Pharmacy & Therapeutics - September 2008 - (Page CB13)

Table 13 Pharmacokinetic Parameters* After 5 Days of 1.5 mg/kg SC Once Daily Doses of Enoxaparin Sodium Using 100 mg/mL or 200 mg/mL Concentrations Concentration Anti-Xa Anti-IIa Heptest Amax (IU/mL or sec) tmax** (h) AUC (ss) (h*IU/mL or h* sec) 100 mg/mL 200 mg/mL 90% CI 100 mg/mL 200 mg/mL 100 mg/mL 1.37 (± 0.23) 0.23 (± 0.05) 1.45 (± 0.22) 0.26 (± 0.05) 102-110% 3 (2-6) 4 (2-5) 3.5 (2-6) 4.5 (2.5-6) 14.26 (± 2.93) 1.54 (± 0.61) 105 (± 17) 111 (± 17) 102-111% 2.5 (2-4.5) 3.3 (2-5) 1321 (± 219) aPTT 19 (± 5) 22 (± 7) 3 (2-4.5) 3 (2-5) 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. Lovenox 40 mg SC, 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 SC in reducing the risk of DVT. The efficacy data are provided below [see Table 14]. Table 14 Efficacy of Lovenox in the Prophylaxis of DVT Following Abdominal Surgery Dosing Regimen Lovenox Heparin 40 mg q.d. SC 5000 U q8h SC Indication n (%) n (%) All Treated Abdominal 555 (100) 560 (100) Surgery Patients Treatment Failures Total VTE1 (%) 56 (10.1) 63 (11.3) (95% CI2: 8 to 13) (95% CI: 9 to 14) DVT Only (%) 54 (9.7) 61 (10.9) (95% CI: 7 to 12) (95% CI: 8 to 13) 1 2 200 mg/mL 15.43 (± 2.96) 1.77 (± 0.67) 1401 (± 227) 90% CI 105-112% 103-109% *Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio **Median (range) Distribution. The volume of distribution of anti-Factor Xa activity is about 4.3 L. Elimination. Following intravenous (IV) dosing, the total body clearance of enoxaparin is 26 mL/min. After IV dosing of enoxaparin labeled with the gamma-emitter, 99mTc, 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 SC dose to about 7 hours after repeated dosing. Significant anti-Factor Xa activity persists in plasma for about 12 hours following a 40 mg SC once a day dose. Following SC 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 SC 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 SC dosing in geriatric subjects were close to those observed in young subjects. Following once a day SC 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 (2.3) and Use in Specific Populations (8.5)]. 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 mild (creatinine clearance 50–80 mL/min) and moderate (creatinine clearance 30-50 mL/min) renal impairment 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 (2.2) and Use in Specific Populations (8.7)]. 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 in patients with hepatic impairment have not been conducted and the impact of hepatic impairment on the exposure to enoxaparin is unknown [see Use in Specific Populations (8.8)]. 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 singlesubcutaneous 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 (8.9)]. Pharmacokinetic interaction: No pharmacokinetic interaction was observed between enoxaparin 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 SC 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 A single SC dose of 46.4 mg/kg enoxaparin was lethal to rats. The symptoms of acute toxicity were ataxia, decreased motility, dyspnea, cyanosis, and coma. 14 CLINICAL STUDEIS 14.1 Prophylaxis of Deep Vein Thrombosis (DVT) 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 DVT or pulmonary embolism. 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, Lovenox 40 mg SC once a day was compared to heparin 5000 U every 8 hours SC 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 Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Colorectal Surgery Dosing Regimen Lovenox Heparin 40 mg q.d. SC 5000 U q8h SC Indication n (%) n (%) All Treated Colorectal 673 (100) 674 (100) Surgery Patients Treatment Failures Total VTE1 (%) 48 (7.1) 45 (6.7) (95% CI2: 5 to 9) (95% CI: 5 to 9) DVT Only (%) 47 (7.0) 44 (6.5) (95% CI: 5 to 9) (95% CI: 5 to 8) VTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin. 2 CI = Confidence Interval 14.2 Prophylaxis of Deep Vein Thrombosis (DVT) Following Hip or Knee Replacement Surgery Lovenox has been shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery. In a double-blind study, Lovenox 30 mg every 12 hours SC 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 Lovenox in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Dosing Regimen Lovenox Placebo 30 mg q12h SC q12h SC Indication n (%) n (%) All Treated Hip 50 (100) 50 (100) Replacement Patients Treatment Failures Total DVT (%) 5 (10)1 23 (46) Proximal DVT (%) 1 (2)2 11 (22) 1 2 p value versus placebo = 0.0002 p value versus placebo = 0.0134 A double-blind, multicenter study compared three dosing regimens of Lovenox 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].

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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