All approved medicinal products in Japan STATINS 2005 Table of Contents 1. Introduction Key Findings 2. Type/generations of statins Table 1. Type/generations of statins 3. Statin products approved in Japan Table 2. Approval classification of the prescription medicinal products Table 3. Approval statistics of statin products in Japan Graph 1. Approval share by type of statins Graph 2. Approval share by approval class Table 4. Alphabetical list of statin products approved in Japan Table 5. Individual statin products approved in Japan Help and further reading Disclaimer and Publisher Information 1. Introduction     The prototype 1 of the product line, known now as statins, was discovered by Dr. Akira Endo in Sankyo's Tokyo laboratories in the early 1970s. The identification of mevastatin 2 (ML-236B, compactin) resulted from nearly a century of biomedical research on the cholesterol biosynthesis, determining HMG-CoA reductase function in the conversion to a key metabolic precursor, mevalonate, provided the opportunity to therapeutically inhibit this enzyme.          The consequential intensive laboratory, preclinical and clinical development led to the first world-wide approval of this prototype statin drug in 1986. Generically known as pravastatin sodium (and more commonly referred to as just "pravastatin"), it was sold in US as Pravachol. In Japan pravastatin was registered by Sankyo as Mevalotin which became the first Japanese domestic "blockbuster" drug with sales over 1 billion US$ annually.          Further scientific endeavor and commercial competition has brought 8 chemical entities from the statin family to the international pharmaceutical market (Table 1). In Japan, five of these statin entities (pravastatin, simvastatin, fluvastatin, atorvastatin and pitavastatin) have gained approval, however in 2001 fluvastatin was withdrawn, while an application for Rosuvastatin was submitted in 2003 and lovastatin is yet to enter development in Japan.          In terms of efficacy, statin entities are unofficially classified as I, II and III generation, or alternatively as "standard" statins (I and II generation) and "strong" or superstatins (III generation). Pitavastatin aside, the general trend has been for the statin entity to be approved abroad before registered in Japan albeit in case of simvastatin the difference between FDA and MHLW approval timelines was on the scale of less than a year (Table 1).          In contrast to other therapeutic classes, the introduction and development of statin medicinal products in Japan have been both commercially highly successful and lacking the cultural controversies 3 normally associated with the launch of foreign based entities in Japan. However, the incremental increase in Japan registered statins has been drastically affected by two milestone events. Firstly, following a series of rhabdomyolysis-related deaths worldwide, Bayer Yakuhin KK decided to voluntarily withdraw in 2001 Baycol thus lowering the number of approved statins in Japan to just three. Secondly the expiration of the patent rights for both pravastatin and simvastatin, resulted in a flurry of generics approved en masse in July 2003. As detailed in Table 3 and Graph 1 and Graph 2, at present, the "standard" statins (or I generation) group is completely dominated by generic versions namely 27 generic products of pravastatin and 17 of simvastatin.          Regarding market prospects, some preliminary figures indicate that market share of "standard" statins will further erode due to both advance of the superstatins - including tentatively rosuvastatin, and ceding to generics competitors. In May 2004, Sankyo KK released the Mevalotin revenues for the fiscal 2002, 2003 and 2004 (estimation) as follows: 110.7, 98.3 and 82.3 billion Yen and in efforts to bolster further sales attrition, have launched a marketing strategy targeting the pleiotropic effects of the drug 4.          The overall outlook of the Japanese statin market is positive as New Chemical Entity statins innovated from Japan pharma will continue to buoy the dyslipidemia market, with a 55% stake of all Japan registered statins; pravastatin continues to be the mainstay. Since expiry of the Mevalotin(r) patent in July 2003, competitiveness of the Japan statin market normally enticed by blockbuster New Chemical Entities has become swamped by "standard" statin generics, totaling a 86% share from both pravastatin and simvastatin Japan registered statins alone. The Japanese superstatin market is still in its infancy with only a mere representation of less than 6% of the total Japan registered statins volume. The combined volume of standard and superstatins is