Australian Public Assessment Report for ceftaroline fosamil Proprietary Product Name: Zinforo Sponsor: AstraZeneca Pty Ltd May 2013 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 <http://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 2013 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 Zinforo Ceftaroline fosamil AstraZeneca Pty Ltd PM-2011-03149-3-2 Page 2 of 52 Final 22 May 2013 Therapeutic Goods Administration Contents I. Introduction to product submission _____________________________________ 4 Submission details ____________________________________________________________________ 4 Product background __________________________________________________________________ 4 Regulatory status _____________________________________________________________________ 5 Product Information__________________________________________________________________ 5 II. Quality findings _____________________________________________________________ 8 Drug substance (active ingredient) _________________________________________________ 8 Drug product __________________________________________________________________________ 8 Advisory committee considerations ________________________________________________ 9 Quality summary and conclusions __________________________________________________ 9 III. Nonclinical findings _____________________________________________________ 10 Introduction __________________________________________________________________________ 10 Pharmacology ________________________________________________________________________ 10 Pharmacokinetics ____________________________________________________________________ 12 Toxicology ____________________________________________________________________________ 13 Nonclinical summary and conclusions _____________________________________________ 18 IV. Clinical findings __________________________________________________________ 20 Introduction __________________________________________________________________________ 20 Pharmacokinetics ____________________________________________________________________ 21 Pharmacodynamics__________________________________________________________________ 22 Efficacy _______________________________________________________________________________ 22 Safety _________________________________________________________________________________ 24 Clinical summary and conclusions _________________________________________________ 26 V. Pharmacovigilance findings ____________________________________________ 27 Risk management plan ______________________________________________________________ 27 VI. Overall conclusion and risk/benefit assessment __________________ 35 Quality ________________________________________________________________________________ 35 Nonclinical ___________________________________________________________________________ 35 Clinical ________________________________________________________________________________ 36 Risk management plan ______________________________________________________________ 46 Risk-benefit analysis ________________________________________________________________ 46 Outcome ______________________________________________________________________________ 51 Attachment 1. Product Information ____________________________________ 51 Attachment 2. Extract from the Clinical Evaluation Report __________ 51 AusPAR Zinforo Ceftaroline fosamil AstraZeneca Pty Ltd PM-2011-03149-3-2 Page 3 of 52 Final 22 May 2013 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of Submission: New Chemical Entity Decision: Approved Date of Decision: 7 February 2013 Active ingredient: ceftaroline fosamil Product Name: Zinforo Sponsor’s Name and Address: AstraZeneca Pty Ltd 5 Alma Road North Ryde NSW 2113 Dose form: Powder for injection Strength: 600 mg Container: Glass vial Pack size: 10 vials per carton Approved Therapeutic use: Zinforo is indicated for the treatment of patients with the following infections proven or strongly suspected to be caused by designated susceptible bacteria: • Complicated skin and soft tissue infections • Community-acquired pneumonia Route of administration: Intravenous (IV) Dosage: Adults: 600 mg every 12 hours by intravenous (IV) infusion over 60 minutes for 5-7 days for community acquired pneumonia (CAP) or 5-14 days for complicated skin and soft tissue infections (cSSTI). Dose reductions are proposed for patients with renal impairment. ARTG Number: 192260 Product background This AusPAR describes the application by AstraZeneca Pty Ltd to register a new chemical entity, ceftaroline fosamil (Zinforo), for the treatment of adults with complicated skin and soft tissue infection (cSSTI) or community-acquired pneumonia (CAP). The proposed indications were: Zinforo is indicated for the empirical and directed treatment of patients with the following infections: AusPAR Zinforo Ceftaroline fosamil AstraZeneca Pty Ltd PM-2011-03149-3-2 Page 4 of 52 Final 22 May 2013 Therapeutic Goods Administration • Complicated skin and soft tissue infections • Community-acquired pneumonia • Ceftaroline fosamil is an N-phosphono-type prodrug of ceftaroline (a cephalosporin antibiotic) and is administered by infusion. The proposed treatment regimen is 600 mg every 12 h by 60-min IV infusion, for 5-7 (CAP) or 5-14 days (cSSTI), in patients 18 years and older. • Ceftaroline fosamil is a semi-synthetic pro- - lactam antibiotics. Ceftaroline fosamil is converted to the active ceftaroline in plasma by a phosphatase enzyme. Ceftaroline is bactericidaldrug from inthe vitro cephalosporin due to inhibition class of of β bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs). • - lactamases such as TEM-1, TEM-2 or SHV-1. However, ceftaroline is not active against GramCeftaroline- is stated to be active against bacteria that produce-lactamases classical (ESBLs) Class Afrom β the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), Class B metallo- - lactamasesnegative or Class bacteria C (AmpC producing cephalosporinases). extended spectrum One βor more of these mechanisms may co-exist in the same bacterium. Unlike other cephalosporins, ceftaroline is statedβ to be active against the altered PBPs found in methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP) that result in resistance to these other antibiotics. There is no cross resistance between ceftaroline and any non- -lactam antibiotics. β Regulatory status Table 1 provides a list of major countries in which a similar application had been submitted and/or approved as of November 2012. Table 1. Submission and approval status of Zinforo vials Product Information The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1. AusPAR Zinforo Ceftaroline fosamil AstraZeneca Pty Ltd PM-2011-03149-3-2 Page 5 of 52 Final 22 May 2013 Therapeutic Goods Administration List of abbreviations