DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. 150 mg capsules with light blue opaquecap imprinted in black with the Boehringer Ingelheim company symboland white opaque body imprinted in black with R150.110 mg capsules with lightblue opaque cap imprinted in black with the Boehringer Ingelheim companysymbol and light blue opaque body imprinted in black with R110.75 mg capsules with white opaque cap imprintedin black with the Boehringer Ingelheim company symbol and whiteopaque body imprinted in black with R75.. Capsules: 75 mg, 110 mg and 150 mg (3).

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following serious adverse reactionsare described elsewhere in the labeling:Increased Risk of Thrombotic Events after Premature Discontinuation [see Warnings and Precautions (5.1)] Risk of Bleeding [see Warnings and Precautions (5.2)] Spinal/Epidural Anesthesia or Puncture [see Warningsand Precautions (5.3)] Thromboembolic and Bleeding Events in Patients with ProstheticHeart Valves [see Warnings and Precautions (5.4)] The most serious adversereactions reported with PRADAXA were related to bleeding [seeWarnings and Precautions (5.2)].. Increased Risk of Thrombotic Events after Premature Discontinuation [see Warnings and Precautions (5.1)] Risk of Bleeding [see Warnings and Precautions (5.2)] Spinal/Epidural Anesthesia or Puncture [see Warningsand Precautions (5.3)] Thromboembolic and Bleeding Events in Patients with ProstheticHeart Valves [see Warnings and Precautions (5.4)] Most common adverse reactions (>15%) aregastritis-like symptoms and bleeding (6.1)To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted underwidely varying conditions, adverse reactions rates observed in theclinical trials of drug cannot be directly compared to rates inthe clinical trials of another drug and may not reflect the ratesobserved in practice.Reduction of Risk of Stroke and Systemic Embolismin Non-valvular Atrial FibrillationThe RE-LY (Randomized Evaluation of Long-termAnticoagulant Therapy) study provided safety information on the useof two doses of PRADAXA and warfarin [see Clinical Studies(14.1)]. The numbers ofpatients and their exposures are described in Table 1. Limited informationis presented on the 110 mg dosing arm because this dose is not approved.Table Summary of Treatment Exposure in RE-LY PRADAXA 110mg twice dailyPRADAXA 150mg twice dailyWarfarinTotal number treated598360595998Exposure 12 months493649395193 24 months238724052470Mean exposure (months)20.520.3 21.3 Total patient-years10,24210,26110,659. Drug Discontinuationin RE-LYThe rates of adverse reactions leading to treatmentdiscontinuation were 21% for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation ofPRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia,nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).. Bleeding [see Warnings and Precautions(5.2)]Table shows the number of adjudicatedmajor bleeding events during the treatment period in the RE-LY study,with the bleeding rate per 100 subject-years (%). Major bleedingis defined as bleeding accompanied by one or more of the following:a decrease in hemoglobin of >=2 g/dL, transfusion of >=2 units ofpacked red blood cells, bleeding at critical site or with fataloutcome. Intracranial hemorrhage included intracerebral (hemorrhagicstroke), subarachnoid, and subdural bleeds.Table Adjudicated Major Bleeding Events in Treated Patientsa aPatients during treatment or within days of stopping study treatment.Major bleeding events within each subcategory were counted once perpatient, but patients may have contributed events to multiple subcategories.bAnnualevent rate per 100 pt-years 100 number of subjects with event/subject-years.Subject-years is defined as cumulative number of days from first drugintake to event date, date of last drug intake 2, death date (whateveroccurred first) across all treated subjects divided by 365.25. Incase of recurrent events of the same category, the first event wasconsidered.cDefined as bleeding accompanied by one or more ofthe following: decrease in hemoglobin of >=2 g/dL, transfusionof or more units of packed red blood cells, bleeding at criticalsite or with fatal outcome.dIntracranial bleedincluded intracerebral (hemorrhagic stroke), subarachnoid, and subduralbleeds.eOn-treatment analysis based on the safety population,compared to ITT analysis presented in Section 14 Clinical Studies.fFatalbleed: Adjudicated major bleed as defined above with investigatorreported fatal outcome and adjudicated death with primary cause frombleeding.gNon-intracranial fatal bleed: Adjudicated major bleedas defined above and adjudicated death with primary cause from bleedingbut without symptomatic intracranial bleed based on investigatorsclinical assessment.EventPRADAXA 150 mgN 6059n (%/yearb)WarfarinN= 5998n (%/yearb)PRADAXA 150 mgvs. WarfarinHR (95% CI)Major Bleedingc 350 (3.47)374 (3.58)0.97 (0.84, 1.12) Intracranial Hemorrhage (ICH)d 23 (0.22)82 (0.77)0.29 (0.18, 0.46) Hemorrhagic Strokee (0.06)40 (0.37)0.16 (0.07, 0.37) Other ICH17 (0.17)46 (0.43)0.38 (0.22, 0.67) Gastrointestinal162 (1.59)111 (1.05)1.51 (1.19, 1.92) Fatal Bleedingf (0.07)16 (0.15)0.45 (0.19, 1.10) ICH3 (0.03)9 (0.08)0.35 (0.09, 1.28) Non-intracranialg (0.04)7 (0.07)0.59 (0.17, 2.02)There was higher rateof any gastrointestinal bleeds in patients receiving PRADAXA 150 mgthan in patients receiving warfarin (6.6% vs. 4.2%, respectively).The risk of major bleeds was similar withPRADAXA 150 mg and warfarin across major subgroups defined by baselinecharacteristics (see Figure 1), with the exception of age, where therewas trend towards higher incidence of major bleeding on PRADAXA(hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients >=75 years of age.Figure Adjudicated MajorBleeding by Baseline Characteristics Including Hemorrhagic StrokeTreated PatientsNote: The figure above presents effects invarious subgroups all of which are baseline characteristics and allof which were pre-specified. The 95% confidence limits that are showndo not take into account how many comparisons were made, nor do theyreflect the effect of particular factor after adjustment for allother factors. Apparent homogeneity or heterogeneity among groupsshould not be over-interpreted.. Figure 1. GastrointestinalAdverse ReactionsPatients on PRADAXA 150 mg had an increased incidenceof gastrointestinal adverse reactions (35% vs. 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominalpain, abdominal discomfort, and epigastric discomfort) and gastritis-likesymptoms (including GERD, esophagitis, erosive gastritis, gastrichemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis,and gastrointestinal ulcer).. HypersensitivityReactionsIn the RE-LY study, drug hypersensitivity (includingurticaria, rash, and pruritus), allergic edema, anaphylactic reaction,and anaphylactic shock were reported in <0.1% of patients receivingPRADAXA.. Treatmentand Reduction in the Risk of Recurrence of Deep Venous Thrombosisand Pulmonary EmbolismPRADAXA was studied in 4387 patients in 4pivotal, parallel, randomized, double-blind trials. Three of thesetrials were active-controlled (warfarin) (RE-COVER, RE-COVER II, andRE-MEDY), and one study (RE-SONULLTE) was placebo-controlled. The demographiccharacteristics were similar among the pivotal studies and betweenthe treatment groups within these studies. Approximately 60% of thetreated patients were male, with mean age of 55.1 years. The majorityof the patients were white (87.7%), 10.3% were Asian, and 1.9% wereblack with mean CrCl of 105.6 mL/min.Bleeding events for the pivotal studieswere classified as major bleeding events if at least one of the followingcriteria applied: fatal bleeding, symptomatic bleeding in criticalarea or organ (intraocular, intracranial, intraspinal or intramuscularwith compartment syndrome, retroperitoneal bleeding, intra-articularbleeding, or pericardial bleeding), bleeding causing fall in hemoglobinlevel of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusionof or more units of whole blood or red cells).RE-COVER and RE-COVER II studies comparedPRADAXA 150 mg twice daily and warfarin for the treatment of deepvein thrombosis and pulmonary embolism. Patients received 5-10 daysof an approved parenteral anticoagulant therapy followed by months,with mean exposure of 164 days, of oral only treatment; warfarin wasoverlapped with parenteral therapy. Table shows the number of patientsexperiencing bleeding events in the pooled analysis of RE-COVER andRE-COVER II studies during the full treatment including parenteraland oral only treatment periods after randomization.Table Bleeding Events in RE-COVER and RE-COVER II TreatedPatientsNote: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigatorassessment. Patients can have more than one site of bleeding. cConfidence interval Bleeding Events-FullTreatment PeriodIncluding Parenteral Treatment PRADAXA150mg twice dailyN (%)WarfarinN(%)Hazard Ratio(95% CI)c PatientsN=2553N=2554 Major bleeding eventa 37 (1.4)51 (2.0)0.73 (0.48, 1.11) Fatal bleeding1 (0.04)2 (0.1) Bleeding in critical area or organ7 (0.3)15 (0.6) Fall in hemoglobin >=2 g/dL or transfusion>=2 units of whole blood or packed red blood cells32 (1.3)38 (1.5) Bleeding sites forMBEb Intracranial2 (0.1)5 (0.2) Retroperitoneal2 (0.1)1 (0.04) Intraarticular2 (0.1)4 (0.2) Intramuscular2 (0.1)6 (0.2) Gastrointestinal15 (0.6)14 (0.5) Urogenital7 (0.3)14 (0.5) Other8 (0.3)8 (0.3) Clinically relevantnon-major bleeding101 (4.0)170 (6.7)0.58 (0.46, 0.75)Any bleeding411 (16.1)567 (22.7)0.70 (0.61, 0.79)The rate of any gastrointestinalbleeds in patients receiving PRADAXA 150 mg in the full treatmentperiod was 3.1% (2.4% on warfarin).The RE-MEDY and RE-SONULLTE studies providedsafety information on the use of PRADAXA for the reduction in therisk of recurrence of deep vein thrombosis and pulmonary embolism.RE-MEDY was an active-controlledstudy (warfarin) in which 1430 patients received PRADAXA 150 mg twicedaily following to 12 months of oral anticoagulant regimen. Patientsin the treatment studies who rolled over into the RE-MEDY study hada combined treatment duration of up to more than years, with meanexposure of 473 days. Table shows the number of patients experiencingbleeding events in the study.Table Bleeding Events in RE-MEDY Treated PatientsNote: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigatorassessment. Patients can have more than one site of bleeding. cConfidence interval PRADAXA150mg twice dailyN (%)WarfarinN(%)Hazard Ratio(95% CI)c PatientsN=1430N=1426 Major bleeding eventa 13 (0.9)25 (1.8)0.54 (0.25, 1.16) Fatal bleeding01 (0.1) Bleeding in critical area or organ7 (0.5)11 (0.8) Fall in hemoglobin >=2 g/dL or transfusion>=2 units of whole blood or packed red blood cells7 (0.5)16 (1.1) Bleeding sites forMBEb Intracranial2 (0.1)4 (0.3) Intraocular4 (0.3)2 (0.1) Retroperitoneal01 (0.1) Intraarticular02 (0.1) Intramuscular04 (0.3) Gastrointestinal4 (0.3)8 (0.6) Urogenital1 (0.1)1 (0.1) Other2 (0.1)4 (0.3) Clinically relevantnon-major bleeding71 (5.0)125 (8.8)0.56 (0.42, 0.75)Any bleeding278 (19.4)373 (26.2)0.71 (0.61, 0.83)In the RE-MEDY study,the rate of any gastrointestinal bleeds in patients receiving PRADAXA150 mg was 3.1% (2.2% on warfarin).RE-SONULLTE was placebo-controlled studyin which 684 patients received PRADAXA 150 mg twice daily following6 to 18 months of oral anticoagulant regimen. Patients in the treatmentstudies who rolled over into the RE-SONULLTE study had combined treatmentduration up to months, with mean exposure of 165 days. Table showsthe number of patients experiencing bleeding events in the study.Table Bleeding Events in RE-SONULLTE Treated PatientsNote: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigatorassessment. Patients can have more than one site of bleeding. cConfidence interval PRADAXA150mg twice dailyN (%)PlaceboN (%)Hazard Ratio(95% CI)c PatientsN=684N=659 Major bleeding eventa (0.3)0 Bleeding in critical area or organ00 Gastrointestinalb (0.3)0 Clinically relevantnon-major bleeding34 (5.0)13 (2.0)2.54 (1.34, 4.82)Any bleeding72 (10.5)40 (6.1)1.77 (1.20, 2.61)In the RE-SONULLTE study,the rate of any gastrointestinal bleeds in patients receiving PRADAXA150 mg was 0.7% (0.3% on placebo).Clinical Myocardial Infarction EventsIn the active-controlled VTE studies, higher rate ofclinical myocardial infarction was reported in patients who receivedPRADAXA [20 (0.66 per 100 patient-years)] than in those who receivedwarfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlledstudy, similar rate of non-fatal and fatal clinical myocardial infarctionwas reported in patients who received PRADAXA [1 (0.32 per 100 patient-years)]and in those who received placebo [1 (0.34 per 100 patient-years)].Gastrointestinal AdverseReactionsIn the four pivotal studies, patientson PRADAXA 150 mg had similar incidence of gastrointestinal adversereactions (24.7% vs. 22.7% on warfarin). Dyspepsia (including abdominalpain upper, abdominal pain, abdominal discomfort, and epigastric discomfort)occurred in patients on PRADAXA in 7.5% vs. 5.5% on warfarin, andgastritis-like symptoms (including gastritis, GERD, esophagitis, erosivegastritis and gastric hemorrhage) occurred at 3.0% vs. 1.7%, respectively.Hypersensitivity ReactionsIn the pivotal studies, drug hypersensitivity (includingurticaria, rash, and pruritus), allergic edema, anaphylactic reaction,and anaphylactic shock were reported in 0.1% of patients receivingPRADAXA.Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement SurgeryPRADAXA wasstudied in 5476 patients, randomized and treated in two double-blind,active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATEII). The demographic characteristics were similar across the twostudies and between the treatment groups within these studies. Approximately45.3 of the treated patients were male, with mean age of 63.2years. The majority of the patients were white (96.1%), 3.6% wereAsian, and 0.3% were black with mean CrCl of 92 mL/min.Bleeding events for the RE-NOVATEand RE-NOVATE II studies were classified as major bleeding eventsif at least one of the following criteria applied: fatal bleeding,symptomatic bleeding in critical area or organ (intraocular, intracranial,intraspinal or retroperitoneal bleeding), bleeding causing fallin hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leadingto transfusion of or more units of whole blood or red cells, requiringtreatment cessation or leading to re-operation.The RE-NOVATE study compared PRADAXA 75mg taken orally 1-4 hours after surgery followed by 150 mg once daily,PRADAXA 110 mg taken orally 1-4 hours after surgery followed by 220mg once daily and subcutaneous enoxaparin 40 mg once daily initiatedthe evening before surgery for the prophylaxis of deep vein thrombosisand pulmonary embolism in patients who had undergone hip replacementsurgery. The RE-NOVATE II study compared PRADAXA 110 mg taken orally1-4 hours after surgery followed by 220 mg once daily and subcutaneousenoxaparin 40 mg once daily initiated the evening before surgery forthe prophylaxis of deep vein thrombosis and pulmonary embolism inpatients who had undergone hip replacement surgery. In the RE-NOVATEand RE-NOVATE II studies, patients received 28-35 days of PRADAXAor enoxaparin with median exposure of 33 days. Tables and showthe number of patients experiencing bleeding events in the analysisof RE-NOVATE and RE-NOVATE II.Table Bleeding Events in RE-NOVATE Treated Patients PRADAXA 220 mgN (%)EnoxaparinN(%)PatientsN=1146N=1154Major bleeding event23 (2.0)18 (1.6)Clinically relevant non-majorbleeding 48 (4.2)40 (3.5)Any bleeding141 (12.3)132 (11.4)Table Bleeding Events in RE-NOVATE II Treated Patients PRADAXA 220 mgN (%)EnoxaparinN(%)PatientsN=1010N=1003Major bleeding event14 (1.4)9 (0.9)Clinically relevant non-majorbleeding 26 (2.6)20 (2.0)Any bleeding98 (9.7)83 (8.3)In the two studies, therate of major gastrointestinal bleeds in patients receiving PRADAXAand enoxaparin was the same (0.1%) and for any gastrointestinal bleedswas 1.4% for PRADAXA 220 mg and 0.9% for enoxaparin.Gastrointestinal Adverse ReactionsIn the two studies, the incidence of gastrointestinaladverse reactions for patients on PRADAXA 220 mg and enoxaparin was39.5% and 39.5%, respectively. Dyspepsia (including abdominal painupper, abdominal pain, abdominal discomfort, and epigastric discomfort)occurred in patients on PRADAXA 220 mg in 4.1% vs. 3.8% on enoxaparin,and gastritis-like symptoms (including gastritis, GERD, esophagitis,erosive gastritis and gastric hemorrhage) occurred at 0.6% vs. 1.0%,respectively.Hypersensitivity ReactionsIn the two studies,drug hypersensitivity (such as urticaria, rash, and pruritus) wasreported in 0.3% of patients receiving PRADAXA 220 mg.Clinical MyocardialInfarction EventsIn the two studies, clinicalmyocardial infarction was reported in (0.1%) of patients who receivedPRADAXA 220 mg and (0.3%) of patients who received enoxaparin.. 6.2 Postmarketing Experience. The following adverse reactions have beenidentified during post approval use of PRADAXA. Because these reactionsare reported voluntarily from population of uncertain size, it isnot always possible to reliably estimate their frequency or establisha causal relationship to drug exposure. The following adverse reactionshave been identified during post approval use of PRADAXA: angioedema,thrombocytopenia, esophageal ulcer.

