The European Commission has approved Praxbind® (idarucizumab), a treatment to rapidly and specifically reverse the anticoagulant effects of Pradaxa® (dabigatran etexilate) in cases of emergency surgery /urgent procedures or in situations of life-threatening or uncontrolled bleeding. (1) Idarucizumab is the first specific reversal agent for a non-vitamin K antagonist oral anticoagulant (NOAC) to be approved in the European union.(1)
"Anticoagulants offer important benefits to patients at risk of thromboembolic events. However, even though rare, there will be situations when reversal of anticoagulation is medically necessary," said Professor Harald Darius, lead investigator for the RE-VERSE AD™ clinical study in Germany, and Director of the Department of Cardiology, Vascular Medicine, Nephrology and Intensive Care Medicine, Vivantes Neukoelln Medical Centre, Berlin. "The approval of Praxbind® now provides me and my colleagues with an important option to manage patients taking Pradaxa® in situations when speed of reversal matters."
"I am delighted that we are now able to offer Praxbind®, the only specific reversal agent for a NOAC, to patients and physicians in Europe," commented Professor Jörg Kreuzer, Vice President Medicine, Therapeutic Area Cardiovascular, Boehringer Ingelheim. "With this approval, Boehringer Ingelheim is again leading the evolution of anticoagulation care, as we did with the introduction of Pradaxa®. And while we anticipate that Praxbind® will be rarely used in clinical practice, the availability of this specific reversal agent can now give physicians and patients added confidence in choosing Pradaxa®."
The approval of idarucizumab by the European Commission follows the positive opinion issued by the Committee for Medicinal Products for Human Use of the European Medicines Agency in September 2015.(5) Idarucizumab was already approved by the U.S. Food and Drug Administration in October 2015.(6)
The approval is based on data from healthy volunteers, as well as results from an interim analysis of the RE-VERSE AD™ clinical study.(2-4,7) In the studies, the reversal effects of idarucizumab were evident immediately, within minutes after administration of 5 grams of idarucizumab.(2-4) Reversal was complete and sustained for a minimum of 12 hours in almost all patients.(2-4) In the data submitted for approval, including 123 patients from REVERSE-AD™ and more than 200 volunteers previously given idarucizumab no safety concerns or prothrombotic signals were observed.(2-4,7,8)
Boehringer Ingelheim is committed to making idarucizumab available as widely as possible and will launch idarucizumab in the European Union countries as soon as national requirements allow.(1)
About the idarucizumab Clinical Trial Programme
Idarucizumab was discovered and developed by Boehringer Ingelheim scientists. The research programme was initiated in 2009,1 before dabigatran (Pradaxa®) was launched in the U.S. in 2010.(9)
The company completed three phase I trials of idarucizumab in human volunteers and is continuing to evaluate idarucizumab in RE-VERSE AD™ (NCT 02104947, EudraCT 2013‐004813‐41), a phase III global study that includes patients taking dabigatran who require emergency procedures or have uncontrolled bleeding.(2-4,7) The study is the first of its kind in patients, and has been underway since May 2014, enrolling patients in more than 35 countries.10 The RE-VERSE AD™ global phase III patient study is ongoing to capture further data on the efficacy and safety profile of idarucizumab.
About idarucizumab
Idarucizumab is a humanized antibody fragment, or Fab, designed as a specific reversal agent to dabigatran.(11) Idarucizumab binds specifically to dabigatran molecules only, neutralising their anticoagulant effect without interfering with the coagulation cascade.(11,12) Idarucizumab is approved for use in adult patients treated with dabigatran when rapid reversal of its anticoagulant effects is required for emergency surgery / urgent procedures or in life-threatening or uncontrolled bleeding.(1)
Regulatory reviews and submissions in other countries are ongoing.(1) Idarucizumab is the only specific reversal agent for a NOAC currently in regulatory review.(1) Boehringer Ingelheim plans to submit idarucizumab in all countries where dabigatran is licensed.(1)
About dabigatran etexilate
Clinical experience of dabigatran equates to more than 5 million patient-years in all licensed indications worldwide.(1) Dabigatran has been in the market for more than 7 years and is approved in over 100 countries.(1)
Currently approved indications for dabigatran are:(9,13)
- Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and a risk factor for stroke
- Primary prevention of venous thromboembolic events in patients undergoing elective total hip replacement surgery or total knee replacement surgery
- Treatment of DVT and PE and the prevention of recurrent DVT and recurrent PE in adults
Dabigatran, a direct thrombin inhibitor (DTI), was the first widely approved drug in a new generation of direct oral anticoagulants, available to target a high unmet medical need in the prevention and treatment of acute and chronic thromboembolic diseases.(13,14) Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin, the central enzyme in the process responsible for clot (thrombus) formation.14 In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran provides effective, predictable and reproducible anticoagulation with a low potential for drug-drug interactions and no drug-food interactions, without the need for routine coagulation monitoring or mandatory dose adjustment.(14,16)
About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 146 affiliates and a total of more than 47,700 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.
Social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.
In 2014, Boehringer Ingelheim achieved net sales of about 13.3 billion euros. R&D expenditure corresponds to 19.9 per cent of its net sales.
1. Boehringer Ingelheim data on file.
2. Pollack C. V., et al. Idarucizumab for Dabigatran Reversal. NEJM. 2015;373:511-520.
3. Glund S, et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet. 2015;386:680–690.
4. Glund S. et al. Idarucizumab, a Specific Antidote for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran Induced Anticoagulation in Elderly and Renally Impaired Subjects. Oral presentation on 8 December 2014 at The 56th American Society of Hematology Annual Meeting & Exposition, San Francisco, USA. Blood. 2014;124:Abstract 344.
5. Committee for Medicinal Products for Human Use (CHMP). Minutes from 21-24 September 2015 meeting. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/003986/WC500194147.pdf Last accessed November 2015.
6. FDA News Release - FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. 16 October 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm Last accessed November 2015.
7. Glund S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost. 2015;113:943–951.
8. Boehringer Ingelheim, Data on File. Information included in the Idarucizumab Summary of Product Characteristics.
9. Pradaxa® US Prescribing Information, 2015.
10. Boehringer Ingelheim Press Release - 22 May 2015. Antidote for rapid reversal of Pradaxa® (dabigatran etexilate) progresses into next stage of clinical investigation with study in patients. http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/22_may_2014_dabigatranetexilate.html Last accessed November 2015.
11. Schiele F. et al. A specific antidote for dabigatran: functional and structural characterization. Blood. 2013;121:3554–62.
12. Pollack C. V. et al. Design and rationale for RE-VERSE AD: A phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost. 2015;114(1):198-20.
13. Pradaxa® European Summary of Product Characteristics, 2015.
14. Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.
15. Di Nisio M. et al. Direct thrombin inhibitors. N Engl J Med. 2005;353:1028-40.
16. Stangier J. et al. Pharmacokinetic Profile of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate in Healthy Volunteers and Patients Undergoing Total Hip Replacement. J Clin Pharmacol. 2005;45:555–63.