Australian Public Assessment Report for Nabiximols Proprietary Product Name: Sativex Sponsor: Novartis Pharmaceuticals Australia Pty Limited September 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 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 <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. 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AusPAR Nabiximols Sativex Novartis Pharmaceuticals Australia Pty Limited PM-2011-00150-3-1 Page 2 of 204 Final 27 September 2013 Therapeutic Goods Administration Contents I. Introduction to product submission ____________________________________ 5 Submission details ____________________________________________________________________ 5 Document outline _____________________________________________________________________ 5 Product background __________________________________________________________________ 6 Regulatory status _____________________________________________________________________ 7 Product Information_________________________________________________________________ 10 List of abbreviations _________________________________________________________________ 10 II. Quality findings _________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 13 Biopharmaceutics ___________________________________________________________________ 13 Recommendations ___________________________________________________________________ 15 III. Nonclinical findings ___________________________________________________ 16 Introduction __________________________________________________________________________ 16 Pharmacology ________________________________________________________________________ 16 Pharmacokinetics ____________________________________________________________________ 18 Toxicology ____________________________________________________________________________ 20 Nonclinical summary and conclusions _____________________________________________ 25 IV. Clinical findings ________________________________________________________ 27 Introduction __________________________________________________________________________ 27 Pharmacokinetics ____________________________________________________________________ 31 Pharmacodynamics__________________________________________________________________ 45 Dose selection for the pivotal studies ______________________________________________ 50 Efficacy _______________________________________________________________________________ 50 Safety _______________________________________________________________________________ 109 First round risk-benefit assessment _____________________________________________ 143 List of questions ___________________________________________________________________ 156 Second round evaluation in response to questions _____________________________ 156 Second round risk-benefit assessment __________________________________________ 162 V. Pharmacovigilance findings __________________________________________ 162 Risk management plan ____________________________________________________________ 162 VI. Overall conclusion and risk-benefit assessment _________________ 170 Quality ______________________________________________________________________________ 170 Nonclinical _________________________________________________________________________ 171 Clinical ______________________________________________________________________________ 171 AusPAR Sativex Nabiximols Novartis Pharmaceuticals Australia Pty Limited PM-2011-00150-3-1 Page 3 of 204 Final 27 September 2013 Therapeutic Goods Administration Risk management plan ____________________________________________________________ 177 Risk-benefit analysis ______________________________________________________________ 178 Response from sponsor ___________________________________________________________ 181 Advisory committee considerations _____________________________________________ 187 Outcome (initial decision) ________________________________________________________ 187 Final outcome (Section 60 decision) _____________________________________________ 189 Attachment 1. Product Information ____________________________________ 203 AusPAR Sativex Nabiximols Novartis Pharmaceuticals Australia Pty Limited PM-2011-00150-3-1 Page 4 of 204 Final 27 September 2013 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New Chemical Entity Decision: Approved Date of decision: 26 November 2012 Active ingredient: Nabiximols Product name: Sativex Sponsor’s name and address: Novartis Pharmaceuticals Australia Pty Limited 54 Waterloo Road North Ryde NSW 2113 Dose form: Oromucosal spray Strength: Nabiximols 80 mg/mL corresponding to 27 mg/mL delta-9 tetrahydrocannabinol (THC) and 25 mg/mL cannabidiol (CBD) Container: Type I amber glass vial with external plastic coating, fitted with a crimped on pump actuator Pack size: 10 mL Approved therapeutic use: Treatment for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. Route of administration: Oromucosal Dosage: Patients should titrate the dose as needed between 1-12 sprays daily (2.7-32.4 mg THC and 2.5-30 mg CBD) in 2 or more divided doses. It is expected to usually be delivered sublingually. A titration schedule (to a maximum of 12 sprays daily) over 2 weeks is proposed. ARTG number: 181978 Document outline This AusPAR follows the sequence of events for the review of the nabiximols (Sativex) submission as follows: · Evaluator reports; · Delegate’s initial considerations (including Conclusion and recommendation); AusPAR Sativex Nabiximols Novartis Pharmaceuticals Australia Pty Limited PM-2011-00150-3-1 Page 5 of 204 Final 27 September 2013 Therapeutic Goods Administration · Pre ACPM (Advisory Committee on Prescription Medicines) response from the sponsor, Novartis Pharmaceuticals Australia Pty Limited; · ACPM Considerations; · ACPM Outcome and Reasons for decision; and · Opinion of the Delegate of the Minister following a sponsor appeal under Section 60 of the Therapeutics Goods Act 1989. Product background This AusPAR describes an application by the sponsor to register nabiximols (Sativex), a mixture of cannabinoid botanical extracts containing 27mg/ml delta-9 tetrahydrocannibinol (THC) and 25 mg/ml cannabidiol (CBD), as a new chemical entity. The proposed indication is for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. Sativex represents a novel therapeutic class: botanical