Pharmacotherapeutic group: Antithrombotic agents, heparin group, ATC code: B01AB05.
Pharmacodynamic effects
Enoxaparin sodium is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons, in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. The active substance is the sodium salt.
It is characterised by a high anti-Xa activity (approximately 100 IU/mg) and a low anti-IIa or antithrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant activities are mediated through antithrombin III (ATIII), resulting in antithrombotic effects in humans.
Beyond its anti-Xa/IIa activity, further anticoagulant and anti-inflammatory properties of enoxaparin sodium have been identified in healthy subjects, patients, and non-clinical models. These properties include ATIII-dependent inhibition of other coagulation factors such as factor VIIa, induction of endogenous Tissue Factor Pathway Inhibitor (TFPI) release, and reduced release of von Willebrand factor (vWF) from the vascular endothelium into the bloodstream. These factors are known to contribute to the overall antithrombotic effect of enoxaparin sodium.
At prophylactic doses, it does not significantly affect aPTT. When used for therapeutic purposes, aPTT may be prolonged to 1.5–2.2 times the control time at peak activity.
Clinical efficacy and safety
Prevention of venous thromboembolic disease associated with surgery
Extended VTE prophylaxis following orthopaedic surgery
In a double-blind study of extended prophylaxis in patients undergoing hip replacement surgery, 179 patients with no venous thromboembolic disease were initially treated during hospitalisation with enoxaparin sodium 4,000 IU (40 mg) subcutaneously and, following discharge, were randomised to one of two regimens: either enoxaparin sodium 4,000 IU (40 mg) once daily subcutaneously (n=90) or placebo (n=89) for 3 weeks. The incidence of DVT during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared with the placebo group. No PE was reported. No bleeding occurred.
Efficacy data are presented in the table below.
| | Enoxaparin sodium 4,000 IU (40 mg) once daily s.c. n (%) | Placebo once daily s.c. n (%) |
|---|---|---|
| All patients treated with extended prophylaxis | 90 (100) | 89 (100) |
| Total VTE | 6 (6.6) | 18 (20.2) |
| Total DVT (%) | 6 (6.6)* | 18 (20.2) |
| Proximal DVT (%) | 5 (5.6)# | 7 (8.8) |
*p value vs placebo = 0.008 #p value vs placebo = 0.537
In a second double-blind study, 262 patients without VTE disease who underwent hip replacement surgery were initially treated during hospitalisation with enoxaparin sodium 4,000 IU (40 mg) s.c. and, following discharge, were treated with enoxaparin sodium 4,000 IU (40 mg) once daily s.c. (n=131) or placebo (n=131) for three weeks. As in the first study, the incidence of VTE during extended prophylaxis was statistically significantly lower in the enoxaparin sodium group compared with placebo, both for total VTE (enoxaparin sodium 21 [16%] versus placebo 45 [34.4%]; p=0.001) and for DVT (enoxaparin sodium 8 [6.1%] versus placebo 28 [21.4%]; p=<0.001). With regard to major bleeding, no difference was observed between the enoxaparin sodium and placebo groups.
Extended DVT prophylaxis following cancer surgery
A double-blind, multicentre clinical study compared the safety and efficacy of a four-week and a one-week regimen of prophylactic enoxaparin sodium in 332 patients undergoing elective surgery for abdominal or pelvic cancer. Patients received enoxaparin sodium (4,000 IU (40 mg) s.c.) daily for 6 to 10 days and were randomised to treatment with enoxaparin sodium or placebo for a further 21 days. Bilateral venography was performed between day 25 and day 31, or earlier if symptoms of venous thromboembolism occurred. Patients were then followed for 3 months. Four weeks of enoxaparin sodium prophylaxis following surgery for abdominal or pelvic cancer statistically significantly reduced the incidence of venographically confirmed thrombosis compared with one week of enoxaparin sodium prophylaxis. The rate of venous thromboembolism at the end of the blinded phase of the study 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 at three months [13.8% vs 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the blinded or follow-up phases.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to result in restricted mobility
In a double-blind, multicentre, parallel-group study, enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU (40 mg) once daily s.c. was compared with placebo for DVT prophylaxis in medical patients with severely restricted mobility during acute illness (defined as a walking distance of <10 metres for ≤3 days). This study included patients with heart failure (NYHA class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency; and acute infection or acute rheumatic illness; provided this was associated with at least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy, and chronic heart or respiratory failure). A total of 1,102 patients were enrolled in the study and 1,073 patients were treated. Treatment continued for 6 to 14 days (mean duration of treatment 7 days). At the dose of 4,000 IU (40 mg) once daily s.c., enoxaparin sodium statistically significantly reduced the incidence of VTE compared with placebo. Efficacy data are presented in the table below.
