Pharmacotherapeutic group: ANTITHROMBOTIC AGENT. ATC code: B01 AB05.
Pharmacology: Pharmacodynamics: Enoxaparin is a low-molecular-weight heparin with a mean molecular weight of approximately 4500 daltons, in which the antithrombotic and anticoagulant activities of standard heparin have been dissociated. The drug 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 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 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 to 2.2 times the control time at peak activity.
Clinical Efficacy and Safety: COMPARATIVE CLINICAL TRIALS: A Single-Dose, randomized, double-blind, two-way crossover pivotal study was conducted to demonstrate the pharmacodynamic equivalence of CRUSIA to CLEXANE (European reference biologic) (Study# ROV-RO20-2015-01).
Efficacy: Efficacy is based on the data from the two pharmacodynamics (PD) clinical trials demonstrating equivalence in primary and secondary PD endpoints using a 95% confidence interval. The 95% CI of the ratio of the geometric least squares means between CRUSIA and CLEXANE for AUEC0-inf, AUEC0-T, and anti-Xamax of anti-Xa activity, and AUEC0-T and anti-IIamax of anti-IIa activity met the equivalence interval 80% to 125%, thereby demonstrating pharmacodynamic biosimilarity of CRUSIA to CLEXANE. The types, frequency and severity of adverse events were comparable between the biosimilar and the reference biologic drug.
CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG (CLEXANE): Prevention of venous thromboembolic disease associated with surgery: Extended prophylaxis of VTE following orthopaedic surgery: In a double-blind study of extended prophylaxis for patients undergoing hip replacement surgery, 179 patients with no venous thromboembolic disease initially treated, while hospitalized, with enoxaparin sodium 4000 IU (40 mg) SC, were randomized to a post-discharge regimen of either enoxaparin sodium 4 000 IU (40 mg) (n=90) once a day SC or to placebo (n=89) for 3 weeks. The incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, no PE was reported. No major bleeding occurred. The efficacy data are provided in the table as follows. (See Table 1.)
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In a second double-blind study, 262 patients without VTE disease and undergoing hip replacement surgery initially treated, while hospitalized, with enoxaparin sodium 4 000 IU (40 mg) SC were randomized to a post-discharge regimen of either enoxaparin sodium 4 000 IU (40 mg) (n=131) once a day SC or to placebo (n=131) for 3 weeks. Similar to the first study the incidence of VTE during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo for both total VTE (enoxaparin sodium: 21 [16%] versus placebo: 45 [34.4%]; p=0.001) and proximal DVT (enoxaparin sodium: 8 [6.1%] versus placebo: 28 [21.4%]; p=<0.001). No difference in major bleeding was found between the enoxaparin sodium and the placebo group.
Extended prophylaxis of DVT following cancer surgery: A double-blind, multicenter trial, compared a four-week and a one-week regimen of enoxaparin sodium prophylaxis in terms of safety and efficacy in 332 patients undergoing elective surgery for abdominal or pelvic cancer. Patients received enoxaparin sodium (4 000 IU (40 mg) SC) daily for 6 to 10 days and were then randomly assigned to receive either enoxaparin sodium or placebo for another 21 days. Bilateral venography was performed between days 25 and 31, or sooner if symptoms of venous thromboembolism occurred. The patients were followed for three months. Enoxaparin sodium prophylaxis for four weeks after surgery for abdominal or pelvic cancer significantly reduced the incidence of venographically demonstrated thrombosis, as compared with enoxaparin sodium prophylaxis for one week. The rates of venous thromboembolism at the end of the double-blind phase were 12.0 % (n=20) in the placebo group and 4.8% (n=8) in the enoxaparin sodium group; p=0.02. This difference persisted at three months [13.8% vs. 5.5% (n=23 vs 9), p=0.01]. There were no differences in the rates of bleeding or other complications during the double-blind or follow-up periods.
