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210428Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210428Orig1s000 OTHER REVIEW(S) DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS Regulatory Project Manager Overview I. GENERAL INFORMATION NDA: 210428 Drug: Metoprolol Succinate Extended-Release Capsules, 25 mg, 50 mg, 100 mg and 200 mg Class: Beta- Blocker Applicant: Sun Pharmaceutical Industries Limited Proposed Indications: Hypertension, Angina Pectoris & Heart Failure Date of submission: March 30, 2017 PDUFA date: January 30, 2018 II. REVIEW TEAM Office of New Drugs, Office of Drug Evaluation I: Division of Cardiovascular & Renal Product Norman Stockbridge, MD, PhD, Director Mary Ross Southworth, PharmD, Deputy Director for Safety Michael Monteleone, MS, RAC, Assistant Director for Labeling Martina Sahre, PhD, Cross Discipline Team Leader Fortunato Senatore, MD, Clinical Reviewer Albert DeFelice, PhD, Non-Clinical Supervisor Muriel Saulnier, PhD, Non-Clinical Reviewer Edward Fromm, RPh, RAC, Chief, Project Management Staff Maryam Changi, PharmD, Regulatory Project Manager Office of Pharmaceutical Quality: Wendy Wilson-Lee, PhD, Application Technical Lead Grafton Adams, Regulatory Business Process Manager Milton Sloan, PhD, Drug Product Reviewer Rohit Tiwari, PhD, Drug Substance Reviewer Ben Stevens, PhD, Drug Substance Team Leader Kaushal Dave, PhD, Biopharmaceutical Reviewer Wu, Ta-Chin, PhD, Biopharmaceutical Team Leader Viviana Matta, PhD, Facility Reviewer Ruth Moore, PhD, Facility Team Leader Chunsheng Cai, PhD, Process Reviewer NDA 210428 RPM review Page 1 Reference ID: 42132034213643 Labeling/PMC-PMR to Sponsor: November 30, 2017 PDUFA Date: January 30, 2018 (Standard, 10-Month) PDUFA Goal Date: January 30, 2018 Approval letter: January 26, 2018 7. Reviews a) Divisional Memorandum: (January 26, 2018) Dr. Stockbridge indicated his concurrence on Dr. Sahre’s CDTL memo. b) Cross-Discipline Team Leader Review : (January 26, 2018) Dr. Sahre recommends approval. Her review summarizes each disciplines finding including consults. She also provided a detailed regulatory history. c) Clinical Pharmacology Review: (December 4, 2017) Dr. Samant recommended approval for this application: The Office of Clinical Pharmacology/Division of Clinical Pharmacology 1(OCP/DCP1) has reviewed the NDA submission. The results of the relative BA study and food effect study support approval of METOPROLOL SUCCINATE Extended-Release Capsules for the proposed indications at the doses as approved for the listed drug TOPROL-XL. She also included: The food effect study results support administration of METOPROLOL SUCCINATE Extended-Release Capsules by sprinkling the contents on soft food and without regards to meal. The clinical pharmacology section of the proposed label was updated to reflect the current Guidance on Clinical Pharmacology Section of Labeling for Human Prescription Drug and Biological Products d) Pharmacology & Toxicology Review: (July 5, 2017) Dr. Saulnier stated in her review: No new safety findings of concern were found and this product is approvable from the preclinical development aspect. Furthermore, an extensive clinical experience in adults and children ≥ 6 years old with metoprolol is available. e) Office of Pharmaceutical Quality Review: (November 30, 2017) OPQ recommended approval of NDA 210428 for Metoprolol Extended-Release Capsules, 25 mg, 50 mg, 100 mg, 200 mg when packaged in the intended commercial container closure and stored at USP controlled room temperature. 8. Consults Please see the following reviews and their corresponding dates: OSE/DMEPA: 10/10/17-10/16/17 OPDP: 11/30/17 DPMH: 12/25/17 NDA 210428 RPM review Page 4 Reference ID: 42132034213643 9. Labeling Labeling discussions occurred with the applicant. The final agreed-upon labeling will be attached to the approval letter. V. CONCLUSION The review team recommended approval. An Approval letter was signed by Dr. Norman Stockbridge on January 26, 2018. NDA 210428 RPM review Page 5 Reference ID: 42132034213643 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- MARYAM K CHANGI 01/26/2018 Reference ID: 42132034213643 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Division of Pediatric and Maternal Health Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration Silver Spring, MD 20993 Tel 301-796-2200 FAX 301-796-9744 Division of Pediatric and Maternal Health Memorandum Date: December 21, 2017 Date consulted: May 16, 2017 From: Christos