CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER: NDA 204063/S-10 Trade Name: Tecfidera Generic Name: Dimethyl fumarate Sponsor: Biogen IDEC Inc. Approval Date: December 03, 2014 Indications: For the treatment of patients with relapsing forms of multiple sclerosis. CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 204063/S-10 CONTENTS Reviews / Information Included in this NDA Review. Approval Letter X Approvable Letter Labeling X Summary Review X Officer/Employee List Office Director Memo Cross Discipline Team Leader Review Medical Review(s) Chemistry Review(s) Environmental Assessment Pharmacology Review(s) Statistical Review(s) Microbiology Review(s) Clinical Pharmacology/Biopharmaceutics Review(s) Risk Assessment and Risk Mitigation Review(s) Proprietary Name Review(s) Other Review(s) X Administrative/Correspondence Document(s) X CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 204063/S-10 APPROVAL LETTER NDA 204063/S-003, 008, and 010 Page 2 We also acknowledge receipt of your amendments to NDA 204063/S-003 dated February 21, 2014 and November 19, 2014; NDA 204063/S-008 dated August 25, 2014, October 17, 2014, October 23, 2014, and October 29, 2014; and NDA 204063/S-010 dated November 7, 2014, November 25, 2014, November 26, 2014, and December 3, 2014. APPROVAL & LABELING We have completed our review of these supplemental applications, as amended. They are approved, effective on the date of this letter, for use as recommended in the enclosed, agreed- upon labeling text. CONTENT OF LABELING As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be identical to the enclosed labeling (text for the package insert, text for the patient package insert), with the addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed labeling. Information on submitting SPL files using eList may be found in the guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As at http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. The SPL will be accessible from publicly available labeling repositories. Also within 14 days, amend all pending supplemental applications that include labeling changes for this NDA, including CBE supplements for which FDA has not yet issued an action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in these supplemental applications, as well as annual reportable changes and annotate each change. To facilitate review of your submission, provide a highlighted or marked- up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should provide appropriate annotations, including supplement number(s) and annual report date(s). PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory comments, (2) the proposed materials in draft or mock-up form with annotated references, and (3) the package insert(s) to: Reference ID: 3666921 NDA 204063/S-003, 008, and 010 Page 3 Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion (OPDP) 5901-B Ammendale Road Beltsville, MD 20705-1266 You must submit final promotional materials and package insert(s), accompanied by a Form FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf. Information and Instructions for completing the form can be found at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For more information about submission of promotional materials to the Office of Prescription Drug Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm. All promotional materials that include representations about your drug product must be promptly revised to be consistent with the labeling changes approved in these supplements, including any new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials should include prominent disclosure of the important new safety information that appears in the revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444. REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). If you have any questions, contact Laurie Kelley, PA-C, Regulatory Project Manager, via telephone at (301) 796-5068 or via email at [email protected]. Sincerely, {See appended electronic signature page} Billy Dunn, M.D. Acting Director Division of Neurology Products Office of Drug Evaluation I Center for Drug Evaluation and Research ENCLOSURE(S): Content of Labeling Reference ID: 3666921 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- WILLIAM H Dunn 12/03/2014 Reference ID: 3666921 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 204063/S-10 LABELING Tecfidera NDA 204063/S-003, S-008, S-010 FDA Approved Labeling Text 12/3/14 HIGHLIGHTS OF PRESCRIBING INFORMATION ___________________ CONTRAINDICATIONS ___________________ These highlights do not include all the information needed to use Known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA safely and effectively. See full prescribing information for TECFIDERA. (4) TECFIDERA. _______________ _______________ WARNINGS AND PRECAUTIONS TECFIDERA® (dimethyl fumarate) delayed-release capsules, for oral use • Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA Initial U.S. Approval: 2013 if these occur. (5.1) • Progressive multifocal leukoencephalopathy (PML): Withhold _________________ RECENT MAJOR CHANGES _________________ TECFIDERA at the first sign or symptom suggestive of PML. (5.2) Dosage and Administration, Dosing Information (2.1) 12/2014 • Lymphopenia: Obtain a CBC including lymphocyte count before initiating TECFIDERA, after 6 months, and every 6 to 12 months thereafter. Contraindications (4) 12/2014 9 Warnings and Precautions, Anaphylaxis and Angioedema (5.1) 12/2014 Consider interruption of TECFIDERA if lymphocyte counts <0 5 x 10 /L Warnings and Precautions, PML (5.2) 12/2014 persist for more than six months. (5.3) Warnings and Precautions, Lymphopenia (5.3) 12/2014 ___________________ ADVERSE REACTIONS ___________________ Most common adverse reactions (incidence ≥10% and ≥2% placebo) were __________________ INDICATIONS AND USAGE _________________ flushing, abdominal pain, diarrhea, and nausea. (6.1) TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis (1) To report SUSPECTED ADVERSE REACTIONS, contact Biogen Idec at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. _______________ ______________ DOSAGE AND ADMINISTRATION ______________ _______________ • Starting dose: 120 mg twice a day, orally, for 7 days (2.1) USE IN SPECIFIC POPULATIONS • Maintenance dose after 7 days: 240 mg twice a day, orally (2.1) Pregnancy: based on animal data, may cause fetal harm. (8.1) • Swallow TECFIDERA capsules whole and intact. Do not crush, chew, or sprinkle capsule contents on food (2 1) See 17 for PATIENT COUNSELING INFORMATION and FDA- • Take TECFIDERA with or without food (2.1) approved patient labeling Revised: 12/2014 ______________ DOSAGE FORMS AND STRENGTHS _____________ Delayed-release capsules: 120 mg and 240 mg (3) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 8.5 Geriatric Use 2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION 2.1. Dosing Information 12 CLINICAL PHARMACOLOGY 2.2 Blood Test Prior to Initiation of Therapy 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics 4 CONTRAINDICATIONS 12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY 5.1 Anaphylaxis and Angioedema 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.2 Progressive Multifocal Leukoencephalopathy 13.2 Animal Toxicology and/or Pharmacology 5.3 Lymphopenia 14 CLINICAL STUDIES 5.4 Flushing 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION 6.1 Clinical Trials Experience 8 USE IN SPECIFIC POPULATIONS *Sections or subsections omitted from the full prescribing information are not 8.1 Pregnancy listed. 8.3 Nursing Mothers 8.4 Pediatric Use 1 Reference ID: 3666921 Tecfidera NDA 204063/S-003, S-008, S-010 FDA Approved Labeling Text 12/3/14 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE TECFIDERA is indicated for the treatment of patients