| | Enoxaparin sodium 2,000 IU (20 mg) once daily s.c. n (%) | Enoxaparin sodium 4,000 IU (40 mg) once daily s.c. n (%) | Placebo n (%) |
|---|---|---|---|
| All medical patients treated during acute illness | 287 (100) | 291 (100) | 288 (100) |
| Total VTE (%) | 43 (15.0) | 16 (5.5)* | 43 (14.9) |
| Total DVT (%) | 43 (15.0) | 16 (5.5) | 40 (13.9) |
| Proximal DVT (%) | 13 (4.5) | 5 (1.7) | 14 (4.9) |
VTE = venous thromboembolic events, which included DVT, PE, and death due to thromboembolism. *p value vs placebo = 0.0002
Approximately 3 months after enrolment, the incidence of VTE remained statistically significantly lower in the group treated with enoxaparin sodium 4,000 IU (40 mg) compared with the placebo group. The overall incidence of bleeding was 8.6% and the incidence of major bleeding was 1.1% in the placebo group, 11.7% and 0.3% in the enoxaparin sodium 2,000 IU (20 mg) group, and 12.6% and 1.7% in the enoxaparin sodium 4,000 IU (40 mg) group.
Treatment of deep vein thrombosis with or without pulmonary embolism
In a multicentre, parallel-group study, 900 patients with acute DVT of the lower limb, with or without pulmonary embolism, were randomised to in-hospital treatment with either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily s.c., (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours s.c., or (iii) an i.v. bolus of heparin (5,000 IU) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomised in the study and all were treated. All patients also received warfarin sodium (the dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), started within 72 hours of the start of enoxaparin sodium or standard heparin treatment and continued for 90 days. Enoxaparin sodium or standard heparin treatment was administered for a minimum of 5 days, until the target warfarin sodium INR was achieved. 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 the table below.
| | 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 aPTT-adjusted i.v. treatment n (%) |
|---|---|---|---|
| All treated patients with DVT with or without PE | 298 (100) | 312 (100) | 290 (100) |
| Total VTE (%) | 13 (4.4)* | 9 (2.9)* | 12 (4.1) |
| DVT only (%) | 11 (3.7) | 7 (2.2) | 8 (2.8) |
| Proximal DVT (%) | 9 (3.0) | 6 (1.9) | 7 (2.4) |
| PE (%) | 2 (0.7) | 2 (0.6) | 4 (1.4) |
VTE = venous thromboembolic event (DVT and/or PE)
*The 95% confidence intervals for treatment differences in total VTE were:
enoxaparin sodium once daily versus heparin (-3.0 to 3.5)
enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7).
Major bleeding occurred in 1.7% of the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily s.c. group, 1.3% of the enoxaparin sodium 100 IU/kg (1 mg/kg) twice daily group, and 2.1% of the heparin group.
Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of their recurrence in patients with active cancer
In clinical studies with a limited number of patients, the incidence of recurrent VTE was comparable in patients treated with enoxaparin administered once or twice daily for 3 to 6 months and patients who received warfarin.
