You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameFondaparinux sodium
Accession NumberDB00569  (APRD00500)
Typesmall molecule
Groupsapproved, investigational
Description

Fondaparinux (Arixtra) is a synthetic pentasaccharide anticoagulant. Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycan heparin and heparan sulfate (HS). This monomeric sequence in heparin and HS is thought to form the high affinity binding site for the natural anti-coagulant factor, antithrombin III (ATIII). Binding of heparin/HS to ATIII has been shown to increase the anti-coagulant activity of antithrombin III 1000-fold. Fondaparinux potentiates the neutralizing action of ATIII on activated Factor X 300-fold. Fondaparinux may be used: to prevent venous thromboembolism in patients who have undergone orthopedic surgery of the lower limbs (e.g. hip fracture, hip replacement and knee surgery); to prevent VTE in patients undergoing abdominal surgery who are are at high risk of thromboembolic complications; in the treatment of deep vein thrombosis (DVT) and pumonary embolism (PE); in the management of unstable angina (UA) and non-ST segment elevation myocardial infarction (NSTEMI); and in the management of ST segment elevation myocardial infarction (STEMI).

Structure
Thumb
Synonyms
SynonymLanguageCode
ArixtraNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
ArixtraGlaxoSmithKline
Brand mixturesNot Available
Categories
CAS number114870-03-0
WeightAverage: 1730.097
Monoisotopic: 1728.786427203
Chemical FormulaC31H45N3Na10O49S8
InChI KeyXEKSTYNIJLDDAZ-JASSWCPGSA-F
InChI
InChI=1S/C31H53N3O49S8.10Na/c1-69-27-9(33-85(48,49)50)13(37)17(6(74-27)3-71-88(57,58)59)76-31-22(83-91(66,67)68)16(40)21(24(81-31)26(43)44)79-29-10(34-86(51,52)53)19(82-90(63,64)65)18(7(75-29)4-72-89(60,61)62)77-30-15(39)14(38)20(23(80-30)25(41)42)78-28-8(32-84(45,46)47)12(36)11(35)5(73-28)2-70-87(54,55)56;;;;;;;;;;/h5-24,27-40H,2-4H2,1H3,(H,41,42)(H,43,44)(H,45,46,47)(H,48,49,50)(H,51,52,53)(H,54,55,56)(H,57,58,59)(H,60,61,62)(H,63,64,65)(H,66,67,68);;;;;;;;;;/q;10*+1/p-8/t5-,6-,7-,8-,9-,10-,11-,12-,13-,14-,15-,16+,17-,18-,19-,20+,21+,22-,23+,24-,27+,28-,29-,30-,31-;;;;;;;;;;/m1........../s1
IUPAC Name
decasodium N-[(2R,3R,4R,5S,6R)-2-{[(2S,3S,4R,5R,6R)-2-carboxy-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-(sulfonatoamino)-2-[(sulfonatooxy)methyl]oxan-3-yl]oxy}-5-(sulfonatooxy)oxan-3-yl]oxy}-5-(sulfonatoamino)-4-(sulfonatooxy)-2-[(sulfonatooxy)methyl]oxan-3-yl]oxy}-4,5-dihydroxyoxan-3-yl]oxy}-4,5-dihydroxy-6-[(sulfonatooxy)methyl]oxan-3-yl]sulfamate
SMILES
[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].CO[C@H]1O[C@H](COS([O-])(=O)=O)[C@@H](O[C@@H]2O[C@H]([C@@H](O[C@H]3O[C@H](COS([O-])(=O)=O)[C@@H](O[C@@H]4O[C@@H]([C@@H](O[C@H]5O[C@H](COS([O-])(=O)=O)[C@@H](O)[C@H](O)[C@H]5NS([O-])(=O)=O)[C@H](O)[C@H]4O)C(O)=O)[C@H](OS([O-])(=O)=O)[C@H]3NS([O-])(=O)=O)[C@H](O)[C@H]2OS([O-])(=O)=O)C(O)=O)[C@H](O)[C@H]1NS([O-])(=O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassOligosaccharides
Direct parentHexose Oligosaccharides
Alternative parentsO-Glucuronides; O-glycosyl Compounds; Amino Sugars; Pyran Carboxylic Acids; Sulfuric Acid Monoesters; Dicarboxylic Acids and Derivatives; Oxanes; 1,2-Diols; Secondary Alcohols; Enolates; Carboxylic Acids; Acetals; Polyamines
Substituents1-o-glucuronide; o-glucuronide; o-glycosyl compound; glucuronic acid or derivative; glycosyl compound; glucosamine; amino sugar; pyran carboxylic acid; pyran carboxylic acid or derivative; dicarboxylic acid derivative; sulfate-ester; oxane; sulfuric acid derivative; secondary alcohol; polyol; 1,2-diol; enolate; polyamine; ether; carboxylic acid derivative; carboxylic acid; acetal; amine; organonitrogen compound; alcohol
Classification descriptionThis compound belongs to the hexose oligosaccharides. These are oligosaccharides in which the saccharide units are hexoses.
Pharmacology
IndicationApproved for: (1) prophylaxis of VTE for up to one month post surgery in patients undergoing orthopedic surgery of the lower limbs such as hip fracture, hip replacement and knee surgery; (2) prophylaxis of VTE patients undergoing abdominal surgery who are at high risk of thromboembolic complications (e.g. patients undergoing abdominal cancer surgery); (3) treatment of acute DVT and PE; (4) management of UA and NSTEMI for the prevention of death and subsequent myocardial infarction (MI); and (5) management of STEMI for the prevention of death and myocardial reinfarction in patients who are managed with thrombolytics or who are initially to receive no form of reperfusion therapy. Fondaparinux should not be used as the sole anticoagulant during percutaneous coronary intervention (PCI) due to an increased risk of guiding catheter thrombosis.
PharmacodynamicsFondaparinux 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%) (PMID 11794148, 12049860). 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 actionThe 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 (PMID 19825921). As a result, fondaparinux has been used as an alternative anticoagulant in heparin-induced thrombocytopenia (HIT) patients (PMID 19737996, 19432027, 18217156). However, it is important to note that rare cases of HIT have been reported in patients treated with fondaparinux (PMID 20351685, 20351686).
Absorption100% bioavailability when administered subcutaneously
Volume of distribution
  • 7 – 11 L (healthy adults), distributed primarily in blood
Protein binding94% in vitro protein binding specifically to ATIII
Metabolism

