (creatinine clearance <30 mL/min), steady-state AUC is significantly increased by an average of 65% after repeated 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 a single intravenous dose of 25 IU, 50 IU, or 100 IU/kg (0.25, 0.50, or 1.0 mg/kg), although AUC was twice as high compared to the control group.

Body weight. After repeated subcutaneous administration of 150 IU/kg (1.5 mg/kg) once daily, mean steady-state AUC of anti-Xa factor activity was slightly higher in obese healthy volunteers (BMI 30–48 kg/m²) compared to the control group without obesity, while peak plasma anti-Xa factor activity was not increased. Weight-adjusted clearance after subcutaneous administration was lower in obese patients.

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

Pharmacokinetic interactions. No pharmacokinetic interactions between sodium enoxaparin and thrombolytics were observed with concomitant administration.

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

Sodium enoxaparin did not show mutagenic activity in in vitro tests, including the Ames test, mouse lymphoma cell direct mutation test, and no clastogenic activity in in vitro chromosomal aberration tests in human lymphocytes or in in vivo chromosomal aberration tests in rat bone marrow cells.

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

Clinical characteristics.

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

• For prophylaxis of venous thromboembolic complications in surgical patients with moderate and high risk, particularly in patients undergoing orthopedic or general surgical procedures, including surgery for oncological diseases.
• For prophylaxis of venous thromboembolic complications in medical patients with acute conditions (such as acute heart failure, respiratory failure, severe infections, or rheumatic diseases) and reduced mobility who are at increased risk of venous thromboembolism.
• For treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), except in cases of PE where thrombolytic therapy or surgical intervention may be required.
• For long-term treatment of DVT and PE and prevention of their recurrence in patients with active cancer.
• For 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), particularly in patients planned for medical treatment or subsequent percutaneous coronary intervention (PCI).

Contraindications.

Sodium enoxaparin is contraindicated in patients with the following conditions:

• Hypersensitivity to sodium enoxaparin, heparin or its derivatives, including other low molecular weight heparins, or to any of the excipients (see section "Composition").
• History of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or presence of circulating antibodies (see also section "Special precautions").
• Active clinically significant bleeding or conditions with a high risk of bleeding, including recent hemorrhagic stroke, gastrointestinal ulcer, presence of a 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 intraspinal or intracerebral vascular abnormalities.
• Spinal or epidural anesthesia or regional 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 agents is not recommended

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

Agents affecting hemostasis 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 "Route of administration and dosage").

Medicinal products requiring caution when used concomitantly

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

• Other medicinal products affecting hemostasis, for example:
  • 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 bleeding risk;
  • dextran 40;
  • systemic glucocorticoids.
• Medicinal products increasing potassium levels:

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

Special precautions for use.

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

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 factor activities, units of activity, dosing regimens, and clinical efficacy and safety. This leads to differences in pharmacokinetics and biological activity (e.g., antithrombin activity, platelet interactions). Therefore, particular attention should be paid to the instructions for medical use specific to each medicinal product, and these should be strictly followed.

History of HIT (> 100 days). The use of sodium enoxaparin in patients with a history of immune-mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in patients with 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 of immune-mediated HIT (> 100 days) but without circulating antibodies. The decision to use sodium enoxaparin in such cases should be made only 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

For cancer patients with platelet counts below 80 × 10⁹/L, anticoagulant therapy should be considered only on a case-by-case basis and requires close monitoring.

The risk of antibody-mediated HIT also exists with the use of LMWHs. If thrombocytopenia occurs, it typically develops between days 5 and 21 after initiation of sodium enoxaparin treatment.

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

Therefore, platelet counts should be determined before starting treatment with sodium enoxaparin 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 should be determined. Patients should be informed that such symptoms may occur and that they must report them to their physician immediately.

In clinical practice, if confirmed significant thrombocytopenia (30–50% decrease from baseline) is observed, treatment with sodium enoxaparin must be immediately discontinued, and the patient should be switched to an alternative non-heparin anticoagulant.

