Report on the Deliberation Results December 4, 2008 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare Brand Name Trerief Tablets 25 mg Non-proprietary Name Zonisamide (JAN*) Applicant Dainippon Sumitomo Pharma Co., Ltd. Date of Application September 28, 2005 Results of Deliberation In its meeting held on November 28, 2008, 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 4 years, and the drug product and its drug substance are both classified as powerful drugs. *Japanese Accepted Name (modified INN) This English translation of this Japanese review report is intended to serve as reference material made available for the convenience of users. In the event of any inconsistency between the Japanese original and this English translation, the Japanese original shall take precedence. PMDA will not be responsible for any consequence resulting from the use of this reference English translation. Review Report November 12, 2008 Pharmaceuticals and Medical Devices Agency The following are the results of the review of the following pharmaceutical product submitted for marketing approval conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). Brand Name Trerief Tablets 25 mg (changed from Tremode Tablets 25 mg [proposed name]) Non-proprietary Name Zonisamide Applicant Dainippon Pharmaceutical Co., Ltd. (currently Dainippon Sumitomo Pharma Co., Ltd.) Date of Application September 28, 2005 (marketing application for a drug) Dosage Form/Strength Film-coated tablets, each containing 25 mg of Zonisamide Application Classification Prescription drug (4) Drug with a new indication, (6) Drug with a new dosage Items Warranting Special Mention None Reviewing Office Office of New Drug II This English translation of this Japanese review report is intended to serve as reference material made available for the convenience of users. In the event of any inconsistency between the Japanese original and this English translation, the Japanese original shall take precedence. PMDA will not be responsible for any consequence resulting from the use of this reference English translation. Review Results November 12, 2008 Brand Name Trerief Tablets 25 mg (changed from Tremode Tablets 25 mg [proposed name]) Non-proprietary Name Zonisamide Applicant Dainippon Pharmaceutical Co., Ltd. (currently Dainippon Sumitomo Pharma Co., Ltd.) Date of Application September 28, 2005 (marketing application for the drug) Results of Review On the basis of the data submitted, PMDA has concluded that Trerief Tablets 25 mg (hereinafter referred to as the product) has efficacy and the safety in the treatment of patients with Parkinson’s disease who had inadequate response to a combination of levodopa-containing drugs with other antiparkinsonian drugs. The efficacy of the product was investigated in a phase III study involving patients with Parkinson’s disease who had inadequate response to a combination of levodopa-containing drugs with other antiparkinsonian drugs, based on the information gained during the product development. Results confirmed the superiority of the zonisamide 25 mg to placebo in the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III total score, the primary endpoint. PMDA considers that the results demonstrated the efficacy of the product. Safety analyses in the phase III study revealed no major differences in the adverse events identified and their incidences between the product and placebo. PMDA considers that there are no major problems in the use of the product to treat patients with Parkinson’s disease. As a result of its review, PMDA has concluded that the product may be approved for the indication and dosage and administration shown below. Indication Parkinson’s disease (for patients who did not respond adequately to a combination of levodopa- containing drugs with other antiparkinsonian drugs) Dosage and Administration Zonisamide should be concomitantly administered with levodopa-containing drugs. The usual adult dosage is 25 mg of zonisamide administered orally once daily. 2 Trerief Tablets 25 mg_Dainippon Pharmaceutical Co., Ltd_review report Review Report (1) September 8, 2008 I. Product Submitted for Approval Brand Name Trerief Tablets 25 mg (changed from Tremode Tablets 25 mg [proposed name]) Non-proprietary Name Zonisamide Applicant Dainippon Pharmaceutical Co., Ltd. (currently Dainippon Sumitomo Pharma Co., Ltd.) Date of Application September 28, 2005 Dosage form/Strength Film-coated tablets, each containing 25 mg of Zonisamide Proposed Indication Parkinson’s disease (for patients who have not responded adequately to a combination of levodopa-containing drugs with other antiparkinsonian drugs) Proposed Dosage and Administration The usual adult dosage is 25 to 50 mg of zonisamide administered orally once daily. II. Summary of the Submitted Data and Outline of the Review by Pharmaceuticals and Medical Devices Agency The following is an outline of the data submitted by the applicant at the application and the applicant’s responses to the inquiries from the Pharmaceuticals and Medical Devices Agency (PMDA). 