Fondaparinux precautions

General
Arixtra Injection should be administered according to the recommended regimen, especially with respect to the timing of the first dose after surgery. In the hip fracture, hip replacement, knee replacement, or abdominal surgery clinical studies, the administration of Arixtra before 6 hours after surgery has been associated with an increased risk of major bleeding.

Arixtra Injection should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension, or a history of recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage.

Arixtra Injection should be used with caution in elderly patients.

Arixtra should be used with caution in patients with a low body weight (<50 kg) for the treatment of PE and DVT.

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

Arixtra Injection should not be mixed with other injections or infusions.

If thrombotic events occur despite prophylaxis with Arixtra, appropriate therapy should be initiated.

Laboratory Tests
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 Injection.

When administered at the recommended doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of Arixtra activity, and are therefore, unsuitable for monitoring.

The anti-Factor Xa activity of fondaparinux sodium can be measured by anti-Xa assay using the appropriate calibrator (fondaparinux). Since the international standards of heparin or LMWH are not appropriate calibrators, 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.

Drug Interactions
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.

Carcinogenesis, Mutagenesis, Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of fondaparinux sodium.

Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test.

At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats.

Teratogenic Effects
Pregnancy Category B. Reproduction studies have been performed in pregnant rats at subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area) and pregnant rabbits at subcutaneous doses up to 10 mg/kg/day (about 65 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to fondaparinux sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers
Fondaparinux sodium was found to be excreted in the milk of lactating rats. However, it is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when fondaparinux sodium is administered to a nursing mother.

Pediatric Use
Safety and effectiveness of Arixtra in pediatric patients have not been established.

Geriatric Use
Arixtra should be used with caution in elderly patients. Over 3,000 patients, 65 years and older, have received Arixtra 2.5 mg in randomized clinical trials. Over 1,200 patients, 65 years and older, have received the Arixtra treatment regimen in the DVT and PE treatment clinical trials. The efficacy of Arixtra in the elderly (equal to or older than 65 years) was similar to that seen in younger patients (younger than 65 years). In the peri-operative hip fracture, hip replacement, or knee replacement surgery clinical trials with patients receiving Arixtra 2.5 mg, the risk of major bleeding associated with use of Arixtra increased with age: 1.8% (23/1,253) in patients <65 years, 2.2% (24/1,111) in those 65-74 years, and 2.7% (33/1,227) in those ≥75 years. Serious adverse events increased with age for patients receiving Arixtra. In patients undergoing 3 weeks of extended prophylaxis following one week of peri-operative prophylaxis after hip fracture surgery, the incidence of major bleeding was: 1.9% (1/52) in patients <65 years, 1.4% (1/71) in those 65-74 years, and 2.9% (6/204) in those ≥75 years. In the abdominal surgery clinical trial, the risk of major bleeding associated with use of Arixtra increased with age: 3.0% (19/644) in patients < 65 years, 3.2% (16/507) in those 65-74 years, and 5.0% (14/282) in those ≥75 years. In the DVT and PE treatment clinical trials with patients receiving the Arixtra treatment regimen, the risk of major bleeding associated with Arixtra increased with age: 0.6% (7/1,151) in patients <65 years, 1.6% (9/560) in those 65-74 years, and 2.1% (12/583) in those ≥75 years. Careful attention to dosing directions and concomitant medications (especially anti-platelet medication) is advised.

Fondaparinux sodium is substantially excreted by the kidney, and the risk of toxic reactions to Arixtra may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.