Bleeding events. As with other anticoagulants, bleeding 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;
• neurosurgical or ophthalmological surgery;
• 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 VTE prophylaxis, has no significant effect on bleeding time, general coagulation parameters, or on platelet aggregation and fibrinogen binding to platelets.

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

Use of the drug 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 procedures involving 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 less. The risk of such events increases with the use of postoperative continuous epidural catheters, concomitant use of additional medicinal products affecting hemostasis (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]), traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity.

To reduce the potential risk of bleeding associated with concomitant use of sodium enoxaparin and procedures involving epidural or spinal 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 lumbar puncture should ideally be performed when the anticoagulant effect of sodium enoxaparin is low, although the exact time to achieve sufficiently low anticoagulant effect in each individual patient 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 "Posology and method of administration").

If the physician decides to use anticoagulant therapy during epidural or spinal anesthesia/analgesia or lumbar puncture, careful monitoring for neurological symptoms such as midline back pain, sensory and 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 should be initiated immediately, including consideration of spinal cord decompression, even though such treatment may not prevent adverse neurological outcomes.

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

Procedures of percutaneous coronary intervention. To minimize the risk of bleeding after vascular interventional 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 treatment with sodium enoxaparin 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 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, such as underlying disease, and the lack of clinical data limit the assessment of these cases. Some of these cases occurred in pregnant women, where 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. Post-marketing reports have included isolated cases of valve thrombosis in pregnant women with mechanical heart valves receiving sodium enoxaparin for thrombosis prophylaxis. Pregnant women with mechanical heart valve prostheses may have an increased risk of thromboembolism.

Elderly patients. When used in the prophylactic dose range, no increased tendency to bleeding has been observed in elderly patients. When used in therapeutic doses, elderly patients (especially those aged 80 years and older) may have an increased risk of hemorrhagic complications. 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 "Posology and method of administration" and "Pharmacokinetics").

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

Sodium enoxaparin is not recommended for use in patients with end-stage renal disease (creatinine clearance < 15 mL/min) due to lack of 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), since exposure is significantly increased, dose adjustment is recommended for both therapeutic and prophylactic use (see section "Posology and method of administration").

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

Hepatic impairment. 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 factor activity levels is unreliable in patients with liver cirrhosis and is not recommended (see section "Pharmacokinetics").

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

Obese patients. Obese patients have an increased risk of thromboembolic events. The safety and efficacy of prophylactic doses of the drug in obese patients (body mass index [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. Such patients require careful monitoring for possible symptoms of thromboembolism.

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

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

Acute generalized exanthematous pustulosis. Cases of acute generalized exanthematous pustulosis (AGEP) of unknown frequency have been reported in association with enoxaparin treatment. At the time of prescribing the medicinal product, patients should be informed about the signs and symptoms of the disease and closely monitored for skin reactions. If signs or symptoms suggestive of such reactions occur, administration of sodium enoxaparin should be immediately discontinued and an alternative treatment considered (if appropriate).

Use during pregnancy or breastfeeding.

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

Animal studies have not revealed any signs of fetotoxicity or teratogenicity (see section "Preclinical safety data"). Animal studies have shown minimal placental transfer of enoxaparin.

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

Pregnant women receiving sodium enoxaparin should be closely monitored for signs of bleeding or excessive anticoagulant effect, and should be warned 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 heart valve prostheses (see section "Special precautions for use"). If epidural anesthesia is planned, it is recommended to discontinue treatment with sodium enoxaparin prior to the procedure (see section "Special precautions for use").

Breastfeeding. It is unknown whether enoxaparin is excreted unchanged in human breast milk. In rats during lactation, transfer of enoxaparin or its metabolites into milk is very low. Oral absorption of sodium enoxaparin is unlikely; therefore, it may be used in women during breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

Sodium enoxaparin has no effect or a negligible effect on the ability to drive a vehicle or operate machinery.

Method of Administration and Dosage.

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

• For patients with moderate thromboembolic risk, the recommended dose of sodium enoxaparin is 2000 IU (20 mg) once daily administered by subcutaneous (s.c.) injection. It has been demonstrated that initiating sodium enoxaparin therapy at a dose of 2000 IU (20 mg) prior to surgery (2 hours before the procedure) is effective and safe in patients undergoing surgery with moderate risk.

