FDA ( Food and Drug Administration ) approved the supplemental New Drug Application (sNDA) for Arixtra ( Fondaparinux ) in the prevention of venous thromboembolism ( VTE ) in patients undergoing abdominal surgery who are at risk of thromboembolic complications.

Arixtra is the first selective inhibitor of Factor Xa, a protein central to the coagulation process.

Arixtra is already approved for the prevention of VTE, which includes deep vein thrombosis ( DVT ) and pulmonary embolism ( PE ), in patients undergoing surgery for hip fracture ( including extended prophylaxis ), knee replacement and hip replacement.
Additionally, Arixtra is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with Warfarin and for the treatment of acute pulmonary embolism when administered in conjunction with Warfarin, when initial therapy is administered in the hospital.

Up to two million cases of VTE develop in the United States each year. About one-third of patients with symptomatic VTE will develop pulmonary embolism.
venous thromboembolism can be fatal; death occurs in about six percent of deep vein thrombosis cases and about 12 percent of pulmonary embolism cases within one month of diagnosis.
Without prophylaxis, up to 25 percent of patients undergoing abdominal surgery will develop deep vein thrombosis, with a 0.5 to 0.8 percent associated risk of PE. In patients undergoing cancer surgery, the risk of venous thromboembolism and fatal pulmonary embolism is two to four times higher.

The recent approval of Arixtra for patients undergoing abdominal surgery is based on the results of the PEntasaccharide GenerAl SUrgery Study ( PEGASUS ).

This non-inferiority study demonstrated that Fondaparinux is at least as effective as Dalteparin in reducing the risk of VTE. In the study, 4.6 percent of patients receiving Arixtra experienced a VTE incident versus 6.1 percent of patients on Dalteparin.
Sixty-nine percent of the patients in the study underwent cancer-related abdominal surgery with 4.7 percent of patients in the Arixtra group experiencing VTE versus 7.7 percent of patients in the Dalteparin group. In non-cancer abdominal surgery patients studied, 4.2 percent of patients receiving Arixtra experienced VTE versus 2.3 percent of patients receiving Dalteparin.

PEGASUS was a double-blind, non-inferiority study performed in 131 centers in 22 countries. A total of 2927 patients were randomized to receive either subcutaneous Fondaparinux 2.5 mg once daily starting six hours after surgery or subcutaneous Dalteparin ( 2500 IU two hours before surgery; 2500 IU on the evening following surgery; then 5000 IU once daily ).
Treatment was continued for 7 +/- 2 days and patients were followed-up for 30 +/- 2 days. The main sites of surgery were colonic/rectal, gastric, hepatic, cholecystectomy or other biliary.

The primary efficacy endpoint was the incidence of VTE, including DVT and/or PE, evaluated up to post-surgical Day 10 ( 4.6 percent for Fondaparinux and 6.1 percent for Dalteparin ).
The primary safety outcome was major bleeding during the initial treatment period, which was comparable between the two groups ( 3.4 percent for Fondaparinux versus 2.4 percent for Dalteparin ). However, in patients treated with Arixtra according to the recommended regimen ( e.g., first dose initiated 6 to 8 hours after surgery ), the rate of major bleeding was 2.9 percent.

Arixtra safety information

Spinal/Epidural Hematomas

When epidural/spinal anesthesia or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low-molecular-weight heparins, heparinoids or Fondaparinux are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. The risk of these events may be higher with postoperative use of indwelling epidural catheters or concomitant use of drugs affecting hemostasis. Patients should be frequently monitored for signs and symptoms of neurological impairment.

Contraindications

Arixtra is contraindicated in patients with severe renal impairment ( creatinine clearance <30 mL/min ), patients undergoing hip fracture, hip replacement or knee replacement surgery and abdominal surgery with body weight <50 kg ( <110 lbs ), patients with active major bleeding, bacterial endocarditis, patients with thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of Fondaparinux, or patients with hypersensitivity to Fondaparinux.

Warnings

- Arixtra is not intended for intramuscular administration.

- Arixtra cannot be used interchangeably with heparin, low-molecular-weight heparins or heparinoids as they differ in manufacturing process, anti-Xa and anti-IIa activity, units, and dosage.

- The risk of hemorrhage increases with increasing renal impairment. Arixtra should be used with caution in patients with moderate renal impairment. Renal function should be assessed periodically in patients receiving Arixtra and should be discontinued immediately in patients who develop severe renal impairment.

- Arixtra, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage.

- Thrombocytopenia can occur with Arixtra. If the platelet count falls below 100,000/mm3, Arixtra should be discontinued.

Source: GlaxoSmithKline, 2005


XagenaMedicine2005