fbpx
Wikipedia

Dabigatran

October 21, 2023

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation.[3][4] Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots.[3] It is used as an alternative to warfarin and does not require monitoring by blood tests.[3] In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing ischemic stroke; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin.[5] It is taken by mouth.[3]

Dabigatran etexilate
Clinical data
Trade namesPradaxa, Pradax, Prazaxa, others
Other namesDabigatran etexilate (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa610024
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability3–7%[3]
Protein binding35%[3]
Elimination half-life12–17 hours[3]
Identifiers
  • Ethyl N-[(2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-N-2-pyridinyl-β-alaninate
CAS Number
  • 211915-06-9 N
PubChem CID
  • 135565674
DrugBank
  • DB06695 Y
ChemSpider
  • 4948999 Y
UNII
  • 2E18WX195X
KEGG
  • D07144
ChEBI
  • CHEBI:70746
ChEMBL
  • ChEMBL539697 Y
CompTox Dashboard (EPA)
  • DTXSID50175419
Chemical and physical data
FormulaC34H41N7O5
Molar mass627.746 g·mol−1
3D model (JSmol)
  • Interactive image
  • CCCCCCOC(=O)N=C(C1=CC=C(C=C1)NCC2=NC3=C(N2C)C=CC(=C3)C(=O)N(CCC(=O)OCC)C4=CC=CC=N4)N
  • InChI=1S/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44) Y
  • Key:KSGXQBZTULBEEQ-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Common side effects include bleeding and gastritis.[3] Other side effects may include bleeding around the spine and allergic reactions such as anaphylaxis.[3] In cases of severe bleeding, it can be reversed with the antidote, idarucizumab.[3] Use is not recommended during pregnancy or breastfeeding.[3] Compared to warfarin it has fewer interactions with other medications.[6] It is a direct thrombin inhibitor.[4]

Dabigatran was approved for medical use in the United States in 2010.[3] It is on the World Health Organization's List of Essential Medicines.[7] In 2020, it was the 306th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[8] Dabigatran is available a generic medication.[9][10]

Medical uses Edit

Dabigatran is used to prevent strokes in those with atrial fibrillation not caused by heart valve issues, as well as deep vein thrombosis and pulmonary embolism in persons who have been treated for 5–10 days with parenteral anticoagulant (usually low molecular weight heparin), and to prevent deep vein thrombosis and pulmonary embolism in some circumstances.[2]

It appears to be as effective as warfarin in preventing non-hemorrhagic strokes and embolic events in those with atrial fibrillation not due to valve problems.[11][12][13]

In 2022, a comparative study was performed on direct oral anticoagulants for patients with atrial fibrillation. Results demonstrated apixaban use was associated with lower risk for gastrointestinal bleeding and similar rates of ischemic stroke or systemic embolism, intracerebral brain hemorrhage, and all-cause mortality compared with dabigatran, edoxaban, and rivaroxaban.[14]

Contraindications Edit

Dabigatran is contraindicated in patients who have active pathological bleeding, since dabigatran can increase bleeding risk and can also cause serious and potentially life-threatening bleeds.[2] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. anaphylaxis or anaphylactic shock).[2] The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valves due to the increased risk of thromboembolic events (e.g. valve thrombosis, stroke, and myocardial infarction) and major bleeding associated with dabigatran in this population.[2][15][16]

Current FDA guidelines states that patients with mechanical heart valves should not be using dabigatran. The safety and efficacy of Pradaxa (dabigatran) were evaluated in the European RE-ALIGN trial in 2012. RE-ALIGN was terminated early because the Pradaxa treatment group had significantly more thromboembolic events and major bleeding than warfarin and determined to be contraindicated for use in patients with mechanical heart valves.[17] Further studies are needed in order to determine effects of dabigatran on patients with bioprosthetic valves.

Dabigatran is poorly excreted in breastmilk and does not appear to require any limitations to breastfeeding.[18] However, data is limited and further studies are needed.

Adverse effects Edit

The most commonly reported side effect of dabigatran is gastrointestinal upset. When compared with people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of gastrointestinal bleeding was significantly higher. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with dyspepsia; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding.[19] If a small amount of GI bleeding is diagnosed, the clinicians may consider adding H2 receptor inhibitor (H2RA), proton pump inhibitors (PPIs) and mucosal protective agent. In severe bleeding, measures include discontinuation of dabigatran immediately, and administration of prothrombin complex concentrate, packed red blood cells, fresh frozen plasma, the use of specific reversal agents such as idarucizumab for dabigatran, and emergency endoscopic management.[20]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[21]

Reduced doses should be used in those with poor kidney function.[22]

Dabigatran intake has also been reported to cause esophageal injury or esophagitis. In a 2016 study by Toya et al., roughly 20% of patients suffered esophageal mucosa damage.[23] It has been theorized that the tartaric-acid core in the drug adheres and damages the esophagus, and then the damaged esophageal mucosa exfoliates after peristalsis.[24] Additionally, patients with limited mobility, reduced salivary secretion, and low water consumption will increase the possibility of contact by dabigatran with the esophageal mucosa.[20]