Prophylaxis of venous thromboembolic disease in medical patients with an acute illness expected to induce limitation of mobility: In a double blind multicentre, parallel group study, enoxaparin sodium 2 000 IU (20 mg) or 4 000 IU (40 mg) once a day SC was compared to placebo in the prophylaxis of DVT in medical patients with severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency, and acute infection or acute rheumatic; if associated with at least one VTE risk factor (age ≥75 years, cancer, previous VTE, obesity, varicose veins, hormone therapy, and chronic heart or respiratory failure).
A total of 1,102 patients were enrolled in the study, and 1,073 patients were treated. Treatment continued for 6 to 14 days (median duration 7 days). When given at a dose of 4 000 IU (40 mg) once a day SC, enoxaparin sodium significantly reduced the incidence of VTE as compared to placebo. The efficacy data are provided in the table as follows. (See Table 2.)
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At approximately 3 months following enrolment, the incidence of VTE remained significantly lower in the enoxaparin sodium 4 000 IU (40 mg) treatment group versus the placebo treatment group. The occurrence of total and major bleeding were respectively 8.6% and 1.1% in the placebo group, 11.7% and 0.3% in the enoxaparin sodium 2 000 IU (20 mg) group and 12.6% and 1.7% in the enoxaparin sodium 4 000 IU (40 mg) group.
Treatment of deep vein thrombosis with or without pulmonary embolism: In a multicentre, parallel group study, 900 patients with acute lower extremity DVT with or without PE were randomized to an inpatient (hospital) treatment of either (i) enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day SC, (ii) enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours SC, or (iii) heparin IV bolus (5 000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. All patients also received warfarin sodium (dose adjusted according to prothrombin time to achieve an INR of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided in the table as follows. (See Table 3.)
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Major bleeding were respectively 1.7% in the enoxaparin sodium 150 IU/kg (1.5 mg/kg) once a day group, 1.3% in the enoxaparin sodium 100 IU/kg (1 mg/kg) twice a day group and 2.1% in the heparin group.
Treatment of unstable angina and non ST elevation myocardial infarction: In a large multicentre study, 3,171 patients enrolled at the acute phase of unstable angina or non-Q-wave myocardial infarction were randomized to receive in association with acetylsalicylic acid (100 to 325 mg once daily), either enoxaparin sodium 100 IU/kg (1 mg/kg) every 12 hours or IV unfractionated heparin adjusted based on aPTT. Patients had to be treated in hospital for a minimum of 2 days and a maximum of 8 days, until clinical stabilization, revascularization procedures or hospital discharge. The patients had to be followed up to 30 days. In comparison with heparin, enoxaparin sodium significantly reduced the combined incidence of angina pectoris, myocardial infarction and death, with a decrease of 19.8 to 16.6% (relative risk reduction of 16.2%) on day 14. This reduction in the combined incidence was maintained after 30 days (from 23.3 to 19.8%; relative risk reduction of 15%). There were no significant differences in major haemorrhages, although a haemorrhage at the site of the SC injection was more frequent.
Treatment of acute ST-segment elevation myocardial infarction: In a large multicentre study, 20 479 patients with STEMI eligible to receive fibrinolytic therapy were randomized to receive either: enoxaparin in a single 3 000 IU (30 mg) IV bolus plus a 100 IU/kg (1 mg/kg) SC dose followed by an SC injection of 100 IU/kg (1 mg/kg) every 12 hours, or IV unfractionated heparin adjusted based on aPTT for 48 hours. All patients were also treated with acetylsalicylic acid for a minimum of 30 days. The enoxaparin sodium dosing strategy was adjusted for severe renally impaired patients and for the elderly of at least 75 years of age. The SC injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days (whichever came first). 4716 patients underwent percutaneous coronary intervention (PCI) receiving antithrombotic support with blinded study drugs. Therefore, for patients on enoxaparin sodium, the PCI was to be performed on enoxaparin sodium (no switch) using the regimen established in previous studies i.e., no additional dosing, if last SC administration given less than 8 hours before balloon inflation, IV bolus of 30 IU/kg (0.3 mg/kg) enoxaparin sodium, if the last SC administration given more than 8 hours before balloon inflation.
