Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Sanofi-aventis One Onslow Street Guildford Surrey, GU1 4YS UK
Pharmacotherapeutic group: Antithrombotic agent, heparin group.
ATC code: B01AB05
Enoxaparin is a low molecular weight heparin with a mean molecular weight of approximately 4,500 daltons. The drug substance is the sodium salt. The molecular weight distribution is:
< 2000 daltons ≤ 20%
2000 to 8000 daltons ≥ 68%
> 8000 daltons ≤ 18%
Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
Enoxaparin sodium is characterised by a higher ratio of antithrombotic activity to anticoagulant activity than unfractionated heparin. At recommended doses, it does not significantly influence platelet aggregation, binding of fibrinogen to platelets or global blood clotting tests such as APTT and prothrombin time.
Enoxaparin binds to anti-thrombin III leading to inhibition of coagulation factors IIa and Xa.
Enoxaparin has been shown to increase the blood concentration of Tissue Factor Pathway Inhibitor in healthy volunteers.
Enoxaparin is rapidly and completely absorbed following subcutaneous injection. The maximum plasma anti-Xa activity occurs 1 to 4 hours after injection with peak activities in the order of 0.16 IU/ml and 0.38 IU/ml after doses of 20 mg or 40 mg respectively. The anti-Xa activity generated is localised within the vascular compartments and elimination is characterised by a half life of 4 to 5 hours. Following a 40 mg dose, anti-Xa activity may persist in the plasma for 24 hours.
A 30mg IV bolus immediately followed by a 1mg/kg SC every 12 hours provided initial peak anti-Factor Xa levels of 1.16IU/ml (n=16) and average exposure corresponding to 88% of steady state levels.
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. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the AUC at steady state is significantly increased by an average of 65% after repeated, once daily subcutaneous doses of 40mg.
Hepatic metabolism by desulphation and depolymerisation also contributes to elimination. The elimination half life may be prolonged in elderly patients although no dosage adjustment is necessary.
A study of repeated, once daily subcutaneous doses of 1.5 mg/kg in healthy volunteers suggests that no dosage adjustment is necessary in obese subjects (BMI 30-48 kg/m2) compared to non-obese subjects.
Enoxaparin, as detected by anti-Xa activity, does not cross the placental barrier during the second trimester of pregnancy.
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 low-weight men (<57 kg) when compared to normal weight control subjects (see section 4.4 Special warnings and precautions for use: Low Body Weight).
No pharmacokinetic interactions were observed between enoxaparin and thrombolytics when administered concomitantly.
No long-term studies in animals have been performed to evaluate the carcinogenic potential of enoxaparin.
Enoxaparin was not mutagenic in in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test.
Enoxaparin was found to have no effect on fertility or reproductive performance of male and female rats at SC doses up to 20 mg/kg/day. Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 30 mg/kg/day. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.
Besides the anticoagulant effects of enoxaparin, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week subcutaneous toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week subcutaneous and intravenous toxicity studies both in rats and monkeys.
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