DABIGATRAN ETEXILATE

The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is N-[[2-[[[4-[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-β-alanine ethyl ester, methanesulfonate. The empirical formula is C 34 H 41 N 7 O 5 .CH 3 SO 3 H and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is: Dabigatran etexilate mesylate is a yellow-white to yellow color powder. Sparingly soluble in methanol. Dabigatran etexilate capsules are supplied in 75 mg, and 150 mg strengths for oral administration. Each capsule contains dabigatran etexilate mesylate as the active ingredient: 150 mg dabigatran etexilate (equivalent to 172.95 mg dabigatran etexilate mesylate), or 75 mg dabigatran etexilate (equivalent to 86.48 mg dabigatran etexilate mesylate) along with the following inactive ingredients: hydroxypropyl cellulose, hypromellose, sugar spheres (sucrose and corn starch), talc and tartaric acid. The capsule shell is composed of iron oxide red, iron oxide yellow, hypromellose and titanium dioxide. The capsules are printed with black ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. structural

Dabigatran etexilate capsules are direct thrombin inhibitors indicated: To reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation ( 1.1 ) For the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in adult patients who have been treated with a parenteral anticoagulant for 5 to 10 days ( 1.2 ) To reduce the risk of recurrence of DVT and PE in adult patients who have been previously treated ( 1.3 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation. 1.2 Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated for the treatment of deep venous thrombosis and pulmonary embolism in adult patients who have been treated with a parenteral anticoagulant for 5 to 10 days. 1.3 Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Dabigatran etexilate capsules are indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Non-valvular Atrial Fibrillation in Adult Patients: o For patients with CrCl >30 mL/min: 150 mg orally, twice daily ( 2.2 ) o For patients with CrCl 15 to 30 mL/min: 75 mg orally, twice daily ( 2.2 ) Treatment of DVT and PE in Adult Patients: o For patients with CrCl >30 mL/min: 150 mg orally, twice daily after 5 to 10 days of parenteral anticoagulation ( 2.2 ) Reduction in the Risk of Recurrence of DVT and PE in Adult Patients: o For patients with CrCl >30 mL/min: 150 mg orally, twice daily after previous treatment ( 2.2 ) Dabigatran etexilate capsules are NOT substitutable on a milligram-to-milligram basis with other dabigatran etexilate dosage forms. Review recommendations for converting to or from other oral or parenteral anticoagulants (2.6 , 2.7 ) Temporarily discontinue dabigatran etexilate capsules before invasive or surgical procedures when possible, then restart promptly ( 2.8 ) 2.1 Important Dosage Information Dabigatran etexilate is available in different dosage forms and not all dosage forms are approved for the same indications and age groups. In addition, there are differences between the dosage forms with respect to dosing due to differences in bioavailability. Do not substitute different dosage forms on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose [see Clinical Pharmacology ( 12.3 )]. 2.2 Recommended Dabigatran Etexilate Capsules Dose for Adults Indication Dosage Reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF CrCl >30 mL/min: CrCl 15 to 30 mL/min: CrCl <15 mL/min or on dialysis: 150 mg twice daily 75 mg twice daily Dosing recommendations cannot be provided CrCl 30 to 50 mL/min with concomitant use of P-gp inhibitors: Reduce dose to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole. CrCl <30 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Treatment of DVT and PE Reduction in the Risk of Recurrence of DVT and PE CrCl >30 mL/min: CrCl ≤30 mL/min or on dialysis: 150 mg twice daily Dosing recommendations cannot be provided CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of dabigatran etexilate capsules is 150 mg taken orally, twice daily. For patients with severe renal impairment (CrCl 15 to 30 mL/min), the recommended dose of dabigatran etexilate capsules is 75 mg twice daily [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided. Treatment of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dose of dabigatran etexilate capsules is 150 mg taken orally, twice daily, after 5 to 10 days of parenteral anticoagulation. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients For patients with CrCl >30 mL/min, the recommended dose of dabigatran etexilate capsules is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Dosage Adjustments Adult patients with renal impairment Assess renal function prior to initiation of treatment with dabigatran etexilate capsules. Periodically assess renal function as clinically indicated (i.e., more frequently in clinical situations that may be associated with a decline in renal function) and adjust therapy accordingly. Discontinue dabigatran etexilate capsules in patients who develop acute renal failure while on dabigatran etexilate capsules and consider alternative anticoagulant therapy. Generally, in adult patients, the extent of anticoagulation does not need to be assessed. When necessary, use aPTT or ECT, and not INR, to assess for anticoagulant activity in adult patients on dabigatran etexilate capsules [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )]. Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation In patients with moderate renal impairment (CrCl 30 to 50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to produce dabigatran exposure similar to that observed in severe renal impairment. Reduce the dose of dabigatran etexilate capsules to 75 mg twice daily [see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dosing recommendations for patients with CrCl ≤30 mL/min cannot be provided. Avoid use of concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see Warnings and Precautions ( 5.5 ), Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 2.5 Administration Dabigatran etexilate capsules should be swallowed whole. Dabigatran etexilate capsules should be taken with a full glass of water. Breaking, chewing, or emptying the contents of the capsule can result in increased exposure [see Clinical Pharmacology ( 12.3 )]. If a dose of dabigatran etexilate capsules is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of dabigatran etexilate capsules should not be doubled to make up for a missed dose. Consider administration with food if gastrointestinal distress occurs with dabigatran etexilate capsules. 2.6 Converting from or to Warfarin When converting patients from warfarin therapy to dabigatran etexilate capsules, discontinue warfarin and start dabigatran etexilate capsules when the INR is below 2.0. When converting from dabigatran etexilate capsules to warfarin, adjust the starting time of warfarin as follows: Adults For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate capsules. For CrCl 30 to 50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate capsules. For CrCl 15 to 30 mL/min, start warfarin 1 day before discontinuing dabigatran etexilate capsules. For CrCl <15 mL/min, no recommendations can be made. Because dabigatran etexilate capsules can increase INR, the INR will better reflect warfarin’s effect only after dabigatran etexilate capsules has been stopped for at least 2 days [see Clinical Pharmacology ( 12.2 )]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.7 Converting from or to Parenteral Anticoagulants For adult patients currently taking dabigatran etexilate capsules wait 12 hours (CrCl ≥30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of dabigatran etexilate capsules before initiating treatment with a parenteral anticoagulant [see Clinical Pharmacology ( 12.3 )]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.7 2.8 Discontinuation for Surgery and Other Interventions If possible, discontinue dabigatran etexilate capsules in adults 1 to 2 days (CrCl ≥50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]. If surgery cannot be delayed, there is an increased risk of bleeding [see Warnings and Precautions ( 5.2 )]. This risk of bleeding should be weighed against the urgency of intervention [see Warnings and Precautions ( 5.1, 5.3 )]. Use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when reversal of the anticoagulant effect of dabigatran is needed in adults. Efficacy and safety of idarucizumab have not been established in pediatric patients [see Warnings and Precautions ( 5.2 )]. Refer to the idarucizumab prescribing information for additional information. Restart dabigatran etexilate capsules as soon as medically appropriate. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Dabigatran etexilate capsules are contraindicated in patients with: Active pathological bleeding [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] 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 Adverse Reactions ( 6.1 )] Mechanical prosthetic heart valve [see Warnings and Precautions ( 5.4 )] Active pathological bleeding ( 4 ) History of serious hypersensitivity reaction to dabigatran etexilate capsules ( 4 ) Mechanical prosthetic heart valve ( 4 )

