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{{drugbox |
__NOTOC__
| IUPAC_name = Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl] carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H- benzimidazol-5-yl)carbonyl] (2-pyridinyl)amino}propanoate
| image = Dabigatran etexilate.png
| width = 135px
| CAS_number = 211915-06-9
| CAS_supplemental = 211914-51-1
| ATC_prefix =
| ATC_suffix =
| ATC_supplemental=
| PubChem = 6445226
| DrugBank =
| chemical_formula =
| C=34 | H=41 | N=7 | I= | Br= | Cl= | F= | O=5 | P= | S= | Se= | Na= | charge=
| molecular_weight = 627.734 (471.511 without etexilate)
| specific_rotation =
| sec_combustion =
| bioavailability =
| protein_bound =
| metabolism =
| elimination_half-life =
| excretion = 
| pregnancy_AU =  <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US =  <!-- A / B            / C / D / X -->
| pregnancy_category = 
| legal_AU =      <!-- Unscheduled / S2 / S3 / S4  / S8 -->
| legal_UK =      <!-- GSL        / P      / POM / CD -->
| legal_US =      <!-- OTC                  / Rx-only  -->
| legal_status =
| dependency_liability = unknown
| routes_of_administration = oral
}}
{{CMG}}.  Dr. Gibson has received research grant support from all major manufacturers of antithrombins and antiplatelets. For full disclosure information click [[C. Michael Gibson|here]].


'''''Synonyms and keywords:''''' Pradaxa, rendix
{{Dabigatran}}
{{CMG}}; {{AE}} {{SS}}


'''To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or [http://www.fda.gov/medwatch the FDA Medwatch site].'''
'''''For patient information, click [[XXXXX (patient information)|here]]'''''


==Overview==
==Overview==
Dabigatran is an [[anticoagulant]] from the class of the [[direct thrombin inhibitor]]s. It is being studied for various clinical indications, for some of which it may replace [[warfarin]] as the preferred anticoagulant. It is orally administered as the [[prodrug]] dabigatran etexilate (planned trade names Rendix and Pradaxa). It was developed by pharmaceutical company [[Boehringer-Ingelheim]].
Dabigatran is an [[anticoagulant]] from the class of the [[direct thrombin inhibitor]]s. It is being studied for various clinical indications, for some of which it may replace [[warfarin]] as the preferred anticoagulant. It is orally administered as the [[prodrug]] dabigatran etexilate (planned trade names Rendix and Pradaxa). It was developed by pharmaceutical company [[Boehringer-Ingelheim]].


==Development==
==Category==
Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to [[benzamidine]]-based thrombin inhibitor &alpha;-NAPAP (''N''-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various [[serine protease]]s, specifically thrombin but also [[trypsin]]. Addition of a hydrophobic side chain led to the orally absorbed prodrug BIBR 1048 (dabigatran etexilate).<ref>Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. ''J Med Chem'' 2002;45:1757-66. PMID 11960487.</ref><br />Phase 3 clinical trials are ongoing in treatment and prevention of secondary venous thromboembolism (VTE) in post-operative orthopedic patients (expected results by Oct 2007); long-term prophylaxis in [[acute coronary syndrome]] and [[stroke]] patients and symptomatic VTE because of various causes (expected results by 2009-2010).<ref>Currently active clinical trials of Dabigatran at ClinicalTrials.gov http://www.clinicaltrials.gov/ct/search?term=Dabigatran&submit=Search</ref>
 
==Indications==
Dabigatran is indicated in the United States for the treatment of non-valvular [[atrial fibrillation]] based upon the results of the RE-LY trial.
 
==Contraindications==
* Active pathological bleeding
* History of serious hypersensitivity reaction to PRADAXA.
 
==Dosing==
===United States===
The dose approved for use in atrial fibrillation in the United States is:
* 150 mg orally twice a day (PO bid) in patients with a CrCl > 30 ml/min
* 75 mg orally twice a day (PO bid) in patients with renal insufficiency ([[CrCl]] 15-30 ml/min).
 
Patients should be instructed not to chew, break, or open capsules. If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
 
===Canada, Japan and Most of World===
In most of the world, Pradaxa is expected to also be approved at the 110 mg dose.
 
