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Important Safety Information

What is PRAXBIND?

Praxbind® (idarucizumab) is indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed:

  • For emergency surgery/urgent procedures

  • In life-threatening or uncontrolled bleeding

PRAXBIND has been specifically developed to reverse the anticoagulant effects of dabigatran, the active ingredient in PRADAXA® (dabigatran etexilate).1,2

  • Ready-to-Use: Learn more about dosing and administration. View now

There are serious risks and adverse reactions to consider when treating patients with PRAXBIND, including warnings and precautions for thromboembolic risk, re-elevation of coagulation parameters, hypersensitivity reactions and risks of serious adverse reactions in patients with hereditary fructose intolerance due to sorbitol excipient. Please see the Important Safety Information and Adverse Reactions sections below.

  • *
    Accurate as of 01/03/20, based on the current information provided to Boehringer Ingelheim Pharmaceuticals, Inc. The company cannot guarantee the availability of PRAXBIND at all facilities in every state.

IN RE-VERSE AD™, PRAXBIND REVERSED THE ANTICOAGULANT EFFECT OF PRADAXA IN EMERGENCY SITUATIONS4

RE-VERSE AD™ Trial: A Study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran

Methods4

Study Design: Multicenter, prospective, open-label study

Patients: Final study analysis included 503† patients taking dabigatran who were administered PRAXBIND. The patients were divided into two groups:

  • Group A (n=301): Patients who presented with life-threatening or uncontrolled bleeding

  • Group B (n=202): Patients who required emergency surgery or urgent procedures

Study Treatment: All patients were to receive 5 g of intravenous PRAXBIND which was administered as two 50-mL bolus infusions, each containing 2.5 g of PRAXBIND, no more than 15 minutes apart

Primary Endpoint: To determine the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of administration of PRAXBIND, based on central laboratory determination of diluted thrombin time (dTT) or ecarin clotting time (ECT) in patients who presented with Pradaxa® (dabigatran etexilate)-related life‑threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B)

  • Reversal was evaluable only for those patients showing prolonged coagulation times prior to idarucizumab treatment1

  • †
    Median age was 78 years and median creatinine clearance (CrCl) was 53 mL/min. Approximately 62% of patients in Group A and 62% of patients in Group B had been treated with dabigatran 110 mg BID.

Results

REVERSAL OF CLOTTING TIME4‡§

Prolongation in the RE-VERSE AD Finalized Analysis: ECT

Reversal was evident seconds after administration

Prolongation in the RE-VERSE AD Finalized Analysis: ECT
Prolongation in the RE-VERSE AD Finalized Analysis: ECT

  • In a limited number of patients, elevation of coagulation parameters have been observed between 12 and 24 hours after administration of 5 g PRAXBIND4

REVERSAL OF CLOTTING TIME4‡§

Prolongation in the RE-VERSE AD Finalized Analysis: aPTT

Up to 99% of patients achieved complete reversal

Change of aPTT From Baseline in PRADAXA-Treated Patients From RE-VERSE AD

Prolongation in the RE-VERSE AD Finalized Analysis: aPTT
Prolongation in the RE-VERSE AD Finalized Analysis: aPTT

 

Key Findings4

  • Rapid: PRAXBIND rapidly reversed the anticoagulant effect of dabigatran in emergency situations

  • Complete: Median maximum reversal in evaluable patients was 100% in the first 4 hours (primary endpoint; n = 503)‖. Most patients achieved complete reversal as measured by ECT (82%), or dTT (99%)

  • ‖
    Based on determination for dTT or ECT.

Additional Findings4

  • Cessation of bleeding: 134 (n=203, 67.7%) of the non-ICH patients who had uncontrolled bleeding had confirmed bleeding cessation within 24 hours, with a median time of 2.5 hours

  • Clotting: Among the patients who underwent emergency surgery or urgent procedures (n=197), periprocedural hemostasis was assessed as normal in 93.4% (n=184) of patients, mild abnormal in 5.1% (n=10), and moderately abnormal in 1.5% (n=3)

  • The time to the cessation of bleeding could not be assessed in the 98 patients with intracranial bleeding, because there is dissociation between the clinical course and the extent of bleeding.