BOXED WARNING SECTION.


WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISKOF THROMBOTIC EVENTS, and (B) SPINULLL/EPIDURAL HEMATOMA. (A) PREMATURE DISCONTINUATIONOF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTSPrematurediscontinuation of any oral anticoagulant, including PRADAXA, increasesthe risk of thrombotic events. If anticoagulation with PRADAXA isdiscontinued for reason other than pathological bleeding or completionof course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.4, 2.5, 2.6) and Warnings and Precautions (5.1)].(B) SPINULLL/EPIDURALHEMATOMAEpidural or spinal hematomas may occur in patientstreated with PRADAXA who are receiving neuraxial anesthesia or undergoingspinal puncture. These hematomas may result in long-term or permanentparalysis. Consider these risks when scheduling patients for spinalprocedures. Factors that can increase the risk of developing epiduralor spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such asnon-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors,other anticoagulants a history of traumatic or repeatedepidural or spinal punctures a history of spinal deformityor spinal surgery optimal timing between the administrationof PRADAXA and neuraxial procedures is not known [see Warningsand Precautions (5.3)].Monitor patientsfrequently for signs and symptoms of neurological impairment. If neurologicalcompromise is noted, urgent treatment is necessary [see Warningsand Precautions (5.3)]. Consider the benefits and risks before neuraxial interventionin patients anticoagulated or to be anticoagulated [see Warningsand Precautions (5.3)].. WARNING: (A) PREMATURE DISCONTINUATIONOF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, and (B) SPINULLL/EPIDURALHEMATOMASee full prescribing informationfor complete boxed warning(A)PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTICEVENTS: Premature discontinuation of any oral anticoagulant, includingPRADAXA, increases the risk of thrombotic events. To reduce thisrisk, consider coverage with another anticoagulant if PRADAXA is discontinuedfor reason other than pathological bleeding or completion of courseof therapy (2.4, 2.5, 2.6, 5.1).(B) SPINULLL/EPIDURAL HEMATOMA: Epidural or spinal hematomasmay occur in patients treated with PRADAXA who are receiving neuraxialanesthesia or undergoing spinal puncture. These hematomas may resultin long-term or permanent paralysis (5.3). Monitor patients frequently for signs and symptoms of neurologicalimpairment and if observed, treat urgently. Consider the benefitsand risks before neuraxial intervention in patients who are or whoneed to be anticoagulated (5.3).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Dabigatran was not carcinogenic when administeredby oral gavage to mice and rats for up to years. The highest dosestested (200 mg/kg/day) in mice and rats were approximately 3.6 and6 times, respectively, the human exposure at MRHD of 300 mg/day basedon AUC comparisons.Dabigatranwas not mutagenic in in vitro tests, including bacterialreversion tests, mouse lymphoma assay and chromosomal aberration assayin human lymphocytes, and the in vivo micronucleusassay in rats.In the rat fertilitystudy with oral gavage doses of 15, 70, and 200 mg/kg, males weretreated for 29 days prior to mating, during mating up to scheduledtermination, and females were treated 15 days prior to mating throughgestation Day 6. No adverse effects on male or female fertility wereobserved at 200 mg/kg or to 12 times the human exposure at MRHDof 300 mg/day based on AUC comparisons. However, the number of implantationsdecreased in females receiving 70 mg/kg, or times the human exposureat MRHD based on AUC comparisons.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Dabigatran and its acyl glucuronides are competitive, direct thrombininhibitors. Because thrombin (serine protease) enables the conversionof fibrinogen into fibrin during the coagulation cascade, its inhibitionprevents the development of thrombus. Both free and clot-boundthrombin, and thrombin-induced platelet aggregation are inhibitedby the active moieties.. 12.2 Pharmacodynamics. At recommended therapeutic doses, dabigatran etexilate prolongs thecoagulation markers such as aPTT, ECT, and TT. INR is relativelyinsensitive to the exposure to dabigatran and cannot be interpretedthe same way as used for warfarin monitoring.The aPTT test provides an approximation of PRADAXAsanticoagulant effect. The average time course for effects on aPTT,following approved dosing regimens in patients with various degreesof renal impairment is shown in Figure 2. The curves represent meanlevels without confidence intervals; variations should be expectedwhen measuring aPTT. While advice cannot be provided on the levelof recovery of aPTT needed in any particular clinical setting, thecurves can be used to estimate the time to get to particular levelof recovery, even when the time since the last dose of PRADAXA isnot precisely known. In the RE-LY trial, the median (10th to 90th percentile) troughaPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.Figure Average Time Course forEffects of Dabigatran on aPTT, Following Approved PRADAXA Dosing Regimensin Patients with Various Degrees of Renal ImpairmentSimulations based onPK data from study in subjects with renal impairment and PK/aPTTrelationships derived from the RE-LY study; aPTT prolongation in RE-LYwas measured centrally in citrate plasma using PTT Reagent Roche DiagnosticsGmbH, Mannheim, Germany. There may be quantitative differences betweenvarious established methods for aPTT assessment.The degree of anticoagulant activity can also be assessedby the ecarin clotting time (ECT). This test is more specific measureof the effect of dabigatran than activated partial thromboplastintime (aPTT). In the RE-LY trial, the median (10th to 90th percentile) trough ECT in patientsreceiving the 150 mg dose was 63 (44 to 103) seconds.. In orthopedic hip surgery patients,maximum aPTT response (Emax) to dabigatran and baseline aPTT werehigher shortly after surgery than at later time points (e.g. >=3 daysafter surgery).Cardiac ElectrophysiologyNo prolongation of the QTc interval was observed withdabigatran etexilate at doses up to 600 mg.. Figure 2. 12.3 Pharmacokinetics. Dabigatran etexilate mesylate is absorbed as the dabigatran etexilateester. The ester is then hydrolyzed, forming dabigatran, the activemoiety. Dabigatran is metabolized to four different acyl glucuronidesand both the glucuronides and dabigatran have similar pharmacologicalactivity. Pharmacokinetics described here refer to the sum of dabigatranand its glucuronides. Dabigatran displays dose-proportional pharmacokineticsin healthy subjects and patients in the range of doses from 10 to400 mg.. AbsorptionThe absolutebioavailability of dabigatran following oral administration of dabigatranetexilate is approximately to 7%. Dabigatran etexilate is substrateof the efflux transporter P-gp. After oral administration of dabigatranetexilate in healthy volunteers, Cmax occursat hour post-administration in the fasted state. Coadministrationof PRADAXA with high-fat meal delays the time to Cmax by approximately hours but has no effect on the bioavailabilityof dabigatran; PRADAXA may be administered with or without food.The oral bioavailability of dabigatran etexilateincreases by 75% when the pellets are taken without the capsule shellcompared to the intact capsule formulation. PRADAXA capsules shouldtherefore not be broken, chewed, or opened before administration.. DistributionDabigatranis approximately 35% bound to human plasma proteins. The red bloodcell to plasma partitioning of dabigatran measured as total radioactivityis less than 0.3. The volume of distribution of dabigatran is 50 to70 L. Dabigatran pharmacokinetics are dose proportional after singledoses of 10 to 400 mg. Given twice daily, dabigatrans accumulationfactor is approximately two.. EliminationDabigatranis eliminated primarily in the urine. Renal clearance of dabigatranis 80% of total clearance after intravenous administration. Afteroral administration of radiolabeled dabigatran, 7% of radioactivityis recovered in urine and 86% in feces. The half-life of dabigatranin healthy subjects is 12 to 17 hours.. MetabolismAfter oraladministration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysisto the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically activeacyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronideexist, and each accounts for less than 10% of total dabigatran inplasma.. Renal ImpairmentAn open,parallel-group single-center study compared dabigatran pharmacokineticsin healthy subjects and patients with mild to moderate renal impairmentreceiving single dose of PRADAXA 150 mg. Exposure to dabigatranincreases with severity of renal function impairment (Table 8). Similarfindings were observed in the RE-LY, RE-COVER and RE-NOVATE II trials.Table Impact of Renal Impairment on Dabigatran Pharmacokinetics+Patientswith severe renal impairment were not studied in RE-LY, RE-COVER andRE-NOVATE II. Dosing recommendations in subjects with severe renalimpairment are based on pharmacokinetic modeling [see Dosageand Administration (2.1, 2.2) and Use in Specific Populations (8.6)].Renal FunctionCrCl (mL/min)Increase inAUCIncrease inCmax t1/2 (h)Normal>= 801x1x13Mild50-801.5x1.1x15Moderate30-503.2x1.7x18Severe+ 15-306.3x2.1x27. Hepatic ImpairmentAdministrationof PRADAXA in patients with moderate hepatic impairment (Child-PughB) showed large inter-subject variability, but no evidence of aconsistent change in exposure or pharmacodynamics.. Drug InteractionsA summary of the effect of coadministered drugs on dabigatran exposureis shown in Figures 3.1 and 3.2.In the orthopedic hip surgery patients,limited clinical data with P-gp inhibitors is available.Figure 3.1 Effect of P-gpInhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposureto Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios(Ratio) and 90% Confidence Interval (90% CI). The Perpetrator andDabigatran Etexilate Dose and Dosing Frequency are given as well asthe Time of Perpetrator Dosing in Relation to Dabigatran EtexilateDose (Time Difference)Figure 3.2 Effect of Non-P-gp Inhibitoror Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran(Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90%Confidence Interval (90% CI). The Perpetrator and Dabigatran EtexilateDose and Dosing Frequency are given as well as the Time of PerpetratorDosing in Relation to Dabigatran Etexilate Dose (Time Difference). Figure 3.1. Figure 3.2. In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, anddigoxin did not appreciably change the trough concentration of dabigatran.Impact of Dabigatran onOther DrugsIn clinical studies exploring CYP3A4,CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alterthe pharmacokinetics of amiodarone, atorvastatin, clarithromycin,diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Reduction of Riskof Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation. The clinical evidence for the efficacy ofPRADAXA was derived from RE-LY (Randomized Evaluation of Long-termAnticoagulant Therapy), multi-center, multi-national, randomizedparallel group trial comparing two blinded doses of PRADAXA (110 mgtwice daily and 150 mg twice daily) with open-label warfarin (dosedto target INR of to 3) in patients with non-valvular, persistent,paroxysmal, or permanent atrial fibrillation and one or more of thefollowing additional risk factors:Previous stroke, transient ischemic attack (TIA), or systemicembolismLeft ventricular ejection fraction <40% Symptomatic heart failure, >= New York Heart AssociationClass 2Age >=75 yearsAge >=65 years and one of the following: diabetes mellitus,coronary artery disease (CAD), or hypertension The primary objective of this studywas to determine if PRADAXA was non-inferior to warfarin in reducingthe occurrence of the composite endpoint, stroke (ischemic and hemorrhagic)and systemic embolism. The study was designed to ensure that PRADAXApreserved more than 50% of warfarins effect as established by previousrandomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.A total of 18,113 patients were randomized and followedfor median of years. The patients mean age was 71.5 years andthe mean CHADS2 score was 2.1. The patientpopulation was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had history of stroke or TIA and 50%were Vitamin antagonist (VKA) naive, defined as less than monthstotal lifetime exposure to VKA. Thirty-two percent of the populationhad never been exposed to VKA. Concomitant diseases of patientsin this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel.For patients randomized to warfarin, the mean percentage of time intherapeutic range (INR to 3) was 64%.Relative to warfarin and to PRADAXA 110 mg twice daily,PRADAXA 150 mg twice daily significantly reduced the primary compositeendpoint of stroke and systemic embolism (see Table and Figure 4).Table First Occurrence of Stroke or Systemic Embolism inthe RE-LY Study Randomized ITT PRADAXA 150 mg twice dailyPRADAXA 110 mg twice dailyWarfarinPatients randomized607660156022Patients (% per yr) with events 135 (1.12%)183 (1.54%)203 (1.72%)Hazard ratio vs. warfarin (95%CI)0.65 (0.52, 0.81)0.89 (0.73, 1.09) P-value for superiority0.00010.27 Hazard ratio vs. PRADAXA 110mg (95% CI)0.72 (0.58, 0.91) P-value for superiority0.005 Figure Kaplan-Meier CurveEstimate of Time to First Stroke or Systemic EmbolismThe contributions of the components of the compositeendpoint, including stroke by subtype, are shown in Table 10. Thetreatment effect was primarily reduction in stroke. PRADAXA 150mg twice daily was superior in reducing ischemic and hemorrhagic strokesrelative to warfarin.Table 10 Strokes and Systemic Embolism in the RE-LY Study PRADAXA150 mg twice dailyWarfarin Hazard ratiovs. warfarin(95% CI) Patients randomized60766022 Stroke 123 187 0.64 (0.51, 0.81) Ischemic stroke1041340.76 (0.59, 0.98) Hemorrhagic stroke12450.26 (0.14, 0.49)Systemic embolism13210.61 (0.30, 1.21)In the RE-LY trial, therate of all-cause mortality was lower on dabigatran 150 mg than onwarfarin (3.6% per year versus 4.1% per year). The rate of vasculardeath was lower on dabigatran 150 mg compared to warfarin (2.3% peryear versus 2.7% per year). Non-vascular death rates were similarin the treatment arms.The efficacyof PRADAXA 150 mg twice daily was generally consistent across majorsubgroups (see Figure 5).Figure Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics Randomized ITTNote: The figureabove presents effects in various subgroups all of which are baselinecharacteristics and all of which were pre-specified. The 95% confidencelimits that are shown do not take into account how many comparisonswere made, nor do they reflect the effect of particular factor afteradjustment for all other factors. Apparent homogeneity or heterogeneityamong groups should not be over-interpreted.In RE-LY, higher rate of clinical myocardial infarctionwas reported in patients who received PRADAXA (0.7 per 100 patient-yearsfor 150 mg dose) than in those who received warfarin (0.6).. Previous stroke, transient ischemic attack (TIA), or systemicembolism. Left ventricular ejection fraction <40% Symptomatic heart failure, >= New York Heart AssociationClass 2. Age >=75 years. Age >=65 years and one of the following: diabetes mellitus,coronary artery disease (CAD), or hypertension Figure 4. Figure 5. 