Enoxaparin Sodium (Page 7 of 11)

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 2.0 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

Indication

Dosing Regimen

Enoxaparin Sodium Injection

Heparin

40 mg daily subcutaneously

n (%)

5000 U q8h subcutaneously

n (%)

n (%)

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)

* VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
† CI = Confidence Interval

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

Indication

Dosing Regimen

Enoxaparin Sodium Injection

Heparin

40 mg daily subcutaneously

5000 U q8h subcutaneously

n (%)

n (%)

All Treated Colorectal Surgery 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)

* VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin
† CI = Confidence Interval

14.2 Prophylaxis of Deep Vein Thrombosis following Hip or Knee Replacement Surgery

Enoxaparin sodium injection has been shown to reduce the risk of postoperative deep vein thrombosis (DVT) following hip or knee replacement surgery.

In a double-blind study, enoxaparin sodium injection 30 mg every 12 hours subcutaneously was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below (see Table 16).

Table 16: Efficacy of Enoxaparin Sodium Injection in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery

Indication

Dosing Regimen

Enoxaparin Sodium Injection

Placebo

30 mg q12h subcutaneously

q12h subcutaneously

n (%)

n (%)

All Treated Hip Replacement Patients

50 (100)

50 (100)

Treatment Failures

Total DVT (%)

5 (10)*

23 (46)

Proximal DVT (%)

1 (2)

11 (22)

* p value versus placebo = 0.0002
† p value versus placebo = 0.0134

A double-blind, multicenter study compared three dosing regimens of enoxaparin sodium injection in patients with hip replacement. A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy data are provided below (see Table 17).

Table 17: Efficacy of Enoxaparin Sodium Injection in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery

Indication

Dosing Regimen

10 mg daily subcutaneously

30 mg q12h subcutaneously

40 mg daily subcutaneously

n (%)

n (%)

n (%)

All Treated Hip Replacement Patients

161 (100)

208 (100)

199 (100)

Treatment Failures

Total DVT (%)

40 (25)

22 (11)*

27 (14)

Proximal DVT (%)

17 (11)

8 (4)

9 (5)

* p value versus enoxaparin sodium injection, 10 mg once a day = 0.0008
† p value versus enoxaparin sodium injection, 10 mg once a day = 0.0168

There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, enoxaparin sodium injection 30 mg every 12 hours subcutaneously was compared to placebo in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly lower for enoxaparin sodium injection compared to placebo. The efficacy data are provided below (see Table 18).

Table 18: Efficacy of Enoxaparin Sodium Injection in the Prophylaxis of Deep Vein Thrombosis Following Total Knee Replacement Surgery

Indication

Dosing Regimen

Enoxaparin Sodium Injection

Placebo

30 mg q12h subcutaneously

q12h subcutaneously

n (%)

n (%)

All Treated Total Knee Replacement Patients

47 (100)

52 (100)

Treatment Failures

Total DVT (%)

5 (11)*

(95% CI: 1 to 21)

32 (62)

(95% CI: 47 to 76)

Proximal DVT (%)

0 (0)‡

(95% Upper CL§: 5)

7 (13)

(95% CI: 3 to 24)

* p value versus placebo = 0.0001
† CI = Confidence Interval
‡ p value versus placebo = 0.013
§ CL = Confidence Limit

Additionally, in an open-label, parallel group, randomized clinical study, enoxaparin sodium injection 30 mg every 12 hours subcutaneously in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours subcutaneously. A total of 453 patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was lower for enoxaparin sodium injection compared to heparin.

Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with enoxaparin sodium injection 40 mg subcutaneously, initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either enoxaparin sodium injection 40 mg (n=90) once a day subcutaneously or to placebo (n=89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium injection compared to placebo. The efficacy data are provided below (see Table 19).

Table 19: Efficacy of Enoxaparin Sodium Injection in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery

Indication (Post-Discharge)

Post-Discharge Dosing Regimen

Enoxaparin Sodium Injection

Placebo

40 mg daily subcutaneously

daily subcutaneously

n (%)

n (%)

All Treated Extended Prophylaxis Patients

90 (100)

89 (100)

Treatment Failures

Total DVT (%)

6 (7)*

(95% CI: 3 to 14)

18 (20)

(95% CI: 12 to 30)

Proximal DVT (%)

5 (6)

(95% CI: 2 to 13)

7 (8)

(95% CI: 3 to 16)

* p value versus placebo = 0.008
† CI = Confidence Interval
‡ p value versus placebo = 0.537

In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with enoxaparin sodium injection 40 mg subcutaneously, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either enoxaparin sodium injection 40 mg (n=131) once a day subcutaneously, or to placebo (n=131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium injection compared to placebo, with a statistically significant difference in both total DVT (enoxaparin sodium injection 21 [16%] versus placebo 45 [34%]; p=0.001) and proximal DVT (enoxaparin sodium injection 8 [6%] versus placebo 28 [21%]; p=<0.001).

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