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Dabigatran

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{{drugbox | verifiedrevid = 407639691 | drug_name = Dabigatran etexilate | IUPAC_name = Ethyl 3-{[(2-{[(4-{N'-hexyloxycarbonyl carbamimidoyl}phenyl)amino]methyl}-1- methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate | image = Dabigatran etexilate structure.svg | width = 135 | tradename = Pradaxa, Pradax, Prazaxa | ChemSpiderID_Ref =  checkY | ChemSpiderID = 4948999 | InChI = 1/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) | smiles = O=C(OCC)CCN(c1ncccc1)C(=O)c4ccc2c(nc(n2C)CNc3ccc(C(=N\C(=O)OCCCCCC)\N)cc3)c4 | InChIKey = KSGXQBZTULBEEQ-UHFFFAOYAL | ChEMBL_Ref =  checkY | ChEMBL = 539697 | StdInChI_Ref =  checkY | StdInChI = 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) | StdInChIKey_Ref =  checkY | StdInChIKey = KSGXQBZTULBEEQ-UHFFFAOYSA-N | CAS_number = 211915-06-9 | ATC_prefix = B01 | ATC_suffix = AE07 | ATC_supplemental= | PubChem = 6445226 | DrugBank = DB06695 | chemical_formula = | C=34 | H=41 | N=7 | O=5 | molecular_weight = 627.734 g/mol | specific_rotation = | sec_combustion = | bioavailability = 3–7%[1] | protein_bound = 35%[1] | metabolism = | elimination_half-life = 12–17 hours[1] | excretion = | pregnancy_AU = | pregnancy_US = C | pregnancy_category = | legal_AU = | legal_CA = Schedule VI | legal_UK = POM | legal_US = Rx-only | legal_status = | dependency_liability = | routes_of_administration = oral | licence_EU = Pradaxa | licence_US = Dabigatran | MedlinePlus = a610024 }}

Dabigatran
Identifiers
  • 3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC25H25N7O3
Molar mass471.511 g/mol g·mol−1
3D model (JSmol)
  • Cn1c(CNc2ccc(cc2)C(=N)N)nc3cc(ccc13)C(=O)N(CCC(=O)O)c4ccccn4
  • 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) checkY
  • Key:KSGXQBZTULBEEQ-UHFFFAOYSA-N checkY
 ☒NcheckY (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] It was developed by the pharmaceutical company Boehringer Ingelheim.

Medical uses

Dabigatran is used to prevent strokes in those with atrial fibrillation due to non heart valve causes, and at least 1 additional risk factor for stroke [5] and to prevent the formation of blood clots in the veins in adults who have had an operation to replace a hip or knee.[6]

Adverse effects

The most common side effect with Pradaxa (seen in more than one patient in 10) is bleeding.[7]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 higher, mostly in older patients over 75 years. 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.[8]

A significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[9]

Comparing risks of warfarin to dabigatran: total bleeding risks are equal if INR control is adequate, but in the Re-Ly trial warfarin had more risk of intracranial bleeding (Absolute Risk Reduction 1% for dabigatran)and hospitalizations (ARR 1,6 % for dabigatran), and dabigatran had more risk of heart attack (Absolute Risk Increase 0.4%), gastrointestinal bleeding (ARI 0.6%) and withdrawal because of serious adverse effect (ARI 1%) or withdrawal because of any adverse effect (ARI 4.1%).[10]. The most frequent adverse reactions leading to discontinuation of Pradaxa were bleeding and gastrointestinal events.[11]

Contraindications

Dabigatran is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min),to minimise the risk of bleeding. A dose reduction and close clinical surveillance should be considered in patients with moderate renal impairment (creatinine clearance 30–50 mL/min), particularly in those at increased risk of bleeding. Similar precautions are recommended for patients older than 75 years. [12] Dabigatran is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to Dabigatran. The concomitant use of Pradaxa and P-gp inhibitors (ketaconazole, amiodarone,verapamil, quinidine, chlarithromycin) in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided. [13] Pradaxa must not be used in patients taking by mouth or injection the medicines against fungal infections ketoconazole and itraconazole or the immunosuppressant medicines cyclosporine and tacrolimus.[14]

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 ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).[15]

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.[16] 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.[17]

Dabigatran has a half-life of approximately 12-14 h and exert a maximum anticoagulation effect within 2-3 h after ingestion.[18] 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.[19] 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.[20]

