Clexane pre-filled syringes Ref.[2796] Active ingredients: Enoxaparin

Low Molecular Weight Heparins should not be used interchangeably since they differ in their manufacturing process, molecular weights, specific anti Xa activities, units and dosage. This results in differences in pharmacokinetics and associated biological activities (e.g. anti-IIa activity, and platelet interactions). Special attention and compliance with the instructions for use specific to each proprietary medicinal product are therefore required.

Enoxaparin is to be used with extreme caution in patients with a history of heparin-induced thrombocytopenia with or without thrombosis.

As there is a risk of antibody-mediated heparin-induced thrombocytopenia also occurring with low molecular weight heparins, regular platelet count monitoring should be considered prior to and during therapy with these agents. Thrombocytopenia, should it occur, usually appears between the 5th and the 21st day following the beginning of therapy. 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. 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 therapy.

Enoxaparin injection, 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 ischaemic stroke, uncontrolled severe arterial hypertension, diabetic retinopathy, recent neuro- or ophthalmologic surgery.

As with other anticoagulants, bleeding may occur at any site (see section 4.8 Undesirable effects). If bleeding occurs, the origin of the haemorrhage should be investigated and appropriate treatment instituted.

Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, a raised plasma potassium or taking potassium sparing drugs. The risk of hyperkalaemia appears to increase with duration of therapy but is usually reversible. Plasma potassium should be measured in patients at risk before starting heparin therapy and monitored regularly thereafter particularly if treatment is prolonged beyond about 7 days.

As with other anti-coagulants, there have been cases of intra-spinal haematomas reported with the concurrent use of enoxaparin sodium and spinal/epidural anaesthesia or spinal puncture resulting in long term or permanent paralysis. These events are rare with enoxaparin sodium dosage regimens 40 mg od or lower. The risk is greater with higher enoxaparin sodium dosage regimens, use of post-operative indwelling catheters or the concomitant use of additional drugs affecting haemostasis such as NSAIDs (see section 4.5 Interaction with other medicinal products and other forms of interaction). The risk also appears to be increased by traumatic or repeated neuraxial 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 anaesthesia/analgesia, the pharmacokinetic profile of the drug should be considered (see section 5.2 Pharmacokinetic properties). Placement and removal of the catheter is best performed when the anticoagulation effect of enoxaparin is low.

Placement or removal of a catheter should be delayed for 10 – 12 hours after administration of DVT prophylactic doses of enoxaparin sodium, whereas patients receiving higher doses of enoxaparin sodium (1.5 mg/kg once daily) will require longer delays (24 hours). The subsequent enoxaparin sodium dose should be given no sooner than 4 hours after catheter removal.

Should the physician decide to administer anticoagulation in the context of epidural/spinal anaesthesia, extreme vigilance and 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. Patients should be instructed to inform their nurse or physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal haematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.

Percutaneous coronary revascularisation procedures

To minimise the risk of bleeding following vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-elevation myocardial infarction, adhere precisely to the intervals recommended between enoxaparin sodium doses. It is important to achieve homeostasis at the puncture site after PCI. If 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 treatment 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 haematoma formation.

For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment such as thrombolysis or surgery may be indicated.

Prosthetic Heart Valves

There have been no adequate studies to assess the safe and effective use of enoxaparin sodium in preventing valve thrombosis in patients with prosthetic heart valves. Prophylactic doses of enoxaparin are not sufficient to prevent valve thrombosis in patients with prosthetic heart valves. Confounding factors, including underlying diseases and insufficient clinical data, limit the evaluation of these cases. Therapeutic failures have been reported in pregnant women with prosthetic heart valves on full anti-coagulant doses (see section 4.6 Pregnancy and lactation). The use of enoxaparin sodium cannot be recommended for this purpose.

Haemorrhage in the elderly: No increased bleeding tendency is observed in the elderly within the prophylactic dosage ranges. Elderly patients (especially patients aged eighty years and above) may be at an increased risk for bleeding complications within the therapeutic dosage ranges. In the treatment of acute ST-segment Elevation Myocardial Infarction (STEMI), an increase in bleeding events was observed in patients aged 65-75 years suggesting these patients might be at particular risk of bleeding. Careful clinical monitoring is advised (see also section 4.2 Posology and method of administration: Elderly; section 5.2 Pharmacokinetic properties).

Renal impairment: In patients with renal impairment, there is an increase in enoxaparin exposure which increases the risk of bleeding. Since enoxaparin exposure is significantly increased in patients with severe renal impairment (creatinine clearance < 30 ml/min) dosage adjustments are recommended in therapeutic and prophylactic dosage ranges. Although no dosage adjustments are recommended in patients with moderate (creatinine clearance 30-50 ml/min) and mild (creatinine clearance 50-80 ml/min) renal impairment, careful clinical monitoring is advised (see also section 4.2 Posology and method of administration: Renal impairment; section 5.2 Pharmacokinetic properties). In the treatment of acute ST-segment Elevation Myocardial Infarction (STEMI), the data are limited in patients with creatinine levels above 220 and 175 µmol/L for males and females respectively.

