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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 201655/S-002
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`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 Supplemental New Drug Application (sNDA) dated February 7, 2012,
`received February 7, 2012, 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 March 30 and June 14 and 18, 2012, and
`your risk evaluation and mitigation strategy (REMS) assessment dated June 8, 2012.
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`This supplemental new drug application proposes modifications to the approved REMS for
`OPANA ER (oxymorphone hydrochloride) Extended-Release tablets.
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`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.
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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
`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, Instructions for Use), 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.
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`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.
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`Reference ID: 3154914
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` NDA 201655/S-002
`Page 2
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications 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).
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`
`We acknowledge your March 30, 2012, submission containing final printed carton and container
`labels.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`You have been 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, 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. The REMS for OPANA
`ER was originally approved on December 9, 2011. The REMS consists of a Medication Guide,
`elements to assure safe use, and a timetable for submission of assessments of the REMS.
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`On April 18, 2011, 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 of ER/LA
`opioids. Your proposed modifications to the REMS consist of changes to conform to the single
`shared REMS system developed for the ER/LA opioids indicated for treatment of pain.
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`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
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
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`result in enforcement action.
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`Your proposed REMS is appended to this letter and approved.
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`This REMS will use a single, shared system for the elements to assure safe use and the REMS
`assessments. This single, shared system, known as the ER/LA Opioid REMS, currently includes
`the products listed in Appendix 1. Other products may be added in the future if additional NDAs
`or ANDAs are approved.
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
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`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.
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`Reference ID: 3154914
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` NDA 201655/S-002
`Page 3
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` Scheduled REMS Assessments
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`1. The first REMS assessment, due not later than six months from the date of REMS approval,
`should provide a report on the actions you have taken to implement the REMS since it was
`approved. The report should include the following information:
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`a. Grant Proposals: The status of the requests for proposals for grants for CE training
`including: 1) how many have issued and when will the next requests for proposals
`issue; 2) the number of proposals submitted in response to each request; 3) the
`number of grants awarded; 4) a list of the grantees; 5) the date when each of the
`grantees will make their CE training available; 6) a high-level description of each
`program (e.g., web based, live); and 7) an estimate of how many prescribers are
`expected to be trained under each program.
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`b. Evaluation Grants: The status of the requests for proposals for special grants to CE
`providers or other CE organizations with expertise in assessing CE outcomes who
`agree to conduct long-term evaluation of prescribers of ER/LA opioids who have
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`taken training funded under this REMS to determine these prescribers’ knowledge
`retention and practice changes 6 months to 1 year after they completed the REMS-
`compliant training including: 1) the number of proposals submitted in response to
`each request, 2) the number of grants awarded, 3) a list of the grantees, 4) the date
`when each of the grantees will conduct their REMS-compliant training, and 5) the
`dates of their follow-up evaluation.
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`c. Functional Components:
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`i. Date when the ER/LA Opioid REMS website was live and functional.
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`ii. Prescriber Letter 1: 1) Date when letter was posted on the ER/LA Opioid
`REMS website 2) number of prescriber letters electronically sent, received,
`undeliverable, and opened, and 3) number of prescriber letters mailed and
`undeliverable.
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`iii. Professional Organization/Licensing Board Letter 1: 1) Date when the letter
`was posted on the ER/LA Opioid REMS website, 2) number of letters
`electronically sent, received, undeliverable, and opened, and 3) number of
`letters mailed and undeliverable.
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`iv. Date when the single number toll free call center was operational.
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`2. The second REMS assessment, due one year from the date of this letter, should include the
`following information:
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`a. Functional Components:
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`i. Training: 1) Date the first REMS-compliant training was available; 2) a high-
`level description of the training (e.g., web based, live); 3) the number of
`prescribers that have undergone the training, and 4) an estimate of how many
`prescribers will be trained under the program(s).
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`ii. Prescriber Letter 2: 1) Date when letter was posted on the ER/LA Opioid
`REMS website, 2) number of prescriber letters electronically sent, received,
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`Reference ID: 3154914
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`undeliverable, and opened, and 3) number of prescriber letters mailed and
`undeliverable.
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`iii. Professional Organization/Licensing Board Letter 2: 1) Date when the letter
`was posted on the ER/LA Opioid REMS website, 2) number of letters
`electronically sent, received, undeliverable, and opened, and 3) number of
`letters mailed and undeliverable.
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`b. Grant Proposals: An update on the status of the requests for proposals for grants for
`REMS-compliant training, including: 1) new grant requests for proposals published;
`2) the number of proposals submitted in response to each request; 3) the number of
`grants awarded; 4) a list of the grantees; 5) the date when each grantee will make or
`has made their REMS-compliant training available; 6) a high-level description of
`each program (e.g., web based, live), and 7) an estimate of how many prescribers will
`be trained under each program.