14.2 Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolism. Inthe randomized, parallel group, double-blind trials, RE-COVER andRE-COVER II, patients with deep vein thrombosis and pulmonary embolismreceived PRADAXA 150 mg twice daily or warfarin (dosed to target INRof to 3) following initial treatment with an approved parenteralanticoagulant for 5-10 days.In RE-COVER, the median treatment durationduring the oral only treatment period was 174 days. total of 2539patients (30.9% patients with symptomatic PE with or without DVT and68.9% with symptomatic DVT only) were treated with mean age of 54.7years. The patient population was 58.4% male, 94.8% white, 2.6% Asian,and 2.6% black. The concomitant diseases of patients in this trialincluded hypertension (35.9%), diabetes mellitus (8.3%), coronaryartery disease (6.5%), active cancer (4.8%), and gastric or duodenalulcer (4.4%). Concomitant medications included agents acting on renin-angiotensinsystem (25.2%), vasodilators (28.4%), serum lipid-reducing agents(18.2%), NSAIDs (21%), beta-blockers (14.8%), calcium channel blockers(8.5%), ASA (8.6%), and platelet inhibitors excluding ASA (0.6%). Patients randomized to warfarin had mean percentage of time inthe INR target range of 2.0 to 3.0 of 60% in RE-COVER study.In RE-COVER II, the median treatmentduration during the oral only treatment period was 174 days. totalof 2568 patients (31.8% patients with symptomatic PE with or withoutDVT and 68.1% with symptomatic DVT only) were treated with meanage of 54.9 years. The patient population was 60.6% male, 77.6% white,20.9% Asian, and 1.5% black. The concomitant diseases of patientsin this trial included hypertension (35.1%), diabetes mellitus (9.8%),coronary artery disease (7.1%), active cancer (3.9%), and gastricor duodenal ulcer (3.8%). Concomitant medications included agentsacting on renin-angiotensin system (24.2%), vasodilators (28.6%),serum lipid-reducing agents (20.0%), NSAIDs (22.3%), beta-blockers(14.8%), calcium channel blockers (10.8%), ASA (9.8%), and plateletinhibitors excluding ASA (0.8%). Patients randomized to warfarinhad mean percentage of time in the INR target range of 2.0 to 3.0of 57% in RE-COVER II study.In studies RE-COVER and RE-COVER II, theprotocol specified non-inferiority margin (2.75) for the hazard ratiowas derived based on the upper limit of the 95% confidence intervalof the historical warfarin effect. PRADAXA was demonstrated to benon-inferior to warfarin (dosed to target INR of to 3) (Table 11)based on the primary composite endpoint (fatal PE or symptomatic non-fatalPE and/or DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVERII) of the historical warfarin effect, respectively.Table 11 Primary Efficacy Endpoint for RE-COVER and RE-COVERII Modified ITTa PopulationaModified ITT analysespopulation consists of all randomized patients who received at leastone dose of study medication.bNumber of patients with one or more event.cNumber of events. For patients with multiple eventseach event is counted independently. PRADAXA150mg twice dailyN (%)WarfarinN(%)Hazard ratio vs.warfarin (95% CI)RE-COVERN=1274N=1265 Primary CompositeEndpointb 34 (2.7)32 (2.5)1.05 (0.65, 1.70) Fatal PEc (0.1)3 (0.2) Symptomatic non-fatal PEc 16 (1.3)8 (0.6) Symptomatic recurrent DVTc 17 (1.3)23 (1.8) RE-COVER IIN=1279N=1289 Primary CompositeEndpointb 34 (2.7)30 (2.3)1.13 (0.69, 1.85) Fatal PEc (0.2)0 Symptomatic non-fatal PEc (0.7)15 (1.2) Symptomatic recurrent DVTc 30 (2.3)17 (1.3) In the randomized, parallelgroup, double-blind, pivotal trial, RE-MEDY, patients received PRADAXA150 mg twice daily or warfarin (dosed to target INR of to 3) following3 to 12 months of treatment with anticoagulation therapy for an acuteVTE. The median treatment duration during the treatment period was534 days. total of 2856 patients were treated with mean age of54.6 years. The patient population was 61% male, and 90.1% white,7.9% Asian and 2.0% black. The concomitant diseases of patients inthis trial included hypertension (38.6%), diabetes mellitus (9.0%),coronary artery disease (7.2%), active cancer (4.2%), and gastricor duodenal ulcer (3.8%). Concomitant medications included agentsacting on renin-angiotensin system (27.9%), vasodilators (26.7%),serum lipid reducing agents (20.6%), NSAIDs (18.3%), beta-blockers(16.3%), calcium channel blockers (11.1%), aspirin (7.7%), and plateletinhibitors excluding ASA (0.9%). Patients randomized to warfarinhad mean percentage of time in the INR target range of 2.0 to 3.0of 62% in the study.In study RE-MEDY, the protocol specified non-inferiority margin (2.85)for the hazard ratio was derived based on the point estimate of thehistorical warfarin effect. PRADAXA was demonstrated to be non-inferiorto warfarin (dosed to target INR of to 3) (Table 12) based on theprimary composite endpoint (fatal PE or symptomatic non-fatal PE and/orDVT) and retains at least 63.0% of the historical warfarin effect. If the non-inferiority margin was derived based on the 50% retentionof the upper limit of the 95% confidence interval, PRADAXA was demonstratedto retain at least 33.4% of the historical warfarin effect based onthe composite primary endpoint.Table 12 Primary Efficacy Endpoint for RE-MEDY ModifiedITTa PopulationaModified ITT analysespopulation consists of all randomized patients who received at leastone dose of study medication.bNumber of patients with one or more event.cNumber of events. For patients with multiple eventseach event is counted independently. PRADAXA150mg twice dailyN=1430N (%)WarfarinN=1426N (%)Hazard ratio vs.warfarin (95% CI)Primary CompositeEndpointb 26 (1.8)18 (1.3)1.44 (0.78, 2.64) Fatal PEc (0.07)1 (0.07) Symptomatic non-fatal PEc 10 (0.7)5 (0.4) Symptomatic recurrent DVTc 17 (1.2)13 (0.9) In randomized, parallelgroup, double-blind, pivotal trial, RE-SONULLTE, patients received PRADAXA150 mg twice daily or placebo following to 18 months of treatmentwith anticoagulation therapy for an acute VTE. The median treatmentduration was 182 days. total of 1343 patients were treated witha mean age of 55.8 years. The patient population was 55.5% male,89.0% white, 9.3% Asian, and 1.7% black. The concomitant diseasesof patients in this trial included hypertension (38.8%), diabetesmellitus (8.0%), coronary artery disease (6.0%), history of cancer(6.0%), gastric or duodenal ulcer (4.5%), and heart failure (4.6%). Concomitant medications included agents acting on renin-angiotensinsystem (28.7%), vasodilators (19.4%), beta-blockers (18.5%), serumlipid reducing agents (17.9%), NSAIDs (12.1%), calcium channel blockers(8.9%), aspirin (8.3%), and platelet inhibitors excluding ASA (0.7%). Based on the outcome of the primary composite endpoint (fatal PE,unexplained death, or symptomatic non-fatal PE and/or DVT), PRADAXAwas superior to placebo (Table 13).Table 13 Primary Efficacy Endpoint for RE-SONULLTE ModifiedITTa PopulationaModified ITT analysespopulation consists of all randomized patients who received at leastone dose of study medication.bNumber of patients with one or more events.cNumber of events. For patients with multiple eventseach event is counted independently. PRADAXA150mg twice dailyN=681N (%)PlaceboN=662N (%)Hazard ratio vs.placebo (95% CI)Primary CompositeEndpointb (0.4)37 (5.6)0.08 (0.02, 0.25)p-value <0.0001 Fatal PE and unexplained deathc 02 (0.3) Symptomatic non-fatal PEc (0.1)14 (2.1) Symptomatic recurrent DVTc (0.3)23 (3.5) 14.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery. In the randomized, parallel group, double-blind,non-inferiority trials, RE-NOVATE and RE-NOVATE II patients receivedPRADAXA 75 mg orally 1-4 hours after surgery followed by 150 mg daily(RE-NOVATE), PRADAXA 110 mg orally 1-4 hours after surgery followedby 220 mg daily (RE-NOVATE and RE-NOVATE II) or subcutaneous enoxaparin40 mg once daily initiated the evening before surgery (RE-NOVATE andRE-NOVATE II) for the prophylaxis of deep vein thrombosis and pulmonaryembolism in patients who have undergone hip replacement surgery.Overall, in RE-NOVATE and RE-NOVATEII, the median treatment duration was 33 days for PRADAXA and 33 daysfor enoxaparin. total of 5428 patients were treated with meanage of 63.2 years. The patient population was 45.3% male, 96.1% white,3.6% Asian, and 0.4 black. The concomitant diseases of patientsin these trials included hypertension (46.1%), venous insufficiency(15.4%), coronary artery disease (8.2%), diabetes mellitus (7.9%),reduced renal function (5.3%), heart failure (3.4%), gastric or duodenalulcer (3.0%), VTE (2.7%), and malignancy (0.1%). Concomitant medicationsincluded cardiac therapy (69.7%), NSAIDs (68%), vasoprotectives (29.7%),agents acting on renin-angiotensin system (29.1%), beta-blockers (21.5%),diuretics (20.8%), lipid modifying agents (18.2%), any antithrombin/anticoagulant(16.0%), calcium channel blockers (13.6%), low molecular weight heparin(7.8%), aspirin (7.0%), platelet inhibitors excluding ASA (6.9%),other antihypertensives (6.7%), and peripheral vasodilators (2.6%).For efficacy evaluation allpatients were to have bilateral venography of the lower extremitiesat days after last dose of study drug unless an endpoint event hadoccurred earlier in the study. In the primary efficacy analysis,PRADAXA 110 mg orally 1-4 hours after surgery followed by 220 mg dailywas non-inferior to enoxaparin 40 mg once daily in composite endpointof confirmed VTE (proximal or distal DVT on venogram, confirmed symptomaticDVT, or confirmed PE) and all cause death during the treatment period(Tables 14 and 15). In the studies 2628 (76.5%) patients in RE-NOVATEand 1572 (78.9%) patients in RE-NOVATE II had evaluable venogramsat study completion.Table 14 Primary Efficacy Endpoint for RE-NOVATE aFull Analysis Set (FAS):The FAS included all randomized patients who received at least onesubcutaneous injection or one oral dose of study medication, underwentsurgery and subjects for whom the presence or absence of an efficacyoutcome at the end of the study was known, i.e., an evaluable negativevenogram for both distal and proximal DVT in both legs or any of thefollowing: positive venography in one or both legs, or confirmed symptomaticDVT, PE, or death during the treatment period. bVTE is defined as proximal DVT and PE PRADAXA220 mgN (%)EnoxaparinN (%)Number of Patientsa N=880N= 897Primary Composite Endpoint53 (6.0)60 (6.7)Risk difference (%) vs. enoxaparin(95% CI)-0.7 (-2.9, 1.6) Number of PatientsN=909N=917Composite endpoint of majorVTEb and VTE related mortality28 (3.1)36 (3.9)Number of PatientsN=905N=914 Proximal DVT23 (2.5)33 (3.6)Number of PatientsN=874N=894 Total DVT46 (5.3)57 (6.4)Number of PatientsN=1137N=1142 Symptomatic DVT6 (0.5)1 (0.1) PE5 (0.4)3 (0.3) Death3 (0.3)0Table 15 Primary Efficacy Endpoint for RE-NOVATE IIaFull Analysis Set (FAS):The FAS included all randomized patients who received at least onesubcutaneous injection or one oral dose of study medication, underwentsurgery and subjects for whom the presence or absence of an efficacyoutcome at the end of the study was known, i.e., an evaluable negativevenogram for both distal and proximal DVT in both legs or any of thefollowing: positive venography in one or both legs, or confirmed symptomaticDVT, PE, or death during the treatment period. bVTE is defined as proximal DVT and PE PRADAXA220 mgN (%)EnoxaparinN (%)Number of Patientsa N=792N= 786Primary Composite Endpoint61 (7.7)69 (8.8)Risk difference (%) vs. enoxaparin(95% CI)-1.1 (-3.8, 1.6) Number of PatientsN=805N=795Composite endpoint of majorVTEb and VTE related mortality18 (2.2)33 (4.2)Number of PatientsN=804N=793 Proximal DVT17 (2.1)31 (3.9)Number of PatientsN=791N=784 Total DVT60 (7.6)67 (8.5)Number of PatientsN=1001N=992 Symptomatic DVT04 (0.4) PE1 (0.1)2 (0.2) Death01 (0.1).

