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`Trade Name:
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`Generic Name:
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`Sponsor:
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`Approval Date:
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`Indications:
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`Approval Package for:
`
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`APPLICATION NUMBER:
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`201655Orig1s000
`
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`OPANA, ER
`
`Oxymorphone Hydrochloride Extended-Release Tablets, CII
`
`Endo Pharmaceuticals, Inc.
`
`12/09/2011
`
`
`OPANA ER is an opioid agonist indicated for the relief of moderate to severe
`pain in patients requiring continuous around-the-clock opioid treatment for an
`extended period of time.
`Not intended for use as an as needed analgesic. Not indicated in the immediate
`post-operative period or if the pain is mild or not expected to persist for an
`extended period of time.
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`X
`Approval Letter
`X
`Other Action Letters
`X
`Labeling
`X
`REMS
`X
`Summary Review
`X
`Officer/Employee List
`
`Office Director Memo
`X
`Cross Discipline Team Leader Review
`X
`Medical Review(s)
`X
`Chemistry Review(s)
`Environmental Assessment X
`Pharmacology Review(s)
`X
`Statistical Review(s)
`X
`Microbiology Review(s)
`X
`Clinical Pharmacology/Biopharmaceutics Review(s)
`X
`Other Reviews
`X
`Risk Assessment and Risk Mitigation Review(s)
`X
`Proprietary Name Review(s)
`X
`Administrative/Correspondence Document(s)
`X
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
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`
`APPROVAL LETTER
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`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
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`NDA 201655
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`
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`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`
`Endo Pharmaceuticals Inc.
`100 Endo Boulevard
`Chadds Ford, PA 19317
`
`Attention: Tara Chapman, Pharm.D.
`
`Director, Regulatory Affairs
`
`
`
`Dear Dr. Chapman:
`
`Please refer to your New Drug Application (NDA) dated July 7, 2010, received July 7, 2010,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`OPANA ER (oxymorphone hydrochloride) Extended-Release Tablets, 5 mg, 7.5 mg, 10 mg, 15
`mg, 20 mg, 30 mg, and 40 mg.
`
`We also refer to our approval letter dated December 9, 2011, which contained the following
`error: The statement granting an expiration dating period of
` months was incorrect.
`
`This replacement approval letter incorporates the correction of the error. The effective approval
`date will remain December 9, 2011, the date of the original approval letter.
`
`We acknowledge receipt of your amendments dated July 23, August 27 and 30, September 9, 14,
`and 29, October 1, 6, 12, 13, and 27, November 4 and 12, and December, 6, 17, 27, 28, and 29,
`2010, and January 3, 6, and 14, February 22, June 13, July 8, September 7 and 30, October 6, and
`November 9, 16, 21, and 30, 2011.
`
`The June 13, 2011, submission constituted a complete response to our January 7, 2011, action
`letter.
`
`This new drug application provides for the use of OPANA ER (oxymorphone hydrochloride)
`Extended-Release Tablets for the management of moderate to severe chronic pain in adults when
`a continuous, around-the-clock opioid analgesic is needed for an extended period of time.
`
`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.
`
`
`
`
`Reference ID: 3071831
`
`(b)
`(4)
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`

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`NDA 201655
`Page 2
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`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`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 and Medication
`Guide). 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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`We acknowledge your November 9, 2011, submission containing final printed carton and
`container labels.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`On April 18, 2011, you were notified that in accordance with section 505-1 of the FDCA, we
`have determined that a risk evaluation and mitigation strategy (REMS) is necessary for certain
`long-acting and extended-release (LA/ER) opioid products, including OPANA ER
`(oxymorphone hydrochloride) Extended-Release Tablets, to ensure that the benefits of the drugs
`continue to outweigh the risks of adverse outcomes (addiction, unintentional overdose, and
`death) resulting from inappropriate prescribing, abuse, and misuse, and we notified you of the
`elements of the REMS that would be required. You were also notified that, in the interest of
`public health and to minimize the burden on the healthcare delivery system of having multiple
`unique REMS programs, a single, shared system should be used to implement the REMS for all
`members of the class.
`
`While the class-wide REMS, including the single shared system, is being developed, your
`proposed interim REMS, submitted on November 21, 2011, and appended to this letter, is
`approved. This interim REMS consists of a Medication Guide, elements to assure safe use, and a
`timetable for submission of assessments of the REMS. We believe this interim REMS provides
`for management of the risks of adverse outcomes (addiction, unintentional overdose, and death)
`that is comparable to the REMS that we have determined is necessary for the class of LA/ER
`opioid products and is designed to ensure that the benefits of OPANA ER (oxymorphone
`hydrochloride) Extended-Release Tablets continue to outweigh its risks while the single shared
`system, class-wide REMS is being developed.
`
`
`
`Reference ID: 3071831
`
`

