Australian Public Assessment Report for Fomepizole Proprietary Product Name: Antizol Sponsor: AFT Pharmaceuticals August 2017 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 Report (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; it provides 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 2017 This work is copyright. 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AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Page 2 of 72 Final 17 August 2017 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 7 Submission details ____________________________________________________________________ 7 Product background __________________________________________________________________ 7 Regulatory status _____________________________________________________________________ 9 Product Information__________________________________________________________________ 9 II. Quality findings ___________________________________________________________ 10 Introduction __________________________________________________________________________ 10 Drug substance (active ingredient) ________________________________________________ 10 Drug product _________________________________________________________________________ 10 Quality summary and conclusions _________________________________________________ 11 III. Nonclinical findings _____________________________________________________ 11 Introduction __________________________________________________________________________ 11 Pharmacology ________________________________________________________________________ 12 Pharmacokinetics ____________________________________________________________________ 13 Toxicology ____________________________________________________________________________ 14 Nonclinical summary and conclusions _____________________________________________ 19 Nonclinical conclusion ______________________________________________________________ 21 IV. Clinical findings __________________________________________________________ 21 Introduction __________________________________________________________________________ 21 Pharmacokinetics ____________________________________________________________________ 23 Pharmacodynamics__________________________________________________________________ 25 Dosage selection for the pivotal studies ___________________________________________ 25 Efficacy _______________________________________________________________________________ 26 Safety _________________________________________________________________________________ 29 First round benefit-risk assessment _______________________________________________ 34 First round recommendation regarding authorisation ___________________________ 36 Second round evaluation of clinical data submitted in response to clinical questions _____________________________________________________________________________ 36 Second round benefit-risk assessment ____________________________________________ 36 V. Pharmacovigilance findings ____________________________________________ 37 Risk management plan ______________________________________________________________ 37 VI. Overall conclusion and risk/benefit assessment __________________ 43 Quality ________________________________________________________________________________ 43 Nonclinical ___________________________________________________________________________ 44 AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Page 3 of 72 Final 17 August 2017 Therapeutic Goods Administration Clinical ________________________________________________________________________________ 45 Risk management plan ______________________________________________________________ 55 Risk-benefit analysis ________________________________________________________________ 55 Outcome ______________________________________________________________________________ 71 Attachment 1. Product Information ______________________________________ 71 Attachment 2. Extract from the Clinical Evaluation Report __________ 71 AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Page 4 of 72 Final 17 August 2017 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning AACT American Academy of Clinical Toxicology ADH aldehyde dehydrogenase AE Adverse event AUC Area under curve APACHE II Acute Physiology and Chronic Health Evaluation II BD Base deficit BP Blood pressure bpm Beats per minute BUN Blood urea nitrogen Cmax Maximum plasma concentration CI Confidence Interval CVVH Continuous-venovenous haemofiltration CVVHD/HDF Continuous veno-venous haemodialysis/ haemodiafiltration DSW Distilled water EAPCCT European Association of Poisons Centres and Clinical Toxicologists ECG Electrocardiogram EEG Electroencephalogram EG Ethylene glycol IHD Intermittent haemodialysis IV Intravenous IQR Inter quartile range GCP Good Clinical Practice 4MP 4-MethylPyrazole (Fomepizole) Kg Kilogram L Litre LLN Lower limit of normal AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Page 5 of 72 Final 17 August 2017 Therapeutic Goods Administration Abbreviation Meaning mg Milligram ml Millilitre NS Normal Saline NCC-MERP National Coordinating Council for Medication Error Reporting and Prevention OG Osmolar Gap PK Pharmacokinetic PD Pharmacodynamic SD Standard deviation SE Standard error SEM Standard error of mean ULN Upper limit of normal µmol Micromoles mmol Millimole Vd Volume of distribution Tmax Time to maximum plasma concentration T1/2 Half life AusPAR Antizol Fomepizole AFT Pharmaceuticals PM-2015-02803-1-3 Page 6 of 72 Final 17 August 2017 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New chemical entity Decision: Approved Date of decision: 25 November 2016 Date of entry onto ARTG 1 December 2016 Active ingredient(s): Fomepizole Product name(s): Antizol Sponsor’s name and address: AFT Pharmaceuticals PO Box 748 North Ryde NSW 1670 Dose form(s): Concentrated injection Strength(s): 1.5 g/ 1.5 mL Container(s): Vials Pack size(s): 1 and 4s Approved therapeutic use: Antizol® (fomepizole) is indicated for the treatment of ethylene glycol or methanol poisoning. (see Dosage and Administration). Route(s) of administration: Intravenous (IV) Dosage: A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 h for 4 doses, then 15 mg/kg every 12 h thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL (ethylene glycol 3.22 mmol/L, methanol 6.24 mmol/L), and the patient is asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion over 30 minutes (see Treatment Guidelines). See Attachment 1 (PI) for further details. ARTG number (s): 263913 Product background This AusPAR describes the application by the sponsor to register fomepizole (as Antizol), a new chemical entity for intravenous infusion in patients with methanol or ethylene glycol