Pradaxa (Dabigatran Etexilate Mesylate)

PRADAXA is contraindicated in patients with:

• Active pathological bleeding
  [see

  5.2 Risk of Bleeding

  PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA Capsules in patients with active pathological bleeding

  [see Dosage and Administration (2.4)].

  Risk factors for bleeding include the concomitant use of other drugs that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA's anticoagulant activity and half-life are increased in patients with renal impairment

  [see Clinical Pharmacology (12.2)].

  Reversal of Anticoagulant Effect

  In adults, a specific reversal agent (idarucizumab) for PRADAXA is available when reversal of the anticoagulant effect of dabigatran is needed:

  • For emergency surgery/urgent procedures
  • In life-threatening or uncontrolled bleeding

  In pediatric patients, the efficacy and safety of idarucizumab have not been established.

  Hemodialysis can remove dabigatran; however the clinical experience supporting the use of hemodialysis as a treatment for bleeding is limited

  [see Overdosage (10)]

  . Prothrombin complex concentrates, or recombinant Factor VIIa may be considered but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

  and

  6.1 Clinical Trials Experience

  Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

  Adult Trials

  Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation

  The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of PRADAXA Capsules and warfarin

  [see Clinical Studies (14.1)]

  . The numbers of patients and their exposures are described in Table 2. Limited information is presented on the 110 mg dosing arm because this dose is not approved.

  Table 2 Summary of Treatment Exposure in RE-LY

  	PRADAXA Capsules 110 mg twice daily	PRADAXA Capsules 150 mg twice daily	Warfarin
  Total number treated	5,983	6,059	5,998
  Exposure
  > 12 months	4,936	4,939	5,193
  > 24 months	2,387	2,405	2,470
  Mean exposure (months)	20.5	20.3	21.3
  Total patient-years	10,242	10,261	10,659

  Drug Discontinuation in RE-LY

  The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA Capsules 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA Capsules were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).

  Bleeding [see Warnings and Precautions (5.2)]

  Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%). Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥ 2 g/dL, a transfusion of ≥ 2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

  Table 3 Adjudicated Major Bleeding Events in Treated Patients^a

  Event	PRADAXA Capsules 150 mg N = 6,059 n (%/yearb)	Warfarin N = 5,998 n (%/yearb)	PRADAXA Capsules 150 mg vs Warfarin HR (95% CI)
  aPatients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. bAnnual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered. cDefined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥ 2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome. dIntracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. eOn-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies. fFatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding. gNon-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator's clinical assessment.
  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	6 (0.06)	40 (0.37)	0.16 (0.07, 0.37)
  Other ICH	17 (0.17)	46 (0.43)	0.38 (0.22, 0.67)
  Gastrointestinal	162 (1.59)	111 (1.05)	1.51 (1.19, 1.92)
  Fatal Bleedingf	7 (0.07)	16 (0.15)	0.45 (0.19, 1.10)
  ICH	3 (0.03)	9 (0.08)	0.35 (0.09, 1.28)
  Non-intracranialg	4 (0.04)	7 (0.07)	0.59 (0.17, 2.02)

  There was a higher rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 150 mg than in patients receiving warfarin (6.6% vs 4.2%, respectively).

  The risk of major bleeds was similar with PRADAXA Capsules 150 mg and warfarin across major subgroups defined by baseline characteristics (see Figure 1), with the exception of age, where there was a trend toward a higher incidence of major bleeding on PRADAXA Capsules (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients ≥ 75 years of age.

  Figure 1 Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients

  

  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.

  

  Gastrointestinal Adverse Reactions

  Patients on PRADAXA Capsules 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).

  Hypersensitivity Reactions

  In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in < 0.1% of patients receiving PRADAXA Capsules.

  Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

  PRADAXA Capsules was studied in 4,387 patients in 4 pivotal, parallel, randomized, double-blind trials. Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies. Approximately 60% of the treated patients were male, with a mean age of 55.1 years. The majority of the patients were white (87.7%), 10.3% were Asian, and 1.9% were black with a mean CrCl of 105.6 mL/min.

  Bleeding events for the 4 pivotal studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells).

  RE-COVER and RE-COVER II studies compared PRADAXA Capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism. Patients received 5-10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table 4 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization.

