A Comprehensive Monograph on Fondaparinux Sodium

Executive Summary

Fondaparinux sodium, marketed principally under the brand name Arixtra®, represents a seminal advancement in anticoagulant therapy as the first-in-class synthetic pentasaccharide and a selective indirect inhibitor of activated coagulation Factor X (Factor Xa). Its development marks a significant departure from traditional, biologically derived anticoagulants such as unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), offering a targeted mechanism of action with a highly predictable pharmacological profile.[1]

The core pharmacological attribute of fondaparinux is its unique mechanism, which involves selectively binding to and potentiating the activity of antithrombin III (ATIII). This action amplifies the natural neutralization of Factor Xa by approximately 300-fold, thereby inhibiting the coagulation cascade upstream of thrombin generation. Crucially, fondaparinux does not directly or indirectly inhibit thrombin (Factor IIa), a key differentiator from heparins.[1] This targeted action, combined with its nature as a single, pure chemical entity, results in a highly predictable pharmacokinetic profile. This profile is characterized by 100% bioavailability following subcutaneous administration, minimal protein binding outside of ATIII, no hepatic metabolism, and a long elimination half-life of 17-21 hours, which permits convenient once-daily dosing without the need for routine coagulation monitoring.[6]

Clinically, fondaparinux has established roles in both the prevention and treatment of venous thromboembolism (VTE). It is indicated for VTE prophylaxis in adult patients undergoing major orthopedic surgery of the lower limbs (e.g., hip fracture, hip or knee replacement) and high-risk abdominal surgery. It is also approved for the treatment of acute deep vein thrombosis (DVT) and pulmonary embolism (PE).[1] Furthermore, fondaparinux plays a significant role in the management of acute coronary syndromes (ACS), with indications in Europe for unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI).[11]

The therapeutic profile of fondaparinux is defined by a distinct efficacy-safety trade-off that varies by clinical context. In surgical VTE prophylaxis, meta-analyses demonstrate its superior efficacy in reducing VTE events compared to LMWH, but this benefit is accompanied by an increased risk of major bleeding.[12] Conversely, in the management of NSTE-ACS, as shown in the landmark OASIS-5 trial, fondaparinux provides a net clinical benefit over enoxaparin by significantly reducing the risk of major bleeding without compromising efficacy in preventing ischemic events.[14]

Several critical considerations govern its clinical use. Its synthetic structure, which lacks the long polysaccharide chains of heparin, confers a substantially lower risk of inducing heparin-induced thrombocytopenia (HIT), making it a valuable therapeutic option in patients with a history of this condition.[2] However, its lack of anti-thrombin activity is implicated in an increased risk of guiding catheter thrombosis when used as the sole anticoagulant during percutaneous coronary intervention (PCI), necessitating the co-administration of an anti-thrombin agent in this setting.[1] Perhaps its most significant clinical limitation is the absence of a specific, approved antidote, which complicates the management of major bleeding or the need for emergency surgery.[1] The fundamental design of fondaparinux as a synthetic, selective Factor Xa inhibitor is thus directly responsible for its primary advantages—predictable pharmacokinetics and low HIT risk—as well as its key liabilities, including its challenges in the PCI setting and the lack of a simple reversal agent.

Drug Identification and Chemical Profile

A precise understanding of the chemical and physical properties of fondaparinux is fundamental to appreciating its unique pharmacological behavior and clinical applications. As a synthetic agent, its identity is defined by a specific, homogenous molecular structure, distinguishing it from the heterogeneous nature of older, biologically-derived heparins.

Nomenclature and Identifiers

Fondaparinux is identified by a variety of names and registry numbers across different chemical, regulatory, and commercial contexts. The active pharmaceutical ingredient is the decasodium salt form.

• Generic Name: Fondaparinux. It is most accurately referred to as fondaparinux sodium, reflecting the salt form used in the final drug product.[1]
• Brand Names: The primary global brand name is Arixtra®.[1] Other trade names that have been associated with the drug include Quixidar, PENTA, and Xantidar.[4]
• Synonyms and Development Codes: During its development and in chemical literature, fondaparinux has been referred to by several codes, including SR-90107A, Org-31540, and IC-851589.[21] The term "fondaparin sodium" is also used synonymously.[26]
• Registry Numbers: Key identifiers used in scientific databases and regulatory filings are consolidated in Table 1. A critical distinction exists between the CAS number for the parent polyacid form and the decasodium salt, which is the clinically utilized entity.

Table 1: Drug Identification Summary for Fondaparinux

Identifier Type	Value	Notes
Generic Name	Fondaparinux Sodium	Refers to the active salt form
Brand Name	Arixtra®	Primary global trade name 2
DrugBank ID	DB00569	1
CAS Number	104993-28-4	For the parent polyacid form 2
CAS Number	114870-03-0	For the decasodium salt form 2
UNII	J177FOW5JL	For the parent polyacid form 2
UNII	X0Q6N9USOZ	For the decasodium salt form 2

Chemical Structure and Physicochemical Properties

Fondaparinux is a small molecule classified as a synthetic pentasaccharide derivative and a member of the Factor Xa inhibitor class of anticoagulants.[1]

• Molecular Formula: The empirical formula for the parent polyacid is C31​H53​N3​O49​S8​.[4] The clinically used decasodium salt has the formula C31​H43​N3​Na10​O49​S8​.[5]
• Molecular Weight: The molar mass of the parent acid is approximately 1508.3 g/mol.[4] The decasodium salt has a molecular weight of approximately 1728.08 g/mol.[24]
• Structural Description: Fondaparinux is a meticulously engineered molecule consisting of a specific sequence of five monomeric sugar units, with an O-methyl group at the reducing end.[1] This sequence is identical to the high-affinity binding site for ATIII that can be isolated from natural heparin and heparan sulfate polymers.[2] Its full chemical name is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)- α-D-glucopyranosyl-(1→4)-O-β-D-glucopyranuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-O-sulfo-α-L-idopyranuronosyl-(1→4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside, decasodium salt.[5] The selection of the decasodium salt form for the final pharmaceutical product is a crucial aspect of its design, as this form confers superior bioavailability compared to the parent polyacid, making it suitable for clinical use.[28]
• Physicochemical Properties: Fondaparinux sodium is a white to almost white, hygroscopic powder.[3] It is freely soluble in water and isotonic sodium chloride solutions, which facilitates its formulation as a sterile injectable solution.[3] The final drug product is a clear, colorless to slightly yellow liquid with a pH ranging from 5.0 to 8.0.[5]

Synthetic Origin and Manufacturing

A defining characteristic of fondaparinux is its origin. Unlike UFH and LMWH, which are extracted and purified from animal tissues (primarily porcine intestinal mucosa), fondaparinux is produced entirely through a complex process of chemical synthesis.[3] This synthetic pathway ensures the production of a single, pure molecular entity with a defined structure and molecular weight, eliminating the molecular heterogeneity inherent in biologically sourced heparins.[6]

This synthetic origin provides two key advantages. First, it eliminates any risk of contamination with animal-derived pathogens, such as those responsible for Transmissible Spongiform Encephalopathies (TSE).[3] Second, it ensures batch-to-batch consistency, which contributes to its predictable pharmacological profile. However, the manufacturing process is noted to be highly complex. Regulatory documents highlight the challenges associated with its multi-step synthesis and the difficulty in detecting and quantifying related impurities, a problem compounded by the low ultraviolet (UV) absorbance of the carbohydrate molecule, which lacks aromatic residues suitable for standard detection methods.[3] This manufacturing complexity represents a significant technical barrier and likely influences the drug's cost and the competitive landscape for generic production.

