ARIXTRA (Page 3 of 10)

5.5 Neuraxial Anesthesia and Post-operative Indwelling Epidural Catheter Use

Spinal or epidural hematomas, which may result in long-term or permanent paralysis, can occur with the use of anticoagulants and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events may be higher with post-operative use of indwelling epidural catheters or concomitant use of other drugs affecting hemostasis such as NSAIDs [see Boxed Warning]. In the postmarketing experience, epidural or spinal hematoma has been reported in association with the use of ARIXTRA by subcutaneous (SC) injection. Monitor patients undergoing these procedures for signs and symptoms of neurologic impairment. Consider the potential risks and benefits before neuraxial intervention in patients anticoagulated or who may be anticoagulated for thromboprophylaxis.

5.6 Monitoring: Laboratory Tests

Routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of the activity of ARIXTRA and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of ARIXTRA. If unexpected changes in coagulation parameters or major bleeding occur during therapy with ARIXTRA, discontinue ARIXTRA. In postmarketing experience, isolated occurrences of aPTT elevations have been reported following administration of ARIXTRA [see Adverse Reactions (6.5)].

Periodic routine complete blood counts (including platelet count), serum creatinine level, and stool occult blood tests are recommended during the course of treatment with ARIXTRA.

The anti-Factor Xa activity of fondaparinux sodium can be measured by anti-Xa assay using the appropriate calibrator (fondaparinux). The activity of fondaparinux sodium is expressed in milligrams (mg) of the fondaparinux and cannot be compared with activities of heparin or low molecular weight heparins. [See Clinical Pharmacology (12.2, 12.3).]

5.7 Latex

The packaging (needle guard) of the prefilled syringe of ARIXTRA contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals.

6 ADVERSE REACTIONS

The most serious adverse reactions reported with ARIXTRA are bleeding complications and thrombocytopenia [see Warnings and Precautions (5)].

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 below is based on data from 8,877 patients exposed to ARIXTRA in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment. These trials consisted of the following:

  • 2 peri-operative dose-response trials (n = 989)
  • 4 active-controlled peri-operative VTE prophylaxis trials with enoxaparin sodium (n = 3,616), an extended VTE prophylaxis trial (n = 327), and an active-controlled trial with dalteparin sodium (n = 1,425)
  • a dose-response trial (n = 111) and an active-controlled trial with enoxaparin sodium in DVT treatment (n = 1,091)
  • an active-controlled trial with heparin in PE treatment (n = 1,092)

6.1 Hemorrhage

During administration of ARIXTRA, the most common adverse reactions were bleeding complications [see Warnings and Precautions (5.1)].

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 are provided in Table 2.

Table 2. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies
Peri-Operative Prophylaxis(Day 1 to Day 7 ± 1 post-surgery) Extended Prophylaxis(Day 8 to Day 28 ± 2 post-surgery)

ARIXTRA

2.5 mg SC

once daily

Enoxaparin Sodiuma, b

ARIXTRA

2.5 mg SC

once daily

Placebo

SC once daily

Major bleedingc 96 (2.7%) 75 (1.9%) 8 (2.4%) 2 (0.6%)
Hip fracture 18/831 (2.2%) 19/842 (2.3%) 8/327 (2.4%) 2/329 (0.6%)
Hip replacement 67/2,268 (3.0%) 55/2,597 (2.1%)
Knee replacement 11/517 (2.1%) 1/517 (0.2%)
Fatal bleeding 0 (0.0%) 1 (<0.1%) 0 (0.0%) 0 (0.0%)
Non-fatal bleeding at critical site 0 (0.0%) 1 (<0.1%) 0 (0.0%) 0 (0.0%)
Re-operation due to bleeding 12 (0.3%) 10 (0.3%) 2 (0.6%) 2 (0.6%)
BI ≥2d 84 (2.3%) 63 (1.6%) 6 (1.8%) 0 (0.0%)
Minor bleedinge 109 (3.0%) 116 (2.9%) 5 (1.5%) 2 (0.6%)

a Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.

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

c Major bleeding was defined as clinically overt bleeding that was (1) fatal, (2) bleeding at critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), (3) associated with re-operation at operative site, or (4) with a bleeding index (BI) ≥2.

d BI ≥2: Overt bleeding associated only with a bleeding index (BI) ≥2 calculated as [number of whole blood or packed red blood cell units transfused + [(pre-bleeding) – (post-bleeding)] hemoglobin (g/dL) values].

e Minor bleeding was defined as clinically overt bleeding that was not major.

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 to 6 hours was 2.3% (28/1,196), 6 to 8 hours was 1.9% (38/1,965). In all studies, the majority (≥75%) of the major bleeding events occurred during the first 4 days after surgery.

Abdominal Surgery: In a randomized study of patients undergoing abdominal surgery, ARIXTRA 2.5 mg once daily (n = 1,433) was compared with dalteparin 5,000 IU once daily (n = 1,425). Bleeding rates are shown in Table 3.

Table 3. Bleeding in the Abdominal Surgery Study

ARIXTRA

2.5 mg SC once daily

Dalteparin Sodium

5,000 IU SC once daily
N = 1,433 N = 1,425
Major bleedinga 49 (3.4%) 34 (2.4%)
Fatal bleeding 2 (0.1%) 2 (0.1%)
Non-fatal bleeding at critical site 0 (0.0%) 0 (0.0%)
Other non-fatal major bleeding
Surgical site 38 (2.7%) 26 (1.8%)
Non-surgical site 9 (0.6%) 6 (0.4%)
Minor bleedingb 31 (2.2%) 23 (1.6%)

a Major bleeding was defined as bleeding that was (1) fatal, (2) bleeding at the surgical site leading to intervention, (3) non-surgical bleeding at a critical site (e.g. intracranial, retroperitoneal, intraocular, pericardial, spinal, or into adrenal gland), or leading to an intervention, and/or with a bleeding index (BI) ≥2.

b Minor bleeding was defined as clinically overt bleeding that was not major.

The rates of major bleeding according to the time interval following the first ARIXTRA injection were as follows: <6 hours was 3.4% (9/263) and 6 to 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 4.

Table 4. Bleedinga in Deep Vein Thrombosis and Pulmonary Embolism Treatment Studies

ARIXTRA

Enoxaparin Sodium

Heparin

aPTT adjusted IV

Major bleedingb 28 (1.2%) 13 (1.2%) 12 (1.1%)
Fatal bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%)
Non-fatal bleeding at a critical site 3 (0.1%) 0 (0.0%) 2 (0.2%)
Intracranial bleeding 3 (0.1%) 0 (0.0%) 1 (0.1%)
Retro-peritoneal bleeding 0 (0.0%) 0 (0.0%) 1 (0.1%)
Other clinically overt bleedingc 22 (1.0%) 13 (1.2%) 10 (0.9%)
Minor bleedingd 70 (3.1%) 33 (3.0%) 57 (5.2%)

a Bleeding rates are during the study drug treatment period (approximately 7 days). Patients were also treated with vitamin K antagonists initiated within 72 hours after the first study drug administration.

b Major bleeding was defined as clinically overt: –and/or contributing to death – and/or in a critical organ including intracranial, retroperitoneal, intraocular, spinal, pericardial, or adrenal gland – and/or associated with a fall in hemoglobin level ≥2 g/dL – and/or leading to a transfusion ≥2 units of packed red blood cells or whole blood.

c Clinically overt bleeding with a 2 g/dL fall in hemoglobin and/or leading to transfusion of PRBC or whole blood ≥2 units.

d Minor bleeding was defined as clinically overt bleeding that was not major.

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