projected to exceed 2, 500 billion Yen in 2004 and near 4,000 billion Yen in 2008 5 . Key Findings * Apart from globally withdrawn cerivastatin, out of all other 7 known New Chemical Entities of statins registered world-wide, 6 are already approved in Japan, as lovastatin has never been submitted. * Post July 2003 expiry of the Mevalotin(r) patent saw the MHLW approved 44 generics comprising of pravastatin (27) and simvastatin (17) formulations, making up 86% of the total Japan registered statins volume. * Pravastatin still dominates the statin prescription registry with 55% of the total Japan registered statins volume, followed by simvastatin at 35%; the superstatin class with pitavastatin and atorvastatin accounts for barely under 6%. * Currently only Mevalotin(r) and Mevatorte are the two Japan registered statins prescribed as a granule formulation in Japan. * Time lag between international and Japanese approvals has been 10 years, 3 years, 2 years, 2 years, 2 years and 0 years for fluvastatin, pravastatin, atorvastatin, pitavastatin, cerivastatin (withdrawn worldwide) and simvastatin respectively. 2. Type/generations of statins Table 1. Type/generations of statins Statin International status Approval in Japan Generic Gene-ration Brand First approval Maker / Marketing Approval Brand Maker / Marketing pravastatin I Pravachol 1986 BMS 1989 Mevalotin (+ 27 generics) Sankyo KK lovastatin I Mevacor 1987 Merck Not entered simvastatin I Zocor 1991 Merck 1991 Lipovas (+ 17 generics) Banyu/Merck KK fluvastatin II Lescol 1993 Novartis 2003 Lochol Novartis Pharma KK cerivastatin III Baycol 1997 Bayer 1999 6 Baycol Bayer Yakuhin KK atorvastatin III Lipitor 1998 Pfizer 2000 Lipitor Pfizer KK pitavastatin III Livalo 2003 Kowa KK / Sankyo KK 2003 Livalo Kowa KK Sankyo KK rosuvastatin III Crestor 2003 AstraZeneca 2005 Crestor AstraZeneca KK 3. Statin products approved in Japan    All formulations of the statin products registered in Japan by August 2005 are listed in Table 5 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, arranged alphabetically. Table 2. Approval classification 7 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. Approval statistics of statin products in Japan Generic Name / Drug Candidate Approved in Japan - n (% of total Statins) Approval Classification - Number in each approval class (% of total Statins)8 Class 1 Class 7 Class 7-2 Class 8 Additional Formulation -n (Other than Tablet e.g. granules) Approval by August 2005 - n (% of total Statins; Class One Approval Date)9 Atorvastatin Calcium Hydrate 1 (1.92) 1 (1.92) - - - - - - (May 2000) Fluvastatin Sodium 2 (3.85) 1 (1.92) - - 1(1.92) - - (June 2003) Pitavastatin Calcium 2 (3.85) 1 (1.92) - - 1(1.92) - - (Sept. 2003) Pravastatin Sodium 28 (53.85) 1 (1.92) 1(1.92) 20(38.46) 6(11.54) 210 (granules) 27 (52.9; Sept 2001)11 Simvastatin 18 (34.62) 1 (1.92) - 12(23.08) 5(9.62) - 17 (33.3; Nov. 1991) Rosuvastatin Calcium 1 (1.92) 1 (1.92) - - - - - (March 2005 ) Total 52 (100) 6 (9.80) 1 (1.92) 32 (61.54) 13 (25.00) 44 (86.2) Graph 1. Approval share by type of statins Note: The pie-chart graph reflects the distribution of approved medicinal products in Japan by NCE and expressed as percentage of the total number. Graph 2. Approval share by approval class Note: The pie-chart graph reflects the distribution of approved medicinal products in Japan by Class and expressed as percentage of the total number. Table 4. Alphabetical list of statin products approved in Japan 1. Alsetin 2. Amel Pravastatin Na 3. Amel Simvastatin 4. Cholerit 5. KN Pravastatin Na 6. KN Pravastatin Na 7. Liduc M 8. Lipitor 9. Lipoblock 10. Lipodown 11. Lipodown 12. Lipokoban 13. Lipo-off 14. Lipovas 15. Lipovatol 16. Lipozart 17. Livalo 18. Livalo 19. Lochol 20. Lochol 21. Maibastan 22. Meek Simvastatin 23. Meek Simvastatin 24. Mevalation 25. Mevalation 26. Mevalect 27. Mevalect 28. Mevalect 29. Mevalocut 30. Mevalotin (Tablet & Granules) 31. Mevan 32. Mevarich 33. Mevarich 34. Mevasrolin 35. Mevastan 36. Mevatorte (Tablet & Granules) 37. Mindorotin 38. Ohara Simvastatin 39. Ohara Simvastatin 40. Ohara Simvastatin 41. Pravalon 42. Pravamate 43. Pravastan 44. Pravastan 45. Pravastatin Sodium 46. Pravatin 47. Ramian 48. Simvamerck 49. Sinstatin 50. Sinstatin 51. Tatsuplamin 52. Crestor Table 5. Individual statin products approved in Japan (cont. from document AJ_T_003) 52. CRESTOR Tablets Brand Generic Name Japan Standard Commodity Classification Number Period for Reexamination CRESTOR Rosuvastatin Calcium 872189 6 years Approval Date/Number Approval Classification Approved Indication(s) Therapeutic Category March 2005 21700AMY00008 Crestor 2.5 mg March 2005 21700AMY00007 Crestor 5.0 mg