Comprehensive Pharmacological Profile

The clinical utility and distinct therapeutic profile of fondaparinux are direct consequences of its precise and selective pharmacological actions. Its mechanism, pharmacodynamics, and pharmacokinetic properties are fundamentally linked to its synthetic, homogenous chemical structure.

Mechanism of Action: Selective Inhibition of Factor Xa

The antithrombotic activity of fondaparinux is achieved through a highly specific, indirect inhibition of a single enzyme in the coagulation cascade: activated Factor X (Xa).[3]

• Binding to Antithrombin III (ATIII): Fondaparinux functions as a potentiator of the natural anticoagulant protein ATIII, a member of the serine protease inhibitor (serpin) family.[1] It binds with high affinity and specificity to a unique pentasaccharide-binding domain on the ATIII molecule.[5] This interaction is highly selective; fondaparinux does not bind significantly to other plasma proteins, including albumin or, most notably, platelet factor 4 (PF4), the primary antigen in HIT.[3]
• Potentiation of ATIII Activity: The binding of fondaparinux to ATIII induces a critical conformational change in the ATIII molecule. This structural alteration dramatically accelerates the rate at which ATIII neutralizes its target protease, Factor Xa. The potentiation is substantial, increasing the neutralizing activity of ATIII against Factor Xa by approximately 300-fold.[1]
• Selective Neutralization of Factor Xa: The fondaparinux-ATIII complex is a highly efficient inhibitor of Factor Xa. By neutralizing Factor Xa, fondaparinux effectively interrupts the coagulation cascade at the convergence of the intrinsic and extrinsic pathways.[1] Factor Xa is the enzyme responsible for the proteolytic cleavage of prothrombin (Factor II) into its active form, thrombin (Factor IIa).
• Downstream Effects on Thrombin Generation: By preventing the formation of thrombin, fondaparinux effectively inhibits all of thrombin's downstream procoagulant actions, including the conversion of fibrinogen to fibrin and the activation of platelets. Furthermore, the reduction in thrombin levels leads to decreased activation of Factor XIII, the enzyme that cross-links and stabilizes the fibrin clot, resulting in a less stable thrombus.[1]
• Key Distinctions from Heparins: The mechanism of fondaparinux is critically different from that of UFH and LMWH in two respects. First, fondaparinux does not inactivate thrombin. The inactivation of thrombin by the heparin-ATIII complex requires the formation of a ternary bridge, for which the heparin molecule must be of sufficient length (at least 18 saccharide units) to bind to both ATIII and thrombin simultaneously. The five-saccharide structure of fondaparinux is too short to form this bridge, rendering it incapable of inhibiting thrombin.[1] Second, fondaparinux has no known direct effect on platelet function. It does not cause platelet aggregation and, due to its minimal interaction with PF4, it does not typically trigger the formation of the immunogenic complexes responsible for HIT.[1] The primary molecular targets of fondaparinux are Coagulation factor X (gene: F10) and Antithrombin-III (gene: SERPINC1).[1]

Pharmacodynamics

The measurable effects of fondaparinux on the coagulation system reflect its selective mechanism of action.

• Anti-Xa Activity: The anticoagulant effect of fondaparinux is directly proportional to its plasma concentration and is best quantified using a chromogenic anti-Factor Xa assay. It is of paramount importance that this assay be calibrated using a fondaparinux-specific standard. The use of international standards for UFH or LMWH is inappropriate and will yield inaccurate results, as the activity of fondaparinux is expressed in milligrams (mg) of the fondaparinux calibrator, not in international units.[4]
• Effect on Routine Coagulation Tests: At recommended therapeutic doses, fondaparinux does not meaningfully prolong standard coagulation tests such as the activated partial thromboplastin time (aPTT), prothrombin time (PT), or International Normalized Ratio (INR).[1] This lack of effect renders these common tests unsuitable for monitoring the anticoagulant intensity of fondaparinux therapy. While rare spontaneous reports of aPTT prolongation have been received, this is not a consistent or reliable finding.[39]
• Comparative Potency: In vitro studies comparing fondaparinux to UFH on a weight basis have shown that fondaparinux is more potent at inhibiting Factor Xa, FIXa, and FVIIa. Conversely, it is substantially less potent than UFH at inhibiting thrombin (Factor IIa) and is less potent in prolonging coagulation time or inducing platelet aggregation.[3]

Pharmacokinetics (ADME)

The pharmacokinetic profile of fondaparinux is remarkably predictable, a direct result of its synthetic, homogenous nature. This predictability is a cornerstone of its clinical utility, allowing for fixed, weight-based dosing without the need for routine monitoring. This stands in stark contrast to the variable pharmacokinetics of UFH, which necessitates frequent laboratory monitoring and dose adjustments. The key pharmacokinetic parameters are summarized in Table 2.

• Absorption: Following subcutaneous injection, fondaparinux is absorbed rapidly and completely, with an absolute bioavailability of 100%.[5] Peak plasma concentrations ( Cmax​) are typically reached within 2 to 3 hours post-administration.[5] With once-daily dosing, steady-state plasma concentrations are achieved after the third or fourth dose.[5]
• Distribution: The distribution of fondaparinux is confined almost exclusively to the blood compartment, with a small apparent volume of distribution (Vd​) of 7 to 11 L in healthy adults. This indicates minimal distribution into extravascular tissues.[1]
• Protein Binding: Fondaparinux is highly and specifically bound (at least 94%) to its target cofactor, ATIII. It does not bind significantly to other plasma proteins, such as albumin or PF4, or to red blood cells. This specific binding minimizes the potential for displacement-based drug interactions.[1]
• Metabolism: Fondaparinux does not undergo any known metabolic transformation in the body.[1] Its lack of hepatic metabolism via the cytochrome P450 system means it is not susceptible to a wide range of metabolic drug-drug interactions that affect other anticoagulants like warfarin.
• Excretion: The drug is eliminated from the body almost entirely by the kidneys, with 64% to 77% of an administered dose recovered as unchanged drug in the urine within 72 hours.[2] This complete reliance on renal excretion is the "Achilles' heel" of fondaparinux. Its clearance is directly dependent on renal function, and any degree of renal impairment will prolong its elimination and increase drug exposure. This direct causal link between renal function and drug clearance is the pharmacological basis for its contraindication in patients with severe renal impairment and the need for cautious dosing in those with moderate impairment.
• Half-life: The elimination half-life (t1/2​) of fondaparinux is long and consistent, ranging from 17 to 21 hours in healthy young and elderly volunteers with normal renal function.[1] This long half-life is what allows for a convenient and effective once-daily subcutaneous dosing regimen.

Table 2: Pharmacokinetic Parameters of Fondaparinux

Parameter	Value / Description	Source(s)
Bioavailability (Subcutaneous)	100%	5
Time to Peak Concentration (Tmax​)	Approx. 2-3 hours	5
Volume of Distribution (Vd​)	7-11 L (primarily in blood)	1
Protein Binding	≥94%, specifically to Antithrombin III (ATIII)	1
Metabolism	Not metabolized	1
Route of Elimination	Renal; excreted unchanged in urine	2
Elimination Half-life (t1/2​)	17-21 hours (in normal renal function)	1

Clinical Efficacy and Therapeutic Applications

The clinical development of fondaparinux has established its role as a key anticoagulant in several major therapeutic areas, including the prevention and treatment of VTE and the management of ACS. Its approval status varies between major regulatory bodies, reflecting different interpretations of the clinical trial evidence and regional healthcare priorities.