Therapy with sodium enoxaparin should be continued for a minimum of 7–10 days in patients with moderate risk, regardless of recovery (e.g., ability to ambulate). Prophylactic treatment should be continued until the patient is no longer experiencing significantly reduced mobility.

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

Prophylaxis of venous thrombosis in medical patients. The recommended dose of sodium enoxaparin is 4000 IU (40 mg) once daily administered by s.c. injection. Sodium enoxaparin therapy should be continued for 6–14 days, regardless of recovery (e.g., ability to ambulate). The benefit of treatment beyond 14 days has not been established.

Treatment of DVT and PE. Sodium enoxaparin should be administered s.c. as an injection at 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 the risk of thromboembolic complications and the risk of hemorrhagic complications. The regimen of 150 IU/kg (1.5 mg/kg) once daily is recommended for uncomplicated patients with low risk of VTE recurrence. The regimen of 100 IU/kg (1 mg/kg) twice daily should be prescribed for all other patients, such as those with obesity, symptomatic PE, cancer, recurrent VTE, or proximal venous thrombosis (iliac vein).

Sodium enoxaparin is typically administered for a mean duration of 10 days. If necessary, oral anticoagulants should be initiated (see "Switching between sodium enoxaparin and direct oral anticoagulants and vice versa" at the end of this section).

For long-term treatment of DVT and PE and prevention of their recurrence in patients with active cancer, physicians should carefully evaluate the individual risks of thromboembolism and bleeding.

The recommended dose is 100 IU/kg (1 mg/kg) administered subcutaneously twice daily for 5–10 days, followed by subcutaneous injection of 150 IU/kg (1.5 mg/kg) once daily for 6 months. After 6 months of treatment, the benefit of continued anticoagulant therapy should be re-evaluated.

Prophylaxis of clot formation during hemodialysis. The recommended dose of sodium enoxaparin is 100 IU/kg (1 mg/kg). In patients at high risk of hemorrhagic complications, the dose should be reduced to 50 IU/kg (0.5 mg/kg) with a double vascular access or to 75 IU/kg (0.75 mg/kg) with a single vascular access.

During hemodialysis, sodium enoxaparin should be administered into the arterial portion of the circuit at the beginning of the dialysis session. This dose is generally sufficient for a 4-hour dialysis session. However, if fibrin rings occur, for example, during 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 patients without contraindications should be given 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 daily long-term, regardless of treatment strategy.
• For treatment of acute STEMI, a single intravenous (i.v.) bolus of 3000 IU (30 mg) of sodium enoxaparin is recommended, followed by a s.c. dose of 100 IU/kg (1 mg/kg), then continued with s.c. administration of 100 IU/kg (1 mg/kg) every 12 hours (maximum 10,000 IU [100 mg] for each of the first two s.c. doses). Concomitant appropriate antiplatelet therapy, such as oral acetylsalicylic acid (75–325 mg once daily), should be administered if not contraindicated. The recommended duration of treatment is 8 days or until hospital discharge, whichever occurs first. When used in combination with thrombolytic therapy (fibrin-specific or non-fibrin-specific), sodium enoxaparin should be administered between 15 minutes before and up to 30 minutes after the initiation of fibrinolytic therapy.
• Dosage specifics for patients aged ≥75 years are provided below ("Elderly Patients").
• For patients undergoing PCI, if the last s.c. dose of sodium enoxaparin was administered less than 8 hours before balloon inflation, no additional doses are required. If the last s.c. dose was administered more than 8 hours before balloon inflation, an i.v. bolus of 30 IU/kg (0.3 mg/kg) of sodium enoxaparin should be administered.

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

Elderly patients. For all indications except ST-segment elevation myocardial infarction (STEMI), dose reduction is not required in elderly patients, except in cases of renal impairment (see below "Renal Impairment" and section "Special Warnings and Precautions"). For treatment of acute STEMI in elderly patients over 75 years of age, the initial intravenous bolus injection should not be administered. Treatment should begin with a dose of 75 IU/kg (0.75 mg/kg) s.c. every 12 hours (maximum 7500 IU [75 mg] for each of the first two s.c. doses), followed by continued administration of 75 IU/kg (0.75 mg/kg) s.c. for subsequent doses. Dosage specifics for elderly patients with renal impairment are described below in the subsection "Renal Impairment" and in the section "Special Warnings and Precautions."