Class 1 Hyperlipidemia Familial hypercholesterolemia HMG-CoA Reductase Inhibitor -Dyslipidemia Medicine Package Insert Revision Regulatory Classification(s) Listing in the National Health Insurance Price List Market Launch in Japan April 2005 (2nd revision compliant to amended PAL) 12 Designated Drug Prescription Medicine April 2005 April 2005 Product information continues on the next page 52. CRESTOR Tablets Bulk Formulation Chemical Characterization Packaging & Formulation Specification Manufacturer/ Marketing Agent Rosuvastatin Calcium 2.5 mg; 5 mg Additives: magnesium stearate; glyceroltriacetate, trace additives: lactose, cellulose, ferric oxide, titanium oxide, hydroxypropylmethylcellulose, crospovidone, calcium phosphate Chemical Formula: Monocalcium bis ((3R,5S,6E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methanesulfonyl (methyl) amino] pyrimidin-5-yl}-3,5-dihydroxyhept-6-enoate) Crestor 2.5 mg: film-coated tablets in PTP (Press through packing) of 100 (10 x10); 500 (10x50) and 700 (14x50) Crestor 5 mg: film-coated tablets in PTP (Press through packing) of 100 (10 x10); 500 (10x50) and 700 (14x50) 2.5 mg: Diameter - 5.5 mm; Weight - 80 mg; Thickness - 3.1 mm Comments: Yellow with a red tinge; 5 mg: Diameter - 7.0 mm; Weight - 150 mg; Thickness - 3.8 mm; Comments: Yellow with a red tinge 2.5 mg 5 mg Manufacturer: AstraZeneca K.K. Umeda Sky Building Tower East 1-88, 1-chome, Ohyodo-naka, Kita-ku, Osaka Marketing Agent: Shionogi Seiyaku K.K. Doshomachi 3-1-8 chome, Chuo-ku, Osaka Help and further reading     The first part of this report (JKS Code: AJ_T_003) was published in third quarter of 2004 as the most comprehensive overview and data source for all statin-based medicinal products approved in Japan by July 2004, and it is available for review and purchase at the JKS Document Store (click on the image to visit). The present report is an important update made to include the data on Crestor (rosuvastatin) approved in Japan in March 2005. Both documents "All in Japan: Statin" and All in Japan: Statins 2005 contain similar parts with two important exceptions. Table 1 to 4, and Graphs 1 and 2 are updated here. Table 5 contains only one entry for Crestor, while the Table 5 in the first parts contains all previous 51 products. Additional information in relevance to the approval status of statin-based medicinal products in Japan could be found in the Japan Approvals Database (JAD). The documents from the Japan Monitor "All in Japan" series provide concise up-to-date description of each product from a definite therapeutic category approved in Japan. Further details could 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 Disclaimer This publication 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. 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Jouhou Koukai Services LLC and its business Jouhou Koukai Publishing provide 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. Worldwide Copyright (c) 2001-2004 by JKS LLC Reproduction in whole or part without permission is forbidden. 1 Kuroda M, Endo A., Inhibition of in vitro cholesterol synthesis by fatty acids. Biochim Biophys Acta. 1976 Jan 18; 486(1): 70-81. 2 Endo, A., The discovery and development of HMG-CoA reductase inhibitors. Journal of Lipid Research, 33, 1992, 1569-1582. 3 For examples of the strong cultural influence in the development of CNS drugs, see the details in All in Japan: Triptans. 4 Statin pleiotropism refers to the non-lipid lowering effects, such as endothelial function, inflammation, coagulation and plaque stability. 5 On the basis of the NHI reimbursement prices in 2003; in-house research. 6 Withdrawn from the market in 2001 - see more info. 7 Modified from the Attached Table 2-1, MHW, Pharmaceutical Affairs Bureau Notification No. 698 dated May 30, 1980. 8 MHW, Pharmaceutical Affairs Bureau Notification No. 698 (May 30, 1980) describes nine different approval classifications of prescription medicinal products in Japan however only those classifications relevant to the Statin class of medicines have been included here: Class 1 - Medicines with new active ingredients; Class 7 - Medicines with additional dosage forms; Class 7-2 - Medicines with similar formulations; Class 8 - Miscellaneous 9 July 2003 was when the Japan Patent for Mevalotin(r) expired 10 Mevalotin(r) and Mevatorte granules 11 Mevalotin(r) was commercially launched as early as October 1989, in September 2003 0.5%/1.0% Mevalotin(r) granules was approved as an additional formulation (Class 7) 12 Revision in compliance to the amended Pharmaceutical Affairs Law (PAL) enforced on April 1, 2005. ?? ?? ?? ?? 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