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Pharmacotherapeutic group: Antithrombotic agent, heparin group.
Pharmacology: Pharmacodynamics: 2000 IU/0.2 mL and 4000 IU/0.4 mL soln for inj: Enoxaparin sodium is an LMWH with a mean molecular weight of approximately 4,500 daltons, in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. The drug substance is sodium salt. In the in vitro purified system, enoxaparin sodium has high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa or antithrombin activity (approximately 28 IU/mg), with a ratio of 3.6. These anticoagulant activities are mediated through anti-thrombin III (ATIII) resulting in anti-thrombotic activities in humans.
Beyond its anti-Xa/IIa activity, further antithrombotic and anti-inflammatory properties of Enoxaparin sodium 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.
When used as a prophylactic treatment, Enoxaparin sodium does not significantly affect the aPTT.
When used as a curative treatment, aPTT can be prolonged by 1.5-2.2 times the control time at peak activity.
Pharmacokinetics: 2000 IU/0.2 mL and 6000 IU/0.6 mL soln for inj: Absorption and Distribution: Maximum anti-Factor Xa and anti-thrombin (anti-Factor) activities occur 3 to 5 hours after SC injection of Enoxaparin.
Mean peak anti-Factor Xa activity was 0.16 IU/mL (1.58 pg/mL) and 0.38 IU/mL (3.83 pg/mL) after the 20 mg and 40 mg clinically tested SC doses, respectively. Mean (n=46) peak anti-Factor Xa activity was 1.1 IU/mL at steady state in patients with unstable angina receiving 1 mg/kg SC every 12 hours for 14 days. Mean absolute bioavailability of Enoxaparin, after 1.5 mg/kg given SC, based on anti-Factor Xa activity is approximately 100% in healthy volunteers.
Enoxaparin pharmacokinetics appears to be linear over the recommended dosage ranges. After repeated subcutaneous administration of 40 mg once daily and 1.5 mg/kg once daily regimens in healthy volunteers, the steady state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. Steady-state Enoxaparin activity levels are well predicted by single-dose pharmacokinetics. After repeated subcutaneous administration of the 1 mg/kg twice daily regimen, the steady state is reached from 4 with mean exposure about 65% higher than after a single dose and mean peak and trough levels of about 1.2 and 0.52 IU/mL, respectively. Based on Enoxaparin sodium pharmacokinetics, this difference in steady state is expected and within the therapeutic range.
4000 IU/0.4 mL soln for inj: General characteristics: The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-Xa activity and also by anti-IIa activity, at the recommended dosage ranges after single and repeated SC administration and after single IV administration. The quantitative determination of anti-Xa and anti-IIa pharmacokinetic activities was conducted by validated amidolytic methods.
Absorption: The absolute bioavailability of enoxaparin sodium after SC injection, based on anti-Xa activity, is close to 100%.
Different doses and formulations and dosing regimens can be used.
The mean maximum plasma anti-Xa activity level is observed 3 to 5 hours after SC injection and achieves approximately 0.2, 0.4, 1.0 and 1.3 anti-Xa IU/mL following single SC administration of 2,000 IU, 4,000 IU, 100 IU/kg and 150 IU/kg (20 mg, 40 mg, 1 mg/kg and 1.5 mg/kg) doses, respectively.
A 3,000 IU (30 mg) IV bolus immediately followed by 100 IU/kg (1 mg/kg) SC every 12 hours provided initial maximum anti-Xa activity level of 1.16 IU/mL (n=16) and average exposure corresponding to 88% of steady-state levels. Steady-state is achieved on the second day of treatment.
After repeated SC administration of 4,000 IU (40 mg) once daily and 150 IU/kg (1.5 mg/kg) once daily regimens in healthy volunteers, the steady-state is reached on day 2 with an average exposure ratio about 15% higher than after a single dose. After repeated SC administration of the 100 IU/kg (1 mg/kg) twice daily regimen, the steady-state is reached from day 3 to 4 with mean exposure about 65% higher than after a single dose and mean maximum and trough anti-Xa activity levels of about 1.2 and 0.52 IU/mL, respectively.
