Dabigatran

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Dabigatran etexilate
Dabigatran etexilate structure.svg
Systematic (IUPAC) name

Ethyl 3-{[(2-{[(4-{N'-hexyloxycarbonyl carbamimidoyl}phenyl)amino]methyl}-1-

methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate
Clinical data
Trade names Pradaxa, Pradax, Prazaxa
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Legal status Schedule VI (CA) POM (UK) -only (US)
Routes oral
Pharmacokinetic data
Bioavailability 3–7%[1]
Protein binding 35%[1]
Half-life 12–17 hours[1]
Identifiers
CAS number 211915-06-9
ATC code B01AE07
PubChem CID 6445226
DrugBank DB06695
ChemSpider 4948999 YesY
ChEMBL CHEMBL539697 YesY
Chemical data
Formula C34H41N7O5 
Mol. mass 627.734 g/mol
 YesY (what is this?)  (verify)
Dabigatran
Dabigatran structure.svg
Systematic (IUPAC) name
3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid
Clinical data
Legal status ?
Identifiers
CAS number 211914-51-1 N
ATC code ?
PubChem CID 216210
ChemSpider 187412 YesY
UNII I0VM4M70GC YesY
KEGG D09707 N
ChEMBL CHEMBL48361 YesY
Chemical data
Formula C25H25N7O3 
Mol. mass 471.511 g/mol
 N (what is this?)  (verify)

Dabigatran (Pradaxa in Australia, Europe and USA, Pradax in Canada, Prazaxa in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant ("blood thinner") since it does not require frequent blood tests for international normalized ratio (INR) monitoring while offering similar results in terms of efficacy. There is no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[2][3] unlike warfarin,[4] although a potential dabigatran antidote (pINN: idarucizumab) is undergoing clinical studies.[5] It was developed by the pharmaceutical company Boehringer Ingelheim.

Medical uses[edit]

Dabigatran is used to prevent strokes in those with atrial fibrillation due to non heart valve causes.[6]

Adverse effects[edit]

The most commonly reported side effect of dabigatran is GI upset. When compared to people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of GI 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.[7]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[8]

Development[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).[9]

Dosing[edit]

A phase II study, comparing dabigatran with enoxaparin, showed increased efficacy in preventing thrombosis in patients undergoing orthopedic surgery, but a possible increased bleeding risk in patients receiving higher doses of dabigatran.[10] A phase III study, comparing dabigatran doses of 150 mg and 220 mg once daily with the standard 40 mg dose of enoxaparin once daily, confirmed that dabigatran performed as well as enoxaparin in preventing thrombosis, with a similar risk profile.[11]

Dabigatran has a half-life of approximately 12-14 h and exert a maximum anticoagulation effect within 2-3 h after ingestion.[12] Fatty foods delay the absorption of dabigatran, although the bio-availability of the drug is unaffected.[1] One study showed that absorption may be moderately decreased if taken with a proton pump inhibitor.[13] Drug 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.[14]

Major trials[edit]

RE-LY study[edit]

A manufacturer-sponsored phase III study, RE-LY, evaluated the efficacy and safety of two different doses of dabigatran relative to warfarin in over 18,000 patients with atrial fibrillation. 18,113 patients with atrial fibrillation were randomized to one of three arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg twice daily, or (3) dabigatran 150 mg twice daily. The warfarin arm was open label, but adverse events were adjudicated by reviewers blinded to treatment. Dabigatran 110 mg was non-inferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg showed similar bleeding to warfarin.[15][16]

Data released in May 2011 show that patients under 75 with atrial fibrillation at risk for stroke have lower risks of both intracranial and extracranial bleeding in both doses of dabigatran compared with warfarin. In patients over 75 years, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran when compared with warfarin.[17]

RE-COVER[edit]

A 2009 large (2539 patients), randomized, double-blind trial by the RE-COVER study group demonstrated non-inferiority of dabigatran when compared to warfarin in the treatment of acute venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus non-major bleeding. Patients randomized to dabigatran had fewer minor bleeds but more dyspepsia and more drug discontinuation. Dabigatran-treated patients did not undergo coagulation testing.[18]

Approval and indications[edit]

On March 18, 2008, the European Medicines Agency granted marketing authorisation for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non-valvular atrial fibrillation.[19]

The National Health Service in Britain authorised the use of dabigatran for use in preventing blood clots in hip and knee 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,.[20]

Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[21] 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.[22][23]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with non-valvular atrial fibrillation.[15][24][25][26] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[27] although caution is still urged by some outside experts.[28]

On February 14, 2011, the American College of Cardiology Foundation and American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation.[29]

On December 7, 2011, the FDA initiated an investigation into serious bleeding events associated with dabigatran stating that the "FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa [RE-LY trial]." In November 2011, Boehringer Ingelheim confirmed 260 fatal bleeding events worldwide between March 2008 and October 2011.[30] In May 2014 the FDA reported the results of a large study comparing dabigatran to 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 that 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 Agency reiterated its opinion that dabigatran's overall risk/benefit ratio is favorable.[31]

On July 26, 2014, the British Medical Journal (BMJ) published a series of investigations that accused Boehringer of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. The investigations also criticized the FDA for choosing to recommend a single dosing format of 150 mg twice per day for all patients despite concerns[who?] that this dose may lead to increased bleeding risk in some patients, particularly the elderly. The FDA was also criticized for recommending a twice daily dose of 75 mg per day for those with renal failure despite what the authors consider a complete lack of clinical research supporting this dose. Review of internal communications between Boehringer researchers and employees, the FDA and the EMA revealed that Boehringer researchers found evidence that serum levels of dabigatran vary widely. The authors conclude that these findings suggest that some patients were at increased risk of stroke due to inadequate serum levels while others were at increased risk of serious or life-threatening bleeds due to elevated serum levels. The researchers concluded that routine monitoring of dabigatran and individualized dose adjustment would result in fewer bleeding events without increasing the risk of stroke. 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. [32] [33]

