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Fondaparinux: Dosing and adverse effects

Fondaparinux: Dosing and adverse effects
Literature review current through: Jan 2024.
This topic last updated: Jul 25, 2023.

INTRODUCTION — Fondaparinux (Arixtra) is a synthetic anticoagulant based on the pentasaccharide sequence that makes up the minimal antithrombin (AT) binding region of heparin. Similar to low molecular weight heparins, it is an indirect inhibitor of factor Xa, but it does not inhibit thrombin at all. Fondaparinux has a longer half-life than heparin and does not interact with platelets, both of which may be advantageous in certain settings.

This topic review discusses the dosing and adverse effects of fondaparinux, including dosing in patients with renal insufficiency and management of bleeding.

Indications for fondaparinux are presented in separate topic reviews:

Deep vein thrombosis and pulmonary embolism – (See "Venous thromboembolism: Initiation of anticoagulation".)

Superficial vein thrombosis – (See "Superficial vein thrombosis and phlebitis of the lower extremity veins".)

Thromboprophylaxis (medical patients) – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Thromboprophylaxis (surgical patients) – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Acute coronary syndrome – (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes".)

Heparin-induced thrombocytopenia (HIT) – (See "Management of heparin-induced thrombocytopenia".)

Information for other anticoagulants is also presented separately:

Heparins – (See "Heparin and LMW heparin: Dosing and adverse effects".)

Warfarin and other vitamin K antagonists – (See "Warfarin and other VKAs: Dosing and adverse effects".)

Direct oral anticoagulants – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

PHARMACOLOGY

Mechanism of action — Fondaparinux consists of a highly sulfated pentasaccharide derived from the minimal antithrombin (AT)-binding region of heparin. It is an indirect factor Xa inhibitor (figure 1). It acts by binding to and inducing a conformational change in AT that increases the ability of AT to inactivate factor Xa (figure 2) [1,2].

Fondaparinux binds to AT with a higher affinity (dissociation constant 50 nmol) than the native pentasaccharide of unfractionated heparin or low molecular weight heparin, and it causes a conformational change in AT that significantly increases the ability of AT to inactivate factor Xa. The binding of fondaparinux to AT is stoichiometric (1:1) and reversible [3-5].

Fondaparinux cannot bind to or inactivate thrombin (factor IIa) because it cannot form a ternary complex with AT and thrombin (figure 2). Ternary complex formation requires pentasaccharide-containing chains at least 18 saccharide units long, such as those present in unfractionated heparin and, to a lesser extent, low molecular weight heparin preparations. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Mechanisms of action'.)

Fondaparinux does not bind to or interact with other plasma proteins or cellular elements. Specifically, fondaparinux does not interact with platelets or platelet factor 4, and thus, unlike heparin, is not expected to be capable of inducing a heparin-induced thrombocytopenia (HIT)-like syndrome [6-11]. In the major trials evaluating the use of fondaparinux for thromboprophylaxis, no cases of HIT were observed [8]. Several case series describe the effective use of fondaparinux in the setting of HIT [12-16]. However, there are rare case reports of HIT in which fondaparinux was administered [17-20]. The use of fondaparinux in HIT is described separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Pathophysiology' and "Management of heparin-induced thrombocytopenia", section on 'Fondaparinux'.)

Metabolism — Fondaparinux is 100 percent bioavailable after subcutaneous injection, with half-maximal and peak serum concentrations reached in 25 minutes and 1.7 hours following subcutaneous injection, respectively [21]. The half-life of fondaparinux is 15 to 17 hours. Anticoagulant activity persists for about three to five half-lives following discontinuation of fondaparinux, or a period of two to four days in individuals with normal renal function.

The majority of an administered dose of fondaparinux is cleared by the kidney and excreted unchanged in the urine. Clearance of this drug is decreased in individuals with reduced creatinine clearance, and use is not recommended in individuals with creatinine clearance <30 mL/min. (See 'Indications and contraindications' below.)

Fondaparinux metabolism is not affected by hepatic failure; however, patients with hepatic failure may be at increased risk of hemorrhage due to a number of hemostatic changes. (See "Hemostatic abnormalities in patients with liver disease".)

Long-acting analogs — Attempts to develop long-acting analogs of fondaparinux have not resulted in any clinically approved agents. The following drugs were evaluated in phase III trials.

Idraparinux was a longer half-life analog of fondaparinux that could be given subcutaneously once per week. Development was halted due to an increased risk of bleeding in nonvalvular atrial fibrillation; decreased efficacy was also found in pulmonary embolism, as compared with standard therapy [22-24].

