INGELHEIM, Germany, March 27 /PRNewswire/ --

- For Media Outside the US

Boehringer Ingelheim today announced that the European Commission has granted marketing authorisation of the novel, oral direct thrombin inhibitor, Pradaxa(R) (dabigatran etexilate) in all 27 EU member states. It is anticipated that Pradaxa(R) will be launched in Germany and the United Kingdom in the coming weeks.

(Photo: http://www.newscom.com/cgi-bin/prnh/20080327/298676a )

(Photo: http://www.newscom.com/cgi-bin/prnh/20080327/298676b )

Pradaxa(R) is approved for the prevention of venous thromboembolic events in adults who have undergone elective total hip or total knee replacement surgery.

Dr Andreas Barner, Member of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine said:

"This first licence for our novel oral anticoagulant Pradaxa(R) marks an important advance and milestone in anticoagulation therapy and the prevention of potentially fatal thrombi (blood clots). In addition, we remain confident in the potential for Pradaxa(R) to satisfy the unmet medical needs of even more patients and physicians in the future as we continue to invest in our extensive RE-VOLUTIONTM clinical trial programme investigating Pradaxa(R) across four further therapeutic areas."

Commenting on this milestone in thromboprophylaxis, Dr Bengt Eriksson, MD, PhD, Principal Investigator of RE-NOVATETM and RE-MODELTM studies, Department of Orthopaedic Surgery, University Hospital Sahlgrenska/ Östra, Gothenburg, Sweden said:

"The risk of a potentially life-threatening thrombosis is a major concern following major orthopaedic surgery. For many years, there has been a need for an effective oral anticoagulant with a good safety profile to enable convenient thromboprophylaxis management in and out of the hospital environment. Now, following the approval of Pradaxa(R), we will have an attractive alternative to other thromboprophylaxis regimens to protect our patients from venous thromboembolism (VTE)."

Patients undergoing hip and knee replacement surgery are at particularly high risk of developing VTE.(1) Without thromboprophylaxis, up to 60 percent of orthopaedic surgery patients have been shown to develop DVT (deep vein thrombosis; including asymptomatic thrombi), and 0.2-10 percent are at risk of a potentially fatal PE (pulmonary embolism) according to previous studies.(1) In addition to the acute risk of mortality, VTE is associated with long term risks of recurrent episodes of VTE and eventually post-thrombotic syndrome (chronic venous insufficiency). These complications contribute substantially to patient morbidity and cost of management.(2)

The risk of VTE in orthopaedic surgery patients extends beyond the usual period of hospitalisation and current guidelines recommend that patients undergoing knee or hip replacement surgery receive thromboprophylaxis such as low molecular weight heparins or vitamin K antagonists for at least 10 days after surgery, extending to 28-35 days for hip replacement surgery.(1) Despite this guidance and the availability of effective thromboprophylaxis options, therapy is often discontinued following discharge due to complexities and inconvenience in administration, although patients are at continued risk.(3) As a result, VTE is one of the most common causes of hospital readmission following orthopaedic surgery.(4)

European approval of Pradaxa(R) follows the submission of efficacy and safety data in February 2007 from the phase III RE-NOVATETM and RE-MODELTM studies.(5,6) Oral, once daily administration of both 150 and 220 mg Pradaxa(R) was demonstrated to be as effective and safe as injectable enoxaparin (40 mg) in preventing VTE and all cause mortality following total hip replacement surgery and total knee replacement surgery in the RE-NOVATETM and RE-MODELTM trials, respectively.(5,6) All test results were evaluated by an independent central adjudication committee blinded to the drug received by any patient.

