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Table 3 ( Cont ' d ) PRADAXA 150 mg twice daily N (%)

Warfarin N (%)

Clinically relevant non-major bleeding

Hazard Ratio ( 95 % CI ) c

Note : MBE can belong to more than one criterion . a

Patients with at least one MBE . b

Bleeding site based on investigator assessment . Patients can have more than one site of bleeding .

c

Confidence interval The rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg in the full treatment period was 3.1 % ( 2.4 % on warfarin ). The RE-MEDY and RE-SONATE studies provided safety information on the use of PRADAXA for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism . RE-MEDY was an activecontrolled study ( warfarin ) in which 1430 patients received PRADAXA 150 mg twice daily following 3 to 12 months of oral anticoagulant regimen . Patients in the treatment studies who rolled over into the RE-MEDY study had a combined treatment duration of up to more than 3 years , with mean exposure of 473 days . Table 4 shows the number of patients experiencing bleeding events in the study .

Figure 1

Subgroup

Major bleeding events , on treatment + 2 days , safety set

Note : MBE can belong to more than one criterion . a

Patients with at least one MBE . b

Bleeding site based on investigator assessment . Patients can have more than one site of bleeding .

c

Confidence interval

In the RE-MEDY study , the rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg was 3.1 % ( 2.2 % on warfarin ). RE-SONATE was a placebo-controlled study in which 684 patients received PRADAXA 150 mg twice daily following 6 to 18 months of oral anticoagulant regimen . Patients in the treatment studies who rolled over into the RE-SONATE study had combined treatment duration up to 9 months , with mean exposure of 165 days . Table 5 shows the number of patients experiencing bleeding events in the study .

c

Confidence interval

In the RE-SONATE study , the rate of any gastrointestinal bleeds in patients receiving PRADAXA 150 mg was 0.7 % ( 0.3 % on placebo ). Clinical Myocardial Infarction Events : In the active-controlled VTE studies , a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA [ 20 ( 0.66 per 100 patient-years )] than in those who received warfarin [ 5 ( 0.17 per 100 patient-years )]. In the placebocontrolled study , a similar rate of non-fatal and fatal clinical myocardial infarction was 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 Adverse Reactions : In the four pivotal studies , patients on PRADAXA 150 mg had a similar incidence of gastrointestinal adverse reactions ( 24.7 % vs . 22.7 % on warfarin ). Dyspepsia ( including abdominal pain upper , abdominal pain , abdominal discomfort , and epigastric discomfort ) occurred in patients on PRADAXA in 7.5 % vs . 5.5 % on warfarin , and gastritis-like symptoms ( including gastritis , GERD , esophagitis , erosive gastritis and gastric hemorrhage ) occurred at 3.0 % vs . 1.7 %, respectively . Hypersensitivity Reactions : In the 4 pivotal studies , drug hypersensitivity ( including urticaria , rash , and pruritus ), allergic edema , anaphylactic reaction , and anaphylactic shock were reported in 0.1 % of patients receiving PRADAXA .

Postmarketing Experience : The following adverse reactions have been identified during post approval use of PRADAXA . Because these reactions are reported voluntarily from a population of uncertain size , it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure . The following adverse reactions have been identified during post approval use of PRADAXA : angioedema , thrombocytopenia , esophageal ulcer .

In RE-LY , a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA ( 0.7 per 100 patient-years for 150 mg dose ) than in those who received warfarin ( 0.6 ).

Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients

PRADAXA 150 vs Warfarin Hazard ratio & 95 % CI

HR ( 95 % CI )

DRUG INTERACTIONS : Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation : The concomitant use of PRADAXA with P-gp inducers ( e . g ., rifampin ) reduces exposure to dabigatran and should generally be avoided . P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran . Concomitant use of P-gp inhibitors in patients with renal impairment is expected to produce increased exposure of dabigatran compared to that seen with either factor alone . In patients with moderate renal impairment ( CrCl 30-50 mL / min ), reduce the dose of PRADAXA to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole . The use of the P-gp inhibitors verapamil , amiodarone , quinidine , clarithromycin , and ticagrelor does not require a dose adjustment of PRADAXA . These results should not be extrapolated to other P-gp inhibitors [ see Warnings and Precautions and Use in Specific Populations ]. The concomitant use of PRADAXA and P-gp inhibitors in patients with severe renal impairment ( CrCl 15-30 mL / min ) should be avoided [ see Warnings and Precautions and Use in Specific Populations ]. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism : Avoid use of PRADAXA and P-gp inhibitors in patients with CrCl < 50 mL / min [ see Warnings and Precautions and Use in Specific Populations ].