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

Renal impairment. (see sections "Special Warnings and 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 the lack of adequate data in this population, except for prophylaxis of clot formation in the extracorporeal circulation during hemodialysis.

Table 6

Dosing for patients with severe renal impairment

(creatinine clearance 15–30 mL/min)

Indications	Dosing regimen
Prevention of venous thromboembolic complications	2000 IU (20 mg) s.c. once daily
Treatment of DVT and PE	100 IU/kg (1 mg/kg) body weight s.c. once daily
Extended treatment of DVT and PE in patients with active cancer	100 IU/kg (1 mg/kg) body weight s.c. once daily
Treatment of unstable angina and NSTEMI	100 IU/kg (1 mg/kg) body weight s.c. once daily
Treatment of acute STEMI (in patients under 75 years of age) Treatment of acute STEMI (in patients over 75 years of age)	1 × 3000 IU (30 mg) i.v. bolus + 100 IU/kg (1 mg/kg) body weight s.c., followed by 100 IU/kg (1 mg/kg) s.c. every 24 hours Without initial i.v. bolus: 100 IU/kg (1 mg/kg) body weight s.c., followed by 100 IU/kg (1 mg/kg) s.c. every 24 hours

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

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

Route of administration. The medicinal product must not be administered intramuscularly.

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

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

The pre-filled syringe is ready for immediate use.

When using ampoules or multidose vials, a tuberculin syringe or equivalent syringe is recommended to ensure accurate withdrawal of the required volume of the medicinal product.

Technique for subcutaneous injection

The medicinal product should preferably be administered while the patient is lying down. Enoxaparin sodium is administered by deep subcutaneous injection. To avoid loss of the drug when using a pre-filled syringe, air bubbles should not be expelled from the syringe before injection. If the dose needs to be adjusted according to the patient's body weight, graduated pre-filled syringes should be used, and the excess volume should be expelled before injection to achieve the required dose. It should be noted that in some cases, an exact dose may not be achievable due to the syringe's graduation scale, and the volume should be rounded to the nearest graduation mark.

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

The needle should be inserted fully, vertically, into a skin fold gently held between the thumb and index finger. The skin fold should be held until the injection is complete. 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, they should be advised to follow the instructions for self-injection with a pre-filled syringe equipped with a needle protection system.

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

For the treatment of acute STEMI, administration of the medicinal product should begin with a single intravenous (IV) bolus injection followed immediately by subcutaneous administration.

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

Enoxaparin sodium should be administered through an IV infusion system. It must not be mixed or co-administered with other medicinal products. To avoid potential mixing of enoxaparin sodium with other drugs, the selected IV access should be flushed with an adequate amount of 0.9% sodium chloride solution or 5% glucose solution before and after the IV bolus of enoxaparin sodium to clear the administration port of other medicinal products. Enoxaparin sodium can be safely administered with 0.9% sodium chloride solution or 5% glucose solution in water for injection.

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

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

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

To obtain a solution with a concentration of 300 IU/ml using a pre-filled syringe containing 6,000 IU (60 mg) of enoxaparin, a 50 ml infusion bag (e.g., 0.9% sodium chloride solution for injection or 5% glucose solution in water for injection) should be used as follows: 30 ml of fluid is withdrawn from the infusion bag using a syringe and discarded. The contents of the pre-filled syringe containing 6,000 IU (60 mg) of enoxaparin are then added to the remaining 20 ml of fluid in the bag. The contents of the bag should be mixed gently.

The required volume of the diluted solution should be withdrawn with a syringe for administration into the IV infusion system.

After dilution, the volume to be administered can be calculated using the following formula: [Volume of diluted solution (ml) = Patient's body weight (kg) × 0.1] — or by referring to Table 7. Dilution should be performed immediately before administration of the drug.

