Australian Public Assessment Report for Clevidipine Proprietary Product Name: Cleviprex Sponsor: Kendle Australia Pty Ltd June 2010 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 2010 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 Cleviprex Clevidipine Kendle Australia Pty Ltd PM-2008-3132-3 Page 2 of 119 Date of Finalisation 12 April 2010 Therapeutic Goods Administration Contents I. Introduction to Product Submission ..................................................................... 4 Submission Details ................................................................................................. 4 Product Background ............................................................................................. 4 Regulatory Status .................................................................................................. 4 Product Information.............................................................................................. 5 II. Quality Findings .................................................................................................... 5 Drug Substance (active ingredient) ....................................................................... 5 Drug Product ......................................................................................................... 6 Bioavailability ........................................................................................................ 7 Consideration by PSC ........................................................................................... 7 Quality Summary and Conclusions ...................................................................... 7 III. Nonclinical Findings .............................................................................................. 7 Introduction ........................................................................................................... 7 Pharmacology ........................................................................................................ 7 Pharmacokinetics ................................................................................................ 10 Toxicology ............................................................................................................ 14 Nonclinical Summary and Conclusions .............................................................. 19 IV. Clinical Findings .................................................................................................. 21 Introduction ......................................................................................................... 21 Pharmacodynamics ............................................................................................. 21 Pharmacokinetics ................................................................................................ 35 Drug Interactions ................................................................................................ 48 Efficacy ................................................................................................................ 48 Safety .................................................................................................................... 75 Clinical Summary and Conclusions .................................................................... 91 V. Pharmacovigilance Findings ............................................................................... 92 Risk Management Plan ....................................................................................... 92 VI. Overall Conclusion and Risk/Benefit Assessment .............................................. 93 Quality ................................................................................................................. 93 Nonclinical ........................................................................................................... 94 Clinical ................................................................................................................. 94 Risk-Benefit Analysis .......................................................................................... 99 Outcome ............................................................................................................. 101 Attachment 1. Product Information ......................................................................... 101 AusPAR Cleviprex Clevidipine Kendle Australia Pty Ltd PM-2008-3132-3 Page 3 of 119 Date of Finalisation 12 April 2010 Therapeutic Goods Administration I. Introduction to Product Submission Submission Details Type of Submission New Chemical Entity Decision: Approved Date of Decision: 12 April 2010 Active ingredient(s): Clevidipine Product Name(s): Cleviprex Sponsor’s Name and Kendle Australia Pty Ltd Address: PO Box 202 Oakleigh Vic 3166 Dose form(s): Injectable emulsion Strength(s): 25 mg in 50 mL and 50 mg in 100 mL Container(s): Sterile, single-use, pre-mixed 50 mL and 100 mL glass vials. Pack size(s): Cleviprex is supplied in single vials inside a carton. Each pack includes 10 cartons containing single-use vials. Approved Therapeutic use: Cleviprex is indicated for the short term treatment of hypertension when oral therapy is not feasible or desirable. Route(s) of administration: Intravenous infusion Dosage: Individualised to patient. In clinical trials, most patients were treated with doses of 4 to 6 mg/hour. ARTG Numbers: 156137, 156138 Product Background Cleviprex (clevidipine) is a new chemical entity belonging to the dihydropyridine class of calcium channel blockers that reduces mean arterial blood pressure by decreasing systemic vascular resistance. It is indicated for the reduction of blood pressure when rapid and predictable control is desired. The intravenous infusion of Cleviprex is initiated at 1-2 mg/h; the dose may be doubled every 90 seconds. Titration should be continued until the desired target blood pressure is achieved. The desired therapeutic response for most patients occurs at doses of 4 to 6 mg/h. In clinical studies most patients were treated with maximum doses of 16 mg/h or less. However, dosage has to be individualised depending on the blood pressure to be obtained and the response of the patient. It is administered by syringe or volumetric pump for patients requiring rapid blood pressure reduction when oral therapy is not feasible or desirable. It has been evaluated in clinical trials in durations up to 72 hours. Regulatory Status A similar application to the current Australian submission has been approved in USA on 2 July 2007 for the indication: Cleviprex is a dihydropyridine calcium channel blocker indicated for the reduction of blood pressure when oral therapy is not feasible or not desirable. An application has also been approved in New Zealand on 31 July 2009 for the indication: AusPAR Cleviprex Clevidipine Kendle Australia Pty Ltd PM-2008-3132-3 Page 4 of 119 Date of Finalisation 12 April 2010 Therapeutic Goods Administration Cleviprex is indicated for the reduction of blood pressure when rapid and predictable control is desired. An application for the same indication has been submitted and is under evaluation in the European Union (EU), Canada and Switzerland. Product Information The approved product information (PI) current at the time this AusPAR was prepared is at Attachment 1. II. Quality Findings Drug Substance (active ingredient) Structure Clevidipine butyrate is a new chemical entity which is presented as a racemic mixture of two enantiomers. It is related