CENTER FOR DRUG EVALUATION AND RESEARCH Approval Package for: APPLICATION NUMBER: NDA 22-399/S-003 Trade Name: Horizant Generic Name: gabapentin enacarbil Sponsor: Xenoport Inc. Approval Date: June 6, 2012 Indications: Management of postherpetic neuralgia (PHN) in adults. CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 22-399/S-003 CONTENTS Reviews / Information Included in this NDA Review. Approval Letter X Approvable Letter Labeling X Summary Review X Officer/Employee List X Office Director Memo Cross Discipline Team Leader Review X Medical Review(s) X Chemistry Review(s) X Environmental Assessment Pharmacology Review(s) X Statistical Review(s) X Microbiology Review(s) Clinical Pharmacology/Biopharmaceutics Review(s) X 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 22-399/S-003 APPROVAL LETTER DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring, MD 20993 NDA 022399/S-003 SUPPLEMENT APPROVAL GlaxoSmithKline Five Moore Drive Research Triangle Park, NC 27709 Attention: Eric Benson, Senior Director Global Regulatory Affairs Dear Mr. Benson: Please refer to your Supplemental New Drug Application (sNDA) dated and received August 9, 2011, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Horizant (gabapentin enacarbil extended-release tablets) We acknowledge receipt of your amendments dated September 20, October 4 and 26, November 8, 21, and 30, and December 6 and 21, 2011, and January 13 and 16, and April 25, 2012. This “Prior Approval” supplemental new drug application proposes the addition of a new indication for the management of postherpetic neuralgia. We have completed our review of this supplemental application, as amended. It is 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 and Medication Guide), 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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. Reference ID: 3140939 NDA 022399/S-003 Page 2 The SPL will be accessible from publicly available labeling repositories. Also within 14 days, amend all pending supplemental applications 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 this supplemental application, 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). REQUIRED PEDIATRIC ASSESSMENTS Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement. 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: 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/opacom/morechoices/fdaforms/cder.html; instructions are provided on page 2 of the form. 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. REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). Reference ID: 3140939 NDA 022399/S-003 Page 3 If you have any questions, call Sharon Turner-Rinehardt, Senior Regulatory Health Project Manager, at (301) 796-2254. Sincerely, {See appended electronic signature page} Rigoberto Roca, M.D. Deputy Director Division of Anesthesia, Analgesia, and Addiction Products Office of Drug Evaluation II Center for Drug Evaluation and Research ENCLOSURE: Content of Labeling Reference ID: 3140939 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- RIGOBERTO A ROCA 06/06/2012 Reference ID: 3140939 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: NDA 22-399/S-003 LABELING HIGHLIGHTS OF PRESCRIBING INFORMATION If the dose is not taken at the recommended time, skip this dose, and the These highlights do not include all the information needed to use next dose should be taken at the time of next scheduled dose. (2.2) HORIZANT safely and effectively. See full prescribing information for Patients with renal impairment: Doses of HORIZANT must be adjusted HORIZANT. in accordance with renal function. (2.3) --------------------- DOSAGE FORMS AND STRENGTHS -------------- HORIZANT (gabapentin enacarbil) Extended-Release Tablets for oral Extended-Release Tablets: 300 mg and 600 mg. (3) use Initial U.S. Approval: 2011 -------------------------------CONTRAINDICATIONS------------------------ None. (4) ---------------------------RECENT MAJOR CHANGES -------------------- Indications and Usage, Management of Postherpetic Neuralgia (1.2) 06/2012 ----------------------- WARNINGS AND PRECAUTIONS ---------------- Dosage and Administration, Postherpetic Neuralgia (2.2) 06/2012 Driving impairment: Warn patients not to drive until they have gained Dosage and Administration, Renal Impairment (2.3) 06/2012 sufficient experience with HORIZANT to assess whether it will impair Warnings and Precautions, Somnolence/Sedation and Dizziness 06/2012 their ability to drive. (5.1) (5.2) Somnolence/sedation and dizziness: May impair the patient’s ability to Warnings and Precautions, DRESS (5.5) 12/2011 operate complex machinery. (5.2) Warnings and Precautions, Discontinuation of HORIZANT (5.6) 06/2012 HORIZANT is not interchangeable with other gabapentin products. (5.3) ----------------------------INDICATIONS AND USAGE--------------------- Suicidal thoughts or behaviors: HORIZANT is a prodrug of gabapentin, HORIZANT is indicated for: an antiepileptic drug (AED). AEDs increase the risk of suicidal thoughts or behaviors. Monitor for suicidal thoughts or behaviors. (5.4) treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. (1.1) ------------------------------ ADVERSE REACTIONS ----------------------- management of postherpetic neuralgia (PHN) in adults. (1.2) RLS: Most common adverse reactions (10% and at least 2 times the rate of placebo) were somnolence/sedation and dizziness. (6.1) ----------------------- DOSAGE AND ADMINISTRATION ---------------- Instruct patients to swallow tablets whole and not to cut, crush, or chew PHN: Most common adverse reactions (10% and greater than placebo) tablets. Take with food. (2) were dizziness, somnolence, and headache. (6.1) RLS: 600 mg once daily taken at about 5 PM. (2.1) To report SUSPECTED ADVERSE REACTIONS, contact A dose of 1,200 mg once daily provided no additional benefit compared GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or with the 600-mg dose, but caused an increase in adverse reactions. (2.1) www.fda.gov/medwatch. If the dose is not taken at the recommended time, the next dose should be ----------------------- USE IN SPECIFIC POPULATIONS ---------------- taken the following day as prescribed. (2.1) Pregnancy: Based on animal data, may cause fetal harm. (8.1) PHN: The starting dose is 600 mg in the morning for 3 days, then increase to 600 mg twice daily beginning on day 4. (2.2) See 17 for PATIENT COUNSELING INFORMATION and