Report on the Deliberation Results December 1, 2010 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Pradaxa Capsules 75 mg Pradaxa Capsules 110 mg (The proposed Japanese brand name will be changed.) [Non-proprietary name] Dabigatran Etexilate Methanesulfonate (JAN*) [Applicant] Nippon Boehringer Ingelheim Co., Ltd. [Date of application] March 4, 2010 [Results of deliberation] In the meeting held on November 24, 2010, the First Committee on New Drugs concluded that the product may be approved and that this result should be presented to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. The product is not classified as a biological product or a specified biological product, the re-examination period is 8 years, and neither the drug substance nor the drug product is classified as a poisonous drug or a powerful drug. *Japanese Accepted Name (modified INN) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version Review Report November 16, 2010 Pharmaceuticals and Medical Devices Agency, Japan The results of a regulatory review by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows. [Brand name] Pradaxa Capsules 75 mg Pradaxa Capsules 110 mg (The proposed Japanese brand name will be changed.) [Non-proprietary name] Dabigatran Etexilate Methanesulfonate [Name of applicant] Nippon Boehringer Ingelheim Co., Ltd. [Date of application] March 4, 2010 [Dosage form/Strength] Hard capsules: Each capsule contains 75 mg or 110 mg of Dabigatran Etexilate Methanesulfonate [Application classification] Prescription drug (1) Drug with a new active ingredient [Chemical structure] CH3 CH3 O N O N O N N H NH O N 2 O N CH 3 . CH3SO3H Molecular formula: C34H41N7O5·CH4O3S Molecular weight: 723.86 Chemical name: Ethyl 3-({[2-({[4-(amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]amino} methyl)-1-methyl-1H-benzoimidazol-5-yl]carbonyl}(pyridin-2-yl)amino)prop anoate monomethanesulfonate [Items warranting special mention] None [Reviewing office] Office of New Drug II This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version Review Results November 16, 2010 [Brand name] Pradaxa Capsules 75 mg Pradaxa Capsules 110 mg (The proposed Japanese brand name will be changed.) [Non-proprietary name] Dabigatran Etexilate Methanesulfonate [Name of applicant] Nippon Boehringer Ingelheim Co., Ltd. [Date of application] March 4, 2010 [Results of review] Based on the submitted data, it is concluded that the efficacy of Pradaxa Capsules 75 mg and Pradaxa Capsules 110 mg in reducing the risk of ischaemic stroke and systemic embolism in patients with non- valvular atrial fibrillation has been demonstrated and their safety is acceptable in view of their observed benefits. Through the post-marketing surveillance, it is considered important to collect the safety information including bleeding risk in patients who receive concomitant antiplatelet therapy, elderly patients, and patients with renal impairment; safety information regarding gastrointestinal disorder or gastrointestinal haemorrhage; and safety information on concomitant drugs that are considered to affect the plasma concentration of dabigatran etexilate, the safety at each dose, and onset of myocardial infarction. As a result of its regulatory review, the Pharmaceuticals and Medical Device Agency has concluded that Pradaxa Capsules 75 mg and Pradaxa Capsules 110 mg may be approved for the following indication, and dosage and administration. [Indication] Reduction in the risk of ischaemic stroke and systemic embolism in patients with non-valvular atrial fibrillation [Dosage and administration] The usual adult dosage is 150 mg (two 75 mg capsules) of dabigatran etexilate administered orally twice daily. The dose should be reduced to 110 mg of dabigatran etexilate (one 110 mg capsule) twice daily, as needed. 3 Review Report (1) October 25, 2010 I. Product Submitted for Registration [Brand name] Pradaxa Capsules 75 mg Pradaxa Capsules 110 mg (The proposed Japanese brand name will be changed.) [Non-proprietary name] Dabigatran Etexilate Methanesulfonate [Name of applicant] Nippon Boehringer Ingelheim Co., Ltd. [Date of application] March 4, 2010 [Dosage form/Strength] Hard capsules: Each capsule contains 75 mg or 110 mg of Dabigatran Etexilate Methanesulfonate [Proposed indication] Reduction in the risk of stroke and systemic embolism in patients with atrial fibrillation [Proposed dosage and administration] The usual adult dosage is 150 mg (two 75 mg capsules) of Dabigatran Etexilate administered orally twice daily. [Items warranting special mention] None II. Summary of the Submitted Data and Outline of the Review by the Pharmaceuticals and Medical Devices Agency A summary of the data submitted in the application and an outline of the review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 1. Origin or history of discovery and usage conditions in foreign countries etc. Dabigatran Etexilate (dabigatran etexilate) Methanesulfonate is an oral pro-drug of a non-peptide, direct thrombin inhibitor developed by Boehringer Ingelheim International GmbH, Germany. Dabigatran etexilate methanesulfonate does not exhibit antithrombin activity, but is converted by esterase to dabigatran that is the active substance when absorbed from the gastrointestinal tract. Dabigatran inhibits thrombogenicity by selectively and reversibly inhibiting thrombin, an important enzyme in the blood coagulation cascade. Large-scale, multiregional clinical studies were conducted in foreign countries, and a marketing application for dabigatran was submitted in December 2009 in both the United States and Europe for the indication of reducing the risk of stroke and systemic embolism in patients with atrial fibrillation. On October 19, 2010, dabigatran gained its first approval in the US for the indication of “reducing the risk of stroke in patients with non-valvular atrial fibrillation.” On the other hand, dabigatran was approved for the indication of “primary prevention of venous thromboembolic events in adult patients who have undergone total hip 4 replacement surgery or total knee replacement surgery” in Europe in March 2008, and since then, it has been approved for the same indication in 74 countries as of May 2010. In Japan, the drug development was started by Nippon Boehringer Ingelheim Co., Ltd. in 20**. A marketing application has been submitted based on the data from clinical studies in Japan and the above mentioned multiregional clinical studies involving Japanese. 2. Data relating to quality 2.A Summary of the submitted data Pradaxa capsules 75 mg and Pradaxa capsules 110 mg (hereinafter collectively called “the proposed product”) are hard capsules containing 86.48 and 126.83 mg, respectively, of dabigatran etexilate methanesulfonate (with a molecular formula of C34H41N7O5·CH4O3S, and a molecular weight of 723.86) (they are equivalent to 75 and 110 mg of dabigatran etexilate, respectively). 2.A.(1) Drug substance 2.A.(1).1) Characterization (a) Structure The chemical structure of the drug substance has been confirmed by elementary analysis, mass spectrometry, ultraviolet and visible absorption spectrum, infrared spectrophotometry (IR), hydrogen nuclear magnetic resonance spectrometry (1H-NMR), and carbon nuclear magnetic resonance spectrometry. (b) General properties The general properties of the drug substance, including description, melting point, dissociation constant (pKa), partition coefficient, hygroscopicity, solubility, and crystalline polymorphism, have been determined. It is a yellow-white to yellow crystalline powder with a melting point around 180C. ******** ************************************************************************************** ************************************************************************************** ************************************************************************************** *************************************************************************** It was freely soluble in methanol, soluble in N,N-Dimethylacetamide, sparingly soluble in ethanol (99.9) and practically insoluble in water. Polymorphism was observed and two different crystalline forms (crystalline form I and II) were identified. 2.A.(1).2) Manufacturing process The drug substance is manufactured by the manufacturing process A or B. Manufacturing process A Step 1:******************************************************************************** ************************************************************************************** ************************************************************************************** ************************************************************************************** 5 ************************************************************************************** **************************************************************************************