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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(fon da PARE i nuks)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Prophylaxis of deep vein thrombosis (DVT) in patients undergoing surgery for hip replacement, knee replacement, hip fracture (including extended prophylaxis following hip fracture surgery), or abdominal surgery (in patients at risk for thromboembolic complications); treatment of acute pulmonary embolism (PE); treatment of acute DVT without PE
Canadian labeling: Additional uses (not approved in U.S.): Unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI) for the prevention of death and subsequent MI; ST segment elevation MI (STEMI) for the prevention of death and myocardial reinfarction
Use: Unlabeled/Investigational
Prophylaxis of DVT in patients with a history of heparin-induced thrombocytopenia (HIT)
Pregnancy Risk Factor
B
Pregnancy Considerations
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
Boxed warnings:
• Neuraxial anesthesia: See “Other warnings/precautions” below.
Concerns related to adverse effects:
• Bleeding: Monitor patient closely for signs or symptoms of bleeding. Certain patients are at increased risk of bleeding. Risk factors include bacterial endocarditis; congenital or acquired bleeding disorders; active ulcerative or angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or use shortly after brain, spinal, or ophthalmology surgery; in patients treated concomitantly with platelet inhibitors; recent GI bleeding; thrombocytopenia or platelet defects; renal impairment; hepatic impairment; hypertensive or diabetic retinopathy; or in patients undergoing invasive procedures. Risk of major bleeding may be increased if initial dose is administered earlier than recommended (initiation recommended at 6-8 hours following surgery). Do not administer with other agents that increase the risk of hemorrhage unless they are essential for the management of the underlying condition (eg, warfarin for treatment of VTE). Although considered an insensitive measure of fondaparinux activity, there have been postmarketing reports of bleeding associated with elevated aPTT. Discontinue if bleeding occurs.
• Thrombocytopenia: Has occurred with administration, including reports of thrombocytopenia with thrombosis similar to heparin-induced thrombocytopenia. Monitor patients closely and discontinue therapy if platelets fall to <100,000/mm3.
Disease-related concerns:
• Renal impairment: Use with caution in patients with moderate renal dysfunction (Clcr 30-50 mL/minute); contraindicated in patients with Clcr <30 mL/minute. Periodically monitor renal function; discontinue if severe dysfunction or labile function develops.
Special populations:
• Elderly: Use with caution in the elderly; elimination half-life prolonged in patients >75 years of age.
• Patients <50 kg: Use with caution in patients <50 kg who are being treated for DVT/PE; fondaparinux clearance may be decreased, increasing the risk for bleeding; dosage reduction recommended. Contraindicated in patients <50 kg when used for prophylactic therapy.
Dosage form specific issues:
• Latex: The needle guard contains natural latex rubber.
Other warnings/precautions:
• Appropriate use: For subcutaneous administration; not for I.M. administration. Do not use interchangeably (unit for unit) with low molecular weight heparins, heparin, or heparinoids.
• Neuraxial anesthesia: [U.S. Boxed Warning]: Spinal or epidural hematomas, including subsequent paralysis, may occur with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients anticoagulated with LMWH, heparinoids, or fondaparinux. Consider risk versus benefit prior to spinal procedures; risk is increased by the use of concomitant agents which may alter hemostasis, the use of indwelling epidural catheters for analgesia, a history of spinal deformity or spinal surgery, as well as a history of traumatic or repeated epidural or spinal punctures. Patient should be observed closely for bleeding and signs and symptoms of neurological impairment if therapy is administered during or immediately following diagnostic lumbar puncture, epidural anesthesia, or spinal anesthesia.
• Primary percutaneous coronary intervention (PCI): The administration of fondaparinux is not recommended prior to and during primary PCI in patients with STEMI, due to an increased risk for guiding-catheter thrombosis. Patients with UA/NSTEMI or STEMI undergoing any PCI should not receive fondaparinux as the sole anticoagulant. Use of an anticoagulant with antithrombin activity (eg, unfractionated heparin) is recommended as adjunctive therapy to PCI even if prior treatment with fondaparinux (must take into account whether GP IIb/IIIa antagonists have been administered) (King, 2008).
• Additional Canadian labeling warnings: Following sheath removal, fondaparinux therapy should not resume for at least 2 hours in patients with UA/NSTEMI and 3 hours in patients with STEMI. Avoid administration 24 hours before and 48 hours after coronary artery bypass graft (CABG) surgery.
