... ~SERVICES (.t., -l DEPARTMENT OF HEALTH &. HUMAN SERVICES .OCi. 3 20111 / A .lhd10 (; Ms. Angela G. Long Food and Drug Administration Rockville MD 20857 Executive Secretariat The United States Pharmacopeial Convention, Inc. 12601 Twinbrook Parkway REF: 10-07-001-0 Rockville, MD 20852 Dear Ms. Long: This letter proposes revisions to the monograph for Levothyroxine Sodium Tablets in USP 30, pages 2470-2471. We propose that the assay range specification in the USP monograph for Levothyroxine Sodium Tablets be nan-owed from the current 90 percent to 110 percent of label claim to 95 percent to 105 percent of label claim. This proposal is part of an ongoing effort to address concerns expressed about the performance of approved levothyroxine sodium products and to help ensure that levothyroxine sodium drug products maintain their quality throughout their shelf-lives. In response to physician and patient concerns about product performance, particularly for patients taking different levothyroxine sodium products after prescription refills that may involve products from different manufacturers, we requested product stability data from manufacturers of all the approved, marketed levothyroxine sodium drug products ...

... Report of Recently Approved Products ' Performance in Bioequivalence Testing Barbara M. Davit, Ph.D Division of Bioequivalence Office of Generic Drugs CDER / FDA Joint Public Meeting on Equivalence of Levothyroxine Sodium Products May 23, 2005 Topics of the approved levothyroxine Overview tablet products compared to each other in bioequivalence (BE) studies How BE was determined In vivo and in vitro data from BE studies Summary and conclusions Approved levothyroxine sodium tablets rated therapeutically equivalent (TE) Test product Reference Product Levo-T ® Levoxyl ® Levo-T ® Synthroid ® Mylan Levoxyl ® Mylan Synthroid ® Mylan Unithroid ® Unithroid ® Levoxyl ® Unithroid ® Synthroid ® Effects of variation in inactive ingredients on BE sodium tablet products that were Levothyroxine tested in BE studies submitted to the FDA varied in inactive ingredients These inactive ingredients are commonly used in a great many drug products In the FDA's experience, these excipients do not affect the bioavailability of any drug product As expected, differences in inactive ingredients had no effect on BE of levothyroxine sodium tablet products How BE is determined for levothyroxine sodium tablets in vivo BE study on highest Conduct strength ...

... Bioavailability / Bioequivalence Studies in Evaluation of New Levothyroxine Products Hank Malinowski, Ph.D. Director, Division of Pharmaceutical Evaluation II Office of Clinical Pharmacology & Biopharmaceutics CDER / FDA Introduction · Introduced in the 1950s (more pure, synthetic form of Thyroid, USP) · Prior to August, 2000, levothyroxine sodium was an unapproved marketed drug · In 1997 at least 37 manufacturers or re-packagers of levothyroxine sodium tablets Federal Register Notice (62 FR 43535) · In an effort to standardize levothyroxine sodium tablets, and to reduce the instances of sub-and super-potency problems, on August 14, 1997, the FDA declared levothyroxine sodium tablets a" new drug" · Sponsors wishing to continue to market their product needed to submit an NDA or file a citizen's petition describing why an NDA was not necessary FDA Guidance for Industry Levothyroxine Sodium Tablets-In Vivo Pharmacokinetic and Bioavailability Studies and In Vitro Dissolution Testing-Feb. 2001 · Introduction and Background · In vivo pharmacokinetic and bioavailability studies ­ Inclusion criteria ­ Single-dose (relative) bioavailability (to solution) ­ Dosage-form proportionality · ...

