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PRADAXA®

Side effects and safety

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)

Safety of PRADAXA® Established

In the RE-LY® Trial, Proven safety with PRADAXA® vs. warfarin in NVAF1

  Bleeding Events in Pivotal RE-LY® Trial
Adjudicated Major Bleeding Events in Treated Patients* PRADAXA® 110 mg BID (N=6,015) PRADAXA® 150 mg BID (N=6,076) Warfarin (N=6,022)
  Events=%/year† (n)
Major Bleeding 2.92 (347) 3.40 (409) 3.61 (426)
HR vs. warfarin (95% CI) 0.81 (0.70, 0.93) 0.94 (0.82, 1.08)  
Intracranial Hemorrhage 0.23 (27) 0.32 (39) 0.77 (91)
HR vs. warfarin (95% CI) 0.29 (0.19, 0.45) 0.42 (0.29, 0.61)  

In a long-term safety extension trial, Safety profile of PRADAXA® supported in RELY-ABLE®2-5

  Bleeding Events in RELY-ABLE®
Event‡ PRADAXA® 110 mg BID (N=2,914) PRADAXA® 150 mg BID (N=2,937) HR (95% CI) 150 mg vs. 110 mg
  Events=%/year (n)
Major Bleeding 2.99 (190) 3.74 (238) 1.26 (1.04-1.53)
Fatal Bleeding 0.25 (16) 0.24 (15) 0.94 (0.46-1.89)
Intracranial Hemorrhage 0.25 (16) 0.33 (21) 1.31 (0.68-2.51)
Gastrointestinal Bleeding 1.56 (99) 1.54 (98) 0.99 (0.75-1.31)

Rates of major bleeding were similar to those seen during the RE-LY® Trial§

SAFETY SUPPORTED IN MULTIPLE REAL-WORLD STUDIES6-11

Results from real-world studies are not intended for comparisons with clinical trials. Real-world studies were observational trials. Differences in study designs, patient populations, outcome definitions, and methods of collecting data make it difficult to make comparisons with clinical trials or with each other. Real-world data should be viewed as complementary information.

DVT/PE

PROVEN SAFETY IN DVT AND PE VS. WARFARIN

In 2 clinical trials for the treatment of DVT and PE, PRADAXA® demonstrated lower rates of total bleeds vs. warfarin¶1,12

Bleeding Events in RE-COVER® and RE-COVER II™1
Full Treatment Period Including Parenteral Treatment
Event PRADAXA® 150 mg BID % (n=2,456) warfarin % (n=2,462) HR (95% CI)
Major Bleeding‖ 1.0 (24/2,456) 1.6 (40/2,462) 0.60 (0.36, 0.99)
Major bleeding events/Clinically relevant bleeds 4.4 (109/2,456) 7.7 (189/2,462) 0.56 (0.45, 0.71)

PROVEN SAFETY IN DVT AND PE VS. WARFARIN AND PLACEBO

In a clinical trial for the reduction in the risk of recurrence of DVT and PE, PRADAXA® demonstrated a lower rate of total bleeds vs. warfarin**13

Bleeding Events in RE-MEDY™13
Event PRADAXA® 150 mg BID % (n=1,430) warfarin % (n=1,426) HR (95% CI)
Major Bleeding‖ 0.9 (13/1,430) 1.8 (25/1,426) 0.52 (0.27, 1.02)
Major or clinically relevant bleeding 5.6 (80/1,430) 10.2 (145/1,426) 0.54 (0.41, 0.71)
Any bleeding event 19.4 (278/1,430) 26.2 (373/1,426) 0.71 (0.61, 0.83)

In a clinical trial for the reduction in the risk of recurrence of DVT and PE, PRADAXA® demonstrated a higher rate of total bleeds vs. placebo**13

Bleeding Events in RE-SONATE®13
Event PRADAXA® 150 mg BID % (n=681) warfarin % (n=662) HR (95% CI)
Major Bleeding‖ 0.3 (2/681) 0  
Major or clinically relevant bleeding 5.3 (36/681) 1.8 (12/662) 2.92 (1.52, 5.60)
Any bleeding event 10.5 (72/681) 5.9 (39/662) 1.82 (1.23, 2.68)

ADVERSE REACTIONS IN CLINICAL TRIALS

The most serious adverse reactions reported with PRADAXA® were related to bleeding1,14