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial showed that impairment of liver function caused by dabigatran occurred in the same frequency as warfarin[25]

Pharmacology Edit

Mechanism of action Edit

Dabigatran reversibly binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors. Furthermore, dabigatran can inactivate thrombin even when thrombin is fibrin-bound; it reduces thrombin-mediated inhibition of fibrinolysis and, therefore, may enhance fibrinolysis.[26]

Pharmacokinetics Edit

Dabigatran has a half-life of approximately 12–14 h and exerts a maximum anticoagulation effect within 2–3 hours after ingestion.[citation needed] Fatty foods delay the intestinal absorption of dabigatran, although the bioavailability of the drug is unaffected.[27] One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor.[28] Dabigatran excretion through P-glycoprotein pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran.[29]

Dabigatran is formulated as the prodrug dabigatran etexilate.[29]

History Edit

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin, but also trypsin. Addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).[30]

On 18 March 2008, the European Medicines Agency (EMA) granted marketing authorization for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non-valvular atrial fibrillation.[31]

The National Health Service (NHS) in Britain authorized dabigatran for use in preventing blood clots in hip and knee replacement surgery patients. According to a BBC article in 2008, Dabigatran was expected to cost the NHS £4.20 per day, which was similar to several other anticoagulants.[32]

Initially, there was no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[33] unlike for warfarin.[34] Since then, the dabigatran-specific antidote idarucizumab, a humanized monoclonal antibody for intravenous administration, was developed, and received Food and Drug Administration (FDA) approval in 2015.[35]

Pradaxa received a Notice of Compliance (NOC) from Health Canada on 10 June 2008,[36] for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.[37][38]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on 19 October 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[39][40][41][42] The approval came after an advisory committee recommended the drug for approval on 20 September 2010[43] although caution is still urged by some outside experts.[44]

On 14 February 2011, the American College of Cardiology Foundation and the American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation.[45]

In May 2014, the FDA reported the results of a large study comparing dabigatran with warfarin in 134,000 Medicare patients. The agency concluded that dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The FDA reiterated its opinion that dabigatran's overall risk/benefit ratio is favorable.[46]

On 26 July 2014, the British Medical Journal (BMJ) published a series of investigations that accused the privately held Boehringer Ingelheim pharmaceutical group of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees by the FDA and the EMA revealed that Boehringer researchers had found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring.[47][48] In August 2012, Pradaxa claims filed in U.S. federal courts were consolidated into a multi-district litigation in the Southern District of Illinois before Chief Judge David R. Herndon. On 28 May 2014, a $650 million settlement was announced on behalf of approximately 3,900 claimants who were injured by the drug Pradaxa made by Boehringer Ingelheim Pharmaceuticals, Inc. The drug was alleged to cause severe bleeding events and/or hemorrhaging to those who were taking the drug.[49]