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 (3% to 11%)
Hematologic: Anemia (1% to 20%)
1% to 10%:
Cardiovascular: Edema (9%), hypotension (4%), hypertension (2%), chest pain (1%), thrombosis PCI catheter (without heparin 1%)
Central nervous system: Insomnia (4% to 5%), headache (2% to 5%), dizziness (4%), confusion (3%), pain (2%), anxiety (1%)
Dermatologic: Rash (8%), purpura (4%), bullous eruption (3%), bruising (1%)
Endocrine & metabolic: Hypokalemia (1% to 4%)
Gastrointestinal: Constipation (5% to 9%), vomiting (1% to 6%), diarrhea (2% to 3%), dyspepsia (2%), abdominal pain (1%)
Genitourinary: Urinary tract infection (2% to 4%), urinary retention (3%)
Hematologic: Minor bleeding (2% to 4%), moderate thrombocytopenia (50,000-100,000/mm3: 3%), hematoma (3%), major bleeding (1% to 3%), prothrombin decreased (1%), risk of major bleeding increased as high as 5% in patients receiving initial dose <6 hours following surgery
Hepatic: ALT increased (≤3%), AST increased (≤2%)
Local: Injection site reaction (bleeding, rash, pruritus)
Neuromuscular & skeletal: Back pain (1%), leg pain (1%)
Respiratory: Cough (2%), pneumonia (2%), epistaxis (1%)
Miscellaneous: Wound drainage increased (5%)
<1%, postmarketing, and/or case reports: aPTT increased (associated with bleeding), heparin-induced thrombocytopenia (1 case report), hepatic dysfunction, severe thrombocytopenia (<50,000/mm3)
Drug Interactions
Anticoagulants: May enhance the anticoagulant effect of other Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy
Drotrecogin Alfa: May enhance the adverse/toxic effect of Fondaparinux. Bleeding may occur. Management: Monitor for increased risk of bleeding during concomitant therapy. Consider avoiding concomitant use, when possible. Risk D: Consider therapy modification
Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk D: Consider therapy modification
Ibritumomab: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy
Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Thrombolytic Agents: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Anticoagulants may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse effects may be increased. Risk C: Monitor therapy
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), grapeseed, 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).
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Canadian labeling: For I.V. administration: Manufacturer recommends immediate use once diluted in NS, but is stable for up to 24 hours at 15°C to 30°C (59°F to 86°F).
Reconstitution
Canadian labeling: For I.V. administration: May mix with 25 mL or 50 mL NS
Compatibility
Do not mix with other injections or infusions.
Canadian labeling: Stable in NS
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: SubQ: Rapid and complete
Distribution: Vd: 7-11 L; mainly in blood
Protein binding: ≥94% to antithrombin III
Bioavailability: SubQ: 100%
Half-life elimination: 17-21 hours; prolonged with renal impairment
Time to peak: SubQ: 2-3 hours
Excretion: Urine (~77%, unchanged drug)
Dosage
SubQ: Adults:
DVT prophylaxis: Adults ≥50 kg: 2.5 mg once daily. Note: Initiate dose after hemostasis has been established, 6-8 hours postoperatively.
DVT prophylaxis with history of HIT (unlabeled use): 2.5 mg once daily
Usual duration: 5-9 days (up to 10 days following abdominal surgery or 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 total).
Acute DVT/PE treatment: Note: Start warfarin on the first treatment day and continue fondaparinux until INR is between 2 and 3 (usually 5-7 days) (Hirsh, 2008):
<50 kg: 5 mg once daily
50-100 kg: 7.5 mg once daily
>100 kg: 10 mg once daily
Usual duration: 5-9 days (has been administered up to 26 days)
Canadian labeling only: Adults:
UA/NSTEMI: SubQ: 2.5 mg once daily; initiate as soon as possible after diagnosis; treat for up to 8 days or until hospital discharge.
STEMI: I.V.: 2.5 mg once; subsequent doses: SubQ: 2.5 mg once daily; treat for up to 8 days or until hospital discharge
Dosage adjustment in renal impairment:
Clcr 30-50 mL/minute: Use caution
Clcr <30 mL/minute: Contraindicated
Dosage adjustment in hepatic impairment:
Mild-to-moderate impairment: Dosage adjustment not required; monitor for signs of bleeding
Severe impairment: No data
Administration: I.M.
Do not administer I.M.
Administration: I.V.
Canadian labeling only: STEMI patients: I.V. push or mixed in 25-50 mL of NS and infused over 2 minutes. Flush tubing with NS after infusion to ensure complete administration of fondaparinux. Infusion bag should not be mixed with other agents.
Administration: Other
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.