Regulatory Landscape: Approved Indications

The approved uses for fondaparinux differ notably between the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as summarized in Table 3.

• U.S. Food and Drug Administration (FDA) Indications:
• Prophylaxis of Deep Vein Thrombosis (DVT): Fondaparinux is approved for the prevention of DVT, which may lead to pulmonary embolism (PE), in adult patients undergoing hip fracture surgery (including an extended prophylaxis period), hip replacement surgery, knee replacement surgery, or abdominal surgery where patients are at high risk for thromboembolic complications.[9]
• Treatment of Acute DVT and PE: It is indicated for the treatment of acute DVT and acute PE in adults when administered in conjunction with a vitamin K antagonist such as warfarin.[9]
• Treatment of VTE in Pediatric Patients: A more recent indication includes the treatment of VTE in pediatric patients who are 1 year of age or older and weigh at least 10 kg.[9]
• European Medicines Agency (EMA) Indications: The EMA has approved a broader range of indications for fondaparinux. In addition to the surgical VTE prophylaxis and DVT/PE treatment indications approved by the FDA, the EMA also approves its use for:
• VTE Prophylaxis in Medical Patients: Prevention of VTE in adult medical patients who are judged to be at high risk and are immobilized due to acute illness such as cardiac insufficiency, acute respiratory disorders, or acute infectious/inflammatory disease.[11]
• Treatment of Superficial-Vein Thrombosis (SVT): Treatment of adults with acute, symptomatic, spontaneous SVT of the lower limbs without concomitant DVT.[11]
• Management of Acute Coronary Syndromes (ACS):
• Treatment of unstable angina (UA) or non-ST-segment-elevation myocardial infarction (NSTEMI) in adults for whom urgent (<120 minutes) invasive management (PCI) is not indicated.[11]
• Treatment of ST-segment elevation myocardial infarction (STEMI) in adults who are managed with thrombolytics or who are initially to receive no other form of reperfusion therapy.[11]

This divergence in approved labels highlights how regulatory bodies can weigh the same body of evidence differently, leading to variations in clinical practice guidelines and therapeutic options available to physicians in different regions.

Table 3: Comparative Summary of FDA and EMA Approved Indications for Fondaparinux

Indication	U.S. FDA	European Medicines Agency (EMA)
VTE Prophylaxis - Surgical (Orthopedic/Abdominal)	Approved	Approved
VTE Prophylaxis - Medical (Immobilized)	Not Approved	Approved
DVT/PE Treatment (Adults)	Approved	Approved
DVT/PE Treatment (Pediatrics)	Approved (≥1 year, ≥10 kg)	Not Recommended (<17 years)
Superficial-Vein Thrombosis (SVT) Treatment	Not Approved	Approved
Unstable Angina / NSTEMI Treatment	Not Approved	Approved
STEMI Treatment	Not Approved	Approved

Summary of Key Clinical Trials and Meta-Analyses

The clinical utility of fondaparinux is supported by a robust program of large-scale clinical trials and subsequent meta-analyses that have compared it against established standards of care, primarily LMWH and UFH. These trials define its therapeutic niche by clearly delineating its relative efficacy and safety. A summary of these pivotal trial outcomes is presented in Table 4.

• Comparison vs. LMWH (Enoxaparin) for Surgical VTE Prophylaxis: A comprehensive meta-analysis of 12 randomized controlled trials (RCTs) involving 14,906 patients undergoing major surgery provided definitive evidence in this setting. The analysis showed that fondaparinux was statistically superior to LMWH in preventing VTE, reducing the odds by 51% (Odds Ratio 0.49; 95% Confidence Interval [CI] 0.38–0.64).[12] This benefit was consistent across total DVT, proximal DVT, and distal DVT. However, this enhanced efficacy was counterbalanced by a statistically significant 48% increase in the odds of major bleeding (OR 1.48; 95% CI 1.15–1.90).[12] Despite the higher bleeding risk, the analysis of net clinical benefit (a composite of VTE and major bleeding) still favored fondaparinux over LMWH.[12] No significant differences were observed for the outcomes of symptomatic VTE or PE alone.[12]
• OASIS-5 Trial (NSTE-ACS): Fondaparinux vs. Enoxaparin: This landmark trial randomized 20,078 patients with UA or NSTEMI to receive either fondaparinux 2.5 mg daily or enoxaparin 1 mg/kg twice daily. The primary efficacy outcome—a composite of death, MI, or refractory ischemia at 9 days—was met, demonstrating that fondaparinux was non-inferior to enoxaparin.[14] The trial's most striking finding was in its safety profile: fondaparinux was associated with a dramatic and highly significant reduction in the rate of major bleeding by more than half compared to enoxaparin (2.2% vs. 4.1%; Hazard Ratio 0.52; p < 0.001).[16] This substantial reduction in bleeding was consistent across all patient subgroups, including the elderly and those undergoing PCI, and translated into a significant reduction in 30-day mortality and a superior net clinical benefit.[15]
• OASIS-6 Trial (STEMI): Fondaparinux vs. Standard Care (UFH or Placebo): This trial enrolled 12,092 patients with STEMI and randomized them to fondaparinux 2.5 mg daily or a control group (placebo for patients not indicated for UFH, or UFH for patients who were). Fondaparinux significantly reduced the primary endpoint of death or reinfarction at 30 days by 14% (HR 0.86; p=0.008) compared to the control arm.[18] This benefit was achieved without a significant increase in severe bleeding.[51] However, a critical interaction with treatment strategy emerged. The benefit was confined to patients who did not undergo primary PCI (i.e., those receiving thrombolytics or no reperfusion). In the subgroup of patients undergoing primary PCI, fondaparinux offered no efficacy benefit and was associated with a significantly higher rate of guiding catheter thrombosis (0.9% vs. 0% with UFH).[18] This finding is a direct clinical consequence of fondaparinux's lack of anti-thrombin activity, which is insufficient to prevent contact-activated thrombosis on the surface of catheters. This has led to the recommendation that patients pre-treated with fondaparinux who require PCI should receive an additional bolus of an anticoagulant with anti-thrombin activity, such as UFH, at the time of the procedure.[16]

Table 4: Summary of Key Clinical Trial Outcomes for Fondaparinux

Trial / Analysis	Patient Population	Comparator	Primary Efficacy Outcome	Primary Safety Outcome
Surgical Prophylaxis Meta-Analysis 12	14,906 patients post-major surgery	LMWH (mostly enoxaparin)	VTE up to Day 15: OR 0.49 (Favors Fondaparinux)	Major Bleeding: OR 1.48 (Favors LMWH)
OASIS-5 Trial 16	20,078 patients with NSTE-ACS	Enoxaparin	Death, MI, or Refractory Ischemia at Day 9: Non-inferior	Major Bleeding at Day 9: HR 0.52 (Favors Fondaparinux)
OASIS-6 Trial 18	12,092 patients with STEMI	Placebo or UFH	Death or Reinfarction at Day 30: HR 0.86 (Favors Fondaparinux)	Severe Bleeding at Day 9: No significant difference

Dosing, Administration, and Special Populations

The predictable pharmacokinetics of fondaparinux allow for standardized, fixed-dosing regimens for most patients, a significant advantage over UFH. However, its complete reliance on renal clearance necessitates careful consideration of patient-specific factors such as renal function, body weight, and age to ensure safe and effective use.