Enoxaparin sodium compared to unfractionated heparin significantly decreased the incidence of the primary end point, a composite of death from any cause or myocardial reinfarction in the first 30 days after randomization [9.9% in the enoxaparin group versus 12.0% in the unfractionated heparin group] with a 17% relative risk reduction (p<0.001).
The treatment benefits of enoxaparin sodium, evident for a number of efficacy outcomes, emerged at 48 hours, at which time there was a 35 percent reduction in the relative risk of myocardial re-infarction, as compared with treatment with unfractionated heparin (p<0.001).
The beneficial effect of enoxaparin sodium on the primary endpoint was consistent across key sub-groups including age, gender, infarct location, history of diabetes or prior myocardial infarction, type of thrombolytic administered and time to treatment with study drug.
There was a significant treatment benefit of enoxaparin sodium, as compared with unfractionated heparin, in patients who underwent percutaneous coronary intervention within 30 days after randomization (23% reduction in relative risk) or who were treated medically (15% reduction in relative risk, p=0.27 for interaction).
The rate of the 30 day composite endpoint of death, myocardial re-infarction or intracranial haemorrhage (a measure of net clinical benefit) was significantly lower (p<0.0001) in the enoxaparin sodium group (10.1%) as compared to the heparin group (12.2%), representing a 17% relative risk reduction in favour of treatment with enoxaparin sodium.
The incidence of major bleeding at 30 days was significantly higher (p<0.0001) in the enoxaparin sodium group (2.1%) versus the heparin group (1.4%). There was a higher incidence of gastrointestinal bleeding in the enoxaparin group (0.5%) versus the heparin group (0.1%), while the incidence of intracranial haemorrhage was similar in both groups (0.8% with enoxaparin sodium versus 0.7% with heparin).
The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period.
Hepatic impairment: 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 Precautions) and no formal dose finding studies have been performed in cirrhotic patients (Child Pugh class A, B nor C).
Pharmacokinetics: General characteristics: The pharmacokinetic parameters of enoxaparin sodium have been studied primarily in terms of the time course of plasma anti-Xa and also by anti-IIa activity, at the recommended dosage ranges after single and repeated sub-cutaneous administration, and after single intravenous injection. 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 IU/ml following single SC administration of 2000 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.
An 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 levels 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 anti-Xa 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 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 10-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 anti-IIa IU/ml and 0.91 IU/ml following repeated administration of a 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 mainly 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 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 renal function is known to decline with age, elderly patients may show reduced elimination of enoxaparin sodium (see Precautions).
Hepatic impairment: In a study conducted in patients with advanced cirrhosis treated with enoxaparin sodium 4000 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.
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 steady state is significantly increased on average by 65% after repeated SC 4 000 IU (40 mg) once daily doses (see Dosage & Administration and Precautions).
Haemodialysis: 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.
Weight: 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 Precautions).
Pharmacokinetic interactions: No pharmacokinetic interactions were observed between enoxaparin sodium and thrombolytics when administered concomitantly.
Toxicology: 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 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.
Comparative Non-clinical Pharmacology and Toxicology: Comparative Non-Clinical Pharmacodynamics: In vitro Studies: Five batches of CRUSIA and five batches of CLEXANE were used to determine the in vitro concentration-response effect on the percentage of anti-Factor Xa and anti-Factor IIa activities inhibition. The percentage of inhibition was calculated and adjusted to a 4 parameter logistic regression (i.e.4PL). From the adjusted curves, the IC50 was calculated for each batch and for each activity. The IC50 values obtained were between 2.97 and 3.99 mcg/mL for anti-Factor Xa activity and between 5.75 and 7.71 mcg/mL for anti-Factor IIa activity. The 90% Confidence Interval of the ratio of the geometric means was within the interval for similarity, thereby demonstrating equivalence between CRUSIA and CLEXANE.