Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying possible adverse events and for approximating rates.

The data described below reflect exposure in 8,877 patients randomized to ARIXTRA Injection in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. Patients received ARIXTRA primarily in 2 large peri-operative dose-response trials (n = 989), 4 active-controlled peri-operative trials with enoxaparin sodium (n = 3,616), and an extended prophylaxis trial (n = 327), an active-controlled trial with dalteparin sodium (n = 1,425), a dose-response trial in DVT treatment (n = 111), an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091), and an active-controlled trial with heparin in PE treatment (n = 1,092) (see Clinical Studies).

Hemorrhage: During administration of ARIXTRA, the most common adverse reactions were bleeding complications (see WARNINGS).

Hip Fracture, Hip Replacement and Knee Replacement Surgery: The rates of major bleeding events reported during the hip fracture, hip replacement, or knee replacement surgery clinical trials with ARIXTRA 2.5 mg Injection are provided in Tables 8 and 9 below.

Table 8. Major Bleeding Episodes¹ in Randomized, Controlled, Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies

Table 9. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement and Knee Replacement Surgery Studies

A separate analysis of major bleeding across all randomized, controlled, peri-operative, prophylaxis clinical studies of hip fracture, hip replacement, or knee replacement surgery according to the time of the first injection of ARIXTRA after surgical closure was performed in patients who received ARIXTRA only post-operatively. In this analysis, the incidences of major bleeding were as follows: <4 hours was 4.8% (5/104), 4-6 hours was 2.3% (28/1196), 6-8 hours was 1.9% (38/1965). In all studies, the majority (≥75%) of the major bleeding events occurred during the first 4 days after surgery.

Abdominal Surgery: The rates of major bleeding reported during the abdominal surgery clinical trial with ARIXTRA 2.5 mg are provided in Table 10 below.

Table 10. Major Bleeding Episodes¹ in Randomized, Controlled, Abdominal Surgery Study

A separate analysis of major bleeding according to the time of the first injection of ARIXTRA after surgical closure was performed. In this analysis the incidences of major bleeding were as follows: <6 hours was 3.4% (9/263) and 6-8 hours was 2.9% (32/1112).

Treatment of Deep Vein Thrombosis and Pulmonary Embolism: The rates of bleeding events reported during the DVT and PE clinical trials with the ARIXTRA injection treatment regimen are provided in Table 11 below.

Table 11. Bleeding¹ in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies

Thrombocytopenia: See WARNINGS: Thrombocytopenia.

Local Reactions: Mild local irritation (injection site bleeding, rash, and pruritus) may occur following subcutaneous injection of ARIXTRA.

Elevations of Serum Aminotransferases: In the peri-operative prophylaxis randomized clinical trials of 7 ± 2 days asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in 1.7% and 2.6% of patients, respectively, during treatment with ARIXTRA 2.5 mg Injection versus 3.2% and 3.9%, of patients, respectively, during treatment with enoxaparin sodium 30 mg every 12 hours or 40 mg once daily enoxaparin sodium. Such elevations are fully reversible and are rarely associated with increases in bilirubin. In the extended prophylaxis clinical trial no significant differences in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels between ARIXTRA 2.5 mg Injection and placebo treated patients were observed.

In the DVT and PE treatment clinical trials asymptomatic increases in aspartate (AST [SGOT]) and alanine (ALT [SGPT]) aminotransferase levels greater than 3 times the upper limit of normal of the laboratory reference range have been reported in 0.7% and 1.3% of patients, respectively, during treatment with the ARIXTRA injection treatment regimen. In comparison, these increases have been reported in 4.8% and 12.3%, of patients, respectively, in the DVT treatment trial during treatment with enoxaparin sodium 1 mg/kg every 12 hours, and in 2.9% and 8.7%, of patients, respectively, in the PE treatment trial during treatment with aPTT adjusted heparin.

Since aminotransferase determinations are important in the differential diagnosis of myocardial infarction, liver disease, and pulmonary emboli, elevations that might be caused by drugs like ARIXTRA should be interpreted with caution.

Other Adverse Events: Other adverse events that occurred during treatment with ARIXTRA, or enoxaparin sodium in clinical trials with patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery and that occurred at a rate of at least 2% in either treatment group, are provided in Table 12 below. Other adverse events that occurred during treatment with ARIXTRA or dalteparin sodium in clinical trials with patients undergoing abdominal surgery and that occurred at a rate of at least 2% in either treatment group are provided in Table 13 below. Other adverse events that occurred during treatment with ARIXTRA, enoxaparin sodium, or heparin in the DVT and PE treatment clinical trials and that occurred at a rate of at least 2% in any treatment group are provided in Table 14 below.

Table 12. Adverse Events Occurring in ≥2% of Patients Treated With ARIXTRA, Enoxaparin Sodium, or Placebo Regardless of Relationship to Study Drug Across Randomized, Controlled, Hip Fracture Surgery, Hip Replacement Surgery, or Knee Replacement Surgery Studies

Table 13: Adverse Events Occurring in ≥2% of Patients Treated With ARIXTRA or Dalteparin Sodium Undergoing Abdominal Surgery Regardless of Relationship to Study Drug

Table 14. Adverse Events Occurring in ≥2% of Patients Treated With ARIXTRA, Enoxaparin Sodium, or Heparin Regardless of Relationship to Study Drug Across VTE Treatment Studies

In clinical studies performed with ARIXTRA, the concomitant use of oral anticoagulants (warfarin), platelet inhibitors (acetylsalicylic acid), NSAIDs (piroxicam), and digoxin did not significantly affect the pharmacokinetics/pharmacodynamics of fondaparinux sodium. In addition, ARIXTRA neither influenced the pharmacodynamics of warfarin, acetylsalicylic acid, piroxicam, and digoxin, nor the pharmacokinetics of digoxin at steady state.

Agents that may enhance the risk of hemorrhage should be discontinued prior to initiation of therapy with ARIXTRA. If co-administration is essential, close monitoring may be appropriate.

In an in vitro study in human liver microsomes, inhibition of CYP2A6 hydroxylation of coumarin by fondaparinux (200 μM i.e., 350 mg/L) was 17-28%. Inhibition of the other isozymes evaluated (CYPs 2A1, 2C9, 2C19, 2D6, 3A4, and 3E1) was 0-16%. Since fondaparinux does not markedly inhibit CYP450s (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4) in vitro,fondaparinux sodium is not expected to significantly interact with other drugs in vivo by inhibition of metabolism mediated by these isozymes.

Since fondaparinux sodium does not bind significantly to plasma proteins other than ATIII, no drug interactions by protein-binding displacement are expected.

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