With all anticoagulant agents it is important to optimize the balance of efficacy and safety. In addition to the critically important bleeding profile, hepatic and cardiac safety need to be considered, as well as tolerability. In both the RE-NOVATETM and RE-MODELTM trials, a low incidence and severity of major bleeding (including those occurring at the surgical site), similar to enoxaparin was reported.(5,6)

Patients were frequently monitored and assessed for liver enzyme elevations by an independent data safety monitoring committee. Rates of liver enzyme alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (3x ULN) were low and comparable to enoxaparin at any time post-baseline with Pradaxa(R), supporting hepatic safety.(5,6)

Pradaxa(R) displayed a favourable cardiac safety profile; no incidences of adjudicated Acute Coronary Syndrome (ACS) events were reported during 3 months follow up with Pradaxa 220 mg, suggesting no rebound coagulation effect once treatment ends.(5,6) A favourable tolerability profile, comparable to enoxaparin, was also reported following a low number of adverse events leading to treatment discontinuation.(5,6)

The standard recommended dosage of Pradaxa(R) is a fixed oral dose of 220 mg given once daily. A single capsule of 110 mg (half-dose) is administered orally between 1 and 4 hours following surgery, continuing with 2 capsules once daily thereafter for a total of 10 days in total knee replacement patients and 28-35 days in total hip replacement patients. A second approved dosage of 150 mg taken as two capsules of 75 mg is recommended for specific patient populations, including patients over 75 years of age and those with moderate renal impairment.

Pradaxa(R) prevents thrombus formation by specifically and selectively inhibiting thrombin, the central and essential enzyme that enables the conversion of fibrinogen into fibrin during the coagulation cascade, and therefore prevents the development of a thrombus.(7,8) Pradaxa(R) has a rapid onset and offset of action and predictable anticoagulation effect, avoiding the need for coagulation monitoring.(9,10) It exhibits no drug-food interactions and has a low potential for drug-drug interactions.(11,12)

Boehringer Ingelheim continues to evaluate the efficacy and safety of Pradaxa(R) in a range of thromboembolic disease conditions. RE-VOLUTION(TM) is an extensive clinical trial programme involving more than 34,000 patients worldwide. Recent progress announcements include the early enrolment completion of 18,114 patients in RE-LY(TM), the largest atrial fibrillation outcomes trial to date. Other ongoing studies are evaluating the efficacy and safety of Pradaxa(R) in the treatment of acute VTE, the secondary prevention of VTE and prevention of cardiac events in patients with acute coronary syndrome.

Please be advised

This release is from the Corporate Headquarters of Boehringer Ingelheim and is intended for international markets. This being the case, please be aware that there may be some differences between countries regarding specific medical information including licensed uses. Please take account of this when referring to the material.

About Boehringer Ingelheim

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 137 affiliates in 47 countries and 38,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2006, Boehringer Ingelheim posted net sales of 10.6 billion euro while spending one fifth of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information please visit http://www.boehringer-ingelheim.com

References

(1) Geerts WH, Heit JA, Clagett GP et al. Prevention of Venous Thromboembolism. Chest. 2004;126:338S-400S

(2) Cohen AT, Tapson VF, Bergmann J-F et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study Lancet 2008;371(9610):361-2

(3) Warwick D, Friedman, Agnelli G et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events. Findings from the global orthopaedic registry. J Bone Joint Surg Br. 2007;89:799-807

(4) American Academy of Orthopedic Surgeons information webpage http://orthoinfo.aaos.org/topic.cfm?topic=A00219#Prevention

(5) Eriksson BI, Dahl OE, Kurth AA et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178-2185

(6) Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate compared with enoxaparin for the extended prevention of venous thromboembolism following total hip replacement. Lancet 2007;370:949-956

(7) Di Nisio M et al. Direct thrombin inhibitors. N Eng J Med. 2005;353:1028-1040

(8) van Ryn J et al. Dabigatran inhibits both clot -bound and fluid phase thrombin in vitro: Effects compared to heparin and hirudin. Abstract Arteriosclerosis, Thrombosis and Vascular Biology (ATVB), Atlanta, GA, USA, May 2008

(9) Stangier J, Rathgen K, Staehle H et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64:292-303

(10) Stangier J et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008;47:47-59

(11) 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;45:555-563

(12) Blech S et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispo. 2008;36:386-399

Contact: Judith von Gordon, Boehringer Ingelheim GmbH, 55216 Ingelheim am Rhein, GERMANY, Phone: +49-6132-77-35-82, Fax: +49-6132-77-66-01, E-mail: press@boehringer-ingelheim.com