Standard Dosing Regimens by Indication

Dosage is tailored to the clinical indication and, for treatment purposes, to patient body weight.

• VTE Prophylaxis (Major Orthopedic or Abdominal Surgery): The standard adult dose is 2.5 mg administered by subcutaneous injection once daily.[54]
• Treatment of Acute DVT and/or PE (Adults): A once-daily, weight-based subcutaneous dosing regimen is used:
• Patients with body weight <50 kg: 5 mg
• Patients with body weight 50 to 100 kg: 7.5 mg
• Patients with body weight >100 kg: 10 mg.[55]
• Treatment of VTE (Pediatric Patients): For children aged 1 year or older and weighing at least 10 kg, the initial dose is 0.1 mg/kg subcutaneously once daily. For children weighing over 20 kg, the dose should be rounded to the nearest available prefilled syringe strength (2.5 mg, 5 mg, or 7.5 mg).[57]
• Acute Coronary Syndromes (EMA/TGA Indications): For UA/NSTEMI and STEMI, the recommended dose is 2.5 mg once daily. For STEMI, the first dose is administered intravenously, with subsequent doses given subcutaneously.[44]

Administration Guidelines

Proper administration technique is crucial for ensuring drug delivery and minimizing local site reactions.

• Route of Administration: Fondaparinux is intended for subcutaneous injection only, with the exception of the initial intravenous dose in STEMI patients. It must not be administered by intramuscular injection, as this can cause hematoma formation.[41]
• Injection Technique: The injection should be administered deep into the subcutaneous fatty tissue of the anterolateral or posterolateral abdominal wall while the patient is in a supine position. Injection sites should be rotated daily. A critical instruction for the prefilled syringe is that the air bubble should not be expelled prior to injection. The syringe is designed for the air bubble to follow the drug solution, ensuring the entire dose is cleared from the needle and delivered to the patient. Expelling the bubble can result in a loss of drug volume and underdosing, which could be clinically significant for a potent anticoagulant.[41]
• Timing of First Dose Post-Surgery: To mitigate the risk of major bleeding, the initial prophylactic dose should be administered no earlier than 6 to 8 hours after surgical closure and only after hemostasis has been confirmed.[54]

Dose Adjustments and Considerations in Special Populations

Adjustments and contraindications in specific patient populations are primarily driven by factors that alter drug clearance and increase bleeding risk.

• Renal Impairment: This is the most critical factor influencing fondaparinux dosing.
• Severe Renal Impairment: Fondaparinux is contraindicated in patients with a creatinine clearance (CrCl) of less than 30 mL/min (per FDA) or less than 20 mL/min (per EMA) due to a high risk of drug accumulation and major bleeding.[29]
• Moderate Renal Impairment: In patients with a CrCl between 30 and 50 mL/min (FDA) or 20 and 50 mL/min (EMA), the drug should be used with caution. The EMA specifically recommends a dose reduction to 1.5 mg once daily for VTE prophylaxis in this population.[41]
• Low Body Weight (<50 kg): This population is at an increased risk of bleeding due to higher drug exposure per kilogram. This risk has led regulators to make a critical distinction based on the clinical context of risk versus benefit.
• For VTE prophylaxis in adults, where the goal is to prevent a potential event, the bleeding risk is considered unacceptable, and fondaparinux is contraindicated in patients weighing <50 kg.[9]
• For the treatment of an established, life-threatening DVT or PE, the benefit of anticoagulation is deemed to outweigh the increased bleeding risk. Therefore, use is permitted with caution at the adjusted dose of 5 mg once daily.[39]
• Hepatic Impairment: No dose adjustment is required for patients with mild to moderate hepatic impairment. However, patients with severe hepatic impairment may have an underlying coagulopathy and should be treated with caution, as pharmacokinetic data in this group are not available.[29]
• Elderly Patients (≥75 years): Fondaparinux should be used with caution in the elderly. This precaution is not due to age itself but rather the high prevalence of age-related decline in renal function, which leads to reduced drug clearance and an increased risk of bleeding.[5]
• Pediatric Population: The FDA has approved fondaparinux for VTE treatment in children aged 1 year and older who weigh at least 10 kg, with specific weight-based dosing and recommendations for anti-Xa level monitoring.[9] The EMA, citing a lack of data, does not recommend its use in children under 17 years of age.[41]

Table 5: Dosage and Administration Guidelines by Indication

Indication	Patient Population	Body Weight	Recommended Dose	Duration of Therapy
VTE Prophylaxis (Surgical)	Adult	N/A	2.5 mg SC once daily	5-9 days (up to 32 days for hip fracture) 54
DVT/PE Treatment	Adult	<50 kg	5 mg SC once daily	At least 5 days and until INR 2-3 with warfarin 55
		50-100 kg	7.5 mg SC once daily
		>100 kg	10 mg SC once daily
VTE Treatment	Pediatric (≥1 yr)	≥10 kg	0.1 mg/kg SC once daily (with adjustments)	Determined by physician 57
UA/NSTEMI	Adult (EMA)	N/A	2.5 mg SC once daily	Up to 8 days or hospital discharge 44
STEMI	Adult (EMA)	N/A	2.5 mg once daily (1st dose IV)	Up to 8 days or hospital discharge 44

Table 6: Dose Adjustments in Special Populations

Population	Condition / Threshold	Recommended Action
Renal Impairment	CrCl <30 mL/min (FDA) / <20 mL/min (EMA)	Contraindicated 29
	CrCl 30-50 mL/min	Use with caution; consider 1.5 mg dose for prophylaxis (EMA) 41
Low Body Weight	<50 kg (Adult)	Contraindicated for VTE prophylaxis; use 5 mg dose for treatment 9
Hepatic Impairment	Severe	Use with caution; no specific dose adjustment recommended 29
Elderly	≥75 years	Use with caution (due to likely reduced renal function) 3

In-depth Safety and Tolerability Assessment

The safety profile of fondaparinux is well-characterized and is dominated by the primary pharmacological effect of anticoagulation: the risk of bleeding. Understanding this profile, including specific adverse reactions, contraindications, and warnings, is essential for its safe clinical use.