Real-world effectiveness was evaluated in a cohort of 4,451 patients with symptomatic VTE and active cancer in the international RIETE registry of patients with VTE and other thrombotic conditions. 3,526 patients received s.c. enoxaparin for up to 6 months and 925 patients received tinzaparin or dalteparin s.c. Of the 3,526 patients treated with enoxaparin, 891 received 1.5 mg/kg once daily for the initial treatment and during extended treatment for up to 6 months (once daily only), 1,854 received an initial dosing regimen of 1.0 mg/kg twice daily with extended treatment for up to 6 months (twice daily only), and 687 received an initial dose of 1.0 mg/kg twice daily followed by 1.5 mg/kg once daily (twice daily to once daily) as extended treatment for up to 6 months. The mean and median time to treatment until the change in dosing regimen was 17 days and 8 days, respectively. No significant difference in the incidence of recurrent VTE was found between the two treatment groups (see table) and enoxaparin met the predefined non-inferiority criterion of 1.5 (HR adjusted for the relevant variables 0.817, 95% CI: 0.499–1.336).
There was no statistically significant difference between the two treatment groups in the relative risks of major (fatal or non-fatal) bleeding or all-cause mortality (see table).
Table. Efficacy and safety results in the RIETECAT study
| Outcome | Enoxaparin n=3,526 | Other LMWH n=925 | Adjusted hazard 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] |
| Non-major bleeding | 87 (2.5%) | 24 (2.6%) | 0.881 [0.550–1.410] |
| All-cause mortality | 666 (18.9%) | 157 (17.0%) | 0.974 [0.813–1.165] |
An overview of results by treatment regimen used in the RIETECAT study in patients who completed 6 months of treatment is presented below:
Table. 6-month results in patients who completed 6 months of treatment, by regimen
| Results n (%) | Enoxaparin all regimens (95% CI) n=1,432 | Enoxaparin once daily n=444 | Enoxaparin twice daily n=529 | Enoxaparin twice daily to once daily n=406 | Enoxaparin once daily to twice daily n=14 | Enoxaparin more than one treatment change n=39 | EU-approved low molecular weight heparins 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%) |
| Non-major clinically relevant 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%) |
| All-cause death | 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%) |
| Fatal PE or fatal bleeding associated with death | 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 (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 multicentre study, 3,171 patients in the acute phase of unstable angina pectoris or non-Q-wave myocardial infarction were enrolled and randomised into two groups; in addition to acetylsalicylic acid (100 to 325 mg once daily), patients in one group received either a s.c. injection of enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or i.v. unfractionated heparin adjusted according to aPTT. Patients were required to be hospitalised for a minimum of 2 days and a maximum of 8 days, until clinical stabilisation, a revascularisation procedure, or discharge from hospital. Patients were followed for 30 days. Compared with heparin, enoxaparin sodium statistically significantly reduced the combined incidence of angina pectoris, myocardial infarction, and death, from 19.8% to 16.6% (relative risk reduction 16.2%) at day 14. This reduction in the combined incidence persisted at 30 days (from 23.3% to 19.8%; relative risk reduction 15%). With regard to major bleeding, no differences were observed, although bleeding at the subcutaneous injection site was more frequent.
Treatment of acute ST-segment elevation myocardial infarction
In a large multicentre study, 20,479 patients with STEMI eligible for fibrinolytic therapy were randomised into two groups; one group received enoxaparin sodium as a single i.v. bolus dose of 3,000 IU (30 mg) plus a subcutaneous injection of enoxaparin sodium 100 IU/kg (1 mg/kg), followed by a subcutaneous injection of enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours, and the other group received intravenous unfractionated heparin adjusted according to aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for patients with severely impaired renal function and for elderly patients over 75 years of age. Subcutaneous injections of enoxaparin sodium were administered until the patient was discharged from hospital or for a maximum of 8 days (whichever occurred first).
4,716 patients underwent percutaneous coronary intervention while receiving antithrombotic support with the blinded study medication. Therefore, for patients treated with enoxaparin sodium, PCI had to be performed with enoxaparin sodium (no switch), using the regimen established in previous studies, i.e. no additional dosing if less than 8 hours had elapsed between the last subcutaneous administration and balloon inflation; an i.v. bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium if more than 8 hours had elapsed between the last subcutaneous administration and balloon inflation.
