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Australian Public Assessment Report for Vernakalant

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Australian Public Assessment Report for Vernakalant Australian Public Assessment Report for Vernakalant Proprietary Product Name: Brinavess Sponsor: Merck Sharp & Dohme (Australia) Pty Ltd November 2012 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices. • The 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 <www.tga.gov.au>. 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 2012 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. AusPAR Brinavess Vernakalant Merck Sharpe & Dohme (Australia) Pty Ltd PM-2010-01025-3-3 Page 2 of 125 Final 12 November 2012 Therapeutic Goods Administration Contents I. Introduction to submission _____________________________________________ 4 Submission details ____________________________________________________________________ 4 Product background __________________________________________________________________ 4 Regulatory status _____________________________________________________________________ 5 II. Quality findings _____________________________________________________________ 5 Drug substance (active ingredient) _________________________________________________ 5 Drug product __________________________________________________________________________ 6 Bioavailability _________________________________________________________________________ 7 Advisory committee considerations ________________________________________________ 7 Quality summary and conclusions __________________________________________________ 7 III. Nonclinical findings _______________________________________________________ 7 Introduction ___________________________________________________________________________ 7 Pharmacology _________________________________________________________________________ 7 Pharmacokinetics and relative drug exposures ___________________________________ 10 Toxicology ____________________________________________________________________________ 12 Nonclinical summary and conclusions _____________________________________________ 15 IV. Clinical findings __________________________________________________________ 17 Introduction __________________________________________________________________________ 17 Pharmacokinetics ____________________________________________________________________ 18 Pharmacodynamics__________________________________________________________________ 26 Efficacy _______________________________________________________________________________ 28 Safety _________________________________________________________________________________ 59 List of questions _____________________________________________________________________ 76 Clinical summary and conclusions _________________________________________________ 87 V. Pharmacovigilance findings ____________________________________________ 94 Risk management plan ______________________________________________________________ 94 VI. Overall conclusion and risk/benefit assessment __________________ 97 Quality ________________________________________________________________________________ 97 Nonclinical ___________________________________________________________________________ 97 Clinical ________________________________________________________________________________ 98 Risk-benefit analysis ______________________________________________________________ 111 Outcome ____________________________________________________________________________ 122 AusPAR Brinavess Vernakalant Merck Sharpe & Dohme (Australia) Pty Ltd PM-2010-01025-3-3 Page 3 of 125 Final 12 November 2012 Therapeutic Goods Administration I. Introduction to submission Submission details Type of Submission New Chemical Entity Decision: Rejected Date of Initial Decision: 5 August 2011 Date of Final Decision: 3 January 20121 Active ingredient(s): Vernakalant (as the hydrochloride) Product Name(s): Brinavess Sponsor’s Name and Address: Merck Sharpe & Dohme (Australia) Pty Ltd Level 4, 66 Waterloo Road North Ryde NSW 2113 Dose form(s): Concentrated injection Strength(s): 500 mg/25 mL, 20 mg/mL Container(s): Type 1 glass vials with rubber stoppers Pack size(s): 1 and 10 vials Approved Therapeutic use: Not applicable Route(s) of administration: Intravenous infusion Dosage: Complex-see Product background below. ARTG Number (s) Not applicable Product background Vernakalant is an antiarrhythmic medicine that acts preferentially in the atria to prolong atrial refractoriness and to rate-dependently slow impulse conduction. These anti- fibrillatory actions on refractoriness and conduction are thought to suppress reentry and are potentiated in the atria during atrial fibrillation. The relative selectivity of vernakalant on atrial versus ventricular refractoriness is postulated to result from the block of currents that are expressed in the atria, but not in the ventricles, as well as the unique electrophysiologic condition of the fibrillating atria. However, blockade of cationic currents, including hERG channels and cardiac voltage-dependent sodium channels, in the ventricles has been documented. This AusPAR describes the evaluation of an application by Merck Sharp & Dohme (Australia) Pty Ltd (the sponsor) to register Vernakalant (Brinavess) for the treatment of 1 The initial Delegate’s decision was taken to be confirmed, in accordance with s.60(4) of the Therapeutic Goods Act 1989 on 3 January 2012. For further details see the Outcome section of this AusPAR. AusPAR Brinavess Vernakalant Merck Sharpe & Dohme (Australia) Pty Ltd PM-2010-01025-3-3 Page 4 of 125 Final 12 November 2012 Therapeutic Goods Administration atrial fibrillation. The sponsor claims that targeted effects on atrial tissue coupled with frequency dependent late sodium channel ion current (INa) block may result in a lower risk of ventricular proarrhythmia for vernakalant than with drugs which predominately block sodium channels (for example, Class Ic agents such as flecainide) or potassium channels (for example, Class III agents such as ibutilide or dofetilide). Given the limitations of current pharmacological agents used to acutely convert atrial fibrillation (AF) and the necessity for conscious sedation or anaesthesia for electrical cardioversion, the sponsor states that there is a clinical need for better pharmacological approaches to convert AF to sinus rhythm. The sponsor claims that rapid pharmacological cardioversion by vernakalant injection, suitable for a broad-based AF population with typical cardiovascular co-morbidities, provides a much needed addition to the treatment algorithm for the acute conversion of AF. The proposed indication is: Brinavess is indicated for the rapid conversion of recent onset atrial fibrillation (≤ 7 days duration) to sinus rhythm. Dosage recommendations are: Brinavess should be administered in a monitored clinical setting appropriate for cardioversion. Brinavess is administered based on patient body weight. The standard recommended dose is 3 mg/kg to be infused over a 10 minute period. If conversion to sinus rhythm does not occur within 15 minutes after the end of the initial infusion, a second 10 minute infusion of 2 mg/kg may be administered. Cumulative doses of greater than 5 mg/kg
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