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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 200533
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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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`Janssen Pharmaceuticals, Inc.
`c/o Johnson & Johnson Pharmaceutical
` Research & Development, L.L.C.
`1125 Trenton-Harbourton Road, P.O. Box 200
`Titusville, NJ 08560-0200
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`Attention: Kathleen F. Dusek, R.Ph., RAC
`Associate Director, Regulatory Affairs
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`Dear Ms. Dusek:
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`Please refer to your New Drug Application (NDA) dated November 30, 2009, received
`December 1, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Nucynta ER (tapentadol) extended-release oral tablets 50, 100, 150, 200, and 250
`mg.
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`We acknowledge receipt of your amendments dated December 11, 2009, and March 11, 12, 25,
`and 30, April 2, 21, 26(2), and 30, May 13 and 21, June 4 and 21, July 23, and August 5 and 19,
`2010, and February 28, March 18 and 21, April 28, May 16 and 25, June 15, 20, and 24, July 18,
`20, 26, and 29, and August 2, 12, 16, and 23(3), 2011.
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`The February 28, 2011, submission constituted a complete response to our October 1, 2010,
`action letter.
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`This new drug application provides for the use of Nucynta ER (tapentadol) extended-release oral
`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.
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`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.
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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.
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`Reference ID: 3006589
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`

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`NDA 200533
`Page 2
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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
`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
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`industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`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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`We acknowledge your August 16, 2011, submission containing final printed carton and container
`labels.
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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
`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.
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`We are waiving the pediatric study requirement for ages less than 7 years, as the product does
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`not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in this
`age group and is not likely to be used in a substantial number of pediatric patients in this group.
`The very low medical need based upon the very low prevalence of chronic pain conditions in this
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`age category together with the immaturity of the metabolic functions in very young children that
`may result in unpredictably higher exposures than in other age groups, support the justification
`that Nucynta ER (tapentadol) extended-release oral tablets does not provide a meaningful
`therapeutic benefit over existing therapies for very young children.
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`We are deferring submission of your pediatric study for ages 7 to less than 17 years for this
`application because this product is ready for approval for use in adults and the pediatric study has
`not been completed.
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`Your deferred pediatric study required by section 505B(a) of the FDCA is a required
`postmarketing study. The status of this postmarketing study must be reported annually according
`to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. This required study is listed below.
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`Reference ID: 3006589
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`

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`NDA 200533
`Page 3
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`1815-1 Deferred pediatric study under PREA: A pharmacokinetic, efficacy, and safety
`study of Nucynta ER for the management of chronic pain in pediatric patients
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`ages 7 to <17 years.
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`Final Protocol Submission: May 2014
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`Trial Completion:
`October 2017
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`Final Report Submission: March 2018
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`Reports of this required pediatric postmarketing study must be submitted as a new drug
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`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`changes you believe are warranted based on the data derived from these studies. When
`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter
`of the submission.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`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 Nucynta ER (tapentadol)
`extended-release oral 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.
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`While the class-wide REMS, including the single shared system, is being developed, your
`proposed interim REMS, submitted on August 23, 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 Nucynta ER (tapentadol) extended-release
`oral tablets continue to outweigh its risks while the single shared system, class-wide REMS is
`being developed.
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`We expect you to be working with the Industry Working Group (IWG) to develop the class-wide
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`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.
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`Reference ID: 3006589
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`

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`NDA 200533
`Page 4
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`Your interim REMS must be fully operational before you introduce Nucynta ER (tapentadol)
`extended-release oral tablets into interstate commerce.
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`The interim REMS assessment plan should include, but is not limited to, the following:
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`1. An evaluation of patients’ understanding of the serious risks of Nucynta ER
`(tapentadol) extended-release oral tablets.
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`2. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24.
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`3. A report on failures to adhere to distribution and dispensing requirements, and
`corrective actions taken to address noncompliance.
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`4. An evaluation of healthcare providers’ understanding of the serious risks of Nucynta
`ER (tapentadol) extended-release oral tablets.
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`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
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`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.
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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
`result in enforcement action.
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`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.
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`Reference ID: 3006589
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`NDA 200533
`Page 5
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`If you plan to distribute an authorized generic product under this NDA, you must submit a
`complete proposed REMS that relates only to the authorized generic product. Submit a proposed
`REMS, REMS supporting document, and any required appended documents as a prior approval
`supplement. Approval of the proposed REMS is required before you may market your authorized
`generic product.
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`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:
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`NDA 200533 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 200533
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 200533
`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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`PROMOTIONAL MATERIALS
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`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:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`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
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`information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`Reference ID: 3006589
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`NDA 200533
`Page 6
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` EXPIRATION DATING PERIOD
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`An expiration dating period of 24 months is granted for Nucynta ER (tapentadol) extended-
`release oral tablets, stored at 25° C (77° F) with excursions permitted from 15° to 30°C (59°­
`86°F).
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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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`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.
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`If you have any questions, call Dominic Chiapperino, Ph.D., Senior Regulatory Health Project
`Manager, at (301) 796-1183.
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`
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`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`REMS
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`Reference ID: 3006589
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`Sincerely,
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` {See appended electronic signature page}
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`Bob A. Rappaport, M.D.
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`Director
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`Division of Anesthesia, Analgesia,
`and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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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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`BOB A RAPPAPORT
`08/25/2011
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`Reference ID: 3006589
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