Adverse Reactions

The most serious adverse reactions reported with PRADAXA were related to bleeding²

Drug discontinuation

The rates of adverse reactions leading to treatment discontinuation were 21% for PRADAXA 150 mg and 16% for warfarin in the RE‑LY^® Trial²
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)²

Clinical MI events²

In the active‑controlled DVT/PE studies, a higher rate of clinical MI was reported in patients who received PRADAXA [20 events (0.66 per 100 patient‑years)] than in those who received warfarin [5 events (0.17 per 100 patient‑years)]
In the placebo‑controlled DVT/PE study, a similar rate of non‑fatal and fatal clinical MI was reported in patients who received PRADAXA [1 event (0.32 per 100 patient‑years)] and in those who received placebo [1 event (0.34 per 100 patient‑years)]
In the DVT/PE after hip replacement studies, clinical MI was reported in 2 (0.1%) patients who received PRADAXA 220 mg and 6 (0.3%) patients who received enoxaparin

Gastrointestinal adverse reactions²

In the RE‑LY^® Trial, increased incidence of GI adverse reactions (35% on PRADAXA vs. 24% on warfarin) were:
- Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort)
- Gastritis‑like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and GI ulcer)
In the 4 pivotal DVT/PE studies, similar incidence of GI adverse reactions (24.7% on PRADAXA vs. 22.7% on warfarin) were:
- Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort), which occurred in 7.5% on PRADAXA vs. 5.5% on warfarin
- Gastritis‑like symptoms (including gastritis, GERD, esophagitis, erosive gastritis, and gastric hemorrhage), which occurred in 3.0% on PRADAXA vs. 1.7% on warfarin
In the DVT/PE after hip replacement studies, the rate of major GI bleeds in patients receiving PRADAXA 220 mg and enoxaparin was the same; rate of any GI bleeds was higher in patients receiving PRADAXA 220 mg vs. enoxaparin. GI adverse reactions were the same in patients receiving PRADAXA 220 mg vs. enoxaparin. These were:
- Dyspepsia (including abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric discomfort)
- Gastritis-like symptoms (including gastritis, GERD, esophagitis, erosive gastritis and gastric hemorrhage)

Hypersensitivity reactions²

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
In the 4 pivotal DVT/PE studies, drug hypersensitivity (including urticaria, rash, and pruritus), allergic edema, anaphylactic reaction, and anaphylactic shock were reported in 0.1% of patients receiving PRADAXA
In the DVT/PE after hip replacement studies, drug hypersensitivity (such as urticaria, rash, and pruritus) was reported in 0.3% of patients receiving PRADAXA 220 mg

IMPORTANT SAFETY INFORMATION AND INDICATIONS

IMPORTANT SAFETY INFORMATION AND INDICATIONS FOR PRADAXA

WARNING: (A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

(A) PREMATURE DISCONTINUATION OF PRADAXA INCREASES THE RISK OF THROMBOTIC EVENTS

Premature discontinuation of any oral anticoagulant, including PRADAXA, increases the risk of thrombotic events. If anticoagulation with PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant

(B) SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas may occur in patients treated with PRADAXA who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

use of indwelling epidural catheters
concomitant use of other drugs that affect hemostasis, such as non-steroidal anti‑inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
a history of traumatic or repeated epidural or spinal punctures
a history of spinal deformity or spinal surgery
optimal timing between the administration of PRADAXA and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients who are or will be anticoagulated.

CONTRAINDICATIONS

PRADAXA is contraindicated in patients with:

active pathological bleeding;
known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to PRADAXA;
mechanical prosthetic heart valve

WARNINGS & PRECAUTIONS

Increased Risk of Thrombotic Events after Premature Discontinuation

Premature discontinuation of any oral anticoagulant, including PRADAXA, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If PRADAXA is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart PRADAXA as soon as medically appropriate.

Risk of Bleeding

PRADAXA 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 PRADAXA in patients with active pathological bleeding.
Risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (e.g., anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs). PRADAXA’s anticoagulant activity and half-life are increased in patients with renal impairment.
Reversal of Anticoagulant Effect: 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
Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited. Prothrombin complex concentrates or recombinant Factor VIIa may be considered but their use has not been evaluated. Protamine sulfate and vitamin K are not expected to affect dabigatran anticoagulant activity. Consider administration of platelet concentrates where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

Thromboembolic and Bleeding Events in Patients with Prosthetic Heart Valves

The use of PRADAXA is contraindicated in patients with mechanical prosthetic valves due to a higher risk for thromboembolic events, especially in the post-operative period, and an excess of major bleeding for PRADAXA vs. warfarin. Use of PRADAXA for the prophylaxis of thromboembolic events in patients with AFib in the setting of other forms of valvular heart disease, including bioprosthetic heart valve, has not been studied and is not recommended.

Effect of P-gp Inducers & Inhibitors on Dabigatran Exposure

Concomitant use of PRADAXA with P‑gp inducers (e.g., rifampin) reduces exposure to dabigatran and should generally be avoided. P‑gp inhibition and impaired renal function are major independent factors in increased exposure to dabigatran. Concomitant use of P‑gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

Reduction of Risk of Stroke/Systemic Embolism in NVAF

For patients with moderate renal impairment (CrCl 30‑50 mL/min), reduce the dose of PRADAXA to 75 mg twice daily when dronedarone or systemic ketoconazole is coadministered with PRADAXA.
For patients with severe renal impairment (CrCl 15‑30 mL/min), avoid concomitant use of PRADAXA and P‑gp inhibitors.

Treatment and Reduction in the Risk of Recurrence of DVT/PE & Prophylaxis of DVT/PE Following Hip Replacement Surgery

For patients with CrCl <50 mL/min, avoid use of PRADAXA and concomitant P‑gp inhibitors

The most serious adverse reactions reported with PRADAXA were related to bleeding.

Other Measures Evaluated

In NVAF patients, a higher rate of clinical MI was reported in patients who received PRADAXA (0.7/100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

INDICATIONS AND USAGE

Pradaxa^® (dabigatran etexilate mesylate) capsules is indicated:

to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation;
for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days;
to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism in patients who have been previously treated
for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip replacement surgery

Please see full Prescribing Information, including boxed WARNING and Medication Guide.

Boehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the trademarks Pradaxa^®, PRADAXA with associated design ^®, RE‑LY^®, RELY‑ABLE^®, RE‑COVER^®, RE‑COVER II™, RE‑MEDY™, RE‑SONATE^®, SolutionsPlus^®, Praxbind^® and related images under license. Other referenced trademarks are owned by third parties.

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Adverse Reactions