Enoxaparin Other names: Enoxaparin sodium

Limited data are available in patients with hepatic impairment and caution should be used in these patients.

Although 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, careful clinical monitoring is advised.

Dose table for patients with severe renal impairment (creatinine clearance [15-30] mL/min):

The recommended dose adjustments do not apply to the haemodialysis indication.

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.

Medicinal products that increase serum potassium levels may be administered concurrently with enoxaparin sodium under careful clinical and laboratory monitoring.

The following medicinal products may be administered with caution concomitantly with enoxaparin sodium.

Medicinal products affecting haemostasis such as:

• Platelet aggregation inhibitors including acetylsalicylic acid used at antiaggregant dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding,
• Dextran 40,
• Systemic glucocorticoids.

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.

Medicinal products affecting haemostasis

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:

• Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including ketorolac,
• Other thrombolytics (e.g. alteplase, reteplase, streptokinase, tenecteplase, urokinase) and anticoagulants.

An increase in exposure of enoxaparin sodium with prophylactic doses (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 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.

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.

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 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.

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).

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. 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.

If an epidural anaesthesia is planned, it is recommended to withdraw enoxaparin sodium treatment before.

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. Enoxaparin can be used during breastfeeding.

Fertility

There are no clinical data for enoxaparin sodium in fertility. Animal studies did not show any effect on fertility.

Enoxaparin sodium has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

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 DVT following orthopaedic or abdominal surgery in patients at risk for thromboembolic complications, 1,169 for prophylaxis of DVT 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 DVT 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 trials 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 trials, haemorrhages, thrombocytopenia and thrombocytosis were the most commonly reported reactions (see 'Description of selected adverse reactions' below).

The safety profile of enoxaparin for extended treatment of DVT and PE in patients with active cancer is similar to its safety profile for the treatment of DVT and PE.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with enoxaparin treatment.

Tabulated list of adverse reactions

Other adverse reactions observed in clinical trials 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.

Blood and the lymphatic system disorders

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.

Immune system disorders

Common: Allergic reaction

Rare: Anaphylactic/Anaphylactoid reactions including shock*

Nervous system disorders

Common: Headache*

Vascular disorders

Rare: Spinal haematoma* (or neuraxial haematoma). These reactions have resulted in varying degrees of neurologic injuries including long-term or permanent paralysis.

Hepatobiliary disorders

Very common: Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality)

Uncommon: Hepatocellular liver injury *

Rare: Cholestatic liver injury*

Skin and subcutaneous tissue disorders

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.

Not known: Acute generalized exanthematous pustulosis (AGEP)

Musculoskeletal and connective tissue disorders

Rare: Osteoporosis* following long term therapy (greater than 3 months)

General disorders and administration site conditions

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

Investigations

Rare: Hyperkalaemia*.

Description of selected adverse reactions

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 medicinal products affecting haemostasis.

^α such as haematoma, ecchymosis other than at injection site, wound haematoma, haematuria, epistaxis and gastro-intestinal haemorrhage.
^b frequency based on a retrospective study on a registry including 3526 patients.

Thrombocytopenia and thrombocytosis:

^β Platelet increased >400 G/L

Paediatric population

The safety and efficacy of enoxaparin sodium in children have not been established.