==Storage Conditions==
* PRADAXA should be stored at room temperature between 59 and 86 degrees F (15 to 30 degrees C).
* PRADAXA comes in a bottle or in a blister package.
===The Drug is Potent for 4 months When Supplied in a Bottle===
* '''''Once the bottle is opened, PRADAXA should be used within a period of 4 months'''''. Any unused PRADAXA after '''4 months''' should be safely thrown away if it is packaged in a bottle. Blister package have a longer half life.
 
==Converting from or to Warfarin==
When converting patients from warfarin therapy to PRADAXA, discontinue [[warfarin]] and start PRADAXA when the international normalized ratio (INR) is below 2.0.
When converting from PRADAXA to [[warfarin]], adjust the starting time of [[warfarin]] based on [[creatinine clearance]] as follows:
* For [[CrCl]] >50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
* For [[CrCl]] 31-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
* For [[CrCl]] 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
* For [[CrCl]] <15 mL/min, no recommendations can be made.
Because PRADAXA can contribute to an elevated [[INR]], the [[INR]] will better reflect [[warfarin]]’s effect after PRADAXA has been stopped for at least 2 days.
 
==Converting from or to Parenteral Anticoagulants==
For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated [[heparin]]). For patients currently taking PRADAXA, wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating treatment with a parenteral anticoagulant.
 
==Monitoring==
Unlike [[coumadin]], no INR monitoring is required.


==Surgery and Interventions==
Anticoagulants:Direct thrombin (II) inhibitors
The best time to temporarily withhold Dabigatran before a surgery or an invasive procedure is dictated by two factors:
*The [[renal function]] of the patient
*The bleeding risk of the surgery.


Given the fact that Dabigatran is 80% renally excreted, renal function must be taken into consideration to decide when to stop Dabigatran preoperatively. In addition, the type of surgery and its associated risk of bleeding influence the decision on the optimal timing to stop Dabigatran. In surgeries with standard risk of bleeding, like [[hernia]] repair, Dabigatran should be stopped two to three half lives prior to the procedures allowing its level to drop to 25%. As for surgeries with high risk of bleeding where complete hemostasis may be required, as in major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, Dabigatran should be stopped four to five half lives before the surgery.<ref name="pmid22700854">{{cite journal| author=Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S et al.| title=Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. | journal=Circulation | year= 2012 | volume= 126 | issue= 3 | pages= 343-8 | pmid=22700854 | doi=10.1161/CIRCULATIONAHA.111.090464 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22700854  }} </ref>
==US Brand Names==


Dabigatran was found to have similar rates of perioperative bleeding and thrombotic complications to those of [[warfarin]]. Dabigatran has the advantages of having a predictable anticoagulation effect and a shorter half life allowing the patients to be four times more likely to undergo their surgeries or invasive procedures when needed on an urgent basis within two days of stopping Dabigatran.<ref name="pmid22700854">{{cite journal| author=Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S et al.| title=Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. | journal=Circulation | year= 2012 | volume= 126 | issue= 3 | pages= 343-8 | pmid=22700854 | doi=10.1161/CIRCULATIONAHA.111.090464 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22700854  }} </ref>
PRADAXA<sup>®</sup>


If surgery cannot be delayed, there is an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention. Bleeding risk can be assessed by the [[ecarin clotting time]] ([[ECT]]). This test is a better marker of the anticoagulant activity of dabigatran than activated [[partial thromboplastin time]] ([[aPTT]]), [[prothrombin time]] (PT)/[[INR]], or [[thrombin time]] ([[TT]]). If ECT is not available, the [[aPTT]] test provides an approximation of PRADAXA’s anticoagulant activity.
==FDA Package Insert==


