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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.
The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study provided safety information on the use of two doses of PRADAXA and warfarin [see Clinical Studies]. 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|
|> 12 months||4936||4939||5193|
|> 24 months||2387||2405||2470|
|Mean exposure (months)||20.5||20.3||21.3|
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).
[see WARNINGS AND PRECAUTIONS]
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**)|
|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)|
|*Patients contributed multiple events and events were counted in multiple
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).
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.
The following adverse reactions have been identified during postapproval use of PRADAXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reaction has been identified during postapproval use of PRADAXA: angioedema, thrombocytopenia.
Read the Pradaxa (dabigatran etexilate mesylate) Side Effects Center for a complete guide to possible side effects »
The concomitant use of PRADAXA with P-gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided [see CLINICAL PHARMACOLOGY].
P-gp inhibition and impaired renal function are the major independent factors that result in increased exposure to dabigatran [see CLINICAL PHARMACOLOGY]. 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 30-50 mL/min), consider reducing the dose of PRADAXA to 75 mg twice daily when administered concomitantly with the P-gp inhibitor dronedarone or systemic ketoconazole. The use of P-gp inhibitors (verapamil, amiodarone, quinidine, and clarithromycin) does not require a dose adjustment of PRADAXA. These results should not be extrapolated to other P-gp inhibitors [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
The concomitant use of PRADAXA and P-gp inhibitors in patients with severe renal impairment (CrCl 15-30 mL/min) should be avoided [see WARNINGS AND PRECAUTIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 5/14/2013
This monograph has been modified to include the generic and brand name in many instances.
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