Drug discontinuation14

  • The rates of adverse reactions leading to treatment discontinuation were 21.2% for PRADAXA® 150 mg and 16.6% for warfarin in the RE-LY® Trial
  • The most frequent adverse reactions leading to discontinuation of PRADAXA® in the RE-LY® Trial were bleeding and GI events (i.e., dyspepsia, nausea, upper abdominal pain, GI hemorrhage, and diarrhea)

Gastrointestinal adverse reactions1

  • Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort), or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, gastrointestinal ulcer).
  • Gastrointestinal (GI) hemorrhage occurred at a higher frequency with PRADAXA® compared to warfarin. GI adjudicated major bleeds were reported at 1.14%, 1.57%, and 1.07% (annualized rates) in the DE 110 mg, DE 150 mg and warfarin groups, respectively. GI life-threatening bleeds occurred with a frequency of 0.57%, 0.79% and 0.49% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. Any GI bleeds occurred with frequency of 5.41%, 6.13% and 4.02% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of GI bleeding has not been established.

Hypersensitivity reactions1

  • In the RE-LY® Trial, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in <0.1% of patients receiving PRADAXA®

Footnotes:

  • * 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 in multiple subcategories.
  • † Annual event rate per 100 pt-years = 100 * number of subjects with event/subject-years. Subject-years is defined as cumulative number of days from first drug intake to event date, date of last drug intake + 2, death date (whatever occurred first) across all treated subjects divided by 365.25. In case of recurrent events of the same category, the first event was considered.
  • ‡ Patients during treatment or within 6 days of stopping study treatment.
  • § There was no adjudication of outcome events occurring in RELY-ABLE®. (Adjudication in RE-LY® confirmed ~93% of reported major bleeds on both doses.) Only half of the patients continued from RE-LY® to RELY-ABLE®. Patients enrolled in RELY-ABLE® were different from those in RE-LY®, and they may have been at lower risk of events. Warfarin patients were not followed as a comparator group. Data analysis was not intention to treat and different from RE-LY® analysis.
  • Patients in the RE-COVER® and RE-COVER II™ Trials had a mean exposure of 164 days during the oral-only treatment period.
  • ‖ Patients with at least one major bleeding event.
  • ** Patients in the treatment studies who rolled over into the RE‑MEDY™ study had a combined treatment duration of up to >3 years, with mean exposure of 473 days.
  • BID, twice daily; CAD, coronary artery disease; CMS, Centers for Medicare & Medicaid Services; CrCl, Creatinine Clearance; DVT, deep vein thrombosis; FDA, U.S. Food and Drug Administration; GERD, gastroesophageal reflux disease; GI, gastrointestinal; ICH, intracerebral hemorrhage; INR, international normalized ratio; LMWH, low-molecular weight heparin; LVEF, left ventricular ejection fraction; NOAC, novel oral anticoagulants; NVAF, non-valvular atrial fibrillation; NYHA, New York Heart Association; PE, pulmonary embolism; QD, once daily; SE, systemic embolism; TIA, transient ischemic attack; US, United States; VTE, acute venous thromboembolism

References:

  1. PRADAXA® approved package insert. Updated in Dec 2019. Approved in Jun 2020.

  2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.

  3. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. N Engl J Med. 2010;363(19):1875-1876.

  4. Connolly SJ, Wallentin L, Yusuf S. N Engl J Med. 2014;371(15):1464-1465.

  5. Connolly SJ, Wallentin L, Ezekowitz MD, et al. Circulation. 2013;128(3):237-243.

  6. Graham DJ. Baro E. Zhang R. et al. Am J Med. 2019;132(5):596-604.

  7. Graham DJ, Reichman ME, Wernecke M, et al. JAMA Intern Med. 2016;176(11):1662-1671.

  8. Graham DJ, Reichman ME, Wernecke M, et al. Circulation. 2015;131(2):157-164.

  9. Southworth MR, Reichman ME, Unger EF. N Engl J Med. 2013;368:1272-1274.

  10. Carmo J, Moscoso Costa F, Ferreira J, Mendes M. Thromb Haemost. 2016;116(4):754-763.

  11. Yao X, Abraham NS, Sangaralingham LR, et al. J Am Heart Assoc. 2016;5(6):1-19.

  12. Schulman S, Kearon C, Kakkar AK, et al. N Engl J Med. 2009;361(24)(suppl):23‍42-23‍52.

  13. Schulman S, Kearon C, Kakkar AK, et al. N Engl J Med. 2013;368(8)(suppl):709-718.

  14. Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med. 2009;361(12):1139-1151.

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