;Shown below is a table summarizing the amended perioperative guidelines for management of Dabigatran for patients having surgery.<ref name="pmid22700854">{{cite journal| author=Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S et al.| title=Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. | journal=Circulation | year= 2012 | volume= 126 | issue= 3 | pages= 343-8 | pmid=22700854 | doi=10.1161/CIRCULATIONAHA.111.090464 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22700854  }} </ref>
'''| [[Dabigatran indications and usage|Indications and Usage]]'''
{|class="wikitable" border="1"
'''| [[Dabigatran dosage and administration|Dosage and Administration]]'''
|-align="left"
'''| [[Dabigatran dosage forms and strengths|Dosage Forms and Strengths]]'''
|colspan="2"|
'''| [[Dabigatran contraindications|Contraindications]]'''
|colspan="2"|'''Time to Stop Dabigatran Before a Surgery or a Procedure'''
'''| [[Dabigatran warnings|Warnings and Precautions]]'''
|-align="center"
'''| [[Dabigatran adverse reactions|Adverse Reactions]]'''
|'''Renal Function Impairement'''
'''| [[Dabigatran drug interactions|Drug Interactions]]'''
'''| [[Dabigatran use in specific populations|Use in Specific Populations]]'''
'''| [[Dabigatran overdosage|Overdosage]]'''
'''| [[Dabigatran description|Description]]'''
'''| [[Dabigatran clinical pharmacology|Clinical Pharmacology]]'''
'''| [[Dabigatran nonclinical toxicology|Nonclinical Toxicology]]'''
'''| [[Dabigatran clinical studies|Clinical Studies]]'''
'''| [[Dabigatran how supplied storage and handling|How Supplied/Storage and Handling]]'''
'''| [[Dabigatran patient counseling information|Patient Counseling Information]]'''
'''| [[Dabigatran labels and packages|Labels and Packages]]'''


'''Creatinine Clearance (mL/min)'''
==Mechanism of Action==
 
|'''Estimated Half Life'''
'''Range (hours)'''
|'''High Risk for Bleeding'''
|'''Standard Risk for Bleeding'''
|-align="center"
|Mild (≥50-80)
|15 (12-18)
|2-3 days
|24 hours (2 doses)
|-align="center"
|Moderate (≥30 to <50)
|18 (18-24)
|4 days
|At least 2 days (48 hours)
|-align="center"
|Severe (<50)
|27 (>24)
|>5 days
|2-4 days
|}
 
==WARNINGS AND PRECAUTIONS==
*Risk of bleeding: PRADAXA can cause serious and, sometimes, fatal bleeding. Promptly evaluate signs and symptoms of blood loss.
*Risk of ACS or MI
*Temporary discontinuation: Avoid lapses in therapy to minimize risk of stroke
*P-gp inducers and inhibitors: Avoid coadministration of rifampin with PRADAXA because of effects on dabigatran exposure
 
===Risk of Bleeding===
PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that increase the risk of bleeding in general (e.g., [[anti-platelet]] agents, [[heparin]], [[fibrinolytic]] therapy, and chronic use of [[NSAID]]s) and labor and delivery. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in [[hemoglobin]] and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding.
 
In the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, a life-threatening bleed (bleeding that met one or more of the following criteria: fatal, symptomatic intracranial, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention) occurred at an annualized rate of 1.5% and 1.8% for PRADAXA 150 mg and warfarin, respectively.
 
===Risk of ACS or MI===
The results of RE-LY study<ref name="pmid19717844">{{cite journal |author=Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L |title=Dabigatran versus warfarin in patients with atrial fibrillation |journal=[[The New England Journal of Medicine]] |volume=361 |issue=12 |pages=1139–51 |year=2009 |month=September |pmid=19717844 |doi=10.1056/NEJMoa0905561 |url=http://dx.doi.org/10.1056/NEJMoa0905561 |accessdate=2012-01-12}}</ref> demonstrates that the use of dabigatran is significantly increases the risk of [[MI]] or [[ACS]](dabigatran:1.19% vs control:0.79%; odds ratio [ORM-H]: 1.33; 95% CI, 1.03-1.71; P = 0.03. A meta analysis of seven trials(N = 30 514): 2 studies of stroke prophylaxis in [[atrial fibrillation]], 1 in acute venous thromboembolism, 1 in ACS, and 3 of short-term prophylaxis of [[deep venous thrombosis]] demonstrated similar trends and were consistent using different methods and measures of association<ref name="pmid22231617">{{cite journal |author=Uchino K, Hernandez AV |title=Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials |journal=[[Archives of Internal Medicine]] |volume= |issue= |pages= |year=2012 |month=January |pmid=22231617 |doi=10.1001/archinternmed.2011.1666 |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=22231617 |accessdate=2012-01-12}}</ref>. Further investigations are required in assessing the cardiac risk of dabigatran in patients with high risk of ACS or MI.
 
===Temporary Discontinuation of PRADAXA===
Discontinuing anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of [[stroke]]. Lapses in therapy should be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.
 
===Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure===
The concomitant use of PRADAXA with P-gp inducers (e.g., [[rifampin]]) reduces exposure to dabigatran and should generally be avoided. P-gp inhibitors [[ketoconazole]], [[verapamil]], [[amiodarone]], [[quinidine]], and [[clarithromycin]] do not require dose adjustments. These results should not be extrapolated to other Pgp
inhibitors.
 