References Edit

  1. ^ "Dabigatran (Pradaxa) Use During Pregnancy". Drugs.com. 27 December 2018. from the original on 1 October 2020. Retrieved 16 May 2020.
  2. ^ a b c d e "Pradaxa- dabigatran etexilate mesylate capsule". DailyMed. 6 July 2020. from the original on 28 June 2021. Retrieved 13 November 2020.
  3. ^ a b c d e f g h i j k l "Dabigatran Etexilate Mesylate Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. from the original on 27 March 2019. Retrieved 27 March 2019.
  4. ^ a b British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 135–137. ISBN 9780857113382.
  5. ^ Romanelli RJ, Nolting L, Dolginsky M, Kym E, Orrico KB (March 2016). "Dabigatran Versus Warfarin for Atrial Fibrillation in Real-World Clinical Practice: A Systematic Review and Meta-Analysis". Circulation: Cardiovascular Quality and Outcomes. 9 (2): 126–134. doi:10.1161/CIRCOUTCOMES.115.002369. PMID 26812933. S2CID 6840541.
  6. ^ Kiser K (2017). Oral Anticoagulation Therapy: Cases and Clinical Correlation. Springer. p. 11. ISBN 9783319546438.
  7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ^ "Dabigatran - Drug Usage Statistics". ClinCalc. from the original on 13 November 2022. Retrieved 7 October 2022.
  9. ^ "Office of Generic Drugs 2020 Annual Report". U.S. Food and Drug Administration (FDA). from the original on 12 February 2021. Retrieved 12 February 2021.
  10. ^ "Dabigatran Etexilate Accord". European Medicines Agency. 31 May 2023. Retrieved 2 June 2023.
  11. ^ Gómez-Outes A, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E (2013). "Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups". Thrombosis. 2013: 640723. doi:10.1155/2013/640723. PMC 3885278. PMID 24455237.
  12. ^ Lowenstern A, Al-Khatib SM, Sharan L, Chatterjee R, Allen LaPointe NM, Shah B, et al. (December 2018). "Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation: A Systematic Review". Annals of Internal Medicine. 169 (11): 774–787. doi:10.7326/M18-1523. PMC 6825839. PMID 30383133.
  13. ^ Sanders GD, Lowenstern A, Borre E, Chatterjee R, Goode A, Sharan L, et al. (October 2018). Stroke Prevention in Patients With Atrial Fibrillation: A Systematic Review Update. Agency for Healthcare Research and Quality (US) (Report). Rockville (MD). doi:10.23970/ahrqepccer214. PMID 30480925. Report No.: 18-EHC018-EFReport No.: 2018-SR-04. from the original on 29 March 2019. Retrieved 31 May 2023.
  14. ^ Lau WC, Torre CO, Man KK, Stewart HM, Seager S, Van Zandt M, et al. (November 2022). "Comparative Effectiveness and Safety Between Apixaban, Dabigatran, Edoxaban, and Rivaroxaban Among Patients With Atrial Fibrillation : A Multinational Population-Based Cohort Study". Annals of Internal Medicine. 175 (11): 1515–1524. doi:10.7326/M22-0511. PMID 36315950. S2CID 253238819.
  15. ^ "FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves". U.S. Food and Drug Administration (FDA). from the original on 2 November 2014. Retrieved 29 October 2014.
  16. ^ Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. (September 2013). "Dabigatran versus warfarin in patients with mechanical heart valves". The New England Journal of Medicine. 369 (13): 1206–1214. doi:10.1056/NEJMoa1300615. PMID 23991661.
  17. ^ "FDA Drug Safety Communication: Pradaxa (dabigatran etexilate mesylate) should not be used in patients with mechanical prosthetic heart valves". Center for Drug Evaluation and Research. U.S. Food and Drug Administration. 21 June 2019. from the original on 27 February 2023. Retrieved 27 February 2023.
  18. ^ "Dabigatran", Drugs and Lactation Database (LactMed®), Bethesda (MD): National Institute of Child Health and Human Development, 2006, PMID 29999803, from the original on 2 May 2023, retrieved 27 February 2023
  19. ^ Blommel ML, Blommel AL (August 2011). "Dabigatran etexilate: A novel oral direct thrombin inhibitor". American Journal of Health-System Pharmacy. 68 (16): 1506–1519. doi:10.2146/ajhp100348. PMID 21817082.
  20. ^ a b Lin S, Wang Y, Zhang L, Guan W (6 May 2019). "Dabigatran must be used carefully: literature review and recommendations for management of adverse events". Drug Design, Development and Therapy. 13: 1527–1533. doi:10.2147/DDDT.S203112. PMC 6511609. PMID 31190734.
  21. ^ Uchino K, Hernandez AV (March 2012). "Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials". Archives of Internal Medicine. 172 (5): 397–402. doi:10.1001/archinternmed.2011.1666. PMID 22231617.
  22. ^ "18/12/2014 Pradaxa -EMEA/H/C/000829 -II/0073".[permanent dead link]
  23. ^ Toya Y, Nakamura S, Tomita K, Matsuda N, Abe K, Abiko Y, et al. (March 2016). "Dabigatran-induced esophagitis: The prevalence and endoscopic characteristics". Journal of Gastroenterology and Hepatology. 31 (3): 610–614. doi:10.1111/jgh.13024. PMID 26102078. S2CID 2601542.