Major trials

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. Analyses by EMA demonstrated that the benefits observed in the comparison of dabigatran to warfarin diminished if INR control was good, with time in therapeutic range TTR >70%.[21]
Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg showed similar bleeding to warfarin.[22][23] The global INR control in RELY, although being comparable to contemporary trials in this indication, was not optimal from a Northern/Western European standard. When mayor bleeding events were analysed by time in therapeutic range (TTR) the outcome of warfarin treatment for the overall population improved with increasing TTR. For centres with TTR ≥ 70% (like Western-Europe) the mayor bleeding events rates were marginally higher for Dabigatran 150 bid vs. warfarin.[24] Intracranial hemorrhages were significantly fewer with dabigatran compared to warfarin. But in Re-Ly there was an unusually high incidence of intracranial hemorrhages by warfarin. The rate was 0.76% per year, what is much more than meta analyses from cochrane 0.3% and 0.45% or individual trials 0.53% in SPORTIF III, 0.28% in SPORTIF V. [25] 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.[26]
There was a trend to decreased mortality with dabigatran compared to warfarin. The FDA clinical reviewer found that the trend toward increased mortality with warfarin was entirely due to investigator sites where INR monitoring was inferior. At sites where INR was within therapeutic range ≥ 67% of the time, relative risk for mortality (RR 1.05) favoured warfarin over dabigatran.[27][28]
There were significantly more withdrawals with dabigatran due to serious adverse events and to any adverse event compared to warfarin. There were significantly more adverse events with dabigatran compared to warfarin. Absolute numbers of serious adverse events were not reported. [29]

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.[30]

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 [31] It was approved for use in patients with non-valvular atrial fibrillation in the EU in August 2011.[32]

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,[33] 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,[34] 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.[35][36]

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.[37][22][38][39] The approval came after an advisory committee recommended the drug for approval on September 20, 2010[40] although caution is still urged by reviewers.[41]

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.[42]

Pharmacovigilance

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. [43]
The Therapeutic Goods Administration in Australia published a Safety Advisory on 3 November 2011 regarding the risk of bleeding in people using dabigatran. The analysis of these reports shows that some of the bleeding adverse events occurred during the transition from warfarin to dabigatran; many of the adverse events are occurring in patients on the reduced dosage regimen; and the most common site of serious bleeding for dabigatran is the gastrointestinal tract, whereas for warfarin it is intracranial. Risk factors for bleeding are: age ≥ 75 years, moderate renal impairment (30-50 mL/min) - severe renal impairment is a contraindication, concomitant use of aspirin (approximately twice the risk), clopidogrel (approximately twice the risk), non-steroidal anti-inflammatory drugs including COX-2 inhibitors. [44]

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 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.[45]

References

  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, 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ van Ryn J, Stangier J, Haertter S; et al. (2010 Jun). "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. {{cite journal}}: Check date values in: |date= (help); Cite uses deprecated parameter |authors= (help); Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  4. ^ Hanley JP, J P (2004 Nov). "Warfarin reversal". Journal of Clinical Pathology. 57 (11): 1132–9. doi:10.1136/jcp.2003.008904. PMC 1770479. PMID 15509671. {{cite journal}}: Check date values in: |date= (help)
  5. ^ http://www.drugs.com/pro/pradaxa.html Pradaxa
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  7. ^ Prdaxa http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&mid=WC0b01ac058001d124]%20and%20to%20http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000829/WC500130142.pdf
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  14. ^ Pradaxa http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&mid=WC0b01ac058001d124]%20and%20to%20http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000829/WC500130142.pdf
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  21. ^ EPAR - Assessment Report - 23/08/2011 P52 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000829/human_med_000981.jsp&mid=WC0b01ac058001d124
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  23. ^ "Breakthrough therapy dabigatran provides consistent benefit across all atrial fibrillation types and stroke risk groups". Boehringer Ingelheim. Ingelheim, Germany. 4 April 2011.
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  31. ^ "Pradaxa EPAR". European Medicines Agency. Retrieved 2011-01-30.
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  33. ^ "Clot drug 'could save thousands'". BBC News Online. 2008-04-20. Retrieved 2008-04-21.
  34. ^ "Summary Basis of Decision (SBD): Pradax" Health Canada. 2008-11-06.
  35. ^ Kirkey, Sharon (29 October 2010). "Approval of new drug heralds 'momentous' advance in stroke prevention". Montreal Gazette. Retrieved 29 October 2010.
  36. ^ "Pradax (Dabigatran Etexilate) Gains Approval In Canada For Stroke Prevention In Atrial Fibrillation" Medical News Today. 28 October 2010.
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  38. ^ "Boehringer wins first US OK in blood-thinner race". Thomson Reuters. 2010-10-19. Retrieved 2010-10-20.
  39. ^ "FDA approves Pradaxa to prevent stroke in people with atrial fibrillation". U.S. Food and Drug Administration (FDA). 2010-10-19.
  40. ^ 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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  43. ^ "FDA Investgating Serious Bleeding Events with Dabigatran". Medscape. 2011-12-7. {{cite news}}: Check date values in: |date= (help)
  44. ^ Dabigatran (Pradaxa) and the risk of bleeding http://www.tga.gov.au/hp/msu-2011-06.htm#pradaxa
  45. ^ "Medication Guide. Pradaxa (dabigatran etexilate)" (PDF). U.S. Food and Drug Administration (FDA). November 2011. 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. {{cite web}}: Check date values in: |accessdate= (help)
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