DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Silver Spring MD 20993 NDA 208401 NDA APPROVAL Silvergate Pharmaceuticals, Inc. Attention: Mr. Michael C. Beckloff Chief Development Officer 7300 West 110th Street, Suite 950 Overland Park, KS 66210 Dear Mr. Beckloff: Please refer to your New Drug Application (NDA) dated and received June 30, 2015, and your amendments received July 14, September 14, 30, October 16, 30, November 16, 23, December 10, 2015, and January 08, 11, 19, February 19, 26, March 14, 18, April 20, 28, June 23, and July 08, 2016, pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Qbrelis (lisinopril) Oral Solution 1 mg/ml. We acknowledge receipt of your major amendment dated April 28, 2016, which extended the goal date by three months. This new drug application provides for the use of Qbrelis (lisinopril) Oral Solution for: • Treatment of hypertension in adults and pediatric patients 6 years of age and older • Adjunct therapy for heart failure • Treatment of Acute Myocardial Infarction 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. 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). 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. Reference ID: 3965616 NDA 208401 Page 2 CARTON AND IMMEDIATE CONTAINER LABELS Submit final printed carton and immediate container labels that are identical to the enclosed carton and immediate container labels 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 208401.” 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. MARKET PACKAGE Please submit one market package of the drug product when it is available to the following address: Sabry Soukehal Food and Drug Administration Center for Drug Evaluation and Research White Oak Building 22, Room: 4170 10903 New Hampshire Avenue Silver Spring, Maryland Use zip code 20903 if shipping via United States Postal Service (USPS). Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx). 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 indications in pediatric patients unless this requirement is waived, deferred, or inapplicable. We are waiving the pediatric study requirement for age birth to 16 years for a) adjunct therapy for heart failure and b) treatment of acute myocardial infarction, because necessary studies are impossible or highly impracticable. The causes and mechanisms of heart failure are different in children compared to adults. The form of heart failure seen in adults is rare in children; hence conducting a trial is highly impractical. There are also too few children with acute myocardial infarctions to conduct a trial in this disease/condition. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) continues until Reference ID: 3965616 NDA 208401 Page 3 approximately 1 to 2 years of age. An outstanding question is whether use of angiotensin converting enzyme inhibitors, such as lisinopril, before renal maturation is complete has long­ term deleterious effects on the kidney. We believe it would be impossible or highly impractical to resolve this question in a feasible clinical trial. Therefore, we are waiving the pediatric study requirement for age birth to less than 2 years for treatment of hypertension because studies are impossible or highly impractical. We are deferring submission of your pediatric study for ages 2 to 6 years for treatment of hypertension for this application because this product is ready for approval for use in adults and the pediatric study has not been completed. Your deferred pediatric study required by section 505B(a) of the FDCA is a required postmarketing study. The status of this postmarketing study must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. This required study is listed below. 3099-1 An efficacy, safety and dose-finding study of Qbrelis in hypertensive pediatric patients two years to less than six years of age Final Protocol Submission: Study Completion: Final Report Submission: 12/2016 06/2020 12/2020 Submit the protocol to your IND 116486, with a cross-reference letter to this NDA. Reports of this required pediatric postmarketing study must be submitted as a new drug application (NDA) or as a supplement to your approved NDA with the proposed labeling changes you believe are warranted based on the data derived from these studies. 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. 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, Medication Guide, and patient PI (as applicable) to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266 Reference ID: 3965616 NDA 208401 Page 4 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 ). 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). If you have any questions, please contact Sabry Soukehal, Regulatory Health Project Manager, at (240) 402 6187. Sincerely, {See appended electronic signature page} Norman Stockbridge, MD, PhD Director Division of Cardiovascular and Renal Products Office of Drug Evaluation 1 Center for Drug Evaluation and Research Enclosure(s): Content of Labeling Carton and Container Labeling Reference ID: 3965616 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------NORMAN L STOCKBRIDGE 07/29/2016 Reference ID: 3965616