USE IN SPECIFIC POPULATIONS : Pregnancy : Pregnancy Category C : There are no adequate and well-controlled studies in pregnant women . Dabigatran has been shown to decrease the number of implantations when male and female rats were treated at a dosage of 70 mg / kg ( about 2.6 to 3.0 times the human exposure at maximum recommended human dose [ MRHD ] of 300 mg / day based on area under the curve [ AUC ] comparisons ) prior to mating and up to implantation ( gestation Day 6 ). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal / uterine bleeding close to parturition . Although dabigatran increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat , it did not induce major malformations in rats or rabbits . Labor and Delivery : Safety and effectiveness of PRADAXA during labor and delivery have not been studied in clinical trials . Consider the risks of bleeding and of stroke in using PRADAXA in this setting [ see Warnings and Precautions ]. Death of offspring and mother rats during labor in association with uterine bleeding occurred during treatment of pregnant rats from implantation ( gestation Day 7 ) to weaning ( lactation Day 21 ) with dabigatran at a dose of 70 mg / kg ( about 2.6 times the human exposure at MRHD of 300 mg / day based on AUC comparisons ). Nursing Mothers : It is not known whether dabigatran is excreted in human milk . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from PRADAXA , a decision should be made whether to discontinue nursing or to discontinue the drug , taking into account the importance of the drug to the mother . Pediatric Use : Safety and effectiveness of PRADAXA in pediatric patients have not been established . Geriatric Use : Of the total number of patients in the RE-LY study , 82 % were 65 and over , while 40 % were 75 and over . The risk of stroke and bleeding increases with age , but the risk-benefit profile is favorable in all age groups [ see Warnings and Precautions and Adverse Reactions ]. Renal Impairment : Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation : No dose adjustment of PRADAXA is recommended in patients with mild or moderate renal impairment . Reduce the dose of PRADAXA in patients with severe renal impairment ( CrCl 15-30 mL / min ). Dosing recommendations for patients with CrCl < 15 mL / min or on dialysis cannot be provided . Adjust dose appropriately in patients with renal impairment receiving concomitant P-gp inhibitors [ see Warnings and Precautions and Drug Interactions ]. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism : Patients with severe renal impairment ( CrCl ≤30 mL / min ) were excluded from RE-COVER . Dosing recommendations for patients with CrCl ≤30 mL / min or on dialysis cannot be provided . Avoid use of PRADAXA with concomitant P-gp inhibitors in patients with CrCl < 50 mL / min [ see Warnings and Precautions and Drug Interactions ].

OVERDOSAGE : Accidental overdose may lead to hemorrhagic complications . In the event of hemorrhagic complications , initiate appropriate clinical support , discontinue treatment with PRADAXA , and investigate the source of bleeding . A specific reversal agent ( idarucizumab ) is available . Dabigatran is primarily eliminated by the kidneys with a low plasma protein binding of approximately 35 %. Hemodialysis can remove dabigatran ; however , data supporting this approach are limited . Using a high-flux dialyzer , blood flow rate of 200 mL / min , and dialysate flow rate of 700 mL / min , approximately 49 % of total dabigatran can be cleared from plasma over 4 hours . At the same dialysate flow rate , approximately 57 % can be cleared using a dialyzer blood flow rate of 300 mL / min , with no appreciable increase in clearance observed at higher blood flow rates . Upon cessation of hemodialysis , a redistribution effect of approximately 7 % to 15 % is seen . The effect of dialysis on dabigatran ’ s plasma concentration would be expected to vary based on patient specific characteristics . Measurement of aPTT or ECT may help guide therapy [ see Warnings and Precautions ].

Revised : November 2015 PXD-BS ( 12-15 )

Copyright 2015 Boehringer Ingelheim Pharmaceuticals , Inc . ALL RIGHTS RESERVED

PC-PXD-0337-PROF

0.1 0.5 1 1.5 2

PRADAXA Better

Warfarin Better

Note : The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified . The 95 % confidence limits that are shown do not take into account how many comparisons were made , nor do they reflect the effect of a particular factor after adjustment for all other factors . Apparent homogeneity or heterogeneity among groups should not be over-interpreted .