Dabigatran
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| 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 |
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| 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  |
| ChEMBL | CHEMBL539697 |
| Chemical data | |
| Formula | C34H41N7O5 |
| Mol. mass | 627.734 g/mol |
| SMILES | eMolecules & PubChem |
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| Systematic (IUPAC) name | |
| 3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid | |
| Clinical data | |
| Pregnancy cat. | ? |
| Legal status | ? |
| Identifiers | |
| CAS number | 211914-51-1  |
| ATC code | ? |
| PubChem | CID 216210 |
| ChemSpider | 187412 |
| UNII | I0VM4M70GC |
| KEGG | D09707 |
| ChEMBL | CHEMBL48361 |
| Chemical data | |
| Formula | C25H25N7O3 |
| Mol. mass | 471.511 g/mol |
| SMILES | eMolecules & PubChem |
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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, unlike warfarin. It was developed by the pharmaceutical company Boehringer Ingelheim.
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[edit] Medical uses
Dabigatran is used to prevent strokes in those with atrial fibrillation due to non heart valve causes.[2]
[edit] Adverse effects
The most commonly reported side effect of dabigatran is GI upset. When compared to patients anticoagulated with warfarin, patients taking dabigatran had life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of GI bleeding was slightly 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.[3]
A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[4]
[edit] Development
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 a the ethyl ester and hexyloxycarbonyl carbamimide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).[5]
[edit] Dosing
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.[6] 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.[7]
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.[8] Drug excretion through p-glycoprotein pumps is slowed in patients taking strong p-gp pump inhibitors such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran.[9]
[edit] Major trials
[edit] RE-LY study
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.[10][11]
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.[12]
[edit] RE-COVER
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.[13]
[edit] Approval and indications
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.[14]
The National Health Service in Britain authorised the use of dabigatran for use in preventing blood clots in hip and knee surgery patients. The British Heart Foundation is campaigning[when?] for the drug to be widely prescribed in place of warfarin, which has the disadvantage of requiring administration up to a week before a target INR level is reached, and heparin, which is administered intravenously or subcutaneously in its low molecular weight form. Dabigatran will[when?] cost the NHS £4.20 per day, which is equivalent to several other anticoagulants,[15] but more than ten times the cost of warfarin. However, the total cost of warfarin use includes the time and cost of INR monitoring which is not required with dabigatran.
Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[16] 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.[17][18]
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.[19][10][20][21] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[22] although caution is still urged by reviewers.[23]
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.[24]
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. [25]
[edit] Expiration of capsules
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 dessicant to reduce the humidity and prevent degradation of the drug. Blister pack do not have that same four month expiration because a capsule is not exposed to humidity until its own blister is opened.[26]
[edit] References
- ^ a b c d Pradaxa Full Prescribing Information. Boehringer Ingelheim. October 2010.
- ^ http://www.drugs.com/pro/pradaxa.html Pradaxa
- ^ ML Blommel, et al. (2011). "Dabigatran etexilate: A novel oral direct thrombin inhibitor". Am J Health Syst Pharm 68(16): 1506-19. PMID 21817082.
- ^ Uchino K, Hernandez AV (2012). "Dabigatran associated with higher risk of acute coronary events - meta-analysis of noninferiority randomized controlled trials". Arch. Intern. Med. Online first. doi:10.1001/archinternmed.2011.1666. http://archinte.ama-assn.org/cgi/content/full/archinternmed.2011.1666.
- ^ 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.
- ^ Eriksson BI, Dahl OE, Büller HR, et al. (January 2005). "A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial". J. Thromb. Haemost. 3 (1): 103–11. doi:10.1111/j.1538-7836.2004.01100.x. PMID 15634273.
- ^ Eriksson BI, Dahl OE, Rosencher N, et al. (September 2007). "Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial". Lancet 370 (9591): 949–56. doi:10.1016/S0140-6736(07)61445-7. PMID 17869635.
- ^ 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.
- ^ "Pradaxa Summary of Product Characteristics". European Medicines Agency.
- ^ 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. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0905561.
- ^ "Breakthrough therapy dabigatran provides consistent benefit across all atrial fibrillation types and stroke risk groups". Boehringer Ingelheim. Ingelheim, Germany. 4 April 2011.
- ^ Eikelboom, JW (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. http://circ.ahajournals.org/cgi/content/full/123/21/2363.
- ^ Schulman S, Kearon C, Kakkar AK, et al. (December 2009). "Dabigatran versus warfarin in the treatment of acute venous thromboembolism" (PDF). N Engl J Med 361 (24): 2342–52. doi:10.1056/NEJMoa0906598. PMID 19966341. http://www.nejm.org/doi/pdf/10.1056/NEJMoa0906598.
- ^ "Pradaxa EPAR". European Medicines Agency. http://www.emea.europa.eu/ema/humandocs/Humans/EPAR/pradaxa/pradaxa.htm. Retrieved 2011-01-30.
- ^ "Clot drug 'could save thousands'". BBC News Online. 2008-04-20. http://news.bbc.co.uk/1/hi/health/7354818.stm. Retrieved 2008-04-21.
- ^ "Summary Basis of Decision (SBD): Pradax" Health Canada. 2008-11-06.
- ^ Kirkey, Sharon (29 October 2010). "Approval of new drug heralds 'momentous' advance in stroke prevention". Montreal Gazette. http://www.montrealgazette.com/health/Approval+drug+heralds+momentous+advance+stroke+prevention/3739714/story.html. Retrieved 29 October 2010.
- ^ "Pradax (Dabigatran Etexilate) Gains Approval In Canada For Stroke Prevention In Atrial Fibrillation" Medical News Today. 28 October 2010.
- ^ Turpie AG (January 2008). "New oral anticoagulants in atrial fibrillation". Eur Heart J 29 (2): 155–65. doi:10.1093/eurheartj/ehm575. PMID 18096568.
- ^ "Boehringer wins first US OK in blood-thinner race". Thomson Reuters. 2010-10-19. http://www.reuters.com/article/2010/10/19/boehringer-pradaxa-idUSN1916563620101019. Retrieved 2010-10-20.
- ^ "FDA approves Pradaxa to prevent stroke in people with atrial fibrillation". U.S. Food and Drug Administration (FDA). 2010-10-19. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm230241.htm.
- ^ Shirley S. Wang (2010-09-20). "New Blood-Thinner Recommended by FDA Panel". The Wall Street Journal. http://blogs.wsj.com/health/2010/09/20/new-blood-thinner-recommended-by-fda-panel/. Retrieved 2010-10-20.
- ^ 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". Ann Surg 250 (2): 219–28. doi:10.1097/SLA.0b013e3181ae6dbe. PMID 19638915.
- ^ 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.
- ^ "FDA Investgating Serious Bleeding Events with Dabigatran". Medscape. 2011-12-7. http://www.medscape.com/viewarticle/754953?sssdmh=dm1.740495&src=nl_newsalert.
- ^ "Medication Guide. Pradaxa (dabigatran etexilate)". U.S. Food and Drug Administration (FDA). November 2011. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM231720.pdf. Retrieved 12/19/2011. "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."
[edit] External links
- Pradaxa.com. Boehringer Ingelheim.
- dabigatran.com. Boehringer Ingelheim.
- Pradaxa For U.S. Health Care Professionals. Boehringer Ingelheim.
- Pradaxa Prescribing Information. Boehringer Ingelheim.
- Pradaxa Medication Guide. Boehringer Ingelheim.
- Dabigatran. MedlinePlus. United States National Library of Medicine (NLM).
- Dabigatran. Drug Information Portal. United States National Library of Medicine (NLM).
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