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Australian Public Assessment Report for Carglumic Acid

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Australian Public Assessment Report for Carglumic Acid Australian Public Assessment Report for Carglumic acid Proprietary Product Name: Carbaglu Sponsor: Emerge Health Pty Ltd September 2015 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health 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 <https://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 2015 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 Carbaglu carglumic acid Emerge Health Pty Ltd PM-2013-02751-1-3 -2 September 2015 Page 2 of 62 Therapeutic Goods Administration Contents List of the most common abbreviations used in this AusPAR _________ 5 I. Introduction to product submission _____________________________________ 7 Submission details ____________________________________________________________________ 7 Product background __________________________________________________________________ 8 Regulatory status _____________________________________________________________________ 9 Product Information_________________________________________________________________ 12 II. Quality findings ___________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 12 Biopharmaceutics ___________________________________________________________________ 13 Quality summary and conclusions _________________________________________________ 13 III. Nonclinical findings _____________________________________________________ 13 Introduction __________________________________________________________________________ 13 Pharmacology ________________________________________________________________________ 13 Pharmacokinetics ____________________________________________________________________ 14 Toxicology ____________________________________________________________________________ 15 Nonclinical summary and conclusions _____________________________________________ 19 IV. Clinical findings __________________________________________________________ 20 Pharmacokinetics ____________________________________________________________________ 22 Pharmacodynamics__________________________________________________________________ 24 Dosage selection for the pivotal studies ___________________________________________ 24 Efficacy - Treatment of NAGS deficiency ___________________________________________ 24 Efficacy - The acute treatment of hyperammonaemia in organic acidaemia____ 24 Safety _________________________________________________________________________________ 25 First round benefit-risk assessment _______________________________________________ 30 First round recommendation regarding authorisation ___________________________ 31 Clinical questions ____________________________________________________________________ 31 Second round evaluation of clinical data submitted in response to questions ______________________________________________________________________ 32 Clinical questions ____________________________________________________________________ 32 Second round benefit-risk assessment ____________________________________________ 33 Second round recommendation regarding authorisation ________________________ 33 V. Pharmacovigilance findings ____________________________________________ 33 Risk management plan ______________________________________________________________ 33 VI. Overall conclusion and risk/benefit assessment __________________ 46 AusPAR Carbaglu carglumic acid Emerge Health Pty Ltd PM-2013-02751-1-3 -2 September 2015 Page 3 of 62 Therapeutic Goods Administration Quality ________________________________________________________________________________ 46 Nonclinical ___________________________________________________________________________ 46 Clinical ________________________________________________________________________________ 47 Risk management plan ______________________________________________________________ 54 Risk-benefit analysis ________________________________________________________________ 54 Outcome ______________________________________________________________________________ 61 Attachment 1. Product Information ______________________________________ 61 Attachment 2. Extract from the Clinical Evaluation Report __________ 61 AusPAR Carbaglu carglumic acid Emerge Health Pty Ltd PM-2013-02751-1-3 -2 September 2015 Page 4 of 62 Therapeutic Goods Administration List of the most common abbreviations used in this AusPAR Abbreviation Meaning ADME absorption, distribution, metabolism and excretion study AE adverse event ALAT Alanine amino transferase ARTG Australian Register of Therapeutic Goods ASA Australian Specific Annexe (of the RMP) ASAT Aspartate aminotransferase AUC area under the plasma concentration time curve CGA carglumic acid CI confidence interval Cmax maximum plasma concentration CNS Central nervous system CPMP Committee for Proprietary Medicinal Products CPS1 carbamyl phosphate synthetase 1 CYP450 Cytochrome P450 DNA deoxyribonucleic acid ECG electrocardiogram EMEA European Medicines Agency ERAUC exposure ratio based on AUC EU European Union FDA Food and Drug Administration GCP Good Clinical Practice GLP Good laboratory practice ICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IV intravenous AusPAR Carbaglu carglumic acid Emerge Health Pty Ltd PM-2013-02751-1-3 -2 September 2015 Page 5 of 62 Therapeutic Goods Administration Abbreviation Meaning IVA isovaleric acidaemia LDH lactate dehydrogenase mg milligram MMA methylmalonic acidaemia NAG N-acetylglutamate NAGS N-acetylglutamate synthase NH3 ammonia OA Organic acidaemias OE Orphan Europe PA propionic acidaemia PCNA Proliferating cell nuclear antigen pH Acidity (pH) PI Product Information PK pharmacokinetics PO Per oral PSURs Periodic Safety Update Reports PT preferred term (medical dictionary for regulatory activities) QT QT interval QTc QT interval, corrected for heart rate SAE(s) serious adverse event(s) SAS special access scheme SD standard deviation SOC system organ class tmax time to reach maximum plasma concentration UCD urea cycle disorder AusPAR Carbaglu carglumic acid Emerge Health Pty Ltd PM-2013-02751-1-3 -2 September 2015 Page 6 of 62 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New chemical entity Decision: Approved Date of decision: 30 January 2015 Active ingredient: Carglumic acid Product name: Carbaglu Sponsor’s name and address: Emerge Health Pty Ltd Suite 3, Level 1, 2 Theatre Place Canterbury VIC 3126 Dose form: Tablet, dispersible Strength: 200 mg Container: Tube Pack size(s): 5 tablets, 60 tablets Approved therapeutic use: Carbaglu is indicated in the treatment of · Hyperammonaemia due to N-acetylglutamate synthase primary deficiency · Hyperammonaemia due to Organic Acidaemias such as: – Hyperammonaemia due to isovaleric acidaemia – Hyperammonaemia due to methymalonic acidaemia – Hyperammonaemia due to propionic acidaemia Route of administration: Oral
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