Fondaparinux is a synthetic pentasaccharide which, apart from the O-methyl group at the reducing end of the molecule, consists of monomeric sugar units which are identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate. It has a role as an anticoagulant. It is an amino sugar, an oligosaccharide sulfate and a pentasaccharide derivative. It is functionally related to a normethylfondaparinux. It is a conjugate acid of a fondaparinux(10-).
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including fondaparinux sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fondaparinux sodium/
Skin, Eye, and Respiratory IrritationsMay cause irritation /to the eyes, skin, and mucous membranes/.
安全と保護具
Fire Fighting Procedures · 2 件
Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials. /Heparin Sodium/
As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing. /Heparin Sodium/
Storage Conditions · 2 件
Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity. /Heparin Sodium/
Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F).
Cleanup Methods · 1 件
Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site. /Heparin Sodium/
Disposal Methods · 2 件
SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
化学と産業
薬理情報
ATC Code · 3 件
B01AX05
B - Blood and blood forming organs
QB - Blood and blood forming organs
Protein Binding94% <i>in vitro</i> protein binding specifically to ATIII
Pharmacodynamics · 1 件
Fondaparinux binds specifically to the natural anticoagulant factor, ATIII. Binding to ATIII potentiates the neutralizing action of ATIII on Factor Xa 300-times. Neutralization of Factor Xa decreases the conversion of prothrombin to thrombin, which subsequently decreases the conversion of fibrinogen to fibrin (loose meshwork). The decrease in thrombin also decreases the activation of Factor XIII, which decreases the conversion of fibrin in its loose meshwork form to its stabilized meshwork form. Disruption of the coagulation cascade effectively decreases the formation of blood clots. Fondaparinux does not inactivate thrombin (activated Factor II). According to the manufacturer, fondaparinux has no known effect on platelet function. In studies comparing fondaparinux to enoxaparin, decreases in platelet levels were observed in similar numbers of patients from both groups (2-5%). At the recommended dose, Fondaparinux does not affect fibrinolytic activity or bleeding time. There is no antidote for fondaparinux. Monitoring of the anticoagulant activity of fondaparinux is not generally required. The anti-factor Xa assay may be used to monitor therapy in special populations such as those with renal impairment or who are pregnant. Complete blood count (CBC) and kidney function should be monitored during treatment.
Mechanism of Action · 5 件
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 a 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.
IC 85158RefChem:55228DTXCID9069394CHEBI:139212(2R,3S,4S,5R,6R)-3-(((2R,3R,4R,5R,6R)-5-(((2R,3R,4R,5S,6S)-6-carboxy-5-(((2R,3R,4R,5S,6R)-4,5-dihydroxy-3-(sulfoamino)-6-((sulfooxy)methyl)oxan-2-yl)oxy)-3,4-dihydroxyoxan-2-yl)oxy)-3-(sulfoamino)-4-(sulfooxy)-6-((sulfooxy)methyl)oxan-2-yl)oxy)-4-hydroxy-6-(((2R,3S,4R,5R,6S)-4-hydroxy-6-methoxy-5-(sulfoamino)-2-((sulfooxy)methyl)oxan-3-yl)oxy)-5-(sulfooxy)oxane-2-carboxylic acid(2S,3S,4R,5R,6R)-6-((2R,3R,4R,5R,6R)-6-((2R,3S,4S,5R,6R)-2-carboxy-4-hydroxy-6-((2R,3S,4R,5R,6S)-4-hydroxy-6-methoxy-5-(sulfoamino)-2-(sulfooxymethyl)oxan-3-yl)oxy-5-sulfooxyoxan-3-yl)oxy-5-(sulfoamino)-4-sulfooxy-2-(sulfooxymethyl)oxan-3-yl)oxy-3-((2R,3R,4R,5S,6R)-4,5-dihydroxy-3-(sulfoamino)-6-(sulfooxymethyl)oxan-2-yl)oxy-4,5-dihydroxyoxane-2-carboxylic acidUNII-J177FOW5JLSR 90107
データベース識別子
CAS
104993-28-4、114870-03-0
PubChem CID
5282448
DTXSID
DTXSID10146903
ChEMBL
CHEMBL1201202
ChEBI
CHEBI:61033
UNII
J177FOW5JL
Nikkaji
J862.320A
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.
Preventive Measures · 4 件
This material is assumed to be combustible. As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity. /Heparin Sodium/
As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling. /Heparin Sodium/
Use safety glasses or goggles and protect exposed skin. Wear chemically compatible gloves. /Heparin Sodium/
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.
