Enoxaparin

Registered South African indications:

• Risk reduction of post-operative venous thrombosis and embolism
  - In high-risk patients (e.g. orthopaedic surgery)
  - In moderate-risk patients (e.g. abdominal surgery)
• Risk reduction of venous thromboembolism in patients bedridden due to debilitating medical illnesses
• Deep venous thrombosis with or without pulmonary embolism
• Risk reduction of ischaemic complications of unstable angina or non-Q-wave myocardial infarction, within 24 hours of onset
• Risk reduction of thrombus formation in extracorporeal circulation during haemodialysis
• Acute ST-segment elevation myocardial infarction (STEMI) including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI)

Contraindications

South African recommendations & Recommendations in other jurisdictions 

• Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including other low molecular weight heparins (LMWH) or to any of the excipients
• History of immune mediated heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies
• Active clinically significant bleeding
• Conditions with a high risk of haemorrhage 
  - 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

Cautions

• Pregnancy (including pregnant women with mechanical prosthetic heart valves)
• Renal impairment
• Hepatic impairment
• Elderly (≥75 years, treated for STEMI)
• History (>100 days) of heparin-induced thrombocytopenia without circulating antibodies
• Risk factors for antibody-mediated heparin-induced thrombocytopenia
  - Postoperative patients mainly after cardiac surgery
  - Cancer patients
• Conditions with increased potential for bleeding
  - Impaired haemostasis
  - History of peptic ulcer
  - Recent ischaemic stroke
  - Severe arterial hypertension
  - Recent diabetic retinopathy
  - Neurosurgery
  - Ophthalmic surgery
  - Use of medications affecting haemostasis
• Spinal/epidural anaesthesia within 24 hours of enoxaparin administration
• Lumbar puncture within 24 hours of enoxaparin administration
• Post-operative indwelling epidural catheters
• Traumatic or repeated epidural or spinal puncture
• History of spinal surgery
• Spinal deformity
• Acute infective endocarditis
• Mechanical prosthetic heart valves
• Women <45kg
• Men <57kg
• Obesity (BMI >30kg/m²)
• Risk factors for hyperkalaemia
  - Diabetes mellitus
  - Chronic renal failure
  - Pre-existing metabolic acidosis
  - Use of agents known to increase potassium
• Sodium restricted diets
• Enoxaparin sodium cannot be used interchangeably (unit-for-unit) with other LMWH

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosage

Risk reduction of post-operative venous thrombosis and embolism
- In high-risk patients (e.g. orthopaedic surgery)

• SC: Orthopaedic surgery: 40mg, dly with first injection given 12hrs pre-operatively; Treatment duration: 7-10 days after surgery or as long as there is a risk of venous thromboembolism until the patient is ambulatory
• SC: Total hip replacement: 40mg, dly; Treatment duration: 3 weeks following the initial therapy has been proven to be beneficial

- In moderate-risk patients (e.g. abdominal surgery)

• SC: General surgery: 20mg, dly with first injection given 2hrs pre-operatively;  Treatment duration: 7-10 days after surgery or as long as there is a risk of venous thromboembolism until the patient is ambulatory

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Treatment is continued for as long as the risk of thromboembolism persists

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Risk reduction of venous thromboembolism in patients bedridden due to debilitating medical illnesses

• SC: 40mg, dly; Treatment duration: ≥6 days and continued until the return to full ambulation; Max duration: 14 days

Deep venous thrombosis with or without pulmonary embolism

• SC: 1mg/kg, 12hrly; Oral anticoagulant therapy should be initiated when appropriate; Enoxaparin treatment should be continued until a therapeutic anticoagulant effect has been achieved (International Normalised Ratio 2-3); Treatment duration: 5-10 days

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Safety of home treatment for this indication has not been established

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Risk reduction of ischaemic complications of unstable angina or non-Q-wave myocardial infarction, within 24hrs of onset (Additional agent required)
- In combination with aspirin (100-325mg, dly) for 8 days, or until stabilisation, revascularisation or discharge from hospital