Table 7

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

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

Administration into the arterial segment of the dialysis circuit. The medicinal product should be administered into the arterial line of the dialysis circuit to prevent clot formation in the extracorporeal circulation during hemodialysis.

Transition from sodium enoxaparin to oral anticoagulants

Transition from sodium enoxaparin to vitamin K antagonists (VKA) and vice versa. Clinical and laboratory monitoring [prothrombin time expressed as International Normalized Ratio (INR)] should be intensified to monitor the effect of VKA.

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

Patients receiving VKA should discontinue VKA and initiate the first dose of sodium enoxaparin when INR decreases to a level below the therapeutic range.

Transition from sodium enoxaparin to direct oral anticoagulants (DOACs) and vice versa. For patients receiving sodium enoxaparin, discontinue sodium enoxaparin and initiate direct oral anticoagulants (DOACs) 0–2 hours (see the DOAC’s medical instructions) before the next scheduled dose of sodium enoxaparin is due.

For patients receiving DOACs, the first dose of sodium enoxaparin should be administered when the next DOAC dose is due.

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

Prophylactic dosing. A minimum interval of at least 12 hours should elapse between the last prophylactic subcutaneous injection of 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.

For patients with creatinine clearance of 15–30 mL/min, consider extending the interval before performing puncture, catheter insertion, or removal to at least 24 hours.

The initial administration of sodium enoxaparin 2,000 IU (20 mg) two hours before surgery does not apply when neuroaxial anesthesia is performed.

Therapeutic dosing. A minimum interval of at least 24 hours should elapse between the last therapeutic dose of 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.

For patients with creatinine clearance of 15–30 mL/min, consider extending the interval before performing puncture, catheter insertion, or removal to at least 48 hours.

Patients receiving the medicinal product 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 factor activity of the drug is still detectable, and adherence to these time intervals does not guarantee prevention of neuroaxial hematomas.

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

Instructions for self-administration of the medicinal product from pre-filled syringes

1. Wash your hands with soap and water. Dry them thoroughly.
2. Sit or lie down in a comfortable position to help you relax. Ensure you can clearly see the injection site. A recliner chair, armchair, or bed with pillows is ideal.
3. 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.

Remember: Do not administer the injection within 5 cm of the navel or near existing scars or bruises. Alternate the injection site between the left and right sides of the abdomen depending on where the previous injection was given.

1. Remove the plastic blister containing the pre-filled syringe from the box. Open the blister and take out the pre-filled syringe.
2. Carefully remove the needle cap from the syringe. Discard the cap. The syringe is pre-filled and ready for use.

Do not press the plunger before administering the injection. After removing the cap, do not allow the needle to touch anything to ensure it remains clean (sterile).

1. Hold the syringe in your dominant hand (like a pencil), and with the other hand, gently pinch the cleaned area of the abdomen between your thumb and index finger to create a skin fold. Ensure you maintain the skin fold throughout the injection.
2. Hold the syringe so that the needle is pointing downward (perpendicular at a 90º angle). Insert the needle fully into the skin fold.
3. Press the plunger with your thumb to administer the medicinal product into the fatty tissue of the abdomen. Ensure you maintain the skin fold throughout the injection.
4. Remove the needle by pulling it straight out.

To avoid bruising, do not rub the injection site after self-injection.

1. Place the used syringe into a sharps container. Close the container tightly with its lid and store it out of the reach of children.

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. Following oral ingestion, 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;
• an 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 before protamine administration or if a second dose of protamine is required;
• protamine administration may not be necessary more than 12 hours after sodium enoxaparin administration.

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

Adverse reactions.

