Dabigatran Etexilate Drug Information

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 . 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 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

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 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 = 6,059 n (%/year b ) Warfarin N = 5,998 n (%/year b ) Dabigatran Etexilate Capsules 150 mg vs. Warfarin HR (95% CI) Major Bleeding c 350 374 0.97 Intracranial Hemorrhage (ICH) d 23 82 0.29 Hemorrhagic Stroke e 6 40 0.16 Other ICH 17 46 0.38 Gastrointestinal 162 111 1.51 Fatal Bleeding f 7 16 0.45 ICH 3 9 0.35 Non-intracranial g 4 7 0.59 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 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 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 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=2,553 N=2,554 Major bleeding event a 37 51 0.73 Fatal bleeding 1 2 Bleeding in a critical area or organ 7 15 Fall in hemoglobin ≥2 g/dL or transfusion ≥2 units of whole blood or packed red blood cells 32 38 Bleeding sites for MBE b Intracranial 2 5 Retroperitoneal 2 1 Intraarticular 2 4 Intramuscular 2 6 Gastrointestinal 15 14 Urogenital 7 14 Other 8 8 Clinically relevant non-major bleeding 101 170 0.58 Any bleeding 411 567

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 1,430 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=1,430 N=1,426 Major bleeding event a 13 25 0.54 Fatal bleeding 0 1 Bleeding in a critical area or organ 7 11 Fall in hemoglobin ≥2 g/dL or transfusion ≥2 units of whole blood or packed red blood cells 7 16 Bleeding sites for MBE b Intracranial 2 4 Intraocular 4 2 Retroperitoneal 0 1 Intraarticular 0 2 Intramuscular 0 4 Gastrointestinal 4 8 Urogenital 1 1 Other 2 4 Clinically relevant non-major bleeding 71 125 0.56 Any bleeding 278 373 0.71 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 Bleeding in a critical area or organ 0 0 Gastrointestinal b 2 0 Clinically relevant non-major bleeding 34 13 2.54 Any bleeding 72 40 1.77 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 than in those who received warfarin. In the placebo-controlled study, a similar rate of nonfatal and fatal clinical myocardial infarction was reported in patients who received dabigatran etexilate capsules and in those who received placebo.

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% 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. Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery Dabigatran etexilate 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 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 dabigatran etexilate capsules 75 mg taken orally 1 to 4 hours after surgery followed by 150 mg once daily, dabigatran etexilate capsules 110 mg taken orally 1 to 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 dabigatran etexilate capsules 110 mg taken orally 1 to 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 to 35 days of dabigatran etexilate 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 Dabigatran Etexilate Capsules 220 mg N (%) Enoxaparin N (%) Patients N=1,146 N=1,154 Major bleeding event 23 18 Clinically relevant non-major bleeding 48 40 Any bleeding 141 132 Table 8: Bleeding Events in RE-NOVATE II Treated Patients Dabigatran Etexilate Capsules 220 mg N (%) Enoxaparin N (%) Patients N=1,010 N=1,003 Major bleeding event 14 9 Clinically relevant non-major bleeding 26 20 Any bleeding 98 83 In the two studies, the rate of major gastrointestinal bleeds in patients receiving dabigatran etexilate capsules and enoxaparin was the same (0.1%) and for any gastrointestinal bleeds was 1.4% for dabigatran etexilate capsules 220 mg and 0.9% for enoxaparin. Gastrointestinal Adverse Reactions In the two studies, the incidence of gastrointestinal adverse reactions for patients on dabigatran etexilate 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 dabigatran etexilate 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%, respectively.

Hypersensitivity Reactions In the two studies, drug hypersensitivity (such as urticaria, rash, and pruritus) was reported in 0.3% of patients receiving dabigatran etexilate capsules 220 mg. Clinical Myocardial Infarction Events In the two studies, clinical myocardial infarction was reported in 2 (0.1%) of patients who received dabigatran etexilate capsules 220 mg and 6 (0.3%) of patients who received enoxaparin. Pediatric Trials Treatment of VTE in Pediatric Patients The safety of dabigatran etexilate capsules 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 dabigatran etexilate capsules 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 dabigatran etexilate capsules and 90 patients treated with SOC. Patients on dabigatran etexilate capsules received age- and weight-adjusted dosages of an age-appropriate formulation of dabigatran etexilate (capsules, pellets, or oral solution) twice daily.