Clinical relevance of findings from Group A and B is undetermined.

aPTT=activated partial thromboplastin time; ECT=ecarin clotting time; dTT=dilute thrombin time; ULN=upper limit of normal

  • ‡
    Determined by mean clotting time below the ULN as measured by ECT and aPTT.
  • §
    Blood samples were obtained at baseline, after the first infusion, at 10-30 min after the second infusion, and at 1, 2, 4, 12, and 24 hours.4

ADVERSE REACTIONS1

In the RE-VERSE AD™ (RE-VERSal Effects of idarucizumab on Active Dabigatran) trial, a total of 503 dabigatran-treated patients were administered idarucizumab either because they required an emergency surgery or urgent procedure, or because they presented with life-threatening or uncontrolled bleeding. The adverse reactions reported in ≥5% of patients were constipation (33/503, 7%) and nausea (23/503, 5%).

Of the 503 dabigatran-treated patients in the entire study period, 101 patients died, 19 within the first day after idarucizumab dosing; each of these deaths could be attributed either as a complication of the index event or associated with co-morbidities.

Thromboembolic Events1

In the RE-VERSE AD trial, 33 of 503 patients reported thrombotic events, 11 patients within 5 days after treatment with idarucizumab and 22 patients 6 days or more after treatment with idarucizumab. Most of these patients were not on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient.

Patients being treated with PRADAXA therapy have underlying disease states that predispose them to thromboembolic events. Reversing PRADAXA therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.1

PRADAXA treatment can be re-initiated 24 hours after administration of PRAXBIND.

Hypersensitivity1

Pyrexia, bronchospasm, hyperventilation, rash, and pruritus have been reported in clinical trials with idarucizumab.

Immunogenicity

As with all proteins, there is a potential for immunogenicity with idarucizumab. Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (10/224) of healthy subjects and 2% (8/501) of patients treated with idarucizumab.1

There are serious risks and adverse reactions to consider when treating patients with PRAXBIND, including warnings and precautions for thromboembolic risk, re-elevation of coagulation parameters, hypersensitivity reactions and risks of serious adverse reactions in patients with hereditary fructose intolerance due to sorbitol excipient. Please see more complete details of these risks in the Important Safety Information below.

The RE-VERSE AD™ Trial

Click here to see full trial results

HIGH-AFFINITY BINDING NEUTRALIZES THE EFFECT OF DABIGATRAN1,5

Mechanism of Action

PRAXBIND is a humanized monoclonal antibody fragment (Fab) that binds to dabigatran and its acyl glucuronide metabolites with higher affinity than the binding affinity of dabigatran to thrombin, neutralizing their anticoagulant effect immediately after administration.1

restore icon
PRAXBIND (idarucizumab):

Restores thrombin activity by binding to dabigatran with ~350-fold higher affinity than dabigatran to thrombin5

Watch How PRAXBIND Reverses the Anticoagulant Effect of Dabigatran

Use in Clinical Situations

When reversal of the anticoagulant effects of dabigatran is needed1,#

use in clinical situations graph
use in clinical situations graph

 

Additional Considerations for PRAXBIND and PRADAXA

PRAXBIND7

  • Normalization of serious bleeding: Observed as early as 21 min after administration in evaluable patients (n=134 non-ICH)‡‡§§

  • Median time to bleeding cessation: Patients presenting with non-ICH bleeding was 2.5 hours (95% CI, 2.2 to 3.9)4

  • Blood clotting: Among the patients who underwent emergency surgery or urgent procedures (Group B; n=197), periprocedural hemostasis was assessed as normal in 93.4% (n=184) of patients, mild abnormal in 5.1% (n=10), and moderately abnormal in 1.5% (n=3)4‡‡

PRADAXA2

Determine reversal strategies as medically appropriate:

  • Blood products (prothrombin complex concentrates or recombinant Factor VIIa)‖‖

  • PRADAXA—the only OAC that is dialyzable (~50% of dabigatran can be cleared from plasma over 4 hours)8‖‖

  • Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of PRADAXA

Half-life: 12-17 hours in healthy subjects

Renal impairment: Increases anticoagulant effect and half-life

If surgery cannot be delayed: there is an increased risk of bleeding and this risk should be weighed against the urgency of the intervention

  • **
    Emergency surgery or urgent procedure is defined as a procedure that cannot be delayed for a minimum of 8 hours.4
  • ††
    Life-threatening or uncontrolled bleeding is defined as overt bleeding that is judged by the treating clinician to require a reversal agent.4
  • ‡‡
    Cessation and normalization assessments were subjective and based upon investigator visualization or measurement.
  • §§
    Click here to learn about the RE-VERSE AD trial.
  • ‖‖
    Coagulation factors and dialysis have not been evaluated in clinical trials and clinical experience for the management of medical emergencies is limited.