• SC: 1mg/kg, 12hrly; Treatment duration: ≥2 days and continue until clinical stabilisation; Usual treatment duration: 2-8 days

Risk reduction of thrombus formation in extracorporeal circulation during haemodialysis

• IV: 1mg/kg; During haemodialysis, enoxaparin should be introduced into the arterial line of the circuit at the beginning of the dialysis session; Effect of this dose is usually sufficient for a 4hr session; If fibrin rings are found, for example after a longer than normal session: Further dose: 0.5-1mg/kg, may be given

- High risk of haemorrhage

• IV: Double vascular access: 0.5mg/kg; Single vascular access: 0.75mg/kg; During haemodialysis, enoxaparin should be introduced into the arterial line of the circuit at the beginning of the dialysis session; Effect of this dose is usually sufficient for a 4hr session; If fibrin rings are found, for example after a longer than normal session: Further dose: 0.5-1mg/kg, may be given

Acute ST-segment elevation myocardial infarction (STEMI)

• IV: 30mg, as a single bolus; Plus: SC: 1mg/kg; Then: SC: 1mg/kg, 12hrly; Max: 100mg for the first 2 doses only, followed by 1mg/kg for the remaining doses; Treatment duration: 8 days or until hospital discharge, whichever comes first

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When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. All patients should receive aspirin as soon as they are identified as having STEMI and maintained on an appropriate dose once daily, unless contraindicated

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Patients managed medically or with subsequent percutaneous coronary intervention (PCI)

• If the last enoxaparin SC administration was given <8hrs before balloon inflation: No additional dosing is requuired
• IV: If the last enoxaparin SC administration was given >8hrs before balloon inflation: 0.3mg/kg, bolus should be administered

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Indications and dosages registered in other jurisdictions

Prophylaxis of venous thromboembolic disease
- In high-risk patients, in particular those undergoing orthopaedic or general surgery including cancer surgery

• SC: 40mg, dly with first injection given preferably 12hrs pre-operatively; Major orthopaedic surgery: Treatment duration: Up to 5 weeks; High venous thromboembolism (VTE) risk after abdominal or pelvic surgery for cancer: Up to 4 weeks 

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If there is a need for earlier than 12 hours enoxaparin sodium preoperative prophylactic initiation (e.g. high risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no later than 12 hours prior to surgery and resumed 12 hours after surgery

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- In moderate-risk patients

• SC: 20mg, dly with first injection given 2hrs pre-operatively; Treatment duration: ≥7-10 days whatever the recovery status (e.g. mobility); Prophylaxis should be continued until the patient no longer has significantly reduced mobility

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Prophylaxis of venous thromboembolic disease (in moderate and high risk surgical patients): Individual thromboembolic risk for patients can be estimated using validated risk stratification model

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Prophylaxis of venous thromboembolic disease in medical patients with an acute illness 
- Such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of venous thromboembolism

• SC: 40mg, dly; Treatment duration: ≥6-14 days whatever the recovery status (e.g. mobility)

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The benefit is not established for a treatment longer than 14 days

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Deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require thrombolytic therapy or surgery
- Uncomplicated patients with low risk of venous thromboembolism (VTE) recurrence

• SC: 1.5mg/kg (150 IU/kg), dly; Treatment duration: 10 days (average period); Oral anticoagulant therapy should be initiated when appropriate 

- All other patients such as those with obesity, with symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis

• SC: 1mg/kg (100 IU/kg), 12hrly; Treatment duration: 10 days (average period); Oral anticoagulant therapy should be initiated when appropriate

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The regimen should be selected by the physician based on an individual assessment including evaluation of the thromboembolic risk and of the risk of bleeding

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Extended treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and prevention of its recurrence in patients with active cancer

• SC: 1mg/kg (100 IU/kg), 12hrly; Treatment duration: 5-10 days; Then: 1.5mg/kg (150 IU/kg), dly; Treatment duration: Up to 6 months