To convert from I.V. unfractionated heparin (UFH) infusion to SubQ fondaparinux (Nutescu, 2007): Calculate specific dose for fondaparinux based on indication, discontinue UFH, and begin fondaparinux within 1 hour
To convert from SubQ fondaparinux to I.V. UFH infusion (Nutescu, 2007): Discontinue fondaparinux; calculate specific dose for I.V. UFH infusion based on indication; omit heparin bolus/loading dose
For subQ fondaparinux dosed every 24 hours: Start I.V. UFH infusion 22-23 hours after last dose of fondaparinux
Monitoring Parameters
Periodic monitoring of CBC, serum creatinine, occult blood testing of stools recommended. Anti-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. If unexpected changes in coagulation parameters or major bleeding occur, discontinue fondaparinux (elevated aPTT associated with bleeding events have been reported in postmarketing data).
Test Interactions
International standards of heparin or LMWH are not the appropriate calibrators for antifactor Xa activity of fondaparinux.
Patient Education
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. May cause bleeding problems, anemia, nausea, and fever. Report unusual bleeding or bruising (bleeding gums, nosebleed, blood in urine, dark stool), pain in joints or back, CNS changes (severe headache, confusion), any falls or accidents, or rash.
Geriatric Considerations
Patients studied for DVT prophylaxis following elective knee or hip fracture surgery averaged 67.5 and 77 years of age, respectively. Use with caution in patients with estimated or actual creatinine clearance between 30-50 mL/minute. Contraindicated in patients with Clcr <30 mL/minute.
Cardiovascular Considerations
The OASIS-5 trial is an international, randomized, double-blind trial in patients with non-ST segment elevation acute coronary syndrome who were randomized to fondaparinux (2.5 mg SubQ once daily) versus enoxaparin (1 mg/kg SubQ twice daily). If patients in the fondaparinux arm had PCI, then route and dose were adjusted. If PCI <6 hours and GPIIb/IIIa was not used, fondaparinux 2.5 mg I.V. was administered. If PCI <6 hours and GPIIb/IIIa was used, no fondaparinux was administered. If PCI >6 hours, fondaparinux was adjusted based on concurrent GPIIb/IIIa use. If a GPIIb/IIIa was used, fondaparinux was administered at 2.5 mg I.V., while fondaparinux 5 mg was administered in patients without concurrent GP IIb/IIIa. In the enoxaparin arm, if PCI <6 hours, then no additional unfractionated heparin (UFH) was used. If PCI >6 hours, I.V. UFH was used (doses varied depending on use of GPIIb/IIIa). The primary outcome was a composite of death, MI, refractory ischemia, and major bleeds at 9 days. Patients were also evaluated at 1 month and 6 months for these endpoints. Over 20,000 patients were enrolled. Patients were excluded if they had any contraindications to enoxaparin, had a hemorrhagic stroke <12 months ago, or serum creatinine >3 mg/dL. The primary efficacy outcome (death, MI, refractory ischemia) at day 9 was similar for both treatment arms. Major bleeding at day 9 was significantly less for fondaparinux (2.1%) than enoxaparin (4%). At one month and at 6 months, there is a significant reduction in mortality with fondaparinux.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Hemorrhage may occur at any site. See Effects on Bleeding.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness or insomnia
Mental Health: Effects on Psychiatric Treatment
May cause thrombocytopenia; use caution with valproic acid
Nursing: Physical Assessment/Monitoring
Assess closely for bleeding; bleeding precautions should be observed. Teach appropriate injection technique, syringe/needle disposal, and bleeding precautions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as sodium [preservative free]:
Arixtra®: 2.5 mg/0.5 mL (0.5 mL); 5 mg/0.4 mL (0.4 mL); 7.5 mg/0.6 mL (0.6 mL); 10 mg/0.8 mL (0.8 mL)
Pricing: U.S. (www.drugstore.com)
Solution (Arixtra)
2.5 mg/0.5 mL (5): $593.04
7.5 mg/0.6 mL (0.6): $140.09
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):14-7.
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 Engl J Med, 2001, 345:1298-304.
Hassell K, “The Management of Patients With Heparin-Induced Thrombocytopenia Who Require Anticoagulation Therapy,” Chest, 2005, 127(2 Suppl):1-8.
Hirsh J, Guyatt G, Albers GW, et al, “Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest, 2008, 133(6 Suppl):71-109.
King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al, “2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee,”Circulation, 2008, 117(2):261-95.
Nutescu EA and Dager W, “Heparin, Low Molecular Weight Heparin, and Fondaparinux,” Managing Anticoagulation Patients in the Hospital, Gulseth M ed, American Society of Health-System Pharmacists®, Bethesda, MD: 2007, 181.
Warkentin TE, Maurer BT, and Aster RH, “Heparin-Induced Thrombocytopenia Associated With Fondaparinux,” N Engl J Med, 2007, 356(25):2653-55.
Yusuf S, Mehta SR, Chrolavicius S, et al, “Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes − The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators,” N Engl J Med, 2006, 354(14):1464-76.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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