European Medicines Agency recommends approval of novel oral anticoagulant, dabigatran etexilate (Pradaxa®)

For medical media, outside the US only
Ingelheim/Germany, January 2008 - Boehringer Ingelheim today announced that the Committee for Medicinal Products in Human Use (CHMP) of the European Medicines Agency has issued a positive opinion to recommend marketing authorisation of their novel, oral direct thrombin inhibitor, dabigatran etexilate. The CHMP recommends approval of dabigatran etexilate for the prevention of venous thromboembolic events in patients who have undergone total hip replacement surgery or total knee replacement surgery.1

The positive opinion is a recommendation to the European Commission that authorization to market the drug should be granted in the European Union which normally occurs within 67 days. Dabigatran etexilate will be marketed by Boehringer Ingelheim exclusively under the brand name Pradaxa®, with a planned launch in all 27 countries of the European Union.

Dr Andreas Barner, Member of the Board of Boehringer Ingelheim and responsible for Research, Development and Medicine said “We welcome the positive opinion of the EMEA which is the first recommendation for approval by a regulatory authority for our novel oral anticoagulant drug Pradaxa®. This announcement represents a major milestone in the advancement of anticoagulation therapy for thromboembolic diseases. We are pleased that our new oral thrombin inhibitor offers the potential for physicians to ensure that patients in need receive effective and safe thromboprophylaxis.”

Patients who have undergone total hip or knee replacement are at high risk of venous thromboembolism (VTE). This risk extends beyond the usual period of hospitalisation, as thromboprophylaxis treatment is often discontinued following discharge due to the complex administration of current anticoagulants.2 As dabigatran etexilate is given as a fixed oral dose, it can be administered conveniently both in and out of the hospital setting, providing patients with effective protection from potentially dangerous thrombi (blood clots).

Dabigatran etexilate has a rapid onset and offset of action and predictable anticoagulation effect, without the need for coagulation monitoring. It specifically and reversibly inhibits thrombin, the central and essential enzyme in the coagulation cascade responsible for thrombus formation. Dabigatran etexilate exhibits no drug-food interactions and has a low potential for drug-drug interactions.3,4

Clinical data from the RE-NOVATETM and RE-MODELTM trials were included in the submission to European authorities in February 2007 for the first intended license indication for dabigatran etexilate. Oral, once daily administration of both 150 or 220 mg dabigatran etexilate was demonstrated to be as effective and safe as injectable enoxaparin (40mg) in preventing VTE and all cause mortality following total hip replacement surgery and following total knee replacement surgery in the RE-NOVATETM and RE-MODELTM trials respectively.5,6 All test results were evaluated by a central adjudication committee that was blinded to the treatment received by any patient.

Anticoagulation-related bleeding is the primary safety concern during hip or knee replacement surgery, since major bleeding into the replaced joint can have a detrimental impact on clinical outcome.5 In both trials, few major bleeding events (including those occurring at the surgical site) were reported and incidence did not differ significantly between dabigatran etexilate and enoxaparin treatment groups (during the RE-NOVATETM trial, major bleeding events occurred at 2.0% and 1.3% for dabigatran etexilate 220 mg and 150mg groups versus 1.6% for enoxaparin and during the RE-MODELTM trial, major bleeding events occurred at 1.5% and 1.3% for dabigatran etexilate 220 mg and 150mg groups versus 1.3% for enoxaparin).5,6

In all phase III trials reported to date, patients were frequently monitored and assessed for liver enzyme elevations by an independent data safety monitoring committee. Liver enzyme aminotransferase (ALT) elevations greater than three time the upper limit of normal (ULN) were low throughout the entire treatment periods with dabigatran etexilate and did not differ significantly between the treatment groups.

Similarly, the incidence of acute coronary events was low, particularly in the three month follow up period, with no significant differences between all treatment groups.

Boehringer Ingelheim continues to evaluate the efficacy and safety of dabigatran etexilate in a range of thromboembolic disease conditions. RE-VOLUTION™ 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 the landmark RE-LY™ trial to evaluate the efficacy and safety of dabigatran etexilate for stroke prevention in patients with atrial fibrillation. Other ongoing studies are evaluating the efficacy and safety of dabigatran etexilate in the treatment of acute VTE, the secondary prevention of VTE and acute coronary syndromes.

Please be advised
This release is from the Corporate Headquarters of Boehringer Ingelheim and is intended for all 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.
References:
1 EMEA press office, http://www.emea.europa.eu/pdfs/human/press/pr/
PressRelease_Jan2861408en.pdf
2 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. Journal of Bone and Joint Surgery 2007;89: 799-807
3 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. British Journal of Clinical Pharmacology 2007;64:292–303
4 Sorbera LA, Bozza J, Castaner J et al. Dabigatran/dabigatran etexilate: prevention of DVT, prevention of ischemic stroke, thrombin inhibitor. Drugs Future 2005;30:877–885
5 Eriksson BI, Dahl OE, Rosencher N et al. Dabigatran etexilate compared with enoxaparin for the extended prevention of venous thromboembolism following total hip replacement. The Lancet 2007;370:949–956
6 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. Journal of Thrombosis and Haemostasis 2007;5:2178–2185