Mastroyannis, M.D., Medical Officer, Maternal Health Division of Pediatric and Maternal Health (DPMH) Through: Tamara Johnson, M.D., MS, Team Leader, Maternal Health Division of Pediatric and Maternal Health Lynne P. Yao, MD, OND, Division Director Division of Pediatric and Maternal Health To: Division of Cardiovascular and Renal Products (DCRP) Drug: Metoprolol ER Capsules Drug Class: Beta-Blocker NDA: 210428 Applicant: Sun Pharmaceutical Industries LTD (SPIL) Subject: Pregnancy and Lactation Labeling Rule (PLLR) Conversion Indication: Metoprolol succinate extended-release capsules are indicated for: Hypertension, to lower blood pressure and thus to reduce cardiovascular morbidity and mortality including stroke and myocardial infarction. It may be administered with other antihypertensive agents. The long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. Heart failure, to reduce the risk of cardiovascular mortality and hospitalization in patients (b) (4) 1 Reference ID: 41997254213643 Materials Reviewed: DPMH consult request dated May 16, 2017 in DARRTS (Reference ID 4098932) Applicant’s submission for NDA 210428 dated March 30, 2017 and the latest Prescribing Information (PI) for Metoprolol ER Capsules dated June 5 and November 13, 2017 Applicant’s response to information request of May 16, 2017 submitted June 6, 2017 Consult Question: DCRP requests DPMH assistance with reviewing the applicant’s Pregnancy and Lactation labeling subsections to comply with PLLR format. INTRODUCTION On March 30, 2017, Sun Pharmaceutical Industries Ltd. (SPIL) submitted a 505(b)(2) New Drug Application (NDA) 210428 for Metoprolol Succinate Extended-Release (ER) Capsules 25 mg, 50 mg, 100 mg and 200 mg. The applicant has developed a new dosage form from Extended Release Tablets to Extended-release Capsules. No pharmacology and/or toxicology studies have been conducted by the applicant. For the nonclinical toxicology and safety & efficacy profile, SPIL depends on previous finding of safety and efficacy for the listed drug Toprol XL, and on several published literature and clinical trials references. The Division of Cardiovascular and Renal Products (DCRP) consulted the Division of Pediatric and Maternal Health (DPMH) on May 16, 2017, to provide input for appropriate labeling of the pregnancy and lactation subsections of Metoprolol ER capsules to comply with the Pregnancy and Lactation Labeling Rule (PLLR) format. This review provides recommended revisions and structuring of information related to the Pregnancy, Lactation, and Females and Males of Reproductive Potential subsections in labeling to provide clinically relevant information for prescribing decisions and to comply with current PLLR regulatory requirements. BACKGROUND Metoprolol ER capsules are indicated in: Hypertension, to lower blood pressure and thus to reduce cardiovascular morbidity and mortality including stroke and myocardial infarction. It may be administered with other antihypertensive agents. The long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. Heart failure, to reduce the risk of cardiovascular mortality and hospitalization in patients (b) (4) Regulatory History This 505(b)(2) NDA submission relies on Toprol XL (metoprolol succinate, NDA 019962), the reference listed drug (RLD), approved on January 10, 1992, for use in the following indications: Hypertension, to lower blood pressure and thus to reduce cardiovascular morbidity and mortality including stroke and myocardial infarction. It may be administered with other antihypertensive agents. The long-term treatment of angina pectoris, to reduce angina attacks and to improve exercise tolerance. Heart failure, to reduce the risk of cardiovascular mortality and hospitalization in 2 Reference ID: 41997254213643 patients (b) (4) Metoprolol Drug Characteristics1 Metoprolol succinate, is a beta1-selective (cardioselective) adrenoceptor blocking agent. Metoprolol crosses the blood-brain barrier and has been reported in the cerebrospinal fluid (CSF) in a concentration 78% of the simultaneous plasma concentration. The molecular weight of metoprolol succinate is 652.82. Plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity. About 12% is bound to human serum albumin. In the US, metoprolol is currently available from different manufacturers, including SPIL, in different salt forms (such as succinate, fumarate and tartrate) and different dosages [such as immediate release tablets (50 mg, and
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