Fondaparinux

Fondaparinux is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Fondaparinux is an anticoagulant used to prevent venous thromboembolism, treat deep vein thrombosis, and improve survival following myocardial infarction.

Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in the blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7 to 11 L. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells. In vivo metabolism of Fondaparinux has not been investigated since most of the administered dose is eliminated unchanged in the urine in individuals with normal kidney function. The elimination half-life is 17 to 21 hours.

Fondaparinux shows common side effects like rash, itching, bruising or bleeding at the injection site, dizziness, Confusion, pale skin, blisters on the skin, and difficulty falling asleep or staying asleep.

Fondaparinux is available in the form of Subcutaneous Injection.

Fondaparinux is available in India, US, UK, Portugal, Greece, Netherlands, Switzerland, China, Japan, Germany, Spain, and Australia.

Fondaparinux belonging to the Factor Xa (FXa) inhibitor, acts as an anticoagulant agent.

The antithrombotic activity of fondaparinux is the result of ATIII-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, Fondaparinux potentiates (about 300 times) the neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. It is thought that fondaparinux is unlikely to induce thrombocytopenia via heparin-induced thrombocytopenia (HIT)-like mechanism given its chemical structure. As a result, fondaparinux has been used as an alternative anticoagulant in heparin-induced thrombocytopenia (HIT) patients. However, it is important to note that rare cases of HIT have been reported in patients treated with fondaparinux.

The data on the onset of action and duration of Action of Fondaparinux is not available.

Fondaparinux is available in the form of Subcutaneous Injection.

Fondaparinux Injection is given subcutaneously usually once daily.

Fondaparinux is an anticoagulant used to prevent venous thromboembolism, treat deep vein thrombosis, and improve survival following myocardial infarction.

Fondaparinux is an anticoagulant agent belonging to Factor Xa (FXa) inhibitor.

Fondaparinux acts as a selective inhibitor of activated factor X. It works by binding selectively to antithrombin III and potentiates the neutralization of factor Xa. This will interrupt the blood coagulation cascade and inhibit both thrombin formation and thrombus development.

Fondaparinux is approved for use in the following clinical indications

• Venous thromboembolism prophylaxis

Fondaparinux is an anticoagulant used to prevent venous thromboembolism.

• Prophylaxis Of Deep Vein Thrombosis

Fondaparinux is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

• In patients undergoing hip fracture surgery, including extended prophylaxis.
• In patients undergoing hip replacement surgery.
• In patients undergoing knee replacement surgery.
• In patients undergoing abdominal surgery who are at risk for thromboembolic complications.
• Treatment Of Acute Deep Vein Thrombosis

Fondaparinux is indicated for the treatment of acute deep-vein thrombosis when administered in conjunction with warfarin sodium.

• Treatment Of Acute Pulmonary Embolism

Fondaparinux is indicated for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital.

Although not approved, there have been certain off-label indications. These include

• Acute coronary syndrome
• Heparin-induced thrombocytopenia treatment (alternative agent)
• Superficial vein thrombosis, acute symptomatic

• Venous thromboembolism prophylaxis

• Medical patients with acute illness at moderate and high risk for venous thromboembolism (off-label use)

Subcutaneously: 2.5 mg once daily; continue for the length of hospital stay or until the patient is fully ambulatory and risk of VTE has diminished.

• Major surgery for cancer (off-label use)

Subcutaneously: 2.5 mg once daily beginning 6 to 8 hours postoperatively. The optimal duration of prophylaxis has not been established; usually given for a minimum of 7 to 10 days. Extending for up to 4 weeks may be considered in patients undergoing major abdominal or pelvic surgery.

• Surgical patients (without cancer)

Subcutaneously: ≥50 kg: 2.5 mg once daily beginning after hemostasis has been established, no earlier than 6 to 8 hours postoperatively.

• Deep vein thrombosis and/or pulmonary embolism treatment

Adult Subcutaneously Dose

<50 kg: 5 mg once daily.

50 to 100 kg: 7.5 mg once daily.

>100 kg: 10 mg once daily.

• Deep vein thrombosis (DVT), treatment

Pediatric Subcutaneously Dose

Children and Adolescents: 0.1 mg/kg/dose once daily; dosing based on 2 pediatric studies including a prospective dose-finding, pharmacokinetic, and safety study in patients (n=24, age: 1 to 18 years) receiving primary treatment for DVT (n=23) or heparin-induced thrombocytopenia (n=1) and a consecutive cohort study evaluating long-term safety, dosing, and efficacy (n=35, age: 9.11 ± 0.95 years [range: 1 to 17 years]).

