FDA label 5db7f199-8752-4d24-85f7-e34ca8f4d02e

5 WARNINGS AND PRECAUTIONS Risk of bleeding: PRADAXA can cause serious and, sometimes, fatal bleeding. Promptly evaluate signs and symptoms of blood loss. (5.1) Temporary discontinuation: Avoid lapses in therapy to minimize risk of stroke (5.2) P-gp inducers and inhibitors: Avoid coadministration of rifampin with PRADAXA because of effects on dabigatran exposure (5.3) 5.1 Risk of Bleeding PRADAXA increases the risk of bleeding and can cause significant and, sometimes, fatal bleeding. Risk factors for bleeding include the use of drugs that increase the risk of bleeding in general (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) and labor and delivery. Promptly evaluate any signs or symptoms of blood loss (e.g., a drop in hemoglobin and/or hematocrit or hypotension). Discontinue PRADAXA in patients with active pathological bleeding. In the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study, a life-threatening bleed (bleeding that met one or more of the following criteria: fatal, symptomatic intracranial, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention) occurred at an annualized rate of 1.5% and 1.8% for PRADAXA 150 mg and warfarin, respectively [see Adverse Reactions (6.1) ] . 5.2 Temporary Discontinuation of PRADAXA Discontinuing anticoagulants, including PRADAXA, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke. Lapses in therapy should be avoided, and if anticoagulation with PRADAXA must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. 5.3 Effect of P-gp Inducers and Inhibitors on Dabigatran Exposure The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see Clinical Pharmacology (12.3) ] . P-gp inhibitors ketoconazole, verapamil, amiodarone, quinidine, and clarithromycin do not require dose adjustments. These results should not be extrapolated to other P-gp inhibitors [see Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS Most common adverse reactions (>15%) are gastritis-like symptoms and bleeding (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience The RE-LY study provided safety information on the use of two doses of PRADAXA and warfarin [see Clinical Studies (14) ] . The numbers of patients and their exposures are described in Table 1. Limited information is presented on the 110 mg dosing arm because this dose is not approved. Table 1 Summary of Treatment Exposure in RE-LY PRADAXA 110 mg twice daily PRADAXA 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 Because clinical studies are conducted under widely varying conditions and over varying lengths of time, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Drug Discontinuation in RE-LY The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal hemorrhage, and diarrhea). Bleeding [see Warnings and Precautions (5.1) ] Table 2 shows the number of patients experiencing serious bleeding during the treatment period in the RE-LY study, with the bleeding rate per 100 patient-years (%). Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding). A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention. Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds. Table 2 Bleeding Events* (per 100 Patient-Years) PRADAXA 150 mg twice daily N (%) Warfarin N (%) Hazard Ratio (95% CI**) * Patients contributed multiple events and events were counted in multiple categories. ** Confidence interval Randomized patients 6076 6022 Patient-years 12,033 11,794 Intracranial hemorrhage 38 (0.3) 90 (0.8) 0.41 (0.28, 0.60) Life-threatening bleed 179 (1.5) 218 (1.9) 0.80 (0.66, 0.98) Major bleed 399 (3.3) 421 (3.6) 0.93 (0.81, 1.07) Any bleed 1993 (16.6) 2166 (18.4) 0.91 (0.85, 0.96) The risk of major bleeds was similar with PRADAXA 150 mg and warfarin across major subgroups defined by baseline characteristics, with the exception of age, where there was a trend towards a higher incidence of major bleeding on PRADAXA (hazard ratio 1.2, 95% CI: 1.0 to 1.4) for patients ≥75 years of age. There was a higher rate of major gastrointestinal bleeds in patients receiving PRADAXA 150 mg than in patients receiving warfarin (1.6% vs. 1.1%, respectively, with a hazard ratio vs. warfarin of 1.5, 95% CI, 1.2 to 1.9), and a higher rate of any gastrointestinal bleeds (6.1% vs. 4.0%, respectively). Gastrointestinal Adverse Reactions Patients on PRADAXA 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 PRADAXA.

