Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand 1685, South Africa
Pharmacotherapeutic group: Antithrombotic agent, heparin group
ATC code: B01AB05
CRUSIA is a biosimilar medicine.
Enoxaparin sodium is a low molecular weight heparin with a mean molecular weight of approximately 4 500 daltons, in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. The medicine substance is the sodium salt.
In the in vitro purified system, enoxaparin sodium has a high anti-Xa activity (approximately 100 IU/mg) and low anti-IIa or anti thrombin 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 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 prophylactic treatment, enoxaparin sodium does not significantly affect the aPTT. When used as curative treatment, aPTT can be prolonged by 1,5-2,2 times the control time at peak activity.
Based on literature data the use of enoxaparin sodium 4 000 IU (40 mg) in cirrhotic patients (Child-Pugh class B-C) appears to be safe and effective in preventing portal vein thrombosis. It should be noted that the literature studies may have limitations. Caution should be used in patients with hepatic impairment as these patients have an increased potential for bleeding (see section 4.4) and no formal dose finding studies have been performed in cirrhotic patients (Child Pugh class A, B nor C).
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.
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 a 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 steadystate 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 steadystate 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.
The volume of distribution of enoxaparin sodium anti-Xa activity is about 4,3 litres and is close to the blood volume.
Enoxaparin sodium is primarily metabolised in the liver by desulfation and/or depolymerisation to lower molecular weight species with much reduced biological potency.
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 40% of the dose.
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 renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium (see sections 4.2 and 4.4).
In a study conducted in 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 a reduced synthesis of ATIII in patients with hepatic 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 steady state is significantly increased on average by 65% after repeated SC 4 000 IU (40 mg) once daily doses (see sections 4.2 and 4.4).
Enoxaparin sodium pharmacokinetics appeared similar than 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.
After repeated SC 150 IU/kg (1,5 mg/kg) once daily dosing, mean AUC of anti-Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m²) 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 (see section 4.4).
No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when administered concomitantly.
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 20mg/kg/day.
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