1. Origin or history of discovery, use in foreign countries, and other information Zonisamide is a 1,2-benzisoxazole derivative synthesized by Dainippon Pharmaceutical Co., Ltd. (currently Sumitomo Dainippon Pharma Co., Ltd.). In Japan, zonisamide was approved on March 31, 1989 as an antiepileptic drug (brand names Excegran Tablets 100 mg and Excegran Powder [changed to Excegran Powder 20% on January 19, 2004). Zonisamide was also approved as an antiepileptic drug in the US in March 2000 and is approved in 36 foreign countries as of May 2008. When zonisamide was administered to Japanese patients with Parkinson’s disease with the purpose of treating intercurrent convulsive seizures, the treatment not only caused the seizures to disappear, but also improved the symptoms of Parkinson’s disease. Therefore, zonisamide was developed as an antiparkinsonian drug from 2001 and, recently, a marketing application has been submitted by the applicant, with the proposed indication of “Parkinson’s disease (for patients who have not responded adequately to a combination of levodopa-containing drugs with other antiparkinsonian drugs),” based on the results of Japanese clinical studies, etc. 3 Trerief Tablets 25 mg_Dainippon Pharmaceutical Co., Ltd_review report At the ****** consultation on ** **, 20** before this application, PMDA recommended the applicant to conduct an additional clinical study for the following reasons: (1) Patients enrolled in clinical studies were not homogeneous, precluding the identification of the patient population indicated for zonisamide, (2) given the results of the clinical and nonclinical studies obtained, it appears difficult to determine the clinical positioning of zonisamide and to interpret the results of the clinical studies, (3) it is necessary to investigate the most appropriate parameter for assessing the efficacy of zonisamide, and (4) it is difficult to conclude that the recommended clinical dose of zonisamide has been established. However, *************************************** ******************************* the applicant submitted the application without conducting a new clinical study. Afterwards, the applicant conducted an additional clinical study from ** 20** in order to resolve problems pointed out at ****** consultation during the review process, and submitted the results of the study. 2. Physicochemical properties and specifications 2.A Summary of the submitted data Zonisamide (molecular formula C8H8N2O3S, molecular weight 212.23) is a compound listed in the Japanese Pharmaceutical Codex (JPC) and is the same as the active ingredient of approved drugs Excegran Tablets 100 mg and Excegran Powder 20%. 2.A.(1) Drug substance No new data were submitted. 2.A.(2) Drug product 2.A.(2).1) Description and composition of the drug product Zonisamide 25 mg drug product (Trerief Tablets 25 mg, hereinafter referred to as the product) is pale yellow, film-coated tablets composed of (1) **** comprising the drug substance, ****** (lactose hydrate and microcrystalline cellulose), ****** (low substituted hydroxypropylcellulose), ****** (hydroxypropylcellulose), and ****** (magnesium stearate and light anhydrous silicic acid) and (2) ************* comprising ************** (hypromellose, macrogol 6000, titanium oxide, talc, and light anhydrous silicic acid) and ****** (yellow ferric oxide). 2.A.(2).2) Formulation development The drug product is ***************************************************************** ********************************************************************************** ********************************************************************************** *********. *********** of the product has been changed from that of Excegran Tablets 100 mg. Also, yellow ferric oxide is added as ****** in order to differentiate the product from white Excegran Tablets 100 mg. The biological equivalence (BE) between Excegran Tablets 100 mg and the product has been confirmed [see Section 4.(i).A.(1)]. 2.A.(2).3) Manufacturing process The product is manufactured through the following 7 processes: **** process: ****************************. 4 Trerief Tablets 25 mg_Dainippon