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DABIGATRAN(PRADAXA)

OBJECTIVE:
Toprovideanoverviewofthemechanismofaction,licensedindications,dosingregimens,andside
effectsofdabigatran.

MECHANISMOFACTION:
Dabigatranisanoraldirectthrombin(factorIIa)inhibitor.Bybindingreversiblytotheactivesiteof
thrombin,dabigatranattenuatesthrombinactivityandreducesfibrinformation.

INDICATIONS:
DabigatraniscurrentlylicensedinCanadaforthefollowingindications:
Preventionofdeepveinthrombosis(DVT)andpulmonaryembolism(PE)afterelectivehiporknee
replacementsurgery.
Preventionofstrokeandsystemicembolisminpatientswithnonvalvularatrialfibrillationwho
arecandidatesfororalanticoagulationtherapy.
TreatmentofacuteDVTandPEinpatientswhohaveinitiallyreceived5to10daysofaparenteral
anticoagulantandpreventionofrecurrentDVTandPE.

DOSING:
a) Thromboprophylaxisafterorthopedicsurgery:startwith110mg14hoursaftersurgeryand
increaseto220mgoncedaily(OD)startingthedayaftersurgery;the220mgODdoseis
continuedforatleast14daysandupto35days.
b) Strokepreventioninatrialfibrillation:110mgtwicedaily(BID)or150mgBID.Patientsaged80
yearsandolder,orover75yearsoldwith1riskfactorforbleedingshouldbetreatedwithadose
of110mgBID.Allotherpatientsshouldreceive150mgBID.Thereisnorecommendeddose
adjustmentforpatientswithmoderaterenalimpairment(creatinineclearance[CrCl]30to50
mL/min).DabigatraniscontraindicatedinpatientswithaCrCl<30mL/min.
c) TreatmentofDVTandPE:Dabigatran150mgBIDisstartedafter5to10daysofinitialtreatment
withaparenteralanticoagulant.Thereisnorecommendeddoseadjustmentinpatientswith
moderaterenalimpairment(CrCl30to50mL/min).Thereduceddoseof110mghasneverbeen
evaluatedinaVTEtreatmentclinicaltrial.
DabigatranshouldnotbeusedinpatientswithaCrCl<30mL/min,womenwhoare
pregnantorarebreastfeeding,orinpatientswithactivecancer.

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MONITORING:
Routinelaboratorymonitoringoftheanticoagulantresponseisunnecessary.Theprothrombin
time/internationalnormalizedratio(PT/INR)doesnotprovideareliablemeasureofitsanticoagulant
activity.Theactivatedpartialthromboplastintime(aPTT)isprolongedbydabigatranbutthe
responsivenessofthetestisreagentdependentandthevaluesplateauwithhigherdabigatran
concentrations.Nonetheless,aprolongedaPTTindicatesthepresenceofdabigatranandanormal
testrendershighdabigatranlevelsunlikely.Thethrombinclottingtime(TCT)isthemostsensitive
assayforthepresenceofdabigatran.Itisalwaysprolongedinthepresenceofdabigatranbutit
shouldnotbeusedtomonitortheanticoagulantactivity.Thedilutethrombinclottingtime
(commerciallyavailableastheHemoclotassay)showsalinearresponsewithdabigatranplasma
concentration.Theecarinclottingtimeorchromogenicassayalsoexhibitsalinearresponsewith
dabigatranconcentrations.Neithertestiswidelyavailableandatherapeuticrangehasnotbeen
established.(SeetheClinicalGuide:New/NovelOralAnticoagulants(NOACs):CoagulationTests).
Althoughnoroutinelaboratorymonitoringisrequiredforlongtermdabigatranuse,periodicclinical
assessmentisimportanttodetermineandreinforceadherence,reviewcomorbidityandprovide
education.Furthermore,formostpatients,atleastyearlyassessmentofcreatinineclearanceis
recommended.Thecreatinineshouldbemeasuredmorefrequentlyinpatientswithanabnormal
valueatbaseline.

ADVERSEEFFECTS:
Themajoradverseeffectofdabigatranisbleeding;concomitantuseofantiplateletdrugsincreases
thisrisk.Dabigatranshouldbeavoidedinpatientswithindwellingepiduralcathetersortraumatic
spinalpuncturesinordertoreducetheriskofepiduralorspinalhematomas.Dabigatranmaybe
associatedwithdyspepsiainupto10%ofusers;thefrequencyofthiscomplicationcanbereducedby
havingpatientstakethedrugwithmeals.Dyspepsiausuallyresolveswithtimeandmayimprovewith
theuseofanantiulcermedicationsuchasaprotonpumpinhibitor,butcautionisadvisedasthe
absorptionofdabigatranisdecreasedwhencoadministeredwithaluminum,magnesiumorcalcium
containingantacids.