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`c. Evaluation Grants: The status of the requests for proposals for special grants to CE
`providers who also agree to conduct long-term evaluation of prescribers of ER/LA
`opioids who have taken their ER/LA Opioid REMS-funded training to determine
`these prescribers’ knowledge retention and practice changes 6 months to 1 year after
`they completed the REMS-compliant training including: 1) the number of proposals
`submitted in response to each request, 2) the number of grants awarded, 3) a list of
`the grantees, 4) the date when each of the grantees will conduct their REMS-
`compliant training, and 5) the dates of their follow-up evaluation.
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`3. The third REMS assessment, due two years from the date of this letter, should include the
`following information:
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`a. Prescriber Letter 3: 1) Date when letter was posted on the ER/LA Opioid REMS
`website, 2) number of prescriber letters electronically sent, received, undeliverable,
`and opened, and 3) number of prescriber letters mailed and undeliverable.
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`b. Prescriber Training: The number of prescribers of ER/LA opioids who have
`completed REMS-compliant training. Performance goals, based on the 2011 estimate
`that 320,000 prescribers are active prescribers of ER/LA opioids (prescribers who
`have prescribed an ER/LA opioid within the last 12 months), are as follows:
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`i. Within two years from the time the first REMS-compliant training becomes
`available, 80,000 prescribers (based on 25% of active prescribers) are to have
`been trained;
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`ii. Within three years from the time the first REMS-compliant training becomes
`available, 160,000 prescribers (based on 50% of active prescribers) are to
`have been trained;
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`iii. Within four years from the time the first REMS- compliant training becomes
`available, 192,000 prescribers (based on 60% of active prescribers) are to
`have been trained.
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`Reference ID: 3154914
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`c. Independent Audit: The results of an independent audit of the quality of the content of
`the educational materials used by providers to provide the REMS-compliant training.
`Audits must be conducted on a random sample of 1) at least 10% of the training
`funded under the ER/LA Opioid REMS, and 2) REMS-compliant training not funded
`under the ER/LA Opioid REMS that will be counted as REMS–compliant training for
`purposes of meeting the milestones in 3a., and must evaluate:
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`i. whether the content of the training covers all elements of the FDA “blueprint”
`approved as part of the REMS;
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`ii. whether the post-course knowledge assessment measures knowledge of all
`sections of the FDA “blueprint”; and
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`iii. whether the training was conducted in accordance with the Accreditation
`Council for Continuing Medication Education (ACCME) standards for CE or
`appropriate standards for accreditation bodies.
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`d. Evaluation of Patient Understanding: The results of an evaluation of patients’
`understanding of the serious risks of these products and their understanding of how to
`use these products safely. This evaluation may include, for example, surveys of
`patients.
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`e. Surveillance Results: Results of surveillance for misuse, abuse, overdose, addiction,
`and death. Surveillance needs to include information on changes in abuse, misuse,
`overdose, addiction, and death for different risk groups (e.g., teens, chronic abusers)
`and different settings (e.g., emergency departments, addiction treatment centers,
`poison control call centers). The information should be drug-specific whenever
`possible.
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`f. Drug Utilization Patterns: An evaluation of drug utilization patterns, including: an
`evaluation of prescribing behaviors of the prescribers of ER/LA opioids, e.g.,
`prescriptions to non-opioid tolerant patients, excessive prescriptions for early refills;
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`g. Patient Access: An evaluation of changes in patients access to ER/LA Opioids.
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`h. Methodologies: A description of the data sources and the methodologies used to
`conduct all of the above described analyses.
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`i. Goals: 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
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`drug, or whether the goal or goals or such elements should be modified.
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`4. The fourth and subsequent REMS assessments should include the following information:
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`a. Prescriber Letter 3: 1) number of prescriber letters electronically sent, received,
`undeliverable, and opened, and 2) number of prescriber letters mailed and
`undeliverable.
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`Reference ID: 3154914
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`b. Prescriber Training: The number of prescribers of ER/LA opioids who have
`completed REMS-compliant training (see 3.a above).
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`c. Independent Audit: The results of an independent audit of the quality of the content
`of the educational materials used by the CE providers to provide the REMS-
`compliant training (see 3.b above).
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`d. Evaluation of Prescriber Understanding:
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`i. The results of an evaluation of ER/LA opioid prescribers’ awareness and
`understanding of the serious risks associated with these products and their
`awareness of appropriate prescribing practices for ER/LA opioids, comparing
`the awareness and understanding of prescribers who have taken the REMS-
`compliant training with those who have not taken such training. This
`evaluation may include, for example, surveys of healthcare providers.
