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INDICATIONS INDICATIONSAND ANDUSAGE USAGE Pradaxa Pradaxa®®(dabigatran (dabigatranetexilate etexilatemesylate) mesylate)capsules capsulesisisindicated: indicated: •• totoreduce reducethe therisk riskof ofstroke strokeand andsystemic systemicembolism embolismininpatients patientswith with non-valvular non-valvularatrial atrialfifibrillation brillation IMPORTANT IMPORTANTSAFETY SAFETYINFORMATION INFORMATION WARNING: WARNING:(A) (A)PREMATURE PREMATUREDISCONTINUATION DISCONTINUATIONOF OFPRADAXA PRADAXAINCREASES INCREASES THE THERISK RISKOF OFTHROMBOTIC THROMBOTICEVENTS, EVENTS,(B) (B)SPINAL/EPIDURAL SPINAL/EPIDURALHEMATOMA HEMATOMA (A) (A)PREMATURE PREMATUREDISCONTINUATION DISCONTINUATIONOF OFPRADAXA PRADAXAINCREASES INCREASESTHE THERISK RISKOF OF THROMBOTIC THROMBOTICEVENTS EVENTS Premature Prematurediscontinuation discontinuationof ofany anyoral oralanticoagulant, anticoagulant,including includingPRADAXA, PRADAXA, increases increasesthe therisk riskof ofthrombotic thromboticevents. events.IfIfanticoagulation anticoagulationwith withPRADAXA PRADAXAisis discontinued discontinuedfor foraareason reasonother otherthan thanpathological pathologicalbleeding bleedingor orcompletion completion of ofaacourse courseof oftherapy, therapy,consider considercoverage coveragewith withanother anotheranticoagulant anticoagulant (B) (B)SPINAL/EPIDURAL SPINAL/EPIDURALHEMATOMA HEMATOMA Epidural Epiduralor orspinal spinalhematomas hematomasmay mayoccur occurin inpatients patientstreated treatedwith withPRADAXA PRADAXA who whoare arereceiving receivingneuraxial neuraxialanesthesia anesthesiaor orundergoing undergoingspinal spinalpuncture. puncture. These Thesehematomas hematomasmay mayresult resultin inlong-term long-termor orpermanent permanentparalysis. paralysis. Consider Considerthese theserisks riskswhen whenscheduling schedulingpatients patientsfor forspinal spinalprocedures. procedures. Factors Factorsthat thatcan canincrease increasethe therisk riskof ofdeveloping developingepidural epiduralor orspinal spinal hematomas hematomasin inthese thesepatients patientsinclude: include: •• use useof ofindwelling indwellingepidural epiduralcatheters catheters •• concomitant concomitantuse useof ofother otherdrugs drugsthat thataffect affecthemostasis, hemostasis,such suchas as non-steroidal non-steroidalanti-infl anti-inflammatory ammatorydrugs drugs(NSAIDs), (NSAIDs),platelet plateletinhibitors, inhibitors, other otheranticoagulants anticoagulants •• aahistory historyof oftraumatic traumaticor orrepeated repeatedepidural epiduralor orspinal spinalpunctures punctures •• aahistory historyof ofspinal spinaldeformity deformityor orspinal spinalsurgery surgery •• optimal optimaltiming timingbetween betweenthe theadministration administrationof ofPRADAXA PRADAXAand andneuraxial neuraxial procedures proceduresisisnot notknown known Monitor Monitorpatients patientsfrequently frequentlyfor forsigns signsand andsymptoms symptomsof ofneurological neurological impairment. impairment.IfIfneurological neurologicalcompromise compromiseisisnoted, noted,urgent urgenttreatment treatmentisis necessary. necessary. Consider Considerthe thebenefi benefitstsand andrisks risksbefore beforeneuraxial neuraxialintervention interventionin in patients patientswho whoare areor orwill willbe beanticoagulated. anticoagulated. CONTRAINDICATIONS CONTRAINDICATIONS PRADAXA PRADAXAisiscontraindicated contraindicatedininpatients patientswith: with: -- active activepathological pathologicalbleeding; bleeding; -- known knownserious serioushypersensitivity hypersensitivityreaction reaction(e.g., (e.g.,anaphylactic anaphylacticreaction reactionor or anaphylactic anaphylacticshock) shock)totoPRADAXA; PRADAXA; -- mechanical mechanicalprosthetic prostheticheart heartvalve valve WARNINGS WARNINGS&&PRECAUTIONS PRECAUTIONS Increased IncreasedRisk Riskof ofThrombotic ThromboticEvents Eventsafter afterPremature PrematureDiscontinuation Discontinuation Premature Prematurediscontinuation discontinuationof ofany anyoral oralanticoagulant, anticoagulant,including includingPRADAXA, PRADAXA, ininthe theabsence absenceof ofadequate adequatealternative alternativeanticoagulation