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Arixtra (Fondaparinux Sodium Subcutaneous) - Warnings and Precautions

 
 



SPINAL/EPIDURAL HEMATOMAS

When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins, heparinoids, or fondaparinux sodium for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.

The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.

Patients should be frequently monitored for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary.

The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (see also WARNINGS: Hemorrhage and PRECAUTIONS: Drug Interactions.)

 

WARNINGS

ARIXTRA Injection is not intended for intramuscular administration.

ARIXTRA cannot be used interchangeably (unit for unit) with heparin, low molecular weight heparins or heparinoids, as they differ in manufacturing process, anti-Xa and anti-IIa activity, units, and dosage. Each of these medicines has its own instructions for use.

Renal Impairment (See also CONTRAINDICATIONS)

Hip Fracture, Hip Replacement and Knee Replacement Surgeries

Major bleeding in patients receiving prophylactic therapy in hip fracture, hip replacement, or knee replacement surgery occurred in 1.6% (25/1,565) of patients with normal renal function, in 2.4% (31/1,288) with mild renal impairment, in 3.8% (19/504) with moderate renal impairment, and in 4.8% (4/83) with severe renal impairment. When ARIXTRA was used according to the recommended timing of the first injection (6 to 8 hours after surgery), major bleeding occurred in 1.8% (16/905) of patients with normal renal function, in 2.2% (15/675)with mild renal impairment, in 2.3% (6/265) with moderate renal impairment, and in 0% (0/40) with severe renal impairment.

Abdominal Surgery

Major bleeding in patients receiving prophylactic therapy in abdominal surgery occurred in 2.1% (13/606) of patients with normal renal function, in 3.6% (22/613) with mild renal impairment, in 6.7% (12/179) with moderate renal impairment, and in 7.1% (1/14) with severe renal impairment. When ARIXTRA was used according to the recommended timing of the first injection (6 to 8 hours after surgery), major bleeding occurred in 2.1% (10/467) of patients with normal renal function, in 3.3% (16/481) with mild renal impairment, in 5.8% (8/137) with moderate renal impairment, and in 7.7% (1/13) with severe renal impairment.

Treatment of Deep Vein Thrombosis and Pulmonary Embolism

Major bleeding in patients receiving treatment for DVT and PE occurred in 0.4% (4/1,132) of patients with normal renal function, in 1.6% (12/733) with mild renal impairment, in 2.2% (7/318) with moderate renal impairment, and in 7.3% (4/55) with severe renal impairment.

ARIXTRA should be used with caution in patients with moderate renal impairment (creatinine clearance 30-50 mL/min). (See CLINICAL PHARMACOLOGY: Special Populations, Renal Impairment.)

Renal function should be assessed periodically in patients receiving ARIXTRA. The drug should be discontinued immediately in patients who develop severe renal impairment while on therapy. After discontinuation of ARIXTRA, its anticoagulant effects may persist for 2-4 days in patients with normal renal function (i.e., at least 3-5 half-lives). The anticoagulant effects of ARIXTRA may persist even longer in patients with renal impairment (see CLINICAL PHARMACOLOGY).

Hemorrhage

ARIXTRA Injection, like other anticoagulants, should be used with extreme caution in conditions with increased risk of hemorrhage, such as congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors.

Laboratory Testing

Because 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 during therapy with ARIXTRA, unexpected changes in coagulation parameters or major bleeding occurs, ARIXTRA should be discontinued (see PRECAUTIONS: Laboratory Tests).

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 for Spinal/Epidural Hematomas). In spontaneous post-marketing reports, there have been several cases of epidural or spinal hematoma that have occurred in association with the use of ARIXTRA by SC injection.

Thrombocytopenia

Thrombocytopenia can occur with the administration of ARIXTRA. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 3.0% in patients given ARIXTRA 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 ARIXTRA 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 ARIXTRA treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the ARIXTRA treatment regimen in the DVT and PE treatment clinical trials.

Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, ARIXTRA should be discontinued.

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 (see ADVERSE REACTIONS: Hemorrhage and DOSAGE AND ADMINISTRATION).

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 (see PRECAUTIONS: Geriatric Use).

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 (see CLINICAL PHARMACOLOGY: Pharmacodynamics and Pharmacokinetics and WARNINGS: Laboratory Testing).

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.

Pregnancy

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 (see CLINICAL PHARMACOLOGY and PRECAUTIONS: General).

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 (see CONTRAINDICATIONS and WARNINGS: Renal Impairment).

Page last updated: 2008-04-25

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