Adverse Drug Reactions

• Most Common and Serious Reactions: Bleeding complications are the most frequently reported and most serious adverse reactions associated with fondaparinux use.[9] These can range from minor events like bruising and injection site hematomas to major, life-threatening hemorrhages. Other commonly reported adverse events include anemia (which may be a consequence of occult bleeding), insomnia, rash, purpura, dizziness, confusion, and local injection site reactions such as pain, itching, or redness.[40]
• Hematologic Effects: Thrombocytopenia can occur with fondaparinux administration, although it is less common than with heparins. Routine monitoring of platelet counts is recommended, and the drug should be discontinued if the platelet count falls below 100,000/mm3.[9] Rare postmarketing reports have described cases of thrombocytopenia with thrombosis, similar to the presentation of HIT.[66]
• Hepatotoxicity: Therapy with fondaparinux is associated with a low incidence (1-3%) of mild, asymptomatic, and transient elevations in serum aminotransferases (AST and ALT). These elevations are typically not associated with jaundice or clinical symptoms and usually resolve without discontinuation of the drug. The rate of these elevations is notably lower than that observed with UFH (~8%) or LMWH (4-12%).[40] There have been no convincing reports of fondaparinux causing severe, idiosyncratic, clinically apparent liver injury.[40]

Bleeding Risk and Hemorrhagic Complications

The principal safety concern with fondaparinux is an increased risk of hemorrhage.[1] The risk is not uniform across all patients and is significantly elevated in specific populations:

• Patients with Pre-existing Risk Factors: The risk of bleeding is heightened in patients with congenital or acquired bleeding disorders, active ulcerative gastrointestinal disease, recent intracranial hemorrhage, uncontrolled severe hypertension, or shortly after brain, spinal, or ophthalmic surgery.[41]
• Renal Impairment: As drug clearance is entirely dependent on renal function, patients with impaired renal function have prolonged elimination and increased drug exposure, leading to a dose-dependent increase in bleeding risk.[5]
• Low Body Weight and Advanced Age: Patients weighing less than 50 kg and those aged 75 years or older are at an increased risk of bleeding, primarily due to higher drug exposure and, in the case of the elderly, a higher likelihood of co-morbid renal impairment.[3]

Contraindications

The use of fondaparinux is strictly contraindicated in situations where the risk of major bleeding is unacceptably high:

• Severe Renal Impairment: Creatinine clearance <30 mL/min (US) or <20 mL/min (EU).[29]
• Active, Clinically Significant Bleeding.[29]
• Bacterial Endocarditis: Due to the high risk of hemorrhagic transformation of septic emboli.[29]
• Thrombocytopenia with a Positive Anti-platelet Antibody Test: In cases where fondaparinux is associated with an immune-mediated thrombocytopenia.[9]
• Body Weight <50 kg (for VTE prophylaxis only).[9]
• Known Severe Hypersensitivity to fondaparinux or its excipients.[9]

FDA Boxed Warning: Spinal/Epidural Hematomas

Fondaparinux carries an FDA Boxed Warning regarding the risk of spinal or epidural hematomas, which can cause long-term or permanent paralysis.[54] This severe adverse event represents a dangerous convergence of the drug's pharmacology with a specific clinical procedure. The long and irreversible half-life of fondaparinux means that its anticoagulant effect cannot be rapidly terminated. When a neuraxial procedure such as a spinal tap or epidural catheter placement is performed, the inevitable minor trauma to the vascular epidural space can lead to uncontrolled bleeding. In the confined, non-expandable space of the spinal canal, this bleeding can form a hematoma that compresses the spinal cord, leading to catastrophic neurological injury.[54] The risk is significantly amplified by the concomitant use of other drugs that impair hemostasis, such as NSAIDs or antiplatelet agents, and by factors such as the use of an indwelling epidural catheter or a history of traumatic spinal puncture.[54] This warning underscores the need for extreme caution, strict adherence to timing protocols for drug administration around such procedures, and vigilant neurological monitoring of patients.

Management of Overdose and Reversal

A major clinical liability of fondaparinux is the lack of a specific, approved antidote.[1] Protamine sulfate, the antidote for UFH, is ineffective against fondaparinux.[73]

• Overdose Management: In the event of an overdose, which may manifest as excessive bleeding, management is primarily supportive.[74] This includes discontinuing the drug, providing local hemostatic measures, and administering blood products (e.g., packed red blood cells, fresh frozen plasma) as needed. Due to the long half-life, the anticoagulant effect may persist for 2-4 days in patients with normal renal function and even longer in those with renal impairment.[76] In cases of massive subcutaneous overdose, a "depot effect" with prolonged absorption may occur, necessitating an extended period of observation.[74]
• Potential Reversal Agents (Off-Label/Investigational): In situations of life-threatening hemorrhage, several agents have been considered for off-label use, though robust clinical evidence is lacking. These agents do not act as direct antidotes but rather as pro-hemostatic agents that attempt to overwhelm the anticoagulant effect.
• Recombinant Activated Factor VII (rFVIIa): In vitro studies and experiments in healthy volunteers have shown that rFVIIa can normalize coagulation times and thrombin generation in the presence of fondaparinux.[77] It is considered a potential therapeutic option for severe bleeding, but its use carries a prothrombotic risk and its clinical efficacy in bleeding patients on fondaparinux has not been established in controlled trials.[71]
• Prothrombin Complex Concentrates (PCCs): Four-factor PCCs (e.g., Kcentra®), which contain coagulation factors II, VII, IX, and X, are used for the reversal of other Factor Xa inhibitors and may be considered in cases of life-threatening bleeding with fondaparinux, though specific data are limited.[75]
• Novel Antidotes: Research is ongoing to develop specific reversal agents. Ciraparantag, a small molecule designed to bind and inactivate several anticoagulants, has shown promise in early trials, and synthetic spermine derivatives are being explored in preclinical studies.[83] However, these are not yet clinically available.

Significant Drug-Drug Interactions

The interaction profile of fondaparinux is dominated by pharmacodynamic effects that potentiate the risk of bleeding. Its lack of hepatic metabolism via the cytochrome P450 (CYP) system makes it less prone to the pharmacokinetic interactions that complicate therapy with agents like warfarin.

Pharmacodynamic Interactions (Increased Bleeding Risk)

The most clinically significant interactions involve the co-administration of other drugs that interfere with hemostasis, leading to a synergistic or additive increase in bleeding risk. Close monitoring is essential when these combinations are unavoidable.

• Other Anticoagulants: The concurrent use of fondaparinux with other anticoagulants, including UFH, LMWHs (e.g., enoxaparin), direct thrombin inhibitors (e.g., argatroban, dabigatran), and oral Factor Xa inhibitors (e.g., apixaban, rivaroxaban), significantly increases the risk of hemorrhage and is generally contraindicated or should be avoided unless part of a carefully managed transition of therapy.[1]
• Antiplatelet Agents: Drugs that inhibit platelet function, such as aspirin, P2Y12 inhibitors (e.g., clopidogrel), and glycoprotein IIb/IIIa receptor antagonists (e.g., abciximab), increase the risk of bleeding when used with fondaparinux. While this combination is often necessary in the management of ACS, it requires heightened vigilance for signs of hemorrhage.[1] Studies have shown that while aspirin prolongs bleeding time, it does not alter the pharmacokinetics of fondaparinux.[88]
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs (e.g., ibuprofen, naproxen, ketorolac) contribute to bleeding risk through two mechanisms: inhibition of platelet aggregation and direct gastrointestinal mucosal injury. Their concomitant use with fondaparinux should be approached with caution, and they should preferably be discontinued prior to initiating fondaparinux therapy if possible.[76] The risk is particularly pronounced in patients undergoing neuraxial anesthesia, where the combination is a key risk factor for spinal hematoma.[54]

Pharmacokinetic Interactions

Fondaparinux has a "clean" pharmacokinetic interaction profile due to its lack of hepatic metabolism and specific protein binding.