anticoagulationincreases increasesthe therisk risk of ofthrombotic thromboticevents. events. IfIfPRADAXA PRADAXAisisdiscontinued discontinuedfor foraareason reasonother otherthan than pathological pathologicalbleeding bleedingor orcompletion completionof ofaacourse courseof oftherapy, therapy,consider considercoverage coverage with withanother anotheranticoagulant anticoagulantand andrestart restartPRADAXA PRADAXAas assoon soonas asmedically medically appropriate. appropriate . Risk Riskof ofBleeding Bleeding andcan cancause causesignifi significant cantand, and, •• PRADAXA PRADAXAincreases increasesthe therisk riskofofbleeding bleedingand sometimes,fatal fatalbleeding. bleeding.Promptly Promptlyevaluate evaluateany anysigns signsor orsymptoms symptomsofof sometimes, bloodloss loss(e.g., (e.g.,aadrop dropininhemoglobin hemoglobinand/or and/orhematocrit hematocritor orhypotension). hypotension). blood DiscontinuePRADAXA PRADAXAininpatients patientswith withactive activepathological pathologicalbleeding. bleeding. Discontinue Riskfactors factorsfor forbleeding bleedinginclude includeconcomitant concomitantuse useofofmedications medicationsthat that •• Risk increasethe therisk riskofofbleeding bleeding(e.g., (e.g.,anti-platelet anti-plateletagents, agents,heparin, heparin,fifibrinolytic brinolytic increase therapy,and andchronic chronicuse useofofNSAIDs). NSAIDs).PRADAXA’s PRADAXA’santicoagulant anticoagulantactivity activityand and therapy, half-lifeare areincreased increasedininpatients patientswith withrenal renalimpairment. impairment. half-life ReversalofofAnticoagulant AnticoagulantEffect: Effect: AAspecifi specificcreversal reversalagent agent(idarucizumab) (idarucizumab) •• Reversal fordabigatran dabigatranisisavailable availablewhen whenreversal reversalofofthe theanticoagulant anticoagulanteffect effectofof for dabigatranisisneeded: needed: dabigatran •• For Foremergency emergencysurgery/urgent surgery/urgentprocedures procedures •• InInlife-threatening life-threateningor oruncontrolled uncontrolledbleeding bleeding COPYRIGHT COPYRIGHT© ©2016 2016BOEHRINGER BOEHRINGERINGELHEIM INGELHEIMPHARMACEUTICALS, PHARMACEUTICALS,INC. INC. WARNINGS WARNINGS&&PRECAUTIONS PRECAUTIONS Risk Riskof ofBleeding Bleeding(cont’d) (cont’d) Hemodialysis Hemodialysiscan canremove removedabigatran; dabigatran;however howeverclinical clinicalexperience experiencefor for hemodialysis hemodialysisas asaatreatment treatmentfor forbleeding bleedingisislimited. limited. Prothrombin Prothrombincomplex complex concentrates concentratesor orrecombinant recombinantFactor FactorVIIa VIIamay maybe beconsidered consideredbut buttheir theiruse use has hasnot notbeen beenevaluated. evaluated. Protamine Protaminesulfate sulfateand andvitamin vitaminKKare arenot notexpected expected totoaffect affectdabigatran dabigatrananticoagulant anticoagulantactivity. activity. Consider Consideradministration administrationofof platelet plateletconcentrates concentrateswhere wherethrombocytopenia thrombocytopeniaisispresent presentor orlong-acting long-acting antiplatelet antiplateletdrugs drugshave havebeen beenused. used. Thromboembolic Thromboembolicand andBleeding BleedingEvents Eventsin inPatients Patientswith withProsthetic Prosthetic Heart HeartValves Valves The Theuse useofofPRADAXA PRADAXAisiscontraindicated contraindicatedininpatients patientswith withmechanical mechanical prosthetic prostheticvalves valvesdue duetotoaahigher higherrisk riskfor forthromboembolic thromboembolicevents, events,especially especially ininthe thepost-operative post-operativeperiod, period,and andan anexcess excessofofmajor majorbleeding bleedingfor forPRADAXA PRADAXA vs. vs.warfarin. warfarin.Use UseofofPRADAXA PRADAXAfor forthe theprophylaxis prophylaxisofofthromboembolic thromboembolicevents events ininpatients patientswith withAFib AFibininthe thesetting settingofofother otherforms formsofofvalvular valvularheart heartdisease, disease, including includingbioprosthetic bioprostheticheart heartvalve, valve,has hasnot notbeen beenstudied studiedand andisisnot not recommended. recommended. Effect Effectof ofP-gp P-gpInducers Inducers&&Inhibitors Inhibitorson onDabigatran DabigatranExposure Exposure Concomitant