AROVI^®▼
(enoxaparin sodium)

Very Common (≥1/10):

Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality), haemorrhage, thrombocytosis.

Common (≥1/100 to <1/10):

Haemorrhage, haemorrhagic anaemia^‡, thrombocytopenia, thrombocytosis, allergic reaction, headache^‡, urticaria, pruritus, erythema, injection site haematoma, injection site pain, other injection site reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction).

Uncommon (≥1/1,000 to <1/100):

Hepatocellular liver injury^‡, bullous dermatitis, local irritation, skin necrosis at injection site, intracranial haemorrhage, retroperitoneal haemorrhage, thrombocytopenia.

Rare (≥1/10,000 to <1/1,000):

Eosinophilia^‡, cases of immunoallergic thrombocytopenia with thrombosis; in some of them thrombosis was complicated by organ infarction or limb ischaemia, anaphylactic/ anaphylactoid reactions including shock^‡, spinal haematoma^‡ (or neuraxial haematoma) – these reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis, cholestatic liver injury^‡, alopecia^‡, 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), osteoporosis^‡ following long term therapy (greater than 3 months), hyperkalaemia^‡, retroperitoneal haemorrhage.

Very Rare (<1/10,000):

Immunoallergic thrombocytopenia.

Not Known (cannot be estimated from the available clinical trial data):

Acute generalized exanthematous pustulosis (AGEP).

^‡Indicates reactions from post-marketing experience

Haemorrhages

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.

*such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage.

^†frequency based on a retrospective study on a registry including 3526 patients.

Thrombocytopenia and thrombocytosis 

^‡Platelet increased >400 G/L

Enoxaparin sodium is contraindicated in patients with:

• Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWH).
• History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies.
• Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding, recent brain, spinal or ophthalmic surgery, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities.
• Spinal or epidural anaesthesia or loco-regional anaesthesia when enoxaparin sodium is used for treatment in the previous 24 hours.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General

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.

History of HIT (>100 days)

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. 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).

Monitoring of platelet counts

In patients with cancer with a platelet count below 80 G/L, anticoagulation treatment can only be considered on a case-by-case basis and careful monitoring is recommended.

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.

Haemorrhage

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:

• impaired haemostasis
• history of peptic ulcer
• recent ischemic stroke
• severe arterial hypertension
• recent diabetic retinopathy
• neuro- or ophthalmologic surgery
• concomitant use of medications affecting haemostasis

Laboratory tests

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

Spinal/epidural anaesthesia or lumbar puncture must not be performed within 24 hours of administration of enoxaparin sodium at therapeutic doses.

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. 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.

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 / cutaneous vasculitis

Skin necrosis and cutaneous vasculitis have been reported with LMWHs and should lead to prompt treatment discontinuation.

Percutaneous coronary revascularization procedures

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.

Acute infective endocarditis

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.

Mechanical prosthetic heart valves

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.

Pregnant women with mechanical prosthetic heart valves

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 post-marketing 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.

Elderly

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.

Renal impairment

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.

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.

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.

Hepatic 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.

Low weight

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.

Obese Patients

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.

Hyperkalaemia

Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia particularly in patients such as those with diabetes mellitus, chronic renal failure, preexisting metabolic acidosis, taking medicinal products known to increase potassium. Plasma potassium should be monitored regularly especially in patients at risk.

Acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) has been reported with frequency not known in association with enoxaparin treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, enoxaparin should be withdrawn immediately and an alternative treatment considered (as appropriate).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.