The following clinically significant adverse reactions are 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 Warnings and Precautions (5.3)] Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves [see Warnings and Precautions (5.4)] Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome [see Warnings and Precautions (5.6)] The most serious adverse reactions reported with dabigatran etexilate capsules were related to bleeding [see Warnings and Precautions (5.2)]. Most common adverse reactions (>15%) are gastrointestinal adverse reactions and bleeding ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact XLCare Pharmaceuticals, Inc. at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 dabigatran etexilate 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 Dabigatran etexilate capsules 110 mg twice daily Dabigatran etexilate capsules 150 mg twice daily Warfarin Total number treated 5983 6059 5998 Exposure > 12 months 4936 4939 5193 > 24 months 2387 2405 2470 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 dabigatran etexilate capsules 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of dabigatran etexilate 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 Dabigatran etexilate capsules 150 mg N = 6059 n (%/year b ) Warfarin N = 5998 n (%/year b ) Dabigatran etexilate capsules 150 mg vs Warfarin HR (95% CI) Major Bleeding c 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 Stroke e 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 Bleeding f 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-intracranial g 4 (0.04) 7 (0.07) 0.59 (0.17, 2.02) a Patients 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. b Annual 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. c Defined 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. d Intracranial bleed included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. e On-treatment analysis based on the safety population, compared to ITT analysis presented in Section 14 Clinical Studies. f Fatal bleed: Adjudicated major bleed as defined above with investigator reported fatal outcome and adjudicated death with primary cause from bleeding. g Non-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. There was a higher rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate capsules 150 mg than in patients receiving warfarin (6.6% vs 4.2%, respectively). The risk of major bleeds was similar with dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate capsules. Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism Dabigatran etexilate capsules were studied in 4387 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 dabigatran etexilate capsules 150 mg twice daily and warfarin for the treatment of deep vein thrombosis and pulmonary embolism. Patients received 5 to 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 Dabigatran etexilate capsules 150 mg twice daily N (%) Warfarin N (%) Hazard Ratio (95% CI) c Patients N=2553 N=2554 Major bleeding event a 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 MBE b 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) 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 dabigatran etexilate 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 dabigatran etexilate 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 1430 patients received dabigatran etexilate 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 Dabigatran etexilate capsules 150 mg twice daily N (%) Warfarin N (%) Hazard Ratio (95% CI) c Patients N=1430 N=1426 Major bleeding event a 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 MBE b 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) 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 dabigatran etexilate capsules 150 mg was 3.1% (2.2% on warfarin). RE-SONATE was a placebo-controlled study in which 684 patients received dabigatran etexilate 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 Dabigatran etexilate capsules 150 mg twice daily N (%) Placebo N (%) Hazard Ratio (95% CI) c Patients N=684 N=659 Major bleeding event a 2 (0.3) 0 Bleeding in a critical area or organ 0 0 Gastrointestinal b 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) 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-SONATE study, the rate of any gastrointestinal bleeds in patients receiving dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate 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 dabigatran etexilate capsules. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. figure1 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dabigatran etexilate capsules. 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 dabigatran etexilate capsules: angioedema, thrombocytopenia, esophageal ulcer, alopecia, neutropenia, agranulocytosis.

P-gp inducers: Avoid coadministration with dabigatran etexilate capsules ( 5.5 ) P-gp inhibitors in adult patients with CrCl 30 to 50 mL/min: Reduce dose or avoid ( 7 ) P-gp inhibitors in adult patients with CrCl <30 mL/min: Not recommended ( 7 ) 7.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients The concomitant use of dabigatran etexilate capsules with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology ( 12.3 )]. P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see Clinical Pharmacology ( 12.3 )]. 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 to 50 mL/min), reduce the dose of dabigatran etexilate capsules 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 dabigatran etexilate capsules. These results 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 concomitant use of dabigatran etexilate capsules and P-gp inhibitors in patients with severe renal impairment (CrCl 15 to 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 Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Avoid use of dabigatran etexilate capsules 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 )]. Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.