  Table 4 Bleeding Events in RE-COVER and RE-COVER II Treated Patients

  	Bleeding Events—Full Treatment Period Including Parenteral Treatment
  Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigator assessment. Patients can have more than one site of bleeding. cConfidence interval
  	PRADAXA Capsules 150 mg twice daily N (%)	Warfarin N (%)	Hazard Ratio (95% CI)c
  Patients	N=2,553	N=2,554
  Major bleeding eventa	37 (1.4)	51 (2.0)	0.73 (0.48, 1.11)
  Fatal bleeding	1 (0.04)	2 (0.1)
  Bleeding in a critical area or organ	7 (0.3)	15 (0.6)
  Fall in hemoglobin ≥ 2 g/dL or transfusion ≥ 2 units of whole blood or packed red blood cells	32 (1.3)	38 (1.5)
  Bleeding sites for MBEb
  Intracranial	2 (0.1)	5 (0.2)
  Retroperitoneal	2 (0.1)	1 (0.04)
  Intraarticular	2 (0.1)	4 (0.2)
  Intramuscular	2 (0.1)	6 (0.2)
  Gastrointestinal	15 (0.6)	14 (0.5)
  Urogenital	7 (0.3)	14 (0.5)
  Other	8 (0.3)	8 (0.3)
  Clinically relevant non-major bleeding	101 (4.0)	170 (6.7)	0.58 (0.46, 0.75)
  Any bleeding	411 (16.1)	567 (22.7)	0.70 (0.61, 0.79)

  The rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 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 Capsules for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.

  RE-MEDY was an active-controlled study (warfarin) in which 1,430 patients received PRADAXA Capsules 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 5 shows the number of patients experiencing bleeding events in the study.

  Table 5 Bleeding Events in RE-MEDY Treated Patients

  	PRADAXA Capsules 150 mg twice daily N (%)	Warfarin N (%)	Hazard Ratio (95% CI)c
  Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigator assessment. Patients can have more than one site of bleeding. cConfidence interval
  Patients	N=1,430	N=1,426
  Major bleeding eventa	13 (0.9)	25 (1.8)	0.54 (0.25, 1.16)
  Fatal bleeding	0	1 (0.1)
  Bleeding in a critical area or organ	7 (0.5)	11 (0.8)
  Fall in hemoglobin ≥ 2 g/dL or transfusion ≥ 2 units of whole blood or packed red blood cells	7 (0.5)	16 (1.1)
  Bleeding sites for MBEb
  Intracranial	2 (0.1)	4 (0.3)
  Intraocular	4 (0.3)	2 (0.1)
  Retroperitoneal	0	1 (0.1)
  Intraarticular	0	2 (0.1)
  Intramuscular	0	4 (0.3)
  Gastrointestinal	4 (0.3)	8 (0.6)
  Urogenital	1 (0.1)	1 (0.1)
  Other	2 (0.1)	4 (0.3)
  Clinically relevant non-major bleeding	71 (5.0)	125 (8.8)	0.56 (0.42, 0.75)
  Any bleeding	278 (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 PRADAXA Capsules 150 mg was 3.1% (2.2% on warfarin).

  RE-SONATE was a placebo-controlled study in which 684 patients received PRADAXA Capsules 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 6 shows the number of patients experiencing bleeding events in the study.

  Table 6 Bleeding Events in RE-SONATE Treated Patients

  	PRADAXA Capsules 150 mg twice daily N (%)	Placebo N (%)	Hazard Ratio (95% CI)c
  Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigator assessment. Patients can have more than one site of bleeding. cConfidence interval
  Patients	N=684	N=659
  Major bleeding eventa	2 (0.3)	0
  Bleeding in a critical area or organ	0	0
  Gastrointestinalb	2 (0.3)	0
  Clinically relevant non-major bleeding	34 (5.0)	13 (2.0)	2.54 (1.34, 4.82)
  Any bleeding	72 (10.5)	40 (6.1)	1.77 (1.20, 2.61)

  In the RE-SONATE study, the rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 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 Capsules [20 (0.66 per 100 patient-years)] than in those who received warfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlled study, a similar rate of nonfatal and fatal clinical myocardial infarction was reported in patients who received PRADAXA Capsules [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 Capsules 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 Capsules 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 Capsules.

  Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery

  PRADAXA Capsules was studied in 5,476 patients, randomized and treated in two double-blind, active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATE II). The demographic characteristics were similar across the two studies and between the treatment groups within these studies. Approximately 45.3% of the treated patients were male, with a mean age of 63.2 years. The majority of the patients were white (96.1%), 3.6% were Asian, and 0.3% were black with a mean CrCl of 92 mL/min.

