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 4500 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 low anti-IIa or antithrombin activity (approximately 28 IU/mg), giving a ratio of 3.6. These anticoagulant activities are mediated through antithrombin III (ATIII), producing 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, in patients and in non-clinical models. These include ATIII-dependent inhibition of other coagulation factors such as factor VIIa, induction of the release of endogenous tissue factor pathway inhibitor (TFPI), and reduced release of von Willebrand factor (vWF) from the vascular endothelium into the circulation. 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 at therapeutic doses, aPTT may be prolonged by 1.5 to 2.2 times the control time at peak activity.
Clinical efficacy and safety
Prevention of venous thromboembolic disease associated with surgery
Extended prophylaxis of VTE following orthopaedic surgery
In a double-blind study of extended prophylaxis in patients undergoing hip replacement surgery, 179 patients with no venous thromboembolic disease received an initial dose of enoxaparin sodium 4,000 IU (40 mg) subcutaneously during hospitalisation and, after discharge, were randomised to one of two regimens: either enoxaparin sodium 4,000 IU (40 mg) (n=90) once daily subcutaneously 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.
The 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 received an initial dose of enoxaparin sodium 4,000 IU (40 mg) s.c. during hospitalisation and, after discharge, were treated with enoxaparin sodium 4,000 IU (40 mg) (n=131) once daily s.c. 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%] vs. placebo 45 [34.4%]; p=0.001) and for DVT (enoxaparin sodium 8 [6.1%] vs. placebo 28 [21.4%]; p=<0.001). With regard to major bleeding, no difference was observed between the enoxaparin sodium and placebo groups.
Extended prophylaxis of DVT following oncological 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 days 25 and 31, or earlier if symptoms of venous thromboembolism occurred. Patients were then followed for 3 months. Prophylaxis with enoxaparin sodium for 4 weeks 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 with regard to the rate of bleeding or other complications during the blinded or follow-up phases.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness and anticipated restricted mobility
A double-blind, multicentre, parallel-group study compared enoxaparin sodium 2,000 IU (20 mg) or 4,000 IU (40 mg) once daily s.c. with placebo in the prophylaxis of DVT in medical patients with severely restricted mobility during an 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 disease, provided this was associated with at least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy, and chronic cardiac 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). When given at a dose of 4,000 IU (40 mg) once daily s.c., enoxaparin sodium statistically significantly reduced the incidence of VTE compared with placebo. The 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 an 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 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 lower-limb DVT, 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 treatment with 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 given for at least 5 days, until the target warfarin sodium INR was reached. Both enoxaparin sodium regimens were equivalent to standard heparin treatment in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The 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 the treatment differences in total VTE were:
enoxaparin sodium once daily vs. heparin (-3.0 to 3.5)
enoxaparin sodium every 12 hours vs. heparin (-4.2 to 1.7).
Major bleeding was 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once daily s.c. group, 1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice daily group and 2.1% in 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 given once or twice daily for 3 to 6 months and in patients receiving warfarin.
Efficacy in real-world clinical practice was assessed in a cohort of 4,451 patients with symptomatic VTE and active cancer in RIETE, an international 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 s.c. tinzaparin or dalteparin. Of the 3,526 patients treated with enoxaparin, 891 were treated at a dose of 1.5 mg/kg once daily during initial treatment and subsequently during extended treatment for up to 6 months (once daily only), 1,854 patients 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 patients received 1.0 mg/kg twice daily during initial treatment followed by 1.5 mg/kg once daily (twice daily–once daily) as extended treatment for up to 6 months. The mean and median time to a change in dosing regimen was 17 days and 8 days, respectively. No significant difference was found in the incidence of recurrent VTE between the two treatment groups (see table), and enoxaparin met the pre-specified 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 with regard to 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 the treatment regimens 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) | Enoxaparin once daily | Enoxaparin twice daily | Enoxaparin twice daily to once daily | Enoxaparin once daily to twice daily | Enoxaparin more than one treatment change | EU-approved low molecular weight heparins
(n=1,432) | (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%)
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-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, such that patients in one group received, together with acetylsalicylic acid (100 to 325 mg once daily), either s.c. injections of enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or i.v. unfractionated heparin adjusted according to aPTT. Patients had to be hospitalised for a minimum of 2 days and a maximum of 8 days, until clinical stabilisation, a revascularisation procedure or hospital discharge. Patients had to be followed for 30 days. Compared with heparin, enoxaparin sodium statistically significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a fall from 19.8% to 16.6% (relative risk reduction of 16.2%) at day 14. This reduction in the combined incidence persisted at 30 days (from 23.3% to 19.8%; relative risk reduction of 15%).