... Sample Letter Dear: The purpose of this letter is to inform you that the Food and Drug Administration (FDA) has decided to require that all levothyroxine sodium products approved for use in humans meet a 95 to 105 percent potency specification throughout their labeled shelf-lives. This action is part of the agency's ongoing efforts to address concerns expressed about the performance of currently approved levothyroxine sodium products. It is consistent with FDA's previous regulatory actions intended to ensure that levothyroxine sodium drug products maintain their quality throughout their shelf-lives. It is based on our evaluation of data submitted as part of the drug approval process, evaluation of stability data provided by applicants in the spring of 2006, evaluation of available clinical data and literature, discussions and opinions expressed at an October 2006 joint meeting of the Endocrine and Metabolic Drugs Advisory Committee (EMDAC) and Advisory Committee for the Pharmaceutical Sciences (ACPS ), and further evaluation of the joint advisory committee panel's recommendation. (See transcript of the October 4, 2006 joint meeting of the EMDAC and ACPS at http :// www.fda.gov / ohrms / dockets ...

... Joint Public Meeting on Equivalence of Levothyroxine Sodium Products Co-sponsored with the FDA by the American Thyroid Association, The Endocrine Society and the American Association of Clinical Endocrinologists Monday, May 23, 2005 National Transportation Safety Board L'Enfant Plaza Washington, DC AGENDA AND SCHEDULE 8: 30 ­ 8: 45 am Welcoming Remarks: Steve K. Galson, M.D, MPH Acting Director, Center for Drug Evaluation and Research (CDER )/ FDA Paul W. Ladenson, M.D. Johns Hopkins University School of Medicine Session I: Background: Clinical Issues and New Drug Applications for Levothyroxine 8: 45 ­ 9: 15 am Levothyroxine Sodium: A Widely Employed Narrow Therapeutic Range Drug Paul W. Ladenson, M.D. Johns Hopkins University, School of Medicine 9: 15 ­ 9: 30 am Overview of FDA General Regulatory Requirements and Methods for Demonstration of Therapeutic Equivalence Dale P. Conner, Pharm.D, CDER / FDA 9: 30 ­ 9: 45 am Manufacturing Standards Eric P. Duffy, PhD, CDER / FDA 9: 45 ­ 10: 00 am Bioavailability / Bioequivalence ...

... to Section Content Menu Skip to Common Links Enter Search terms A-Z Index Home Food Drugs Medical Devices Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Radiation-Emitting Products Tobacco Products-Drugs Home >Drugs >Drug Safety and Availability >Postmarket Drug Safety Information for Patients and Providers Section Contents Menu Drug Safety and Availability Postmarket Drug Safety Information for Patients and Providers Index to Drug-Specific Information Approved Risk Evaluation and Mitigation Strategies (REMS) Postmarketing Safety Evaluation of New Molecular Entities: Final Report Drug Safety Information for Healthcare Professionals-Questions and Answers on Levothyroxine Sodium Products 1. What action is FDA taking today? FDA has decided to require each approved levothyroxine sodium product to meet a 95-105 percent potency specification throughout its shelf life, that is, to degrade by no more than 5 percent from its labeled potency amount. Currently, these products are required to meet a USP-authorized potency specification of 90-110 percent, which is typical for most drug products. The potency specification provides for limited, permissible degradation over a productâ €™ s shelf life. 2. What are levothyroxine sodium drug products and ...

... LEVOTHYROXINE SODIUM TABLETS An FDA Overview from the CMC Standpoint Eric P. Duffy, PhD Joint Public Meeting on Equivalence of Levothyroxine Sodium Products Co-sponsored with the FDA by the American Thyroid Association, The Endocrine Society and the American Association of Clinical Endocrinologists Monday, May 23, 2005 National Transportation Safety Board L'Enfant Plaza Washington, DC Outline · Description · History · Regulatory History · Current status Levothyroxine drug products · Active substance is an endogenous thyroid principle, designated as T4. ­ Half-life of T4 is approximately 7 days · Formulated as immediate-release tablets ­ Manufactured via compression ­ In vitro dissolution characteristics vary History · Levothyroxine (T4) drug products marketed without NDA from the 1950's until 2001 ­ Products were often chemically unstable. ­ Formulated with >100 %labeled claim of T4. ­ Some lost as much as 20 %of initial T4 during expiry. ­ Degradation products not monitored. ­ No standardized specifications / protocols. ­ Inconsistent quality Inconsistent quality · Non-NDA (pre-1997) T4 tablets exhibited poor consistency and uniformity ­ Product ­ to ­ product ­ Batch ­ to ­ ...

