All in Japan: Triptans Single User License - All regulated medicinal products in Japan TRIPTANS Table of Contents 1. Introduction 2. Type/generations of triptans Table 1. Generations of triptans 3. Triptan products approved in Japan Table 2. Approval classification of the prescription medicinal products Table 3. Individual triptan products approved in Japan Disclaimer Note: The documents from the Japan Monitor "All in Japan" series provide concise up-to-date description of each product from a specific therapeutic category approved in Japan. Further details can be found in the web site of JKS, in the Key and Basic documents available in the JKS Document Store or by enquiring directly to JKS at regulatory@jouhoukoukai.com. 1. Introduction    In the early 1990s, a new class of serotonin 5-hydroxytryptamine (5-HT1B/1D) agonists - collectively termed as triptans, entered the pharmaceutical market for migraine and clustered headache treatment.        The first commercial product of sumatriptan was launched by Glaxo Wellcome (see Table 1 below) under the brand Imigran (r), thus becoming the first and only triptan of the first generation. While offering improved efficacy and tolerability over the ergot-derived compounds - then the anti-migraine drugs of choice, in the late nineties three new triptan products of the second generation were launched internationally. By the Year 2000 the global market for antimigraine preparations was reported to reach 1.9 billion US$ and to be 85% dominated by the maker of triptans. The rapid expansion of the triptans market share was reflecting not only the improved pharmacokinetic properties and/or tolerability profiles of the second generation, but also the successful development of non-injectables (tablets and nasal sprays).        In the same time the migraine market in Japan remained considerably different - smaller to a size, not corresponding to the position of Japan as the world's second largest single country healthcare market, but also distinguished in the dynamics of the patients' populations and prescription practice. Until 2001, no triptan product was available in Japan, as the domestic migraine market was not only dominated by older therapeutic options such as analgesics and ergots, but found to be no more than 2.6% of the North American market, in spite of nearly 8.8 millions estimated Japanese sufferers. The consensus among the scientific and business experts is that profound cultural stigma on the mental conditions as a "character's flow" and thus correctable only by innate willpower would cripple the commercial prospects of the new therapeutic agents. Analogously, the contemporary medical practice was to admit and treat only patients with severe forms requiring hospitalization.        However, starting from 2001 the situation of the Japanese migraine market changed dramatically due to deregulations, scientific advances and the increasing of the public awareness, with consequent introduction of four triptan products in seven different formulations (see Table 2 below).        As a party to the ICH process, the implementation in Japan of the ICH E5: Guidelines on Ethnic Factors in Acceptability of Foreign Clinical Data provided the legal ground for acceptance for domestic approval of the foreign data in the Clinical Data Packages generated outside Japan. Remarkably, one of the first and best known examples of a product approved in Japan by submitting bridging studies data was Relpax (eletriptan) - where the Phase I studies revealed that the pharmacokinetic profiles of Japanese healthy subjects was not significantly different to the profile of adults from other ethnic groups. Furthermore, late Phase II studies confirmed the efficacy and safety of eletriptan in Japanese migraineurs.        As a result of both the deregulation and the advances of the pharmacological research, the newly introduced triptan products made rapid inroads into the migraine market, as reflected in the 1.5 billion Yen revenue sales and 38,000 treated patient volume in the first year after the launch of the Imigran tablet formulation.        Due to the considerable growth potential of the migraine and headache market in Japan, JKS has include triptan report in its customized Niche Reports series and has provided a sample of a Case Study research. 2. Type/generations of triptans    A comparative overview of the worldwide and domestic status of the all seven triptan products in clinical use is presented in Table 1. Four triptans are already approved in Japan; Naratriptan is under clinical development and makers of Frovatriptan and Almotriptan are currently negotiating with potential partners in Japan.     