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 ) 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. 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 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 <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: CrCl <30 mL/min with concomitant use of P-gp inhibitors: Reduce dosage to 75 mg twice daily if given with P-gp inhibitors dronedarone or systemic ketoconazole. 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 Prophylaxis of DVT and PE Following Hip Replacement Surgery 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 <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 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 <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 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 cann…

5 WARNINGS AND PRECAUTIONS • Bleeding: Dabigatran Etexilate Capsules can cause serious and fatal bleeding ( 5.2 ) • Bioprosthetic heart valves: Dabigatran Etexilate Capsules use not recommended ( 5.4 ) • Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran Etexilate Capsules use not recommended ( 5.6 ) 5.1 Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including Dabigatran Etexilate Capsules, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If Dabigatran Etexilate Capsules is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart Dabigatran Etexilate Capsules as soon as medically appropriate [see Dosage and Administration (2.6, 2.7, 2.8)]. 5.2 Risk of Bleeding Dabigatran Etexilate Capsules 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 Dabigatran Etexilate 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). Dabigatran Etexilate Capsules’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 Dabigatran Etexilate Capsules 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. 5.3 Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning] . To reduce the potential risk of bleeding associated with the concurrent use of Dabigatran Etexilate Capsules and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dabigatran [see Clinical Pharmacology (12.3)]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not p…

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 )

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)] . 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.

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).

8.3 Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including dabigatran should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

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 …