Fondaparinux Sodium (Page 3 of 13)

5.4 Body Weight <50 kg and Bleeding Risk

Fondaparinux sodium increases the risk for bleeding in patients who weigh less than 50 kg, compared to patients with higher weights.

In patients who weigh less than 50 kg:

Do not administer fondaparinux sodium as prophylactic therapy for patients undergoing hip fracture, hip replacement, or knee replacement surgery and abdominal surgery [see Contraindications (4)].

During the randomized clinical trials of VTE prophylaxis in the peri-operative period following hip fracture, hip replacement, or knee replacement surgery and abdominal surgery, major bleeding occurred at a higher rate among patients with a body weight <50 kg compared to those with a body weight >50 kg (5.4% versus 2.1% in patients undergoing hip fracture, hip replacement, or knee replacement surgery; 5.3% versus 3.3% in patients undergoing abdominal surgery).

5.5 Thrombocytopenia

Thrombocytopenia can occur with the administration of fondaparinux sodium. Thrombocytopenia of any degree should be monitored closely. Discontinue fondaparinux sodium if the platelet count falls below 100,000/mm3. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 3.0% in patients given fondaparinux sodium 2.5 mg in the peri-operative hip fracture, hip replacement, or knee replacement surgery and abdominal surgery clinical trials. Severe thrombocytopenia (platelet counts less than 50,000/mm3) occurred at a rate of 0.2% in patients given fondaparinux sodium 2.5 mg in these clinical trials. During extended prophylaxis, no cases of moderate or severe thrombocytopenia were reported.

Moderate thrombocytopenia occurred at a rate of 0.5% in patients given the fondaparinux sodium treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the fondaparinux sodium treatment regimen in the DVT and PE treatment clinical trials.

Occurrences of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported with the use of fondaparinux sodium in postmarketing experience [see Adverse Reactions (6.5)].

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 fondaparinux sodium and international standards of heparin or LMWH are not calibrators to measure anti-Factor Xa activity of fondaparinux sodium. If unexpected changes in coagulation parameters or major bleeding occur during therapy with fondaparinux sodium, discontinue fondaparinux sodium. In postmarketing experience, occurrences of aPTT elevations have been reported following administration of fondaparinux sodium [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 fondaparinux sodium.

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 fondaparinux sodium injection contains dry natural latex rubber that may cause allergic reactions in latex sensitive individuals.

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Spinal or epidural hematomas [see Warnings and Precautions (5.1)]
Hemorrhage [see Warnings and Precautions (5.2)]
Renal impairment and bleeding risk [see Warnings and Precautions (5.3)]
Body weight <50 kg and bleeding risk [see Warnings and Precautions (5.4)]
Thrombocytopenia [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

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 fondaparinux sodium in controlled trials of hip fracture, hip replacement, major knee, or abdominal surgeries, and DVT and PE treatment.

Hemorrhage

During administration of fondaparinux sodium, the most common adverse reactions were bleeding complications [see Warnings and Precautions (5.2)].

Hip Fracture, Hip Replacement, and Knee Replacement Surgery

The rates of major bleeding events reported during 3 active-controlled peri-operative VTE prophylaxis trials with enoxaparin sodium in hip fracture, hip replacement, or knee replacement surgery (N = 3,616) and in an extended VTE prophylaxis trial (n = 327) with fondaparinux sodium 2.5 mg are provided in Table 2.

Table 2. Bleeding Across Randomized, Controlled Hip Fracture, Hip Replacement, and Knee Replacement Surgery Studies
*
Enoxaparin sodium dosing regimen: 30 mg every 12 hours or 40 mg once daily.
Not approved for use in patients undergoing hip fracture surgery.
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.
§
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].
Minor bleeding was defined as clinically overt bleeding that was not major.

Peri-Operative Prophylaxis (Day 1 to Day 7 ± 1 post-surgery)

Extended Prophylaxis (Day 8 to Day 28 ± 2 post-surgery)

Fondaparinux Sodium

2.5 mg SC

once daily

N = 3,616

Enoxaparin Sodium * ,

N = 3,956

Fondaparinux Sodium

2.5 mg SC

once daily

N = 327

Placebo

SC once daily

N = 329

Major bleeding

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 ≥2§

84 (2.3%)

63 (1.6%)

6 (1.8%)

0 (0.0%)

Minor bleeding

109 (3.0%)

116 (2.9%)

5 (1.5%)

2 (0.6%)

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 fondaparinux sodium after surgical closure was performed in patients who received fondaparinux sodium 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.

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