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Pronunciation:

(fon da PARE i nuks)

U.S. Brand Names:

Arixtra®

Synonyms:

Fondaparinux Sodium

Generic Available:

Canadian Brand Names:

Arixtra®

Use:

Prophylaxis of deep vein thrombosis (DVT) in patients undergoing surgery for hip replacement, knee replacement, or hip fracture surgery (including extended prophylaxis following hip fracture surgery); treatment of acute pulmonary embolism (PE); treatment of acute DVT without PE

Pregnancy Risk Factor:

Pregnancy Implications:

Reproductive animal studies have not shown fetal harm. Based on case reports, small amounts of fondaparinux have been detected in the umbilical cord following multiple doses during pregnancy. There are no adequate and well-controlled studies in pregnant women; use only if clearly needed.

Lactation:

Excretion in breast milk unknown/use caution

Contraindications:

Hypersensitivity to fondaparinux or any component of the formulation; severe renal impairment (Clcr<30 mL/minute); body weight <50 kg (prophylaxis); active major bleeding; bacterial endocarditis; thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux

Warnings/Precautions:

Patients with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) are at risk of spinal or epidural hematoma and subsequent paralysis. Consider risk versus benefit prior to neuraxial anesthesia; risk is increased by concomitant agents which may alter hemostasis, as well as traumatic or repeated epidural or spinal puncture. Patient should be observed closely for bleeding if administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia.

Not to be used interchangeably (unit-for-unit) with heparin, low molecular weight heparins (LMWHs), or heparinoids. Use caution in patients with moderate renal dysfunction (Clcr 30-50 mL/minute). Patients with serum creatinine >2 mg/dL were excluded from clinical trials. Periodically monitor renal function; discontinue if severe dysfunction or labile function develops.

Use caution in conditions with increased risk of hemorrhage such as congenital or acquired bleeding disorders; active ulcerative or angiodysplastic gastrointestinal disease; hemorrhagic stroke; shortly after brain, spinal, or ophthalmologic surgery; or in patients taking platelet inhibitors. Risk of major bleeding may be increased if initial dose is administered earlier then recommended (initiation recommended at 6-8 hours following surgery). Discontinue agents that may enhance the risk of hemorrhage if possible. If thrombocytopenia occurs, discontinue fondaparinux. Use caution in the elderly, patients with a history of heparin-induced thrombocytopenia, patients with a bleeding diathesis, uncontrolled hypertension, recent gastrointestinal ulceration, diabetic retinopathy, and hemorrhage. Use caution in patients <50 kg who are being treated for DVT/PE; fondaparinux clearance may be decreased. Safety and efficacy in pediatric patients have not been established.

Adverse Reactions:

As with all anticoagulants, bleeding is the major adverse effect. Hemorrhage may occur at any site. Risk appears increased by a number of factors including renal dysfunction, age (>75 years), and weight (<50 kg).

>10%:

Central nervous system: Fever (4% to 14%)

Gastrointestinal: Nausea (11%)

Hematologic: Anemia (20%)

1% to 10%:

Cardiovascular: Edema (9%), hypotension (4%), confusion (3%)

Central nervous system: Insomnia (5%), dizziness (4%), headache (2% to 5%), pain (2%)

Dermatologic: Rash (8%), purpura (4%), bullous eruption (3%)

Endocrine & metabolic: Hypokalemia (1% to 4%)

Gastrointestinal: Constipation (5% to 9%), nausea (3%), vomiting (6%), diarrhea (3%), dyspepsia (2%)

Genitourinary: Urinary tract infection (4%), urinary retention (3%)

Hematologic: Moderate thrombocytopenia (50,000-100,000/mm³: 3%), major bleeding (1% to 3%), minor bleeding (3% to 4%), hematoma (3%); risk of major bleeding increased as high as 5% in patients receiving initial dose <6 hours following surgery

Hepatic: SGOT increased (2%), SGPT increased (3%)

Local: Injection site reaction (bleeding, rash, pruritus)

Miscellaneous: Wound drainage increased (5%)

<1%: Hepatic enzymes increased, severe thrombocytopenia (<50,000/mm³)

Overdosage/Toxicology:

Treatment is symptom-directed and supportive. Hemodialysis may increase clearance by 20%.

Drug Interactions:

Anticoagulants: May enhance the effects of other anticoagulants.

Antiplatelet agents (including abciximab, anagrelide, cilostazol, clopidogrel, dipyridamole, eptifibatide, ticlopidine, tirofiban): May enhance the anticoagulant effect of fondaparinux.

Drotrecogin alfa: May enhance the bleeding potential with drotrecogin alfa.

NSAIDs: May enhance the anticoagulant effect of fondaparinux.

Salicylates: May enhance the anticoagulant effect of fondaparinux.

Thrombolytic agents: Increase the risk of hemorrhage.