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. PRADAXA is contraindicated in patients with:Active pathological bleeding [see Warningsand Precautions (5.2) and AdverseReactions (6.1)].History of serious hypersensitivity reaction to PRADAXA(e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions (6.1)].Mechanical prosthetic heart valve [see Warningsand Precautions (5.4)].. Active pathological bleeding [see Warningsand Precautions (5.2) and AdverseReactions (6.1)].. History of serious hypersensitivity reaction to PRADAXA(e.g., anaphylactic reaction or anaphylactic shock) [see Adverse Reactions (6.1)].. Mechanical prosthetic heart valve [see Warningsand Precautions (5.4)].. Active pathological bleeding (4)History of serious hypersensitivity reaction to PRADAXA(4)Mechanical prosthetic heart valve (4). Active pathological bleeding (4). History of serious hypersensitivity reaction to PRADAXA(4). Mechanical prosthetic heart valve (4).

DESCRIPTION SECTION.


11 DESCRIPTION. The chemical name for dabigatran etexilatemesylate, direct thrombin inhibitor, is -Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethylester, methanesulfonate. The empirical formula is C34H41N7O5 CH4O3S and the molecularweight is 723.86 (mesylate salt), 627.75 (free base). The structuralformula is:Dabigatran etexilate mesylate is yellow-white to yellow powder. saturated solution in pure water has solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, andsparingly soluble in isopropanol.PRADAXA capsules are supplied in 75, 110,and 150 mg strengths for oral administration. Each capsule containsdabigatran etexilate mesylate as the active ingredient: 172.95 mgdabigatran etexilate mesylate (equivalent to 150 mg dabigatran etexilate),126.83 mg dabigatran etexilate mesylate (equivalent to 110 mg dabigatranetexilate), or 86.48 mg dabigatran etexilate mesylate (equivalentto 75 mg dabigatran etexilate) along with the following inactive ingredients:acacia, dimethicone, hypromellose, hydroxypropyl cellulose, talc,and tartaric acid. The capsule shell is composed of carrageenan,hypromellose, potassium chloride, titanium dioxide, black edible ink,and FD&C Blue No. (150 mg and 110 mg capsules only).. Praxada (dabigatran etexilate mesylate) structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION Non-valvular Atrial Fibrillation:For patients with CrCl >30 mL/min: 150 mg orally, twicedaily (2.1)For patients with CrCl 15-30 mL/min: 75 mg orally, twicedaily (2.1)Treatment of DVT and PE:For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after 5-10 days of parenteral anticoagulation (2.1)Reduction in the Risk of Recurrence of DVT andPE:For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after previous treatment (2.1)Prophylaxis of DVT and PE Following Hip ReplacementSurgery:For patients with CrCl >30 mL/min: 110 mg orally first day,then 220 mg once daily (2.1)Review recommendations for converting to or from other oralor parenteral anticoagulants (2.4, 2.5)Temporarily discontinue PRADAXA before invasive or surgicalprocedures when possible, then restart promptly (2.6). Non-valvular Atrial Fibrillation:For patients with CrCl >30 mL/min: 150 mg orally, twicedaily (2.1)For patients with CrCl 15-30 mL/min: 75 mg orally, twicedaily (2.1). For patients with CrCl >30 mL/min: 150 mg orally, twicedaily (2.1). For patients with CrCl 15-30 mL/min: 75 mg orally, twicedaily (2.1). Treatment of DVT and PE:For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after 5-10 days of parenteral anticoagulation (2.1). For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after 5-10 days of parenteral anticoagulation (2.1). Reduction in the Risk of Recurrence of DVT andPE:For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after previous treatment (2.1). For patients with CrCl >30 mL/min: 150 mg orally, twicedaily after previous treatment (2.1). Prophylaxis of DVT and PE Following Hip ReplacementSurgery:For patients with CrCl >30 mL/min: 110 mg orally first day,then 220 mg once daily (2.1). For patients with CrCl >30 mL/min: 110 mg orally first day,then 220 mg once daily (2.1). Review recommendations for converting to or from other oralor parenteral anticoagulants (2.4, 2.5). Temporarily discontinue PRADAXA before invasive or surgicalprocedures when possible, then restart promptly (2.6). 2.1 Recommended Dose. IndicationDosageReductionin Risk of Stroke and Systemic Embolism in Non-valvular AFCrCl >30 mL/min: 150 mg twice daily CrCl 15 to 30 mL/min: 75 mg twice daily CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl 30 to 50 mL/min with concomitant use of P-gpinhibitors: Reduce dose to 75 mg twice daily if givenwith P-gp inhibitors dronedarone or systemic ketoconazole. CrCl <30 mL/min with concomitant use ofP-gp inhibitors: Avoid co-administration Treatment of DVT and PE Reduction in the Riskof Recurrence of DVT and PECrCl >30 mL/min: 150 mg twice daily CrCl <=30 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl <50 mL/min with concomitant useof P-gp inhibitors: Avoid co-administration Prophylaxis of DVT and PE Following Hip Replacement SurgeryCrCl >30 mL/min: 110 mg for first day, then220 mg once daily CrCl <=30 mL/min or on dialysis: Dosing recommendations cannotbe provided CrCl <50 mL/min with concomitantuse of P-gp inhibitors: Avoid co-administration Reductionof Risk of Stroke and Systemic Embolism in Non-valvular Atrial FibrillationFor patients with creatinineclearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150mg taken orally, twice daily. For patients with severe renal impairment(CrCl 15-30 mL/min), the recommended dose of PRADAXA is 75 mg twicedaily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Dosing recommendations for patients witha CrCl <15 mL/min or on dialysis cannot be provided.Treatment ofDeep Venous Thrombosis and Pulmonary EmbolismFor patients withCrCl >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally,twice daily, after 5-10 days of parenteral anticoagulation. Dosingrecommendations for patients with CrCl <=30 mL/min or on dialysiscannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Reduction in the Riskof Recurrence of Deep Venous Thrombosis and Pulmonary EmbolismFor patientswith CrCl >30 mL/min, the recommended dose of PRADAXA is 150 mg takenorally, twice daily after previous treatment. Dosing recommendationsfor patients with CrCl <=30 mL/min or on dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. Prophylaxis of Deep Vein Thrombosis and Pulmonary EmbolismFollowing Hip Replacement SurgeryFor patients with CrCl >30 mL/min,the recommended dose of PRADAXA is 110 mg taken orally 1-4 hours aftersurgery and after hemostasis has been achieved, then 220 mg takenonce daily for 28-35 days. If PRADAXA is not started on the day ofsurgery, after hemostasis has been achieved initiate treatment with220 mg once daily. Dosing recommendations for patients with CrCl<=30 mL/min or on dialysis cannot be provided [see Use in SpecificPopulations (8.6) and Clinical Pharmacology(12.2, 12.3)].. 2.2 Dosing Adjustments. Assess renal function prior to initiationof treatment with PRADAXA. Periodically assess renal function asclinically indicated (i.e., more frequently in clinical situationsthat may be associated with decline in renal function) and adjusttherapy accordingly. Discontinue PRADAXA in patients who developacute renal failure while on PRADAXA and consider alternative anticoagulanttherapy.Generally, the extentof anticoagulation does not need to be assessed. When necessary, useaPTT or ECT, and not INR, to assess for anticoagulant activity inpatients on PRADAXA [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].Reduction of Risk of Stroke and SystemicEmbolism in Non-valvular Atrial FibrillationIn patients with moderate renalimpairment (CrCl 30-50 mL/min), concomitant use of the P-gp inhibitordronedarone or systemic ketoconazole can be expected to produce dabigatranexposure similar to that observed in severe renal impairment. Reducethe dose of PRADAXA to 75 mg twice daily [see Warnings andPrecautions (5.5), Drug Interactions(7.1) and Clinical Pharmacology (12.3)].Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolismDosing recommendations for patients withCrCl <=30 mL/min cannot be provided. Avoid use of concomitant P-gpinhibitors in patients with CrCl <50 mL/min [see Warningsand Precautions (5.5), Drug Interactions(7.2) and Clinical Pharmacology (12.3)].Prophylaxis of Deep VeinThrombosis and Pulmonary Embolism Following Hip Replacement SurgeryDosingrecommendations for patients with CrCl <=30 mL/min or on dialysis cannotbe provided. Avoid use of concomitant P-gp inhibitors in patientswith CrCl <50 mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.3) and Clinical Pharmacology (12.2, 12.3)].. 2.3 Instructions to Patients. Instruct patients to swallow the capsuleswhole. PRADAXA should be taken with full glass of water. Breaking,chewing, or emptying the contents of the capsule can result in increasedexposure [see Clinical Pharmacology (12.3)].If dose of PRADAXA is not taken at thescheduled time, the dose should be taken as soon as possible on thesame day; the missed dose should be skipped if it cannot be takenat least hours before the next scheduled dose. The dose of PRADAXAshould not be doubled to make up for missed dose.. 2.4 Converting from orto Warfarin. When convertingpatients from warfarin therapy to PRADAXA, discontinue warfarin andstart PRADAXA when the INR is below 2.0.When converting from PRADAXA to warfarin, adjust thestarting time of warfarin based on creatinine clearance as follows:For CrCl >=50 mL/min, start warfarin days before discontinuingPRADAXA.For CrCl 30-50 mL/min, start warfarin days before discontinuingPRADAXA.For CrCl 15-30 mL/min, start warfarin day before discontinuingPRADAXA.For CrCl <15 mL/min, no recommendations can be made.Because PRADAXA can increase INR,the INR will better reflect warfarins effect only after PRADAXA hasbeen stopped for at least days [see Clinical Pharmacology(12.2)].. For CrCl >=50 mL/min, start warfarin days before discontinuingPRADAXA.. For CrCl 30-50 mL/min, start warfarin days before discontinuingPRADAXA.. For CrCl 15-30 mL/min, start warfarin day before discontinuingPRADAXA.. For CrCl <15 mL/min, no recommendations can be made.. 2.5 Converting from orto Parenteral Anticoagulants. For patients currently receiving parenteral anticoagulant,start PRADAXA to hours before the time that the next dose of theparenteral drug was to have been administered or at the time of discontinuationof continuously administered parenteral drug (e.g., intravenousunfractionated heparin).For patientscurrently taking PRADAXA, wait 12 hours (CrCl >=30 mL/min) or 24 hours(CrCl <30 mL/min) after the last dose of PRADAXA before initiatingtreatment with parenteral anticoagulant [see ClinicalPharmacology (12.3)].. 2.6 Discontinuation forSurgery and Other Interventions. If possible, discontinue PRADAXA to days (CrCl >=50mL/min) or to days (CrCl <50 mL/min) before invasive or surgicalprocedures because of the increased risk of bleeding. Consider longertimes for patients undergoing major surgery, spinal puncture, or placementof spinal or epidural catheter or port, in whom complete hemostasismay be required [see Use in Specific Populations(8.6) and Clinical Pharmacology (12.3)].If surgery cannot be delayed, there is anincreased risk of bleeding [see Warnings and Precautions(5.2)]. This riskof bleeding should be weighed against the urgency of intervention [see Warnings and Precautions (5.1, 5.3)]. Use specific reversal agent (idarucizumab) in case of emergencysurgery or urgent procedures when reversal of the anticoagulant effectof dabigatran is needed. Refer to the idarucizumab prescribing informationfor additional information. Restart PRADAXA as soon as medically appropriate.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. P-gp inducers rifampin: Avoid coadministration with PRADAXA(5.5)P-gp inhibitors in patients with CrCl 30-50 mL/min: Reducedose or avoid (7)P-gp inhibitors in patients with CrCl <30 mL/min: Notrecommended (7). P-gp inducers rifampin: Avoid coadministration with PRADAXA(5.5). P-gp inhibitors in patients with CrCl 30-50 mL/min: Reducedose or avoid (7). P-gp inhibitors in patients with CrCl <30 mL/min: Notrecommended (7). 7.1 Reduction of Riskof Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation. The concomitant use of PRADAXAwith P-gp inducers (e.g., rifampin) reduces exposure to dabigatranand should generally be avoided [see Clinical Pharmacology(12.3)].P-gp inhibition and impaired renal functionare the major independent factors that result in increased exposureto dabigatran [see Clinical Pharmacology (12.3)]. Concomitant use of P-gpinhibitors in patients with renal impairment is expected to produceincreased exposure of dabigatran compared to that seen with eitherfactor alone.In patientswith moderate renal impairment (CrCl 30-50 mL/min), reduce the doseof PRADAXA to 75 mg twice daily when administered concomitantly withthe P-gp inhibitors dronedarone or systemic ketoconazole. The useof the P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin,and ticagrelor does not require dose adjustment of PRADAXA. Theseresults should not be extrapolated to other P-gp inhibitors [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].The concomitantuse of PRADAXA and P-gp inhibitors in patients with severe renal impairment(CrCl 15-30 mL/min) should be avoided [see Warnings and Precautions(5.5), Use in Specific Populations(8.6), and Clinical Pharmacology (12.3)].. 7.2 Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolism. Avoiduse of PRADAXA and P-gp inhibitors in patients with CrCl <50 mL/min [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].. 7.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery. In patients with CrCl >=50 mL/min who haveconcomitant administration of P-gp inhibitors such as dronedaroneor systemic ketoconazole, it may be helpful to separate the timingof administration of dabigatran and the P-gp inhibitor by severalhours. The concomitant use of PRADAXA and P-gp inhibitors in patientswith CrCl <50 mL/min should be avoided [see Warnings andPrecautions (5.5), Use in SpecificPopulations (8.6) and Clinical Pharmacology(12.2, 12.3)].