Not metabolized

Route of eliminationIn individuals with normal kidney function, fondaparinux is eliminated in urine mainly as unchanged drug.
Half life17-21 hours
ClearanceNot Available
ToxicityAs with other anticoagulants, the main concern is increased bleed risk. The risk of hemorrhage may increase with decreased renal function, body mass less than 50 kg, and moderate to severe hepatic function.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Fondaparinux Action PathwayDrug actionSMP00273
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.9857
Blood Brain Barrier - 0.8953
Caco-2 permeable - 0.6312
P-glycoprotein substrate Non-substrate 0.6876
P-glycoprotein inhibitor I Non-inhibitor 0.6169
P-glycoprotein inhibitor II Non-inhibitor 0.9493
Renal organic cation transporter Non-inhibitor 0.9327
CYP450 2C9 substrate Non-substrate 0.8037
CYP450 2D6 substrate Non-substrate 0.8179
CYP450 3A4 substrate Non-substrate 0.5537
CYP450 1A2 substrate Non-inhibitor 0.7505
CYP450 2C9 substrate Non-inhibitor 0.7664
CYP450 2D6 substrate Non-inhibitor 0.8799
CYP450 2C19 substrate Non-inhibitor 0.757
CYP450 3A4 substrate Non-inhibitor 0.9208
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9172
Ames test Non AMES toxic 0.5944
Carcinogenicity Non-carcinogens 0.763
Biodegradation Not ready biodegradable 0.8922
Rat acute toxicity 2.4465 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8431
hERG inhibition (predictor II) Non-inhibitor 0.6468
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline
Packagers
Dosage forms
FormRouteStrength
SolutionSubcutaneous10 mg/0.8 ml
SolutionSubcutaneous2.5 mg/0.5 ml
SolutionSubcutaneous5 mg/0.4 ml
SolutionSubcutaneous7.5 mg/0.6 ml
Prices
Unit descriptionCostUnit
Arixtra 7.5 mg/0.6ml Solution 0.6ml Syringe148.62USDsyringe
Arixtra 2.5 mg/0.5ml Solution 0.5ml Syringe63.15USDsyringe
Arixtra (0.5 Ml Syringe) 2.5 mg/syr Syringe17.38USDsyringe
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP0.4Not Available
Predicted Properties
PropertyValueSource
logP-10ChemAxon
pKa (strongest acidic)-3ChemAxon
physiological charge-10ChemAxon
hydrogen acceptor count44ChemAxon
hydrogen donor count11ChemAxon
polar surface area828.12ChemAxon
rotatable bond count27ChemAxon
refractivity246.87ChemAxon
polarizability119.2ChemAxon
number of rings5ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Jean-Francois Branellec, Christian Morello, Pierre Potier, Patrick Trouilleux, Petrus Marcus Bastiaansen, Henricus Cornelis Claassen, “Highly pure fondaparinux sodium composition, process for preparing said composition and pharmaceutical compositions containing it as active principle.” U.S. Patent US20050020536, issued January 27, 2005.

