Dabigatran

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Dabigatran etexilate
Dabigatran etexilate structure.svg
Systematic (IUPAC) name
Ethyl N-[(2-{[(4-{N '​-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-N-2-pyridinyl-β-alaninate
Clinical data
Trade names Pradaxa, Pradax, Prazaxa
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
Bioavailability 3–7%[1]
Protein binding 35%[1]
Half-life 12–17 hours[1]
Identifiers
CAS number 211915-06-9 N
ATC code B01AE07
PubChem CID 6445226
DrugBank DB06695
ChemSpider 4948999 YesY
ChEMBL CHEMBL539697 YesY
Chemical data
Formula C34H41N7O5 
Mol. mass 627.734 g/mol
 N (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, Canada, Europe and USA, 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, as well as deep venous thrombosis (DVT) and pulmonary embolism (PE) in persons who have been treated for 5-10 days with parenteral anticoagulant (usually low molecular weight heparin), and to prevent DVT and PE in some circumstances.[6]

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.[7] Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g. anaphylaxis or anaphylactic shock).[7] The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valve 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.[7][8][9]

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.[10]

A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[11]

Pharmacology[edit]

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]


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).[15]

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.[16]

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,.[17]

Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[18] 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.[19][20]

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.[21][22][23][24] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[25] although caution is still urged by some outside experts.[26]

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.[27]

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.[28] 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 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 Agency reiterated its opinion that dabigatran's overall risk/benefit ratio is favorable.[29]

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. [30] [31]

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. [32]

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." 
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External links[edit]