DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 205649/S-003 SUPPLEMENT APPROVAL AstraZeneca AB c/o Astra Zeneca Pharmaceuticals LP Attention: Mike Angioli Senior Director, Regulatory Affairs One MedImmune Way Gaithersburg, MD 20878 Dear Mr. Angioli: Please refer to your supplemental New Drug Application (sNDA) dated and received October 23, 2015, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Xigduo XR (dapagliflozin and metformin HCl extended release) tablets, 5/500 mg, 5/1000 mg, 10/500 mg, and 10/1000 mg. We also refer to our letter dated September 25, 2015, notifying you, under Section 505(o)(4) of the FDCA, of new safety information that we believe should be included in the labeling for sodium-glucose cotransporter-2 (SGLT-2) inhibitor products. This information pertains to the risk of ketoacidosis and urosepsis in patients treated with SGLT-2 inhibitors. This “Prior Approval” sNDA provides for revisions to the labeling to address the risks of ketoacidosis and urosepsis, with the use of SGLT-2 inhibitors, consistent with our September 25, 2015, letter. APPROVAL & LABELING 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 and with the minor editorial revisions listed below and indicated in the enclosed labeling. • Revision date changed to reflect the date of approval of this supplement • Solid line border added to the left of Section 5.5, Ketoacidosis, and Section 5.6, Urosepsis and Pyelonephritis, of the Full Prescribing Information to denote Recent Major Changes • Removal of an extra comma (“,”) from the first line of Section 5.5, Ketoacidosis Reference ID: 3855978 NDA 205649/S-003 Page 2 WAIVER OF HIGHLIGHTS SECTION Please note that we have previously granted a waiver of the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of prescribing information. 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/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U CM072392.pdf . The SPL will be accessible via 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 none of these criteria apply to your application, you are exempt from this requirement. POSTMARKETING REQUIREMENT UNDER 505(o) Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute. Reference ID: 3855978 NDA 205649/S-003 Page 3 As previously communicated to you in our letter dated September 25, 2015, we have determined that an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess the known serious risk of ketoacidosis in patients treated with SGLT-2 inhibitors. Furthermore, the new pharmacovigilance system that FDA is required to establish under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk. Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following: 3006-1 An enhanced pharmacovigilance study of ketoacidosis in patients treated with dapagliflozin. The study will include reports of ketoacidosis or diabetic ketoacidosis for a period of 5 years, and will include assessment and analysis of spontaneous reports of ketoacidosis in patients treated with dapagliflozin, with specialized follow-up to collect additional information on these cases. We refer to your submission dated October 23, 2015, which states your intention to conduct one study to address this postmarketing requirement (PMR) for all currently approved products containing dapagliflozin. Therefore, this PMR will also apply to Farxiga (dapagliflozin) tablets, per our approval letter issued to NDA 202293/S-008. The timetable you submitted on November 20, 2015, states that you will conduct this study according to the following schedule: Final Protocol Submission: 06/2016 Interim Report Submission: 12/2017 12/2018 12/2019 12/2020 Study Completion: 06/2021 Final Report Submission: 12/2021 Submit the protocol to your IND 068652, with a cross-reference letter to this NDA. Submit all interim and final reports to your NDA. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate: “Required Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under 505(o)”, “Required Postmarketing Correspondence Under 505(o)”. Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section. This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to report annually on the status of any postmarketing commitments or required studies or clinical trials. Reference ID: 3855978 NDA 205649/S-003 Page 4 FDA will consider the submission of your annual report under section 506B and 21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o) on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action. 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: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion (OPDP) 5901-B Ammendale Road Beltsville, MD 20705-1266 Alternatively, you may submit a request for advisory comments electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Guidance for Industry (available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM443702.pdf ). 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 this supplement, 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, by fax to 301-847-8444, or electronically in eCTD format. For more information about submitting promotional materials in eCTD format, see the draft Guidance for Industry (available at: Reference ID: 3855978 NDA 205649/S-003 Page 5 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U CM443702.pdf ). 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, call Abolade (Bola) Adeolu, Regulatory Project Manager, at 301-796-4264. Sincerely, {See appended electronic signature page} Jennifer Rodriguez Pippins, M.D., M.P.H. Deputy Director for Safety Division of Metabolism and Endocrinology Products Office of Drug Evaluation II Center for Drug Evaluation and Research ENCLOSURE: Content of Labeling Reference ID: 3855978 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JENNIFER R PIPPINS 12/04/2015 Reference ID: 3855978