  Bleeding events for the RE-NOVATE and RE-NOVATE II studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or retroperitoneal bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells, requiring treatment cessation or leading to re-operation.

  The RE-NOVATE study compared PRADAXA Capsules 75 mg taken orally 1-4 hours after surgery followed by 150 mg once daily, PRADAXA Capsules 110 mg taken orally 1-4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery. The RE-NOVATE II study compared PRADAXA Capsules 110 mg taken orally 1-4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery. In the RE-NOVATE and RE-NOVATE II studies, patients received 28-35 days of PRADAXA Capsules or enoxaparin with median exposure of 33 days. Tables 7 and 8 show the number of patients experiencing bleeding events in the analysis of RE-NOVATE and RE-NOVATE II.

  Table 7 Bleeding Events in RE-NOVATE Treated Patients

  	PRADAXA Capsules 220 mg N (%)	Enoxaparin N (%)
  Patients	N=1,146	N=1,154
  Major bleeding event	23 (2.0)	18 (1.6)
  Clinically relevant non-major bleeding	48 (4.2)	40 (3.5)
  Any bleeding	141 (12.3)	132 (11.4)

  Table 8 Bleeding Events in RE-NOVATE II Treated Patients

  	PRADAXA Capsules 220 mg N (%)	Enoxaparin N (%)
  Patients	N=1,010	N=1,003
  Major bleeding event	14 (1.4)	9 (0.9)
  Clinically relevant non-major bleeding	26 (2.6)	20 (2.0)
  Any bleeding	98 (9.7)	83 (8.3)

  In the two studies, the rate of major gastrointestinal bleeds in patients receiving PRADAXA Capsules and enoxaparin was the same (0.1%) and for any gastrointestinal bleeds was 1.4% for PRADAXA Capsules 220 mg and 0.9% for enoxaparin.

  Gastrointestinal Adverse Reactions

  In the two studies, the incidence of gastrointestinal adverse reactions for patients on PRADAXA Capsules 220 mg and enoxaparin was 39.5% and 39.5%, respectively. Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred in patients on PRADAXA Capsules 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 Reactions

  In the two studies, drug hypersensitivity (such as urticaria, rash, and pruritus) was reported in 0.3% of patients receiving PRADAXA Capsules 220 mg.

  Clinical Myocardial Infarction Events

  In the two studies, clinical myocardial infarction was reported in 2 (0.1%) of patients who received PRADAXA Capsules 220 mg and 6 (0.3%) of patients who received enoxaparin.

  Pediatric Trials

  Treatment of VTE in Pediatric Patients

  The safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with PRADAXA and 90 patients treated with SOC. Patients on PRADAXA received age- and weight-adjusted dosages of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily.

  Patients had a median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with PRADAXA was 85 days (range: 1-105). Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m²were excluded from the trial.

  Bleeding

  Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the PRADAXA group and the SOC group in the DIVERSITY study, are reported in Table 9. There was no statistically significant difference in the time to first major bleeding event.

  Table 9 Summary of All Adjudicated Bleeding Events During On-Treatment Period in DIVERSITY

  	PRADAXA N (%)	Standard of Care (SOC) N (%)
  1Major bleeding event if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.
  Patients	N=176	N=90
  Major bleeding event1	4 (2.3)	2 (2.2)
  Fatal bleeding	0	1 (1.1)
  Clinically relevant non-major bleeding	2 (1.1)	1 (1.1)
  Minor bleeding	33 (19)	21 (23)
  Major and clinically relevant non-major bleeding	6 (3.4)	3 (3.3)
  Any bleeding	38 (22)	22 (24)

  Site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in PRADAXA arm vs 1.8% in SOC arm).

  Gastrointestinal Adverse Reactions

  The incidence of gastrointestinal adverse reactions for patients on PRADAXA and SOC was 32% and 12%, respectively, with the following occurring in ≥ 5% of patients taking PRADAXA: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%).

  Reduction in Risk of Recurrence of VTE in Pediatric Patients

  The safety of PRADAXA in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2). Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to a maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in a similar fashion as in the DIVERSITY trial.

  Patients had a median age of 14 years (range: 0-18 years), 91% were white, and 55% of patients were male. Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 2 was 42 weeks (range: 0-56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation.

