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 eva luate 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 eva luation 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)] .

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.

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)] .

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.

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.

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

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: blee