`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 022272/S-027
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring, MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`
`
`
`Beth Connelly
`
`Associate Director, Regulatory Affairs
`
` Purdue Pharma L.P.
`
`
` One Stamford Forum
`
`Stamford, CT 06901-3431
`
`Attention:
`
`
`
`
`Dear Ms. Connelly:
`
`
`Please refer to your supplemental New Drug Application (sNDA) dated December 8, 2014,
`
`received December 10, 2014, submitted under section 505(b) of the Federal Food, Drug, and
`
`Cosmetic Act (FDCA), for OXYCONTIN (oxycodone hydrochloride) extended-release tablets.
`
`
`
`
`
`We acknowledge receipt of your amendments dated April 3; May 11, 14, and 18; June 2, 3, 8,
`
`
`and 25; and July 13, 15 and 31, 2015.
`
`
`
`
`
`
`This Prior Approval supplemental application proposes revisions to the Package Insert to include
`language for the use in the pediatric population and provides for updates to the approved risk
`
`evaluation and mitigation strategy (REMS) for OXYCONTIN.
`
`
`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.
`
`
`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 patient 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.
`
`
`
`Reference ID: 3805894
`
`

`

`
`
` NDA 022272/S-027
`
` Page 2
`
`
`
`
` 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 from publicly available labeling repositories.
`
`
`
`
` Also within 14 days, amend all pending supplemental applications that include labeling changes
`
` 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).
`
`
` We request that the labeling approved today be available on your website within 10 days of
`
` receipt of this letter.
`
`
`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 REQUIREMENTS UNDER 505(o)
`
`
`
`
`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (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.
`
`
`
`
`Since OXYCONTIN was approved on April 5, 2010, we have become aware of clinical trial
`
`
`results in opioid-tolerant pediatric patients primarily aged 11-17. During the trial, there were two
`
`
`
`
`
`patients (an 11 year old female and a 15 year old female) with treatment-emergent clinically
`significant oxygen desaturations. Additionally, there were four patients in the total population
`
`
`
`(two each in the 6-11 age group and 12-17 age group) that experienced the treatment-emergent
`
`
`
`adverse event of “oxygen saturation decreased.” We have also become aware of a study in the
`published literature describing the frequency of unintentional overdose with opioids in children
`
`
`
`covered by Tennessee Medicaid. In this study, designed to develop coding algorithms to identify
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3805894
`
`

`

`
`
` NDA 022272/S-027
`
`
` Page 3
`
`
`
`
` serious opioid-related adverse events in pediatric patients, 25 of the 31 cases identified by the
` algorithm for unintentional overdose were confirmed by medical records ((positive predictive
`
`
`
`value of 81%).1 We have also become aware of reports of adverse events, accidental injury,
`
`
`
`
`accidental exposure, and medication errors, which are of particular concern for the pediatric
`population.2 We consider this information to be “new safety information” as defined in section
`
`
`
`
`505-1(b)(3) of the FDCA.
`
`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 risks
`of respiratory depression, accidental injury, overdose, misuse, accidental exposure, and
`
`
`medication errors in pediatric patients aged 17 years and younger.
`
`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 these serious risks.
`
`
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`
`
`conduct the following to assess these serious risks:
`
`
`
`2923 – 1
`
`
`
`To assess the serious risks of respiratory depression, accidental injury, overdose,
`
`
`misuse, accidental exposure, and medication errors associated with the use of
`OxyContin in opioid-tolerant pediatric patients aged 11-17, and to assess the
`
`serious risks of respiratory depression, accidental injury, overdose, misuse,
`
`
`
`
`
`accidental exposure, and medication errors associated with the use of the product
`
`
`
`in children who are either younger than the approved age range or who do not
`
`
`
`meet the labeled criteria for opioid tolerance, provide reports of all postmarket
`
`
`
`adverse events occurring in children aged 17 and younger related to respiratory
`
`depression, accidental injury, overdose, misuse, accidental exposure, and all
`
`
`medication errors, regardless of outcome. After three years of submitting reports,
`
`submit a comprehensive analysis of these adverse event and medication errors
`
`
`reports, and provide an explanation of how you have addressed them.
`
`
`
`
`
`The timetable you submitted on July 13, 2015, states that you will conduct this
`
`reporting according to the following schedule:
`
`
`
`Final Protocol Submission: 08/2015
`
`
`Interim Report Submission: 12/2015
`
`
`Interim Report Submission: 12/2016
`
`Interim Report Submission: 12/2017
`
`
`Interim Report Submission: 12/2018
`
`
`Final Report Submission: 04/2019
`
`
`
`
`
`
`
` 1 Chung CP, Callahan ST, Cooper WO, et al. Development of an algorithm to identify serious opioid toxicity in
`
`
` children. BMC Research Notes 2015; 8: 293.
`
`
`
`2 NDA 22272, Periodic Safety Update Report, June 9, 2015.
`
`
`
`
`
`
`
`
`Reference ID: 3805894
`
`