Patients had a median age of 14 years (range: 0 to 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 dabigatran etexilate capsules was 85 days (range: 1 to 105). Patients with estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73m 2 were excluded from the trial. Bleeding Data on adjudicated major bleeding, clinically relevant non-major (CRNM) bleeding and minor bleeding events, for the dabigatran etexilate 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 Dabigatran Etexilate Capsules N (%) Standard of Care (SOC) N (%) Patients N=176 N=90 Major bleeding event 1 4 2 Fatal bleeding 0 1 Clinically relevant non-major bleeding 2 1 Minor bleeding 33 21 Major and clinically relevant non-major bleeding 6 3 Any bleeding 38 22 1 Major 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 g/dL (1.24 mmol/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells.

Site-specific bleeding rates were comparable between the two arms, with the exception of the rate of any gastrointestinal bleeds (5.7% in dabigatran etexilate arm vs 1.8% in SOC arm). Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions for patients on dabigatran etexilate capsules and SOC was 32% and 12%, respectively, with the following occurring in ≥ 5% of patients taking dabigatran etexilate capsules: 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 dabigatran etexilate capsules 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 dabigatran etexilate capsules until the clinical risk factor resolved, or up to a maximum of 12 months. There were 213 pediatric patients treated with dabigatran etexilate capsules, in a similar fashion as in the DIVERSITY trial. Patients had a median age of 14 years (range: 0 to 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 dabigatran etexilate capsules arm and 14% from SOC arm). The median duration of treatment with dabigatran etexilate capsules in Study 2 was 42 weeks (range: 0 to 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. dabigatran-figure1.jpg

Postmarketing Experience

The following adverse reactions have been identified during post approval use of dabigatran etexilate. 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. Blood and Lymphatic System Disorders : Agranulocytosis, neutropenia, thrombocytopenia Gastrointestinal Disorders : Esophageal ulcer Immune System Disorders : Angioedema Renal and Urinary Disorders : Anticoagulant-related nephropathy Skin and Subcutaneous Tissue Disorders : Alopecia

• 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 dosage 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 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 dosage of dabigatran etexilate 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 dosage adjustment of dabigatran etexilate. 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 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 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 in Adult Patients Following Hip Replacement Surgery In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours. The concomitant use of dabigatran etexilate and P-gp inhibitors in patients with CrCl <50 mL/min should be avoided [see Warnings and Precautions (5.5), Use in Specific Populations (8.6) and Clinical Pharmacology (12.2, 12.3)] . 7.4 Treatment and Reduction in Risk of Recurrence of VTE in Pediatric Patients The concomitant use of dabigatran etexilate capsules with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran [see Warnings and Precautions (5.5)] .

Pregnancy Risk Summary The limited available data on dabigatran etexilate use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes. There are risks to the mother associated with untreated venous thromboembolism in pregnancy and a risk of hemorrhage in the mother and fetus associated with the use of anticoagulants (see Clinical Considerations). In pregnant rats treated from implantation until weaning, dabigatran increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition at an exposure 2.6 times the human exposure. At a similar exposure, dabigatran decreased the number of implantations when rats were treated prior to mating and up to implantation (gestation Day 6). Dabigatran administered to pregnant rats and rabbits during organogenesis up to exposures 8 and 13 times the human exposure, respectively, did not induce major malformations.

However, the incidence of delayed or irregular ossification of fetal skull bones and vertebrae was increased in the rat (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnancy confers an increased risk for thromboembolism that is higher for women with underlying thromboembolic disease and certain high-risk pregnancy conditions. Published data describe that women with a previous history of venous thrombosis are at high risk for recurrence during pregnancy. Fetal/Neonatal adverse reaction Use of anticoagulants, including dabigatran etexilate, may increase the risk of bleeding in the fetus and neonate.

Monitor neonates for bleeding. Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Dabigatran etexilate use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas.

Consider discontinuation or use of shorter acting anticoagulant as delivery approaches . Data Animal Data 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 times the human exposure at MRHD of 300 mg/day based on area under the curve 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. Dabigatran administered to pregnant rats and rabbits during organogenesis up to maternally toxic doses of 200 mg/kg (8 and 13 times the human exposure, respectively, at a MRHD of 300 mg/day based on AUC comparisons) did not induce major malformations, but increased the incidence of delayed or irregular ossification of fetal skull bones and vertebrae in the rat. 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).

Pediatric Use The safety and effectiveness of dabigatran etexilate capsules for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients 8 to less than 18 years of age. Use of dabigatran etexilate capsules for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients. These studies included an open-label, randomized, parallel-group study and an open-label, single-arm safety study.

Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age for these indications. Safety and effectiveness of dabigatran etexilate capsules have not been established in pediatric patients with non-valvular atrial fibrillation or those who have undergone hip replacement surgery.

• 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 )

Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with dabigatran etexilate, and investigate the source of bleeding. A specific reversal agent (idarucizumab) is available for adult patients.

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.