  24. ^ Bytzer P, Connolly SJ, Yang S, Ezekowitz M, Formella S, Reilly PA, Aisenberg J (March 2013). "Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial". Clinical Gastroenterology and Hepatology. 11 (3): 246–252.e5. doi:10.1016/j.cgh.2012.10.021. PMID 23103906.
  25. ^ Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 361 (12): 1139–1151. doi:10.1056/NEJMoa0905561. hdl:11343/221723. PMID 19717844.
  26. ^ Comin J, Kallmes DF (March 2012). "Dabigatran (Pradaxa)". AJNR. American Journal of Neuroradiology. 33 (3): 426–428. doi:10.3174/ajnr.A3000. PMC 7966436. PMID 22345499.
  27. ^ Pradaxa Full Prescribing Information 2015-08-10 at the Wayback Machine. Boehringer Ingelheim. October 2010.
  28. ^ Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stähle H, et al. (May 2005). "Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement". Journal of Clinical Pharmacology. 45 (5): 555–563. doi:10.1177/0091270005274550. PMID 15831779. S2CID 26441767.
  29. ^ a b "Pradaxa Summary of Product Characteristics" (2018) 2019-07-05 at the Wayback Machine. European Medicines Agency.
  30. ^ Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (April 2002). "Structure-based design of novel potent nonpeptide thrombin inhibitors". Journal of Medicinal Chemistry. 45 (9): 1757–1766. doi:10.1021/jm0109513. PMID 11960487.
  31. ^ "Pradaxa EPAR". European Medicines Agency. Archived from the original on 2 August 2012. Retrieved 30 January 2011.
  32. ^ "Clot drug 'could save thousands'". BBC News Online. 20 April 2008. from the original on 15 January 2009. Retrieved 21 April 2008.
  33. ^ van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (June 2010). "Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity". Thrombosis and Haemostasis. 103 (6): 1116–1127. doi:10.1160/TH09-11-0758. PMID 20352166. S2CID 37404563. Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran, due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity.
  34. ^ Hanley JP (November 2004). "Warfarin reversal". Journal of Clinical Pathology. 57 (11): 1132–1139. doi:10.1136/jcp.2003.008904. PMC 1770479. PMID 15509671.
  35. ^ Syed YY (August 2016). "Idarucizumab: A Review as a Reversal Agent for Dabigatran". American Journal of Cardiovascular Drugs. 16 (4): 297–304. doi:10.1007/s40256-016-0181-4. PMID 27388764. S2CID 11596083.
  36. ^ "Summary Basis of Decision (SBD): Pradax" 14 July 2016 at the Wayback Machine Health Canada. 2008-11-06.
  37. ^ Kirkey S (29 October 2010). . Montreal Gazette. Archived from the original on 16 June 2011. Retrieved 29 October 2010.
  38. ^ "Pradax (Dabigatran Etexilate) Gains Approval In Canada For Stroke Prevention In Atrial Fibrillation" 24 April 2011 at the Wayback Machine Medical News Today. 28 October 2010.
  39. ^ Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 361 (12): 1139–1151. doi:10.1056/NEJMoa0905561. hdl:11343/221723. PMID 19717844.
  40. ^ Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". European Heart Journal. 29 (2): 155–165. doi:10.1093/eurheartj/ehm575. PMID 18096568.
  41. ^ "Boehringer wins first US OK in blood-thinner race". Reuters. 19 October 2010. from the original on 4 May 2016. Retrieved 20 October 2010.
  42. ^ (Press release). U.S. Food and Drug Administration (FDA). 19 October 2010. Archived from the original on 20 October 2010.
  43. ^ Shirley S. Wang (20 September 2010). "New Blood-Thinner Recommended by FDA Panel". The Wall Street Journal. from the original on 24 April 2016. Retrieved 20 October 2010.
  44. ^ Merli G, Spyropoulos AC, Caprini JA (August 2009). "Use of emerging oral anticoagulants in clinical practice: translating results from clinical trials to orthopedic and general surgical patient populations". Annals of Surgery. 250 (2): 219–228. doi:10.1097/SLA.0b013e3181ae6dbe. PMID 19638915. S2CID 44917732.
  45. ^ Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, et al. (March 2011). "2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines". Circulation. 123 (10): 1144–1150. doi:10.1161/CIR.0b013e31820f14c0. PMID 21321155.
  46. ^ "FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin". U.S. Food and Drug Administration (FDA). 21 June 2019. from the original on 11 November 2020. Retrieved 13 November 2020.
  47. ^ Cohen D (July 2014). "Dabigatran: how the drug company withheld important analyses". BMJ. 349: g4670. doi:10.1136/bmj.g4670. PMID 25055829.
  48. ^ Moore TJ, Cohen MR, Mattison DR (July 2014). "Dabigatran, bleeding, and the regulators". BMJ. 349: g4517. doi:10.1136/bmj.g4517. PMID 25056265. S2CID 29090410.
  49. ^ Thomas K (28 May 2014). "$650 Million to Settle Blood Thinner Lawsuits". The New York Times. from the original on 11 June 2021. Retrieved 26 November 2020.