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Carefully assess the individual thromboembolic and bleeding risks of the patient. The benefit of continuous anticoagulant therapy should be reassessed after 6 months of treatment

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Prevention of thrombus formation in extra corporeal circulation during haemodialysis

• IV: 1mg/kg (100 IU/kg); During haemodialysis, enoxaparin should be introduced into the arterial line of the circuit at the beginning of the dialysis session; Effect of this dose is usually sufficient for a 4hr session; If fibrin rings are found, for example after a longer than normal session: Further dose: 0.5-1mg/kg, may be given

- High risk of haemorrhage

• IV: Double vascular access: 0.5mg/kg (50 IU/kg); Single vascular access: 0.75mg/kg (75 IU/kg); During haemodialysis, enoxaparin should be introduced into the arterial line of the circuit at the beginning of the dialysis session; Effect of this dose is usually sufficient for a 4hr session; If fibrin rings are found, for example after a longer than normal session: Further dose: 0.5-1mg/kg, may be given

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No data are available in patients using enoxaparin sodium for prophylaxis or treatment and during haemodialysis sessions

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Acute coronary syndrome
- Unstable angina and Non ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid

• SC: 1mg/kg (100 IU/kg), 12hrly; Treatment duration: ≥2 days and continued until clinical stabilization; Usual treatment duration: 2-8 days

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Acetylsalicylic acid is recommended for all patients without contraindications at an initial oral loading dose of 150–300mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325mg/day long-term regardless of treatment strategy

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Acute ST-segment elevation myocardial infarction (STEMI)

• IV: 30mg (3000 IU (three thousand IU)), as a single bolus; Plus: SC: 1mg/kg (100 IU/kg); Then: SC: 1mg/kg, 12hrly; Max: 100mg (10000 IU (ten thousand IU) for each of the first 2 SC doses; Treatment duration: 8 days or until hospital discharge, whichever comes first

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Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75-325mg once daily) should be administered concomitantly unless contraindicated. When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy

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Patients to be managed medically or with subsequent percutaneous coronary intervention (PCI)

• If the last enoxaparin SC administration was given <8hrs before balloon inflation: No additional dosing is requuired
• IV: If the last enoxaparin SC administration was given >8hrs before balloon inflation: 0.3mg/kg (30 IU/kg), bolus should be administered

Not established for use in children

Pregnancy 

• Caution
• 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

Breastfeeding 

• Compatible
• 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 sodium 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

Renal Impairment

• Mild to moderate (CrCl 30-80ml/min) : Caution; no dose adjustment recommended
• Severe (CrCl 15-30ml/min) Caution; dose adjustment recommended
  Refer to table below for dosing regimen recommendations
• End stage renal disease (CrCl <15ml/min): Caution; no information available
  Not recommended for patients with end stage renal disease (CrCl <15ml/min) due to lack of data in this population outside the prevention of thrombus formation in extracorporeal circulation during haemodialysis

Indication	Dosing regimen
Prophylaxis of venous thromboembolic disease	SC: 20mg, dly
Treatment of deep vein thrombosis and pulmonary embolism	SC: 1mg/kg, dly
Treatment of unstable angina and NSTEMI	SC: 1mg/kg, dly
Treatment of STEMI (<75 years)	IV/SC: Initial: 30mg IV as a single bolus; Plus 1mg/kg SC; Then 1mg/kg SC, dly
Treatment of STEMI (>75 years)	SC: Initial: 1mg/kg; Then 1mg/kg SC, dly No IV initial bolus

Hepatic Impairment 

• Caution; no information available 
  Limited data are available in patients with hepatic impairment and caution should be used in these patients

Elderly

• Non-STEMI indications: No dose adjustment recommended
  Unless renal function is impaired (see renal impairment for dosing regimen recommendations)
• Acute STEMI: Caution; dose adjustment recommended
  ≥75 years: IV bolus should not be used; SC: Initial: 0.75mg/kg, 12hrly; Max: 75mg/dose (for each of the first two SC doses only); Followed by 0.75mg/kg for the remaining doses