GERIATRIC USE SECTION.


8.5 Geriatric Use. Ofthe 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 increaseswith age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5),Adverse Reactions (6.1), and ClinicalStudies (14.1)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGEAND HANDLING. Product: 63629-8242NDC: 63629-8242-1 30 CAPSULE in BOTTLE.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. PRADAXA is direct thrombin inhibitor indicated:To reduce the risk of stroke and systemic embolism in patientswith non-valvular atrial fibrillation (1.1)For the treatment of deep venous thrombosis (DVT) and pulmonaryembolism (PE) in patients who have been treated with parenteralanticoagulant for 5-10 days (1.2)To reduce the risk of recurrence of DVT and PE in patientswho have been previously treated (1.3)For the prophylaxis of DVT and PE in patients who have undergonehip replacement surgery (1.4). To reduce the risk of stroke and systemic embolism in patientswith non-valvular atrial fibrillation (1.1). For the treatment of deep venous thrombosis (DVT) and pulmonaryembolism (PE) in patients who have been treated with parenteralanticoagulant for 5-10 days (1.2). To reduce the risk of recurrence of DVT and PE in patientswho have been previously treated (1.3). For the prophylaxis of DVT and PE in patients who have undergonehip replacement surgery (1.4). 1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial Fibrillation. PRADAXA is indicated to reduce the riskof stroke and systemic embolism in patients with non-valvular atrialfibrillation.. 1.2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism. PRADAXA is indicated for thetreatment of deep venous thrombosis and pulmonary embolism in patientswho have been treated with parenteral anticoagulant for 5-10 days.. 1.3 Reduction in the Risk of Recurrence of Deep Venous Thrombosisand Pulmonary Embolism. PRADAXA is indicated to reduce the risk ofrecurrence of deep venous thrombosis and pulmonary embolism in patientswho have been previously treated.. 1.4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism FollowingHip Replacement Surgery. PRADAXA is indicated for the prophylaxisof deep vein thrombosis and pulmonary embolism, in patients who haveundergone hip replacement surgery.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patientlabeling (Medication Guide).. 17.1 Instructions forPatients. Tell patients to take PRADAXA exactly as prescribed.Remind patients not to discontinue PRADAXA without talkingto the health care provider who prescribed it.Keep PRADAXA in the original bottle to protect from moisture.Do not put PRADAXA in pill boxes or pill organizers.When more than one bottle is dispensed to the patient, instructthem to open only one bottle at time.Instruct patient to remove only one capsule from the openedbottle at the time of use. The bottle should be immediately and tightlyclosed.Advise patients not to chew or break the capsules beforeswallowing them and not to open the capsules and take the pelletsalone. Advise patients that the capsule should be taken with afull glass of water.. Tell patients to take PRADAXA exactly as prescribed.. Remind patients not to discontinue PRADAXA without talkingto the health care provider who prescribed it.. Keep PRADAXA in the original bottle to protect from moisture.Do not put PRADAXA in pill boxes or pill organizers.. When more than one bottle is dispensed to the patient, instructthem to open only one bottle at time.. Instruct patient to remove only one capsule from the openedbottle at the time of use. The bottle should be immediately and tightlyclosed.. Advise patients not to chew or break the capsules beforeswallowing them and not to open the capsules and take the pelletsalone. Advise patients that the capsule should be taken with afull glass of water.. 17.2 Bleeding. Inform patients that they may bleed moreeasily, may bleed longer, and should call their health care providerfor any signs or symptoms of bleeding.Instruct patients to seek emergency care right awayif they have any of the following, which may be sign or symptomof serious bleeding:Unusual bruising (bruises that appear without known causeor that get bigger)Pink or brown urineRed or black, tarry stoolsCoughing up bloodVomiting blood, or vomit that looks like coffee groundsInstruct patients to call their healthcare provider or to get prompt medical attention if they experienceany signs or symptoms of bleeding:Pain, swelling or discomfort in jointHeadaches, dizziness, or weaknessReoccurring nose bleedsUnusual bleeding from gumsBleeding from cut that takes long time to stopMenstrual bleeding or vaginal bleeding that is heavier thannormalIf patients have had neuraxialanesthesia or spinal puncture, and particularly, if they are takingconcomitant NSAIDs or platelet inhibitors, advise patients to watchfor signs and symptoms of spinal or epidural hematoma, such as backpain, tingling, numbness (especially in the lower limbs), muscle weakness,and stool or urine incontinence. If any of these symptoms occur, advisethe patient to contact his or her physician immediately [see Boxed Warning].. Unusual bruising (bruises that appear without known causeor that get bigger). Pink or brown urine. Red or black, tarry stools. Coughing up blood. Vomiting blood, or vomit that looks like coffee grounds. Pain, swelling or discomfort in joint. Headaches, dizziness, or weakness. Reoccurring nose bleeds. Unusual bleeding from gums. Bleeding from cut that takes long time to stop. Menstrual bleeding or vaginal bleeding that is heavier thannormal. 17.3 GastrointestinalAdverse Reactions. Instructpatients to call their health care provider if they experience anysigns or symptoms of dyspepsia or gastritis:Dyspepsia (upset stomach), burning, or nauseaAbdominal pain or discomfort Epigastric discomfort, GERD (gastric indigestion). Dyspepsia (upset stomach), burning, or nausea. Abdominal pain or discomfort Epigastric discomfort, GERD (gastric indigestion). 17.4 Invasive or SurgicalProcedures. Instructpatients to inform their health care provider that they are takingPRADAXA before any invasive procedure (including dental procedures)is scheduled.. 17.5 Concomitant Medications. Ask patients to list all prescription medications,over-the-counter medications, or dietary supplements they are takingor plan to take so their health care provider knows about other treatmentsthat may affect bleeding risk (e.g., aspirin or NSAIDs) or dabigatranexposure (e.g., dronedarone or systemic ketoconazole).. 17.6 Prosthetic HeartValves. Instruct patientsto inform their health care provider if they will have or have hadsurgery to place prosthetic heart valve.. 17.7 Pregnancy. Advise patients to inform their healthcare provider immediately ifthey become pregnant or intend to become pregnant during treatmentwith PRADAXA [see Use in Specific Populations (8.1)].. 17.8 Lactation. Advise patients not to breastfeedif they are taking PRADAXA [see Use in Specific Populations(8.2)].Distributed by:Boehringer Ingelheim Pharmaceuticals, Inc.Ridgefield,CT 06877 USACopyright 2018 BoehringerIngelheim Pharmaceuticals, Inc.ALL RIGHTS RESERVEDIT5060AKC142018.

LABOR & DELIVERY SECTION.


8.2 Lactation. Risk SummaryThere areno data on the presence of dabigatran in human milk, the effects onthe breastfed child, or on milk production. Dabigatran and/or itsmetabolites were present in rat milk. Breastfeeding is not recommendedduring treatment with PRADAXA.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. Dabigatran and its acyl glucuronides are competitive, direct thrombininhibitors. Because thrombin (serine protease) enables the conversionof fibrinogen into fibrin during the coagulation cascade, its inhibitionprevents the development of thrombus. Both free and clot-boundthrombin, and thrombin-induced platelet aggregation are inhibitedby the active moieties.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Dabigatran was not carcinogenic when administeredby oral gavage to mice and rats for up to years. The highest dosestested (200 mg/kg/day) in mice and rats were approximately 3.6 and6 times, respectively, the human exposure at MRHD of 300 mg/day basedon AUC comparisons.Dabigatranwas not mutagenic in in vitro tests, including bacterialreversion tests, mouse lymphoma assay and chromosomal aberration assayin human lymphocytes, and the in vivo micronucleusassay in rats.In the rat fertilitystudy with oral gavage doses of 15, 70, and 200 mg/kg, males weretreated for 29 days prior to mating, during mating up to scheduledtermination, and females were treated 15 days prior to mating throughgestation Day 6. No adverse effects on male or female fertility wereobserved at 200 mg/kg or to 12 times the human exposure at MRHDof 300 mg/day based on AUC comparisons. However, the number of implantationsdecreased in females receiving 70 mg/kg, or times the human exposureat MRHD based on AUC comparisons.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Accidentaloverdose may lead to hemorrhagic complications. In the event of hemorrhagiccomplications, initiate appropriate clinical support, discontinuetreatment with PRADAXA, and investigate the source of bleeding. Aspecific reversal agent (idarucizumab) is available.Dabigatran is primarily eliminated by thekidneys with low plasma protein binding of approximately 35%. Hemodialysiscan remove dabigatran; however, data supporting this approach arelimited. Using high-flux dialyzer, blood flow rate of 200 mL/min,and dialysate flow rate of 700 mL/min, approximately 49% of totaldabigatran can be cleared from plasma over hours. At the same dialysateflow rate, approximately 57% can be cleared using dialyzer bloodflow rate of 300 mL/min, with no appreciable increase in clearanceobserved at higher blood flow rates. Upon cessation of hemodialysis,a redistribution effect of approximately 7% to 15% is seen. The effectof dialysis on dabigatrans plasma concentration would be expectedto vary based on patient specific characteristics. Measurement ofaPTT or ECT may help guide therapy [see Warnings and Precautions(5.2) and Clinical Pharmacology (12.2)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Dabigatran Etexilate 150mg Capsule. Label Image.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safetyand effectiveness of PRADAXA in pediatric patients have not been established.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. At recommended therapeutic doses, dabigatran etexilate prolongs thecoagulation markers such as aPTT, ECT, and TT. INR is relativelyinsensitive to the exposure to dabigatran and cannot be interpretedthe same way as used for warfarin monitoring.The aPTT test provides an approximation of PRADAXAsanticoagulant effect. The average time course for effects on aPTT,following approved dosing regimens in patients with various degreesof renal impairment is shown in Figure 2. The curves represent meanlevels without confidence intervals; variations should be expectedwhen measuring aPTT. While advice cannot be provided on the levelof recovery of aPTT needed in any particular clinical setting, thecurves can be used to estimate the time to get to particular levelof recovery, even when the time since the last dose of PRADAXA isnot precisely known. In the RE-LY trial, the median (10th to 90th percentile) troughaPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.Figure Average Time Course forEffects of Dabigatran on aPTT, Following Approved PRADAXA Dosing Regimensin Patients with Various Degrees of Renal ImpairmentSimulations based onPK data from study in subjects with renal impairment and PK/aPTTrelationships derived from the RE-LY study; aPTT prolongation in RE-LYwas measured centrally in citrate plasma using PTT Reagent Roche DiagnosticsGmbH, Mannheim, Germany. There may be quantitative differences betweenvarious established methods for aPTT assessment.The degree of anticoagulant activity can also be assessedby the ecarin clotting time (ECT). This test is more specific measureof the effect of dabigatran than activated partial thromboplastintime (aPTT). In the RE-LY trial, the median (10th to 90th percentile) trough ECT in patientsreceiving the 150 mg dose was 63 (44 to 103) seconds.. In orthopedic hip surgery patients,maximum aPTT response (Emax) to dabigatran and baseline aPTT werehigher shortly after surgery than at later time points (e.g. >=3 daysafter surgery).Cardiac ElectrophysiologyNo prolongation of the QTc interval was observed withdabigatran etexilate at doses up to 600 mg.. Figure 2.

PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. Dabigatran etexilate mesylate is absorbed as the dabigatran etexilateester. The ester is then hydrolyzed, forming dabigatran, the activemoiety. Dabigatran is metabolized to four different acyl glucuronidesand both the glucuronides and dabigatran have similar pharmacologicalactivity. Pharmacokinetics described here refer to the sum of dabigatranand its glucuronides. Dabigatran displays dose-proportional pharmacokineticsin healthy subjects and patients in the range of doses from 10 to400 mg.. AbsorptionThe absolutebioavailability of dabigatran following oral administration of dabigatranetexilate is approximately to 7%. Dabigatran etexilate is substrateof the efflux transporter P-gp. After oral administration of dabigatranetexilate in healthy volunteers, Cmax occursat hour post-administration in the fasted state. Coadministrationof PRADAXA with high-fat meal delays the time to Cmax by approximately hours but has no effect on the bioavailabilityof dabigatran; PRADAXA may be administered with or without food.The oral bioavailability of dabigatran etexilateincreases by 75% when the pellets are taken without the capsule shellcompared to the intact capsule formulation. PRADAXA capsules shouldtherefore not be broken, chewed, or opened before administration.. DistributionDabigatranis approximately 35% bound to human plasma proteins. The red bloodcell to plasma partitioning of dabigatran measured as total radioactivityis less than 0.3. The volume of distribution of dabigatran is 50 to70 L. Dabigatran pharmacokinetics are dose proportional after singledoses of 10 to 400 mg. Given twice daily, dabigatrans accumulationfactor is approximately two.. EliminationDabigatranis eliminated primarily in the urine. Renal clearance of dabigatranis 80% of total clearance after intravenous administration. Afteroral administration of radiolabeled dabigatran, 7% of radioactivityis recovered in urine and 86% in feces. The half-life of dabigatranin healthy subjects is 12 to 17 hours.. MetabolismAfter oraladministration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysisto the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically activeacyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronideexist, and each accounts for less than 10% of total dabigatran inplasma.. Renal ImpairmentAn open,parallel-group single-center study compared dabigatran pharmacokineticsin healthy subjects and patients with mild to moderate renal impairmentreceiving single dose of PRADAXA 150 mg. Exposure to dabigatranincreases with severity of renal function impairment (Table 8). Similarfindings were observed in the RE-LY, RE-COVER and RE-NOVATE II trials.Table Impact of Renal Impairment on Dabigatran Pharmacokinetics+Patientswith severe renal impairment were not studied in RE-LY, RE-COVER andRE-NOVATE II. Dosing recommendations in subjects with severe renalimpairment are based on pharmacokinetic modeling [see Dosageand Administration (2.1, 2.2) and Use in Specific Populations (8.6)].Renal FunctionCrCl (mL/min)Increase inAUCIncrease inCmax t1/2 (h)Normal>= 801x1x13Mild50-801.5x1.1x15Moderate30-503.2x1.7x18Severe+ 15-306.3x2.1x27. Hepatic ImpairmentAdministrationof PRADAXA in patients with moderate hepatic impairment (Child-PughB) showed large inter-subject variability, but no evidence of aconsistent change in exposure or pharmacodynamics.. Drug InteractionsA summary of the effect of coadministered drugs on dabigatran exposureis shown in Figures 3.1 and 3.2.In the orthopedic hip surgery patients,limited clinical data with P-gp inhibitors is available.Figure 3.1 Effect of P-gpInhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposureto Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios(Ratio) and 90% Confidence Interval (90% CI). The Perpetrator andDabigatran Etexilate Dose and Dosing Frequency are given as well asthe Time of Perpetrator Dosing in Relation to Dabigatran EtexilateDose (Time Difference)Figure 3.2 Effect of Non-P-gp Inhibitoror Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran(Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90%Confidence Interval (90% CI). The Perpetrator and Dabigatran EtexilateDose and Dosing Frequency are given as well as the Time of PerpetratorDosing in Relation to Dabigatran Etexilate Dose (Time Difference). Figure 3.1. Figure 3.2. In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, anddigoxin did not appreciably change the trough concentration of dabigatran.Impact of Dabigatran onOther DrugsIn clinical studies exploring CYP3A4,CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alterthe pharmacokinetics of amiodarone, atorvastatin, clarithromycin,diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.

PREGNULLNCY SECTION.


8.1 Pregnancy. Risk SummaryThe limited available data on PRADAXA use in pregnant women are insufficientto determine drug-associated risks for adverse developmental outcomes.There are risks to the mother associated with untreated venous thromboembolismin pregnancy and risk of hemorrhage in the mother and fetus associatedwith the use of anticoagulants (see Clinical Considerations). In pregnant rats treatedfrom implantation until weaning, dabigatran increased the number ofdead offspring and caused excess vaginal/uterine bleeding close toparturition at an exposure 2.6 times the human exposure. At similarexposure, dabigatran decreased the number of implantations when ratswere treated prior to mating and up to implantation (gestation Day6). Dabigatran administered to pregnant rats and rabbits during organogenesisup to exposures and 13 times the human exposure, respectively, didnot induce major malformations. However, the incidence of delayedor irregular ossification of fetal skull bones and vertebrae was increasedin the rat (see Data).The estimated background riskof major birth defects and miscarriage for the indicated populationis unknown. All pregnancies have background risk of birth defect,loss, or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical ConsiderationsDisease-associated maternal and/or embryo/fetalriskPregnancy confers an increased risk for thromboembolismthat is higher for women with underlying thromboembolic disease andcertain high-risk pregnancy conditions. Published data describe thatwomen with previous history of venous thrombosis are at high riskfor recurrence during pregnancy.Fetal/Neonatal adverse reactionUse of anticoagulants, including PRADAXA, may increasethe risk of bleeding in the fetus and neonate. Monitor neonates forbleeding [see Warnings and Precautions (5.2)].Labor or deliveryAll patients receivinganticoagulants, including pregnant women, are at risk for bleeding.PRADAXA use during labor or delivery in women who are receiving neuraxialanesthesia may result in epidural or spinal hematomas. Consider discontinuationor use of shorter acting anticoagulant as delivery approaches [see Warnings and Precautions (5.2, 5.3)].. DataAnimal DataDabigatran has been shown to decrease the number of implantationswhen male and female rats were treated at dosage of 70 mg/kg (about2.6 to 3.0 times the human exposure at MRHD of 300 mg/day based onarea under the curve [AUC] comparisons) prior to mating and up toimplantation (gestation Day 6). Treatment of pregnant rats after implantationwith dabigatran at the same dose increased the number of dead offspringand caused excess vaginal/uterine bleeding close to parturition. Dabigatran administered to pregnant rats and rabbits during organogenesisup to maternally toxic doses of 200 mg/kg (8 and 13 times the humanexposure, respectively, at MRHD of 300 mg/day based on AUC comparisons)did not induce major malformations, but increased the incidence ofdelayed or irregular ossification of fetal skull bones and vertebraein the rat.Deathof offspring and mother rats during labor in association with uterinebleeding occurred during treatment of pregnant rats from implantation(gestation Day 7) to weaning (lactation Day 21) with dabigatran ata dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of300 mg/day based on AUC comparisons).

SPL MEDGUIDE SECTION.


