List Item Withdrawal Assessment Report for Ramelteon
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European Medicines Agency Evaluation of Medicines for Human Use London, 23 October 2008 Doc.Ref.: EMEA/CHMP/551287/2008 WITHDRAWAL ASSESSMENT REPORT FOR Ramelteon Takeda Global Research and Development Centre (Europe) LTD International Non-proprietary Name: ramelteon Procedure No. EMEA/H/C/000838 CHMP Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted. This should be read in conjunction with the “Question and Answer” document on the withdrawal of the application: the Assessment Report may not include all available information on the product if the CHMP assessment of the latest submitted information was still ongoing at the time of the withdrawal of the application. 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, 2008. 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 2 SCIENTIFIC DISCUSSION................................................................................................. 4 2.1 Introduction.............................................................................................................................. 4 2.2 Quality aspects......................................................................................................................... 4 2.3 Non-clinical aspects................................................................................................................. 7 2.4 Clinical aspects ...................................................................................................................... 16 2.5 Pharmacovigilance................................................................................................................. 59 2.6 Overall conclusions, risk/benefit assessment and recommendation ...................................... 59 2/62 1. BACKGROUND INFORMATION ON THE PROCEDURE 1.1 Submission of the dossier The applicant Takeda Global Research and Development Centre (Europe) Ltd. submitted on 1 March 2007 an application for Marketing Authorisation to the European Medicines Agency (EMEA) for Ramelteon, 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 18 October 2006. The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application The applicant applied for the following indication “Ramelteon is indicated for the treatment of primary insomnia” 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 and/or bibliographic literature substituting/supporting certain test(s) or study(ies). Scientific Advice: The applicant did not seek scientific advice at the CHMP. Licensing status: Ramelteon has been given a Marketing Authorisation in the United States on 22 July 2005. The Rapporteur and Co-Rapporteur appointed by the CHMP were: Rapporteur: Barbara van Zwieten-Boot Co-Rapporteur: Cristina Sampaio 1.2 Steps taken for the assessment of the product • The application was received by the EMEA on 1 March 2007. • The procedure started on 21 March 2007. • The Rapporteur's first Assessment Report was circulated to all CHMP members on 11 June 2007. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on 19 June 2007. • During the meeting on 16-19 July 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 24 July 2007. • The applicant submitted the responses to the CHMP consolidated List of Questions on 3 October 2007. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the List of Questions to all CHMP members on 27 November 2007. • During the CHMP meeting on 10-13 December 2007, the CHMP agreed on a list of outstanding issues to be addressed in writing and/or in an oral explanation by the applicant. • The applicant submitted the responses to the CHMP list of outstanding issues on 19 March 2008. • The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the list of outstanding issues to all CHMP members on 10 April 2008. • During the CHMP meeting on 21-24 April 2008, outstanding issues were addressed by the applicant during an oral explanation before the CHMP on 23 April 2008. 3/62 • During the meeting on 27-30 May 2008, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a negative opinion for granting a Marketing Authorisation to Ramelteon on 30 May 2008. 2 SCIENTIFIC DISCUSSION 2.1 Introduction This application concerns Ramelteon, film coated tablets for oral administration. The tablets are immediate release formulations. Ramelteon is a selective agonist of the melatonin type 1 (MT1) and type 2 (MT2) receptors in the suprachiasmatic nucleus (SCN). Physiologically, these receptors are associated with biorhythm and sleep-wake rhythm, regulated by circadian excretion of endogenous melatonin. The originally sought indication was for: the treatment of primary insomnia in adults. Following discussion at the CHMP, the applicant proposed to narrow down the indication to the treatment of sleep latency, and to limit the duration of treatment to five weeks: Treatment of primary insomnia characterised by difficulty falling asleep in patients 18 years and older. The dose recommendation is 4 or 8 mg given 30 minutes before bedtime. DSM-IV-TR defines Primary Insomnia as a complaint consisting of difficulty initiating or maintaining sleep, or non-restorative sleep, for at least 1 month (criterion A) that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning (criterion B). The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, or a parasomnia (criterion C) or mental disorder (criterion D). The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (criterion E). Current pharmacologic treatments for insomnia involve mainly GABAergic mechanisms: most currently prescribed sleep agents are benzodiazepine receptor agonists (BZRAs), which induce sleep by binding to the benzodiazepine receptor site of the GABA-A receptors. The use of these compounds is limited to a short time interval due to risk of dependence. 2.2 Quality aspects Introduction The medicinal product is a film-coated tablet with a new active substance Ramelteon, in two dosage strengths: 4 mg and 8 mg. It is an immediate release dosage form and the core consists of standard excipients ( lactose, maize starch, hydroxypropylcellulose and magnesium stearate ) as defined in section 6.1 of the SPC. The product is presented in transparent PVC/Al blisters. Active Substance Ramelteon INN is a chiral tetrahydro-indenofuran derivative, purified as the S-isomer, freely soluble in organic solvents but less soluble in water. 4/62 Structure of the active substance (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide Site of labelling (see structure). Isomerism. no Molecular weight. 259.34 Solubility in water. 0.21 mg/mL Pka. -0.84 (computer simulation) Distribution coefficient. 320 (octanol/water) Solubility in other solvents. Benzyl alcohol 440 mg/mL Methanol 300 mg/mL Dimethylsulfoxide 290 mg/mL Ethanol 200 mg/mL Octanol 90 mg/mL Acetonitrile 68 mg/mL Diethyl ether 6.9 mg/mL Stability. Possible chirality and its consequences. The S-form is included. A major metabolite (M-II) is a diastereoisomer. Only the (2S,8S) is formed in humans. This metabolite has been tested separately in monkeys. • Manufacture The synthesis is a 4-step process. Starting materials are characterised and controlled to maintain the purity of the resulting active substance. The chiral centre is introduced during synthesis and process investigations demonstrate the satisfactory retention of this centre resulting in the S-isomer. The active substance is purified by recrystallisation and micronised. The molecular structure has been confirmed by a wide range of spectroscopic methods, and there is no evidence of polymorphism. Concerning impurities, a range of theoretical impurities has been described and those that are actually found have been isolated, investigated and the proposed limits have been justified and qualified. Process validation studies have been performed with three production scale batches, manufactured at the proposed sites, according to the proposed synthesis. Batch analytical data confirm the satisfactory uniformity of the process with regard to chemical and physical characteristics of the active substance. • Specification The specification includes tests for assay (non chiral HPLC ), content of R-isomer ( chiral HPLC), a range of related impurities by HPLC, heavy