`

`
`
` NDA 022272/S-027
`
` Page 4
`
`
` 2923 - 2
`
`
`
`
`
`
`
`
`
`
` Conduct a nationally representative drug utilization study of sufficient detail to
` characterize use of OxyContin in children aged 17 years and younger. The data
`
`
` from this study will provide a denominator for the risks assessed in PMR #2923­
`
` 1and any future safety studies and clinical trials used to assess those risks. The
`
`
` following analyses should be conducted with the data collected:
`
`
`
`
`
`1) Total number of prescriptions dispensed across all settings of care
`
`a. stratify by age group (0-1, 2-5, 6-10, 11-17), indication, setting of care,
`
`
`and prescriber specialty, and geographic location
`
`b. provide characteristics of dose dispensed (mean, median, range)
`
`
`
`
`2) Total number of unique patients receiving dispensed prescriptions across all
`
`
`
`settings of care
`
`a. stratify by age group (0-1, 2-5, 6-10, 11-17), indication, setting of care,
`
`
`and prescriber specialty
`
`
`i. provide unique incident users every quarter-year
`
`b. patient demographics of users of the product
`
`
`c. clinical characteristics of users of the product (including what
`
`
`
`percentage of patients are opioid tolerant at the time they get the
`
`
`OxyContin prescription)
`
`
`
`3) Duration of therapy (include definitions of allowable gaps in drug therapy in
`
`calculating duration of therapy)
`
`a. total and stratified by indication
`
`b. exploration of possible ‘intermittent’ use
`
`c. percentage of patients switching from immediate-release opioids to
`
`
`OxyContin
`
`d. percentage of patients switching from other extended-release opioids to
`OxyContin
`
`e. dose adjustments over time
`
`
`
`
`The timetable you submitted on July 13, 2015, states that you will conduct this study according
`
`
`
`
`
`
`to the following schedule:
`
`
`
`Final Protocol Submission: 10/2015
`
`
`
`Interim Report Submission: 01/2016
`
`
`
`Interim Report Submission: 12/2016
`
`
`
`Interim Report Submission: 12/2017
`
`
`
`12/2018
`
`Final Report Submission:
`
`
`
`
`
`
`
`
`Reference ID: 3805894
`
`

`

`
`
`
`
` NDA 022272/S-027
`
` Page 5
`
`
` RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`
`
`
`The REMS for extended release and long-acting (ER/LA) opioid analgesic products, of which
`
`
`OXYCONTIN is a member, was originally approved on July 9, 2012, and the most recent REMS
`
`modification was approved on June 26, 2015. The REMS consists of a Medication Guide,
`
`elements to assure safe use, and a timetable for submission of assessments of the REMS.
`
`
`
`
`In order to ensure the benefits of OXYCONTIN outweigh its risks, we determined that you were
`
`required to make the following REMS modifications:
`
`
`Changes to the ER/LA Opioid Analgesics REMS Blueprint to include the
`
`
`
`
`
`following information:
`
`
`
`Incorporation of information regarding use of
`
`
`
`
`•
`OXYCONTIN in the pediatric population
`
`
`
`• Addition of information to the titration recommendations
`
`
`
`
`
`for adult patients
`
`
`
`
`
`
`Your proposed modified REMS, submitted on July 31, 2015, and appended to this letter, is
`
`approved.
`
`
`
`
`There are no changes to the REMS assessment plan described in our June 26, 2015, letter.
`
`
`
`This REMS uses a shared system for the elements to assure safe use and the REMS assessments.
`
`
`This shared system, known as the ER/LA Opioid Analgesics REMS Program, currently includes
`
`
`the products listed on the FDA REMS website, available at http://www.fda.gov/rems. Other
`products may be added in the future if additional NDAs or ANDAs are approved.
`
`
`
`
`We remind you that in addition to the REMS assessments submitted according to the timetable in
`
`
`the approved REMS, you must include an adequate rationale to support a proposed REMS
`
`modification for the addition, modification, or removal of any of goal or element of the REMS,
`
`
`
`as described in section 505-1(g)(4) of the FDCA.
`
`
`
`We also remind you that you must submit a REMS assessment when you submit a supplemental
`
`
`application for a new indication for use as described in section 505-1(g)(2)(A) of the FDCA.
`
`
`This assessment should include:
`
`
`
`
`a) An evaluation of how the benefit-risk profile will or will not change with the new
`
`
`
`indication;
`
`b) A determination of the implications of a change in the benefit-risk profile for the current
`
`
`
`
`REMS;
`
`c) If the new, proposed indication for use introduces unexpected risks: A description of
`
`
`those risks and an evaluation of whether those risks can be appropriately managed with
`the currently approved REMS.
`
`
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`
`
`supplemental application for a new indication for use: A statement about whether the
`
`
`
`Reference ID: 3805894
`
`

