DABIGATRAN 75 mg Capsule, 60-count

5 WARNINGS AND PRECAUTIONS • Bleeding: Dabigatran can cause serious and fatal bleeding ( 5.2 ) • Bioprosthetic heart valves: Dabigatran use not recommended ( 5.4 ) • Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome: Dabigatran use not recommended ( 5.6 )

5.1Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including dabigatran, 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 )].

5.2Risk of Bleeding Dabigatran 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'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 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.

5.3Spinal/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 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 prevent or reverse neurological sequelae.

5.4Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves The safety and…

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 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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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

21.3Total 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 Patientsa Event Dabigatran etexilate capsules 150 mg N = 6,059 n (%/yearb) Warfarin N = 5,998 n (%/yearb) Dabigatran etexilate capsules 150 mg vs Warfarin HR (95% CI) Major Bleedingc 350 (3.47) 374 (3.58) 0.97 (0.84, 1.12) Intracranial Hemorrhage (ICH)d 23 (0.22) 82 (0.77) 0.29 (0.18, 0.46) Hemorrhagic Strokee 6 (0.06) 40 (0.37) 0.16 (0.07, 0.37) Other ICH 17 (0.17) 46 (0.43) 0.38 (0.22, 0.67) Gastrointestinal 162 (1.59) 111 (1.05) 1.51 (1.19, 1.92) Fatal Bleedingf 7 (0.07) 16 (0.15) 0.45 (0.19, 1.10) ICH 3 (0.03) 9 (0.08) 0.35 (0.09, 1.28) Non-intracranialg 4 (0.04) 7 (0.07) 0.59 (0.17, 2.02) 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…

7 DRUG INTERACTIONS • P-gp inducers: Avoid coadministration with dabigatran ( 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 )

7.1Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation in Adult Patients The concomitant use of dabigatran 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 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. 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 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 )].

7.2Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism in Adult Patients Avoid use of dabigatran 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 )].

7.3Prophylaxis 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 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.