`
`Trade Name:
`
`Generic or Proper
`Name:
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`
`205103Orig1s000
`
` Yosprala delayed release tablets
`
`aspirin 81 mg/omeprazole 40 mg, and aspirin 325
`mg/omeprazole 40 mg
`
`Aralez Pharmaceuticals R&D Inc.
`
`September 14, 2016
`
`Provides for the use of Yosprala delayed-release tablets
`(aspirin 81 mg/omeprazole 40 mg, and aspirin 325
`mg/omeprazole 40 mg) for the following:
`• Secondary prevention of cardiovascular and
`cerebrovascular events in patients at risk of
`developing aspirin associated gastric ulcers due to
`age (≥ 55) or documented history of gastric ulcers.
`• Decreasing the risk of developing aspirin
`associated gastric ulcers in patients at risk for
`developing aspirin-associated gastric ulcers due to
`age (≥ 55) or documented history of gastric ulcers.
`
`Sponsor:
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`205103Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`
`

`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`205103Orig1s000
`
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 205103
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Aralez Pharmaceuticals R&D Inc.
`Attention: Peggy Berry
`Regulatory Lead
`400 Alexander Park Drive
`Princeton, NJ 08540-6539
`
`Dear Ms. Berry:
`
`Please refer to your New Drug Application (NDA) dated and received March 25, 2013,
`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Yosprala (aspirin 81 mg/omeprazole 40 mg, and aspirin 325 mg/omeprazole 40 mg) delayed-
`release tablets.
`
`The March 14, 2016, submission constituted a complete response to our December 16, 2014
`action letter.
`
`This new drug application provides for the use of Yosprala delayed-release tablets (aspirin 81
`mg/omeprazole 40 mg, and aspirin 325 mg/omeprazole 40 mg) for the following:
`• Secondary prevention of cardiovascular and cerebrovascular events in patients at risk of
`developing aspirin associated gastric ulcers due to age (≥ 55) or documented history of
`gastric ulcers.
`
`• Decreasing the risk of developing aspirin associated gastric ulcers in patients at risk for
`developing aspirin-associated gastric ulcers due to age (≥ 55) or documented history of
`gastric ulcers.
`
`
`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, Medication
`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
`
`Reference ID: 3985760
`
`

`

`NDA 205103
`Page 2
`
`
`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 enclosed
`carton and immediate container labels and submitted carton and immediate container labels,
`except with the revisions listed above, 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 205103.” 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.
`
`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 studies requirement for this application because necessary studies
`are impossible or highly impracticable.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`
`Reference ID: 3985760
`
`

`

`NDA 205103
`Page 3
`
`
`
`3111-1
`
`
`3111-2
`
`Conduct an in vitro study to characterize and quantify the degradants of the
`immediate release omeprazole of Yosprala at various pHs (i.e., pH 1, 1.5, 2, 2.5,
`3, 3.5, 4) following a minimum of 1 hour of exposure at 37°C, and evaluate the
`differences in the profiles across pHs. Submit the chromatograms and a summary
`of quantitative data generated during the study.
`
`
`The timetable you submitted on August 30, 2016, states that you will conduct this trial according
`to the following schedule:
`
`
`Final Protocol Submission: 01/2017
`Study Completion:
`
`04/2017
`Final Report Submission:
`06/2017
`
`Conduct a clinical PK trial evaluating the systemic exposures of the omeprazole
`degradants that are shown to be present at a higher level at pH <3.0 compared to
`higher pHs in the in vitro studies (PMC #3111-1). This trial will include both
`Yosprala and the reference product for the omeprazole component of Yosprala.
`Compare the individual omeprazole degradant exposures between the two
`products.
`
`
`The timetable you submitted on August 30, 2016, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission: 11/2017
`Study Completion:
`
`03/2018
`Final Report Submission:
`06/2018
`
`
`Submit clinical protocols to your IND 78747 for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all postmarketing final reports to this NDA. In
`addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status
`summary of each commitment in your annual report to this NDA. The status summary should
`include expected summary completion and final report submission dates, any changes in plans
`since the last annual report, and, for clinical studies/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.”
`
`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:
`
`Reference ID: 3985760
`
`

`

`NDA 205103
`Page 4
`
`
`
`
`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
`
`
`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, call CAPT Mimi T. Phan, Regulatory Project Manager, at (301) 796-
`5408.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Donna Griebel, M.D.
`Director
`Division of Gastroenterology and Inborn
`Errors Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`
`Enclosure(s):
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 3985760
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DONNA J GRIEBEL
`09/14/2016
`
`Reference ID: 3985760
`
`(
`
`
`
`