Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Laboratorios Farmacéuticos ROVI, S.A., Julián Camarillo, 35, 2803, Madrid, Spain
Enoxaparin sodium is contraindicated in patients with:
Enoxaparin sodium cannot be used interchangeably (unit for unit) with other LMWHs. These medicinal products differ in their manufacturing process, molecular weights, specific anti-Xa and anti-IIa activities, units, dosage and clinical efficacy and safety. This results in differences in pharmacokinetics and associated biological activities (e.g. anti-thrombin activity, and platelet interactions). Special attention and compliance with the instructions for use specific to each proprietary medicinal product are therefore required.
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 several years.
Enoxaparin sodium is to be used with extreme caution in patients with a history (>100 days) of heparin-induced thrombocytopenia without circulating antibodies. The decision to use enoxaparin sodium in such a case must be made only after a careful benefit risk assessment and after non-heparin alternative treatments are considered (e.g. danaparoid sodium or lepirudin).
The risk of antibody-mediated HIT also exists with LMWHs. Should thrombocytopenia occur, it usually appears between the 5th and the 21st day following the beginning of enoxaparin sodium treatment.
The risk of HIT is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer.
Therefore, it is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment.
If there are clinical symptoms suggestive of HIT (any new episode of arterial and/or venous thromboembolism, any painful skin lesion at the injection site, any allergic or anaphylactoid reactions on treatment), platelet count should be measured. Patients must be aware that these symptoms may occur and if so, that they should inform their primary care physician.
In practice, if a confirmed significant decrease of the platelet count is observed (30 to 50% of the initial value), enoxaparin sodium treatment must be immediately discontinued and the patient switched to another non-heparin anticoagulant alternative treatment.
As with other anticoagulants, bleeding may occur at any site. If bleeding occurs, the origin of the haemorrhage should be investigated and appropriate treatment instituted.
Enoxaparin sodium, as with any other anticoagulant therapy, should be used with caution in conditions with increased potential for bleeding, such as:
At doses used for prophylaxis of venous thromboembolism, enoxaparin sodium does not influence bleeding time and global blood coagulation tests significantly, nor does it affect platelet aggregation or binding of fibrinogen to platelets.
At higher doses, increases in activated partial thromboplastin time (aPTT), and activated clotting time (ACT) may occur. Increases in aPTT and ACT are not linearly correlated with increasing enoxaparin sodium antithrombotic activity and therefore are unsuitable and unreliable for monitoring enoxaparin sodium activity.
Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of enoxaparin sodium at therapeutic doses (see also section 4.3).
There have been cases of neuraxial haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia or spinal puncture procedures resulting in long term or permanent paralysis. These events are rare with enoxaparin sodium dosage regimens 4,000 IU (40 mg) once daily or lower. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting haemostasis such as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), with 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 the concurrent use of enoxaparin sodium and epidural or spinal anaesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin sodium (see section 5.2). Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. For patients with creatinine clearance [15-30 mL/minute], additional considerations are necessary because elimination of enoxaparin sodium is more prolonged (see section 4.2).
Should the physician decide to administer anticoagulation in the context of epidural or spinal anaesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment discontinuation.
To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation.
Use of heparin is usually not recommended in patients with acute infective endocarditis due to the risk of cerebral haemorrhage. If such use is considered absolutely necessary, the decision must be made only after a careful individual benefit risk assessment.
The use of enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients with mechanical prosthetic heart valves. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received enoxaparin sodium for thromboprophylaxis. Confounding factors, including underlying disease and insufficient clinical data, limit the evaluation of these cases. Some of these cases were pregnant women in whom thrombosis led to maternal and foetal death.
The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin sodium (100 IU/kg (1 mg/kg ) twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and foetal death. There have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin sodium for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism.
No increased bleeding tendency is observed in the elderly with the prophylactic dosage ranges. Elderly patients (especially patients eighty years of age and older) may be at an increased risk for bleeding complications with the therapeutic dosage ranges. Careful clinical monitoring is advised and dose reduction might be considered in patients older than 75 years treated for STEMI (see sections 4.2 and 5.2).