  During the on-treatment period of Study 2, 3 patients (1.4%) had a major bleeding event, 3 patients (1.4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. The most common drug-related adverse reactions were dyspepsia (5%), epistaxis (3.3%), nausea (3.3%) and menorrhagia (2.8%).

  The adverse reaction profile in pediatric patients was generally consistent with that of adult patients.

  ]
• History of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of the product (e.g., anaphylactic reaction or anaphylactic shock)
  [see

  6.1 Clinical Trials Experience

  Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

  Adult Trials

  Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation

  The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of PRADAXA Capsules and warfarin

  [see Clinical Studies (14.1)]

  . The numbers of patients and their exposures are described in Table 2. Limited information is presented on the 110 mg dosing arm because this dose is not approved.

  Table 2 Summary of Treatment Exposure in RE-LY

  	PRADAXA Capsules 110 mg twice daily	PRADAXA Capsules 150 mg twice daily	Warfarin
  Total number treated	5,983	6,059	5,998
  Exposure
  > 12 months	4,936	4,939	5,193
  > 24 months	2,387	2,405	2,470
  Mean exposure (months)	20.5	20.3	21.3
  Total patient-years	10,242	10,261	10,659

  Drug Discontinuation in RE-LY

  The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA Capsules 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA Capsules were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea).

  Bleeding [see Warnings and Precautions (5.2)]

  Table 3 shows the number of adjudicated major bleeding events during the treatment period in the RE-LY study, with the bleeding rate per 100 subject-years (%). Major bleeding is defined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥ 2 g/dL, a transfusion of ≥ 2 units of packed red blood cells, bleeding at a critical site or with a fatal outcome. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

  Table 3 Adjudicated Major Bleeding Events in Treated Patients^a

  Event	PRADAXA Capsules 150 mg N = 6,059 n (%/yearb)	Warfarin N = 5,998 n (%/yearb)	PRADAXA Capsules 150 mg vs Warfarin HR (95% CI)
  aPatients during treatment or within 2 days of stopping study treatment. Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. bAnnual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered. cDefined as bleeding accompanied by one or more of the following: a decrease in hemoglobin of ≥ 2 g/dL, a transfusion of 2 or more units of packed red blood cells, bleeding at a critical site or with fatal outcome. dIntracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. eOn-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies. fFatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding. gNon-intracranial fatal bleed: Adjudicated major bleed as defined above and adjudicated death with primary cause from bleeding but without symptomatic intracranial bleed based on investigator's clinical assessment.
  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	6 (0.06)	40 (0.37)	0.16 (0.07, 0.37)
  Other ICH	17 (0.17)	46 (0.43)	0.38 (0.22, 0.67)
  Gastrointestinal	162 (1.59)	111 (1.05)	1.51 (1.19, 1.92)
  Fatal Bleedingf	7 (0.07)	16 (0.15)	0.45 (0.19, 1.10)
  ICH	3 (0.03)	9 (0.08)	0.35 (0.09, 1.28)
  Non-intracranialg	4 (0.04)	7 (0.07)	0.59 (0.17, 2.02)

  There was a higher rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 150 mg than in patients receiving warfarin (6.6% vs 4.2%, respectively).

  The risk of major bleeds was similar with PRADAXA Capsules 150 mg and warfarin across major subgroups defined by baseline characteristics (see Figure 1), with the exception of age, where there was a trend toward a higher incidence of major bleeding on PRADAXA Capsules (hazard ratio 1.2, 95% CI: 1.0 to 1.5) for patients ≥ 75 years of age.

  Figure 1 Adjudicated Major Bleeding by Baseline Characteristics Including Hemorrhagic Stroke Treated Patients

  

  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.

  

  Gastrointestinal Adverse Reactions

  Patients on PRADAXA Capsules 150 mg had an increased incidence of gastrointestinal adverse reactions (35% vs 24% on warfarin). These were commonly dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) and gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gastrointestinal ulcer).

  Hypersensitivity Reactions

  In the RE-LY study, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in < 0.1% of patients receiving PRADAXA Capsules.

  Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism

  PRADAXA Capsules was studied in 4,387 patients in 4 pivotal, parallel, randomized, double-blind trials. Three of these trials were active-controlled (warfarin) (RE-COVER, RE-COVER II, and RE-MEDY), and one study (RE-SONATE) was placebo-controlled. The demographic characteristics were similar among the 4 pivotal studies and between the treatment groups within these studies. Approximately 60% of the treated patients were male, with a mean age of 55.1 years. The majority of the patients were white (87.7%), 10.3% were Asian, and 1.9% were black with a mean CrCl of 105.6 mL/min.