Personal Protective Equipment (PPE) · 2 件
Engineering controls such as exhaust ventilation are recommended. /Heparin Sodium/
Use a NIOSH approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. /Heparin Sodium/
毒性情報
Interactions · 3 件
To investigate the in vitro metabolism of the antithrombotic agent fondaparinux sodium in mammalian liver fractions and to evaluate its potential inhibitory effect on human cytochrome P450 (CYP)-mediated metabolism of other drugs. Metabolism was evaluated by incubating radioisotope-labelled fondaparinux sodium with postmitochondrial liver fractions of rat, rabbit, monkey or human origin (three subjects). Human liver microsomal preparations and an NADPH-generating system were incubated with phenacetin, coumarin, tolbutamide, S-mephenytoin, bufuralol, chlorzoxazone or nifedipine. These are selectively metabolised by CYP isoforms: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4, respectively. Experiments were designed to determine apparent K(i) (inhibitory constant) values for fondaparinux sodium against each CYP isoform, by varying concentrations of fondaparinux sodium and the selective substrate. Each experiment included control reaction mixtures containing an isoform-selective inhibitor. After incubation, the mixtures were analysed by LC-MS/MS or with fluorometric detection. All liver fractions were enzymatically active, as demonstrated by degradation of [(14)C]testosterone. No metabolism of fondaparinux sodium was detectable in postmitochondrial liver fractions. Apparent K(i) values for fondaparinux sodium against the CYP isoforms could not be determined because the oxidative metabolism of the isoform-selective CYP substrates was not significantly inhibited in pooled microsomal reaction mixtures. In the presence of selective CYP inhibitors, metabolism of each substrate was significantly reduced, confirming that inhibition could be observed in these assays. The demonstrated lack of mammalian hepatic metabolism of fondaparinux sodium is consistent with animal and human studies. The absence of inhibition of the human CYP isoforms commonly involved in the metabolism of drugs suggests that clinical treatment with fondaparinux sodium is unlikely to interfere with the pharmacokinetics and metabolism of a wide range of other drugs which are associated with CYP inhibition.
... Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers. In the first study a single dose of aspirin 975mg was assessed initially, followed by single doses of aspirin or placebo on the fourth day of an 8-day regimen of subcutaneous fondaparinux sodium (10mg once daily). The second study was a three-way crossover, double-blind, randomised study which investigated fondaparinux sodium 10mg + placebo, fondaparinux sodium 10mg + piroxicam 20mg, or placebo + piroxicam 20mg. ... Neither aspirin nor piroxicam influenced the pharmacokinetics of fondaparinux sodium at steady state. Two hours after administration, prolongation of bleeding time with aspirin alone or with aspirin plus fondaparinux sodium was significantly greater than with fondaparinux sodium alone (p = 0.003 and p = 0.004, respectively). No significant differences were observed between aspirin alone or aspirin + fondaparinux sodium in effect on bleeding time. A small decrease in collagen-induced platelet aggregation was observed after administration of piroxicam alone or piroxicam + fondaparinux sodium. A small effect on aPTT was observed; it was similar for fondaparinux sodium whether administered alone or in combination with either aspirin or piroxicam. No serious adverse events were reported.
... In this study /investigators/ assessed the possible pharmacokinetic and pharmacodynamic interaction of fondaparinux sodium with digoxin at steady state in healthy male volunteers. In a phase I randomised, crossover study, volunteers (n = 24) were treated in two periods. The first period was once-daily administration of fondaparinux sodium 10mg subcutaneously alone for 7 days; the second period was 7 days of digoxin 0.25mg orally alone followed by 7 days of coadministration with fondaparinux sodium 10mg. Each period was separated by a washout of 12 days. ... The pharmacokinetic profiles of both digoxin and fondaparinux sodium were unaffected by coadministration. Bioequivalence was concluded, based on the 90% confidence intervals of the ratio of adjusted geometric means calculated for the 2-by-2 comparison of peak concentration, area under the concentration-time curve and cumulative urinary excretion, which lay within the 0.80 to 1.25 reference interval. There were no clinically significant fluctuations in vital signs and ECG parameters. The coadministration of digoxin with fondaparinux sodium was well tolerated and no significant changes were observed in vital signs.
Hepatotoxicity · 1 件
Fondaparinux therapy is associated with a low rate of serum aminotransferase elevations during therapy, with levels above 3 times the upper limit of normal occurring in 1% to 3% of patients, a lower rate than occurs with heparin (~8%) or low molecular weight heparins (4% to 12%) but higher than occurs with placebo (
Human Toxicity Excerpts · 5 件
/CASE REPORTS/ /The authors/ present the case of a 78 year-old man who developed a spontaneous rupture of the lumbar artery leading to a retroperitoneal hematoma while receiving fondaparinux therapy after a total hip replacement. A selective angiographic embolization stopped the bleeding. Fondaparinux was discontinuated and the patient presented a complete resolution of his medical status. ...