A 2012 Institute for Safe Medication Practices QuarterWatch report analysed all the adverse events submitted to the FDA's reporting system in 2011. The report identified dabigatran and warfarin as the most commonly identified drugs reported to the FDA. Adverse events associated with dabigatran included 542 deaths and 2367 reports of hemorrhage, while warfarin was associated with 72 deaths. The authors note that these numbers cannot be used to conclude that dabigatran causes more bleeding episodes than warfarin, as adverse event reporting rates are higher for new and actively marketed drugs than for older generics. [34]

Expiration of capsules[edit]

Once a bottle of dabigatran is opened, the medication expires after four months. This unusually short period exists because the drug can be affected by humidity. The bottle-cap contains a desiccant to reduce the humidity and prevent degradation of the drug. Blister packs do not have that same four month expiration because a capsule is not exposed to humidity until its own blister is opened.[35]

References[edit]

  1. ^ a b c d Pradaxa Full Prescribing Information. Boehringer Ingelheim. October 2010.
  2. ^ Eerenberg, ES; Kamphuisen, PW; Sijpkens, MK; Meijers, JC; Buller, HR; Levi, M (2011-10-04). "Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects". Circulation 124 (14): 1573–9. doi:10.1161/CIRCULATIONAHA.111.029017. PMID 21900088. Retrieved 2012-03-15. 
  3. ^ van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (Department of Drug Discovery Support, Boehringer Ingelheim Pharma) (Jun 2010). "Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity". Thrombosis and Haemostasis 103 (6): 1116–27. doi:10.1160/TH09-11-0758. PMID 20352166. Retrieved 2012-03-15. "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." 
  4. ^ Hanley JP, J P (Nov 2004). "Warfarin reversal". Journal of Clinical Pathology 57 (11): 1132–9. doi:10.1136/jcp.2003.008904. PMC 1770479. PMID 15509671. 
  5. ^ "Boehringer Ingelheim’s Investigational Antidote for Pradaxa® (dabigatran etexilate mesylate) Receives FDA Breakthrough Therapy Designation" (Press release). Ridgefield, CT: Boehringer Ingelheim’. 2014-06-26. Retrieved 2014-07-26. 
  6. ^ http://www.drugs.com/pro/pradaxa.html Pradaxa
  7. ^ ML Blommel, et al. (2011). "Dabigatran etexilate: A novel oral direct thrombin inhibitor". Am J Health Syst Pharm 68 (16): 1506–19. doi:10.2146/ajhp100348. PMID 21817082. 
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  9. ^ Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W (April 2002). "Structure-based design of novel potent nonpeptide thrombin inhibitors". J Med Chem 45 (9): 1757–66. doi:10.1021/jm0109513. PMID 11960487. Lay summary. 
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  12. ^ Chongnarungsin D; Ratanapo S; Srivali N; Ungprasert P; Suksaranjit P; Ahmed S; Cheungpasitporn W (2012). "In-Depth Review of Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation". Am. Med. J. 3 (2). doi:10.3844/amjsp.2012.100.103. 
  13. ^ Stangier J, Eriksson BI, Dahl OE, et al. (May 2005). "Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement". J Clin Pharmacol 45 (5): 555–63. doi:10.1177/0091270005274550. PMID 15831779. 
  14. ^ "Pradaxa Summary of Product Characteristics". European Medicines Agency.
  15. ^ a b Connolly, SJ; Ezekowitz, MD; Yusuf, S et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation" (PDF). N Engl J Med 361 (12): 1139–51. doi:10.1056/NEJMoa0905561. PMID 19717844. 
  16. ^ "Breakthrough therapy dabigatran provides consistent benefit across all atrial fibrillation types and stroke risk groups". Boehringer Ingelheim. Ingelheim, Germany. 4 April 2011.
  17. ^ Eikelboom, JW; Wallentin, L.; Connolly, S. J.; Ezekowitz, M.; Healey, J. S.; Oldgren, J.; Yang, S.; Alings, M. et al. (31 May 2011). "Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial". Circulation 123 (21): 2363–72. doi:10.1161/CIRCULATIONAHA.110.004747. PMID 21576658. 
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  27. ^ Shirley S. Wang (2010-09-20). "New Blood-Thinner Recommended by FDA Panel". The Wall Street Journal. Retrieved 2010-10-20. 
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  29. ^ Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK (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): 1144–50. doi:10.1161/CIR.0b013e31820f14c0. PMID 21321155. 
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  31. ^ "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". 
  32. ^ Cohen, D (July 2014). "Dabigatran: how the drug company withheld important analyses.". BMJ 349: g4670. doi:10.1136/bmj.g4670. PMID 25055829. 
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  34. ^ "Anticoagulants the leading reported drug risk in 2012". Institute for Safe Medication Practices. 2012. 
  35. ^ "Medication Guide. Pradaxa (dabigatran etexilate)". U.S. Food and Drug Administration (FDA). November 2011. Retrieved 2011-12-19. "Store PRADAXA at room temperature between 59°F to 86°F (15°C to 30°C). After opening the bottle, use PRADAXA within 4 months. Safely throw away any unused PRADAXA after 4 months." 

External links[edit]