  Bleeding events for the 4 pivotal studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L or more, or leading to transfusion of 2 or more units of whole blood or red cells).

  RE-COVER and RE-COVER II studies compared PRADAXA Capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism. Patients received 5-10 days of an approved parenteral anticoagulant therapy followed by 6 months, with mean exposure of 164 days, of oral only treatment; warfarin was overlapped with parenteral therapy. Table 4 shows the number of patients experiencing bleeding events in the pooled analysis of RE-COVER and RE-COVER II studies during the full treatment including parenteral and oral only treatment periods after randomization.

  Table 4 Bleeding Events in RE-COVER and RE-COVER II Treated Patients

  	Bleeding Events—Full Treatment Period Including Parenteral Treatment
  Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigator assessment. Patients can have more than one site of bleeding. cConfidence interval
  	PRADAXA Capsules 150 mg twice daily N (%)	Warfarin N (%)	Hazard Ratio (95% CI)c
  Patients	N=2,553	N=2,554
  Major bleeding eventa	37 (1.4)	51 (2.0)	0.73 (0.48, 1.11)
  Fatal bleeding	1 (0.04)	2 (0.1)
  Bleeding in a critical area or organ	7 (0.3)	15 (0.6)
  Fall in hemoglobin ≥ 2 g/dL or transfusion ≥ 2 units of whole blood or packed red blood cells	32 (1.3)	38 (1.5)
  Bleeding sites for MBEb
  Intracranial	2 (0.1)	5 (0.2)
  Retroperitoneal	2 (0.1)	1 (0.04)
  Intraarticular	2 (0.1)	4 (0.2)
  Intramuscular	2 (0.1)	6 (0.2)
  Gastrointestinal	15 (0.6)	14 (0.5)
  Urogenital	7 (0.3)	14 (0.5)
  Other	8 (0.3)	8 (0.3)
  Clinically relevant non-major bleeding	101 (4.0)	170 (6.7)	0.58 (0.46, 0.75)
  Any bleeding	411 (16.1)	567 (22.7)	0.70 (0.61, 0.79)

  The rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 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 Capsules for the reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.

  RE-MEDY was an active-controlled study (warfarin) in which 1,430 patients received PRADAXA Capsules 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 5 shows the number of patients experiencing bleeding events in the study.

  Table 5 Bleeding Events in RE-MEDY Treated Patients

  	PRADAXA Capsules 150 mg twice daily N (%)	Warfarin N (%)	Hazard Ratio (95% CI)c
  Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigator assessment. Patients can have more than one site of bleeding. cConfidence interval
  Patients	N=1,430	N=1,426
  Major bleeding eventa	13 (0.9)	25 (1.8)	0.54 (0.25, 1.16)
  Fatal bleeding	0	1 (0.1)
  Bleeding in a critical area or organ	7 (0.5)	11 (0.8)
  Fall in hemoglobin ≥ 2 g/dL or transfusion ≥ 2 units of whole blood or packed red blood cells	7 (0.5)	16 (1.1)
  Bleeding sites for MBEb
  Intracranial	2 (0.1)	4 (0.3)
  Intraocular	4 (0.3)	2 (0.1)
  Retroperitoneal	0	1 (0.1)
  Intraarticular	0	2 (0.1)
  Intramuscular	0	4 (0.3)
  Gastrointestinal	4 (0.3)	8 (0.6)
  Urogenital	1 (0.1)	1 (0.1)
  Other	2 (0.1)	4 (0.3)
  Clinically relevant non-major bleeding	71 (5.0)	125 (8.8)	0.56 (0.42, 0.75)
  Any bleeding	278 (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 PRADAXA Capsules 150 mg was 3.1% (2.2% on warfarin).

  RE-SONATE was a placebo-controlled study in which 684 patients received PRADAXA Capsules 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 6 shows the number of patients experiencing bleeding events in the study.