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`ii. The results of any long-term evaluation of prescribers of ER/LA opioids who
`have taken ER/LA Opioid REMS-funded training to determine these
`prescribers’ knowledge retention and practice changes 6 months to 1 year
`after they completed the REMS-compliant training.
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`e. Evaluation of Patient Understanding: The results of an evaluation of patients’
`understanding of the serious risks of these products and their understanding of how to
`use these products safely. (See 3.c above).
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`f. Surveillance Results: Results of surveillance and monitoring for misuse, abuse,
`overdose, addiction, and death (see 3.d above).
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`g. Drug Utilization Patterns: An evaluation of drug utilization patterns (see 3.e above).
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`h. Patient Access: An evaluation of changes in patient access to ER/LA opioids.
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`i. Methodologies: A description of the data sources and the methodologies used to
`conduct all of the above described analyses.
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`j. Goals: 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
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`drug, or whether the goal or goals or such elements should be modified.
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`Definitions: For purposes of these REMS assessments, the following definitions apply:
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`1. REMS-compliant training: Training will be considered “REMS-compliant training” if 1)
`it, for training provided by CE providers, is offered by an accredited provider to licensed
`prescribers, 2) it includes all elements of the FDA “blueprint”, 3) it includes a post-course
`knowledge assessment of all of the sections of the “FDA blueprint”, and 4) it is subject to
`independent audit to confirm that conditions of the REMS training have been met.
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`Reference ID: 3154914
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` NDA 201655/S-002
`Page 7
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`2. FDA Blueprint: A document entitled, “Blueprint for Prescriber Continuing Education
`Programs Extended-Release and Long-Acting Opioids,” approved as part of this REMS,
`that contains core messages to be conveyed to prescribers in the training about the risks
`and appropriate prescribing practices for the safe use of ER/LA opioids.
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`Other REMS Assessment Requirements
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`All assessments of an approved REMS must also include, under section 505-1(g)(3)(B) and (C),
`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. Submit this information, if applicable, to your individual application. Failure to
`comply with the REMS assessments provisions in section 505-1(g) could result in enforcement
`action.
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`Under section 505-1(g)(2)(C) and (D), FDA may require the submission of a REMS assessment
`if FDA determines that new safety or effectiveness information indicates that a REMS element
`should be modified or included in the strategy.
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`We 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.
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`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:
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`NDA 201655 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`METHODOLOGY)
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`Reference ID: 3154914
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`

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` NDA 201655/S-002
`Page 8
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`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 of the REMS with the following wording in bold capital letters at the top of the
`first page of the submission as appropriate:
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`NDA 201655 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 201655
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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` NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 201655
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`REPORTING REQUIREMENTS
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`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}
`
`
`Bob A. Rappaport, M.D.
`
`Division Director
`Division of Anesthesia, Analgesia,
`and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
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`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`REMS
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`Reference ID: 3154914
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` NDA 201655/S-002
`Page 9
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`Appendix 1 List of applications
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`NDA 021260
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`NDA 021306
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`AVINZA (morphine sulfate) extended-release capsules
`BUTRANS (buprenorphine) Transdermal System for transdermal
`administration
`DOLOPHINE (methadone hydrochloride) tablets and its generic
`equivalents
`Methadone Oral Solution and its generic equivalents
`Methadone Oral Solution and its generic equivalents
`Methadone Oral Concentrate
`DURAGESIC (Fentanyl Transdermal System) for transdermal
`administration and its generic equivalents
`EMBEDA (morphine sulfate and naltrexone hydrochloride) extended-
`release capsules
`EXALGO (hydromorphone HCl) Extended-Release Tablets
`KADIAN (morphine sulfate) extended-release capsules and its generic
`equivalent
`MS CONTIN (morphine sulfate) controlled-release tablets and its generic
`equivalents
`NUCYNTA ER (tapentadol) extended-release oral tablets
`NDA 200533
`
`OPANA ER (oxymorphone hydrochloride) Extended-Release tablets
` NDA 201655
`
`OPANA ER (oxymorphone hydrochloride) Extended-Release tablets and
`NDA 021610
`its generic equivalents
`OXYCONTIN (oxycodone hydrochloride controlled-release) Tablets
`OXYCONTIN (oxycodone hydrochloride controlled-release) Tablets
`
`NDA 006134
`
`ANDA 087997
`ANDA 087393
`ANDA 089897
`NDA 019813
`
`NDA 022321
`
`NDA 021217
`NDA 020616
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`NDA 019516
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`NDA 020553
`NDA 022272
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`Reference ID: 3154914
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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/
`----------------------------------------------------
`
`JUDITH A RACOOSIN on behalf of BOB A RAPPAPORT
`07/09/2012
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`Reference ID: 3154914
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`