Ethanol/Nutrition/Herb Interactions:

Herb/Nutraceutical: Avoid alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, celery, coleus, cordyceps, dong quai, evening primrose oil, fenugreek, feverfew, garlic, ginger, ginkgo biloba, ginseng (American/Panax/Siberian), grape seed, green tea, guggul, horse chestnut seed, horseradish, licorice, prickly ash, red clover, reishi, sweet clover, turmeric, white willow (all possess anticoagulant or antiplatelet activity and as such, may enhance the anticoagulant effects of fondaparinux).

Stability:

Store at 15°C to 30°C (59°F to 86°F).

Mechanism of Action:

Fondaparinux is a synthetic pentasaccharide that causes an antithrombin III-mediated selective inhibition of factor Xa. Neutralization of factor Xa interrupts the blood coagulation cascade and inhibits thrombin formation and thrombus development.

Pharmacodynamics/Kinetics:

Absorption: Rapid and complete

Distribution: Vd: 7-11 L; mainly in blood

Protein binding: 94% to antithrombin III

Bioavailability: 100%

Half-life elimination: 17-21 hours; prolonged with worsening renal impairment

Time to peak: 2-3 hours

Excretion: Urine (as unchanged drug)

Dosage:

SubQ:

DVT prophylaxis: Adults 50 kg: 2.5 mg once daily. Note: Initiate dose after hemostasis has been established, 6-8 hours postoperatively.

Usual duration: 5-9 days (up to 11 days) following hip replacement or knee replacement. Extended prophylaxis is recommended following hip fracture surgery (has been tolerated for up to 32 days).

Acute DVT/PE treatment: SubQ: Adults:

<50 kg: 5 mg once daily

50-100 kg: 7.5 mg once daily

>100 kg: 10 mg once daily

Dosage adjustment in renal impairment:

Clcr 30-50 mL/minute: Use caution

Clcr<30 mL/minute: Contraindicated

Administration:

Do not administer I.M.; for SubQ administration only. Do not mix with other injections or infusions. Do not expel air bubble from syringe before injection. Administer according to recommended regimen; early initiation (before 6 hours after surgery) has been associated with increased bleeding.

Monitoring Parameters:

Periodic monitoring of CBC, serum creatinine, occult blood testing of stools recommended. Antifactor Xa activity of fondaparinux can be measured by the assay if fondaparinux is used as the calibrator. PT and aPTT are insensitive measures of fondaparinux activity.

Test Interactions:

International standards of heparin or LMWH are not the appropriate calibrators for antifactor Xa activity of fondaparinux.

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. This drug can only be administered by injection. Report pain, burning, redness, or swelling at injection site. You may have a tendency to bleed easily while taking this drug (brush teeth with soft brush, floss with waxed floss, use electric razor, avoid scissors or sharp knives, and avoid potentially harmful activities). May cause nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or dizziness, headache, insomnia (use caution when driving or engaging in tasks that require alertness until response to drug is known). Report unusual bleeding or bruising (bleeding gums, nosebleed, blood in urine, dark stool); pain in joints or back; CNS changes (fever, confusion); unusual fever; persistent nausea or GI upset; changes in urinary pattern; or other persistent adverse response. Breast-feeding precaution: Consult prescriber if breast-feeding.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Hemorrhage may occur at any site; risk increased in renal dysfunction, patients >75 years and/or <50 kg; major bleeding increased as high as 5% in patients receiving initial dose <6 hours postsurgery.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dosage Forms:

Injection, solution, as sodium: 2.5 mg/0.5 mL (0.5 mL) [prefilled syringe]

International Brand Names:

Arixtra® (AT, BE, CA, CH, CO, DE, DK, ES, FI, FR, GB, IT, NO, PT, SE)

References

Bauer KA, Eriksson BI, Lassen MR, et al, "Fondaparinux Compared With Enoxaparin for the Prevention of Venous Thromboembolism After Elective Major Knee Surgery,"N Engl J Med, 2001, 345: 1305-10.

Bauer KA, "Fondaparinux Sodium: A Selective Inhibitor of Factor Xa,"Am J Health-Syst Pharm, 2001, 58(Suppl 2):14-17.

Buller HR, Davidson BL, Decousus H, et al, "Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis: A Randomized Trial,"Ann Intern Med, 2004, 140(11):867-73.

Buller HR, Davidson BL, Decousus H, et al, "Subcutaneous Fondaparinux Versus Intravenous Unfractionated Heparin in the Initial Treatment of Pulmonary Embolism,"N Engl J Med, 2003, 349(18):1695-702.

Dempfle CE, "Minor Transplacental Passage of Fondaparinux in vivo,"N Engl J Med, 2004, 350(18):1914-5.

Eriksson BI, Bauer KA, Lassen MR, et al, "Fondaparinux Compared With Enoxaparin for the Prevention of Venous Thromboembolism After Hip-Fracture Surgery,"N Eng J Med, 2001, 345: 1298-304.

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