Restarting PRADAXA1

Patients being treated with PRADAXA therapy have underlying disease states that predispose them to thromboembolic events. Reversing PRADAXA therapy exposes patients to the thrombotic risk of their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate.

PRAXBIND is a specific reversal agent for PRADAXA, with no impact on the effect of other anticoagulant or antithrombotic therapies.

  • PRADAXA can be re-initiated after 24 hours following PRAXBIND administration.

#These recommendations are not intended to replace clinical judgment or to dictate individual patient care.

References:

  1. PRAXBIND [Prescribing Information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 

  2. PRADAXA [Prescribing Information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. 

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

  4. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal – full cohort analysis. N Engl J Med. 2017; 377(5):431-441; 1-13 [suppl appendix].

  5. Schiele F, van Ryn J, Canada K, et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013; 121(18):3554-3562.

  6. Tomaselli GF, et al. 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76:594-622.

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

  8. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [published correction appears in Circulation. 2014; 130:e199-e267.] Circulation. 2014; 129:1-123.

INDICATIONS AND USAGE FOR PRADAXA

Pradaxa® (dabigatran etexilate) Capsules is indicated:

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.

INDICATIONS AND USAGE FOR PRADAXA

Praxbind® (idarucizumab) is indicated in patients treated with Pradaxa® when

Praxbind® (idarucizumab) is indicated in patients treated with Pradaxa® when reversal of the anticoagulant effects of dabigatran is needed:

  • For emergency surgery/urgent procedures
  • In life-threatening or uncontrolled bleeding
IMPORTANT SAFETY INFORMATION ABOUT PRADAXA

WARNINGS AND PRECAUTIONS

Thromboembolic Risk

  • Dabigatran-treated patients have underlying diseases predisposing them to thromboembolic events. Reversing dabigatran therapy exposes patients to thrombotic risk. Consider resumption of anticoagulant therapy as soon as medically appropriate.

Re-elevation of Coagulation Parameters

  • Elevated coagulation parameters (e.g., activated partial thromboplastin time or ecarin clotting time) have been observed in a limited number of PRAXBIND-treated patients. If reappearance of clinically relevant bleeding together with elevated coagulation parameters is observed, or if patients requiring a second emergency surgery/urgent procedure have elevated coagulation parameters, an additional full dose may be considered.

Hypersensitivity Reactions

  • There is insufficient clinical experience evaluating risk of hypersensitivity to idarucizumab, but a possible relationship could not be excluded. Risk of hypersensitivity (e.g., anaphylactoid reaction) to idarucizumab or excipients needs to be weighed cautiously against the potential benefit. If serious allergic reaction occurs, immediately discontinue PRAXBIND and institute appropriate treatment.

Risk in Patients With Hereditary Fructose Intolerance

  • PRAXBIND contains 4 g sorbitol as an excipient. When prescribing PRAXBIND in patients with hereditary fructose intolerance, consider the total daily amount of sorbitol/fructose consumption from all sources, as serious adverse reactions (e.g., hypoglycemia, hypophosphatemia, metabolic acidosis, increase in uric acid, acute liver failure, and death) may occur.

ADVERSE REACTIONS

  • The most frequently reported adverse reaction in ≥5% of idarucizumab-treated healthy volunteers was headache (5%). The most frequently reported adverse reactions in ≥5% of patients were constipation (7%) and nausea (5%).
  • Treatment-emergent antibodies with low titers were observed in 4% of healthy subjects and 2% of patients treated with idarucizumab.

USE IN SPECIFIC POPULATIONS

Pregnancy and Lactation

  •  PRAXBIND should be given to a pregnant woman only if clearly needed. Caution should be exercised when PRAXBIND is administered to a nursing woman.

CL-PB-100001 April 2018

Please click here for full Prescribing Information for PRAXBIND.