DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 205649 NDA APPROVAL AstraZeneca AB Attention: Mike Angioli Sr. Director, Regulatory Affairs 1800 Concord Pike PO Box 8355 Wilmington, DE 19803-8355 Dear Mr. Angioli: Please refer to your New Drug Application (NDA) dated October 29, 2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA), for Xigduo XR (dapagliflozin and metformin HCl extended-release) tablets. We acknowledge receipt of your amendments dated October 31, November 18, 2013, January 24, 30, February 26, 28(2), March 5, April 4, 8, 10, 14, May 20, 21, June 20, August 13(2), 29, and September 18, 2014. This new drug application provides for the use of Xigduo XR (dapagliflozin and metformin HCl extended-release) tablets as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate. We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling text. WAIVER OF HIGHLIGHTS SECTION We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of prescribing information. This waiver applies to all future supplements containing revised labeling unless we notify you otherwise. 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 Reference ID: 3650523 NDA 205649 Page 2 Guide. Information on submitting SPL files using eLIST may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf. The SPL will be accessible via publicly available labeling repositories. CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and immediate container labels that are identical to the carton and immediate container labels submitted on August 13, 2014, as soon as they are available, but no more than 30 days after they are printed. Please submit these labels electronically according to the guidance for industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar material. For administrative purposes, designate this submission “Final Printed Carton and Container Labels for approved NDA 205649.” Approval of this submission by FDA is not required before the labeling is used. Marketing the product with FPL that is not identical to the approved labeling text may render the product misbranded and an unapproved new drug. ADVISORY COMMITTEE Your application for Xigduo XR (dapagliflozin and metformin HCl extended-release) was not referred to an FDA advisory committee because this drug is not the first in its class and the safety profile is similar to that of other drugs acceptable for the treatment of type 2 diabetes. Also, outside expertise was not necessary; there were no controversial issues that would benefit from advisory committee discussion. 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. We are waiving the pediatric study requirement for ages 0 through 9 years (inclusive) because necessary studies are impossible or highly impracticable. This is because there are too few children in this age range with type 2 diabetes mellitus to study. We are deferring submission of your pediatric studies for ages 10 to 17 years (inclusive) for this application because this product is ready for approval for use in adults and the pediatric studies have not been completed. Reference ID: 3650523 NDA 205649 Page 3 Your deferred pediatric studies required by section 505B(a) of the FDCA are required postmarketing studies. The status of these postmarketing studies must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are listed below. 2807-1 A study to evaluate whether pediatric patients with type 2 diabetes mellitus or healthy pediatric subjects ages 10 to 17 years (inclusive) can safely swallow Xigduo XR(dapagliflozin and metformin HCl extended-release) tablets. The study should evaluate tablets that are at least as large as the largest Xigduo XR tablet (dapagliflozin and metformin HCl extended-release). Placebo tablets should be used if the study population consists of healthy subjects. Final Protocol Submission: Study Completion: Final Report Submission: October 2015 April 2018 October 2018 Submit the protocol to your IND 106890, with a cross-reference letter to this NDA. Reports of this required pediatric postmarketing study must be submitted as an NDA or as a supplement to your approved NDA with the proposed labeling changes you believe are warranted based on the data derived from this study. When submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of the submission. We also remind you that your requirements under PREA as stated in the approval letter for NDA 202293 for Farxiga (dapagliflozin) tablets, dated January 8, 2014, also apply to NDA 205649: 2121-1 Complete a randomized, multicenter, parallel, single-dose study to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin in children, 10 to 17 years of age with type 2 diabetes mellitus (T2DM) receiving one of the three dose levels of dapagliflozin over the range of 2.5 to 10 mg. At least 30% of randomized subjects in each dose group will be 10 - 15 years of age. Final Protocol Submission: Study Completion: Final Report Submission: 2121-2 Reference ID: 3650523 April 2012 August 2014 February 2015 A 26-week randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of dapagliflozin for the treatment of pediatric subjects ages 10 to <18 years of age with type 2 diabetes mellitus (T2DM), as add-on to metformin or as monotherapy, followed by a 26-week double-blind, placebo- or active-controlled extension period (Week 26 to Week 52). At least 30% of randomized subjects will be 10 to 14 years of age and at least one-third and not more than two-thirds of subjects in both age subsets (10 to 14 years and 15 to <18 years) will be female. Secondary safety endpoints should include the NDA 205649 Page 4 effect of dapagliflozin on mineral and bone metabolism, and the effect of dapagliflozin on growth. Final Protocol Submission: Study Completion: Final Report Submission: August 2015 February 2020 August 2020 Please cross-reference NDA 205649 when you submit your final reports for requirements 2121-1 and 2121-2 to NDA 202293. PROMOTIONAL MATERIALS You may request advisory comments on proposed introductory advertising and promotional labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package insert to: Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266 As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253. 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. REPORTING REQUIREMENTS We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81). PDUFA V APPLICANT INTERVIEW FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim and final assessment of the Program for Enhanced Review Transparency and Communication for NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment Letter states that these assessments will include interviews with applicants following FDA action on applications reviewed in the Program. For this purpose, first-cycle actions include approvals, complete responses, and withdrawals after filing. The purpose of the interview is to better Reference ID: 3650523 NDA 205649 Page 5 understand applicant experiences with the Program and its ability to improve transparency and communication during FDA review. ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about the interview process. Your responses during the interview will be confidential with respect to the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any identifying information to anyone outside their project team. They will report only anonymized results and findings in the interim and final assessments. Members of the FDA review team will be interviewed by ERG separately. While your participation in the interview is voluntary, your feedback will be helpful to these assessments. If you have any questions, call Elizabeth Chen, Regulatory Project Manager, at (240) 402-3729. Sincerely, {See appended electronic signature page} Jean-Marc Guettier, M.D. Director Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research Enclosures: Package Insert Medication Guide Carton and Container Labeling Reference ID: 3650523 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JEAN-MARC P GUETTIER 10/29/2014 Reference ID: 3650523