Fondaparinux

from Wikipedia, the free encyclopedia
Structural formula
1.svg0.svg Na + .svg Fondaparinux.svg
General
Non-proprietary name Fondaparinux sodium
other names

Fondaparinuxum ( Latin )

Molecular formula C 31 H 43 N 3 Na 10 O 49 S 8
External identifiers / databases
CAS number
  • 104993-28-4
  • 114870-03-0 (deca sodium salt)
PubChem 5282448
DrugBank DB00569
Wikidata Q27077698
Drug information
ATC code

B01 AX05

Drug class

Anticoagulants , antithrombotics

Mechanism of action

Factor Xa - inhibitor

properties
Molar mass 1728 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
07 - Warning

Caution

H and P phrases H: 332
P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Fondaparinux is a prophylactic and therapeutic employed drug for anticoagulation and is the first in a separate class of substances, the selective factor Xa - inhibitors (see clotting factor ).

Fondaparinux is a synthetically produced, selective inhibitor of activated factor X (Xa). The antithrombotic activity of fondaparinux is based on an antithrombin III (AT III) -mediated selective inhibition of factor Xa. Due to the selective binding to AT III, fondaparinux increases (approx. 300-fold) the antithrombin III -mediated inhibition of factor Xa. The inhibition of factor Xa causes an interruption of the blood coagulation cascade and thus prevents both thrombin formation and thrombus growth.

Treatment with fondaparinux leads to a more selective anticoagulation and fewer side effects, including those on platelet function, compared to standard heparin or low molecular weight heparin (LMWH) . Fondaparinux does not bind to platelet factor 4 and therefore cannot cause heparin-induced thrombocytopenia. Chemically, Fondaparinux consists of the five pharmacophoric sugars in the heparin molecule , which are responsible for precisely this inhibition of the coagulation factor Xa. Fondaparinux, however, has one more sulfate group (on the first sugar).

Fondaparinux is approved for the prophylaxis of thrombosis and pulmonary embolism in patients after major orthopedic interventions, general surgery and internal medicine patients. Also for the therapy of deep vein thrombosis and pulmonary embolism, for the therapy of thrombophlebitis of the lower extremities and for the therapy of acute coronary syndrome (non-ST-lifting myocardial infarction (NSTEMI) and unstable angina pectoris (UA) as well as transmural infarction (STEMI)).

Thrombosis prophylaxis and anticoagulation e.g. B. in heparin-induced thrombocytopenia type II (HIT-II).

marketing

Fondaparinux was developed by the company Sanofi-Synthélabo . As part of the merger of the company to form Sanofi-Aventis , the marketing rights to the substance had to be sold due to antitrust requirements and were acquired by GlaxoSmithKline . On September 30, 2013, GlaxoSmithKline announced the sale of the Arixtra and Fraxiparine brands to the South African pharmaceutical company Aspen Holdings for around EUR 835 million , including the production facility in Notre Dame de Bondeville , France. The rights in China, India and Pakistan are excluded from the worldwide sales agreement. Aspen sold the US Fondaparinux (premium brand and generic) business to Mylan for $ 300 million.

Effectiveness and tolerance

In a very extensive clinical development program with more than 40,000 patients, the clinical benefit of fondaparinux compared to some previous treatment regimens has been demonstrated for a considerable number of indications :

  • So, showed that fondaparinux, the incidence of VTE ( venous thrombo - embolism ) in large orthopedic and trauma surgery compared with the low molecular weight heparin (LMWH) enoxaparin could reduce by more than 50% without the risk of bleeding to increase. For the administration when replacing a defective hip, no superiority to enoxaparin in the effect could be determined; all other studies on major orthopedic surgical interventions found an improved effect against VTE.
  • Even with major general surgical interventions and internal high-risk patients, a positive risk / benefit ratio of fondaparinux compared to the previous standard regimens has been demonstrated in some cases. Compared to both placebo and dalteparin , a low molecular weight heparin, studies have shown that fewer postoperative VTE incidents occurred. However, there was a slightly higher rate of serious bleeding due to fondaparinux compared to the comparison substance (dalteparin).
  • In the treatment of deep vein thrombosis (phlebothrombosis) and pulmonary embolism , the once-daily administration of fondaparinux proved to be at least as effective and in some cases as tolerable as the twice-daily administration of body weight-adapted LMWH or the iv administration of unfractionated heparin (UFH) with blood coagulation diagnostics ( aPTT ) controlled dosage. Both studies were designed for and demonstrated non-inferiority in preventing deep vein thrombosis. Fondaparinux had a slightly lower major bleeding rate than enoxaparin, but was slightly inferior to unfractionated heparin for major bleeding rates. In the Fondaparinux versus enoxaparin study, a slightly increased mortality was found in the patient group treated with Fondaparinux.
  • In two very large studies (OASIS 5 and OASIS 6) with over 30,000 patients in the treatment of acute coronary syndromes , Fondaparinux was able to demonstrate a significantly better tolerability profile compared to the previous therapy regimens with LMWH or UFH . An improved efficacy was found only compared to placebo and treatment with unfractionated heparin, the comparison with enoxaparin showed a comparable efficacy. Overall, a significant reduction in all-cause mortality was found in both studies.

