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Report on the Deliberation Results June 7, 2017 Pharmaceutical Report on the Deliberation Results June 7, 2017 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau Ministry of Health, Labour and Welfare Brand Name Istodax Injection 10 mg Non-proprietary Name Romidepsin (JAN*) Applicant Celgene K.K. Date of Application September 2, 2016 Results of Deliberation In the meeting held on May 30, 2017, the Second 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 10 years. The drug product and its drug substance are classified as powerful drugs and poisonous drugs, respectively. Conditions of Approval The applicant is required to develop and appropriately implement a risk management plan. * 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 May 10, 2017 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. Brand Name Istodax Injection 10 mg Non-proprietary Name Romidepsin Applicant Celgene K.K. Date of Application September 2, 2016 Dosage Form/Strength Lyophilized powder for reconstitution for injection: Each vial contains 11 mg of Romidepsin. Application Classification Prescription drug, (1) Drug with a new active ingredient Chemical Structure Molecular formula: C24H36N4O6S2 Molecular weight: 540.70 Chemical name: (1S,4S,10S,16E,21R)-7-[(2Z)-Ethylidene]-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia- 5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone Items Warranting Special Mention Orphan drug (Orphan Drug Designation No. 387 of 2016 [28 yaku]; PSEHB/PED Notification No. 0824-7 dated August 24, 2016, issued by the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare) Reviewing Office Office of New Drug V 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. Results of Review The Pharmaceuticals and Medical Devices Agency (PMDA) has concluded that the data submitted demonstrate the efficacy of the product in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma and acceptable safety in view of the benefits indicated by the data submitted, as shown in Attachment. As a result of its regulatory review, PMDA has concluded that the product may be approved for the indication and dosage and administration shown below, with the following conditions. The occurrences of bone marrow depression, infection, cardiac disorders (abnormal electrocardiogram such as QT interval prolongation, among others), tumour lysis syndrome, hypersensitivity, haemorrhage, and venous thromboembolism need to be further investigated via post-marketing surveillance. Indication Relapsed or refractory peripheral T-cell lymphoma Dosage and Administration The usual adult dosage is 14 mg/m2 (body surface area) of romidepsin administered as an intravenous infusion over 4 hours on Days 1, 8, and 15, followed by a rest period (Days 16-28). This 28-day cycle is repeated. The dose may be reduced according to the patient’s condition. Conditions of Approval The applicant is required to develop and appropriately implement a risk management plan. 2 Attachment Review Report (1) March 27, 2017 The following is an outline of the data submitted by the applicant and content of the review conducted by the Pharmaceuticals and Medical Devices Agency. Product Submitted for Approval Brand Name Istodax Injection 10 mg Non-proprietary Name Romidepsin Applicant Celgene K.K. Date of Application September 2, 2016 Dosage Form/Strength Lyophilized powder for reconstitution for injection: Each vial contains 11 mg of Romidepsin. Proposed Indication Relapsed or refractory peripheral T-cell lymphoma Proposed Dosage and Administration The usual adult dosage is 14 mg/m2 (body surface area) of romidepsin administered as an intravenous infusion over 4 hours on Days 1, 8, and 15, followed by a rest period (Days 16-28). This 28-day cycle is repeated. The dose may be reduced according to the patient’s condition. Table of Contents 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information ..................... 4 2. Data Relating to Quality and Outline of the Review Conducted by PMDA ................................. 4 3. Non-clinical Pharmacology and Outline of the Review Conducted by PMDA ............................ 7 4. Non-clinical Pharmacokinetics and Outline of the Review Conducted by PMDA .................... 11 5. Toxicity and Outline of the Review Conducted by PMDA ........................................................ 15 6. Summary of Biopharmaceutic Studies and Associated Analytical Methods, Clinical Pharmacology, and Outline of the Review Conducted by PMDA .............................................. 23 7. Clinical Efficacy and Safety and Outline of the Review Conducted by PMDA ......................... 27 8. Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached by PMDA .................................................................................................. 55 9. Overall Evaluation during Preparation of the Review Report (1) ............................................... 55 List of Abbreviations 14C- romidepsin 14C-labeled romidepsin 5-FU 5-fluorouracil A/G ratio albumin/globulin ratio AITL angioimmunoblastic T-cell lymphoma ALCL anaplastic large cell lymphoma ALK anaplastic lymphoma kinase ALP alkaline phosphatase ALT alanine aminotransferase APA action potential amplitude APD90 action potential duration at 90% repolarization Application marketing application APTT activated partial thromboplastin time AST aspartate aminotransferase ATP adenosine triphosphate BCRP breast cancer resistance protein Brentuximab brentuximab vedotin (genetical recombination) 1 BSEP bile salt export pump BUN blood urea nitrogen CBDCA carboplatin CI confidence interval CK creatine kinase CMV cytomegalovirus CPT-11 irinotecan hydrochloride hydrate CR complete response CRu complete response unconfirmed CTCL cutaneous T cell lymphoma CYP cytochrome P450 DLT dose limiting toxicity DMSO dimethyl sulfoxide DNA deoxyribonucleic acid dV/dt max maximum rate of rise DXR doxorubicin hydrochloride EBV Epstein-Barr virus ESMO European Society for Medical Oncology FDA Food and Drug Administration GC gas chromatography Hb hemoglobin HBV hepatitis B virus HCT hematocrit value HDAC histone deacetylase hERG human ether-a-go-go related gene HPLC high performance liquid chromatography IR infrared absorption spectrum IRB institutional review board Istodax Istodax Injection ITT intent-to-treat IWC International Workshop Response Criteria for non-Hodgkin’s lymphomas Japanese Clinical Clinical Practice Guideline for the Management of Hematologic Practice Guideline Malignancy 2013, edited by the Japanese Society of Hematology (Kanehara & Co., Ltd., 2013) JCOG Japan Clinical Oncology Group JCOG criteria Criteria established by JCOG (JCOG-LSG Manual Committee for Clinical Research of Lymphoma and Myeloma, 2003) KATP channel ATP-sensitive potassium channels Ki inhibition constant LC-MS/MS liquid chromatography-tandem mass spectrometry LDH lactate dehydrogenase LSG Lymphoma Study Group MCB master cell bank MCH mean corpuscular hemoglobin MCHC mean corpuscular hemoglobin concentration MCV mean corpuscular volume MedDRA Medical Dictionary for Regulatory Activities MedDRA/J Medical Dictionary for Regulatory Activities Japanese version mIWC modified International Workshop Response Criteria for non-Hodgkin’s lymphomas MMC mitomycin C Mogamulizumab Mogamulizumab (genetical recombination) mRNA messenger ribonucleic acid MRP multidrug resistance-associated protein 2 MST median survival time MTD maximum tolerated dose MWCB manufacturing working cell bank NADPH nicotinamide adenine dinucleotide phosphate hydrogen NCCN Guidelines National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Non-Hodgkin’s Lymphomas NCI National Cancer Institute NCI-ODWG National Cancer Institute Organ Dysfunction Working Group NCI-PDQ National Cancer Institute Physician Data Query, Adult Non-Hodgkin Lymphoma Treatment NE not evaluated NK2 neurokinin2 NMR nuclear magnetic resonance spectrum NZW New Zealand White OAT organic anion transporter OATP organic anion transporting polypeptide OCT organic cation transporter OS overall survival Papp A→B apparent permeability in apical to basolateral direction Papp B→A apparent permeability in basolateral to apical direction PD progressive disease PFS progression-free survival P-gp P-glycoprotein
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