Australian Public Assessment Report for Aliskiren, Amlodipine and Hydrochlorothiazide Proprietary Product Name: Rasilamlo HCT
Total Page：16
File Type：pdf, Size：1020Kb
Australian Public Assessment Report for Aliskiren, Amlodipine and Hydrochlorothiazide Proprietary Product Name: Rasilamlo HCT Sponsor: Novartis Pharmaceuticals Australia Pty Ltd June 2012 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (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. 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 Rasilamlo HCT Aliskiren/amlodipine/hydrochlorothiazide Novartis Page 2 of 82 Pharmaceuticals Australia Pty Ltd PM-2010-02677-3-3 Final 15 June 2012 Therapeutic Goods Administration Contents I. Introduction to Product Submission ___________________________________ 4 Submission Details ________________________________________________________________________ 4 Product Background ______________________________________________________________________ 4 Regulatory Status _________________________________________________________________________ 6 Product Information ______________________________________________________________________ 6 II. Quality Findings ___________________________________________________________ 6 Introduction _______________________________________________________________________________ 6 Drug Substances (active ingredients) ___________________________________________________ 6 Drug Product ______________________________________________________________________________ 7 Biopharmaceutics _________________________________________________________________________ 8 Advisory Committee Considerations __________________________________________________ 11 Quality Summary and Conclusions ____________________________________________________ 11 III. Nonclinical Findings ____________________________________________________ 12 Introduction _____________________________________________________________________________ 12 Pharmacology ___________________________________________________________________________ 12 Pharmacokinetics _______________________________________________________________________ 13 Toxicology _______________________________________________________________________________ 16 Nonclinical Summary and Conclusions ________________________________________________ 17 IV. Clinical Findings ________________________________________________________ 18 Introduction _____________________________________________________________________________ 18 Pharmacokinetics _______________________________________________________________________ 18 Pharmacodynamics _____________________________________________________________________ 18 Efficacy ___________________________________________________________________________________ 24 Safety _____________________________________________________________________________________ 26 List of Questions ________________________________________________________________________ 52 Clinical Summary and Conclusions ____________________________________________________ 62 V. Pharmacovigilance Findings ___________________________________________ 67 Risk Management Plan _________________________________________________________________ 67 VI. Overall Conclusion and Risk/Benefit Assessment _________________ 71 Quality ___________________________________________________________________________________ 71 Nonclinical _______________________________________________________________________________ 72 Clinical ___________________________________________________________________________________ 72 Risk Management Plan _________________________________________________________________ 76 Risk-Benefit Analysis ___________________________________________________________________ 76 Outcome _________________________________________________________________________________ 81 Attachment 1. Product Information ____________________________________ 81 AusPAR Rasilamlo HCT Aliskiren/amlodipine/hydrochlorothiazide Novartis Page 3 of 82 Pharmaceuticals Australia Pty Ltd PM-2010-02677-3-3 Final 15 June 2012 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission: New Combination (of previously approved active ingredients) Decision: Approved Date of Decision: 16 March 2012 Active ingredient(s): Aliskiren Amlodipine Hydrochlorothiazide Product Name(s): Rasilamlo HCT Sponsor’s Name and Address: Novartis Pharmaceuticals Australia Pty Ltd 54 Waterloo Road North Ryde NSW 2113 Dose form(s): Film coated tablet Strength(s): Aliskiren 150 mg, amlodipine 5 mg, hydrochlorothiazide 12.5 mg Aliskiren 300 mg, amlodipine 5 mg, hydrochlorothiazide 12.5 mg Aliskiren 300 mg, amlodipine 5 mg, hydrochlorothiazide 25 mg Aliskiren 300 mg, amlodipine 10 mg, hydrochlorothiazide 12.5 mg Aliskiren 300 mg, amlodipine 10 mg, hydrochlorothiazide 25 mg Container(s): Blister pack Pack size(s): Packs of 7 and 28. Approved Therapeutic use: Rasilamlo HCT is only indicated as substitution therapy for the treatment of hypertension in patients whose blood pressure is already adequately controlled on the triple combination of aliskiren, amlodipine and hydrochlorothiazide taken either as three single component formulations or as dual-component formulation with single-component formulation, all components at the same dose level. Treatment should not be initiated with these fixed-dose combinations (see "Dosage and Administration"). Route(s) of administration: Oral Dosage: One tablet daily ARTG Number (s) 176176, 176182, 176185, 176187 and 176189 Product Background Cardiovascular disease is a significant contributor to the total disease burden in Australia, accounting for nearly 18%.1 Hypertension is the most frequently managed problem in general practice in Australia, accounting for approximately 8% of encounters and 1 Mathers CD, Vos ET, Stevenson CE, Begg SJ. The Australian Burden of Disease Study: measuring the loss of health from diseases, injuries and risk factors. Med J Aust 2000; 172: 592-596. AusPAR Rasilamlo HCT Aliskiren/amlodipine/hydrochlorothiazide Novartis Page 4 of 82 Pharmaceuticals Australia Pty Ltd PM-2010-02677-3-3 Final 15 June 2012 Therapeutic Goods Administration prescriptions in general practice.2 There is good evidence that blood pressure reduction decreases the risk of cardiovascular disease.3 Aliskiren belongs to a class of antihypertensives called direct renin inhibitors (DRI) that inhibit the renin angiotensin system (RAS) at the initial rate limiting step, the conversion of angiotensinogen to angiotensin I (Ang I), which is a precursor to angiotensin II, the potent vasoconstrictor in the renin angiotensin system of the kidney. Aliskiren is a Novartis drug currently registered since 2008 under the name Rasilez for the treatment of hypertension up to 300 mg and also registered in combination with hydrochlorothiazide (HCT) as Rasilez HCT for the second line treatment of hypertension in April 2010. Its product information (PI) allows for combination use with other antihypertensives. Amlodipine is a long acting, dihydropyridine calcium channel blocker (CCB) and the most commonly prescribed drug in this class. Amlodipine was first