Injection volume and dose concentration over the range 100-200 mg/mL does not affect pharmacokinetic parameters in healthy volunteers.
Enoxaparin sodium pharmacokinetics appears to be linear over the recommended dosage ranges. Intra-patient and inter-patient variability is low. Following repeated SC administration, no accumulation takes place.
Plasma anti-IIa activity after SC administration is approximately ten-fold lower than anti-Xa activity. The mean maximum anti-IIa activity level is observed approximately 3 to 4 hours following SC injection and reaches 0.13 IU/mL and 0.19 IU/mL following repeated administration of 100 IU/kg (1 mg/kg) twice daily and 150 IU/kg (1.5 mg/kg) once daily, respectively.
Distribution: The volume of distribution of enoxaparin sodium anti-Xa activity is about 4.3 liters and is close to the blood volume.
Biotransformation: Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency.
Elimination: Enoxaparin sodium is a low clearance drug with a mean anti-Xa plasma clearance of 0.74 L/h after a 150 IU/kg (1.5 mg/kg) 6-hour IV infusion.
Elimination appears monophasic with a half-life of about 5 hours after a single SC dose to about 7 hours after repeated dosing.
Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments is 40% of the dose.
Special populations: Elderly: Based on the results of a population pharmacokinetic analysis, the enoxaparin sodium kinetic profile is not different in elderly subjects compared to younger subjects when renal function is normal. However, since the renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium.
Hepatic impairment: In a study conducted on patients with advanced cirrhosis treated with enoxaparin sodium 4,000 IU (40 mg) once daily, a decrease in maximum anti-Xa activity was associated with an increase in the severity of hepatic impairment (assessed by Child-Pugh categories). This decrease was mainly attributed to a decrease in ATIII level secondary to reduced synthesis of ATIII in patients with hepatic impairment.
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 represented by AUC, at steady-state, is marginally increased in mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment after repeated SC 4,000 IU (40 mg) once daily doses. In patients with severe renal impairment (creatinine clearance <30 mL/min), the AUC at a steady state is significantly increased on average by 65% after repeated SC 4,000 IU (40 mg) once daily doses.
Hemodialysis: Enoxaparin sodium pharmacokinetics appeared similar than the control population, after a single 25 IU, 50 IU or 100 IU/kg (0.25, 0.50 or 1.0 mg/kg) IV dose however, AUC was two-fold higher than control.
Weight: After repeated SC 150 IU/kg (1.5 mg/kg) once daily dosing, the mean AUC of anti-Xa activity is marginally higher at a steady state in obese healthy volunteers (BMI 30-48 kg/m) compared to non-obese control subjects, while maximum plasma anti-Xa activity level is not increased. There is a lower weight-adjusted clearance in obese subjects with SC dosing.
When non-weight adjusted dosing was administered, it was found after a single-SC 4,000 IU (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.
Pharmacokinetic interactions: No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when administered concomitantly.
Toxicology: 4000 IU/0.4 mL soln for inj: Preclinical safety data: Besides the anticoagulant effects of enoxaparin sodium, there was no evidence of adverse effects at 15 mg/kg/day in the 13-week SC toxicity studies both in rats and dogs and at 10 mg/kg/day in the 26-week SC and IV toxicity studies both in rats, and monkeys.
Enoxaparin sodium has shown no mutagenic activity based on in vitro tests, including the Ames test, mouse lymphoma cell forward mutation test, and no clastogenic activity based on an in vitro human lymphocyte chromosomal aberration test, and the in vivo rat bone marrow chromosomal aberration test. Studies conducted in pregnant rats and rabbits at SC doses of enoxaparin sodium up to 30 mg/kg/day did not reveal any evidence of teratogenic effects or fetotoxicity. Enoxaparin sodium 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.