Low body weight: In low-weight women (< 45 kg) and low-weight men (< 57 kg), an increase in enoxaparin exposure has been observed within the prophylactic dosage ranges (non-weight adjusted), which may lead to a higher risk of bleeding. Therefore, careful clinical monitoring is advised in these patients (see also section 5.2 Pharmacokinetic properties).

Monitoring: Risk assessment and clinical monitoring are the best predictors of the risk of potential bleeding. Routine anti-Xa activity monitoring is usually not required. However, anti-Xa activity monitoring might be considered in those patients treated with LMWH who also have either an increased risk of bleeding (such as those with renal impairment, elderly and extremes of weight) or are actively bleeding.

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 APTT (activated partial thromboplastin time) and ACT (activated clotting time) 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.

It is recommended that agents which affect haemostasis should be discontinued prior to enoxaparin therapy unless their use is essential, such as: systemic salicylates, acetylsalicylic acid, NSAIDs including ketorolac, dextran, and clopidogrel, systemic glucocorticoids, thrombolytics and anticoagulants. If the combination cannot be avoided, enoxaparin should be used with careful clinical and laboratory monitoring.

Pregnancy: Animal studies have not shown any evidence of foetotoxicity or teratogenicity. In the pregnant rat, the transfer of ³⁵S-enoxaparin across the maternal placenta to the foetus is minimal.

In humans, there is no evidence that enoxaparin crosses the placental barrier during the second trimester of pregnancy. There is no information available concerning the first and the third trimesters.

As there are no adequately powered and well-controlled studies in pregnant women and because animal studies are not always predictive of human response, this drug should be used during pregnancy only if the physician has established a clear need.

Pregnant women with mechanical prosthetic heart valves

The use of enoxaparin 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 (1 mg/kg bid) 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 for thromboprophylaxis. Pregnant women with mechanical prosthetic heart valves may be at higher risk for thromboembolism. Enoxaparin sodium is not recommended for use in pregnant women with prosthetic heart valves (see section 4.4 Special warnings and precautions for use: Prosthetic heart valves).

Lactation: In lactating rats, the concentration of ³⁵S-enoxaparin or its labelled metabolites in milk is very low.

It is not known whether unchanged enoxaparin is excreted in human breast milk. The oral absorption of enoxaparin is unlikely. However, as a precaution, lactating mothers receiving enoxaparin should be advised to avoid breast-feeding.

Enoxaparin has no effect on the ability to drive and operate machines.

The adverse reactions observed in clinical studies and reported in 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).

Adverse events which have not been observed in clinical trials, but were reported in post-marketing experience are ranked under the frequency “Rare”.

Haemorrhages

In clinical studies, haemorrhages were the most commonly reported reaction. These included major haemorrhages, reported at most in 4.2 % of the patients (surgical patients1). Some of these cases have been fatal.

As with other anticoagulants, haemorrhage may occur during enoxaparin therapy 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 section 4.5 Interaction with other medicinal products and other forms of interaction ). The origin of the bleeding should be investigated and appropriate treatment instituted.

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

In addition, in post marketing experience

Rare: Cases of spinal haematoma (or neuraxial haematoma) have been reported with the concurrent use of enoxaparin sodium as well as spinal/epidural anaesthesia or spinal puncture and post operative indwelling catheters. These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis (see section 4.4 Special warnings and precautions for use).

¹ In surgical patients, haemorrhage complications were considered major: (1) if the haemorrhage caused a significant clinical event, or (2) if accompanied by an haemoglobin decrease ≥ 2 g/dL or transfusion of 2 or more units of blood products. Retroperitoneal and intracranial haemorrhages were always considered major.

Thrombocytopenia and thrombocytosis

* Platelet increased > 400 G/L

In addition, in post marketing experience

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 Special warnings and precautions for use: Monitoring).

Other clinically relevant adverse reactions

These reactions are presented below, whatever the indications, by system organ class, frequency grouping and decreasing order of seriousness.

* such as injection site oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction (NOS)
==**==transaminases levels > 3 times the upper limit of normality

In addition, in post marketing experience

Skin and subcutaneous disorders

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). Treatment with enoxaparin sodium must be discontinued.
• Injection site nodules (inflammatory nodules, which were not cystic enclosure of enoxaparin). They resolve after a few days and should not cause treatment discontinuation.

Valve thrombosis in patients with prosthetic heart valves have been reported rarely, usually associated with inadequate dosing (see section 4.4 Special warnings and precautions for use).

Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with enoxaparin the risk of osteoporosis cannot be excluded.

Heparin products can cause hypoaldosteronism which may result in an increase in plasma potassium. Rarely, clinically significant hyperkalaemia may occur particularly in patients with chronic renal failure and diabetes mellitus (see section 4.4 Special warnings and precautions for use).

Subcutaneous Injection: Clexane should not be mixed with any other injections or infusions.

Intravenous (Bolus) Injection for acute STEMI indication only:
Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.