Clexane ®

Enoxaparin is a low molecular weight heparin marketed as Lovenox or Clexane. It is used to prevent and treat deep vein thrombosis or pulmonary embolism, and is given as a subcutaneous injection (by a health care provider or the patient). Its use is evolving in acute coronary syndromes (ACS).

Enoxaparin is manufactured by Sanofi-Aventis and is derived from the intestinal mucosa of pigs.

Indications

In the UK and Australia, enoxaparin is approved for six indications:

• The prophylaxis of thromboembolism disorders of venous origin, in particular those which may be associated with orthopaedic surgery. There is limited evidence supporting the use of enoxaparin in orthoapedic patients^[1], although evidence is reasonable for colorectal patients^[2]
• The prophylaxis of venous thromboembolism (VTE) in medical patients bedridden due to acute illness.
• The treatment of venous thromboembolism disease (VTED) presenting with deep vein thrombosis (DVT), pulmonary embolism (PE) or both.
• The treatment of unstable angina (UA) and non-Q-wave myocardial infarction (NQMI), administered concurrently with aspirin.
• The prevention of thrombus formation in the extracorporeal circulation during haemodialysis.
• The prevention of thrombus formation during episodes of lone Atrial Fibrillation, administered concurrently with aspirin (in the absence of long term blood thinning treatment with warfarin).

In the United States, enoxaparin is FDA approved for eight indications:

• Prophylaxis of DVT in medically ill patient,
• Total hip & knee replacement,
• Extended hip-replacement,
• Abdominal surgery.
• Treatment of DVT with or without PE inpatient and
• Treatment of DVT inpatient, with ACS, including STEMI.

Mechanism of action

Enoxaparin binds to and accelerates the activity of antithrombin III. By activating antithrombin III, enoxaparin preferentially potentiates the inhibition of coagulation factors Xa and IIa. The anticoagulant effect of enoxaparin can be directly correlated to its ability to inhibit factor Xa. Factor Xa catalyzes the conversion of prothrombin to thrombin, so enoxaparin’s inhibition of this process results in decreased thrombin and ultimately the prevention of fibrin clot formation.

Monitoring

• Enoxaparin does not affect the international normalized ratio (INR), prothrombin time (PT) or activated partial thromboplastin time (aPTT)
• Anti-factor Xa levels can be measured, and are often used to monitor enoxaparin activity

Pregnancy

• Category B: enoxaprin is safe for use in the second trimester as it does not cross the placenta and safe while breast feeding

Renal Dosing

Decreased dose recommended in renal failure or ESRD patients. For DVT prophylaxis in a patient with GFR < 30, a dose of 30mg daily is recommended. For DVT prophylaxis in a patient with GFR > 30, full dose (40mg daily) can be given. For treatment of DVT/PE, the standard recommended dose is 1.5mg/kg once daily. If the GFR < 30, the dose should be changed to 1mg/kg daily.

Side effects

• Bleeding^[3]
• Thrombocytopenia, i.e. can be associated with heparin-induced thrombocytopenia (0.5-5.0% of patients treated for at least five days^[4]
• Pain, bruising or irritation; hard, inflamed nodules or an itchy red rash at the injection site
• Symptoms similar to those of hayfever
• Abdominal/chest pain
• Headache

Reversal Agent

• Protamine, although not as effective at reversal as it is for heparin due to more activity at the Xa clotting factor (enoxaparin); as heparin has both Xa and IIa. Protamine sulfate will reverse enoxaparin by 66% per package insert.

Availability

100 mg/mL concentration

• Prefilled Syringes: 30mg/0.3mL, 40mg/0.4mL
• Graduated Prefilled Syringes: 60mg/0.6mL, 80mg/0.8mL, 100mg/1mL
• Multiple Dose Vials: 300mg/3.0mL

150mg/mL concentration

• Graduated Prefilled Syringes: 120mg/0.8mL, 150mg/1mL

Market

Annual sales approx $3.1bn. Enoxaparin is no longer protected by US patent due to inequitable conduct on the filing of Patent No. 5,389,618 (Fed. Cir. 2008 No. 2007-1280 Aventis Pharma v. Amphastar and Teva)

References

1.       ^ Warwick D, Williams MH, Bannister GC. Death and thromboembolic disease after total hip replacement. A series of 1162 cases with no routine chemical prophylaxis. J Bone Joint Surg Br. 1995 Jan;77(1):6-10. PMID 7822397

2.       ^ Bergqvist D. Venous thromboembolism: a review of risk and prevention in colorectal surgery patients. Dis Colon Rectum. 2006 Oct;49(10):1620-8. PMID 17019655

3.       ^ Warwick D, Bannister GC, Glew D, Mitchelmore A, Thornton M, Peters TJ, Brookes S. Perioperative low-molecular-weight heparin. Is it effective and safe. J Bone Joint Surg Br. 1995 Sep;77(5):715-9. PMID 7559695

4.       ^ Levy JH, Tanaka KA, Hursting MJ. Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg. 2007 Sep;105(3):570-82. PMID 17717208