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Report on the Deliberation Results February 28, 2019 Pharmaceutical Report on the Deliberation Results February 28, 2019 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau Ministry of Health, Labour and Welfare Brand Name Smyraf Tablets 50 mg, Smyraf Tablets 100 mg Non-proprietary Name Peficitinib Hydrobromide (JAN*) Applicant Astellas Pharma Inc. Date of Application May 31, 2018 Results of Deliberation In its meeting held on February 22, 2019, 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 8 years. The drug product and its drug substance are both classified as powerful drugs. Conditions of Approval 1. The applicant is required to develop and appropriately implement a risk management plan. 2. The applicant is required to conduct a drug use-results survey covering all patients treated with the product after its market launch until data from a certain number of patients have been accumulated, to early collect the safety and efficacy data on the product and to take necessary measures to facilitate the proper use of the product. *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 February 14, 2019 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 Smyraf Tablets 50 mg, Smyraf Tablets 100 mg Non-proprietary Name Peficitinib Hydrobromide Applicant Astellas Pharma Inc. Date of Application May 31, 2018 Dosage Form/Strength A tablet containing 62.4 mg of peficitinib hydrobromide (50 mg of peficitinib) or 124.8 mg of peficitinib hydrobromide (100 mg of peficitinib) Application Classification Prescription drug, (1) Drug with a new active ingredient Chemical Structure Molecular formula: C18H22N4O2·HBr Molecular weight: 407.30 Chemical name: 4-{[(1R, 2s, 3S, 5s, 7s)-5-Hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5- carboxamide monohydrobromide Reviewing Office Office of New Drug IV Results of Review On the basis of the data submitted, PMDA has concluded that the product has efficacy in the treatment of rheumatoid arthritis (including prevention of structural joint damage) in patients who have an inadequate response to conventional therapies and that the product has acceptable safety in view of its benefits. As a result of its review, PMDA has concluded that the product may be approved for the indication and dosage and administration shown below with the following conditions. In view of the risk of serious infections or serious adverse reactions such as malignancy associated with the product, safety measures required in its clinical use are the same as that taken for approved Janus kinase (JAK) inhibitors or biological products for the treatment of rheumatoid arthritis. The applicant should conduct a drug use-results survey covering all patients 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. treated with the product after its market launch until data from a certain number of patients have been accumulated to early grasp the safety profile of the product including unknown adverse events. The applicant also should conduct a survey to trace the occurrence of serious infections and malignant tumors, etc. in prolonged use of the product. Indication Treatment of rheumatoid arthritis (including prevention of structural joint damage) in patients who have an inadequate response to conventional therapies. Dosage and Administration The usual adult dosage is 150 mg of peficitinib administered orally once daily after a meal. A 100-mg dose may be administered once daily according to the patient’s condition. Conditions of Approval 1. The applicant is required to develop and appropriately implement a risk management plan. 2. The applicant is required to conduct a drug use-results survey covering all patients treated with the product after its market launch until data from a certain number of patients have been accumulated, to early collect the safety and efficacy data on the product and to take necessary measures to facilitate the proper use of the product. 2 SmyrafTablets50mg_AstellasPharma_ReviewReport Attachment Review Report (1) January 25, 2019 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 Smyraf Tablets 50 mg, Smyraf Tablets 100 mg Non-proprietary Name Peficitinib Hydrobromide Applicant Astellas Pharma Inc. Date of Application May 30, 2018 Dosage Form/Strength A tablet containing 62.4 mg of peficitinib hydrobromide (50 mg of peficitinib) or 124.8 mg of peficitinib hydrobromide (100 mg of peficitinib) Proposed Indication Treatment of rheumatoid arthritis (including prevention of structural joint damage) in patients who have an inadequate response to conventional therapies. Proposed Dosage and Administration The usual adult dosage is 100 to 150 mg of peficitinib administered orally once daily after a meal. The dose can be reduced to 50 mg per dose according to the patient’s condition. Table of Contents 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information ................................... 2 2. Data Relating to Quality and Outline of the Review Conducted by PMDA ............................................... 2 3. Non-clinical Pharmacology and Outline of the Review Conducted by PMDA .......................................... 5 4. Non-clinical Pharmacokinetics and Outline of the Review Conducted by PMDA .................................. 10 5. Toxicity and Outline of the Review Conducted by PMDA ...................................................................... 19 6. Summary of Biopharmaceutic Studies and Associated Analytical Methods, Clinical Pharmacology, and Outline of the Review Conducted by PMDA ............................................................................................. 33 7. Clinical Efficacy and Safety and Outline of the Review Conducted by PMDA ......................................... 41 8. Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached by PMDA .................................................................................................................................................... 98 9. Overall Evaluation during Preparation of the Review Report (1) ............................................................... 98 10. Other ........................................................................................................................................................... 99 1 SmyrafTablets50mg_AstellasPharma_ReviewReport List of Abbreviations See Appendix. 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information Peficitinib hydrobromide (to be referred as to peficitinib), the active ingredient of Smyraf Tablets 50 mg or 100 mg, is a Janus kinase (JAK) inhibitor developed by Astellas Pharma Inc. Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, and autoimmune disease that is characterized by destruction of the synovial membrane of joints. The currently recommended treatment for RA aims to relieve arthritis symptoms as soon as possible to induce sustainable remission (Japan College of Rheumatology [JCR], Clinical Practice Guidelines for Rheumatoid Arthritis 2014). In pharmacotherapy for RA, use of conventional disease-modifying antirheumatic drugs (cDMARDs) including methotrexate (MTX) is recommended as soon as RA is confirmed, and biological agents including tumor necrosis factor (TNF) inhibitors are recommended for patients responding insufficiently to these cDMARDs. JAK inhibitors are recommended as alternative therapeutic options (Ann Rheum Dis. 2017;76:960-77). In Japan, tofacitinib and baricitinib were approved as JAK inhibitors in 2013 and 2017, respectively, for the indication of treatment in RA patients with an inadequate response to conventional therapies. The JAK family is a family of intracellular tyrosine kinases consisting of JAK1, JAK2, JAK3, and TYK2, and involves in signal transduction mediated by type I and II cytokine receptors. JAKs associate with intracellular domains of various cytokine receptors and growth factor receptors and play an important role in signal transduction of cytokines and growth factors. In response to the suggested association of the signaling pathway of the Janus kinase/signal transduction and activator of transcription (JAK-STAT) with the pathogenesis of autoimmune diseases including RA (Drugs. 2017;77:521-46), Astellas
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