In an extensive retrospective study (retrospective study, "register study") with more than 144,000 patients who had to undergo major orthopedic operations, it was shown that prophylaxis with fondaparinux instead of LMWH (enoxaparin or dalteparin) or UFH both the incidence of clinically manifest thromboembolism and the overall mortality in everyday clinical practice could be significantly reduced. The informative value of retrospective case-control studies, which are generated from completed treatments on the basis of patient files, is limited, but in this case supports the results of previous clinical studies that the use of fondaparinux can be advantageous for certain indications .

Side effects

  • As with any anticoagulation , severe bleeding can occur in rare cases. There is no classic antidote for fondaparinux. In the event of bleeding, recombinant activated factor VII (NovoSeven ® ) can be given to stop the bleeding , but clinical experience with patients is very limited. In the case of regional anesthesia procedures close to the spinal cord ( spinal anesthesia or epidural anesthesia ), Fondaparinux should be discontinued 36–42 hours beforehand and given again at least six to twelve hours after the procedure.
  • One of the h eparin- i nduzierten T hrombozytopenie (HIT type II) similar reaction in 2007 in the New England Journal of Medicine described. The author (T. Warkentin) comes to the conclusion that fondaparinux can be a triggering factor for HIT. However, the latest immunological studies refute this theory, since fondaparinux does not show any cross-reactivity to HIT-II sera.
  • Thrombocytopenias under fondaparinux are just as common in the prophylaxis or therapy of deep vein thrombosis as with unfractionated or low molecular weight heparin (not to be confused with heparin-induced thrombocytopenia).

elimination

Fondaparinux is excreted unchanged via the kidneys .

  • In patients with renal insufficiency (creatinine clearance 20-50 ml / min) the dose should therefore be reduced to 1.5 mg fondaparinux.
  • In patients with renal insufficiency (creatinine clearance <20 ml / min) Fondaparinux is contraindicated .

Trade names

  • Arixtra
  • Fondaparinux (generic, D)