PERIPROCEDURALMANAGEMENT:
SeeClinicalGuide:New/NovelOralAnticoagulants(NOAC):PeriOperativeManagement

SPECIALCONSIDERATIONS:
Administrationandstorage:Dabigatranmaybetakenwithorwithoutfood.Capsulesshouldbe
swallowedwhole.Thecapsuleshouldnotbecrushed,chewedoropenedbeforeswallowing.Capsules
shouldbestoredintheirblisterpackagetoprotectthemfrommoisture.
Bleeding:Idarucizumab,ahumanizedantibodyfragmentagainstdabigatran,isnowavailableasan
antidotefordabigatran.Idarucizumab,whichisgivenasanintravenousbolusatadoseof5grams,

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rapidlyreversestheanticoagulanteffectofdabigatran.Approachestothemanagementofbleeding
canbefoundintheClinicalGuide:New/NovelOralAnticoagulants(NOACs):Managementof
Bleeding.
DrugInteractions:DabigatranabsorptionisdecreasedbyagentsthatincreasegastricpH(i.e.
magnesiumoraluminumcontainingantacids);howeverthereisnocontraindicationtoconcurrent
useofprotonpumpinhibitors.
Selectiveserotoninreuptakeinhibitors(SSRIs)increasedbleedingby50to100%andselective
serotoninnorepinephrinereuptakeinhibitors(SNRIs)increasedbleedingby100%inatrialfibrillation
patientsintheRELYtrial.Concomitantuseofthesedrugsshouldbeavoided.
BecausedabigatranetexilateisasubstrateofthePglycoproteintransportsystem,potentinhibitors
orinducersareexpectedtoimpactexposuretodabigatran.
a)InhibitorsofPglycoprotein:Drugsthatinhibitthistransportsystemcanincreasesystemicexposure
todabigatran.ConcomitantuseofthestrongPglycoproteininhibitors(e.g.ketoconazole,
dronedarone)iscontraindicated.Cautionisadvisediftakenwithmoderateinhibitors(e.g.
cyclosporine,itraconazole,ritanovir,andtacrolimus).PatientswhoaretakingthePglycoprotein
inhibitorsquinidineandverapamil,thelatterofwhichiscommonlyusedinpatientswithatrial
fibrillation,shouldtakethedabigatrandose2hourspriortoadoseofverapamilorquinidine.No
dosageadjustmenttodabigatranisrecommendedforpatientsconcurrentlytakingtheseinteracting
medicationsforatrialfibrillationorVTEtreatment,butdosereductionto150mgoncedailyis
recommendedbythemanufacturerforthromboprophylaxisinhiporkneereplacement.
b)InducersofPglycoprotein:DrugsthatinducePglycoproteincandecreasethesystemicexposure
todabigatran.Coadministrationwithpotentinducerssuchascarbamazepine,phenytoin,rifampin
andSaintJohnswort,shouldbeavoided.
Renalandhepaticdysfunction:DabigatraniscontraindicatedinpatientswithCrCl<30mL/min.Dose
modificationisnotneededinpatientswithhepaticimpairmentbutdabigatranshouldbeusedwith
cautioninthosewithcirrhosisorbaselinecoagulopathywhoareathighriskofbleeding.
Mechanicalheartvalves:Dabigatraniscontraindicatedinpatientswithmechanicalheartvalves.
Pregnancyandbreastfeeding:Dabigatrancrossestheplacentaandshouldnotbeusedinpregnancy.
Itisunknownwhetherdabigatranpassesintothebreastmilk;therefore,dabigatranshouldnotbe
usedinnursingmothers.
Pediatrics:Dabigatranisnotrecommendedforuseinchildrenuntilongoingstudiesestablishthe
pharmacokinetics,pharmacodynamics,safety,andefficacyofdabigatraninneonatesandchildren.

OTHERRELEVANTTHROMBOSISCANADACLINICALGUIDES:

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New/NovelOralAnticoagulants(NOACs):ComparisonandFrequentlyAskedQuestions
New/NovelOralAnticoagulants(NOACs):CoagulationTests
New/NovelOralAnticoagulants(NOACs):ManagementofBleeding
New/NovelOralAnticoagulants(NOACs):PeriOperativeManagement
Pediatrics:NewAnticoagulants
StrokePreventioninAtrialFibrillation
Thromboprophylaxis:OrthopedicSurgery

REFERENCES:
BoehringerIngelheimCanadaLtd.Pradaxa(DabigatranEtexelate)ProductMonographRevised24
June2014.
ConnollySJ,etal.Dabigatranversuswarfarininpatientswithatrialfibrillation.NEnglJMed
2009;361(12):11391351.
ErikssonBI,etal.Dabigatranetexilateversusenoxaparinforpreventionofvenousthromboembolism
aftertotalhipreplacement:arandomised,doubleblind,noninferioritytrial.Lancet
2007;370(9591):949956.
ErikssonBI,etal.Oraldabigatranetexilatevs.subcutaneousenoxaparinforthepreventionofvenous
thromboembolismaftertotalkneereplacement:theREMODELrandomizedtrial.JThrombHaemost
2007;5(11):21782185.
SchulmanS,CrowtherMA.HowItreatwithanticoagulantsin2012:newandoldanticoagulants,and
whenandhowtoswitch.Blood2012;119(13):30163023.
SchulmanS,etal.Dabigatranversuswarfarininthetreatmentofacutevenousthromboembolism.N
EnglJMed2009;361(24):23422352.

DateofVersion:2015Oct10

Pleasenotethattheinformationcontainedhereinisnottobeinterpretedasanalternativetomedicaladvice
from your doctor or other professional healthcare provider. If you have any specific questions about any
medical matter, you should consult your doctor or other professional healthcare providers, and as such you
shouldneverdelayseekingmedicaladvice,disregardmedicaladviceordiscontinuemedicaltreatmentbecause
oftheinformationcontainedherein.

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