External links Edit

  • "Dabigatran". Drug Information Portal. U.S. National Library of Medicine.
  • "Dabigatran etexilate". Drug Information Portal. U.S. National Library of Medicine.
  • "Dabigatran etexilate mesylate". Drug Information Portal. U.S. National Library of Medicine.

October 21, 2023
dabigatran, sold, under, brand, name, pradaxa, among, others, anticoagulant, used, treat, prevent, blood, clots, prevent, stroke, people, with, atrial, fibrillation, specifically, used, prevent, blood, clots, following, knee, replacement, those, with, history,. Dabigatran sold under the brand name Pradaxa among others is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation 3 4 Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots 3 It is used as an alternative to warfarin and does not require monitoring by blood tests 3 In a meta analysis of 7 different studies there was no benefit of dabigatran over warfarin in preventing ischemic stroke however dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin but also had a higher risk of gastrointestinal bleeding relative to warfarin 5 It is taken by mouth 3 Dabigatran etexilateClinical dataTrade namesPradaxa Pradax Prazaxa othersOther namesDabigatran etexilate USAN US AHFS Drugs comMonographMedlinePlusa610024License dataEU EMA by INN US DailyMed DabigatranPregnancycategoryAU C 1 Routes ofadministrationBy mouthATC codeB01AE07 WHO Legal statusLegal statusAU S4 Prescription only CA Schedule VI UK POM Prescription only US only 2 EU Rx onlyPharmacokinetic dataBioavailability3 7 3 Protein binding35 3 Elimination half life12 17 hours 3 IdentifiersIUPAC name Ethyl N 2 4 N hexyloxy carbonyl carbamimidoyl phenyl amino methyl 1 methyl 1H benzimidazol 5 yl carbonyl N 2 pyridinyl b alaninateCAS Number211915 06 9 NPubChem CID135565674DrugBankDB06695 YChemSpider4948999 YUNII2E18WX195XKEGGD07144ChEBICHEBI 70746ChEMBLChEMBL539697 YCompTox Dashboard EPA DTXSID50175419Chemical and physical dataFormulaC 34H 41N 7O 5Molar mass627 746 g mol 13D model JSmol Interactive imageSMILES CCCCCCOC O N C C1 CC C C C1 NCC2 NC3 C N2C C CC C3 C O N CCC O OCC C4 CC CC N4 NInChI InChI 1S C34H41N7O5 c1 4 6 7 10 21 46 34 44 39 32 35 24 12 15 26 16 13 24 37 23 30 38 27 22 25 14 17 28 27 40 30 3 33 43 41 20 18 31 42 45 5 2 29 11 8 9 19 36 29 h8 9 11 17 19 22 37H 4 7 10 18 20 21 23H2 1 3H3 H2 35 39 44 YKey KSGXQBZTULBEEQ UHFFFAOYSA N Y N Y what is this verify Common side effects include bleeding and gastritis 3 Other side effects may include bleeding around the spine and allergic reactions such as anaphylaxis 3 In cases of severe bleeding it can be reversed with the antidote idarucizumab 3 Use is not recommended during pregnancy or breastfeeding 3 Compared to warfarin it has fewer interactions with other medications 6 It is a direct thrombin inhibitor 4 Dabigatran was approved for medical use in the United States in 2010 3 It is on the World Health Organization s List of Essential Medicines 7 In 2020 it was the 306th most commonly prescribed medication in the United States with more than 1 million prescriptions 8 Dabigatran is available a generic medication 9 10 Contents 1 Medical uses 2 Contraindications 3 Adverse effects 4 Pharmacology 4 1 Mechanism of action 4 2 Pharmacokinetics 5 History 6 References 7 External linksMedical uses EditDabigatran is used to prevent strokes in those with atrial fibrillation not caused by heart valve issues as well as deep vein thrombosis and pulmonary embolism in persons who have been treated for 5 10 days with parenteral anticoagulant usually low molecular weight heparin and to prevent deep vein thrombosis and pulmonary embolism in some circumstances 2 It appears to be as effective as warfarin in preventing non hemorrhagic strokes and embolic events in those with atrial fibrillation not due to valve problems 11 12 13 In 2022 a comparative study was performed on direct oral anticoagulants for patients with atrial fibrillation Results demonstrated apixaban use was associated with lower risk for gastrointestinal bleeding and similar rates of ischemic stroke or systemic embolism intracerebral brain hemorrhage and all cause mortality compared with dabigatran edoxaban and rivaroxaban 14 Contraindications EditDabigatran is contraindicated in patients who have active pathological bleeding since dabigatran can increase bleeding risk and can also cause serious and potentially life threatening bleeds 2 Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran e g anaphylaxis or anaphylactic shock 2 The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valves due to the increased risk of thromboembolic events e g valve thrombosis stroke and myocardial infarction and major bleeding associated with dabigatran in this population 2 15 16 Current FDA guidelines states that patients with mechanical heart valves should not be using dabigatran The safety and efficacy of Pradaxa dabigatran were evaluated in the European RE ALIGN trial in 2012 RE ALIGN was terminated early because the Pradaxa treatment group had significantly more thromboembolic events and major bleeding than warfarin and determined to be contraindicated for use in patients with mechanical heart valves 17 Further studies are needed in order to determine effects of dabigatran on patients with bioprosthetic valves Dabigatran is poorly excreted in breastmilk and does not appear to require any limitations to breastfeeding 18 However data is limited and further studies are needed Adverse effects EditThe most commonly reported side effect of dabigatran is gastrointestinal upset When compared with