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Report on the Deliberation Results February 5, 2010 Evaluation And Report on the Deliberation Results February 5, 2010 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Rozerem Tablets 8 mg [Non-proprietary name] Ramelteon (JAN*) [Applicant] Takeda Pharmaceutical Company Limited [Date of application] February 29, 2008 [Results of deliberation] In the meeting held on January 29, 2010, the First Committee on New Drugs concluded that the product may be approved and that this result should be presented to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. The product is not classified as a biological product or a specified biological product, the re-examination period is 8 years, and the drug substance is classified as a powerful drug and the drug product is not classified as a poisonous drug or a powerful drug. *Japanese Accepted Name (modified INN) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Report January 15, 2010 Pharmaceuticals and Medical Devices Agency The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows. [Brand name] Rozerem Tablets 8 mg [Non-proprietary name] Ramelteon [Name of applicant] Takeda Pharmaceutical Company Limited [Date of application] February 29, 2008 [Dosage form/Strength] Tablets: each tablet contains 8 mg of Ramelteon [Application classification] Prescription drug (1) Drug with a new active ingredient [Chemical structure] O CH3 O N H H Empirical formula: C16H21NO2 Molecular weight: 259.34 Chemical name: N-{2-[(8S)-1,6,7,8-Tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide [Items warranting special mention] None [Reviewing office] Office of New Drug III This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version. Review Results January 15, 2010 [Brand name] Rozerem Tablets 8 mg [Non-proprietary name] Ramelteon [Name of applicant] Takeda Pharmaceutical Company Limited [Date of application] February 29, 2008 [Results of review] Based on the submitted data, the efficacy of the product in improving sleep-onset insomnia has been demonstrated and its safety is considered acceptable in view of its observed benefits. The relationship of the presence or absence of prior therapy with other hypnotics or the duration of disease with the efficacy and safety of the product, the occurrence of impaired consciousness (memory impairment during interim periods of wakefulness, etc.), the occurrence of withdrawal symptoms, rebound insomnia, abuse and dependence, and muscle relaxation such as staggering, which are problematic events associated with currently marketed hypnotics, and the impact of the product on next-day functioning etc. need to be further investigated via post-marketing surveillance. As a result of its regulatory review, the Pharmaceuticals and Medical Devices Agency has concluded that the product may be approved for the following indication and dosage and administration. [Indication] Improvement of sleep-onset insomnia [Dosage and administration] The usual adult dose is 8 mg as Ramelteon taken orally at bedtime. 3 Review Report (1) November 27, 2009 I. Product Submitted for Registration [Proposed brand name] Rozerem Tablets 8 [Non-proprietary name] Ramelteon [Name of applicant] Takeda Pharmaceutical Company Limited [Date of application] February 29, 2008 [Dosage form/Strength] Tablets: each tablet contains 8 mg of Ramelteon [Proposed indication] Insomnia [Proposed dosage and administration] The usual adult dose is 8 mg as Ramelteon taken orally at bedtime. II. Summary of the Submitted Data and Outline of Review by Pharmaceuticals and Medical Devices Agency A summary of the submitted data and an outline of the review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 1. Origin or history of discovery and usage conditions in foreign countries etc. Currently, for the treatment of insomnia, benzodiazepine (BZD) and nonbenzodiazepine (non-BZD) hypnotics have been used, and these agents work by binding to the GABAA receptor in the central nervous system and by promoting central nervous system depression (Miura S, Consulting ed. An outline of antipsychotic agents, Rev ed. 2001, Vol 2. Seiwa Shoten Co., Ltd., Tokyo, Japan; 2001), but reducing their adverse reactions, e.g. dependence, amnesia, residual effects, muscle relaxation, rebound insomnia, and withdrawal syndrome, is considered a future challenge (Uchimura M, Chief Researcher, MHLW-sponsored research project on psychiatric/neurological disorders, Research Project Report for FY 1999-2001: Development of guidelines for the diagnosis and treatment of sleep disorders and its empirical research, 2002; 61-66). The active ingredient of the product, Ramelteon, is a selective melatonin MT1 and MT2 receptor agonist discovered by Takeda Pharmaceutical Company Limited in 1996. Clinical trials were initiated in ** 19** in Japan and in ** 19** overseas. Since its U.S. approval in July 2005, the product has been approved in 4 countries as of October 2009. As the efficacy and safety of the product in patients with insomnia have been confirmed, the applicant has filed a marketing application. 4 Although the proposed brand name was “Rozerem Tablets 8,” it was requested that the brand name should clearly indicate the strength of the active ingredient, and then the applicant explained that the proposed brand name would be changed to “Rozerem Tablets 8 mg” and PMDA accepted it. In the EU, a marketing authorization application for Ramelteon was submitted in March 2007. However, the European Medicines Agency (EMA) issued a negative opinion for granting a marketing authorization to Ramelteon in June 2008, and the application was withdrawn in September 2008 [for the situation in the EU, see “4.(iii).B.(4) Reasons and other factors for refusal of authorization in the EU”]. 2. Data relating to quality 2.A Summary of the submitted data 2.A.(1) Drug substance The Ramelteon drug substance is a white crystalline powder. Its general properties including description, solubility, hygroscopicity, melting point and ******, specific rotation, partition coefficient, and crystalline polymorphism have been determined. Ramelteon is not hygroscopic and has no polymorphs. The manufacturing process for the drug substance uses ************************************************************************************** ******* as starting materials and consists of Step 1 *************************************** ************************************************) synthesis), Step 2 (*************** ************************************************************************) synthesis), Step 3 *****), Step 4 (*************** synthesis), Step 5 (***********), and Step 6 *****) and reprocessing procedures have been established for Step *, Step *, and Step *. Step *, Step *, and Step * have been defined as critical steps and ********** and ************* have been defined as critical intermediates and their control parameters and action limits have been established. The chemical structure of the drug substance has been elucidated by elementary analysis, mass spectrometry, ultraviolet-visible (UV) spectroscopy, infrared (IR) spectrophotometry, nuclear magnetic resonance spectrometry (1H-NMR, 13C-NMR), optical rotation, isomerism, crystalline polymorphism, and ** ******* **********. Ramelteon has one chiral center and is produced as the (S) form. Although the (R)-enantiomer exists, *********************** in the drug substance and drug product and ********* has not been detected also in stability studies of the drug substance or drug product and *****************. Impurities including related substances, residual solvents, and ******** have been analyzed. The proposed specifications for the drug substance include description, identification (UV spectrum, IR spectrum), purity *************, ************* [********************], related substances [HPLC], residual solvents [***************************), ****, ********, and assay (HPLC). *****, ******* ***, ****, ***, and ************* have also been determined, but are not included in the drug substance specification. The specification limits for related substances have been established for Related Substance 1, Related Substance 2, Related Substance 3, others (individual), and total related substances and the 5 specification limits for residual solvents have been established for Residual Solvent 1 and Residual Solvent 2. In order to assess the stability of the drug substance, long-term testing (25°C/60% RH/dark place, 36 months) and accelerated testing (40°C/75% RH/dark place, 6 months) were performed on 3 pilot-scale drug substance batches primary packaged in low-density polyethylene bags. Using 1 pilot-scale drug substance batch, stress testing (temperature [**°C/*****************, *************, * months], temperature [**°C/**********************, *****************, ** months], humidity [**°C/**%
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