Compared with unfractionated heparin, enoxaparin sodium statistically significantly reduced the incidence of the primary endpoint — death from any cause or recurrent myocardial infarction within the first 30 days after randomisation [9.9% in the enoxaparin sodium group compared with 12.0% in the unfractionated heparin group] — with a relative risk reduction of 17% (p<0.001). The benefits of enoxaparin sodium treatment (evident across multiple efficacy measures) appeared as early as 48 hours, when the relative risk reduction of recurrent myocardial infarction was 35% compared with unfractionated heparin treatment (p<0.001). The benefit of enoxaparin sodium on the primary endpoint was consistent across key subgroups, including age, sex, infarct location, history of diabetes, history of prior myocardial infarction, type of fibrinolytic used, and time to study drug treatment. A statistically significant benefit of enoxaparin sodium compared with unfractionated heparin was observed in patients who underwent percutaneous coronary intervention within 30 days of randomisation (23% relative risk reduction) and in those treated conservatively (pharmacologically) (15% relative risk reduction, p = 0.27 for interaction). The incidence of the composite endpoint of death, reinfarction, or intracranial haemorrhage at day 30 (measured as net clinical benefit) was statistically significantly lower (p<0.0001) in the enoxaparin sodium group (10.1%) compared with heparin (12.2%), representing a 17% relative risk reduction in favour of enoxaparin sodium treatment. The incidence of major bleeding at 30 days was statistically significantly higher (p<0.0001) in the enoxaparin sodium group (2.1%) than in the heparin group (1.4%). The incidence of gastrointestinal bleeding was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin). The beneficial effect of enoxaparin sodium on the primary endpoint observed during the first 30 days was maintained over 12 months.
Hepatic impairment
According to literature data, the use of enoxaparin sodium at a dose of 4,000 IU (40 mg) in patients with cirrhosis (Child-Pugh class B-C) appears to be safe and effective in the prevention of portal vein thrombosis. It should be noted that the literature studies may have certain limitations. Caution is required in patients with hepatic impairment, as these patients have an increased potential for bleeding (see section 4.4), and no formal dose-finding studies have been conducted in patients with cirrhosis (Child-Pugh class A, B, C).
⚠️ Warnings
General:
Low molecular weight heparins (LMWH) cannot be used interchangeably (unit for unit) with enoxaparin sodium. These products differ in their manufacturing process, molecular weight, specific anti-Xa activity and anti-IIa activity, units, dosage, and clinical efficacy and safety. As a result, they have different pharmacokinetics and biological activities (e.g. antithrombin activity, platelet interaction). Particular attention should therefore be paid to the instructions for use of each product.
History of HIT (>100 days)
The use of enoxaparin sodium in patients with a history of immune-mediated HIT within the past 100 days or in the presence of circulating antibodies is contraindicated (see section 4.3). Circulating antibodies may persist for several years.
In patients with a history (>100 days) of heparin-induced thrombocytopenia without circulating antibodies, enoxaparin sodium should be used with extreme caution. In such cases, the decision to use enoxaparin sodium may be made only after careful assessment of the benefit/risk balance and after consideration of non-heparin alternative treatments (e.g. danaparoid sodium or lepirudin).
Monitoring of platelet count
In cancer patients with a platelet count below 80 x 10⁹/L, anticoagulant treatment may only be considered on a case-by-case basis, and careful monitoring of patients is recommended.
There is also a risk of antibody-mediated heparin-induced thrombocytopenia with low molecular weight heparins. If thrombocytopenia occurs, it usually appears between day 5 and day 21 after the start of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients, especially after cardiac surgery, and in cancer patients. It is therefore recommended to measure the platelet count at the start of enoxaparin sodium treatment and then regularly during treatment.
If clinical signs suggestive of HIT occur (a new episode of arterial and/or venous thromboembolism, painful skin lesions at the injection site, allergic or anaphylactic reactions to treatment), the platelet count should be measured. Patients should be informed that such signs may occur and that, if they do, they should inform their doctor.