• CYP450 System: Fondaparinux is not metabolized by and does not inhibit CYP450 enzymes. Therefore, interactions with drugs that are substrates, inhibitors, or inducers of this system are not expected.[40]
• Protein Binding: As fondaparinux binds almost exclusively to ATIII, interactions due to displacement from other plasma proteins like albumin are unlikely.[5]
• Clinical Studies: Formal interaction studies have confirmed a lack of significant pharmacokinetic interaction with several commonly co-administered drugs. Fondaparinux did not affect the pharmacokinetics or pharmacodynamics of warfarin, aspirin, piroxicam, or digoxin, and these drugs, in turn, did not alter the pharmacokinetics of fondaparinux.[88]
• Renal Excretion: While numerous potential interactions related to competition for renal excretion pathways are listed in drug databases, the clinical significance of most of these is not well-established.[1] The primary clinical focus remains on monitoring renal function itself rather than specific inhibitors of renal transport.

Table 7: Clinically Significant Drug Interactions with Fondaparinux

Drug Class / Agent	Interaction Type	Clinical Management / Recommendation
Anticoagulants (e.g., Heparins, Warfarin, DOACs)	Pharmacodynamic	Increased risk of major hemorrhage. Generally avoid co-administration unless transitioning therapy. Monitor closely for bleeding.1
Antiplatelet Agents (e.g., Aspirin, Clopidogrel, GPIIb/IIIa inhibitors)	Pharmacodynamic	Increased risk of bleeding. Use with caution. Essential in ACS but requires heightened vigilance.57
NSAIDs (e.g., Ibuprofen, Ketorolac)	Pharmacodynamic	Increased risk of bleeding, particularly GI. Potentiates risk of spinal hematoma with neuraxial procedures. Avoid if possible; use with caution and monitor closely.76
Thrombolytic Agents (e.g., Alteplase)	Pharmacodynamic	Significantly increased risk of severe hemorrhage. Co-administration should be approached with extreme caution.1

Concluding Analysis and Recommendations

Fondaparinux sodium stands as a landmark achievement in anticoagulant drug development, successfully translating a targeted pharmacological concept into a clinically effective therapy. As a synthetic, selective, indirect Factor Xa inhibitor, it offers a predictable and reliable anticoagulant effect that overcomes many of the limitations of older, biologically derived heparins. Its therapeutic position is defined by a nuanced balance of superior efficacy or safety in specific clinical scenarios against a set of distinct liabilities that demand careful clinical management.

Synthesis of Fondaparinux's Therapeutic Position

The evidence positions fondaparinux as a highly effective agent for VTE prophylaxis, where it is demonstrably superior to LMWH in preventing thromboembolic events, albeit at the cost of an increased risk of major bleeding. This trade-off necessitates careful patient selection to maximize the net clinical benefit. In the setting of NSTE-ACS, the paradigm shifts, with fondaparinux offering a clear advantage over enoxaparin by providing equivalent ischemic protection with a significantly lower risk of major hemorrhage, a benefit that translates into reduced mortality. This makes it a compelling first-line agent in this population.

Its most valuable attribute may be its safety profile with respect to HIT. Its minimal interaction with platelet factor 4 provides a reliable and effective alternative for anticoagulation in patients with a history of this life-threatening immune complication, filling a critical therapeutic gap.[2]

However, the drug's liabilities are equally significant. The lack of thrombin inhibition, a key feature of its selectivity, becomes a disadvantage during the intensely prothrombotic environment of PCI, leading to an unacceptable risk of catheter thrombosis when used alone. This necessitates a more complex "hybrid" anticoagulation strategy in this setting. The most profound limitation is the absence of a specific reversal agent. This single factor elevates the risk associated with major bleeding events or the need for emergency surgery, making it a less forgiving agent than heparin in high-risk scenarios.

Recommendations for Clinical Practice and Monitoring

Based on the comprehensive evidence, the following recommendations are crucial for the optimal use of fondaparinux:

1. Prioritize Patient Selection: The safe use of fondaparinux begins with meticulous patient assessment. Renal function must be evaluated at baseline and periodically thereafter. The drug is contraindicated in patients with severe renal impairment (CrCl <30 mL/min). Body weight is also a critical factor; fondaparinux is contraindicated for VTE prophylaxis in adults weighing less than 50 kg. A thorough assessment of baseline bleeding risk is mandatory.
2. Adhere to Indication-Specific Dosing: Use the established fixed-dose or weight-based regimens appropriate for the clinical indication. Strict adherence to post-operative timing (no earlier than 6-8 hours after hemostasis) is essential to minimize surgical bleeding.
3. Implement Safety Monitoring: While routine coagulation monitoring is not required, periodic laboratory assessment is a key safety measure. This should include complete blood counts to monitor for anemia (suggesting occult blood loss) and thrombocytopenia, as well as serum creatinine to detect any decline in renal function that would necessitate dose adjustment or discontinuation.[4]
4. Manage Procedural Anticoagulation Carefully: In patients with ACS pre-treated with fondaparinux who require PCI, an additional anticoagulant with anti-thrombin activity (e.g., UFH) must be administered at the time of the procedure to prevent catheter thrombosis. For patients undergoing neuraxial anesthesia or spinal puncture, strict adherence to institutional timing protocols for stopping and restarting fondaparinux is critical to mitigate the risk of spinal hematoma, as highlighted in the FDA Boxed Warning.

Future Research Directions

Despite its established role, several areas warrant further investigation to optimize the use of fondaparinux and similar agents:

• Development of a Reversal Agent: The most urgent unmet need is the development of a specific, safe, and effective antidote. The advancement of agents like ciraparantag or novel synthetic binders is a research priority that would fundamentally change the risk-benefit calculus for fondaparinux and other Factor Xa inhibitors.
• Studies in Special Populations: While the FDA has approved its use in some pediatric patients, more robust data are needed in this population, as well as in patients with severe hepatic impairment and during pregnancy, to establish clear efficacy and safety profiles.
• Management of Bleeding: Prospective, randomized trials are needed to determine the optimal strategy for managing major bleeding in patients treated with fondaparinux, comparing supportive care against off-label use of pro-hemostatic agents like rFVIIa and PCCs to establish clear, evidence-based guidelines.