Idrabiotaparinux (SSR 126517) is a biotinylated version of idraparinux that could be neutralized by intravenous infusion of avidin, which binds biotin [25-27].

Advantages and disadvantages compared with other anticoagulants — The choice of anticoagulant should be based on evidence for the given clinical setting. In settings in which fondaparinux is considered clinically equivalent with other anticoagulants, the following advantages and disadvantages may be worth considering:

Advantages

Longer half-life allows once daily dosing

Lack of platelet interaction makes risk of HIT negligible

Monitoring not required with routine use

Disadvantages

Must be given parenterally

No approved antidote or reversal agent (although andexanet alfa may be used) (See 'Bleeding/emergency surgery' below.)

Inability to monitor at most centers due to lack of availability of fondaparinux-calibrated anti-factor Xa levels

INDICATIONS AND CONTRAINDICATIONS

Fondaparinux can be used for prophylaxis and treatment of venous thromboembolism (VTE) in a number of medical and perioperative settings. Evidence for its efficacy and comparison with other anticoagulants is discussed in separate topic reviews on the specific clinical setting:

Surgical patients – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Medical patients – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

Patients with VTE – (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Venous thromboembolism: Anticoagulation after initial management" and "Venous thromboembolism: Initiation of anticoagulation".)

Patients with superficial vein thrombosis – (See "Superficial vein thrombosis and phlebitis of the lower extremity veins".)

Patients with acute coronary syndromes – (See "Anticoagulant therapy in non-ST elevation acute coronary syndromes".)

Patients with heparin-induced thrombocytopenia (HIT) – (See "Management of heparin-induced thrombocytopenia".)

We generally avoid using fondaparinux in the following patient groups:

Pregnant women, unless there is a contraindication to heparin (see 'Pregnancy' below)

Individuals with a creatinine clearance <30 mL/min

Individuals weighing <50 kg in the prophylactic setting (dose reduction is used in the therapeutic setting for individuals <50 kg)

Individuals with bacterial endocarditis or other relative or absolute contraindication for an anticoagulant

Individuals undergoing neurosurgery or spine surgery

Additional possible contraindications that apply to the use of anticoagulants in general are listed in the table (table 1); this is not intended to substitute for the judgement of the treating clinician who can weigh the risks and benefits for the individual patient.

A lower dose of fondaparinux typically is used in patients weighing <50 kg receiving fondaparinux for VTE therapy. (See 'Dosing' below.)

Therapy is individualized for those with thrombocytopenia depending on the reason for thrombocytopenia and the estimated bleeding risk. As an example, we may avoid using fondaparinux in individuals with a platelet count <70,000/microL due to bone marrow suppression; however, if thrombocytopenia is due to HIT and the platelet count is expected to rise, it may be appropriate to give fondaparinux since the major concern is thrombosis rather than bleeding.

DOSING — Fondaparinux is given subcutaneously once daily. The dose in individuals with normal renal function is based on body weight and the indication for anticoagulant use (eg, prophylaxis for venous thromboembolism [VTE] versus therapy) [28]:

VTE prophylaxis or acute coronary syndromes – 2.5 mg once daily. In the perioperative setting, the first dose is given six to eight hours postoperatively (after skin closure) as was done in all of the major clinical trials. A 1.5 mg dose is available for orthopedic VTE prophylaxis in Europe, but not in the United States. The 1.5 mg dose is suggested for individuals with creatinine clearance of 20 to 50 mL/min, although safety and efficacy of this dose has not been well-studied. (See 'Elective surgery' below.)

Superficial vein thrombosis (treatment) – 2.5 mg once daily. Duration of therapy and other interventions are presented separately.

VTE (treatment)

Patients weighing <50 kg – 5 mg once daily

Patients weighing 50 to 100 kg – 7.5 mg once daily

Patients weighing >100 kg – 10 mg once daily

The duration of therapy is discussed in topic reviews on the specific indications. (See 'Indications and contraindications' above.)

Fondaparinux cannot be given intramuscularly.

MONITORING — Fondaparinux does not require monitoring in routine clinical use. Monitoring of drug levels or coagulation testing was not performed in clinical trials. However, when therapeutic dosing is used in individuals at extremes of body weight, dose adjustments may be appropriate and drug levels may be obtained.

