DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Arixtra (Fondaparinux Sodium Subcutaneous) - Description and Clinical Pharmacology

 
 



ARIXTRA®
(fondaparinux sodium)
Injection

DESCRIPTION

ARIXTRA® (fondaparinux sodium) Injection is a sterile solution containing fondaparinux sodium. It is a synthetic and specific inhibitor of activated Factor X (Xa). Fondaparinux sodium is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-β-D-glucopyra-nuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-O-sulfo-α-L-idopyranuronosyl-(1→4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside, decasodium salt.

The molecular formula of fondaparinux sodium is C31H43N3Na10O49S8 and its molecular weight is 1728. The structural formula is provided below:

ARIXTRA is supplied as a sterile, preservative-free injectable solution for subcutaneous use.

Each single dose, prefilled syringe of ARIXTRA, affixed with an automatic needle protection system, contains 2.5 mg of fondaparinux sodium in 0.5 mL, 5.0 mg of fondaparinux sodium in 0.4 mL, 7.5 mg of fondaparinux sodium in 0.6 mL, or 10.0 mg of fondaparinux sodium in 0.8 mL of an isotonic solution of sodium chloride and water for injection. The final drug product is a clear and colorless to slightly yellow liquid with a pH between 5.0 and 8.0.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Mechanism of Action

The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development.

Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time.

Anti-Xa Activity

The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations quantified via anti-Factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. (The international standards of heparin or LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately 3 hours.

Pharmacokinetics

Absorption

Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of fondaparinux sodium 2.5 mg in young male subjects, Cmax of 0.34 mg/L is reached in approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-state plasma concentration is, on average, 0.39-0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14-0.19 mg/L. In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg) and 10 mg (body weight >100 kg) once daily, the body-weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20-1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46-0.62 mg/L.

Distribution

In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7-11 L. Similar fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture surgery. In vitro , fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells.

Metabolism

In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.

Elimination

In individuals with normal kidney function fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72 hours. The elimination half-life is 17-21 hours.

Special Populations

Renal Impairment

Fondaparinux elimination is prolonged in patients with renal impairment since the major route of elimination is urinary excretion of unchanged drug. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance of fondaparinux is approximately 25% lower in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), and approximately 55% lower in patients with severe renal impairment (<30 mL/min) compared to patients with normal renal function. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients. (See CONTRAINDICATIONS and WARNINGS: Renal Impairment.)

Hepatic Impairment

The pharmacokinetic properties of fondaparinux have not been studied in patients with hepatic impairment.

Elderly Patients

Fondaparinux elimination is prolonged in patients older than 75 years. In studies evaluating fondaparinux sodium 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients older than 75 years as compared to patients younger than 65 years. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients.

Patients Weighing Less Than 50 kg

Total clearance of fondaparinux sodium is decreased by approximately 30% in patients weighing less than 50 kg (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

Gender

The pharmacokinetic properties of fondaparinux sodium are not significantly affected by gender.

Race

Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopedic surgery.

Drug Interactions

See PRECAUTIONS: Drug Interactions.

CLINICAL STUDIES

Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

In a randomized, double-blind, clinical trial in patients undergoing hip fracture surgery, ARIXTRA Injection 2.5 mg SC once daily was compared to enoxaparin sodium 40 mg SC once daily, which is not approved for use in patients undergoing hip fracture surgery. A total of 1,711 patients were randomized and 1,673 were treated. Patients ranged in age from 17-101 years (mean age 77 years) with 25% men and 75% women. Patients were 99% Caucasian, 1% other races. Patients with multiple traumas affecting more than one organ system, serum creatinine level more than 2 mg/dL (180 μmol/L), or platelet count less than 100,000/mm3 were excluded from the trial. ARIXTRA was initiated after surgery in 88% of patients (mean 6 hours) and enoxaparin sodium was initiated after surgery in 74% of patients (mean 18 hours). For both drugs, treatment was continued for 7 ± 2 days. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported up to Day 11. The efficacy data are provided in Table 1 below and demonstrate that under the conditions of the trial fondaparinux sodium was associated with a VTE rate of 8.3% compared with a VTE rate of 19.1% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 39%, 70%; p<0.001). Major bleeding episodes occurred in 2.2% of patients receiving ARIXTRA and 2.3% of enoxaparin sodium patients (see Tables 8 and 9 under ADVERSE REACTIONS: Hemorrhage).