==Adverse Reactions==
===Gastrointestinal Adverse Reactions===
Patients on PRADAXA 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly [[dyspepsia]] (including [[abdominal pain]] upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including [[GERD]], esophagitis, erosive [[gastritis]], gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).
 
===Hypersensitivity Reactions===
In the RE-LY study, drug hypersensitivity (including [[urticaria]], [[rash]], and [[pruritus]]), allergic [[edema]], [[anaphylactic reaction]], and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA.
 
==Use in Specific Populations==
===Pregnancy===
Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg/kg (about 2.6 to 3.0 times the human exposure at maximum recommended human dose [MRHD] of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation(gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat, it did not induce major malformations in rats or rabbits.
 
===Labor and Delivery===
Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials. Consider the risks of bleeding and of stroke in using PRADAXA in this setting. Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation (gestation Day 7) to
weaning (lactation Day 21) with dabigatran at a dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of 300 mg/day based on AUC comparisons).
 
===Nursing Mothers===
It is not known whether dabigatran is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PRADAXA is administered to a nursing woman.
 
===Pediatric Use===
Safety and effectiveness of PRADAXA in pediatric patients has not been established.
 
===Geriatric Use===
Of the total number of patients in the RE-LY study, 82% were 65 and over, while 40% were 75 and over. The risk of stroke and bleeding increases with age, but the risk-benefit profile is favorable in all age groups.
 
===Renal Impairment===
No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment. Reduce the dose of PRADAXA in patients with severe renal impairment (CrCl 15-30 mL/min). ''Dosing recommendations for patients with CrCl <15 mL/min or on dialysis cannot be provided.''
 
==Overdosage==
Accidental overdose may lead to hemorrhagic complications. There is no antidote to dabigatran etexilate or dabigatran. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with PRADAXA, and investigate the source of bleeding. Dabigatran is primarily excreted in the urine; therefore, maintain adequate [[diuresis]]. Dabigatran can be [[dialyzed]] (protein binding is low), with the removal of about 60% of drug over 2 to 3 hours; however, data supporting this approach are limited. Consider surgical hemostasis or the transfusion of [[fresh frozen plasma]] or red blood cells. There is some experimental evidence to support the role of activated prothrombin complex concentrates (e.g., [[FEIBA]]), or [[recombinant Factor VIIa]], or concentrates of coagulation factors II, IX or X; however, their usefulness in clinical settings has not been established. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used. Measurement of [[aPTT]] or [[ECT]] may help guide therapy.
 
==[[Clinical Pharmacology of Dabigatran]]==
 
==[[FDA Review of Data From the RE-LY Trial on September 20th, 2010]]==
 
 
 
==[[A comparison of the RE-LY and Rocket AF Trials]]==
 
==[[Estimates of Cost Per Year of Life Saved for Dabigatran]]==


==References==
==References==
<references/>


{{Antithrombotics}}
{{Reflist|2}}




[[Category:Amidines]]
[[Category:Direct thrombin (II) inhibitors]]
[[Category:Anticoagulants]]
[[Category:Anticoagulants]]
[[Category:Benzimidazoles]]
[[Category:Cardiovascular Drugs]]
[[Category:Drugs]]
[[Category:Cardiology]]
 
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Revision as of 14:57, 31 January 2014


Dabigatran
Black Box Warning
Adult Indications and Dosage
Pediatric Indications and Dosage
Contraindications
Warnings
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration and Monitoring
IV Compatibility
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient information
Precautions with Alcohol
Brand Names
Look-Alike Drug Names
Drug Shortage Status
Price

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

For patient information, click here

Overview

Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications, for some of which it may replace warfarin as the preferred anticoagulant. It is orally administered as the prodrug dabigatran etexilate (planned trade names Rendix and Pradaxa). It was developed by pharmaceutical company Boehringer-Ingelheim.

Category

Anticoagulants:Direct thrombin (II) inhibitors

US Brand Names

PRADAXA®

FDA Package Insert

| Indications and Usage | Dosage and Administration | Dosage Forms and Strengths | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Use in Specific Populations | Overdosage | Description | Clinical Pharmacology | Nonclinical Toxicology | Clinical Studies | How Supplied/Storage and Handling | Patient Counseling Information | Labels and Packages

Mechanism of Action

References

Template:WikiDoc Sources

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