people anticoagulated with warfarin patients taking dabigatran had fewer life threatening bleeds fewer minor and major bleeds including intracranial bleeds but the rate of gastrointestinal bleeding was significantly higher Dabigatran capsules contain tartaric acid which lowers the gastric pH and is required for adequate absorption The lower pH has previously been associated with dyspepsia some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding 19 If a small amount of GI bleeding is diagnosed the clinicians may consider adding H2 receptor inhibitor H2RA proton pump inhibitors PPIs and mucosal protective agent In severe bleeding measures include discontinuation of dabigatran immediately and administration of prothrombin complex concentrate packed red blood cells fresh frozen plasma the use of specific reversal agents such as idarucizumab for dabigatran and emergency endoscopic management 20 A small but significantly increased risk of myocardial infarctions heart attacks has been noted when combining the safety outcome data from multiple trials 21 Reduced doses should be used in those with poor kidney function 22 Dabigatran intake has also been reported to cause esophageal injury or esophagitis In a 2016 study by Toya et al roughly 20 of patients suffered esophageal mucosa damage 23 It has been theorized that the tartaric acid core in the drug adheres and damages the esophagus and then the damaged esophageal mucosa exfoliates after peristalsis 24 Additionally patients with limited mobility reduced salivary secretion and low water consumption will increase the possibility of contact by dabigatran with the esophageal mucosa 20 The Randomized Evaluation of Long Term Anticoagulation Therapy RE LY trial showed that impairment of liver function caused by dabigatran occurred in the same frequency as warfarin 25 Pharmacology EditMechanism of action Edit Dabigatran reversibly binds to the active site on the thrombin molecule preventing thrombin mediated activation of coagulation factors Furthermore dabigatran can inactivate thrombin even when thrombin is fibrin bound it reduces thrombin mediated inhibition of fibrinolysis and therefore may enhance fibrinolysis 26 Pharmacokinetics Edit Dabigatran has a half life of approximately 12 14 h and exerts a maximum anticoagulation effect within 2 3 hours after ingestion citation needed Fatty foods delay the intestinal absorption of dabigatran although the bioavailability of the drug is unaffected 27 One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor 28 Dabigatran excretion through P glycoprotein pumps is slowed in patients taking strong p glycoprotein pump inhibitors such as quinidine verapamil and amiodarone thus raising plasma levels of dabigatran 29 Dabigatran is formulated as the prodrug dabigatran etexilate 29 History EditDabigatran then compound BIBR 953 was discovered from a panel of chemicals with similar structure to benzamidine based thrombin inhibitor a NAPAP N alpha 2 naphthylsulfonylglycyl 4 amidinophenylalanine piperidide which had been known since the 1980s as a powerful inhibitor of various serine proteases specifically thrombin but also trypsin Addition of ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug BIBR 1048 dabigatran etexilate 30 On 18 March 2008 the European Medicines Agency EMA granted marketing authorization for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non valvular atrial fibrillation 31 The National Health Service NHS in Britain authorized dabigatran for use in preventing blood clots in hip and knee replacement surgery patients According to a BBC article in 2008 Dabigatran was expected to cost the NHS 4 20 per day which was similar to several other anticoagulants 32 Initially there was no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event 33 unlike for warfarin 34 Since then the dabigatran specific antidote idarucizumab a humanized monoclonal antibody for intravenous administration was developed and received Food and Drug Administration FDA approval in 2015 35 Pradaxa received a Notice of Compliance NOC from Health Canada on 10 June 2008 36 for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery Approval for atrial fibrillation patients at risk of stroke came in October 2010 37 38 The U S Food and Drug Administration FDA approved Pradaxa on 19 October 2010 for prevention of stroke in patients with non valvular atrial fibrillation 39 40 41 42 The approval came after an advisory committee recommended the drug for approval on 20 September 2010 43 although caution is still urged by some outside experts 44 On 14 February 2011 the American College of Cardiology Foundation and the American Heart Association added dabigatran to their guidelines for management of non valvular atrial fibrillation with a class I recommendation 45 In May 2014 the FDA reported the results of a large study comparing dabigatran with warfarin in 134 000 Medicare patients The agency concluded that dabigatran is associated with a lower risk of overall mortality ischemic stroke and bleeding in the brain than warfarin Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin The risk of heart attack was similar between the two drugs The FDA reiterated its opinion that dabigatran s overall risk benefit ratio is favorable 46 On 26 July 2014 the British Medical Journal BMJ published a series of investigations that accused the privately held Boehringer Ingelheim pharmaceutical group of withholding critical information about the need for monitoring to protect patients from severe bleeding particularly in the elderly Review of