... Skip to Section Content Menu Skip to Common Links Enter Search terms A-Z Index Home Food Drugs Medical Devices Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Radiation-Emitting Products Tobacco Products-Drugs Home >Drugs >Drug Safety and Availability >Postmarket Drug Safety Information for Patients and Providers Section Contents Menu Drug Safety and Availability Postmarket Drug Safety Information for Patients and Providers Index to Drug-Specific Information Approved Risk Evaluation and Mitigation Strategies (REMS) Postmarketing Safety Evaluation of New Molecular Entities: Final Report Drug Safety Information for Healthcare Professionals-Table of Approved Levothyroxine Sodium Oral Formulations (Tablet or Capsule) Proprietary Name Active Ingredient Applicant Levolet levothyroxine sodium Vintage (not marketed in the U.S) Levo-T levothyroxine sodium Alara Pharm Levothroid levothyroxine sodium Lloyd (distributed by Forest) Levothyroxine Sodium levothyroxine sodium Genpharm Levothyroxine Sodium levothyroxine sodium Mylan Levoxyl levothyroxine sodium Jones Pharma / King Synthroid levothyroxine sodium Abbott Tirosint levothyroxine sodium Institute Biochimique Unithroid levothyroxine sodium Jerome Stevens-- Links on this page: Page Last Updated: 06 / 18 / 2009 Note: If you need help accessing information in different file formats, see Instructions ...

... to Topics Menu Skip to Section Content Menu Skip to Common Links Enter Search terms A-Z Index Home Food Drugs Medical Devices Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Radiation-Emitting Products Tobacco Products-Drugs Home >Drugs >Drug Safety and Availability >Postmarket Drug Safety Information for Patients and Providers Section Contents Menu Drug Safety and Availability Postmarket Drug Safety Information for Patients and Providers Index to Drug-Specific Information Approved Risk Evaluation and Mitigation Strategies (REMS) Postmarketing Safety Evaluation of New Molecular Entities: Final Report Drug Safety Information for Healthcare Professionals-Levothyroxine Sodium Product Information The Food and Drug Administration (FDA) has issued letters to all new drug application (NDA) and abbreviated new drug application (ANDA) holders requiring that they change the specifications for their products so that all levothyroxine sodium products approved for use in humans will meet a 95 %to 105 %potency specification throughout their labeled shelf-lives. In addition, FDA will work with the United States Pharmacopeia (USP) to revise the potency specification indicated in the USP monograph for levothyroxine sodium tablets. This action is part of ...

... Skip to Section Content Menu Skip to Common Links Enter Search terms A-Z Index Home Food Drugs Medical Devices Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Radiation-Emitting Products Tobacco Products-Drugs Home >Drugs >Drug Safety and Availability >Postmarket Drug Safety Information for Patients and Providers Section Contents Menu Drug Safety and Availability Postmarket Drug Safety Information for Patients and Providers Index to Drug-Specific Information Approved Risk Evaluation and Mitigation Strategies (REMS) Postmarketing Safety Evaluation of New Molecular Entities: Final Report Drug Safety Information for Healthcare Professionals-Public Meeting for Levothyroxine Sodium Therapeutic Equivalence May 23, 2005, Washington, DC Presentations Overview of FDA General Regulatory Requirements and Methods for Demonstration of Therapeutic Equivalence (PDF-155KB), Dale P. Conner, Pharm.D, FDA Report of Recently Approved Productsâ €™ Performance in Bioequivalence Testing (PDF-107KB), Barbara M. Davit, Ph.D, FDA Levothyroxine Sodium Tables: An FDA Overview from the CMC Standpoint (PDF-99KB), Eric P. Duffy, PhD, FDA Limitations of Current Bioequivalence Standards, James V. Hennessey M.D, ...