Table 1. Efficacy of ARIXTRA Injection in the Peri-operative Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

Endpoint

Peri-operative Prophylaxis

(Day 1 to Day 7 ± 2 post-surgery)

Fondaparinux Sodium

2.5 mg SC

once daily 1

Enoxaparin Sodium

40 mg SC

once daily 1,2

All Treated Hip Fracture Surgery Patients

N = 831

N = 840

All Evaluable 3 Hip Fracture Surgery Patients

VTE4

52/626

8.3%5

(6.3, 10.8)6

119/624

19.1%

(16.1, 22.4)

All DVT

49/624

7.9%5

(5.9, 10.2)

117/623

18.8%

(15.8, 22.1)

Proximal DVT

6/650

0.9%5

(0.3, 2.0)

28/646

4.3%

(2.9, 6.2)

Symptomatic PE

3/831

0.4%7

(0.1, 1.1)

3/840

0.4%

(0.1, 1.0)

1ARIXTRA was initiated after surgery in 88% of patients (mean 6 hours) and enoxaparin sodium was initiated after surgery in 74% of patients (mean 18 hours).

2Not approved for use in patients undergoing hip fracture surgery.

3Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip fracture surgery of the upper third of the femur), with an adequate efficacy assessment up to Day 11.

4VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

5p value <0.001.

6Numbers in parentheses indicate 95% confidence interval.

7p value: NS.

Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with ARIXTRA 2.5 mg once daily for 7 ± 1 days. Eighty-one (81) of the 737 patients were not eligible for randomization into the 3-week double-blind period. Three hundred twenty six (326) patients and 330 patients were randomized to receive ARIXTRA 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21 ± 2 days. Patients ranged in age from 23 to 96 years (mean age 75 years) and were 29% men and 71% women. Patients were 99% Caucasian and 1% other races. Patients with multiple traumas affecting more than one organ system or serum creatinine level more than 2 mg/dL (180 μmol/L) were excluded from the trial. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported for up to 24 days following randomization. The efficacy data are provided in Table 2 below and demonstrate that extended prophylaxis with fondaparinux sodium was associated with a VTE rate of 1.4% compared with a VTE rate of 35.0% for placebo for a relative risk reduction of 95.9% (95% CI = [98.7; 87.1], p<0.0001). Major bleeding rates during the 3-week extended prophylaxis period for ARIXTRA (2.4%) and placebo (0.6%) are provided in Tables 8 and 9 (see ADVERSE REACTIONS: Hemorrhage).

Table 2. Efficacy of ARIXTRA Injection in the Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

Endpoint

Extended Prophylaxis

(Day 8 to Day 28 ± 2 post-surgery)

Fondaparinux Sodium

2.5 mg SC once daily

Placebo

SC once daily

All Randomized

Treated Hip Fracture

Surgery Patients

N = 326

N = 330

All Randomized Evaluable Hip Fracture Surgery Patients 1

VTE2

3/208

1.4%3

(0.3, 4.2)4

77/220

35.0%

(28.7, 41.7)

All DVT

3/208

1.4%3

(0.3, 4.2)

74/218

33.9%

(27.7, 40.6)

Proximal DVT

2/221

0.9%3

(0.1, 3.2)

35/222

15.8%

(11.2, 21.2)

Symptomatic VTE (all)

1/326

0.3%5

(0.0, 1.7)

9/330

2.7%

(1.3, 5.1)

Symptomatic PE

0/326

0.0%6

(0.0, 1.1)

3/330

0.9%

(0.2, 2.6)

1Evaluable patients were those who were treated in the post-randomization period, with an adequate efficacy assessment for up to 24 days following randomization .

2VTE was a composite of documented DVT and/or documented symptomatic PE reported for up to 24 days following randomization.

3p value <0.001.

4Number in parentheses indicates 95% confidence interval.

5p value = 0.021.

6p value = NS.

Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery

In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, ARIXTRA 2.5 mg SC once daily was compared to either enoxaparin sodium 30 mg SC every 12 hours (Study 1) or to enoxaparin sodium 40 mg SC once a day (Study 2). In Study 1, a total of 2,275 patients were randomized and 2,257 were treated. Patients ranged in age from 18 to 92 years (mean age 65 years) with 48% men and 52% women. Patients were 94% Caucasian, 4% black, <1% Asian, and 2% others. In Study 2, a total of 2,309 patients were randomized and 2,273 were treated. Patients ranged in age from 24 to 97 years (mean age 65 years) with 42% men and 58% women. Patients were 99% Caucasian, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 μmol/L), or platelet count less than 100,000/mm3 were excluded from both trials. In Study 1, ARIXTRA was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 20.25 hours) after surgery in 97% of patients. In Study 2, ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 86% of patients and enoxaparin sodium was initiated 12 hours before surgery in 78% of patients. The first post-operative enoxaparin sodium dose was given before 12 hours after surgery in 60% of patients and 12 to 24 hours after surgery in 35% of patients with a mean of 13 hours. For both studies, both study treatments were continued for 7 ± 2 days. The efficacy data are provided in Table 3 below. Under the conditions of Study 1, fondaparinux sodium was associated with a VTE rate of 6.1% compared with a VTE rate of 8.3% for enoxaparin sodium for a relative risk reduction of 26% (95% CI: -11%, 53%; p = NS). Under the conditions of Study 2, fondaparinux sodium was associated with a VTE rate of 4.1% compared with a VTE rate of 9.2% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 33%, 73%; p<0.001). For the 2 studies combined, the major bleeding episodes occurred in 3.0% of patients receiving ARIXTRA and 2.1% of enoxaparin sodium patients (see Tables 8 and 9 under ADVERSE REACTIONS: Hemorrhage).

Table 3. Efficacy of ARIXTRA Injection in the Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery

Endpoint

Study 1

Study 2

Fondaparinux Sodium

2.5 mg SC

once daily 1

Enoxaparin Sodium

30 mg SC

every 12 hr 3

Fondaparinux Sodium

2.5 mg SC

once daily 2

Enoxaparin Sodium

40 mg SC

once daily 4

All Treated Hip Replacement Surgery Patients

N = 1,126

N = 1,128

N = 1,129

N = 1,123

All Evaluable 5 Hip Replacement Surgery Patients

VTE6

48/787

6.1%7

(4.5, 8.0)8

66/797

8.3%

(6.5, 10.4)

37/908

4.1%10

(2.9, 5.6)

85/919

9.2%

(7.5, 11.3)

All DVT

44/784

5.6%9

(4.1, 7.5)

65/796

8.2%

(6.4, 10.3)

36/908

4.0%10

(2.8, 5.4)

83/918

9.0%

(7.3, 11.1)

Proximal DVT

14/816

1.7%7

(0.9, 2.9)

10/830

1.2%

(0.6, 2.2)

6/922

0.7%11

(0.2, 1.4)

23/927

2.5%

(1.6, 3.7)

Symptomatic PE

5/1,126

0.4%7

(0.1, 1.0)

1/1,128

0.1%

(0.0, 0.5)

2/1,129

0.2%7

(0.0, 0.6)

2/1,123

0.2%

(0.0, 0.6)

1In Study 1, ARIXTRA was initiated after surgery in 92% of patients (mean 6.5 hours).

2In Study 2, ARIXTRA was initiated after surgery in 86% of patients (mean 6.25 hours).

3In Study 1, enoxaparin sodium was initiated after surgery in 97% of patients (mean 20.25 hours).

4In Study 2, enoxaparin sodium was initiated before surgery in 78% of patients. The first postoperative dose was given a mean of 13 hours after surgery.

5Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip replacement surgery), with an adequate efficacy assessment up to Day 11.

6VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

7p value versus enoxaparin sodium: NS.

8Numbers in parentheses indicates 95% confidence interval.

9p value versus enoxaparin sodium in study 1: <0.05.

10p value versus enoxaparin sodium in study 2: <0.001.

11p value versus enoxaparin sodium in study 2: <0.01.

Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery

In a randomized, double-blind, clinical trial in patients undergoing knee replacement surgery (i.e., surgery requiring resection of the distal end of the femur or proximal end of the tibia), ARIXTRA 2.5 mg SC once daily was compared to enoxaparin sodium 30 mg SC every 12 hours. A total of 1,049 patients were randomized and 1,034 were treated. Patients ranged in age from 19 to 94 years (mean age 68 years) with 41% men and 59% women. Patients were 88% Caucasian, 8% black, <1% Asian, and 3% others. Patients with serum creatinine level more than 2 mg/dL (180 μmol/L), or platelet count less than 100,000/mm3 were excluded from the trial. ARIXTRA was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 94% of patients, and enoxaparin sodium was initiated 12 to 24 hours (mean 21 hours) after surgery in 96% of patients. For both drugs, treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 4 below and demonstrate that under the conditions of the trial, fondaparinux sodium was associated with a VTE rate of 12.5% compared with a VTE rate of 27.8% for enoxaparin sodium for a relative risk reduction of 55% (95% CI: 36%, 70%; p<0.001). Major bleeding episodes occurred in 2.1% of patients receiving ARIXTRA and 0.2% of enoxaparin sodium patients (see Tables 8 and 9 under ADVERSE REACTIONS: Hemorrhage).

