Enoxaparin Sodium (Page 9 of 16)

Distribution

The volume of distribution of anti-Factor Xa activity is about 4.3 L.

Elimination

Following intravenous dosing, the total body clearance of enoxaparin is 26 mL/min. After intravenous dosing of enoxaparin labeled with the gamma-emitter, 99m Tc, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours. Elimination half-life based on anti-Factor Xa activity was 4.5 hours after a single subcutaneous dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg subcutaneous once a day dose.

Following subcutaneous dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min.

Metabolism

Enoxaparin sodium is primarily metabolized in the liver by desulfation and/or depolymerization to lower molecular weight species with much reduced biological potency. 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
Gender
Apparent clearance and Amax derived from anti-Factor Xa values following single subcutaneous dosing (40 mg and 60 mg) were slightly higher in males than in females. The source of the gender difference in these parameters has not been conclusively identified; however, body weight may be a contributing factor.
Geriatric
Apparent clearance and Amax derived from anti-Factor Xa values following single and multiple subcutaneous dosing in geriatric subjects were close to those observed in young subjects. Following once a day subcutaneous dosing of 40 mg enoxaparin, the Day 10 mean area under anti-Factor Xa activity versus time curve (AUC) was approximately 15% greater than the mean Day 1 AUC value [see Dosage and Administration () and Use in Specific Populations ()].
Renal Impairment
A linear relationship between anti-Factor 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-Factor Xa exposure represented by AUC, at steady state, is marginally increased in patients with creatinine clearance 50 to 80 mL/min and patients with creatinine clearance 30 to<50 mL/min 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 Dosage and Administration () and Use in Specific Populations ()].
Hemodialysis
In a single study, elimination rate appeared similar but AUC was two-fold higher than control population, after a single 0.25 or 0.5 mg/kg intravenous dose.
Hepatic Impairment
Studies with enoxaparin sodium in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown.
Weight
After repeated subcutaneous 1.5 mg/kg once-daily dosing, mean AUC of anti-Factor Xa activity is marginally higher at steady state in obese healthy volunteers (BMI 30-48 kg/m2) compared to non-obese control subjects, while Amax is not increased.
When non-weight adjusted dosing was administered, it was found after a single-subcutaneous 40 mg dose, that anti-Factor 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 Use in Specific Populations ()].
Pharmacokinetic Interaction No pharmacokinetic interaction was observed between enoxaparin sodium and thrombolytics when administered concomitantly.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 subcutaneous doses up to 20 mg/kg/day or 141 mg/m2 /day. The maximum human dose in clinical trials was 2 mg/kg/day or 78 mg/m2 /day (for an average body weight of 70 kg, height of 170 cm, and body surface area of 1.8 m2).

13.2 Animal Toxicology and/or Pharmacology

A single subcutaneous dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were ataxia, decreased motility, dyspnea, cyanosis, and coma.

13.3 Reproductive and Developmental Toxicology

Teratology studies have been conducted in pregnant rats and rabbits at subcutaneous doses of enoxaparin up to 30 mg/kg/day corresponding to 211 mg/m2 /day and 410 mg/m2 /day in rats and rabbits respectively. There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin.

14 CLINICAL STUDIES

14.1 Prophylaxis of Deep Vein Thrombosis following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE).

In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others. Enoxaparin sodium injection 40 mg subcutaneously, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours subcutaneously in reducing the risk of DVT. The efficacy data are provided below (see Table 14).

Table 14: Efficacy of Enoxaparin Sodium Injection in the Prophylaxis of Deep Vein Thrombosis following Abdominal Surgery
Dosing Regimen
Indication Enoxaparin Sodium Injection 40 mg daily subcutaneously n (%) Heparin 5000 U q8h subcutaneously n (%)
*
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
CI = Confidence Interval

All Treated Abdominal Surgery Patients

555 (100)

560 (100)

Treatment Failures

Total VTE * (%)

56 (10.1)(95% CI : 8 to 13)

63 (11.3)(95% CI: 9 to 14)

DVT Only (%)

54 (9.7)(95% CI: 7 to 12)

61 (10.9)(95% CI: 8 to 13)

In a second double-blind, parallel group study, enoxaparin sodium injection 40 mg subcutaneously once a day was compared to heparin 5000 U every 8 hours subcutaneously in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery. The efficacy data are provided below (see Table 15).

Table 15: Efficacy of Enoxaparin Sodium Injection in the Prophylaxis of Deep Vein Thrombosis following Colorectal Surgery
Dosing Regimen
Indication Enoxaparin Sodium Injection 40 mg daily subcutaneously n (%) Heparin 5000 U q8h subcutaneously n (%)
*
VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
CI = Confidence Interval

All Treated ColorectalSurgery Patients

673 (100)

674 (100)

Treatment Failures

Total VTE * (%)

48 (7.1)(95% CI : 5 to 9)

45 (6.7)(95% CI: 5 to 9)

DVT Only (%)

47 (7.0)(95% CI: 5 to 9)

44 (6.5)(95% CI: 5 to 8)

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