Works cited

1. Fondaparinux: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 3, 2025, https://go.drugbank.com/drugs/DB00569
2. Fondaparinux - Wikipedia, accessed August 3, 2025, https://en.wikipedia.org/wiki/Fondaparinux
3. Arixtra, INN: Fondaparinux sodium - EMA, accessed August 3, 2025, https://www.ema.europa.eu/en/documents/scientific-discussion/arixtra-epar-scientific-discussion_en.pdf
4. Heparin Pentasaccharide | C31H53N3O49S8 | CID 5282448 ..., accessed August 3, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/104993-28-4
5. ARIXTRA® - accessdata.fda.gov, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021345s010lbl.pdf
6. The clinical use of Fondaparinux: A synthetic heparin pentasaccharide - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/31030756/
7. The Pharmacokinetics of Fondaparinux Sodium in Healthy Volunteers - ResearchGate, accessed August 3, 2025, https://www.researchgate.net/publication/11077924_The_Pharmacokinetics_of_Fondaparinux_Sodium_in_Healthy_Volunteers
8. Fondaparinux: A cornerstone drug in acute coronary syndromes - PMC, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8788176/
9. ARIXTRA (fondaparinux sodium injection), for ... - accessdata.fda.gov, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021345s052lbl.pdf
10. ARIXTRA (fondaparinux sodium injection), for subcutaneous use - This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021345Orig1s043lbl.pdf
11. Arixtra | European Medicines Agency (EMA), accessed August 3, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/arixtra
12. Fondaparinux Sodium Compared With Low‐Molecular‐Weight ..., accessed August 3, 2025, https://www.ahajournals.org/doi/10.1161/JAHA.119.012184
13. Fondaparinux Sodium Compared With Low‐Molecular‐Weight Heparins for Perioperative Surgical Thromboprophylaxis: A Systematic Review and Meta‐analysis | Journal of the American Heart Association, accessed August 3, 2025, https://www.ahajournals.org/doi/abs/10.1161/JAHA.119.012184
14. Fondaparinux Sodium - ResearchGate, accessed August 3, 2025, https://www.researchgate.net/publication/257284939_Fondaparinux_Sodium
15. Clinical benefit and practical use of fondaparinux in the invasive management of patients with acute coronary syndromes - Oxford Academic, accessed August 3, 2025, https://academic.oup.com/eurheartjsupp/article/10/suppl_C/C14/395007
16. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/17964037/
17. Why is Fondaparinux (Arixtra) an Alternative Anticoagulant for Heparin Induced Thrombocytopenia (HIT), but not Low-Molecular Weight Heparins (LMWH)? - EBM Consult, accessed August 3, 2025, https://www.ebmconsult.com/articles/fondaparinux-arixtra-hit-heparin-induced-thrombocytopenia-lmwh
18. The OASIS-6 Trial: Description and Results, accessed August 3, 2025, https://www.medscape.com/viewarticle/532029
19. VirtualTaste, accessed August 3, 2025, https://insilico-cyp.charite.de/VirtualTaste/index.php?site=drug_taste&sort=drugbankid&page_no=19
20. FONDAPARINUX INJ,SOLN - VA Formulary Advisor - VA.gov, accessed August 3, 2025, https://www.va.gov/formularyadvisor/drugs/4015843-FONDAPARINUX-INJ-SOLN
21. Fondaparinux sodium | CAS# 114870-03-0 | factor Xa inhibitor - MedKoo Biosciences, accessed August 3, 2025, https://www.medkoo.com/products/20439
22. Fondaparinux - brand name list from Drugs.com, accessed August 3, 2025, https://www.drugs.com/ingredient/fondaparinux.html
23. Fondaparinux (sodium salt) (SR 90107A, CAS Number: 114870-03-0) | Cayman Chemical, accessed August 3, 2025, https://www.caymanchem.com/product/24033/fondaparinux-(sodium-salt)
24. Fondaparinux Sodium, accessed August 3, 2025, https://www.drugfuture.com/chemdata/fondaparinux-sodium.html
25. Fondaparinux sodium (Synonyms: Fondaparin sodium; SR-90107A), accessed August 3, 2025, https://www.medchemleader.com/product-CL3107
26. Fondaparinux | Sigma-Aldrich, accessed August 3, 2025, https://www.sigmaaldrich.com/ES/en/search/fondaparinux?focus=products&page=1&perpage=30&sort=relevance&term=fondaparinux&type=product
27. Fondaparinux | 104993-28-4 - SynZeal, accessed August 3, 2025, https://www.synzeal.com/en/fondaparinux-2
28. Fondaparinux - American Chemical Society, accessed August 3, 2025, https://www.acs.org/molecule-of-the-week/archive/f/fondaparinux.html
29. Drugs Information: Fondaparinux - DDInter 2.0, accessed August 3, 2025, https://ddinter2.scbdd.com/server/drug-detail/DDInter775/
30. Fondaparinux = 95 HPLC 114870-03-0 - Sigma-Aldrich, accessed August 3, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/sml1240
31. pubmed.ncbi.nlm.nih.gov, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/31030756/#:~:text=Fondaparinux%20is%20a%20synthetic%20heparin,a%20molecular%20weight%20of%201728Da.
32. Fondaparinux sodium - Fondaparin sodium, Methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino), accessed August 3, 2025, https://www.sigmaaldrich.com/US/en/substance/fondaparinuxsodium172808114870030
33. Fondaparinux Sodium (Org 31540) | 97%(HPLC) | Factor Xa inhibitor - Selleckchem.com, accessed August 3, 2025, https://www.selleckchem.com/products/fondaparinux-sodium.html
34. Fondaparinux sodium | 114870-03-0 | OF04094 - Biosynth, accessed August 3, 2025, https://www.biosynth.com/p/OF04094/114870-03-0-fondaparinux-sodium
35. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux) - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/12679126/
36. Fondaparinux sodium Gene Set - Ma'ayan Laboratory, Computational Systems Biology, accessed August 3, 2025, https://maayanlab.cloud/Harmonizome/gene_set/Fondaparinux+sodium/DrugBank+Drug+Targets
37. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/12383040/
38. Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin | Blood | American Society of Hematology, accessed August 3, 2025, https://ashpublications.org/blood/article/105/1/139/19965/Effect-of-fondaparinux-on-platelet-activation-in
39. Arixtra 7.5 mg/0.6 ml solution for injection, pre-filled syringe - Summary of Product Characteristics (SmPC) - (emc) | 3336, accessed August 3, 2025, https://www.medicines.org.uk/emc/product/3336/smpc
40. Fondaparinux - LiverTox - NCBI Bookshelf, accessed August 3, 2025, https://www.ncbi.nlm.nih.gov/books/NBK548551/
41. Arixtra, INN-fondaparinux - EMA, accessed August 3, 2025, https://www.ema.europa.eu/en/documents/product-information/arixtra-epar-product-information_en.pdf
42. Arixtra Fondaparinux sodium solution for injection 1.5 mg/ 0.3 ml - Summary of Product Characteristics (SmPC) - (emc) | 3359, accessed August 3, 2025, https://www.medicines.org.uk/emc/product/3359/smpc
43. GSK receives CHMP positive opinion for a new indication for Arixtra, accessed August 3, 2025, https://www.gsk.com/en-gb/media/press-releases/gsk-receives-chmp-positive-opinion-for-a-new-indication-for-arixtra/
44. Arixtra 2.5 mg/0.5 ml solution for injection, pre-filled syringe ..., accessed August 3, 2025, https://www.medicines.org.uk/emc/product/3335/smpc
45. Evidence suggests fondaparinux is more effective than LMWH in prevention of VTE and total DVT in the postoperative setting - The Hospitalist, accessed August 3, 2025, https://www.the-hospitalist.org/hospitalist/article/130459/perioperative-medicine/evidence-suggests-fondaparinux-more-effective-lmwh
46. Fondaparinux Sodium Compared With Low‐Molecular‐Weight ..., accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6585337/
47. Fondaparinux versus Enoxaparin - Which is the Best Anticoagulant for Acute Coronary Syndrome? - Brazilian Registry Data, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5053192/