  Table 6 Bleeding Events in RE-SONATE Treated Patients

  	PRADAXA Capsules 150 mg twice daily N (%)	Placebo N (%)	Hazard Ratio (95% CI)c
  Note: MBE can belong to more than one criterion. aPatients with at least one MBE. bBleeding site based on investigator assessment. Patients can have more than one site of bleeding. cConfidence interval
  Patients	N=684	N=659
  Major bleeding eventa	2 (0.3)	0
  Bleeding in a critical area or organ	0	0
  Gastrointestinalb	2 (0.3)	0
  Clinically relevant non-major bleeding	34 (5.0)	13 (2.0)	2.54 (1.34, 4.82)
  Any bleeding	72 (10.5)	40 (6.1)	1.77 (1.20, 2.61)

  In the RE-SONATE study, the rate of any gastrointestinal bleeds in patients receiving PRADAXA Capsules 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 Capsules [20 (0.66 per 100 patient-years)] than in those who received warfarin [5 (0.17 per 100 patient-years)]. In the placebo-controlled study, a similar rate of nonfatal and fatal clinical myocardial infarction was reported in patients who received PRADAXA Capsules [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 Capsules 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 Capsules 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 Capsules.

  Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery

  PRADAXA Capsules was studied in 5,476 patients, randomized and treated in two double-blind, active-controlled non-inferiority trials (RE-NOVATE and RE-NOVATE II). The demographic characteristics were similar across the two studies and between the treatment groups within these studies. Approximately 45.3% of the treated patients were male, with a mean age of 63.2 years. The majority of the patients were white (96.1%), 3.6% were Asian, and 0.3% were black with a mean CrCl of 92 mL/min.

  Bleeding events for the RE-NOVATE and RE-NOVATE II studies were classified as major bleeding events if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or retroperitoneal bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells, requiring treatment cessation or leading to re-operation.

  The RE-NOVATE study compared PRADAXA Capsules 75 mg taken orally 1-4 hours after surgery followed by 150 mg once daily, PRADAXA Capsules 110 mg taken orally 1-4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery. The RE-NOVATE II study compared PRADAXA Capsules 110 mg taken orally 1-4 hours after surgery followed by 220 mg once daily and subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who had undergone hip replacement surgery. In the RE-NOVATE and RE-NOVATE II studies, patients received 28-35 days of PRADAXA Capsules or enoxaparin with median exposure of 33 days. Tables 7 and 8 show the number of patients experiencing bleeding events in the analysis of RE-NOVATE and RE-NOVATE II.

  Table 7 Bleeding Events in RE-NOVATE Treated Patients

  	PRADAXA Capsules 220 mg N (%)	Enoxaparin N (%)
  Patients	N=1,146	N=1,154
  Major bleeding event	23 (2.0)	18 (1.6)
  Clinically relevant non-major bleeding	48 (4.2)	40 (3.5)
  Any bleeding	141 (12.3)	132 (11.4)

  Table 8 Bleeding Events in RE-NOVATE II Treated Patients

  	PRADAXA Capsules 220 mg N (%)	Enoxaparin N (%)
  Patients	N=1,010	N=1,003
  Major bleeding event	14 (1.4)	9 (0.9)
  Clinically relevant non-major bleeding	26 (2.6)	20 (2.0)
  Any bleeding	98 (9.7)	83 (8.3)

  In the two studies, the rate of major gastrointestinal bleeds in patients receiving PRADAXA Capsules and enoxaparin was the same (0.1%) and for any gastrointestinal bleeds was 1.4% for PRADAXA Capsules 220 mg and 0.9% for enoxaparin.

  Gastrointestinal Adverse Reactions

  In the two studies, the incidence of gastrointestinal adverse reactions for patients on PRADAXA Capsules 220 mg and enoxaparin was 39.5% and 39.5%, respectively. Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort) occurred in patients on PRADAXA Capsules 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 Reactions

  In the two studies, drug hypersensitivity (such as urticaria, rash, and pruritus) was reported in 0.3% of patients receiving PRADAXA Capsules 220 mg.

  Clinical Myocardial Infarction Events

  In the two studies, clinical myocardial infarction was reported in 2 (0.1%) of patients who received PRADAXA Capsules 220 mg and 6 (0.3%) of patients who received enoxaparin.

  Pediatric Trials

  Treatment of VTE in Pediatric Patients

  The safety of PRADAXA in the treatment of VTE in pediatric patients was studied in one phase III trial (DIVERSITY). The DIVERSITY study was a randomized, open-label, active-controlled, parallel-group trial comparing PRADAXA with standard of care – SOC (vitamin K antagonists, low molecular weight heparin, or fondaparinux). There were 266 pediatric patients who received study treatment, 176 patients treated with PRADAXA and 90 patients treated with SOC. Patients on PRADAXA received age- and weight-adjusted dosages of an age-appropriate formulation of PRADAXA (capsules, pellets, or oral solution) twice daily.