MEDICATION GUIDEPRADAXA (pra dax a)(dabigatranetexilate mesylate)capsulesRead this MedicationGuide before you start taking PRADAXA and each time you get refill. There may be new information. This Medication Guide does not takethe place of talking with your doctor about your medical conditionor your treatment.What is themost important information should know about PRADAXAFor people taking PRADAXA for atrial fibrillation:People with atrial fibrillation (a type of irregularheartbeat) are at an increased risk of forming blood clot in theheart, which can travel to the brain, causing stroke, or to otherparts of the body. PRADAXA lowers your chance of having stroke byhelping to prevent clots from forming. If you stop taking PRADAXA,you may have increased risk of forming clot in your blood.Do not stop taking PRADAXA without talking tothe doctor who prescribes it for you. Stopping PRADAXA increases yourrisk of having stroke.PRADAXA mayneed to be stopped, if possible, prior to surgery or medical ordental procedure. Ask the doctor who prescribed PRADAXA for you whenyou should stop taking it. Your doctor will tell you when you maystart taking PRADAXA again after your surgery or procedure. If youhave to stop taking PRADAXA, your doctor may prescribe another medicineto help prevent blood clot from forming.PRADAXA can cause bleeding which can be serious, and sometimeslead to death. This is because PRADAXA is blood thinner medicinethat lowers the chance of blood clots forming in your body.You may have higher risk of bleeding if you takePRADAXA and:are over 75 years oldhave kidney problemshave stomach or intestine bleeding that is recent or keepscoming back, or you have stomach ulcertake other medicines that increase your risk of bleeding,including:aspirin or aspirin containing productslong-term (chronic) use of non-steroidal anti-inflammatorydrugs (NSAIDs)warfarin sodium (Coumadin(R), Jantoven(R))a medicine that contains heparinclopidogrel bisulfate (Plavix(R))prasugrel (Effient(R)) have certain kidney problems and also take the medicinesdronedarone (Multaq(R)) or ketoconazole tablets(Nizoral(R)).Tell your doctorif you take any of these medicines. Ask your doctor or pharmacistif you are not sure if your medicine is one listed above.PRADAXA can increase your risk of bleeding because it lessensthe ability of your blood to clot. While you take PRADAXA:you may bruise more easilyit may take longer for any bleeding to stop Call your doctor or get medical help right away if youhave any of these signs or symptoms of bleeding: unexpected bleeding or bleeding that lasts long time,such as:unusual bleeding from the gumsnose bleeds that happen oftenmenstrual bleeding or vaginal bleeding that is heavier thannormal bleeding that is severe or you cannot controlpink or brown urinered or black stools (looks like tar)bruises that happen without known cause or get largercough up blood or blood clotsvomit blood or your vomit looks like coffee groundsunexpected pain, swelling, or joint painheadaches, feeling dizzy or weak Take PRADAXA exactly as prescribed. Do not stop takingPRADAXA without first talking to the doctor who prescribes it foryou. Stopping PRADAXA may increase your risk of stroke. PRADAXA may need to be stopped, if possible, for one or more daysbefore any surgery, or medical or dental procedure. If you need tostop taking PRADAXA for any reason, talk to the doctorwho prescribed PRADAXA for you to find out when you should stop takingit. Your doctor will tell you when to start taking PRADAXA again afteryour surgery or procedure.Spinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like PRADAXA,and have medicine injected into their spinal and epidural area, orhave spinal puncture have risk of forming blood clot that cancause long-term or permanent loss of the ability to move (paralysis).Your risk of developing spinal or epidural blood clot is higherif:a thin tube called an epidural catheter is placed in yourback to give you certain medicine.you take NSAIDs or medicine to prevent blood from clottingyou have history of difficult or repeated epidural orspinal puncturesyou have history of problems with your spine or have hadsurgery on your spine.If you take PRADAXA and receive spinal anesthesia or have aspinal puncture, your doctor should watch you closely for symptomsof spinal or epidural blood clots. Tell your doctor right away ifyou have back pain, tingling, numbness, muscle weakness (especiallyin your legs and feet), loss of control of the bowels or bladder (incontinence).See What are the possible side effects of PRADAXAfor more information about side effects.What is PRADAXAPRADAXA is prescription blood thinner medicine thatlowers the chance of blood clots forming in your body. PRADAXA isused to:reduce the risk of stroke and blood clots in people whohave medical condition called atrial fibrillation. With atrial fibrillation,part of the heart does not beat the way it should. This can leadto blood clots forming and increase your risk of stroke.treat blood clots in the veins of your legs (deep vein thrombosis)or lungs (pulmonary embolism) and reduce the risk of them occurringagain.to help prevent blood clots in the legs and lungs of peoplewho have just had hip replacement surgery.PRADAXA is not for use in people with artificial (prosthetic)heart valves.It is not known if PRADAXA is safe and worksin children.Who shouldnot take PRADAXADo not take PRADAXA if you:currently have certain types of abnormal bleeding. Talkto your doctor before taking PRADAXA if you currently have unusualbleeding.have had serious allergic reaction to PRADAXA. Ask yourdoctor if you are not sure.have ever had or plan to have valve in your heart replacedWhat shouldI tell my doctor before taking PRADAXABeforeyou take PRADAXA, tell your doctor if you:have kidney problemshave ever had bleeding problemshave ever had stomach ulcershave any other medical conditionare pregnant or plan to become pregnant. It is not knownif PRADAXA will harm your unborn baby. Tell your doctor right awayif you become pregnant during treatment with PRADAXA.are breastfeeding or plan to breastfeed. It is not knownif PRADAXA passes into your breast milk. You and your doctor shoulddecide if you will take PRADAXA or breastfeed.Tell all of your doctors and dentists that you are taking PRADAXA. They should talk to the doctor who prescribed PRADAXA for you, beforeyou have any surgery, or medical or dental procedure. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbalsupplements.Some of your other medicines may affect theway PRADAXA works. Certain medicines may increase your risk of bleeding. See What is the most important information should know aboutPRADAXAEspecially tell your doctor if you take:rifampin (Rifater(R), Rifamate(R), Rimactane(R), Rifadin(R)) Know the medicines you take. Keep list of themand show it to your doctor and pharmacist when you get new medicine.How shouldI take PRADAXAYour doctor will decide how long you should take PRADAXA. Do not stop taking PRADAXA without first talking with your doctor.Stopping PRADAXA may increase your risk of having stroke or formingblood clots. Take PRADAXA exactly as prescribed by your doctor.Take PRADAXA capsules twice day (approximately every 12hours).If you miss dose of PRADAXA, take it as soon as you remember.If your next dose is less than hours away, skip the missed dose. Do not take two doses of PRADAXA at the same time.Swallow PRADAXA capsules whole. Do not break, chew, or emptythe pellets from the capsule.You can take PRADAXA with or without food.You should take PRADAXA with full glass of water.Do not run out of PRADAXA. Refill your prescription beforeyou run out. If you plan to have surgery, or medical or dentalprocedure, tell your doctor and dentist that you are taking PRADAXA.You may have to stop taking PRADAXA for short time. See What isthe most important information should know about PRADAXA.If you take too much PRADAXA, go to the nearest hospitalemergency room or call your doctor.Call your doctor or healthcare provider right away if youfall or injure yourself, especially if you hit your head. Your doctoror healthcare provider may need to check you.PRADAXA comes in bottle or in blister package.Only open bottle of PRADAXA at time. Finish your openedbottle of PRADAXA before opening new bottle.After opening bottle of PRADAXA, use within months.See How should store PRADAXAWhen it is time for you to take dose of PRADAXA, onlyremove your prescribed dose of PRADAXA from your open bottle or blisterpackage.Tightly close your bottle of PRADAXA right away after youtake your dose.What are the possibleside effects of PRADAXAPRADAXA can causeserious side effects, including:See What is the most important information should knowabout PRADAXAAllergic Reactions. In some people, PRADAXA can cause symptomsof an allergic reaction, including hives, rash, and itching. Tellyour doctor or get medical help right away if you get any of the followingsymptoms of serious allergic reaction with PRADAXA:chest pain or chest tightnessswelling of your face or tonguetrouble breathing or wheezingfeeling dizzy or faint Common side effectsof PRADAXA include:indigestion, upset stomach, or burningstomach painTell your doctor if you have any side effect that bothers youor that does not go away.These are not all of the possibleside effects of PRADAXA. For more information, ask your doctor orpharmacist.Call your doctor for medical advice about sideeffects. You may report side effects to FDA at 1-800-FDA-1088.How shouldI store PRADAXAStore PRADAXA at room temperature 68F to 77F (20C to25C). After opening the bottle, use PRADAXA within months. Safelythrow away any unused PRADAXA after months.Keep PRADAXA in the original bottle or blister packageto keep it dry (protect the capsules from moisture). Do not put PRADAXAin pill boxes or pill organizers.Tightly close your bottle of PRADAXA right away afteryou take your dose.Keep PRADAXA and all medicines out of the reach of children.General informationabout the safe and effective use of PRADAXAMedicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. Do not use PRADAXA for condition for which itwas not prescribed. Do not give PRADAXA to other people, even if theyhave the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important informationabout PRADAXA. If you would like more information, talk with yourdoctor. You can ask your pharmacist or doctor for information aboutPRADAXA that is written for health professionals.For moreinformation, go to www.pradaxa.com or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257or (TTY) 1-800-459-9906, or scan here to go to www.pradaxa.com. What are theingredients in PRADAXAActive ingredient: dabigatranetexilate mesylateInactive ingredients: acacia, dimethicone,hypromellose, hydroxypropyl cellulose, talc, and tartaric acid. Thecapsule shell is composed of carrageenan, hypromellose, potassiumchloride, titanium dioxide, black edible ink, and FD&C Blue No.2 (150 mg and 110 mg capsules only).Distributedby: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877USAThe brands listed above are trademarksof their respective owners and are not trademarks of Boehringer IngelheimPharmaceuticals, Inc. The owners of these brands are not affiliatedwith and do not endorse Boehringer Ingelheim Pharmaceuticals, Inc.,or its products.Copyright 2018 BoehringerIngelheim Pharmaceuticals, Inc.ALL RIGHTS RESERVEDIT5060AKC142018This Medication Guidehas been approved by the U.S. Food and Drug Administration. Revised:March 2018. For people taking PRADAXA for atrial fibrillation:People with atrial fibrillation (a type of irregularheartbeat) are at an increased risk of forming blood clot in theheart, which can travel to the brain, causing stroke, or to otherparts of the body. PRADAXA lowers your chance of having stroke byhelping to prevent clots from forming. If you stop taking PRADAXA,you may have increased risk of forming clot in your blood.Do not stop taking PRADAXA without talking tothe doctor who prescribes it for you. Stopping PRADAXA increases yourrisk of having stroke.PRADAXA mayneed to be stopped, if possible, prior to surgery or medical ordental procedure. Ask the doctor who prescribed PRADAXA for you whenyou should stop taking it. Your doctor will tell you when you maystart taking PRADAXA again after your surgery or procedure. If youhave to stop taking PRADAXA, your doctor may prescribe another medicineto help prevent blood clot from forming.. PRADAXA can cause bleeding which can be serious, and sometimeslead to death. This is because PRADAXA is blood thinner medicinethat lowers the chance of blood clots forming in your body.. You may have higher risk of bleeding if you takePRADAXA and:are over 75 years oldhave kidney problemshave stomach or intestine bleeding that is recent or keepscoming back, or you have stomach ulcertake other medicines that increase your risk of bleeding,including:aspirin or aspirin containing productslong-term (chronic) use of non-steroidal anti-inflammatorydrugs (NSAIDs)warfarin sodium (Coumadin(R), Jantoven(R))a medicine that contains heparinclopidogrel bisulfate (Plavix(R))prasugrel (Effient(R)) have certain kidney problems and also take the medicinesdronedarone (Multaq(R)) or ketoconazole tablets(Nizoral(R)).Tell your doctorif you take any of these medicines. Ask your doctor or pharmacistif you are not sure if your medicine is one listed above.. are over 75 years old. have kidney problems. have stomach or intestine bleeding that is recent or keepscoming back, or you have stomach ulcer. take other medicines that increase your risk of bleeding,including:aspirin or aspirin containing productslong-term (chronic) use of non-steroidal anti-inflammatorydrugs (NSAIDs)warfarin sodium (Coumadin(R), Jantoven(R))a medicine that contains heparinclopidogrel bisulfate (Plavix(R))prasugrel (Effient(R)) aspirin or aspirin containing products. long-term (chronic) use of non-steroidal anti-inflammatorydrugs (NSAIDs). warfarin sodium (Coumadin(R), Jantoven(R)). medicine that contains heparin. clopidogrel bisulfate (Plavix(R)). prasugrel (Effient(R)). have certain kidney problems and also take the medicinesdronedarone (Multaq(R)) or ketoconazole tablets(Nizoral(R)).Tell your doctorif you take any of these medicines. Ask your doctor or pharmacistif you are not sure if your medicine is one listed above.. PRADAXA can increase your risk of bleeding because it lessensthe ability of your blood to clot. While you take PRADAXA:you may bruise more easilyit may take longer for any bleeding to stop Call your doctor or get medical help right away if youhave any of these signs or symptoms of bleeding: unexpected bleeding or bleeding that lasts long time,such as:unusual bleeding from the gumsnose bleeds that happen oftenmenstrual bleeding or vaginal bleeding that is heavier thannormal bleeding that is severe or you cannot controlpink or brown urinered or black stools (looks like tar)bruises that happen without known cause or get largercough up blood or blood clotsvomit blood or your vomit looks like coffee groundsunexpected pain, swelling, or joint painheadaches, feeling dizzy or weak Take PRADAXA exactly as prescribed. Do not stop takingPRADAXA without first talking to the doctor who prescribes it foryou. Stopping PRADAXA may increase your risk of stroke. PRADAXA may need to be stopped, if possible, for one or more daysbefore any surgery, or medical or dental procedure. If you need tostop taking PRADAXA for any reason, talk to the doctorwho prescribed PRADAXA for you to find out when you should stop takingit. Your doctor will tell you when to start taking PRADAXA again afteryour surgery or procedure.. you may bruise more easily. it may take longer for any bleeding to stop. unexpected bleeding or bleeding that lasts long time,such as:unusual bleeding from the gumsnose bleeds that happen oftenmenstrual bleeding or vaginal bleeding that is heavier thannormal unusual bleeding from the gums. nose bleeds that happen often. menstrual bleeding or vaginal bleeding that is heavier thannormal. bleeding that is severe or you cannot control. pink or brown urine. red or black stools (looks like tar). bruises that happen without known cause or get larger. cough up blood or blood clots. vomit blood or your vomit looks like coffee grounds. unexpected pain, swelling, or joint pain. headaches, feeling dizzy or weak. Spinal or epidural blood clots (hematoma). People who take blood thinner medicine (anticoagulant) like PRADAXA,and have medicine injected into their spinal and epidural area, orhave spinal puncture have risk of forming blood clot that cancause long-term or permanent loss of the ability to move (paralysis).Your risk of developing spinal or epidural blood clot is higherif:a thin tube called an epidural catheter is placed in yourback to give you certain medicine.you take NSAIDs or medicine to prevent blood from clottingyou have history of difficult or repeated epidural orspinal puncturesyou have history of problems with your spine or have hadsurgery on your spine.If you take PRADAXA and receive spinal anesthesia or have aspinal puncture, your doctor should watch you closely for symptomsof spinal or epidural blood clots. Tell your doctor right away ifyou have back pain, tingling, numbness, muscle weakness (especiallyin your legs and feet), loss of control of the bowels or bladder (incontinence).. thin tube called an epidural catheter is placed in yourback to give you certain medicine.. you take NSAIDs or medicine to prevent blood from clotting. you have history of difficult or repeated epidural orspinal punctures. you have history of problems with your spine or have hadsurgery on your spine.. reduce the risk of stroke and blood clots in people whohave medical condition called atrial fibrillation. With atrial fibrillation,part of the heart does not beat the way it should. This can leadto blood clots forming and increase your risk of stroke.. treat blood clots in the veins of your legs (deep vein thrombosis)or lungs (pulmonary embolism) and reduce the risk of them occurringagain.. to help prevent blood clots in the legs and lungs of peoplewho have just had hip replacement surgery.. currently have certain types of abnormal bleeding. Talkto your doctor before taking PRADAXA if you currently have unusualbleeding.. have had serious allergic reaction to PRADAXA. Ask yourdoctor if you are not sure.. have ever had or plan to have valve in your heart replaced. have kidney problems. have ever had bleeding problems. have ever had stomach ulcers. have any other medical condition. are pregnant or plan to become pregnant. It is not knownif PRADAXA will harm your unborn baby. Tell your doctor right awayif you become pregnant during treatment with PRADAXA.. are breastfeeding or plan to breastfeed. It is not knownif PRADAXA passes into your breast milk. You and your doctor shoulddecide if you will take PRADAXA or breastfeed.. rifampin (Rifater(R), Rifamate(R), Rimactane(R), Rifadin(R)). Your doctor will decide how long you should take PRADAXA. Do not stop taking PRADAXA without first talking with your doctor.Stopping PRADAXA may increase your risk of having stroke or formingblood clots. Take PRADAXA exactly as prescribed by your doctor.. Take PRADAXA capsules twice day (approximately every 12hours).. If you miss dose of PRADAXA, take it as soon as you remember.If your next dose is less than hours away, skip the missed dose. Do not take two doses of PRADAXA at the same time.. Swallow PRADAXA capsules whole. Do not break, chew, or emptythe pellets from the capsule.. You can take PRADAXA with or without food.. You should take PRADAXA with full glass of water.. Do not run out of PRADAXA. Refill your prescription beforeyou run out. If you plan to have surgery, or medical or dentalprocedure, tell your doctor and dentist that you are taking PRADAXA.You may have to stop taking PRADAXA for short time. See What isthe most important information should know about PRADAXA.. If you take too much PRADAXA, go to the nearest hospitalemergency room or call your doctor.. Call your doctor or healthcare provider right away if youfall or injure yourself, especially if you hit your head. Your doctoror healthcare provider may need to check you.. PRADAXA comes in bottle or in blister package.. Only open bottle of PRADAXA at time. Finish your openedbottle of PRADAXA before opening new bottle.. After opening bottle of PRADAXA, use within months.See How should store PRADAXA. When it is time for you to take dose of PRADAXA, onlyremove your prescribed dose of PRADAXA from your open bottle or blisterpackage.. Tightly close your bottle of PRADAXA right away after youtake your dose.. See What is the most important information should knowabout PRADAXA. Allergic Reactions. In some people, PRADAXA can cause symptomsof an allergic reaction, including hives, rash, and itching. Tellyour doctor or get medical help right away if you get any of the followingsymptoms of serious allergic reaction with PRADAXA:. chest pain or chest tightness. swelling of your face or tongue. trouble breathing or wheezing. feeling dizzy or faint. indigestion, upset stomach, or burning. stomach pain. Store PRADAXA at room temperature 68F to 77F (20C to25C). After opening the bottle, use PRADAXA within months. Safelythrow away any unused PRADAXA after months.. Keep PRADAXA in the original bottle or blister packageto keep it dry (protect the capsules from moisture). Do not put PRADAXAin pill boxes or pill organizers.. Tightly close your bottle of PRADAXA right away afteryou take your dose.. pradaxa-qrcode.