Web links

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A labeling of methyl O-2-deoxy-6-O-sulfo-2- (sulfoamino) -α-D-glucopyranosyl- (1 → 4) -O-β-D-glucopyranuronosyl- is shown, which is derived from a self-classification by the distributor (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 in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on 27. March 2020.
  2. ↑ JM Walenga, WP Jeske, MM Samama, FX Frapaise, RL Bick, J. Fareed: Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent. In: Expert Opin Investig Drugs . Volume 11, No. 3, March 2002, pp. 397-407. PMID 11866668 . doi: 10.1517 / 13543784.11.3.397
  3. ↑ Lülmann et al: Pharmacology and Toxicology. 17th edition, p. 198.
  4. ↑ Moneyweb: Acquisition by Aspen of GlaxoSmithKline plc's Arixtra and Fraxiparine / Fraxodi brands . Retrieved January 20, 2016.
  5. ↑ DrugStoreNews: Mylan acquires rights for Aspen's Arixtra injection ( Memento from January 20, 2017 in the Internet Archive ). Retrieved January 20, 2016.
  6. ↑ AG Turpie, KA Bauer, BI Eriksson, MR Lassen: Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. In: Arch Intern Med . 162 (16), September 9, 2002, pp. 1833-1840. PMID 12196081 .
  7. ^ MR Lassen, KA Bauer, BI Eriksson, AG Turpie; European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee: Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomized double-blind comparison. In: The Lancet . 359 (9319), May 18, 2002, pp. 1715-1720. PMID 12049858 .
  8. ↑ AG Turpie, KA Bauer, BI Eriksson, MR leave; PENTATHALON 2000 Study Steering Committee: Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomized double-blind trial. In: Lancet. 359 (9319), May 18, 2002, pp. 1721-1726. PMID 12049860 .
  9. ^ KA Bauer, BI Eriksson, MR Lassen, AG Turpie; Steering Committee of the Pentasaccharide in Major Knee Surgery Study: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. In: N Engl J Med . 345 (18), Nov 1, 2001, pp. 1305-1310. PMID 11794149 .
  10. ^ BI Eriksson, KA Bauer, MR Lassen, AG Turpie; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. In: N Engl J Med. 345 (18), November 1, 2001, pp. 1298-1304. PMID 11794148
  11. ^ BI Eriksson, MR Lassen; PENTasaccharide in HIp-FRActure Surgery Plus Investigators: Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. In: Arch Intern Med . 163 (11), June 9, 2003, pp. 1337-1342. PMID 12796070 .
  12. ↑ G. Agnelli, D. Bergqvist, AT Cohen, AS Gallus, M. Gent; PEGASUS investigators: Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. In: Br J Surg . 92 (10), Oct 2005, pp. 1212-1220. PMID 16175516 .
  13. ^ AT Cohen, BL Davidson, AS Gallus, MR Lassen, MH Prins, W. Tomkowski, AG Turpie, JF Egberts, AW Lensing; ARTEMIS Investigators: Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. In: BMJ . 332 (7537), Feb. 11, 2006, pp. 325-329. Epub 2006 Jan 26. PMID 16439370 .
  14. ^ HR Büller, BL Davidson, H. Decousus, A. Gallus, M. Gent, F. Piovella, MH Prins, G. Raskob, AE van den Berg-Segers, R. Cariou, O. Leeuwenkamp, ​​AW Lensing; Matisse Investigators: Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. In: N Engl J Med. 349 (18), October 30, 2003, pp. 1695-1702. PMID 14585937 .
  15. ^ HR Büller, BL Davidson, H. Decousus, A. Gallus, M. Gent, F. Piovella, MH Prins, G. Raskob, AE Segers, R. Cariou, O. Leeuwenkamp, ​​AW Lensing; Matisse Investigators: Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. In: Ann Intern Med. 140 (11), June 1, 2004, pp. 867-173. PMID 15172900 .
  16. ↑ S. Yusuf, SR Mehta, S. Chrolavicius, R. Afzal, J. Pogue, CB Granger, A. Budaj, RJ Peters, JP Bassand, L. Wallentin, C. Joyner, KA Fox, Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators: Comparison of fondaparinux and enoxaparin in acute coronary syndromes. In: N Engl J Med. 354 (14), April 6, 2006, pp. 1464-1476. Epub 2006 Mar 14. PMID 16537663 .
  17. ^ S. Yusuf, SR Mehta, S. Chrolavicius, R. Afzal, J. Pogue, CB Granger, A. Budaj, RJ Peters, JP Bassand, L. Wallentin, C. Joyner, KA Fox; OASIS-6 Trial Group: Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. In: JAMA . 295 (13), April 5, 2006, pp. 1519-1530. Epub March 14, 200. PMID 16537725 .
  18. ↑ AF Shorr, LM Kwong, M. Sarnes, L. Happe, E. Farrelly, N. Mody-Patel: Venous thromboembolism after orthopedic surgery: implications of the choice for prophylaxis. In: Thromb Res. 121 (1), 2007, pp. 17-24. Epub, April 20, 200. PMID 17449088 .
  19. ↑ a b c d Technical information Arixtra, March 2008.
  20. ↑ Wiebke Gogarten, Hugo Van Aken: Perioperative thrombosis prophylaxis - platelet aggregation inhibitors - importance for anesthesia In: AINS - anesthesiology · intensive care medicine · emergency medicine · pain therapy. 47, 2012, pp. 242-252, doi: 10.1055 / s-0032-1310414 .
  21. ↑ SA Kozek-Langenecker, D. Fries, M. Gütl, N. Hofmann, P. Innerhofer, W. Kneifl, L. Neuner, P. Perger, T. Pernerstorfer, G. Pfanner et al.: Locoregional anesthesia under anticoagulant medication. Recommendations of the Perioperative Coagulation Working Group (AGPG) of the Austrian Society for Anaesthesiology and Intensive Care Medicine (ÖGARI). In: The Anesthesiologist. Volume 54, No. 5 (2005), pp. 476-484, doi: 10.1007 / s00101-005-0827-0 .
  22. ↑ TE Warkentin, BT Maurer, RH Aster: Heparin-induced thrombocytopenia associated with fondaparinux. In: N Engl J Med. 356 (25), Jun 21, 2007, pp. 2653-2655. PMID 17582083 (without abstract).
  23. ↑ I. Elalamy, C. Lecrubier, C. Potevin et al .: Absence of in vitro cross-reaction of pentasaccharide with the plasma heparin-dependent factor of twenty-five patients with heparin-associated thrombocytopenia. In: Thromb. Haemost. 74, 1995, pp. 1384-1385.