Fondaparinux Sodium

Pronunciation

Pronunciation: FON-da-PAR-in-ux SOE-dee-um
Class: Selective factor Xa inhibitor

Trade Names

Arixtra
- Injection, solution 2.5 mg per 0.5 mL
- Injection, solution 5 mg per 0.4 mL
- Injection, solution 7.5 mg per 0.6 mL
- Injection, solution 10 mg per 0.8 mL

Pharmacology

Selective inhibition of antithrombin III (ATIII), which potentiates the innate neutralization of factor Xa by ATIII. Neutralization of factor Xa interrupts the blood coagulation cascade and inhibits thrombin formation and thrombus development.

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Pharmacokinetics

Absorption

Following subcutaneous administration, rapidly and completely absorbed. C max is 0.34 mg/L and is reached in about 2 h. Peak steady-state plasma level is 0.39 to 0.5 mg/L and is reached approximately 3 h postdose.

Distribution

Distributes primarily in the blood and to a minor extent in extravascular fluid. Protein binding is at least 94%, specifically to ATIII, and does not bind significantly to other plasma proteins. Vd is 7 to 11 L.

Metabolism

Because the majority of the drug is eliminated unchanged in the urine, the metabolism has not been studied.

Elimination

Up to 77% of an administered dose is eliminated unchanged in the urine within 72 h. Elimination half-life is 17 to 21 h.

Special Populations

Renal Function Impairment

Elimination is prolonged. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total Cl of fondaparinux is approximately 25% lower in patients with mild renal impairment (CrCl 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (CrCl 30 to 50 mL/min), and approximately 55% lower in patients with severe renal impairment (less than 30 mL/min) compared with patients with healthy renal function. A similar relationship between fondaparinux Cl and extent of renal impairment was observed in deep vein thrombosis (DVT) treatment patients.

Hepatic Function Impairment

Following a single dose of 7.5 mg in patients with moderate hepatic impairment (Child-Pugh class B), C max and AUC were decreased by 22% and 39%, respectively. In addition, a higher incidence of hemorrhage was observed in these patients. Pharmacokinetics have not been studied in patients with severe hepatic impairment.

Elderly

Elimination is prolonged in patients older than 75 y. In studies evaluating fondaparinux 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total Cl of fondaparinux was approximately 25% lower in patients older than 75 y. A similar relationship between fondaparinux Cl and age was observed in DVT treatment patients.

Children

Pharmacokinetics have not been investigated.

Gender

The pharmacokinetic properties of fondaparinux are not significantly affected by gender.

Race

Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in healthy Asian (Japanese) subjects did not reveal a different pharmacokinetic profile compared with healthy white subjects. Similarly, no plasma Cl differences were observed between black and white patients undergoing orthopedic surgery.

Weight

Total Cl is decreased approximately 30% in patients weighing less than 50 kg.

Indications and Usage

For the treatment of acute DVT when administered in conjunction with warfarin; for the treatment of acute pulmonary embolism (PE) when administered in conjunction with warfarin when initial therapy is administered in the hospital; for the prophylaxis of DVT, which may lead to PE in the following patients undergoing: hip fracture surgery, including extended prophylaxis; hip replacement surgery; knee replacement surgery; and abdominal surgery in patients who are at risk for thromboembolic complications.

Contraindications

Patients with severe renal impairment (CrCl less than 30 mL/min); body weight less than 50 kg (venous thromboembolism prophylaxis only); active major bleeding; bacterial endocarditis; thrombocytopenia associated with positive in vitro test for antiplatelet antibody in the presence of fondaparinux; hypersensitivity to any component of the product.

Dosage and Administration

Deep Vein Thrombosis Prophylaxis
Adults

Subcutaneous 2.5 mg once daily. After hemostasis is established, give the initial dose 6 to 8 h after surgery. Usual duration of therapy is 5 to 9 days (up to 11 days following hip or knee replacement surgery or up to 10 days following abdominal surgery). An extended prophylaxis course of up to 24 additional days (up to 32 days total) is recommended following hip fracture surgery.

Acute Deep Vein Thrombosis and Acute Pulmonary Embolism Treatment
Adults

Subcutaneous 5 mg if body weight is less than 50 kg, 7.5 mg if body weight is 50 to 100 kg, and 10 mg if body weight is more than 100 kg, given once daily. Continue treatment for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR, 2 to 3). Initiate coadministration of warfarin as soon as possible, usually within 72 h. Usual duration of therapy is 5 to 9 days (up to 26 days).