In practice, if a significant decrease in platelet count (30 to 50% of the baseline value) is confirmed, enoxaparin sodium treatment must be discontinued immediately and the patient switched to an alternative non-heparin anticoagulant treatment.
Bleeding
As with other anticoagulants, bleeding may occur at any site. If it occurs, the source of the bleeding should be investigated and appropriate treatment initiated. As with other anticoagulant therapy, enoxaparin sodium should be used with caution in conditions with an increased potential for bleeding, such as:
impaired haemostasis,
a history of peptic ulcer,
recent ischaemic stroke,
severe arterial hypertension,
recent diabetic retinopathy,
neurological or ophthalmological surgery,
concomitant use of medicinal products affecting haemostasis (see section 4.5).
Laboratory tests
When administered at doses for venous thromboembolism prophylaxis, enoxaparin sodium does not significantly affect bleeding time or other global coagulation tests, has no effect on platelet aggregation, and does not significantly affect the binding of fibrinogen to platelets.
At higher doses, prolongation of the activated partial thromboplastin time (aPTT) or the activated clotting time (ACT) may occur. However, this prolongation and the increased antithrombotic effect are not linearly correlated and are therefore not suitable for monitoring enoxaparin sodium activity.
Spinal/epidural anaesthesia or lumbar puncture
Spinal/epidural anaesthesia must not be performed within 24 hours of administration of therapeutic doses of enoxaparin sodium (see section 4.3).
Cases of neuraxial haematomas resulting in long-term or permanent paralysis have been reported with the concomitant use of enoxaparin sodium and spinal/epidural anaesthesia or spinal puncture. These cases are rare with doses of enoxaparin sodium of 4,000 anti-Xa IU (40 mg) subcutaneously once daily or lower. The risk may be higher with higher doses of enoxaparin sodium, with the use of postoperative epidural catheters, with concomitant use of medicinal products affecting haemostasis such as NSAIDs, with repeated epidural/spinal punctures, or in patients with a history of spinal surgery or spinal deformity.
When enoxaparin sodium is used concomitantly with epidural/spinal anaesthesia or analgesia or spinal puncture, the pharmacokinetic profile of enoxaparin sodium should be taken into account (see section 5.2). Insertion and removal of the catheter or lumbar puncture are best performed when the anticoagulant activity of enoxaparin sodium is low; however, the exact timing to achieve a sufficiently low anticoagulant activity in an individual patient is not known. In patients with creatinine clearance [15 to 30 mL/min], additional considerations are necessary, as the elimination of enoxaparin sodium takes longer (see section 4.2).
If the physician decides to administer anticoagulation in the context of epidural/spinal anaesthesia or analgesia or lumbar puncture, frequent monitoring must be carried out to detect any signs and symptoms of neurological impairment, such as lower back pain, sensory and motor deficits (numbness or weakness of the lower limbs), and bowel or bladder dysfunction. Patients should be instructed to inform their doctor immediately if they experience any of the above-mentioned signs and symptoms. If signs of a spinal canal haematoma are suspected, urgent diagnosis and treatment must be initiated, including spinal cord decompression, even though such treatment may not prevent or reverse the neurological sequelae.
Skin necrosis / cutaneous vasculitis
Skin necrosis and cutaneous vasculitis have been reported with LMWH. In such cases, treatment must be discontinued immediately.
Percutaneous coronary revascularisation
To minimise the risk of bleeding following removal of the vascular sheath after catheterisation performed during treatment of unstable angina pectoris, NSTEMI, and acute STEMI, strictly adhere to the recommended intervals between doses of enoxaparin sodium. This is important to achieve haemostasis at the puncture site after PCI. If a closure device is used, the sheath may be removed immediately. If a manual compression method is used, the sheath should be removed 6 hours after the last i.v./s.c. administration of enoxaparin sodium. If enoxaparin sodium treatment is to be continued, the next dose should not be administered earlier than 6 to 8 hours after sheath removal. The procedure site should be monitored for signs of bleeding or haematoma formation.
Acute infective endocarditis
In patients with acute infective endocarditis, the use of heparin is generally not recommended because of the risk of cerebral haemorrhage. If its use is considered absolutely essential, the decision should be made only after careful individual assessment of the benefit/risk balance.