internal communications between Boehringer researchers and employees by the FDA and the EMA revealed that Boehringer researchers had found evidence that serum levels of dabigatran vary widely The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring 47 48 In August 2012 Pradaxa claims filed in U S federal courts were consolidated into a multi district litigation in the Southern District of Illinois before Chief Judge David R Herndon On 28 May 2014 a 650 million settlement was announced on behalf of approximately 3 900 claimants who were injured by the drug Pradaxa made by Boehringer Ingelheim Pharmaceuticals Inc The drug was alleged to cause severe bleeding events and or hemorrhaging to those who were taking the drug 49 References Edit Dabigatran Pradaxa Use During Pregnancy Drugs com 27 December 2018 Archived from the original on 1 October 2020 Retrieved 16 May 2020 a b c d e Pradaxa dabigatran etexilate mesylate capsule DailyMed 6 July 2020 Archived from the original on 28 June 2021 Retrieved 13 November 2020 a b c d e f g h i j k l Dabigatran Etexilate Mesylate Monograph for Professionals Drugs com American Society of Health System Pharmacists Archived from the original on 27 March 2019 Retrieved 27 March 2019 a b British national formulary BNF 76 76 ed Pharmaceutical Press 2018 pp 135 137 ISBN 9780857113382 Romanelli RJ Nolting L Dolginsky M Kym E Orrico KB March 2016 Dabigatran Versus Warfarin for Atrial Fibrillation in Real World Clinical Practice A Systematic Review and Meta Analysis Circulation Cardiovascular Quality and Outcomes 9 2 126 134 doi 10 1161 CIRCOUTCOMES 115 002369 PMID 26812933 S2CID 6840541 Kiser K 2017 Oral Anticoagulation Therapy Cases and Clinical Correlation Springer p 11 ISBN 9783319546438 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO Dabigatran Drug Usage Statistics ClinCalc Archived from the original on 13 November 2022 Retrieved 7 October 2022 Office of Generic Drugs 2020 Annual Report U S Food and Drug Administration FDA Archived from the original on 12 February 2021 Retrieved 12 February 2021 Dabigatran Etexilate Accord European Medicines Agency 31 May 2023 Retrieved 2 June 2023 Gomez Outes A Terleira Fernandez AI Calvo Rojas G Suarez Gea ML Vargas Castrillon E 2013 Dabigatran Rivaroxaban or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation A Systematic Review and Meta Analysis of Subgroups Thrombosis 2013 640723 doi 10 1155 2013 640723 PMC 3885278 PMID 24455237 Lowenstern A Al Khatib SM Sharan L Chatterjee R Allen LaPointe NM Shah B et al December 2018 Interventions for Preventing Thromboembolic Events in Patients With Atrial Fibrillation A Systematic Review Annals of Internal Medicine 169 11 774 787 doi 10 7326 M18 1523 PMC 6825839 PMID 30383133 Sanders GD Lowenstern A Borre E Chatterjee R Goode A Sharan L et al October 2018 Stroke Prevention in Patients With Atrial Fibrillation A Systematic Review Update Agency for Healthcare Research and Quality US Report Rockville MD doi 10 23970 ahrqepccer214 PMID 30480925 Report No 18 EHC018 EFReport No 2018 SR 04 Archived from the original on 29 March 2019 Retrieved 31 May 2023 Lau WC Torre CO Man KK Stewart HM Seager S Van Zandt M et al November 2022 Comparative Effectiveness and Safety Between Apixaban Dabigatran Edoxaban and Rivaroxaban Among Patients With Atrial Fibrillation A Multinational Population Based Cohort Study Annals of Internal Medicine 175 11 1515 1524 doi 10 7326 M22 0511 PMID 36315950 S2CID 253238819 FDA Drug Safety Communication Pradaxa dabigatran etexilate mesylate should not be used in patients with mechanical prosthetic heart valves U S Food and Drug Administration FDA Archived from the original on 2 November 2014 Retrieved 29 October 2014 Eikelboom JW Connolly SJ Brueckmann M Granger CB Kappetein AP Mack MJ et al September 2013 Dabigatran versus warfarin in patients with mechanical heart valves The New England Journal of Medicine 369 13 1206 1214 doi 10 1056 NEJMoa1300615 PMID 23991661 FDA Drug Safety Communication Pradaxa dabigatran etexilate mesylate should not be used in patients with mechanical prosthetic heart valves Center for Drug Evaluation and Research U S Food and Drug Administration 21 June 2019 Archived from the original on 27 February 2023 Retrieved 27 February 2023 Dabigatran Drugs and Lactation Database LactMed Bethesda MD National Institute of Child Health and Human Development 2006 PMID 29999803 archived from the original on 2 May 2023 retrieved 27 February 2023 Blommel ML Blommel AL August 2011 Dabigatran etexilate A novel oral direct thrombin inhibitor American Journal of Health System Pharmacy 68 16 1506 1519 doi 10 2146 ajhp100348 PMID 21817082 a b Lin S Wang Y Zhang L Guan W 6 May 2019 Dabigatran must be used carefully literature review and recommendations for management of adverse events Drug Design Development and Therapy 13 1527 1533 doi 10 2147 DDDT S203112 PMC 6511609 PMID 31190734 Uchino K Hernandez AV March 2012 Dabigatran association with higher risk of acute coronary events meta analysis of noninferiority randomized controlled trials Archives of Internal Medicine 172 5 397 402 doi 10 1001 archinternmed 2011 1666 PMID 22231617 18 12 2014 Pradaxa EMEA H C 000829 II 0073 permanent dead link Toya Y Nakamura S Tomita K Matsuda N Abe K Abiko Y et al March 2016 Dabigatran induced esophagitis The prevalence and endoscopic characteristics Journal of Gastroenterology and Hepatology 31 3 610 614 doi 10 1111 jgh 13024 PMID 26102078 S2CID 2601542 Bytzer P Connolly SJ Yang S Ezekowitz M Formella S Reilly PA Aisenberg J March 2013 Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE LY trial Clinical Gastroenterology and Hepatology 11 3 246 252 e5 doi 10 1016 j cgh 2012 10 021 PMID 23103906 Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A et al September 2009 Dabigatran versus warfarin in patients with atrial fibrillation The New England Journal of Medicine 361 12 1139 1151 doi 10 1056 NEJMoa0905561 hdl 11343 221723 PMID 19717844 Comin J Kallmes DF March 2012 Dabigatran Pradaxa AJNR American Journal of Neuroradiology 33 3 426 428 doi 10 3174 ajnr A3000 PMC 7966436 PMID 22345499 Pradaxa Full Prescribing Information Archived 2015 08 10 at the Wayback Machine Boehringer Ingelheim October 2010 Stangier J Eriksson BI Dahl OE Ahnfelt L Nehmiz G Stahle H et al May 2005 Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement Journal of Clinical Pharmacology 45 5 555 563 doi 10 1177 0091270005274550 PMID 15831779 S2CID 26441767 a b Pradaxa Summary of Product Characteristics 2018 Archived 2019 07 05 at the Wayback Machine European Medicines Agency Hauel NH Nar H Priepke H Ries U Stassen JM Wienen W April 2002 Structure based design of novel potent nonpeptide thrombin inhibitors Journal of Medicinal Chemistry 45 9 1757 1766 doi 10 1021 jm0109513 PMID 11960487 Pradaxa EPAR European Medicines Agency Archived from the original on 2 August 2012 Retrieved 30 January 2011 Clot drug could save thousands BBC News Online 20 April 2008 Archived from the original on 15 January 2009 Retrieved 21 April 2008 van Ryn J Stangier J Haertter S Liesenfeld KH Wienen W Feuring M Clemens A June 2010 Dabigatran etexilate a novel reversible oral direct thrombin inhibitor interpretation of coagulation assays and reversal of anticoagulant activity Thrombosis and Haemostasis 103 6 1116 1127 doi 10 1160 TH09 11 0758 PMID 20352166 S2CID 37404563 Although there is no specific antidote to antagonise the anticoagulant effect of dabigatran due to its short duration of effect drug discontinuation is usually sufficient to reverse any excessive anticoagulant activity Hanley JP November 2004 Warfarin reversal Journal of Clinical Pathology 57 11 1132 1139 doi 10 1136 jcp 2003 008904 PMC 1770479 PMID 15509671 Syed YY August 2016 Idarucizumab A Review as a Reversal Agent for Dabigatran American Journal of Cardiovascular Drugs 16 4 297 304 doi 10 1007 s40256 016 0181 4 PMID 27388764 S2CID 11596083 Summary Basis of Decision SBD Pradax Archived 14 July 2016 at the Wayback Machine Health Canada 2008 11 06 Kirkey S 29 October 2010 Approval of new drug heralds momentous advance in stroke prevention Montreal Gazette Archived from the original on 16 June 2011 Retrieved 29 October 2010 Pradax Dabigatran Etexilate Gains Approval In Canada For Stroke Prevention In Atrial Fibrillation Archived 24 April 2011 at the Wayback Machine Medical News Today 28 October 2010 Connolly SJ Ezekowitz MD Yusuf S Eikelboom J Oldgren J Parekh A et al September 2009 Dabigatran versus warfarin in patients with atrial fibrillation The New England Journal of Medicine 361 12 1139 1151 doi 10 1056 NEJMoa0905561 hdl 11343 221723 PMID 19717844 Turpie AG January 2008 New oral anticoagulants in atrial fibrillation European Heart Journal 29 2 155 165 doi 10 1093 eurheartj ehm575 PMID 18096568 Boehringer wins first US OK in blood thinner race Reuters 19 October 2010 Archived from the original on 4 May 2016 Retrieved 20 October 2010 FDA approves Pradaxa to prevent stroke in people with atrial fibrillation Press release U S Food and Drug Administration FDA 19 October 2010 Archived from the original on 20 October 2010 Shirley S Wang 20 September 2010 New Blood Thinner Recommended by FDA Panel The Wall Street Journal Archived from the original on 24 April 2016 Retrieved 20 October 2010 Merli G Spyropoulos AC Caprini JA August 2009 Use of emerging oral anticoagulants in clinical practice translating results from clinical trials to orthopedic and general surgical patient populations Annals of Surgery 250 2 219 228 doi 10 1097 SLA 0b013e3181ae6dbe PMID 19638915 S2CID 44917732 Wann LS Curtis AB Ellenbogen KA Estes NA Ezekowitz MD Jackman WM et al March 2011 2011 ACCF AHA HRS focused update on the management of patients with atrial fibrillation update on Dabigatran a report of the American College of Cardiology Foundation American Heart Association Task Force on practice guidelines Circulation 123 10 1144 1150 doi 10 1161 CIR 0b013e31820f14c0 PMID 21321155 FDA Drug Safety Communication FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa dabigatran compared to warfarin U S Food and Drug Administration FDA 21 June 2019 Archived from the original on 11 November 2020 Retrieved 13 November 2020 Cohen D July 2014 Dabigatran how the drug company withheld important analyses BMJ 349 g4670 doi 10 1136 bmj g4670 PMID 25055829 Moore TJ Cohen MR Mattison DR July 2014 Dabigatran bleeding and the regulators BMJ 349 g4517 doi 10 1136 bmj g4517 PMID 25056265 S2CID 29090410 Thomas K 28 May 2014 650 Million to Settle Blood Thinner Lawsuits The New York Times Archived from the original on 11 June 2021 Retrieved 26 November 2020 External links Edit Dabigatran Drug Information Portal U S National Library of Medicine Dabigatran etexilate Drug Information Portal U S National Library of Medicine Dabigatran etexilate mesylate Drug Information Portal U S National Library of Medicine Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Dabigatran amp oldid 1180050224, wikipedia, wiki, book, books, library,

article

, read, download, free, free download, mp3, video, mp4, 3gp, jpg, jpeg, gif, png, picture, music, song, movie, book, game, games.