In patients with renal impairment, there is an increase in exposure of enoxaparin sodium which increases the risk of bleeding. In these patients, careful clinical monitoring is advised, and biological monitoring by anti-Xa activity measurement might be considered (see sections 4.2 and 5.2).
Enoxaparin sodium is not recommended for patients with end stage renal disease (creatinine clearance <15 mL/min) due to lack of data in this population outside the prevention of thrombus formation in extra corporeal circulation during haemodialysis.
In patients with severe renal impairment (creatinine clearance 15-30 mL/min), since exposure of enoxaparin sodium is significantly increased, a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges (see section 4.2).
No dose adjustment is recommended in patients with moderate (creatinine clearance 30-50 mL/min) and mild (creatinine clearance 50-80 mL/min) renal impairment.
Enoxaparin sodium should be used with caution in patients with hepatic impairment due to an increased potential for bleeding. Dose adjustment based on monitoring of anti-Xa levels is unreliable in patients with liver cirrhosis and not recommended (see section 5.2).
An increase in exposure of enoxaparin sodium with prophylactic dosages (non-weight adjusted) has been observed in low-weight women (<45 kg) and low-weight men (<57 kg), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients (see section 5.2).
Obese patients are at higher risk for thromboembolism. The safety and efficacy of prophylactic doses in obese patients (BMI >30 kg/m2) has not been fully determined and there is no consensus for dose adjustment. These patients should be observed carefully for signs and symptoms of thromboembolism.
Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia (see section 4.8), particularly in patients such as those with diabetes mellitus, chronic renal failure, preexisting metabolic acidosis, taking medicinal products known to increase potassium (see section 4.5). Plasma potassium should be monitored regularly especially in patients at risk.
LMWHs are biological medicinal products. In order to improve the LMWH traceability, it is recommended that health care professionals record the trade name and batch number of the administered product in the patient file.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.
Medicinal products affecting haemostasis (see section 4.4):
It is recommended that some agents which affect haemostasis should be discontinued prior to enoxaparin sodium therapy unless strictly indicated. If the combination is indicated, enoxaparin sodium should be used with careful clinical and laboratory monitoring when appropriate. These agents include medicinal products such as:
The following medicinal products may be administered with caution concomitantly with enoxaparin sodium:
Other medicinal products affecting haemostasis such as:
Medicinal products increasing potassium levels:
Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin sodium under careful clinical and laboratory monitoring (see sections 4.4 and 4.8).
In humans, there is no evidence that enoxaparin crosses the placental barrier during the second and third trimester of pregnancy. There is no information available concerning the first trimester.
Animal studies have not shown any evidence of foetotoxicity or teratogenicity (see section 5.3). Animal data have shown that enoxaparin passage through the placenta is minimal. Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need.
Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or excessive anticoagulation and should be warned of the haemorrhagic risk. Overall, the data suggest that there is no evidence for an increased risk of haemorrhage, thrombocytopenia or osteoporosis with respect to the risk observed in non-pregnant women, other than that observed in pregnant women with prosthetic heart valves (see section 4.4).
If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before (see section 4.4).
It is not known whether unchanged enoxaparin is excreted in human breast milk. In lactating rats, the passage of enoxaparin or its metabolites in milk is very low. The oral absorption of enoxaparin sodium is unlikely. Arovi can be used during breastfeeding.
There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on fertility (see section 5.3).
Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.
Enoxaparin sodium has been evaluated in more than 15,000 patients who received enoxaparin sodium in clinical trials. These included 1,776 for prophylaxis of deep vein thrombosis following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications, 1,169 for prophylaxis of deep vein thrombosis in acutely ill medical patients with severely restricted mobility, 559 for treatment of DVT with or without PE, 1,578 for treatment of unstable angina and non-Q-wave myocardial infarction and 10,176 for treatment of acute STEMI.