  Patients had a median age of 14 years (range: 0-17 years), 92% were white, and half the patients were male (50%). Following at least 5 days of parenteral anticoagulant therapy, the median duration of treatment with PRADAXA was 85 days (range: 1-105). Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m²were excluded from the trial.

  Bleeding

  Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the PRADAXA group and the SOC group in the DIVERSITY study, are reported in Table 9. There was no statistically significant difference in the time to first major bleeding event.

  Table 9 Summary of All Adjudicated Bleeding Events During On-Treatment Period in DIVERSITY

  	PRADAXA N (%)	Standard of Care (SOC) N (%)
  1Major bleeding event if at least one of the following criteria applied: fatal bleeding, symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding), bleeding causing a fall in hemoglobin level of 2.0 g/dL (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.
  Patients	N=176	N=90
  Major bleeding event1	4 (2.3)	2 (2.2)
  Fatal bleeding	0	1 (1.1)
  Clinically relevant non-major bleeding	2 (1.1)	1 (1.1)
  Minor bleeding	33 (19)	21 (23)
  Major and clinically relevant non-major bleeding	6 (3.4)	3 (3.3)
  Any bleeding	38 (22)	22 (24)

  Site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in PRADAXA arm vs 1.8% in SOC arm).

  Gastrointestinal Adverse Reactions

  The incidence of gastrointestinal adverse reactions for patients on PRADAXA and SOC was 32% and 12%, respectively, with the following occurring in ≥ 5% of patients taking PRADAXA: dyspepsia (including term gastro-esophageal reflux disease, gastric pH decreased and esophagitis) in 9% (vs 2%), upper abdominal pain in 5% (vs 1%), vomiting in 8% (vs 2%), nausea 5% (vs 4%), and diarrhea 5% (vs 1%).

  Reduction in Risk of Recurrence of VTE in Pediatric Patients

  The safety of PRADAXA in the reduction in the risk of recurrence of VTE in pediatric patients was studied in one open-label single-arm trial (Study 2). Study 2 enrolled patients who required further anticoagulation due to the presence of a clinical risk factor after completing the initial treatment for confirmed VTE (for at least 3 months) or after completing the DIVERSITY study and received PRADAXA until the clinical risk factor resolved, or up to a maximum of 12 months. There were 213 pediatric patients treated with PRADAXA, in a similar fashion as in the DIVERSITY trial.

  Patients had a median age of 14 years (range: 0-18 years), 91% were white, and 55% of patients were male. Patients previously enrolled on DIVERSITY accounted for 43% of patients enrolled on Study 2 (29% from PRADAXA arm and 14% from SOC arm). The median duration of treatment with PRADAXA in Study 2 was 42 weeks (range: 0-56 weeks), with 45% of patients completing the 12-month planned duration, 17% stopping due to resolution of VTE risk factors, 12% stopping due to failure to attain target dabigatran concentration and 6% had an adverse event leading to discontinuation.

  During the on-treatment period of Study 2, 3 patients (1.4%) had a major bleeding event, 3 patients (1.4%) had a clinically relevant non-major bleeding event, and 44 patients (20%) had a minor bleeding event. The most common drug-related adverse reactions were dyspepsia (5%), epistaxis (3.3%), nausea (3.3%) and menorrhagia (2.8%).

  The adverse reaction profile in pediatric patients was generally consistent with that of adult patients.

  ]
• Mechanical prosthetic heart valve
  [see

  5.4 Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

  The safety and efficacy of PRADAXA Capsules in adult patients with bileaflet mechanical prosthetic heart valves was evaluated in the RE-ALIGN trial, in which patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than three months prior to enrollment) were randomized to dose-adjusted warfarin or 150 mg, 220 mg, or 300 mg of PRADAXA Capsules twice a day. RE-ALIGN was terminated early due to the occurrence of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) in the PRADAXA Capsules treatment arm as compared to the warfarin treatment arm. These bleeding and thromboembolic events were seen both in patients who were initiated on PRADAXA Capsules postoperatively within three days of mechanical bileaflet valve implantation, as well as in patients whose valves had been implanted more than three months prior to enrollment. Therefore, the use of PRADAXA is contraindicated in all patients with mechanical prosthetic valves

  [see Contraindications (4)].

  The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of a bioprosthetic heart valve, has not been studied and is not recommended.

  ]