48. Original Article - Fondaparinux versus Enoxaparin in the Treatment of Obese Patients with Acute Coronary Syndrome - ABC Cardiol, accessed August 3, 2025, https://abccardiol.org/wp-content/uploads/articles_xml/0066-782X-abc-121-08-e20230793/0066-782X-abc-121-08-e20230793-en.x65822.pdf
49. Efficacy and Safety of Fondaparinux Versus Enoxaparin in Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: Results From the OASIS-5 Trial - JACC Journals, accessed August 3, 2025, https://www.jacc.org/doi/abs/10.1016/j.jacc.2007.07.042
50. Fondaparinux and acute coronary syndromes: Update on the OASIS 5-6 studies, accessed August 3, 2025, https://www.researchgate.net/publication/43227515_Fondaparinux_and_acute_coronary_syndromes_Update_on_the_OASIS_5-6_studies
51. Fondaparinux in the management of patients with ST-elevation acute myocardial infarction - PMC - PubMed Central, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1994017/
52. Organization for the Assessment of Strategies for Ischemic Syndromes 6 - OASIS-6, accessed August 3, 2025, https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2010/02/23/19/13/OASIS6
53. OASIS-6 TRIAL - CardiologyTrials.org, accessed August 3, 2025, http://cardiologytrials.org/detail/53/
54. Approved Label - accessdata.fda.gov, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf
55. Fondaparinux Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed August 3, 2025, https://www.drugs.com/dosage/fondaparinux.html
56. This label may not be the latest approved by FDA. For current labeling information, please visit https://www.fda.gov/drugsatfda, accessed August 3, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021345s023lbl.pdf
57. Arixtra (fondaparinux) dosing, indications, interactions, adverse effects, and more, accessed August 3, 2025, https://reference.medscape.com/drug/arixtra-fondaparinux-342172
58. Fondaparinux (Arixtra) – UW Medicine Anticoagulation Services, accessed August 3, 2025, https://sites.uw.edu/anticoag/drugs/fondaparinux/
59. Adult Enoxaparin and Fondaparinux Protocol, accessed August 3, 2025, http://vcportal.ventura.org/VCHCA/Hospitals/Pharmacy%20Resources/lmwh-vault-(1).pdf
60. Fondaparinux (subcutaneous route) - Side effects & dosage - Mayo Clinic, accessed August 3, 2025, https://www.mayoclinic.org/drugs-supplements/fondaparinux-subcutaneous-route/description/drg-20067481
61. Attachment: Product Information for Fondaparinux - Therapeutic Goods Administration (TGA), accessed August 3, 2025, https://www.tga.gov.au/sites/default/files/auspar-fondaparinux-200511-pi.pdf
62. annex i summary of product characteristics - Arixtra, INN-fondaparinux sodium, accessed August 3, 2025, https://ec.europa.eu/health/documents/community-register/2016/20160915135796/anx_135796_en.pdf
63. Arixtra (Fondaparinux Sodium): Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 3, 2025, https://www.rxlist.com/arixtra-drug.htm
64. Clinical Policy: Fondaparinux (Arixtra) - Superior Health Plan, accessed August 3, 2025, https://www.superiorhealthplan.com/content/dam/centene/Superior/policies/pharmacy-policies/Fondaparinux%20(Arixtra)%20(CP.PHAR.226)%20(PDF).pdf
65. Safety and Efficacy of Fondaparinux in Renal Impairment - PMC, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5990183/
66. Fondaparinux Sodium: Package Insert / Prescribing Info - Drugs.com, accessed August 3, 2025, https://www.drugs.com/pro/fondaparinux-sodium.html
67. Fondaparinux: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed August 3, 2025, https://www.rxlist.com/fondaparinux/generic-drug.htm
68. Fondaparinux | Davis's Drug Guide for Rehabilitation Professionals, accessed August 3, 2025, https://fadavispt.mhmedical.com/content.aspx?bookid=1873§ionid=139012310
69. Fondaparinux Side Effects: Common, Severe, Long Term - Drugs.com, accessed August 3, 2025, https://www.drugs.com/sfx/fondaparinux-side-effects.html
70. Label: ARIXTRA- fondaparinux sodium injection, solution - DailyMed, accessed August 3, 2025, https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ec235119-cb58-4939-942c-11d3923d289f
71. Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery - PMC, accessed August 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1994024/
72. 16. Anticoagulant reversal | The International Society of Blood Transfusion (ISBT), accessed August 3, 2025, https://www.isbtweb.org/isbt-working-parties/clinical-transfusion/resources/patient-blood-management-resources/16-anticoagulant-reversal.html
73. Heparin vs LMWHs vs Fondaparinux What's the Difference? - University Health, accessed August 3, 2025, https://hr.universityhealthsystem.com/secure/xwebdocs/Pharmacy/Pathways_and_Guidelines/Anticoagulation/Education/10-Heparin%20vs%20LMWHs%20vs%20Fondaparinux%20%28Formulary%20Flash%20from%20Feb%202009%20comparing%20these%20anticoagulants%29.pdf
74. Acute Fondaparinux (Arixtra) Intentional Overdose via Self-injection: A Case Report - LVHN Scholarly Works, accessed August 3, 2025, https://scholarlyworks.lvhn.org/cgi/viewcontent.cgi?article=1559&context=emergency-medicine
75. GUIDELINES FOR REVERSAL OF ANTICOAGULANTS – 9:17 - UAMS College of Medicine, accessed August 3, 2025, https://medicine.uams.edu/surgery/wp-content/uploads/sites/5/2016/12/Pharmacy-Guidelines-for-Reversal-of-Anticoagulants.pdf
76. Fondaparinux: Drug information - sniv3r2.github.io, accessed August 3, 2025, https://sniv3r2.github.io/d/topic.htm?path=fondaparinux-drug-information
77. Ability of Recombinant Factor VIIa to Reverse the Anticoagulant ..., accessed August 3, 2025, https://www.ahajournals.org/doi/10.1161/01.cir.0000038501.87442.02
78. Recombinant factor VIIa partially reverses the inhibitory effect of ..., accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/14983229/
79. Chapter 7 Recombinant factor VIIa reverses the ... - DSpace, accessed August 3, 2025, https://dspace.library.uu.nl/bitstream/1874/447/8/c7.pdf
80. Ability of Recombinant Factor VIIa to Reverse the Anticoagulant Effect of the Pentasaccharide Fondaparinux in Healthy Volunteers | Circulation - American Heart Association Journals, accessed August 3, 2025, https://www.ahajournals.org/doi/abs/10.1161/01.cir.0000038501.87442.02
81. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/12427650/
82. Anticoagulation Reversal Guideline for Adults - American Heart Association, accessed August 3, 2025, https://www.heart.org/-/media/files/professional/quality-improvement/hemorrhagic--stroke/hemorrhagic-stroke-toolkit-page/5_18_2021/anticoagulation-reversal-guideline-for-adults-5182021.pdf
83. Efficient Small-Molecule Reversal Agents for Anticoagulant Fondaparinux | ACS Pharmacology & Translational Science, accessed August 3, 2025, https://pubs.acs.org/doi/10.1021/acsptsci.4c00747
84. Fondaparinux Interactions Checker - Drugs.com, accessed August 3, 2025, https://www.drugs.com/drug-interactions/fondaparinux.html
85. Drug Interactions between fondaparinux and warfarin - Drugs.com, accessed August 3, 2025, https://www.drugs.com/drug-interactions/fondaparinux-with-warfarin-1134-0-2311-0.html?professional=1
86. Aspirin and fondaparinux Interactions - Drugs.com, accessed August 3, 2025, https://www.drugs.com/drug-interactions/aspirin-with-fondaparinux-243-0-1134-0.html?professional=1
87. Conundrums in the Combined Use of Anticoagulants and Antiplatelet Drugs | Circulation, accessed August 3, 2025, https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.106.655910
88. Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/12383043/
89. Fondaparinux and ibuprofen Interactions - Drugs.com, accessed August 3, 2025, https://www.drugs.com/drug-interactions/fondaparinux-with-ibuprofen-1134-0-1310-0.html
90. Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin - PubMed, accessed August 3, 2025, https://pubmed.ncbi.nlm.nih.gov/12236851/