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Australian Public Assessment Report for Zoledronic Acid

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Australian Public Assessment Report for Zoledronic Acid Australian Public Assessment Report for Zoledronic Acid Proprietary Product Name: Aclasta/Osteovan Sponsor: Novartis Australia Pty Ltd August 2011 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The 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. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General’s Department, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/cca AusPAR Aclasta/Osteovan Zoledronic acid Novartis Australia Pty Ltd PM-2010-01920-3-5 Page 2 of 129 Final 31 August 2011 Therapeutic Goods Administration Contents I. Introduction to Product Submission ____________________________________ 4 Product Background _______________________________________________________________________4 Regulatory Status ___________________________________________________________________________6 Product Information _______________________________________________________________________6 II. Quality Findings ____________________________________________________________ 7 III. Nonclinical Findings ______________________________________________________ 7 IV. Clinical Findings ___________________________________________________________ 7 Introduction _________________________________________________________________________________7 Pharmacokinetics___________________________________________________________________________7 Pharmacodynamics_________________________________________________________________________9 Efficacy ____________________________________________________________________________________ 11 Safety ______________________________________________________________________________________ 18 Clinical Summary and Conclusions _____________________________________________________ 35 V. Pharmacovigilance Findings ___________________________________________ 36 Risk Management Plan ___________________________________________________________________ 36 VI. Overall Conclusion and Risk/Benefit Assessment _________________ 37 Quality _____________________________________________________________________________________ 37 Nonclinical ________________________________________________________________________________ 37 Clinical _____________________________________________________________________________________ 37 Risk Management Plan ___________________________________________________________________ 39 Risk-Benefit Analysis _____________________________________________________________________ 39 Summary of the Response from Sponsor _______________________________________________ 40 Advisory Committee Considerations ___________________________________________________ 42 Outcome ___________________________________________________________________________________ 43 References ____________________________________________________________________ 44 Attachment 1. Product Information _____________________________________ 51 AusPAR Aclasta/Osteovan Zoledronic acid Novartis Australia Pty Ltd PM-2010-01920-3-5 Page 3 of 129 Final 31 August 2011 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission Major Variation Decision: Approved Date of Decision: 29 July 2011 Active ingredient(s): Zoledronic acid Product Name(s): Aclasta/Osteovan Sponsor’s Name and Address: Novartis Australia Pty Ltd, PO Box 101, North Ryde, NSW 1670 Dose form(s): Solution for Injection Strength(s): 5 mg/100 mL Container(s): Vial Pack size(s): One vial. Also Multipacks of 3 or 6 vials. Approved Therapeutic use: Treatment of osteoporosis in postmenopausal women to reduce the incidence of hip, vertebral and non-vertebral fractures. Treatment of osteoporosis in patients over 50 years of age with a history of at least one low trauma hip fracture, to reduce the incidence of further fracture. To increase bone mineral density in men with osteoporosis. To increase bone mineral density in patients with osteoporosis associated with long term glucocorticoid use. To prevent glucocorticoid-induced bone mineral density loss. Treatment of Paget's disease of bone. Route(s) of administration: Intravenous (IV) Dosage: Single IV infusion of 5 mg Aclasta administered once a year.a ARTG Number (s) 134665 and 13466 All published references referred to in this AusPAR are listed under the heading References at the end of the document. Product Background Zoledronic acid belongs to the class of nitrogen-containing bisphosphonates which act primarily on bone. The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid is rapidly distributed to bone and, like other bisphosphonates, localises preferentially at sites of bone resorption and inhibits of osteoclast-mediated bone resorption. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase (FPPS), but this does not exclude other mechanisms. Most agents currently employed in the treatment of osteoporosis, including zoledronic acid (ZA), are osteoclast inhibitors. ZA, like other amino-bisphosphonates, acts in a stepwise fashion. (1) It a For osteoporosis, the duration of therapy should be restricted to no more than three annual doses, that is, three years. AusPAR Aclasta/Osteovan Zoledronic acid Novartis Australia Pty Ltd PM-2010-01920-3-5 Page 4 of 129 Final 31 August 2011 Therapeutic Goods Administration has a strong binding affinity for hydroxyapatite1 which takes up some 50% of the injected dose within minutes. (2) The drug is ingested by osteoclasts at resorbing surfaces of bone, so that the concentration within these cells is several orders of magnitude greater than in other cells. (3) Within the osteoclast, amino bisphosphonates act as cellular toxins. They competitively inhibit farnesyl diphosphate synthase2, an enzyme in the mevalonate pathway. Inhibition of this enzyme prevents the biosynthesis of farnesyl diphosphate and geranyl diphosphate, hydrophobic lipids which combine with guanosine triphosphate (GTP)-binding proteins (such as Ras, Rab and Rho) and without which, the signalling pathways of these proteins are impaired. While osteoblastic activity is also diminished by bisphosphonates, the anti-osteoclastic action of these agents (which may be due to other mechanisms as well as those associated with the inhibition of farnesyl diphosphate synthase) predominates, so that bone mineral loss is prevented and the incidence of fractures is reduced. Figure 1. The structure of zoledronic acid. The P-C-P backbone is common to all bisphosphonates. The affinity for hydroxyapatite and the inhibition of farnesyl diphosphate synthase varies with the structure of the side-chain. For reasons that are probably related to its heterocyclic ring structure (see Figure 1), ZA has a greater affinity for hydroxyapatite than most other bisphosphonates,3 and it is a more effective inhibitor of farnesyl diphosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of FPPS and its strong binding affinity to bone mineral. On a milligram for milligram basis, ZA is the most potent amino-bisphosphonate currently available regardless of the assay employed.4 The Advisory Committee for Prescription Medicines (ACPM) has considered zoledronic acid on several occasions. The Committee recommended that treatment be restricted to three annual doses at its April 2008 meeting; this was mainly because there were safety concerns relating to bisphosphonates that were not fully addressed in the limited data set submitted. In the current Australian submission, the sponsor has not requested any changes to
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