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders 

• Headache
• Intracranial haemorrhage

Cardiovascular Disorders 

• Spinal haematoma
• Neuraxial haematoma

Hepatobiliary Disorders 

• Increased hepatic enzymes
• Hepatocellular liver injury
• Cholestatic liver injury

Endocrine and Metabolic Disorders 

• Hyperkalaemia

Musculoskeletal Disorders 

• Osteoporosis (>3 months use)

Skin and Subcutaneous Tissue Disorders 

• Urticaria
• Pruritus
• Erythema
• Bullous dermatitis
• Cutaneous vasculitis
• Injection site nodules
• Alopecia
• Injection site haematoma
• Injection site pain
• Injection site reactions
  - Oedema
  - Haemorrhage
  - Hypersensitivity
  - Inflammation
  - Mass
  - Pain
• Local irritation
• Skin necrosis
  - Preceded by purpura or infiltrated and painful erythematous plaques

Immune, Blood and Lymphatic System Disorders 

• Haemorrhage
  - Haematoma
  - Ecchymosis other than at injection site
  - Wound haematoma
  - Haematuria
  - Epistaxis
  - Gastrointestinal haemorrhage
• Retroperitoneal haemorrhage
• Haemorrhagic anaemia
• Thrombocytopenia
• Thrombocytosis
• Eosinophilia
• Immuno-allergic thrombocytopenia with thrombosis
  - May be complicated by organ infarction or limb ischaemia
• Allergic reaction
• Anaphylactic reaction Including shock

• Agents affecting haemostasis
• Systemic salicylates
• Acetylsalicylic acid at anti-inflammatory doses
• Acetylsalicylic acid at antiaggregant dose (cardioprotection)
• Non-steroidal anti-inflammatory drugs
• Ketorolac
• Platelet aggregation inhibitors
• Clopidogrel
• Ticlopidine
• Glycoprotein IIb/IIIa antagonists
• Dextran 40
• Systemic glucocorticoids
• Other thrombolytic agents
• Alteplase
• Reteplase
• Streptokinase
• Tenecteplase
• Urokinase
• Anticoagulants
• Agents increasing potassium levels

• Platelet count
• Haemoglobin
• Haematocrit
• Serum creatinine
• Faecal occult blood test

None routine. Specific cases may require

• Anti-factor Xa levels
• Renal function
• Serum potassium
• Neurological examination

Additional observations

• Signs and symptoms of bleeding

Traceability 

• 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

Enoxaparin is a low molecular weight heparin in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. The drug substance is the sodium salt. In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity and low anti-IIa or antithrombin activity. These anticoagulant activities are mediated through antithrombin III (ATIII) resulting in antithrombotic activities in humans. Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of enoxaparin have been identified in healthy subjects and patients as well as in non-clinical models. These include ATIII-dependent inhibition of other coagulation factors like factor VIIa, induction of endogenous Tissue Factor Pathway Inhibitor (TFPI) release as well as a reduced release of von Willebrand factor (vWF) from the vascular endothelium into the blood circulation. These factors are known to contribute to the overall antithrombotic effect of enoxaparin sodium. 

Injection (per 0.2ml) 20mg

• Clexane (Sanofi Aventis) originator
• Noxfibra 20 (Sandoz)

Injection (per 0.4ml) 40mg

• Clexane (Sanofi Aventis) originator
• Noxfibra 40 (Sandoz)

Injection (per 0.6ml) 60mg

• Clexane (Sanofi Aventis) originator
• Noxfibra 60 (Sandoz)

Injection(per 0.8ml) 80mg

• Clexane (Sanofi Aventis) originator
• Noxfibra 80 (Sandoz)

Injection (per ml) 100mg

• Clexane (Sanofi Aventis) originator

Injection (per 3ml) 300mg

• Clexane (Sanofi Aventis) originator