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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 205103
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`Food and Drug Administration
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` Silver Spring MD 20993
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` NDA APPROVAL
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`Aralez Pharmaceuticals R&D Inc.
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`Attention: Peggy Berry
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`Regulatory Lead
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`400 Alexander Park Drive
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`Princeton, NJ 08540-6539
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`Dear Ms. Berry:
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`Please refer to your New Drug Application (NDA) dated and received March 25, 2013,
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`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
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`for Yosprala (aspirin 81 mg/omeprazole 40 mg, and aspirin 325 mg/omeprazole 40 mg) delayed-
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`release tablets.
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`The March 14, 2016, submission constituted a complete response to our December 16, 2014
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`action letter.
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`This new drug application provides for the use of Yosprala delayed-release tablets (aspirin 81
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`mg/omeprazole 40 mg, and aspirin 325 mg/omeprazole 40 mg) for the following:
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`• Secondary prevention of cardiovascular and cerebrovascular events in patients at risk of
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`developing aspirin associated gastric ulcers due to age (≥ 55) or documented history of
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`gastric ulcers.
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`• Decreasing the risk of developing aspirin associated gastric ulcers in patients at risk for
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`developing aspirin-associated gastric ulcers due to age (≥ 55) or documented history of
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`gastric ulcers.
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`We have completed our review of this application, as amended. It is approved, effective on the
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`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert, Medication
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`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
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`Reference ID: 3985760
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` NDA 205103
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` Page 2
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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` CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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` CARTON AND IMMEDIATE CONTAINER LABELS
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` Submit final printed carton and immediate container labels that are identical to the enclosed
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` carton and immediate container labels and submitted carton and immediate container labels,
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` except with the revisions listed above, as soon as they are available, but no more than 30 days
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` after they are printed. Please submit these labels electronically according to the guidance for
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` industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
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`Product Applications and Related Submissions Using the eCTD Specifications (June 2008).
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`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
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`“Final Printed Carton and Container Labels for approved NDA 205103.” Approval of this
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`submission by FDA is not required before the labeling is used.
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`Marketing the product with FPL that is not identical to the approved labeling text may render the
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`product misbranded and an unapproved new drug.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`We are waiving the pediatric studies requirement for this application because necessary studies
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`are impossible or highly impracticable.
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`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
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`UNDER SECTION 506B
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`We remind you of your postmarketing commitments:
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`Reference ID: 3985760
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` NDA 205103
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` Page 3
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` 3111-1
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`3111-2
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` Conduct an in vitro study to characterize and quantify the degradants of the
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`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
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`differences in the profiles across pHs. Submit the chromatograms and a summary
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`of quantitative data generated during the study.
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`Final Protocol Submission: 01/2017
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`04/2017
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`Study Completion:
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`Final Report Submission:
`06/2017
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` The timetable you submitted on August 30, 2016, states that you will conduct this trial according
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` to the following schedule:
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`Conduct a clinical PK trial evaluating the systemic exposures of the omeprazole
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`degradants that are shown to be present at a higher level at pH <3.0 compared to
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`higher pHs in the in vitro studies (PMC #3111-1). This trial will include both
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`Yosprala and the reference product for the omeprazole component of Yosprala.
`Compare the individual omeprazole degradant exposures between the two
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`products.
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`The timetable you submitted on August 30, 2016, states that you will conduct this study
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`according to the following schedule:
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`Final Protocol Submission: 11/2017
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`03/2018
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`Study Completion:
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`Final Report Submission:
`06/2018
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`Submit clinical protocols to your IND 78747 for this product. Submit nonclinical and chemistry,
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`manufacturing, and controls protocols and all postmarketing final reports to this NDA. In
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`addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status
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`summary of each commitment in your annual report to this NDA. The status summary should
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`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
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`study/trial. All submissions, including supplements, relating to these postmarketing
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`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
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`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.”
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
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`proposed materials in draft or mock-up form with annotated references, and the package insert,
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` Medication Guide, and patient PI (as applicable) to:
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`Reference ID: 3985760
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` NDA 205103
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` Page 4
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` OPDP Regulatory Project Manager
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` Food and Drug Administration
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` Center for Drug Evaluation and Research
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` Office of Prescription Drug Promotion
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` 5901-B Ammendale Road
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` Beltsville, MD 20705-1266
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`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
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` Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
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`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
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`2253. Form FDA 2253 is available at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, call CAPT Mimi T. Phan, Regulatory Project Manager, at (301) 796­
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`5408.
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`Sincerely,
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`{See appended electronic signature page}
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`Donna Griebel, M.D.
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`Director
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`Division of Gastroenterology and Inborn
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`Errors Products
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`Office of Drug Evaluation III
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`Center for Drug Evaluation and Research
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`Enclosure(s):
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`Content of Labeling
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`Carton and Container Labeling
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`Reference ID: 3985760
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`DONNA J GRIEBEL
`09/14/2016
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`Reference ID: 3985760
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