/CASE REPORTS/ Hypersensitivity to unfractionated and low-molecular-weight heparins and semisynthetic heparinoids is increasingly common. 7 female patients between 30 and 74 years with delayed-type allergy to heparins and semisynthetic heparinoids were investigated for (cross)-reactivity to fondaparinux, a new pentasaccharide with selective factor Xa inhibition. All patients showed delayed-type reactions to heparins and some additional cross-reaction to a heparinoid on intracutaneous testing. 6/7 tolerated fondaparinux on intradermal testing as well as on subcutaneous challenge testing. However, the 7th patient developed a characteristic delayed-type reaction to both skin tests with fondaparinux. ...
/CASE REPORTS/ /Investigators/ report on a 48-year-old woman who underwent bilateral knee replacement without apparent perioperative or postoperative exposure to heparin. (A thorough search of hospital records revealed no use of intraarterial or central venous catheters and showed that a cell-saver device had been flushed with saline rather than heparin.) Prophylaxis against thrombosis with fondaparinux (2.5 mg given subcutaneously once daily) was initiated on postoperative day 1. On day 7, she reported abdominal and flank pain, which was found to be due to a bilateral adrenal infarction. The platelet count was 39,000 per cubic millimeter. Ultrasonography revealed asymptomatic deep-vein thrombosis. Argatroban and warfarin were given, with full recovery except for adrenocortical insufficiency requiring long-term replacement therapy with adrenal hormones. The platelet serotonin-release assay of the patient's serum was strongly positive for heparin-induced thrombocytopenia antibodies (90% release with no added drug; 96% release with 0.2 U of heparin per milliliter [normal value, <20%], reduced to 0% release with 100 U of heparin per milliliter). The anti-PF4-polyanion enzyme immunoassay was also positive, at 1.871 units (normal value, <0.40). Fondaparinux is occasionally associated with platelet-activating anti-PF4-heparin antibodies that are indistinguishable from those associated with heparin-induced thrombocytopenia, but a heparin-induced thrombocytopenia syndrome does not develop in these cases. The failure of these antibodies to cause heparin-induced thrombocytopenia has been attributed to the inability of fondaparinux to react with PF4 in a way that reveals sites for antibody binding. In /this/ patient, strong serum-induced platelet activation in the absence of heparin - a serologic feature of delayed-onset heparin-induced thrombocytopenia - was a prominent finding.
Non-Human Toxicity Excerpts · 3 件
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies have been performed in 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.
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ At subcutaneous doses up to 10 mg/kg/day (about 32 times the recommended human dose based on body surface area), fondaparinux sodium was found to have no effect on fertility and reproductive performance of male and female rats.
/GENOTOXICITY/ Fondaparinux sodium was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, ... the rat hepatocyte unscheduled DNA synthesis (UDS) test, or the rat micronucleus test.
Populations at Special Risk · 2 件
Anticoagulant effects of fondaparinux may persist (eg, for longer than 2-4 days) after drug discontinuance in patients with renal impairment, and risk of hemorrhage is increased with fondaparinux therapy in such patients. Use with caution in those with moderate renal impairment (creatinine clearance 30-50 mL/minute); contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/minute). Renal function should be assessed periodically (eg, serum creatinine determinations) in patients receiving fondaparinux therapy and the drug discontinued immediately in patients who develop severe renal impairment during therapy.
Use with caution in geriatric patients older than 75 years of age. No substantial differences in efficacy relative to younger adults; however, major bleeding or other serious adverse effects occurred more frequently in patients 75 years of age or older than in younger adults. Fondaparinux is substantially eliminated by the kidneys. Because geriatric patients may have decreased renal function, monitoring renal function in such patients may be useful. Careful attention to fondaparinux sodium dosage and cautious use of concomitant therapy (particularly platelet-aggregation inhibitors) is advised
Antidote and Emergency Treatment · 5 件
There is no known antidote for ARIXTRA. ... 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 ARIXTRA can increase by 20% during hemodialysis.
Remove to fresh air. Avoid contact. Flush /eyes/ with copious quantities of water for at least 15 minutes. Flush /contaminated skin/ with copious quantities of water. /Heparin Sodium/
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
For more Antidote and Emergency Treatment (Complete) data for Fondaparinux (6 total), please visit the HSDB record page.
