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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 201655/S-012
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`
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`Endo Pharmaceuticals, Inc.
`1400 Atwater Drive
`Malvern, PA 19355
`
`Attention:
`
`Tara Chapman, PharmD
`
`Director, Regulatory Affairs
`
`
`
`
`
`
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`Food and Drug Administration
`
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
`REMS MODIFICATION NOTIFICATION
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`
`
`Dear Dr. Chapman:
`
`
`Please refer to your October 9, 2013, Supplemental New Drug Application (sNDA) submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for OPANA ER
`(oxymorphone hydrochloride) Extended-Release Tablets.
`
`We acknowledge receipt of your amendments dated October 23 and 29, 2013, and March 17,
`2014.
`
`We also refer to our letter dated September 10, 2013, notifying you, under Section 505(o)(4) of
`the FDCA, of new safety information that we believe should be included in the labeling for the
`class of extended-release and long-acting (ER/LA) opioid analgesics, of which OPANA ER is a
`member. This information pertains to the risks of misuse, abuse, hyperalgesia, addiction,
`overdose, death, and neonatal opioid withdrawal syndrome.
`
`
`This supplemental new drug application provides for revisions to the labeling consistent with our
`
`September 10, 2013, letter.
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`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
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`Reference ID: 3490234
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`

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`NDA 201655/S-012
`Page 2
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`of labeling must be identical to the enclosed labeling (text for the package insert, 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 draft guidance for industry,
`SPL Standard for Content of Labeling Technical Qs and As, available 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 includes 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.
`
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`RISK EVALUATION AND MITIGATION STRATEGIES (REMS)
`
`
`The REMS for the ER/LA opioid analgesics was originally approved on July 9, 2012, and the
`most recent REMS modification was approved on April 15, 2013. The REMS consists of a
`Medication Guide, elements to assure safe use, an implementation system, and a timetable for
`submission of assessments of the REMS.
`
`In accordance with section 505-1(g)(4)(B) of the FDCA, we have determined that the approved
`REMS for the ER/LA opioid analgesics must be modified to conform the REMS to the safety
`labeling changes for the ER/LA opioid analgesics class that are approved in this letter, to ensure
`that the benefits of the drugs outweigh their risks. Your proposed REMS modification
`submission must include the following changes to the REMS appended materials:
`
`
`Revisions to the ER/LA Opioid Analgesics REMS Blueprint, ER/LA opioid analgesic
`REMS Website, and the Dear Prescriber Letter (DHCP) letter to incorporate the
`following safety labeling changes:
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` New indication for ER/LA opioid analgesics.
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` New warning for Neonatal Opioid Withdraw Syndrome (NOWS).
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` Updated language for the following Warnings and Precautions:
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` Addiction, Abuse, and Misuse
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` Life-Threatening Respiratory Depression
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` Accidental Ingestion
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` Cytochrome P450 3A4 Interaction (for applicable products)
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` Revisions to the Blueprint to incorporate updated product-specific titration
`language.
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`Reference ID: 3490234
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`

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`NDA 201655/S-012
`Page 3
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`The timetable for submission of assessments of the proposed modified REMS may remain the
`same as that approved on July 9, 2012.
`
`The proposed REMS modification submission should include a new proposed REMS that shows
`the complete previously approved REMS with all proposed modifications highlighted and the
`revised REMS materials as described above. Shortly following this letter, FDA will provide the
`ER/LA Opioid Analgesics REMS Program Companies with FDA’s recommended changes to the
`REMS.
`
`
`In addition, the submission should include an update to the REMS supporting document that
`includes the rationale for and description of all proposed modifications and any impact the
`proposed modifications would have on other REMS elements. Revisions to the REMS
`supporting document should be submitted with all changes marked and highlighted.
`
`Because we have determined that a modified REMS with the changes described above is
`necessary to ensure the benefits of ER/LA opioid analgesics outweigh their risks, you must
`submit a proposed REMS modification within 60 days of the date of this letter, as a Prior
`Approval supplement 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:
`
`
`NEW SUPPLEMENT FOR NDA 201655
`PROPOSED REMS MODIFICATION
`
`
`Prominently identify subsequent submissions related to the proposed REMS modification with
`the following wording in bold capital letters at the top of the first page of the submission:
`
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`NDA 201655/S-XX
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`PROPOSED REMS MODIFICATION-AMENDMENT
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`If you do not submit electronically, please send 5 copies of your submission.
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`PROMOTIONAL MATERIALS
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`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:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`Reference ID: 3490234
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`

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`NDA 201655/S-012
`Page 4
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` You must submit final promotional materials and package insert(s), accompanied by a Form
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` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`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.
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`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.
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`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Lisa Basham, Senior Regulatory Health Project Manager, at (301)
`796-1175.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Judith A. Racoosin, MD, MPH
`Deputy Director for Safety
`Division of Anesthesia, Analgesia,
`and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
`Content of Labeling
`
`
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`Reference ID: 3490234
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`

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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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`SHARON H HERTZ on behalf of JUDITH A RACOOSIN
`04/16/2014
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`Reference ID: 3490234
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`