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BLEEDING DEFINITIONS IN PRADAXA CLINICAL TRIALS

Major bleeds in the NVAF, DVT, and PE trials fulfilled 1 or more of the following criteria: fatal bleeding, bleeding associated with a reduction in hemoglobin of at least 2.0 g/dL 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).1-3

Major bleeds in the hip replacement surgery trials fulfilled 1 or more of the following criteria: fatal bleeding, bleeding associated with a reduction in hemoglobin of at least 2.0 g/dL or leading to a transfusion of 2 or more units of blood, requiring treatment cessation, or leading to re-operation, or symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal, or retroperitoneal).3

Intracranial bleeds in the RE‑LY® trial included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.3

Fatal bleeds in the RE-LY® trial were defined as major bleeds with investigator-reported fatal outcomes and deaths with primary cause from bleeding.3

Non-intracranial fatal bleeds in the RE‑LY® trial were defined as major bleeds and deaths with primary cause from bleeding but without symptomatic intracranial bleeds based on investigator's clinical assessment.3

Clinically relevant nonmajor bleeds in the DVT and PE trials fulfilled at least one of the following criteria: spontaneous skin hematoma of at least 25 cm2; spontaneous nose bleed of more than 5 minutes duration; macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours; spontaneous rectal bleeding (more than spotting on toilet paper); gingival bleeding for more than 5 minutes; bleeding leading to hospitalization and/or requiring surgical treatment; bleeding leading to a transfusion of less than 2 units of whole blood or red cells; or any other bleeding event considered clinically relevant by the investigator.4-6

Clinically relevant nonmajor bleeds in the hip replacement surgery trials were defined as: spontaneous skin hematoma of at least 25 cm2; wound hematoma of at least 100 cm2; epistaxis of more than 5 min; macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours; spontaneous rectal bleeding; gingival bleeding for more than 5 minutes; and any other bleeding event judged as clinically significant by the investigator.7-9

References:

  1. Data on File. Boehringer Ingelheim Pharmaceuticals, Inc.

  2. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study. Circulation. 2013;128(3):237-243.

  3. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.

  4. Schulman S, Kearon C, Kakkar AK, et al; for the RE‑COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24)(suppl):2342-2352.

  5. Schulman S, Kearon C, Kakkar AK, et al; for the RE‑MEDY and the RE‑SONATE Trials Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8)(suppl):709-718.

  6. Schulman S, Kakkar AK, Goldhaber SZ, et al; for the RE‑COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7)(suppl):764-772.

  7. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials. Thromb J. 2015;13:36.

  8. Erikkson BI, Dahl OE, Büller HR, et al; for the BISTRO II study group. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. Thromb Haemost. 2005;3:103-111.

  9. The European Agency for the Evaluation of Medicinal Products. Guideline on clinical investigation of medicinal products for prevention of venous thromboembolism (VTE) in patients undergoing high VTE-risk surgery. CPMP/EWP/707/98 Rev. 1.2007. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500143764.pdf. Accessed 15 July 2016.

INDICATIONS AND USAGE

Pradaxa® (dabigatran etexilate) Capsules is indicated:

  • to reduce the risk of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation;
  • for the treatment of deep venous thrombosis and pulmonary embolism in adult 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 adult patients who have been previously treated;
  • for the prophylaxis of deep vein thrombosis and pulmonary embolism in adult patients who have undergone hip replacement surgery.
IMPORTANT SAFETY INFORMATION ABOUT 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;

  • history of a serious hypersensitivity reaction to dabigatran, dabigatran etexilate, or to one of the excipients of PRADAXA (e.g., anaphylactic reaction or anaphylactic shock);

  • 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 Capsules is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant and restart PRADAXA Capsules 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 Capsules 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: In adults, a specific reversal agent (idarucizumab) for PRADAXA 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 all 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 in Adult Patients.

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

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

  • For patients with CrCl <50 mL/min, avoid use of PRADAXA Capsules and concomitant P-gp inhibitors.

Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome

There is an increased risk of thrombosis in patients with triple-positive antiphospholipid syndrome. PRADAXA use is not recommended.

ADVERSE REACTIONS

The most common adverse reactions (>15%) reported with PRADAXA are gastrointestinal adverse reactions and 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).

USE IN SPECIFIC POPULATIONS

Pregnancy: The limited available data on PRADAXA use in pregnant women are insufficient to determine drug-associated risks for adverse developmental outcomes.

Lactation: Breastfeeding is not recommended.

Females and Males of Reproductive Potential: Discuss pregnancy planning with females of reproductive potential requiring anticoagulation. Assess the risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, in females of reproductive potential and those with abnormal uterine bleeding.

Pediatric Use: The safety and effectiveness of PRADAXA Capsules for the treatment and the reduction in risk of recurrence of venous thromboembolism have been established in pediatric patients 8 to less than 18 years of age. Other age-appropriate pediatric dosage forms of dabigatran etexilate are available for pediatric patients less than 8 years of age for these indications. Safety and effectiveness of PRADAXA Capsules have not been established in pediatric patients with non-valvular atrial fibrillation or those who have undergone hip replacement surgery.

Geriatric: Risk of bleeding increases with age.

CL-PX-100063 06.28.2021

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