Dabigatran Etexilate

1 INDICATIONS AND USAGE Dabigatran Etexilate Capsules is a direct thrombin inhibitor 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 ) For the prophylaxis of DVT and PE in adult patients who have undergone hip replacement surgery ( 1.4 ) For the treatment of venous thromboembolic events (VTE) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days ( 1.5 ) To reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated ( 1.6 ) 1.1 Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients Dabigatran Etexilate Capsules is 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 is 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 is indicated to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in adult patients who have been previously treated. 1.4 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery Dabigatran Etexilate Capsules is indicated for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery. 1.5 Treatment of Venous Thromboembolic Events in Pediatric Patients Dabigatran Etexilate Capsules is indicated for the treatment of venous thromboembolic events (VTE) in pediatric patients 8 to less than 18 years of age who have been treated with a parenteral anticoagulant for at least 5 days [see Dosage and Administration ( 2.3 )]. 1.6 Reduction in the Risk of Recurrence of Venous Thromboembolic Events in Pediatric Patients Dabigatran Etexilate Capsules is indicated to reduce the risk of recurrence of VTE in pediatric patients 8 to less than 18 years of age who have been previously treated [see Dosage and Administration ( 2.3 )].

2 DOSAGE AND ADMINISTRATION • 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 ) • Prophylaxis of DVT and PE Following Hip Replacement Surgery in Adult Patients: o For patients with CrCl >30 mL/min: 110 mg orally first day, then 220 mg once daily ( 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 Dosage 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 30 mL/min: CrCl ≤30 mL/min or on dialysis: 150 mg twice daily Dosing recommendations cannot be provided CrCl 30 mL/min: 110 mg for first day, then 220 mg once daily CrCl ≤30 mL/min or on dialysis: Dosing recommendations cannot be provided CrCl 30 mL/min, the recommended dosage 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 dosage 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 30 mL/min, the recommended dosage 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 dosage 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)] . Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery For patients with CrCl >30 mL/min, the recommended dosage of Dabigatran Etexilate Capsules is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then 220 mg taken once daily for 28 to 35 days. If Dabigatran Etexilate Capsules is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once daily. Dosing recommendations for patients with a CrCl ≤30 mL/min or on dialysis cannot be provided [see Dosage and Administration (2.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.2, 12.3)] . Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Pradaxa (dabigatran etexilate) capsules. However, due to Boehringer Ingelh …

3 DOSAGE FORMS AND STRENGTHS 150 mg capsules with a white to pale yellow pellets filled in HPMC capsule size “0EL” light navy blue opaque cap and light cream opaque body imprinted with “150” on body and “DAB” on cap in black ink. 110 mg capsules with a white to pale yellow pellets filled in HPMC capsule size "0" light blue opaque body and light blue opaque cap imprinted with "110" on body and "Dab" on cap in black ink. 75 mg capsules with a white to pale yellow pellets filled in HPMC capsule size “1” light cream opaque cap and light cream opaque body imprinted with “DAB” on cap and “75” on body in black ink. Capsules: 75 mg, 110 mg and 150 mg ( 3 )

4 CONTRAINDICATIONS Dabigatran Etexilate Capsules is 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 )

6 ADVERSE REACTIONS 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 Ascend Laboratories, LLC at 1-877-272-7901 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 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 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 = 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 (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 …

7 DRUG INTERACTIONS 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 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 dosage 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 dosage 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 )] . 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 Etexilate Capsules and the P-gp inhibitor by several hours. The concomitant use of Dabigatran Etexilate Capsules 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 )].

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended ( 8.2 ) Geriatric Use: Risk of bleeding increases with age ( 8.5 ) 8.1 Pregnancy Risk Summary The limited available data on Dabigatran Etexilate Capsules 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 Capsules, may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding [see Warnings and Precautions (5.2)]. Labor or delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Dabigatran Etexilate Capsules 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 [see Warnings and Precautions (5.2, 5.3)]. 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 3.0 times the human exposure at MRHD of 300 mg/day based on area under the curve [AUC] comparisons) prior to mating and up to implantation (gestation Day 6). Treatment of pregnant rats after implantation with dabigatran at the same dose increased the number of dead offspring and caused excess vaginal/uterine bleeding close to parturition. 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). 8.2 Lactation Risk Summary There are insufficient data to assess the presence of dabigatran in human milk. There are no data on the effects of dabigatran on the breastfed child or on milk production. Dabigatran and/or its meta …

12.1 Mechanism of Action Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

11 DESCRIPTION The chemical name for dabigatran etexilate mesylate, a direct thrombin inhibitor, is β-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-,ethyl ester, methanesulfonate. The empirical formula is C 34 H 41 N 7 O 5 ⋅ CH 4 O 3 S and the molecular weight is 723.86 (mesylate salt), 627.75 (free base). The structural formula is: Dabigatran etexilate mesylate is a white to pale yellow powder. A saturated solution in pure water has a solubility of 1.8 mg/mL. It is freely soluble in methanol, slightly soluble in ethanol, and sparingly soluble in isopropanol. Dabigatran Etexilate Capsules are supplied in 75 mg, 110 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), 110 mg dabigatran etexilate (equivalent to 126.83 mg dabigatran etexilate mesylate), or 75 mg dabigatran etexilate (equivalent to 86.48 mg dabigatran etexilate mesylate) along with the following inactive ingredients: Butylated hydroxy toluene, citric acid monohydrate crystal, hydroxy propyl cellulose, hypromellose, hypromellose phthalate, macrogol, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol 600, polyvinyl alcohol, povidone (k-value-25), sodium bicarbonate, talc, tartaric acid and titanium dioxide. The capsule shell is composed of hypromellose, titanium dioxide, FD&C red #40 & FD&C blue #1 (150 mg and 110 mg), FD&C yellow #6 (75 mg and 150 mg). The imprinting ink contains shellac, propylene glycol, strong ammonia solution, black iron oxide & potassium hydroxide. dab-igatran-str

10 OVERDOSAGE Accidental overdose may lead to hemorrhagic complications. In the event of hemorrhagic complications, initiate appropriate clinical support, discontinue treatment with Dabigatran Etexilate Capsules, 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 [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )].

16 HOW SUPPLIED/STORAGE AND HANDLING Dabigatran Etexilate Capsules 75 mg capsules have a light cream opaque cap and light cream opaque body imprinted with “DAB” on cap and “75” on body in black ink. The capsules are supplied in the packages listed: • NDC 67877-474-60 Unit of use bottle of 60 capsules • NDC 67877-474-31 Blister package containing 60 capsules (6 x 10 Unit-dose) Dabigatran Etexilate Capsules 110 mg capsules have a light blue opaque body and light blue opaque cap imprinted with "110" on body and "Dab" on cap in black ink. The capsules are supplied in the packages listed: • NDC 67877-624-60 Unit of use bottle of 60 capsules • NDC 67877-624-31 Blister package containing 60 (10 x 6) Unit-dose Capsules Dabigatran Etexilate Capsules 150 mg capsules have a light navy blue opaque cap and light cream opaque body imprinted with “150” on body and “DAB” on cap in black ink. The capsules are supplied in the packages listed: • NDC 67877-475-60 Unit of use bottle of 60 capsules • NDC 67877-475-31 Blister package containing 60 capsules (6 x 10 Unit-dose) Bottles Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture. Blisters Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original package to protect from moisture. Keep out of the reach of children.