<table border="1" ID="id_76607668-d819-4d56-857f-566e4fd3b1e0"> <caption ID="id_99d97eb3-6f26-4acd-9a14-de1983af9f87">Table 1 Summary of Treatment Exposure in RE-LY</caption> <col width="30%"/> <col width="25%" align="center"/> <col width="25%" align="center"/> <col width="20%" align="center"/> <thead> <tr ID="id_089b243e-b11d-4945-99fd-98145993b767" styleCode="Botrule"> <td align="left" valign="top"/> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">PRADAXA 110 mg twice daily</content> </content> </td> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">PRADAXA 150 mg twice daily</content> </content> </td> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Warfarin</content> </content> </td> </tr> </thead> <tbody> <tr ID="id_07d63b3d-d903-482d-8814-a06ba8105e99" styleCode="Toprule"> <td align="left" valign="top">Total number treated</td> <td align="left" valign="top" styleCode="Toprule">5983</td> <td align="left" valign="top" styleCode="Toprule">6059</td> <td align="left" valign="top">5998</td> </tr> <tr ID="id_bfd30a53-ae7c-465b-a763-8f69fe38e4d3"> <td align="left" valign="top">Exposure</td> <td align="left" valign="top"> </td> <td align="left" valign="top"> </td> <td align="left" valign="top"> </td> </tr> <tr ID="id_a4be7cc1-6fe4-4562-b60d-7104f2021493"> <td align="left" valign="top"> &gt; 12 months</td> <td align="left" valign="top">4936</td> <td align="left" valign="top">4939</td> <td align="left" valign="top">5193</td> </tr> <tr ID="id_4de746d5-f8d3-4e8e-9544-696565b1c3ae"> <td align="left" valign="top"> &gt; 24 months</td> <td align="left" valign="top">2387</td> <td align="left" valign="top">2405</td> <td align="left" valign="top">2470</td> </tr> <tr ID="id_b5ee2276-7155-48e2-90bd-94f845cbe9f2"> <td align="left" valign="top">Mean exposure (months)</td> <td align="left" valign="top">20.5</td> <td align="left" valign="top">20.3 </td> <td align="left" valign="top">21.3 </td> </tr> <tr ID="id_66cedf45-6930-46ac-897e-540a72ba08b4" styleCode="Botrule"> <td align="left" valign="top">Total patient-years</td> <td align="left" valign="top">10,242</td> <td align="left" valign="top">10,261</td> <td align="left" valign="top">10,659</td> </tr> </tbody> </table>

<table border="0" ID="id_e126fb55-6aa4-44e0-90fb-458c42ba8727"> <caption ID="id_06ebdd34-c9ec-4fa8-ae2f-9e2c006b5c39">Table 2 Bleeding Events* (per 100 Patient-Years)</caption> <col width="25%"/> <col width="25%" align="center"/> <col width="25%" align="center"/> <col width="25%" align="center"/> <thead> <tr ID="id_562c2b3c-49f6-4516-ba6c-2889fa04364e" styleCode="Botrule"> <td align="left" valign="top" styleCode="Lrule"> </td> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">PRADAXA 150 mg twice daily N (%)</content> </content> </td> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Warfarin N (%)</content> </content> </td> <td align="left" valign="top" styleCode="Rrule"> <content styleCode="bold"> <content styleCode="emphasis">Hazard Ratio (95% CI**)</content> </content> </td> </tr> </thead> <tfoot ID="id_29308ad2-012c-4b8c-8601-95ef3df7ab71"> <tr> <td align="left" valign="top" colspan="4" styleCode="Lrule Rrule"> * Patients contributed multiple events and events were counted in multiple categories. ** Confidence interval</td> </tr> </tfoot> <tbody> <tr ID="id_2ea7ac77-e758-4633-8639-56a1bbaec043" styleCode="Toprule"> <td align="left" valign="top" styleCode="Lrule">Randomized patients</td> <td align="left" valign="top" styleCode="Toprule">6076</td> <td align="left" valign="top" styleCode="Toprule">6022</td> <td align="left" valign="top" styleCode="Rrule"> </td> </tr> <tr ID="id_950d7c53-363b-4b25-baeb-34409e5826a2"> <td align="left" valign="top" styleCode="Lrule">Patient-years</td> <td align="left" valign="top">12,033</td> <td align="left" valign="top">11,794</td> <td align="left" valign="top" styleCode="Rrule"> </td> </tr> <tr ID="id_1dbf27a7-584d-4116-8e6b-85a8c0a94e3e"> <td align="left" valign="top" styleCode="Lrule"> Intracranial hemorrhage</td> <td align="left" valign="top">38 (0.3)</td> <td align="left" valign="top">90 (0.8)</td> <td align="left" valign="top" styleCode="Rrule">0.41 (0.28, 0.60)</td> </tr> <tr ID="id_6a002250-5608-4766-9d9d-e288585a704d"> <td align="left" valign="top" styleCode="Lrule"> Life-threatening bleed</td> <td align="left" valign="top">179 (1.5)</td> <td align="left" valign="top">218 (1.9)</td> <td align="left" valign="top" styleCode="Rrule">0.80 (0.66, 0.98)</td> </tr> <tr ID="id_9073444f-c891-41db-9293-20578e4f80ed"> <td align="left" valign="top" styleCode="Lrule"> Major bleed</td> <td align="left" valign="top">399 (3.3)</td> <td align="left" valign="top">421 (3.6)</td> <td align="left" valign="top" styleCode="Rrule">0.93 (0.81, 1.07) </td> </tr> <tr ID="id_1265930e-2f78-46fa-9b94-e859dae1b4c7"> <td align="left" valign="top" styleCode="Lrule"> Any bleed</td> <td align="left" valign="top">1993 (16.6)</td> <td align="left" valign="top">2166 (18.4)</td> <td align="left" valign="top" styleCode="Rrule">0.91 (0.85, 0.96)</td> </tr> </tbody> </table>