Table 4. Efficacy of ARIXTRA Injection in the Prophylaxis of Thromboembolic Events Following Knee Replacement Surgery

Endpoint

Fondaparinux Sodium

2.5 mg SC

once daily 1

Enoxaparin Sodium

30 mg SC

every 12 hours 2

All Treated Knee Replacement Surgery Patients

N = 517

N = 517

All Evaluable 3 Knee Replacement Surgery Patients

VTE4

45/361

12.5%5

(9.2, 16.3)6

101/363

27.8%

(23.3, 32.7)

All DVT

45/361

12.5%5

(9.2, 16.3)

98/361

27.1%

(22.6, 32.0)

Proximal DVT

9/368

2.4%7

(1.1, 4.6)

20/372

5.4%

(3.3, 8.2)

Symptomatic PE

1/517

0.2%7

(0.0, 1.1)

4/517

0.8%

(0.2, 2.0)

1Patients randomized to ARIXTRA 2.5 mg received the first injection 6 ± 2 hours after surgery providing that hemostasis had been achieved.

2Patients randomized to enoxaparin sodium received the first injection at 21 ± 2 hours after surgery closure providing that hemostasis had been achieved.

3Evaluable patients were those who were treated and underwent the appropriate surgery (i.e. knee replacement surgery), with an adequate efficacy assessment up to Day 11.

4VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.

5p value <0.001.

6Numbers in parentheses indicates 95% confidence interval.

7p value: NS.

Prophylaxis of Thromboembolic Events Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

Abdominal surgery patients at risk included the following: Those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 60 years with or without additional risk factors; and those undergoing surgery under general anesthesia lasting longer than 45 minutes who are older than 40 years with additional risk factors. Risk factors included neoplastic disease, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, history of deep vein thrombosis (DVT) or pulmonary embolism (PE), or congestive heart failure.

In a randomized, double-blind, clinical trial in patients undergoing abdominal surgery, ARIXTRA 2.5 mg SC once daily started postoperatively was compared to dalteparin sodium 5,000 IU SC once daily, with one 2,500 IU SC preoperative injection and a 2,500 IU SC first postoperative injection. A total of 2,927 patients were randomized and 2,858 were treated. Patients ranged in age from 17 to 93 years (mean age 65 years) with 55% men and 45% women. Patients were 97% Caucasian, 1% black, 1% Asian, and 1% others. Patients with serum creatinine level more than 2 mg/dL (180 μmol/L), or platelet count less than 100,000/mm3 were excluded from the trial. Sixty-nine percent (69%) of study patients underwent cancer-related abdominal surgery. Study treatment was continued for 7 ± 2 days. The efficacy data are provided in Table 5 below and demonstrate that prophylaxis with fondaparinux sodium was associated with a VTE rate of 4.6% compared with a VTE rate of 6.1% for dalteparin sodium (p = NS).

Table 5. Efficacy of ARIXTRA Injection In Prophylaxis of Thromboembolic Events Following Abdominal Surgery

Endpoint

Fondaparinux Sodium

2.5 mg SC

once daily

Dalteparin Sodium

5,000 IU SC

once daily

All Treated Abdominal Surgery Patients

N = 1,433

N = 1,425

All Evaluable 1 Abdominal Surgery Patients

VTE2

47/1,027

4.6%3

(3.4, 6.0)4

62/1,021

6.1%

(4.7, 7.7)

All DVT

43/1,024

4.2%

(3.1, 5.6)

59/1,018

5.8%

(4.4, 7.4)

Proximal DVT

5/1,076

0.5%

(0.2, 1.1)

5/1,077

0.5%

(0.2, 1.1)

Symptomatic VTE

6/1,465

0.4%

(0.2, 0.9)

5/1,462

0.3%

(0.1, 0.8)

1Evaluable patients were those who were randomized and had an adequate efficacy assessment up to Day 10; non-treated patients and patients who did not undergo surgery did not get a VTE assessment.

2VTE was a composite of venogram positive DVT, symptomatic DVT, non-fatal PE and/or fatal PE reported up to Day 10.

3p value versus dalteparin sodium: NS.

4Numbers in parenthesesindicate 95% confidence interval.