With regard to major bleeding, no differences were observed, although bleeding at the site of the subcutaneous injection 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; in one group they 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, while in the second group they 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 modified for patients with severely impaired renal function and for elderly patients aged over 75 years. Subcutaneous injections of enoxaparin sodium were given until the patient was discharged from hospital or for a maximum of 8 days (whichever came first).
4,716 patients underwent percutaneous coronary intervention while receiving antithrombotic adjunctive therapy with the blinded study medications. 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 dose if less than 8 hours had elapsed between the last subcutaneous administration and balloon inflation; an i.v. bolus of enoxaparin sodium 30 IU/kg (0.3 mg/kg) 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] — a relative risk reduction of 17% (p<0.001). The benefits of enoxaparin sodium treatment (apparent across several efficacy measures) emerged as early as 48 hours, when the relative risk reduction for 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 the heparin group (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%) compared with the heparin group (1.4%). The higher incidence of gastrointestinal bleeding was similar in both groups (0.8% with enoxaparin sodium vs. 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 the literature, 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 literature studies may have certain limitations. Caution is required in patients with hepatic impairment, as these patients have a higher potential for bleeding (see section 4.4), and no formal dose-finding studies have been carried out in patients with cirrhosis (Child-Pugh class A, B, C).
⚠️ Warnings
General:
Low molecular weight heparins (LMWHs) cannot be used interchangeably (unit for unit) with enoxaparin sodium. These medicinal 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 consequence, they have different pharmacokinetics and biological activities (for example antithrombin activity and interaction with platelets). Particular attention must therefore be paid to the instructions for use of each individual 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 should be made only after a 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 g/L, anticoagulant treatment may be considered only on a case-by-case basis and close monitoring of the patient is recommended.
With low molecular weight heparins, too, there is a risk of thrombocytopenia caused by heparin-induced antibodies. If thrombocytopenia occurs, it usually appears between days 5 and 21 after the start of enoxaparin sodium treatment.
The risk of HIT is higher in post-surgical patients, particularly after cardiac surgery, and in cancer patients. It is therefore recommended that the platelet count be measured at the start of enoxaparin sodium treatment and then measured regularly during treatment.
If there are clinical signs suggestive of HIT (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 must be informed that such symptoms may occur and, in such cases, must inform their physician.
In practice, if a significant fall in the platelet count is confirmed (30 to 50% from the baseline value), enoxaparin sodium treatment must be stopped 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 must be investigated and appropriate treatment started. As with other anticoagulant therapy, enoxaparin sodium should be used with caution in conditions with an increased potential for bleeding, such as:
impaired haemostasis,
history of peptic ulcer,
recent ischaemic stroke,
severe arterial hypertension,
recent diabetic retinopathy,
neurological or ophthalmological surgery,
concomitantly administered medicinal products affecting haemostasis (see section 4.5).
Laboratory tests
When administered at doses for the prophylaxis of venous thromboembolism, enoxaparin sodium does not significantly affect bleeding time or other complex coagulation tests, has no effect on platelet aggregation and does not significantly affect the binding of fibrinogen to platelets.
At higher doses, a prolongation of the activated partial thromboplastin time (aPTT) or activated clotting time (ACT) may occur. However, this prolongation and the increased antithrombotic effect are not linearly related, and therefore are not suitable for monitoring the activity of enoxaparin sodium.
Spinal/epidural anaesthesia or lumbar puncture
Spinal/epidural anaesthesia must not be performed within 24 hours of administration of enoxaparin sodium at therapeutic doses (see section 4.3).