SPL UNCLASSIFIED SECTION.


1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial Fibrillation. PRADAXA is indicated to reduce the riskof stroke and systemic embolism in patients with non-valvular atrialfibrillation.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended.(8.2)Geriatric use: Riskof bleeding increases with age (8.5). 8.1 Pregnancy. Risk SummaryThe limited available data on PRADAXA use in pregnant women are insufficientto determine drug-associated risks for adverse developmental outcomes.There are risks to the mother associated with untreated venous thromboembolismin pregnancy and risk of hemorrhage in the mother and fetus associatedwith the use of anticoagulants (see Clinical Considerations). In pregnant rats treatedfrom implantation until weaning, dabigatran increased the number ofdead offspring and caused excess vaginal/uterine bleeding close toparturition at an exposure 2.6 times the human exposure. At similarexposure, dabigatran decreased the number of implantations when ratswere treated prior to mating and up to implantation (gestation Day6). Dabigatran administered to pregnant rats and rabbits during organogenesisup to exposures and 13 times the human exposure, respectively, didnot induce major malformations. However, the incidence of delayedor irregular ossification of fetal skull bones and vertebrae was increasedin the rat (see Data).The estimated background riskof major birth defects and miscarriage for the indicated populationis unknown. All pregnancies have background risk of birth defect,loss, or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2-4% and 15-20%, respectively.. Clinical ConsiderationsDisease-associated maternal and/or embryo/fetalriskPregnancy confers an increased risk for thromboembolismthat is higher for women with underlying thromboembolic disease andcertain high-risk pregnancy conditions. Published data describe thatwomen with previous history of venous thrombosis are at high riskfor recurrence during pregnancy.Fetal/Neonatal adverse reactionUse of anticoagulants, including PRADAXA, may increasethe risk of bleeding in the fetus and neonate. Monitor neonates forbleeding [see Warnings and Precautions (5.2)].Labor or deliveryAll patients receivinganticoagulants, including pregnant women, are at risk for bleeding.PRADAXA use during labor or delivery in women who are receiving neuraxialanesthesia may result in epidural or spinal hematomas. Consider discontinuationor use of shorter acting anticoagulant as delivery approaches [see Warnings and Precautions (5.2, 5.3)].. DataAnimal DataDabigatran has been shown to decrease the number of implantationswhen male and female rats were treated at dosage of 70 mg/kg (about2.6 to 3.0 times the human exposure at MRHD of 300 mg/day based onarea under the curve [AUC] comparisons) prior to mating and up toimplantation (gestation Day 6). Treatment of pregnant rats after implantationwith dabigatran at the same dose increased the number of dead offspringand caused excess vaginal/uterine bleeding close to parturition. Dabigatran administered to pregnant rats and rabbits during organogenesisup to maternally toxic doses of 200 mg/kg (8 and 13 times the humanexposure, respectively, at MRHD of 300 mg/day based on AUC comparisons)did not induce major malformations, but increased the incidence ofdelayed or irregular ossification of fetal skull bones and vertebraein the rat.Deathof offspring and mother rats during labor in association with uterinebleeding occurred during treatment of pregnant rats from implantation(gestation Day 7) to weaning (lactation Day 21) with dabigatran ata dose of 70 mg/kg (about 2.6 times the human exposure at MRHD of300 mg/day based on AUC comparisons).. 8.2 Lactation. Risk SummaryThere areno data on the presence of dabigatran in human milk, the effects onthe breastfed child, or on milk production. Dabigatran and/or itsmetabolites were present in rat milk. Breastfeeding is not recommendedduring treatment with PRADAXA.. 8.4 Pediatric Use. Safetyand effectiveness of PRADAXA in pediatric patients have not been established.. 8.5 Geriatric Use. Ofthe 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 increaseswith age, but the risk-benefit profile is favorable in all age groups [see Warnings and Precautions (5),Adverse Reactions (6.1), and ClinicalStudies (14.1)].. 8.6 Renal Impairment. Reduction ofRisk of Stroke and Systemic Embolism in Non-valvular Atrial FibrillationNo dose adjustmentof PRADAXA is recommended in patients with mild or moderate renalimpairment [see Clinical Pharmacology (12.3)]. Reduce the dose of PRADAXA in patients withsevere renal impairment (CrCl 15-30 mL/min) [see Dosage andAdministration (2.1, 2.2) and Clinical Pharmacology (12.3)]. Dosing recommendationsfor patients with CrCl <15 mL/min or on dialysis cannot be provided.Adjust dose appropriately in patients withrenal impairment receiving concomitant P-gp inhibitors [seeWarnings and Precautions (5.5), DrugInteractions (7.1), and Clinical Pharmacology(12.3)].. Treatmentand Reduction in the Risk of Recurrence of Deep Venous Thrombosisand Pulmonary EmbolismPatients with severe renal impairment (CrCl<=30 mL/min) were excluded from RE-COVER.Dosing recommendations for patients withCrCl <=30 mL/min or on dialysis cannot be provided. Avoid use of PRADAXAwith concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.2), and ClinicalPharmacology (12.3)]. Prophylaxisof Deep Vein Thrombosis and Pulmonary Embolism Following Hip ReplacementSurgeryPatients with severe renalimpairment (CrCl <30 mL/min) were excluded from RE-NOVATE and RE-NOVATEII.Dosing recommendationsfor patients with CrCl <30 mL/min or on dialysis cannot be provided.Avoid use of PRADAXA with concomitantP-gp inhibitors in patients with CrCl <50 mL/min [see Warningsand Precautions (5.5), Drug Interactions(7.3) and Clinical Pharmacology (12.2, 12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Bleeding: PRADAXA can cause serious and fatal bleeding (5.2)Bioprosthetic heart valves: PRADAXA use not recommended(5.4). Bleeding: PRADAXA can cause serious and fatal bleeding (5.2). Bioprosthetic heart valves: PRADAXA use not recommended(5.4). 5.1 Increased Risk ofThrombotic Events after Premature Discontinuation. Premature discontinuation ofany oral anticoagulant, including PRADAXA, in the absence of adequatealternative anticoagulation increases the risk of thrombotic events. If PRADAXA is discontinued for reason other than pathological bleedingor completion of course of therapy, consider coverage with anotheranticoagulant and restart PRADAXA as soon as medically appropriate [see Dosage and Administration (2.4, 2.5, 2.6)]. 5.2 Risk of Bleeding. PRADAXA increases the risk of bleeding andcan cause significant and, sometimes, fatal bleeding. Promptly evaluateany signs or symptoms of blood loss (e.g., drop in hemoglobin and/orhematocrit or hypotension). Discontinue PRADAXA in patients withactive pathological bleeding [see Dosage and Administration(2.2)].Risk factors for bleeding include the concomitantuse of other drugs that increase the risk of bleeding (e.g., anti-plateletagents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXAs anticoagulant activity and half-life are increased in patientswith renal impairment [see Clinical Pharmacology(12.2)].Reversal of AnticoagulantEffect:A specific reversalagent (idarucizumab) for dabigatran is available when reversal ofthe anticoagulant effect of dabigatran is needed:For emergency surgery/urgent proceduresIn life-threatening or uncontrolled bleedingHemodialysis can removedabigatran; however the clinical experience supporting the use ofhemodialysis as treatment for bleeding is limited [see Overdosage(10)]. Prothrombin complexconcentrates, or recombinant Factor VIIa may be considered but theiruse has not been evaluated in clinical trials. Protamine sulfate andvitamin are not expected to affect the anticoagulant activity ofdabigatran. Consider administration of platelet concentrates in caseswhere thrombocytopenia is present or long-acting antiplatelet drugshave been used.. For emergency surgery/urgent procedures. In life-threatening or uncontrolled bleeding. 5.3 Spinal/Epidural Anesthesiaor Puncture. When neuraxialanesthesia (spinal/epidural anesthesia) or spinal puncture is employed,patients treated with anticoagulant agents are at risk of developingan epidural or spinal hematoma which can result in long-term or permanentparalysis [see Boxed Warning].To reducethe potential risk of bleeding associated with the concurrent useof dabigatran and epidural or spinal anesthesia/analgesia or spinalpuncture, consider the pharmacokinetic profile of dabigatran [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbarpuncture is best performed when the anticoagulant effect of dabigatranis low; however, the exact timing to reach sufficiently low anticoagulanteffect in each patient is not known.Should the physician decide to administeranticoagulation in the context of epidural or spinal anesthesia/analgesiaor lumbar puncture, monitor frequently to detect any signs or symptomsof neurological impairment, such as midline back pain, sensory andmotor deficits (numbness, tingling, or weakness in lower limbs), boweland/or bladder dysfunction. Instruct patients to immediately reportif they experience any of the above signs or symptoms. If signs orsymptoms of spinal hematoma are suspected, initiate urgent diagnosisand treatment including consideration for spinal cord decompressioneven though such treatment may not prevent or reverse neurologicalsequelae.. 5.4 Thromboembolic andBleeding Events in Patients with Prosthetic Heart Valves. The safety and efficacy of PRADAXAin patients with bileaflet mechanical prosthetic heart valves wasevaluated in the RE-ALIGN trial, in which patients with bileafletmechanical prosthetic heart valves (recently implanted or implantedmore than three months prior to enrollment) were randomized to doseadjusted warfarin or 150, 220, or 300 mg of PRADAXA twice day. RE-ALIGNwas terminated early due to the occurrence of significantly more thromboembolicevents (valve thrombosis, stroke, transient ischemic attack, and myocardialinfarction) and an excess of major bleeding (predominantly post-operativepericardial effusions requiring intervention for hemodynamic compromise)in the PRADAXA treatment arm as compared to the warfarin treatmentarm. These bleeding and thromboembolic events were seen both in patientswho were initiated on PRADAXA post-operatively within three days ofmechanical bileaflet valve implantation, as well as in patients whosevalves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in patients withmechanical prosthetic valves [see Contraindications (4)]. The use of PRADAXA for the prophylaxis ofthromboembolic events in patients with atrial fibrillation in thesetting of other forms of valvular heart disease, including the presenceof bioprosthetic heart valve, has not been studied and is not recommended.. 5.5 Effect of P-gp Inducersand 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 [see Clinical Pharmacology (12.3)].P-gp inhibitionand impaired renal function are the major independent factors thatresult in increased exposure to dabigatran [see Clinical Pharmacology(12.3)]. Concomitant useof P-gp inhibitors in patients with renal impairment is expected toproduce increased exposure of dabigatran compared to that seen witheither factor alone.Reduction of Risk of Stroke and Systemic Embolism in Non-valvularAtrial FibrillationReduce the dose of PRADAXA to 75 mg twicedaily when dronedarone or systemic ketoconazole is coadministeredwith PRADAXA in patients with moderate renal impairment (CrCl 30-50mL/min). Avoid use of PRADAXA and P-gp inhibitors in patients withsevere renal impairment (CrCl 15-30 mL/min) [see Drug Interactions(7.1) and Use in Specific Populations(8.6)].Treatment and Reductionin the Risk of Recurrence of Deep Venous Thrombosis and PulmonaryEmbolismAvoid use of PRADAXA and concomitant P-gpinhibitors in patients with CrCl <50 mL/min [see Drug Interactions(7.2) and Use in Specific Populations(8.6)].Prophylaxis of Deep VeinThrombosis and Pulmonary Embolism Following Hip Replacement SurgeryAvoid useof PRADAXA and concomitant P-gp inhibitors in patients with CrCl <50mL/min [see Drug Interactions (7.3) and Use in Specific Populations (8.6)].