Treatment of Deep Vein Thrombosis

In a randomized, double-blind, clinical trial in patients with a confirmed diagnosis of acute symptomatic DVT without PE, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg), or 10 mg (body weight >100 kg) SC once daily (ARIXTRA treatment regimen) was compared to enoxaparin sodium 1 mg/kg SC every 12 hours. Almost all patients started study treatment in hospital. Approximately 30% of patients in both groups were discharged home from the hospital while receiving study treatment. A total of 2,205 patients were randomized and 2,192 were treated. Patients ranged in age from 18-95 years (mean age 61 years) with 53% men and 47% women. Patients were 97% Caucasian, 2% black, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 μmol/L), or platelet count less than 100,000/mm3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range of 7 ± 2 days, and both treatment groups received Vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 6 below.

Table 6. Efficacy of ARIXTRA Injection in the Treatment of Deep Vein Thrombosis

Endpoint

Fondaparinux Sodium 1

5, 7.5, or 10 mg SC once daily

(Treatment Regimen)

Enoxaparin Sodium 1

1 mg/kg SC q 12h

All Randomized

DVT Patients

N = 1,098

N = 1,107

Total VTE2

433

3.9%

(2.8, 5.2)4

45

4.1%

(3.0, 5.4)

DVT only

18

1.6%

(1.0, 2.6)

28

2.5%

(1.7, 3.6)

Non-fatal PE

20

1.8%

(1.1, 2.8)

12

1.1%

(0.6, 1.9)

Fatal PE

5

0.5%

(0.1, 1.1)

5

0.5%

(0.1, 1.1)

1Patients were also treated with Vitamin K antagonists initiated within 72 hours after the first study drug administration.

2VTE was a composite of symptomatic recurrent non fatal VTE or fatal PE reported up to Day 97.

3The 95% confidence interval for the treatment difference for total VTE was: (-1.8% to 1.5%).

4Number in parentheses indicates 95% confidence interval.

During the initial treatment period, 18 (1.6%) of patients treated with fondaparinux sodium and 10 (0.9%) of patients treated with enoxaparin sodium had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-enoxaparin sodium] for VTE rates: -0.2%; 1.7%).

Treatment of Pulmonary Embolism

In a randomized, open-label, clinical trial in patients with a confirmed diagnosis of acute symptomatic PE, with or without DVT, ARIXTRA 5 mg (body weight <50 kg), 7.5 mg (body weight 50-100 kg), or 10 mg (body weight >100 kg) SC once daily (ARIXTRA treatment regimen) was compared to heparin IV bolus (5,000 USP units) followed by a continuous IV infusion adjusted to maintain 1.5-2.5 times aPTT control value. Patients with a PE requiring thrombolysis or surgical thrombectomy were excluded from the trial. All patients started study treatment in hospital. Approximately 15% of patients were discharged home from the hospital while receiving fondaparinux therapy. A total of 2,213 patients were randomized and 2,184 were treated. Patients ranged in age from 18-97 years (mean age 62 years) with 44% men and 56% women. Patients were 94% Caucasian, 5% black and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 μmol/L), or platelet count less than 100,000/mm3 were excluded from the trial. For both groups, treatment continued for at least 5 days with a treatment duration range 7 ± 2 days, and both treatment groups received Vitamin K antagonist therapy initiated within 72 hours after the first study drug administration and continued for 90 ± 7 days, with regular dose adjustments to achieve an INR of 2-3. The primary efficacy endpoint was confirmed, symptomatic, recurrent VTE reported up to Day 97. The efficacy data are provided in Table 7 below.

Table 7. Efficacy of ARIXTRA Injection in the Treatment of Pulmonary Embolism

Endpoint

Fondaparinux Sodium 1

5, 7.5, or 10 mg SC once daily 1

(Treatment Regimen)

Heparin 1

aPTT adjusted IV

All Randomized PE Patients

N = 1,103

N = 1,110

Total VTE2

423

3.8%

(2.8, 5.1)4

56

5.0%

(3.8, 6.5)

DVT only

12

1.1%

(0.6, 1.9)

17

1.5%

(0.9, 2.4)

Non-fatal PE

14

1.3%

(0.7, 2.1)

24

2.2%

(1.4, 3.2)

Fatal PE

16

1.5%

(0.8, 2.3)

15

1.4%

(0.8, 2.2)

1Patients were also treated with Vitamin K antagonists initiated within 72 hours after the first study drug administration.

2VTE was a composite of symptomatic recurrent non fatal VTE or fatal PE reported up to Day 97.

3The 95% confidence interval for the treatment difference for total VTE was: (-3.0% to 0.5%).

4Number in parentheses indicates 95% confidence interval.

During the initial treatment period, 12 (1.1%) of patients treated with fondaparinux sodium and 19 (1.7%) of patients treated with heparin had a VTE endpoint (95% CI for the treatment difference [fondaparinux sodium-heparin] for VTE rates: -1.6%; 0.4%).

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2014