Prosthetic mechanical heart valves
The use of enoxaparin sodium for thromboprophylaxis in patients with prosthetic mechanical heart valves has not been adequately studied. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with prosthetic mechanical heart valves who received enoxaparin sodium for thromboprophylaxis. Confounding factors, including the underlying disease and insufficient clinical data, limit the assessment of these cases. Some of these cases were in pregnant women, in whom the thrombosis caused the death of both mother and foetus.
Pregnant women with prosthetic mechanical heart valves
The use of enoxaparin sodium for thromboprophylaxis in pregnant women with prosthetic mechanical heart valves has not been adequately studied. In a clinical study of pregnant women with prosthetic mechanical heart valves, in which enoxaparin sodium 100 IU/kg (1 mg/kg) was administered twice daily to reduce the risk of thromboembolism, 2 of 8 women developed blood clots that blocked the valve and caused the death of mother and foetus. In the post-marketing setting, isolated cases of valve thrombosis have been reported in pregnant women with prosthetic mechanical heart valves who received enoxaparin sodium prophylactically. Pregnant women with prosthetic mechanical heart valves may be at increased risk of thromboembolism.
Elderly patients
No increased tendency to bleeding was observed with prophylactic doses. Elderly patients (mainly aged 80 years and over) may be at increased risk of bleeding complications with therapeutic doses of enoxaparin sodium. Careful clinical monitoring is therefore recommended, and in patients over 75 years of age treated for STEMI, a dose reduction may be considered (see sections 4.2 and 5.2).
Renal impairment
Patients with renal impairment are exposed to increased enoxaparin sodium activity, which increases the risk of bleeding. Careful clinical monitoring is recommended in these patients, and biological monitoring by measuring anti-Xa activity may also be considered (see sections 4.2 and 5.2). Enoxaparin sodium is not recommended in patients with end-stage renal disease (creatinine clearance <15 mL/min) due to a lack of data in this population, except for the prevention of thrombus formation in the extracorporeal circulation during dialysis. Patients with severe renal impairment (creatinine clearance 15-30 mL/min) are exposed to markedly increased enoxaparin sodium activity; therefore, adjustment of therapeutic and prophylactic dosing regimens is recommended (see section 4.2). No dose adjustment is required in patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment.
Hepatic impairment
Caution is required when using enoxaparin sodium in patients with hepatic impairment because of the increased potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with hepatic cirrhosis and is not recommended (see section 5.2).
Low body weight
Patients with low body weight (women <45 kg, men <57 kg) are exposed to increased activity of enoxaparin sodium when given prophylactic doses (not adjusted for body weight), which may lead to an increased risk of bleeding. Careful monitoring of such patients is therefore recommended (see section 5.2).
Obese patients
Obese patients are at increased risk of thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI >30 kg/m²) have not been fully established, and there is no consensus regarding dose adjustment. These patients should be carefully monitored for signs and symptoms of thromboembolism.
Hyperkalaemia
Heparins can suppress adrenal secretion of aldosterone, leading to hyperkalaemia (see section 4.8), particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, and patients taking medicinal products known to increase potassium levels (see section 4.5). Plasma potassium levels should be monitored regularly, especially in at-risk patients.
Traceability
Low molecular weight heparins (LMWHs) are biological medicinal products. Healthcare professionals are advised to record the trade name and batch number of the administered product in the patient's medical record in order to improve the traceability of LMWHs.
Sodium
For patients receiving doses higher than 210 mg/day: this medicinal product contains more than 24 mg sodium per dose, equivalent to 1.2% of the WHO recommended maximum daily dietary intake of sodium for an adult, which is 2 g of sodium.
Acute generalised exanthematous pustulosis
Acute generalised exanthematous pustulosis (AGEP) has been reported in association with enoxaparin treatment, with an unknown frequency. At the time of prescribing, patients should be informed of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms of these reactions appear, enoxaparin should be discontinued immediately and alternative treatment considered (as appropriate).
