European Medicines Agency WITHDRAWAL ASSESSMENT REPORT FOR Lunivia International Non-proprietary Name: eszopiclone Procedure No. EMEA/H/C/000895 Final Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK Tel. (44-20) 74 18 84 00 Fax (44-20) 75 23 70 51 E-mail: [email protected] http://www.emea.europa.eu © European Medicines Agency, 2009. Reproduction is authorised provided the source is acknowledged. TABLE OF CONTENTS 1. BACKGROUND INFORMATION ON THE PROCEDURE ........................................... 3 1.1. Submission of the dossier ........................................................................................................ 3 1.2. Steps taken for the assessment of the product.......................................................................... 3 1.3. Steps taken for the re-examination procedure.......................................................................... 4 2. SCIENTIFIC DISCUSSION................................................................................................. 5 2.1. Introduction.............................................................................................................................. 5 2.2. Quality aspects ......................................................................................................................... 5 2.3. Non-clinical aspects ................................................................................................................. 9 2.4. Clinical aspects ...................................................................................................................... 16 2.5. Pharmacovigilance................................................................................................................. 53 2.6. Overall conclusions, risk/benefit assessment and recommendation ...................................... 59 3.7 New Active Substance status (NAS)...................................................................................... 61 3. RE-EXAMINATION OF THE CHMP OPINION ........................................................... 65 3.1. Grounds for re-examination ................................................................................................... 65 3.2. Detailed Positions .................................................................................................................. 68 3.3. CHMP Overall conclusions from the Joined Assessment Report.......................................... 98 3.4. The following questions were addressed by the CHMP to the Clinical Neurosciences Scientific Advisory Group...................................................................................................................... 98 th 3.5. Questions addressed during the Oral Explanation on 16 February 2009............................. 99 3.6. Overall conclusions of the re-examination procedure.......................................................... 101 Lunivia 2/101 1. BACKGROUND INFORMATION ON THE PROCEDURE 1.1. Submission of the dossier The applicant Sepracor Pharmaceuticals, Ltd. submitted on 23 July 2007 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for Lunivia, through the centralised procedure under Article 3 (2) (a) of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMEA/CHMP on 27 February 2007. The legal basis for this application refers to: A - Centralised / Article 8(3) / New active substance. Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application The application submitted is a complete dossier: Composed of administrative information, complete quality data, non-clinical and clinical data based on applicants’ own tests and studies The applicant applied for the following indication treatment of insomnia. Licensing status: Lunivia has been given a Marketing Authorisation in US on 15 December 2004 (marketed as product called Lunesta). The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were: Rapporteur: Dr David Lyons Co-Rapporteur: Prof Cristina Sampaio 1.2. Steps taken for the assessment of the product • The application was received by the EMEA on 23 July 2007. • The procedure started on 15 August 2007. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 7 November 2007. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 14 November 2007. In accordance with Article 6(3) of Regulation (RC) No 726/2004, the Rapporteur and Co-Rapporteur declared that they had completed their assessment report in less than 80 days. • During the meeting on 10-13 December 2007, the CHMP agreed on the consolidated List of Questions to be sent to the applicant. The final consolidated List of Questions was sent to the applicant on 14 December 2007. • The applicant submitted the responses to the CHMP consolidated List of Questions on 28 March 2008. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 12 May 2008. • During the CHMP meeting on 27-29 May 2008, the CHMP agreed on a list of outstanding issues to be addressed in writing and in an oral explanation by the applicant. • During the CHMP meeting on 22-25 September 2008, outstanding issues were addressed by the applicant during an oral explanation before the CHMP. • During the meeting on 20-23 October 2008, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to Lunivia on 23 October 2008. The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on 17 October 2008. Lunivia 3/101 1.3. Steps taken for the re-examination procedure • The applicant submitted written notice to the EMEA on 04 November 2008 to request a re-examination of the Lunivia CHMP positive opinion of 23 October 2008. • During its meeting on 15-18 December 2008, the CHMP appointed Dr. K. Broich as Rapporteur and Dr Votava as Co-Rapporteur. The Rapporteur and Co-Rapporteur appointed by the CHMP and the re-examination evaluation teams were: Rapporteur: Dr Karl Broich Co-Rapporteur: Dr Martin Votava • The detailed grounds for the re-examination request were submitted by the applicant on 23 December 2008. The re-examination procedure started on 23 December 2008. • The Rapporteur's Assessment Report was circulated to all CHMP members on 28 January 2009. The Co-Rapporteur's Assessment Report was circulated to all CHMP members on 23 January 2009. • During its meeting on 19-22 January 2009, the CHMP adopted a List of Participants for the Scientific Advisory Group (SAG) meeting on Clinical Neuroscience meeting to be held on 5 February 2009. • During the SAG meeting on 5 February 2009, experts were convened to consider the grounds for re-examination. During this meeting the applicant presented an oral explanation. A report of this meeting was forwarded to the CHMP. • The Rapporteurs’ Joint Assessment Report was circulated to all CHMP members on 11 February 2009. • During the CHMP meeting on 16 - 19 February 2009, the applicant presented an oral explanation before the CHMP on 16 February 2009. • During the meeting on 16 – 19 February 2009, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a final Opinion confirming the favourable benefit/risk balance of Lunivia as determined in the original opinion of October 2008. However, the CHMP also reconfirmed its opinion of October 2008, concluding that no meaningful clinical difference could be established between eszopiclone and zopiclone regarding safety and efficacy and therefore recommending the refusal of the New Active Substance Status to eszopiclone. The applicant provided the revised letter of undertaking on the follow-up measures to be fulfilled on 19 February 2009. Lunivia 4/101 2. SCIENTIFIC DISCUSSION 2.1. Introduction Sepracor Pharmaceuticals Ltd. has submitted an application for a marketing authorisation through the centralised procedure for Lunivia 2 mg and 3 mg film coated tablets. Racemic zopiclone is already marketed in Europe, and eszopiclone is approved on the market in the United States of America. The product contains the active substance eszopiclone. Racemic zopiclone is a mixture of the enantiomers (S)-zopiclone and (R)-zopiclone whereas eszopiclone is comprised of pure (S)-zopiclone, a single isomer associated with hypnotic activity. The applied indication for Lunivia is for the treatment of insomnia, including difficulty falling asleep, nocturnal awakening or early awakening, in adults, usually for short term duration. Insomnia is a heterogeneous condition featuring reduced quality, duration, or efficiency of sleep; it is a common condition characterised by sleep disruption lasting at least one month. Disruption of sleep may include difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening. An additional complaint is diminished sleep quality or non-restorative sleep and may cause consequent daytime impairment or distress with fatigue and poor concentration. 2.2. Quality aspects Introduction Sepracor Pharmaceuticals Ltd. has submitted an application for a marketing authorisation through the centralised procedure for Lunivia 2 mg and 3 mg film coated tablets. The product contains the active substance