Cases of neuraxial haematoma 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 exceptional at a dose of 4,000 anti-Xa IU (40 mg) subcutaneously once daily or lower. The risk may be higher with the use of higher doses of enoxaparin sodium, with the use of postoperative epidural catheters or with the concomitant administration of products affecting haemostasis such as NSAIDs, with repeated epidural/spinal punctures, or in patients with a history of spinal surgery or spinal deformity.
With the concomitant use of enoxaparin sodium and epidural/spinal anaesthesia or analgesia or spinal puncture, the pharmacokinetic profile of enoxaparin sodium must be taken into account (see section 5.2). Insertion and removal of the catheter or lumbar puncture is best performed when the anticoagulant activity of enoxaparin sodium is low; however, the precise timing for achieving sufficiently low anticoagulant activity in an individual patient is not known. In patients with a creatinine clearance of [15 to 30 mL/min], further considerations must be taken into account, as the elimination of enoxaparin sodium takes longer (see section 4.2).
If the physician decides to administer anticoagulants 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 back pain in the lumbar region of the spine, sensory and motor deficits (numbness or weakness of the lower limbs), or bowel or bladder dysfunction. Patients should be instructed to inform their physician 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, including spinal decompression, must be initiated, 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 LMWHs. In such cases, treatment must be stopped immediately.
Percutaneous coronary revascularisation
To minimise the risk of bleeding following the 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 in order 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 continue, the next dose should not be given until 6 to 8 hours after removal of the sheath. 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 unavoidable, the decision must be made only after a careful individual assessment of the benefit/risk balance.
Mechanical prosthetic heart valve
The use of enoxaparin sodium for thromboprophylaxis in patients with a mechanical prosthetic heart valve has not been adequately studied. Isolated cases of thrombosis of a mechanical prosthetic heart valve have been reported in patients with a mechanical prosthetic heart valve who received enoxaparin sodium for thromboprophylaxis. Confounding circumstances, including the underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom the thrombosis caused the death of both mother and foetus.
Pregnant women with a mechanical prosthetic heart valve
The use of enoxaparin sodium for thromboprophylaxis in pregnant women with a mechanical prosthetic heart valve has not been adequately studied. In a clinical study of pregnant women with a mechanical prosthetic valve who received enoxaparin sodium 100 IU/kg (1 mg/kg) twice daily to reduce the risk of thromboembolism, 2 of 8 women developed blood clots that blocked the valve and caused the death of the mother and foetus. Isolated cases of valve thrombosis have been reported post-marketing in pregnant women with a mechanical prosthetic heart valve who received enoxaparin sodium prophylactically. Pregnant women with a mechanical prosthetic heart valve may be at higher risk of thromboembolism.
Elderly patients
No increased tendency to bleeding was observed with the administration of prophylactic doses.
Elderly patients (particularly those aged 80 years and over) may be at higher risk of bleeding complications with the administration of therapeutic doses of enoxaparin sodium. Careful clinical monitoring is therefore recommended, and a dose reduction may be considered in patients over 75 years of age treated for STEMI (see sections 4.2 and 5.2).
Renal impairment
Patients with renal impairment are exposed to a higher effect of enoxaparin sodium, which increases the risk of bleeding. Careful clinical monitoring is recommended in these patients, and biological monitoring by measurement of anti-Xa activity could 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 a markedly higher effect of enoxaparin sodium, and adjustment of the therapeutic and prophylactic dosing regimens is therefore recommended (see section 4.2).
No dose adjustment is necessary 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, due to 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 a higher effect of the medicinal product when given prophylactic doses of enoxaparin sodium (not adjusted for the patient's body weight), which may lead to a higher risk of bleeding. Careful monitoring of such patients is therefore recommended (see section 5.2).
Obese patients
Obese patients are at higher 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. In these patients, the signs and symptoms of thromboembolism should be carefully monitored.
Hyperkalaemia
Heparins can suppress the secretion of aldosterone by the adrenal glands, causing 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, particularly in at-risk patients.
Traceability of the medicinal product
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 of 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) with an unknown frequency of occurrence has been reported in association with enoxaparin treatment. Patients should be informed of the signs and symptoms at the time of prescribing 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).
