Source: Web Search Revision Year: 2020 Publisher: Sandoz SA (Pty) Ltd<sup>1</sup>, 72 Steel Road, Spartan, Kempton Park, 1619 1 Company Reg. No.: 1990/001979/07
A 8.2 Anticoagulants
Enoxaparin is a low molecular weight heparin which, potentiates the actions of antithrombin III an endogenous inhibitor of blood coagulation.
Enoxaparin acts primarily by increasing antithrombin III-mediated inhibition of the formation and activity of factor Xa (anti Factor Xa). This activity, in turn, reduces thrombin generation. These actions decrease thrombin-mediated events in coagulation, including the conversion of fibrinogen to fibrin, thereby inhibiting fibrin clot formation. Unlike unfractionated heparin, which has an anti-factor Xa (antithrombotic) to anti-factor IIa (anticoagulant) activity ratio of approximately 1 to 1, enoxaparin has an anti-factor Xa to anti-factor IIa activity ratio of approximately 3 to 1.
Enoxaparin’s higher ratio of antithrombotic to anticoagulant activity is thought to result in an antithrombotic effect equivalent to that of unfractionated heparin with a lower risk of bleeding. However, it has not been consistently demonstrated that the risk of bleeding is lower with enoxaparin than with unfractionated heparin. Enoxaparin also decreases inhibition of platelet function and disrupts vascular permeability to a lesser extent than does unfractionated heparin.
Enoxaparin is measured by its anticoagulant mechanism that is expressed as anti-factor Xa activity (IU/mg).
Enoxaparin sodium is well absorbed after subcutaneous injection with bioavailability of 92%. Peak anti-factor Xa concentration occurs at 3 to 5 hours after SC administration.
A 30 mg IV bolus immediately followed by a 1 mg/kg sub-cutaneous (SC) dose every 12 hours provided initial peak anti-Factor Xa levels of 1,16 IU/ml and average exposure corresponding to 88% of steadystate levels. Steady-state is achieved on the second day of treatment.
The volume of distribution (Vd) of enoxaparin sodium anti-factor Xa is 5 to 6 litres. The anti-Factor Xa activity disappears within 24 hours after administration of the recommended dose. Enoxapirin is metabolised in the liver by depolymerisation and disulfation.
Elimination of enoxaparin sodium is primarily renal with a half-life of the anti-factor Xa activity of 4,5 hours. This is increased to 6,7 hours in the elderly. Total body clearance after an intravenous dose is approximately 26 ml/min and 15 ml/min. After subcutaneous (SC) administration. The clearance is decreased approximately 30% in patients with severe renal failure.
Since renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium (see “WARNINGS AND SPECIAL PRECAUTIONS – Haemorrhage in the elderly”, “DOSAGE AND DIRECTIONS FOR USE – Elderly” and “PHARMACOLOGICAL ACTION – Renal impairment”).
A linear relationship between anti-Xa plasma clearance and creatinine clearance at steady-state has been observed, which indicates decreased clearance of enoxaparin sodium in patients with reduced renal function. Anti-Xa exposure presented by AUC, at steady-state, is marginally increased in mild (creatinine clearance 50 to 80 ml/min) and moderate (creatinine clearance 30 to 50 ml/min) renal impairment after repeated subcutaneous 40 mg once daily doses. In patients with severe renal impairment (creatinine clearance <30 ml/min), the AUC at steady state is significantly increased on average by 65% after repeated subcutaneous 40 mg once daily doses (see “WARNINGS AND SPECIAL PRECAUTIONS – Renal impairment” and “DOSAGE AND DIRECTIONS FOR USE – Renal impairment”).
After repeated subcutaneous 1,5 mg/kg once daily dosing, mean AUC of anti-Xa activity is marginally higher at steady-state in obese healthy volunteers (BMI 30 to 48 kg/m²) compared to non-obese control subjects, while Amax is not increased. There is a lower weight-adjusted clearance in obese subjects with subcutaneous dosing.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Xa exposure is 52% higher in low-weight women (<45 kg) and 27% higher in lowweight men (<57 kg) when compared to normal weight control subjects (see “WARNINGS AND SPECIAL PRECAUTIONS – Low weight”).
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