2014

Data from First Phase I Study of Antidote for Pradaxa® (dabigatran etexilate mesylate) Presented at American Heart Association Scientific Sessions Data indicate the antidote may be able to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation in healthy humans

RIDGEFIELD, Conn., Nov. 18, 2013 /PRNewswire/ -- Boehringer Ingelheim Pharmaceuticals, Inc. today announced results showing that its investigational fully humanized antibody fragment (Fab) rapidly reversed the anticoagulation effect of dabigatran in healthy male volunteers. These results, presented today during the American Heart Association's Scientific Sessions 2013, represent the first clinical data involving the compound, which was discovered and developed by the company (ClinicalTrials.gov Identifier: NCT01955720).

In this randomized, double-blind, placebo-controlled study of 145 healthy male volunteers, investigators evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of the Fab. In part one of the study, subjects received single, progressively increasing intravenous doses of up to 8 g of the Fab. In part two, the potential for reversal of dabigatran-induced anticoagulation was evaluated, with 5-minute intravenous infusions using doses of 1 g, 2 g and 4 g following pre-treatment with dabigatran (220 mg twice-daily for 3 days). The anticoagulant effect of dabigatran and its reversal were assessed using diluted thrombin time (Hemoclot® DTI assay), thrombin time (TT), activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and activated clotting time (ACT). Dabigatran prolonged clotting times of all coagulation markers.

Results of the study showed:

  • The on-set of action of the antidote was detected immediately following a 5-minute infusion
  • Thrombin time, which is a measurement of the time it takes for a clot to form in a blood sample and the most sensitive indicator of dabigatran's anticoagulant effect, was reversed with the Fab 
  • With this assay, reversal of the anticoagulation effect was complete and sustained in 7 of 9 subjects who received the 2 g dose and in 8 out of 8 subjects who received the 4 g dose
  • The 1 g dose resulted in complete reversal of anticoagulation effect; however, after approximately 30 minutes there was some return of the anticoagulation effects of dabigatran
  • All Fab-related adverse events (AEs) were of mild intensity:
    • In part I of the study, 5 of 110 subjects experienced a total of 6 AEs considered as drug-related, of which 3 occurred after receiving the Fab: headache, erythema and migraine
    • In part II, 5 of 35 subjects experienced a total of 6 AEs considered as drug-related, of which 2 occurred after the Fab: feeling hot and erythema

"Boehringer Ingelheim was the leader in bringing the first novel, oral anticoagulant treatment to reduce the risk of stroke in patients with non-valvular atrial fibrillation. Through our commitment to scientific innovation, our scientists continue to lead research which may further improve outcomes in patients treated with PRADAXA whose bleeding event may not be adequately managed by standard measures alone," said Sabine Luik, M.D., senior vice president, Medicine & Regulatory Affairs, U.S. Regional Medical Director, Boehringer Ingelheim Pharmaceuticals, Inc. "Even in the absence of a specific antidote, PRADAXA's stroke risk reduction is well-documented through the pivotal RE-LY® trial. These new findings represent an important step in the development of a specific antidote for PRADAXA."

Currently, no specific antidotes for new oral anticoagulants (NOACs) are available to complement the existing range of bleed management options during critical care situations. In the absence of approved antidotes for NOACs, standard clinical support for bleeding is similar for anticoagulant treatments, and may include applying direct pressure to the site of the bleeding, administering fluids and/or blood products (e.g., blood transfusions or plasma-derived clotting factor therapies) as needed, or stopping the bleeding through surgery. 

About Pradaxa® (dabigatran etexilate mesylate) Capsules

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.

IMPORTANT SAFETY INFORMATION ABOUT PRADAXA


WARNING: DISCONTINUING PRADAXA IN PATIENTS WITHOUT ADEQUATE CONTINUOUS ANTICOAGULATION INCREASES RISK OF STROKE. Discontinuing PRADAXA places patients at an increased risk of thrombotic events.   If anticoagulation with PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

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 Stroke with Discontinuation of PRADAXA
Discontinuing PRADAXA in absence of adequate alternative anticoagulation increases the risk of thrombotic events.  If PRADAXA must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.

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.
  • A specific reversal agent for dabigatran is not available. Hemodialysis can remove dabigatran; however clinical experience for hemodialysis as a treatment for bleeding is limited.  Activated prothrombin complex concentrates, recombinant Factor VIIa, or concentrates of factors II, IX or X 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 safety and efficacy of PRADAXA in patients with bileaflet mechanical prosthetic heart valves (recently implanted or implanted more than 3 months prior to enrollment) was evaluated in the phase 2 RE-ALIGN trial.  RE-ALIGN was terminated early because of significantly more thromboembolic events (valve thrombosis, stroke, transient ischemic attack, and myocardial infarction) and an excess of major bleeding (predominantly post-operative pericardial effusions requiring intervention for hemodynamic compromise) for PRADAXA vs warfarin.  Therefore, the use of PRADAXA is contraindicated in patients with mechanical prosthetic valves.

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
The 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.

  • For patients with moderate renal impairment (CrCl 30-50 mL/min), consider reducing 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.

ADVERSE REACTIONS
In the pivotal trial comparing PRADAXA to warfarin, the most frequent adverse reactions leading to discontinuation of PRADAXA were bleeding and gastrointestinal (GI) events.

  • PRADAXA 150 mg resulted in higher rates of major GI bleeds and any GI bleeds compared to warfarin.
  • In patients > or = 75 years of age, the risk of major bleeding may be greater with PRADAXA than with warfarin.
  • Patients on PRADAXA 150 mg had an increased incidence of GI adverse reactions.
  • 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 GI ulcer).  Drug hypersensitivity reactions were reported in <0.1% of patients receiving PRADAXA.

Other Measures Evaluated
In the pivotal trial, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

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

About the Boehringer Ingelheim Cares Foundation Patient Assistance Programs
For more than 125 years, Boehringer Ingelheim has been focused on improving the lives of patients. In keeping with the company commitment to do the most good for the most people, Boehringer Ingelheim works hard to ensure its medicines are accessible to everyone who needs them, including senior citizens and families on limited incomes. The Boehringer Ingelheim Cares Foundation Patient Assistance Programs (BI-PAP) make Boehringer Ingelheim medicines available free of charge to patients who are without pharmaceutical insurance coverage, and who meet certain household income levels.

About Boehringer Ingelheim Pharmaceuticals, Inc.
Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

As a central element of its culture, Boehringer Ingelheim has a demonstrated commitment to corporate social responsibility. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim's endeavors.

In 2012, Boehringer Ingelheim achieved net sales of about $19.1 billion (14.7 billion euro). R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

For more information please visit www.us.boehringer-ingelheim.com.   

PRADAXA® is a registered trademark of Boehringer Ingelheim Pharma GmBH and Co. KG and used under license.

RE-LY® is a registered service mark of Boehringer Ingelheim International GmBH and used under license.

SOURCE Boehringer Ingelheim Pharmaceuticals, Inc.



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