General Advice

  • For subcutaneous administration only. Not for intradermal, IM, IV, or intra-arterial administration.
  • Follow manufacturer's instructions for preparing syringe, administering dose, and discarding used syringe. To avoid loss of medication, do not expel air bubble from syringe before administration.
  • Administer in the fatty tissue, alternating injection sites between the left and right anterolateral or left and right posterolateral abdominal wall.
  • Visually inspect solution to ensure the solution is clear and free from particles.
  • Do not mix with other medications or solutions.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Drugs that affect hemostasis (eg, anticoagulants [eg, warfarin], antithrombin, NSAIDs [eg, indomethacin, ketorolac], platelet inhibitors, salicylates [eg, aspirin], selective factor Xa inhibitors [eg, rivaroxaban], thrombin inhibitors [eg, dabigatran, desirudin], thrombolytic agents [eg, alteplase, tenecteplase])

Risk of developing epidural or spinal hematomas, or severe bleeding may be increased. If coadministration cannot be avoided, closely monitor for signs and symptoms of bleeding.

Palifermin

Palifermin plasma concentrations and pharmacologic effects may be increased. Avoid coadministration.

Adverse Reactions

CNS

Insomnia (5%); dizziness (4%); confusion (3%).

Dermatologic

Purpura (4%); bullous eruption (3%).

Hematologic

Anemia (20%); major bleeding (5%); minor bleeding, thrombocytopenia (3%); bleeding index 2 or more, postoperative hemorrhage (2%); clinically overt bleeding, epistaxis, reoperation caused by bleeding (1%); bleeding complications.

Lab Tests

Asymptomatic ALT elevations (3%); asymptomatic AST elevations (2%); elevated APTT temporally associated with bleeding, thrombocytopenia that manifested similar to heparin-induced thrombocytopenia.

Local

Nonfatal bleeding at surgical site (3%); nonfatal bleeding at nonsurgical site (1%); local irritation (injection-site bleeding, rash, pruritus).

Miscellaneous

Increased wound drainage, postoperative wound infection (5%); hypokalemia, hypotension (4%); hematoma (3%).

Precautions

Warnings

Epidural or spinal hematomas may occur in patients who are anticoagulated with low-molecular-weight heparins, heparinoids, or fondaparinux and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as NSAIDs, platelet inhibitors, or other anticoagulants; a history of traumatic or repeated epidural or spinal puncture; or a history of spinal deformity or spinal surgery. Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.


Monitor

Perform periodic CBCs (including platelet count), serum creatinine level, and stool occult blood tests during course of therapy. Assess patient for signs/symptoms of bleeding. Closely monitor patients for signs/symptoms of neurologic impairment. Periodically assess renal function. The anti–factor Xa activity of fondaparinux can be measured by anti-Xa assay using the appropriate calibrator (fondaparinux).


Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Use with caution.

Renal Function

Risk of hemorrhage increases with increasing renal impairment. Do not use fondaparinux for venous thromboembolism prophylaxis and treatment in patients with CrCl less than 30 mL/min.

Hepatic Function

May have a higher incidence of hemorrhage, especially mild hematomas at the blood sampling or injection site.

Hemorrhage

Use with extreme caution in conditions of increased risk of hemorrhage (eg, congenital bleeding disorder; active ulcerative GI disease; hemorrhagic stroke; uncontrolled arterial hypertension; diabetic retinopathy; shortly after brain, spinal, or ophthalmic surgery). Isolated cases of elevated APTT temporally associated with bleeding events have been reported. Do not administer the initial dose earlier than 6 to 8 h after surgery. In addition, fondaparinux increases the risk for bleeding in patients who weigh less than 50 kg. In these patients, do not administer as prophylactic therapy for patients undergoing orthopedic and abdominal surgery; use with caution in the treatment of PE and DVT.

Latex allergy

The needle guard of the Arixtra prefilled syringe contains dry natural latex rubber.

Thrombocytopenia

May occur. Discontinue fondaparinux if platelet count falls below 100,000/mm 3 . Isolated cases of thrombocytopenia with thrombosis that manifested similar to heparin-induced thrombocytopenia have been reported.

Overdosage

Symptoms

Hemorrhagic complications.

Patient Information

  • Inform patients who have had neuraxial anesthesia or spinal puncture, particularly if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, that they should watch for signs and symptoms of spinal or epidural hematomas, such as tingling, numbness (especially in the lower limbs), and muscular weakness.
  • Inform patients that the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their use should be discontinued prior to therapy whenever possible.
  • Patients who will be administering fondaparinux at home must be instructed in the proper technique for administration.
  • Inform patients they may bruise and/or bleed more easily when they are treated with fondaparinux, and it may take longer than usual to stop bleeding.
  • Instruct patients to immediately report any signs or symptoms of bleeding (eg, black, tarry stools; blood in the urine; dizziness when standing; excessive bruising; nosebleed; paleness).

Copyright © 2009 Wolters Kluwer Health.

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