Enoxaparin sodium regimen administered during these clinical trials varies depending on indications. The enoxaparin sodium dose was 4,000 IU (40 mg) SC once daily for prophylaxis of deep vein thrombosis following surgery or in acutely ill medical patients with severely restricted mobility. In treatment of DVT with or without PE, patients receiving enoxaparin sodium were treated with either a 100 IU/kg (1 mg/kg) SC dose every 12 hours or a 150 IU/kg (1.5 mg/kg) SC dose once a day. In the clinical studies for treatment of unstable angina and non-Q-wave myocardial infarction, doses were 100 IU/kg (1 mg/kg) SC every 12 hours, and in the clinical study for treatment of acute STEMI enoxaparin sodium regimen was a 3,000 IU (30 mg) IV bolus followed by 100 IU/kg (1 mg/kg) SC every 12 hours.
In clinical studies, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported reactions (see section 4.4 and ‘Description of selected adverse reactions’ below).
Other adverse reactions observed in clinical studies and reported in post-marketing experience (* indicates reactions from post-marketing experience) are detailed below.
Frequencies are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); and very rare (<1/10,000) or not known (cannot be estimated from available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.
Common: Haemorrhage, haemorrhagic anaemia*, thrombocytopenia, thrombocytosis
Rare: Eosinophilia*
Rare: Cases of immuno-allergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia (see section 4.4).
Common: Allergic reaction
Rare: Anaphylactic/Anaphylactoid reactions including shock*
Common: Headache*
Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see section 4.4).
Very common: Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality)
Uncommon: Hepatocellular liver injury*
Rare: Cholestatic liver injury*
Common: Urticaria, pruritus, erythema
Uncommon: Bullous dermatitis
Rare: Alopecia*
Rare: Cutaneous vasculitis*, skin necrosis* usually occurring at the injection site (these phenomena have been usually preceded by purpura or erythematous plaques, infiltrated and painful).
Injection site nodules* (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation.
Rare: Osteoporosis* following long term therapy (greater than 3 months)
Common: Injection site haematoma, injection site pain, other injection site reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction)
Uncommon: Local irritation, skin necrosis at injection site
Rare: Hyperkalaemia* (see sections 4.4 and 4.5).
These included major haemorrhages, reported at most in 4.2% of the patients (surgical patients). Some of these cases have been fatal. In surgical patients, haemorrhage complications were considered major: (1) if the haemorrhage caused a significant clinical event, or (2) if accompanied by haemoglobin decrease ≥2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always considered major.
As with other anticoagulants, haemorrhage may occur in the presence of associated risk factors such as: organic lesions liable to bleed, invasive procedures or the concomitant use of medications affecting haemostasis (see sections 4.4 and 4.5).
| System Organ Class | Prophylaxis in surgical patients | Prophylaxis in medical patients | Treatment in patients with DVT with or without PE | Treatment in patients with unstable angina and non-Q-wave MI | Treatment in patients with acute STEMI |
|---|---|---|---|---|---|
| Blood and lymphatic system disorders | Very common: Haemorrhageα Rare: Retroperitoneal haemorrhage | Common: Haemorrhageα | Very common: Haemorrhageα Uncommon: Intracranial haemorrhage, Retroperitoneal haemorrhage | Common: Haemorrhageα Rare: Retroperitoneal haemorrhage | Common: Haemorrhageα Uncommon: Intracranial haemorrhage, Retroperitoneal haemorrhage |
α such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage.
| System Organ Class | Prophylaxis in surgical patients | Prophylaxis in medical patients | Treatment in patients with DVT with or without PE | Treatment in patients with unstable angina and non-Q-wave MI | Treatment in patients with acute STEMI |
|---|---|---|---|---|---|
| Blood and lymphatic system disorders | Very common: Thrombocytosisβ Common: Thrombocytopenia | Uncommon: Thrombocytopenia | Very common: Thrombocytosisβ Common: Thrombocytopenia | Uncommon: Thrombocytopenia | Common: Thrombocytosisβ, Thrombocytopenia Very rare: Immuno-allergic thrombocytopenia |
β Platelet increased >400 G/L
The safety and efficacy of enoxaparin sodium in children have not been established (see section 4.2).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at:www.mhra.gov.uk/yellowcard.
SC injection: Do not mix with other products.
IV (Bolus) Injection (for acute STEMI indication only): Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water (see section 4.2).
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