• Acute coronary syndrome (off-label use)
• Non-ST-elevation acute coronary syndrome

Subcutaneously: 2.5 mg once daily; treat for the duration of hospitalization or until percutaneous coronary intervention (PCI) is performed. If PCI is performed, an alternative anticoagulant with antithrombin activity (ie, unfractionated heparin) is recommended during the procedure. Fondaparinux as the sole anticoagulant is not recommended during PCI due to an increased risk for guiding-catheter thrombosis.

• ST-elevation myocardial infarction

IV: 2.5 mg once; subsequent doses (starting the following day)

Subcutaneously: 2.5 mg once daily; treat for the duration of the hospitalization, up to 8 days, or until PCI is performed. If PCI is performed, an alternative anticoagulant with antithrombin activity (ie, unfractionated heparin) is recommended during the procedure. Fondaparinux as the sole anticoagulant is not recommended during PCI due to an increased risk for guiding-catheter thrombosis.

• Heparin-induced thrombocytopenia treatment (alternative agent) (off-label use)

Subcutaneously:

<50 kg: 5 mg once daily.

50 to 100 kg: 7.5 mg once daily.

>100 kg: 10 mg once daily.

• Superficial vein thrombosis, acute symptomatic (off-label use)

Subcutaneously: 2.5 mg once daily for 45 days

Fondaparinux is available in the form of Subcutaneous Injection.

• Dosage Adjustment in Kidney Patient

CrCl less than 30 mL/min: Contraindicated.

CrCl 30 to 50 mL/min: Use with caution.

• Dosage Adjustment in Hepatic impairment Patient
  

Mild to moderate hepatic impairment: No adjustment recommended.

Severe hepatic impairment: Observe closely for signs of bleeding.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Additive anticoagulant activity may increase the risk of bleeding (e.g garlic, ginger, bilberry, danshen, piracetam, and ginkgo biloba).

Fondaparinux is contraindicated in patients with

• Severe renal impairment (creatinine clearance [CrCl] <30 mL/min).
• Active major bleeding.
• Bacterial endocarditis.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium.
• Body weight <50 kg (venous thromboembolism [VTE] prophylaxis only).
• History of serious hypersensitivity reaction (e.g., angioedema, anaphylactoid/anaphylactic reactions) to Fondaparinux.

• Hemorrhage

Fondaparinux increases the risk of hemorrhage in patients at risk for bleeding, including conditions such as congenital or acquired bleeding disorders, active ulcerative and angiodysplasia gastrointestinal disease, hemorrhagic stroke, uncontrolled arterial hypertension, diabetic retinopathy, or shortly after brain, spinal, or ophthalmological surgery. Cases of elevated aPTT temporally associated with bleeding events have been reported following the administration of Fondaparinux (with or without concomitant administration of other anticoagulants). Do not administer agents that enhance the risk of hemorrhage with Fondaparinux unless essential for the management of the underlying condition, such as vitamin K antagonists for the treatment of VTE. If co-administration is essential, closely monitor patients for signs and symptoms of bleeding. Do not administer the initial dose of Fondaparinux earlier than 6 to 8 hours after surgery. The administration earlier than 6 hours after surgery increases the risk of major bleeding.

• Thrombocytopenia

Thrombocytopenia can occur with the administration of Fondaparinux. Thrombocytopenia of any degree should be monitored closely. Discontinue Fondaparinux if the platelet count falls below 100,000/mm³. Moderate thrombocytopenia (platelet counts between 100,000/mm³ and 50,000/mm³) occurred at a rate of 3.0% in patients given Fondaparinux 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 Fondaparinux 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 Fondaparinux treatment regimen in the DVT and PE treatment clinical trials. Severe thrombocytopenia occurred at a rate of 0.04% in patients given the Fondaparinux treatment regimen in the DVT and PE treatment clinical trials. Occurrences of thrombocytopenia with thrombosis that manifested similarly to heparin-induced thrombocytopenia have been reported with the use of Fondaparinux in post-marketing experience.