Concomitantuse useofofPRADAXA PRADAXAwith withP-gp P-gpinducers inducers(e.g., (e.g.,rifampin) rifampin)reduces reduces exposure exposuretotodabigatran dabigatranand andshould shouldgenerally generallybe beavoided. avoided. P-gp P-gpinhibition inhibition and andimpaired impairedrenal renalfunction functionare aremajor majorindependent independentfactors factorsininincreased increased exposure exposuretotodabigatran. dabigatran. Concomitant Concomitantuse useofofP-gp P-gpinhibitors inhibitorsininpatients patientswith with renal renalimpairment impairmentisisexpected expectedtotoincrease increaseexposure exposureofofdabigatran dabigatrancompared compared totoeither eitherfactor factoralone. alone. Reduction ReductionofofRisk RiskofofStroke/Systemic Stroke/SystemicEmbolism EmbolismininNVAF NVAF •• For Forpatients patientswith withmoderate moderaterenal renalimpairment impairment(CrCl (CrCl30-50 30-50mL/min), mL/min),reduce reduce the thedose doseofofPRADAXA PRADAXAtoto75 75mg mgtwice twicedaily dailywhen whendronedarone dronedaroneor orsystemic systemic ketoconazole ketoconazoleisiscoadministered coadministeredwith withPRADAXA. PRADAXA. •• For Forpatients patientswith withsevere severerenal renalimpairment impairment(CrCl (CrCl15-30 15-30mL/min), mL/min),avoid avoid concomitant concomitantuse useofofPRADAXA PRADAXAand andP-gp P-gpinhibitors. inhibitors. ADVERSE ADVERSEREACTIONS REACTIONS The Themost mostserious seriousadverse adversereactions reactionsreported reportedwith withPRADAXA PRADAXAwere wererelated related totobleeding. bleeding. •• Most Mostfrequent frequentadverse adversereactions reactionsleading leadingtotodiscontinuation discontinuationofofPRADAXA PRADAXA were werebleeding bleeding&&gastrointestinal gastrointestinal(GI) (GI)events. events. •• PRADAXA PRADAXA150 150mg mgresulted resultedininhigher higherrates ratesofofmajor majorand andany anyGI GIbleeds bleeds comparedtotowarfarin. warfarin. compared patients≥75 ≥75years yearsofofage, age,the therisk riskofofmajor majorbleeding bleedingmay maybe begreater greater •• InInpatients withPRADAXA PRADAXAvs vswarfarin. warfarin. with Patientson onPRADAXA PRADAXA150 150mg mghad hadan anincreased increasedincidence incidenceofofGI GIadverse adverse •• Patients reactions. These Thesewere werecommonly commonlydyspepsia dyspepsia(including (incl udingabdominal abdominalpain pain reactions. upper,abdominal abdominalpain, pain,abdominal abdominaldiscomfort, discomfort,and andepigastric epigastricdiscomfort) discomfort) upper, and andgastritis-like gastritis-likesymptoms symptoms(including (includingGERD, GERD,esophagitis, esophagitis,erosive erosivegastritis, gastritis, gastric gastrichemorrhage, hemorrhage,hemorrhagic hemorrhagicgastritis, gastritis,hemorrhagic hemorrhagicerosive erosivegastritis, gastritis, and andGI GIulcer). ulcer). Other OtherMeasures MeasuresEvaluated Evaluated NVAFpatients, patients,aahigher higherrate rateofofclinical clinicalMI MIwas wasreported reportedininpatients patientswho who InInNVAF receivedPRADAXA PRADAXA(0.7/100 (0.7/100patient-years patient-yearsfor for150 150mg mgdose) dose)than thanininthose those received whoreceived receivedwarfarin warfarin(0.6). (0.6). who NOAC=novel NOAC=noveloral oralanticoagulant; anticoagulant;NVAF=non-valvular NVAF=non-valvularatrial atrialfifibrillation; brillation; SE=systemic SE=systemicembolism; embolism;RE-LY=Randomized RE-LY=RandomizedEvaluation Evaluationof ofLong-term Long-term anticoagulant anticoagulanttherapY; therapY;HR=hazard HR=hazardratio; ratio;CI=confi CI=confidence denceinterval. interval. Please Pleasesee seeaccompanying accompanyingbrief briefsummary summaryof offull fullPrescribing PrescribingInformation. Information. References: References:1. 1.Data Dataon onfifile. le.Boehringer BoehringerIngelheim IngelheimPharmaceuticals, Pharmaceuticals,Inc. Inc. 2. 2.Connolly ConnollySJ, SJ,Wallentin WallentinL,L,Yusuf YusufS. S.Additional Additionalevents eventsininthe theRE-LY RE-LYTrial Trial [Letter [Letterto tothe theEditor]. Editor].NNEngl EnglJJMed. Med.2014;371(15):1464-1465. 2014;371(15):1464-1465. ALL ALLRIGHTS RIGHTSRESERVED. RESERVED. PRINTED PRINTEDIN IN U.S.A. U.S.A. [8/16] [8/16] PC-PX-0342-PROF PC-PX-0342-PROF