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

Dosing regimens of enoxaparin sodium in these clinical trials varied depending on the indication. The dose of enoxaparin sodium for VTE prophylaxis after surgery or in patients with acute medical conditions and acute mobility limitation was 4,000 IU (40 mg) subcutaneously once daily. For treatment of VTE without PE, patients received enoxaparin sodium either at a dose of 100 IU/kg (1 mg/kg) subcutaneously every 12 hours or 150 IU/kg (1.5 mg/kg) subcutaneously once daily. In clinical trials where the drug was used for treatment of unstable angina and non-Q-wave myocardial infarction (MI), doses were 100 IU/kg (1 mg/kg) subcutaneously every 12 hours. In the clinical trial where the drug was used for treatment of acute ST-segment elevation MI, the enoxaparin sodium regimen was as follows: 3,000 IU (30 mg) intravenous bolus, 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 events were hemorrhagic events, thrombocytopenia, and thrombocytosis (see sections "Special precautions" and "Description of selected adverse reactions" below).

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

Cases of HIT associated with enoxaparin use have been reported (see section "Special precautions").

List of adverse reactions. Other adverse reactions observed in clinical trials and adverse reactions reported during post-marketing use of the drug (marked with *) are described in detail below.

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

Blood and lymphatic system disorders: common — hemorrhagic events, hemorrhagic anemia*, thrombocytopenia, thrombocytosis; rare — eosinophilia*, cases of immune-mediated thrombocytopenia with thrombosis; in some of these cases, thrombosis was complicated by organ infarction or limb ischemia (see section "Special precautions").

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 prolonged or permanent paralysis (see section "Special precautions").

Hepatobiliary disorders: very common — increased levels of liver enzymes (mainly transaminases more than 3 times the upper limit of normal); uncommon — hepatocellular liver injury*; rare — cholestatic liver injury*.

Skin and subcutaneous tissue disorders: common — urticaria, pruritus, erythema; uncommon — bullous dermatitis; rare — alopecia*, cutaneous vasculitis*, skin necrosis*, which usually occurs at the injection site (these events are typically preceded by purpura or erythematous, infiltrated, 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.

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" and "Interaction with other medicinal products and other forms of interaction").

Description of selected adverse reactions

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

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

Table 8

Body system	Prophylaxis in surgical patients	Prophylaxis in internal medicine patients	Treatment of patients with DVT, with or without PE	Long-term treatment of DVT and PE in patients with active cancer	Treatment of patients with unstable angina and non–Q-wave MI	Treatment of patients with acute STEMI
Blood and lymphatic system	Very common: hemorrhagic eventsα Uncommon: retroperitoneal hemorrhage	Common: hemorrhagic eventsα	Very common: hemorrhagic eventsα Uncommon: intracranial hemorrhage, retroperitoneal hemorrhage	Commonb: hemorrhagic eventsα	Common: hemorrhagic eventsα Uncommon: retroperitoneal hemorrhage	Common: hemorrhagic eventsα Uncommon: intracranial hemorrhage, retroperitoneal hemorrhage

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

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

Table 9

Thrombocytopenia and thrombocytosis

Body system	Prophylaxis in surgical patients	Prophylaxis in medical patients	Treatment of patients with DVT, with or without PE	Long-term treatment of DVT and PE in patients with active cancer	Treatment of patients with unstable angina and non-Q-wave MI	Treatment of patients with acute STEMI
Blood and lymphatic system	Very common: thrombocytosisβ Common: thrombocytopenia	Uncommon: thrombocytopenia	Very common: thrombocytosisβ Common: thrombocytopenia	Frequency unknown: thrombocytopenia	Uncommon: thrombocytopenia	Common: thrombocytosisβ, thrombocytopenia Very rare: immune-mediated thrombocytopenia

β Increase in platelet count > 400 G/L.

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

Reporting of suspected adverse reactions

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

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

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

Incompatibilities.

Subcutaneous injection. Do not mix with other medicinal products.

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

Packaging. 0.2 mL (2000 anti-Xa IU), 0.4 mL (4000 anti-Xa IU), or 0.6 mL (6000 anti-Xa IU) in pre-filled syringes, 2 syringes per blister, 1 or 5 blisters per carton.

0.8 mL (8000 anti-Xa IU) or 1 mL (10000 anti-Xa IU) in pre-filled syringes, 2 syringes per blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Production from in bulk manufactured by Shenzhen Techdow Pharmaceutical Co., Ltd., China.

Manufacturer's address and place of business. Ukraine, 61115, Kharkiv region, city of Kharkiv, Severin Pototskoho Street, 36.