US20050020536
General Reference
  1. GlaxoSmithKline. Arixtra® (fondaparinux sodium) injection prescribing information. Mississauga, ON. 2010 May.
  2. Eriksson BI, Bauer KA, Lassen MR, Turpie AG: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001 Nov 1;345(18):1298-304. Pubmed
  3. Turpie AG, Bauer KA, Eriksson BI, Lassen MR: Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet. 2002 May 18;359(9319):1721-6. Pubmed
  4. Lassen MR, Bauer KA, Eriksson BI, Turpie AG: Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet. 2002 May 18;359(9319):1715-20. Pubmed
  5. Bauer KA, Eriksson BI, Lassen MR, Turpie AG: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001 Nov 1;345(18):1305-10. Pubmed
  6. Bauer KA, Eriksson BI, Lassen MR, Turpie AG: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001 Nov 1;345(18):1305-10. Pubmed
  7. Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M: Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005 Oct;92(10):1212-20. Pubmed
  8. Buller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, Segers AE, Cariou R, Leeuwenkamp O, Lensing AW: Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004 Jun 1;140(11):867-73. Pubmed
  9. Buller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, van den Berg-Segers AE, Cariou R, Leeuwenkamp O, Lensing AW: Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003 Oct 30;349(18):1695-702. Pubmed
  10. Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA: Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006 Apr 6;354(14):1464-76. Epub 2006 Mar 14. Pubmed
  11. Bassand JP, Richard-Lordereau I, Cadroy Y: Efficacy and safety of fondaparinux in patients with acute coronary syndromes. Expert Rev Cardiovasc Ther. 2007 Nov;5(6):1013-26. Pubmed
  12. Steg PG, Jolly SS, Mehta SR, Afzal R, Xavier D, Rupprecht HJ, Lopez-Sendon JL, Budaj A, Diaz R, Avezum A, Widimsky P, Rao SV, Chrolavicius S, Meeks B, Joyner C, Pogue J, Yusuf S: Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA. 2010 Sep 22;304(12):1339-49. Epub 2010 Aug 31. Pubmed
  13. Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, Budaj A, Peters RJ, Bassand JP, Wallentin L, Joyner C, Fox KA: Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006 Apr 5;295(13):1519-30. Epub 2006 Mar 14. Pubmed
  14. Kovacs MJ: Successful treatment of heparin induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost. 2005 May;93(5):999-1000. Pubmed
  15. Ortel TL: Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation. Hematology Am Soc Hematol Educ Program. 2009:225-32. Pubmed
  16. Moser M, Bode C: New antithrombotic agents in acute coronary syndromes. Curr Opin Cardiol. 2009 Jul;24(4):313-7. Pubmed
  17. Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI: Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):141S-159S. Pubmed
  18. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW: Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):381S-453S. Pubmed
  19. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ: Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S-545S. Pubmed
  20. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE 2nd, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B: ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007 Aug 14;50(7):e1-e157. Pubmed
  21. Goodman SG, Menon V, Cannon CP, Steg G, Ohman EM, Harrington RA: Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):708S-775S. Pubmed
  22. Warkentin TE, Greinacher A, Koster A, Lincoff AM: Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):340S-380S. Pubmed
  23. Harrington RA, Becker RC, Cannon CP, Gutterman D, Lincoff AM, Popma JJ, Steg G, Guyatt GH, Goodman SG: Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):670S-707S. Pubmed
External Links
ResourceLink
KEGG DrugD01844
ChEBI31632
ChEMBLCHEMBL1200644
Therapeutic Targets DatabaseDNC000658
PharmGKBPA164746297
Drug Product Database2245531
RxListhttp://www.rxlist.com/cgi/generic3/arixtra.htm
Drugs.comhttp://www.drugs.com/cdi/fondaparinux.html
WikipediaFondaparinux_sodium
ATC CodesB01AX05
AHFS Codes
  • 20:12.04.92
PDB Entries
FDA labelshow(289 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
Drotrecogin alfaDrotrecogin alfa may increase the adverse effects of fondaparinux, resulting in excessive bleeding. Concomitant use should be avoided.
Ginkgo bilobaAdditive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Food InteractionsNot Available

Targets

1. Antithrombin-III

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Antithrombin-III P01008 Details

References:

  1. Paolucci F, Clavies MC, Donat F, Necciari J: Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clin Pharmacokinet. 2002;41 Suppl 2:11-8. Pubmed
  2. Cheng JW: Fondaparinux: a new antithrombotic agent. Clin Ther. 2002 Nov;24(11):1757-69; discussion 1719. Pubmed
  3. Dager WE, Andersen J, Nutescu E: Special considerations with fondaparinux therapy: heparin-induced thrombocytopenia and wound healing. Pharmacotherapy. 2004 Jul;24(7 Pt 2):88S-94S. Pubmed
  4. Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, de Greef R: The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002;41 Suppl 2:1-9. Pubmed

2. Coagulation factor X

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Coagulation factor X P00742 Details

References:

  1. Grouzi E, Kyriakou E, Panagou I, Spiliotopoulou I: Fondaparinux for the treatment of acute heparin-induced thrombocytopenia: a single-center experience. Clin Appl Thromb Hemost. 2010 Dec;16(6):663-7. Epub 2009 Oct 13. Pubmed

Comments
comments powered by Disqus
Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:11