Table 1. Generations of triptans and approval status in Japan (as of January 2004) Triptan International status Approval in Japan Generic Genera tion First approval Brand Maker/ Marketing Approval Brand Maker/ Marketing Sumatriptan I 1991 Imigran Imitrex GSK 2000 Imigran GSK Zolmitriptan II 1997 Zomig AstraZeneca 2001 Zomig AstraZeneca KK Rizatriptan II 1998 Maxalt Merck 2003 Maxalt Eisai KK Naratriptan II 1998 Amerge Naramig GSK Phase II /Sumitomo Pharma KK Frovatriptan II 2001 Frova Miguard Migard Frovelan Vernalis Menarini Elan UCB Not entered Almotriptan II 2001 Axert Almirall Not entered Eletriptan II 2002 Relpax Pfizer 2002 Relpax Pfizer KK 3. Triptan products approved in Japan    All seven formulations of the four triptan products registered in Japan by January 2004 are listed in Table 3 below. Included are a comprehensive profile of each product's approval and market entry timeline, as well as relevant medical, regulatory, formulation and therapeutic remarks on the product. The formulations are grouped by brand and the year of approval, starting with the first approved product under the Imigran brand. Table 2. Approval classification of the prescription medicinal products in Japan Class Description 1 Medicines with new active ingredients 2 New combination medicines excluding medicines Class 7-2 and trivial combinations 3 Medicines with new route of administration 4 Medicines with new indications 5 Medicines with new dosage forms 6 Medicines with new doses 7 Medicines with additional dosage forms: excluding the medicines Class 5 7-2 Medicines with similar formulations 8 Miscellaneous Table 3. Individual triptan products approved in Japan 1. IMIGRAN Injection Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination IMIGRAN (r) Sumatriptan succinate 87216 6 years Approval Date/Number Approval Classification Approved Indication(s) Therapeutic Category April 2000 21200AMZ00018000 Class 1 Migraine and cluster headache Selective 5-HT1B/1D receptor agonist analgesic Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan May 2003 (4th revision) High potency; Ethical medicine Prescription only April 2000 April 2000 Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Ampule volume 1 mL Content: Sumatriptan succinate (as Sumatriptan) 4.2 mg (3.0 mg) Additive: Sodium chloride 3-[2-(dimethylamino)ethyl]-N-methylindole-5-metha nesulfonamide monosuccinate (C14H21N3O2S・C4H6O4) Imigran Injection: 2 ampules (1 mL/ampule) Colorless to pale yellow transparent liquid pH 4.2-5.3. Osmotic diuresis about 1 (c.a. physiologic saline) GlaxoSmithKline K.K. GSK Bldg. 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 Japan 2. IMIGRAN Tablets Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination IMIGRAN (r) Sumatriptan succinate 87216 6 years Approval Date Approval Number Approval Classification Approved Indication(s) Therapeutic Category June 2001 21300AMZ004800000 Class 3 / Class 5 Migraine Selective 5-HT1B/1D receptor agonist analgesic Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan May 2003 (3rd revision) High potency; Ethical medicine Prescription only August 2001 August 2001 Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Sumatriptan succinate 70 mg per tablet (50 mg as Sumatriptan) Excipients: Lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, methylhydroxypropylcellu- lose, titanium dioxide, triacetin and iron oxide 3-[2-(dimethylamino)ethyl]-N-methylindole-5-metha nesulfonamide monosuccinate (C14H21N3O2S・C4H6O4) Imigran 50 mg: 12, 60 tablets (Press-through-packaging PTP): White film coated tablet with following identifying code and size: diameter 7.6 mm, thickness 3.4 mm and weight 153 mg GlaxoSmithKline K.K. GSK Bldg. 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 Japan 3. IMIGRAN Nasal Spray Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination IMIGRAN (r) Sumatriptan succinate 87216 6 years Approval Date/Number/Number Approval Classification Approved Indication(s) Therapeutic Category April 2003 21500AMY00075000 Class 3 Migraine Selective 5-HT1B/1D receptor agonist analgesic Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan April 2003 (1st revision) High potency; Ethical medicine Prescription only June 2003 June 2003 Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Device Capacity: 0.1 mL Sumatriptan content (in one device container): 20 mg Excipients: Potassium dihydrogen Phosphate, dibasic sodium phosphate anhydrous, Sulphuric acid, Sodium hydroxide, purified water 3-[2-(dimethylamino)ethyl]-N-methylindole-5-metha nesulfonamide monosuccinate (C14H21N3O2S*C4H6O4) IMIGRAN Nasal Spray 20 mg: 0.1 ml 6 Fine mist nasal spray Contains yellow to dark yellow clear liquid. Nasal spray device in a quantitative single dose GlaxoSmithKline K.K. GSK Bldg. 6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 Japan 4. ZOMIG Tablets Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination ZOMIG (r) Zolmitriptan 87216 6 years Approval Date/Number Approval Classification Approved Indication(s) Therapeutic Category June 2001 21300AMY00274 Class 1 Migraine Selective 5-HT1B/1D receptor agonist Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan October 2003 (4th revision) High potency; Ethical medicine Prescription only August 2001 August 2001 Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Each tablet contains 2.5 mg of Zolmitriptan. Excipients: Lactose, cellulose, Sodium starch glycolate, Magnesium stearate, hydroxypropyl methylcellulose, Polyethylene glycol 400, Polyethylene 6000, Titanium dioxide, Iron oxide (S)-4-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}met hyl)-2-oxazolidinone (C16H21N3O2) Zomig Tablets 2.5 mg: [PTP] 20 tablets (10 tablets 2), 100 tablets (10 tablets 10) Slightly yellowish film coated tablet. Diameter 7.5 mm, thickness 2.8 mm, weight 0.13 g Astra Zeneca K.K. 1-1-88 Ooyodo-naka, Kita-ku, Osaka-city Japan 5. ZOMIG RM Tablets Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination ZOMIG (r) Zolmitriptan 87216 6 years Approval Date/Number Approval Classification Approved Indication(s) Therapeutic Category June 2002 21400AMY00136 Class 1 Migraine Selective 5-HT1B/1D receptor agonist analgesic Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan October 2003 (4th revision) High potency; Ethical medicine Prescription only June 2002 June 2002 Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Each tablet contains 2.5 mg of Zolmitriptan. Excipients: Mannitol, Cellulose, Glycosylated starch, Aspartame (containing L - phenylalanine), Sodium hydrogen carbonate, Citric acid, Anhydrous silicic acid, Magnesium stearate (S)-4-({3-[2-(Dimethylamino)ethyl]-1H-indol-5-yl}met hyl)-2-oxazolidinone (C16H21N3O2) Zomig 2.5 mg RM tablets: [blister sheets] 12 tablets (6 tablets 2 sheets), 120 tablets (6 tablets 20 sheets) Slightly orange flavored white tablet Diameter 6.4 mm, thickness 2.9 mm, weight 0.1 g Astra Zeneca K.K. 1-1-88 Ooyodo-naka, Kita-ku, Osaka-city Japan 6. RELPAX Tablets Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination RELPAX (r) Eletriptan hydrobromide 87216 6 years Approval Date/Number Approval Classification Approved Indication(s) Therapeutic Category April 2002 21400AMZ00463000 Class 1 Migraine Selective 5-HT1B/1D receptor agonist Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan August 2003 (4th revision) High potency; Ethical medicine Prescription only July 2002 August 2002 Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Each tablet contains 24.2 mg of Eletriptan hydrobromide (20 mg as Eletriptan). Excipients: Crystalline cellulose, lactose, Croscarmellose sodium, Magnesium stearate, Hydroxypropyl methylcellulose, Titanium oxide, Triacetin, No. 5 yellow (+)-(R)-3-(1-methylpyrrolidin-2-ylmethyl)-5-(2-pheny lsulfonylethyl)-1H-indole monohydrobromide (C22H26N2O2S*HBr) RELPAX Tablets 20 mg: 10 tablets (PTP), 10 tablets (PTP Patient Pack), 50 tablets (PTP Patient Pack) Orange coloured film coated tablets/ Pfizer・REP20 Diameter 6.3 mm, thickness 3.0 mm Pfizer K.K. 3-22-7 Yoyogi, Shibuya-ku, Tokyo 151-8589 Japan 7. Maxalt Tablets Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination MAXALT (r) Rizatriptan benzoate 87216 6 years Approval Date/Number Approval Classification Approved Indication(s) Therapeutic Category July 2003 21500AMY00109000 Class 1 Migraine Selective 5-HT1B/1D receptor agonist Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan July 2003 (1st revision) High potency; Ethical medicine Prescription only September 2003 September 2003 Cont. 7. Maxalt Tablets (cont.) Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Each tablet contains 14.53 mg of Rizatriptan benzoate (10 mg as Rizatriptan), slightly red oval shaped tablet Excipients: Lactose, crystalline cellulose, modified starch, Iron oxide, Magnesium stearate 3-[2-(Dimethylamino)ethyl]-5-(1H-1,2,4- triazol -1-ylmethyl) indole monobenzoate (C15H19N5*C7H6O2) Maxalt 10 mg in PTP packages of 6 (6 tablets 1), 18 (6 tablets 3) Maxalt 10 mg in RPD packages of 6 (3 tablet case 2) 18 (3 tablet case 6) Maxalt PTP 10 mg Diameter 11.9 mm, thickness 3.8 mm, weight 190 mg; Maxalt RPD 10 mg Diameter 12-13.8 mm, thickness 5.1 mm, weight 64 mg PTP Tablet RPD Tablet Importer: Kyorin Pharmaceutical K.K. 5, Kanda Surugadai 2-chome,Chiyoda-ku, Tokyo, 101-8311 Japan Marketing Agent: Eisai K.K. 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088 Japan Disclaimer This study is based on information obtained through in-house research and from sources available to public and it is not a complete analysis of every material fact. Statements of fact have been obtained from sources considered reliable but no representation is made as to their completeness or accuracy. The Japanese Government does not provide authorized (officially sanctioned) translations of its documents. In case of legal dispute, the original texts in Japanese will prevail. Jouhou Koukai Services LLC provides information and intelligence on the Japanese pharmaceutical market in the fields of medicine, pharmaceuticals, patents, licensing, copyrights and data protection, business and corporate development, information technology, including e-health, and medical communication, however, this information does not constitute for nor can it be used as such for a substitute of medical, legal or investment advice. The authoring, translation, formatting, indexing and hyperlinking of the text are copyrights of the Jouhou Koukai Services LLC Worldwide Copyright (c) 2001-2004 by JKS LLC Reproduction in whole or part without permission is forbidden. www.jouhoukoukai.com Class N2C - Anatomical Classification Guidelines (ATC version 2004) IMS Health: Antimigraine preparations, October 2001. Datamonitor, 2000: Winners and Losers in the CNS Market. (Report) ICH: The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Ministry of Health and Welfare, Pharmaceutical and Medical Safety Bureau, Evaluation and Licensing Division - Notification No. 739 dated August 11, 1998. Rinsho Hyoka, 2001, April; vol. 28, Suppl. XV, pp. 169-173. Cephalalgia. 2002 July; 22(6), pp. 416-423. JKS Research, 2002. Modified from the Attached Table 2-1, MHW, Pharmaceutical Affairs Bureau Notification No. 698 dated May 30, 1980. 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