`

`NDA 201655
`Page 3
`
`
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`We expect you to be working with the Industry Working Group (IWG) to develop the class-wide
`REMS. Prior to the implementation of the class-wide REMS, we will notify you in writing and
`you will be required to submit a proposed modified REMS that conforms to the class-wide
`REMS. The assessment plan requirements for this REMS were also described in the April 18,
`2011, letter, and in that letter, FDA strongly recommended that sponsors make provision in the
`single shared system for joint assessments of the effectiveness of the REMS.
`
`Your interim REMS must be fully operational before you introduce OPANA ER (oxymorphone
`hydrochloride) Extended-Release Tablets into interstate commerce.
`
`The interim REMS assessment plan should include, but is not limited to, the following:
`
`
`1. An evaluation of patients’ understanding of the serious risks of OPANA ER
`(oxymorphone hydrochloride) Extended-Release Tablets.
`
`
`2. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24.
`
`
`3. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance.
`
`4. An evaluation of healthcare providers’ understanding of the serious risks of OPANA
`ER (oxymorphone hydrochloride) Extended-Release Tablets
`
`
`5. An assessment of the extent to which the elements to assure safe use are meeting the
`goal or goals to mitigate a specific serious risk listed in the labeling of the drug, or
`whether the goal or goals or such elements should be modified.
`
`
`
`
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`6. Information on the status of any postapproval study or clinical trial required under
`section 505(o) or otherwise undertaken to investigate a safety issue. With respect to
`any such postapproval study, you must include the status of such study, including
`whether any difficulties completing the study have been encountered. With respect to
`any such postapproval clinical trial, you must include the status of such clinical trial,
`including whether enrollment has begun, the number of participants enrolled, the
`expected completion date, whether any difficulties completing the clinical trial have
`been encountered, and registration information with respect to requirements under
`subsections (i) and (j) of section 402 of the Public Health Service Act. You can
`satisfy these requirements in your REMS assessments by referring to relevant
`information included in the most recent annual report required under section 506B
`and 21 CFR 314.81(b)(2)(vii) and including any material or significant updates to the
`status information since the annual report was prepared. Failure to comply with the
`REMS assessments provisions in section 505-1(g) could result in enforcement action.
`
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval
`
`
`
`Reference ID: 3071831
`
`

`

`NDA 201655
`Page 4
`
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`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
`
`We also remind you that, in addition to the assessments submitted according to the timetable
`included in the approved REMS, you must submit a REMS assessment and may propose a
`modification to the approved REMS when you submit a supplemental application for a new
`indication for use as described in section 505-1(g)(2)(A) of the FDCA.
`
`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.
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`NDA 201655 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 201655
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 201655
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`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, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`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. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`information about submission of promotional materials to the Division of Drug Marketing,
`
`
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`Reference ID: 3071831
`
`

`

`NDA 201655
`Page 5
`
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`Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`EXPIRATION DATING PERIOD
`
`An expiration dating period of 36 months is granted for OPANA ER (oxymorphone
`hydrochloride) Extended-Release Tablets, stored at 25° C (77° F) with excursions permitted
`from 15° to 30°C (59°-86°F).
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`In addition to the standard reporting requirements for an approved NDA, we request that you
`submit as 15-day expedited reports, all post-marketing and clinical trial cases of choking,
`gagging, sticking, and gastrointestinal obstruction, regardless of whether these reports are
`classified as serious or unexpected, and that you provide analyses of clinical trial and post-
`marketing reports of these adverse events of special interest in your periodic safety update
`reports.
`
`If you have any questions, call Lisa Basham, M.S., Senior Regulatory Health Project Manager, at
`(301) 796-1175.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia, Analgesia,
` and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`REMS
`
`
`
`
`
`Reference ID: 3071831
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`12/09/2011
`
`Reference ID: 3071831
`
`