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
法規制情報
FDA Requirements · 1 件
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including fondaparinux sodium, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Fondaparinux sodium/
安全データ
有毒物質データの
104993-28-4(Hazardous Substances Data)
Antithrombin III generally neutralizes coagulation factor Xa, thrombin, and other coagulation factors, but these reactions are slow in the absence of heparin or fondaparinux. Fondaparinux accelerates the rate at which antithrombin neutralizes factor Xa by inducing a conformational change in antithrombin. This conformational change increases the affinity of antithrombin III for factor Xa, a key enzyme in the coagulation cascade. With fondaparinux therapy, anticoagulation appears to result from rapid inhibition of factor Xa by antithrombin III (about 300-fold greater than innate activity), which inhibits the conversion of prothrombin to thrombin and subsequent thrombus formation. Unlike heparin, which interacts with many plasma components, fondaparinux binds selectively to antithrombin III. Because of its small molecular size, fondaparinux cannot bind simultaneously to antithrombin III and thrombin and therefore is unable to inactivate thrombin itself. At the recommended dosage, fondaparinux does not affect fibrinolytic activity and cannot lyse established thrombi. Fondaparinux generally does not affect platelet function or global clotting function tests (eg, prothrombin time [PT], bleeding time, activated partial thromboplastin time [aPTT]) when administered at the recommended dosage.
The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time.
The limitations of conventional anticoagulants have stimulated the development of new anticoagulants. The central position of factor Xa (FXa) at the junction of the intrinsic and extrinsic pathways in the coagulation cascade means that direct and indirect FXa inhibitors have increasingly changed antithrombotic strategies. FXa inhibitors potently and selectively inhibit thrombin formation rather than thrombin activity. Direct FXa inhibitors may directly bind to FXa, whereas indirect inhibitors are dependent on antithrombin. Direct inhibitors may bind free FXa and, in contrast to indirect inhibitors, FXa within the prothrombinase complex or within clots as well. Fondaparinux is the prototype indirect FXa inhibitor and has been extensively studied in the prevention and treatment of thromboembolic diseases, including acute coronary syndromes. ...
Fondaparinux is a selective inhibitor of activated factor X. Its structure is the copy of the heparin pentasaccharide sequence, the shortest chain required for antithrombin inhibition of activated factor X without antithrombin action. Fondaparinux has no effect on coagulation tests and does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. Fondaparinux inhibits thrombin generation and the growth of thrombi in in vitro and in vivo models.
Biological Half-Life · 2 件
17-21 hours
The elimination half-life is 17 to 21 hours.
Metabolism/Metabolites · 2 件
Not metabolized
In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.
FDA Pharmacological Classification · 5 件
J177FOW5JL
FONDAPARINUX
Established Pharmacologic Class [EPC] - Factor Xa Inhibitor
Mechanisms of Action [MoA] - Factor Xa Inhibitors
Fondaparinux is a Factor Xa Inhibitor. The mechanism of action of fondaparinux is as a Factor Xa Inhibitor.
MeSH Pharmacological ClassificationEndogenous factors and drugs that inhibit or block the activity of FACTOR XA.
Absorption, Distribution and Excretion · 6 件
100% bioavailability when administered subcutaneously
In individuals with normal kidney function, fondaparinux is eliminated in urine mainly as unchanged drug.
7 - 11 L (healthy adults), distributed primarily in blood
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, 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 <50 kg), 7.5 mg (body weight 50 to 100 kg), and 10 mg (body weight >100 kg) once daily, the body-weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight 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.
In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in 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.
Cellular LocationsCytoplasm
Metabolite PathwaysFondaparinux Action Pathway
用途と製造
UsesMEDICATION
Methods of ManufacturingUS Pat 4,818,816 (1989). /Fondaparinux sodium/
Synthetic pentasaccharide based on the structure of the antithrombin binding region of heparin ... does not cause thrombin inhibition due to its short polymer length
定義ChEBI: A synthetic pentasaccharide which, apart from the O-methyl group at the reducing end of the molecule, consists of monomeric sugar units which are identical to a sequence of five monomeric sugar units that can be isolated after either che ical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate.
/CASE REPORTS/ /Investigators/ describe a patient with delayed-onset HIT triggered by low-molecular-weight heparin (LMWH) which occurred during fondaparinux prophylaxis and which was complicated by microangiopathic hemolytic anemia. Patient serum contained high-titer anti-PF4/heparin antibodies demonstrating heparin-dependent platelet activation with serial dilutions. ... Low dose fondaparinux does not necessarily prevent thrombotic complications of HIT.
For more Human Toxicity Excerpts (Complete) data for Fondaparinux (10 total), please visit the HSDB record page.
