Australian Public Assessment Report for Dutasteride/Tamsulosin Proprietary Product Name: Duodart Sponsor: GlaxoSmithKline Australia Pty Ltd January 2011 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The TGA is a division of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. · TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website. About AusPARs · An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications. · An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2011 This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General’s Department, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/cca AusPAR Duodart Dutasteride/Tamsulosin GlaxoSmithKline Australia Pty Ltd PM-2009-01559-3-3 Page 2 of 97 Date of Finalisation 20 October 2010 Therapeutic Goods Administration Contents I. Introduction to Product Submission .............................................................. 4 Submission Details........................................................................................................ 4 Product Background ..................................................................................................... 4 Regulatory Status .......................................................................................................... 7 Product Information ...................................................................................................... 7 II. Quality Findings .................................................................................................. 7 Introduction..................................................................................................................... 7 Drug Substance (active ingredient)............................................................................ 7 Drug Product .................................................................................................................. 8 Consideration by PSC ................................................................................................. 11 Quality Summary and Conclusions.......................................................................... 11 III. Nonclinical Findings ........................................................................................ 12 Introduction................................................................................................................... 12 Pharmacology .............................................................................................................. 13 Pharmacokinetics ........................................................................................................ 14 Toxicology ..................................................................................................................... 15 Nonclinical Summary and Conclusions .................................................................. 17 IV. Clinical Findings ............................................................................................... 17 Introduction................................................................................................................... 17 Pharmacodynamics ..................................................................................................... 18 Pharmacokinetics ........................................................................................................ 18 Efficacy .......................................................................................................................... 21 Safety ............................................................................................................................. 36 Clinical Summary and Conclusions ......................................................................... 49 V. Pharmacovigilance Findings .......................................................................... 49 Risk Management Plan ............................................................................................... 49 VI. Overall Conclusion and Risk/Benefit Assessment .................................... 51 Quality ............................................................................................................................ 51 Nonclinical .................................................................................................................... 51 Clinical ........................................................................................................................... 52 Risk Management Plan ............................................................................................... 67 Risk -Benefit Analysis .................................................................................................. 67 Outcome ........................................................................................................................ 75 Attachment 1. Product Information ...................................................................... 75 AusPAR Duodart Dutasteride/Tamsulosin GlaxoSmithKline Australia Pty Ltd PM-2009-01559-3-3 Page 3 of 97 Date of Finalisation 20 October 2010 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission New fixed dose combination Decision: Approved Date of Decision: 20 October 2010 Active ingredient(s): Dutasteride and tamsulosin (as the hydrochloride) Product Name(s): Duodart Sponsor’s Name and GlaxoSmithKline Australia Pty Ltd Address: PO Box 18095 Melbourne Vic 3067 Dose form(s): Capsules – hard Strength(s): 400 µg of dutasteride and 500 µg of tamsulosin hydrochloride Container(s): HDPE Bottles with Child-Resistant Closures Pack size(s): Packs of 7, 30 and 90 Approved Therapeutic use: Duodart is indicated for the management of moderate to severe symptomatic benign prostatic hyperplasia (BPH). Route(s) of administration: Oral Dosage: The recommended dose of Duodart is one capsule (500 μg dutasteride /400 μg tamsulosin) taken orally approximately 30 minutes after the same meal each day. ARTG Number: 162530 Product Background Benign prostatic hyperplasia (BPH) is a chronic and progressive disease, and is the most common benign neoplasm in ageing males. Pathological changes were found in 88% of men ≥80 years, and symptoms have been reported in nearly 50% of men over 50 years of age.1 The cause of BPH is age related prostate growth which is stimulated by dihydrotestosterone (DHT), which is formed from testosterone by the action of 5α-reductase isoenzymes type 1 and 2. This prostatic growth may eventually lead to urethral obstruction, causing lower urinary tract symptoms (LUTS), including both voiding symptoms (for example, hesitancy, weak stream, terminal dribbling) and storage symptoms (urgency, frequency, nocturia). The progressive nature of the disease leads to increased need for surgery and episodes of acute urinary retention (AUR).2 There are two components that lead to symptoms. There is a static component that is attributed to the increased pressure in the prostatic urethra secondary to obstruction caused by hyperplasia of the prostatic tissue. There is also a dynamic 1 Napalkov P, Maisonneuve P, Boyle P. Worldwide patterns of prevalence and mortality from benign prostatic hyperplasia. Urology 1995; 46: 41-46. 2 McConnell JD, Bruskewitz R, Walsh P et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Eng J Med 1998; 338: 557-563. AusPAR Duodart Dutasteride/Tamsulosin GlaxoSmithKline Australia Pty Ltd PM-2009-01559-3-3 Page 4 of 97 Date of Finalisation 20 October 2010 Therapeutic Goods Administration component which is influenced by the adrenergic tone of the prostatic stromal smooth muscle and bladder neck. The aim of therapy is to improve symptoms and quality of life, and also to prevent complications such as AUR and upper urinary tract