Drug levels – In cases where fondaparinux is required and levels can be obtained in a timely fashion (eg, extremes of very high or very low body weight), anti-factor Xa activity can be measured approximately three hours after the dose is administered. The anti-factor Xa activity assay must be calibrated using fondaparinux as a reference standard. Results are presented as fondaparinux levels in mcg/mL. The therapeutic range has not been established, but typical levels are in the range of 0.39 to 0.5 mcg/mL for prophylactic-dose fondaparinux and 0.5 to 1.5 mcg/mL for therapeutic-dose fondaparinux. Communication with the testing laboratory is advised.

The activated partial thromboplastin time (aPTT) cannot be used to monitor fondaparinux, although it may become prolonged at therapeutic doses.

Renal function – Renal function should be assessed before starting fondaparinux because patients with impaired renal function may require a dose adjustment (or use of a different anticoagulant if renal insufficiency is severe). In patients taking fondaparinux for an extended period of time (eg, many months to years), renal function should be monitored periodically and the drug discontinued if the creatinine clearance decreases to <30 mL/min or shows a trend toward worsening.

For individuals with stable renal insufficiency and a creatinine clearance between 30 and 50 mL/minute, it may be appropriate to switch to low molecular weight heparin or unfractionated heparin, unless levels are available in a timely fashion.

Platelet count – Routine platelet count monitoring is not required with fondaparinux administration, given the negligible risk for the development of heparin-induced thrombocytopenia (HIT) [29]. However, patients at risk of developing thrombocytopenia for other reasons should undergo periodic monitoring of the platelet count.

TRANSITIONING BETWEEN ANTICOAGULANTS

From other anticoagulants to fondaparinux – The onset of action of fondaparinux is rapid, so it is generally started at the time another anticoagulant is discontinued. For patients on warfarin, it is generally started when the international normalized ratio (INR) drops below 2.

From fondaparinux to other agents – For patients receiving fondaparinux who will be transitioned to warfarin in the setting of acute venous thromboembolism, we typically start warfarin and fondaparinux at the same time and continue fondaparinux for at least five days until the INR is in the therapeutic range. For patients receiving fondaparinux who will be transitioned to a direct acting oral anticoagulant (DOAC; eg, dabigatran, apixaban, edoxaban, rivaroxaban), we typically start the DOAC 24 hours after the last dose of fondaparinux.

USE IN SPECIAL POPULATIONS

Extremes of weight — In the prophylactic setting, fondaparinux is avoided for patients weighing <50 kg; dosing of fondaparinux for patients ≥50 kg is not generally adjusted for weight.

In the therapeutic setting, dosing of fondaparinux is based on weight, as discussed above. (See 'Dosing' above.)

Renal insufficiency — As noted above, we do not use fondaparinux for individuals with creatinine clearance <30 mL/min. Clinical trials of fondaparinux excluded individuals with creatinine clearance <30 mL/min or serum creatinine >1.8 mg/dL [30].

For individuals with creatinine clearance between 30 and 50 mL/minute, fondaparinux may be used with caution. This decision, along with the specific dose and potential use of anti-factor Xa monitoring in this setting, is individualized. (See 'Monitoring' above.)

Unfractionated heparin may be a better alternative in some patients with renal insufficiency. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.)

Older adults — Use of fondaparinux in individuals over the age of 75 years appears to be safe, provided that the patient weighs >50 kg and has normal renal function.

Pregnancy — Clinical experience with fondaparinux in pregnancy is less than that with low molecular weight (LMW) heparin, but use in pregnancy has been reported. Potential concerns include its longer half-life than LMW heparin and the possibility of underdosing as pregnancy weight increases; there is also concern regarding potential passage of drug across the placenta to the fetus.

We limit the use of fondaparinux in pregnancy to individuals who require an anticoagulant but are unable to tolerate heparin (due to severe hypersensitivity reactions or heparin-induced thrombocytopenia [HIT]). Anticoagulation during pregnancy is discussed separately. (See "Use of anticoagulants during pregnancy and postpartum".)

Children — Clinical experience with fondaparinux in children is extremely limited [31,32]. Its use is generally limited to children with HIT who require cessation of heparin and ongoing anticoagulation with a non-heparinoid agent other than argatroban. (See "Neonatal thrombosis: Management and outcome" and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

ADVERSE EFFECTS

Bleeding — Fondaparinux increases the risk of bleeding, similar to other anticoagulants. Bleeding risk may be increased in those with underlying impairment of platelet function or coagulation (eg, liver disease, decreased kidney function, concomitant use of nonsteroidal antiinflammatory drugs [NSAIDs]). Bleeding risk with fondaparinux may be of greater concern than with other anticoagulants because fondaparinux lacks an approved antidote or reversal agent, although andexanet alfa may be used. (See 'Bleeding/emergency surgery' below.)