`

`
`
` NDA 022272/S-027
`
` Page 6
`
`
`
`
`
`
`
`
`
` REMS was meeting its goals at the time of that the last assessment and if any
`
`
`
` modifications of the REMS have been proposed since that assessment.
`
` e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
`
`
`
` supplemental application for a new indication for use: Provision of as many of the
`
` currently listed assessment plan items as is feasible.
`
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
`
`
` because of the new indication of use, submit an adequate rational to support the
`
` modification, including: Provision of the reason(s) why the proposed REMS
`
` modification is necessary, the potential effect on the serious risk(s) for which the REMS
`
`
`
` was required, on patient access to the drug, and/or on the burden on the health care
`delivery system; and other appropriate evidence or data to support the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
`proposed modified REMS. If you are not proposing a REMS modification, provide a
`
`rationale for why the REMS does not need to be modified.
`
`
`
`
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`
`
`the REMS supporting document, or if you propose changes to the submitted assessment
`
`
`instruments or methodology, you should update the REMS supporting document to include
`
`specific assessment instrument and methodology information at least 90 days before the
`
`
`
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`
`new document that references previous REMS supporting document submission(s) for
`
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`
`submission containing the assessment instruments and methodology with the following wording
`
`
`in bold capital letters at the top of the first page of the submission:
`
`
`
`NDA 022272 REMS CORRESPONDENCE
`
`insert concise description of content in bold capital letters, e.g.,
`
`
`
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`
`
`METHODOLOGY
`
`
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`
`contact us to discuss what will be required in the authorized generic drug REMS submission.
`
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`
`
`application from using any element to assure safe use to block or delay approval of an
`
`
`application under section 505(b)(2) or (j) or to prevent application of such element under 505­
`1(i)(1)(B) to a drug that is subject of an ANDA. A violation of this provision in 505-1(f) could
`result in enforcement action.
`
`
`Prominently identify any submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of the
`
`first page of the submission as appropriate:
`
`
`
`
`
`Reference ID: 3805894
`
`

`

`
`
` NDA 022272/S-027
`
` Page 7
`
`
`
`
`
` NDA 022272 REMS ASSESSMENT
`
`
`NEW SUPPLEMENT FOR NDA 022272/S-000
`
`
`CHANGES BEING EFFECTED IN 30 DAYS
`
`
`PROPOSED MINOR REMS MODIFICATION
`
`
`
`
`or
`
`
`
`NEW SUPPLEMENT FOR NDA 022272/S-000
`
`
`PRIOR APPROVAL SUPPLEMENT
`
`
`PROPOSED MAJOR REMS MODIFICATION
`
`
`
`or
`
`
`
`NEW SUPPLEMENT FOR NDA 022272/S-000
`
`PRIOR APPROVAL SUPPLEMENT
`
`
`
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`
`SUBMITTED IN SUPPLEMENT XXX
`
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`
`FOR NDA 022272/S-000
`
`
`REMS ASSESSMENT
`
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`REMS REVISION FOR NDA 022272
`
`
`
`Should you choose to submit a REMS revision, prominently identify the submission containing
`
`the REMS revisions with the following wording in bold capital letters at the top of the first page
`
`of the submission:
`
`
`
`
`
`
`To facilitate review of your submission, we request that you submit your proposed modified
`
`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
`
`
`as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
`
`
`
`is to include as many as possible in Word format.
`
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`
`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:
`
`
`
`
`Reference ID: 3805894
`
`

`

`
`
` NDA 022272/S-027
`
` Page 8
`
`
`
` Food and Drug Administration
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion (OPDP)
`
` 5901-B Ammendale Road
` Beltsville, MD 20705-1266
`
`
`
`
`
`
`
`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 or by fax to 301-847-8444.
`
`
`
`
`
`
`
`
`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 Diana L. Walker, PhD, Senior Regulatory Health Project
`
`
`
`
`
`Manager, at (301) 796-4029.
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Sharon Hertz, MD
`
`Director
`
`Division of Anesthesia, Analgesia,
`and Addiction Products
`
`
`Office of Drug Evaluation II
`
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`ENCLOSURES:
`
`Content of Labeling
`
`
`REMS
`
`
`Reference ID: 3805894
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON H HERTZ
`08/13/2015
`
`Reference ID: 3805894
`
`