• Bleeding

Monitor the 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 and angiodysplasia GI disease; uncontrolled arterial hypertension; hemorrhagic stroke; recent intracranial hemorrhage; use shortly after brain, spinal, or ophthalmology surgery; in patients treated concomitantly with platelet inhibitors; thrombocytopenia or platelet defects; renal impairment; diabetic retinopathy; and/or patients <50 kg. The risk of major bleeding may be increased if the initial dose is administered earlier than recommended (initiation recommended at 6 to 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, vitamin K antagonists for the treatment of venous thromboembolism). Prothrombin time and activated partial thromboplastin time (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 post-marketing data). No specific antidote for fondaparinux exists.

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 is administered to a nursing mother.

Based on case reports, small amounts of Fondaparinux have been detected in the umbilical cord following multiple doses during pregnancy. Use of Fondaparinux in pregnancy should be limited to those women who have severe allergic reactions. Fondaparinux should be used during pregnancy only if clearly needed.

Avoid herbs and supplements with anticoagulant/antiplatelet activity. Additive anticoagulant activity may increase the risk of bleeding (eg. garlic, ginger, bilberry, danshen, piracetam, and ginkgo Biloba).

• Common Adverse effects

Anemia, Hypotension, Insomnia, dizziness, confusion, increased wound secretion, skin blister, Hypokalemia, Purpura, thrombocytopenia, hematoma, hemorrhage, postoperative hemorrhage, postoperative wound infection, Epistaxis.

• Rare Adverse effects

• Anticoagulants

Fondaparinux may enhance the anticoagulant effect of Anticoagulants.

• Agents with Antiplatelet Properties

May enhance the anticoagulant effect of Anticoagulants.

• Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective)

May enhance the anticoagulant effect of Anticoagulants.

• Omacetaxine

Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL.

• Desirudin

Anticoagulants may enhance the anticoagulant effect of Desirudin. Management: Discontinue treatment with other anticoagulants prior to desirudin initiation. If concomitant use cannot be avoided, monitor patients receiving these combinations closely for clinical and laboratory evidence of excessive anticoagulation.

The common side effects of Fondaparinux include the following

Common

● Rash, itching, bruising, or bleeding at the injection site, dizziness, Confusion, pale skin, blisters on the skin, difficulty falling asleep or staying asleep.

Rare

● Unusual bleeding or bruising, dark red spots under the skin or in the mouth, hives, swelling of the face, throat, tongue, lips, or eyes, difficulty swallowing or breathing.

• Pregnancy

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 on pregnant women. Because animal reproduction studies are not always predictive of human response, Fondaparinux 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 is administered to a nursing mother.

• Pediatric Use

The safety and effectiveness of Fondaparinux in pediatric patients have not been established.

• Geriatric Use

In clinical trials the efficacy of Fondaparinux in the elderly (65 years or older) was similar to that seen in patients younger than 65 years; however, serious adverse events increased with age. Exercise caution when using Fondaparinux in elderly patients, paying particular attention to dosing directions and concomitant medications (especially anti-platelet medication).

There is no known antidote for Fondaparinux. Overdose of Fondaparinux may lead to hemorrhagic complications. Discontinue treatment and initiate appropriate therapy if bleeding complications associated with overdosage occur. Data obtained in patients undergoing chronic intermittent hemodialysis suggest that clearance of Fondaparinux can increase by 20% during hemodialysis.

Pharmacodynamic

The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations quantified via anti-Factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. (The international standards of heparin or LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately three hours.

Pharmacokinetics

• Absorption

Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of fondaparinux sodium 2.5 mg in young male subjects, a Cmax of 0.34 mg/L is reached in approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-state plasma concentration is, on average, 0.39 to 0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14 to 0.19 mg/L. In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection 5 mg (body weight 100 kg) once daily, the body-weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all bodyweight categories. The mean peak steady-state plasma concentration is in the range of 1.20 to 1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46 to 0.62 mg/L.

• Distribution

In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in the blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7 to 11 L. Similar fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture surgery. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells.

• Metabolism and Excretion

In vivo metabolism of fondaparinux has not been investigated since most of the administered dose is eliminated unchanged in the urine in individuals with normal kidney function. In individuals with normal kidney function, fondaparinux is eliminated in the urine mainly as an unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as an unchanged drug in 72 hours. The elimination half-life is 17 to 21 hours.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf
• https://www.rxlist.com/arixtra-drug.htm#indications
• https://reference.medscape.com/drug/arixtra-fondaparinux-342172
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