Several randomized trials comparing fondaparinux with unfractionated heparin or low molecular weight (LMW) heparin have documented comparable bleeding rates, typically on the order of 1 to 2 percent for major bleeding and 6 to 8 percent for clinically relevant non-major bleeding [21,30,33-38].

Initial studies using higher prophylactic doses in the orthopedic setting found a higher rate of major bleeding [3]. Bleeding risk in the perioperative setting was also greater if fondaparinux was started sooner than six hours after skin closure [39]. A review of data from several large randomized trials also noted increased risk of major bleeding in patients who were older, male, and had body weight <50 kg and impaired kidney function [40].

Spinal/epidural hematoma — Like other anticoagulants, fondaparinux product labeling includes a Boxed Warning regarding the risk of spinal or epidural hematoma in patients receiving neuraxial anesthesia or undergoing spinal puncture [28]. The risk is increased in those with indwelling epidural catheters, other drugs that impair hemostasis (eg, anti-platelet agents), traumatic or repeated epidural or spinal puncture, or a history of spinal surgery. According to the manufacturer, no spinal or epidural hematomas were reported when fondaparinux was withheld until at least two hours after removal of epidural catheters. An epidural hematoma has been reported related to multiple attempts at placing an epidural catheter.

Effect on coagulation testing — Fondaparinux at prophylactic doses (eg, 2.5 mg once daily) does not appreciably prolong the prothrombin time (PT) or activated partial thromboplastin time (aPTT) [41,42]; the aPTT may become prolonged at higher doses. There is no effect on the thrombin time, platelet function, or fibrinolysis.

Fondaparinux does have anti-factor Xa activity; in the rare cases when anti-factor Xa activity is used for monitoring, the assay should be calibrated for fondaparinux. (See 'Monitoring' above.)

MANAGEMENT AND PREVENTION OF BLEEDING

Bleeding/emergency surgery — There are very few data to guide the management of bleeding or emergency surgery in patients anticoagulated with fondaparinux. Most clinical data come from studies in healthy volunteers; there are no high-quality data to show that available hemostatic therapies improve outcomes in patients with bleeding on fondaparinux [43]. Our approach is based largely on preclinical or indirect data and an understanding of the mechanisms of action of the drug.

Andexanet alfa, a catalytically inactive form of factor Xa, is able to sequester direct factor Xa inhibitors and is likely to be effective for reversing indirect-acting factor Xa inhibitors such as fondaparinux [44,45]. Andexanet was approved by the US Food and Drug Administration (FDA) in May of 2018 for the reversal of rivaroxaban and apixaban. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors'.)

We individualize the management of bleeding, taking into account clinical variables for each patient and balancing the risks of bleeding complications with the risks of thrombosis from drug discontinuation, andexanet, or prohemostatic therapies. For those for whom a reversal agent is deemed to be necessary, andexanet is a good option because it will specifically neutralize the anticoagulant activity of fondaparinux. However, clinicians should be aware that andexanet has only gained FDA approval for the reversal of the oral direct factor Xa inhibitors rivaroxaban and apixaban, and the dose of andexanet for the reversal of fondaparinux has not been established.

Activated prothrombin complex concentrates (aPCC; eg, factor eight inhibitor bypassing agent [FEIBA]), or recombinant activated factor VII (rFVIIa) may provide some reversal of fondaparinux activity, although clinical data are limited to studies using in vitro coagulation testing rather than management of patients with bleeding [46,47]. In the one study that compared aPCC and rFVIIa using coagulation testing in non-bleeding volunteers, aPCC was better able to normalize thrombin generation time than rFVIIa [47]. The agents carry risks of thrombosis that must be balanced with the risks of bleeding for each patient. (See "Recombinant factor VIIa: Administration and adverse effects" and "Plasma derivatives and recombinant DNA-produced coagulation factors", section on 'PCCs'.)

Measurement of fondaparinux drug levels using an anti-factor Xa assay calibrated to fondaparinux is appropriate in patients with major bleeding; however, this test is not widely available. Fondaparinux may be dialyzable [46].

Additional general measures that should be taken in any patient with anticoagulant-associated severe bleeding are presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Major bleeding'.)

Evidence supporting a role for these agents includes the following:

aPCC – In an animal model, aPCC was able to correct endogenous thrombin potential and lessen the duration of bleeding [48].

rFVIIa – High doses of recombinant factor VIIa (90 mcg/kg) were shown to partially normalize the prolonged aPTT, the endogenous thrombin potential, and prothrombin activation in vivo (as measured by prothrombin fragment F1+2 levels) in healthy volunteers given therapeutic doses of fondaparinux [41,49]. (See "Recombinant factor VIIa: Administration and adverse effects".)

In contrast to the therapies discussed above (andexanet alfa, aPCC, rFVIIa), protamine sulfate is not effective in reversing fondaparinux. Vitamin K has no role in fondaparinux reversal.

Elective surgery — Anticoagulant activity of fondaparinux persists for about three to five half-lives following discontinuation, or a period of two to four days in individuals with normal renal function.

Thus, major elective surgery requiring anticoagulant discontinuation should be delayed until two to four days after the last fondaparinux dose. For certain low bleeding risk procedures, 24 hours may be sufficient. These time frames should be extended for individuals with renal insufficiency due to reduced drug clearance. Information regarding the bleeding risk of various procedures, the need for anticoagulant discontinuation, and the need for perioperative bridging anticoagulation is presented separately. (See "Perioperative management of patients receiving anticoagulants".)

For individuals receiving postoperative thromboprophylaxis, the major clinical trials administered the first postoperative dose six to eight hours after skin closure.

Providing the first postoperative dose on the morning after orthopedic surgery appears to be an acceptable alternative, as was demonstrated in the Flexibility in Administration of Fondaparinux for Prevention of Symptomatic Venous Thromboembolism in Orthopedic Surgery (FLEXTRA) trial [50]. Over 2000 patients were randomly assigned to receive the first dose of fondaparinux either six to eight hours after surgery or on the morning after surgery; at six weeks, the incidences of symptomatic venous thromboembolism and major bleeding were similar with either schedule (1.9 versus 1.8 percent and 1.2 versus 0.7 percent, respectively).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

SUMMARY AND RECOMMENDATIONS

Mechanism of action and metabolismFondaparinux is a synthetic anticoagulant based on the pentasaccharide sequence present in heparin and low molecular weight (LMW) heparin. It acts as an indirect inhibitor of factor Xa (figure 1); it does not inhibit thrombin (figure 2). It is metabolized by the kidneys and has a half-life of approximately 15 to 17 hours. (See 'Pharmacology' above.)

Indications – Indications are discussed in topic reviews listed above. We do not use fondaparinux in children, individuals with creatinine clearance <30 mL/min, or individuals weighing <50 kg (for venous thromboembolism [VTE] prophylaxis). We generally avoid fondaparinux in pregnancy, unless heparin cannot be used. (See 'Indications and contraindications' above.)

Dose – Typical dosing (subcutaneous, once daily) (see 'Dosing' above):

VTE prophylaxis or acute coronary syndrome – 2.5 mg

VTE treatment (weight-based) – 5, 7.5, or 10 mg for body weight <50 kg, 50 to 100 kg, or >100 kg

Monitoring – Routine monitoring generally is not required. If needed, anti-factor Xa levels can be used, provided the assay is calibrated for fondaparinux. Kidney function should be checked periodically during prolonged fondaparinux use. (See 'Monitoring' above.)

Risks – Like other anticoagulants, fondaparinux increases the risk of bleeding; there is a Boxed Warning regarding risk of spinal/epidural hematoma. Bleeding risk was comparable to LMW heparin in VTE prophylaxis trials. Fondaparinux typically does not prolong the prothrombin time (PT) or activated partial thromboplastin time (aPTT) at the 2.5 mg per day dose, but the aPTT may become prolonged at higher doses. (See 'Adverse effects' above.)

Bleed management – For patients with major or life-threatening bleeding, the decision to use a prohemostatic agent is individualized based on bleed severity or bleeding risk in emergency surgery. Options include activated prothrombin complex concentrate (aPCC; factor eight inhibitor bypassing agent [FEIBA]), recombinant activated factor VII (rFVIIa), or the reversal agent andexanet alfa. There are little data on these agents with fondaparinux-associated bleeding. Activated clotting factors and reversal of anticoagulation also carry a thrombotic risk and should not be used for minor bleeding or bleeding that can be controlled by other means. (See 'Bleeding/emergency surgery' above.)

Perioperative – For elective surgery, we generally discontinue fondaparinux two to four days before the procedure. Postoperative thromboprophylaxis is generally initiated six to eight hours after skin closure, although giving the first dose the morning after surgery is also reasonable. (See 'Elective surgery' above.)

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Topic 1319 Version 36.0

References

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