CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`200533Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`August 24, 2011
`Bob A. Rappaport, M.D., Director
`Division of Anesthesia and Analgesia Products (DAAP)
`Claudia Karwoski, Pharm.D., Director
`Division of Risk Management (DRISK)
`
`DRISK Scientific Lead
`Doris Auth, Pharm.D., Drug Risk Management Analyst (RMA)
`
`DRISK Review Team
`Megan Moncur, M.S., RMA, Team Leader
`Cynthia LaCivita, Pharm.D., RMA, Team Leader
`Kate Heinrich, M.A., Health Education Reviewer
`Jodi Duckhorn, MA, Social Scientist
`Sharon Mills, Patient Labeling Reviewer
`
`Division of Drug Marketing, Advertising and Communications
`(DDMAC)
`Mathilda Fienkeng, Regulatory Review Officer
`
`Office of Compliance
`Marcia Britt Williams, Ph.D., Consumer Safety Officer
`
`Final Review of the Proposed Risk Evaluation and Mitigation Strategy
`(REMS) for Nucynta ER (tapentadol) extended-release tablets
`
`Nucynta®ER (tapentadol) Extended-Release tablets
`
`
`50, 100, 150, 200, 250 mg tablets
`
`Resubmission Class 2, Sequence 0023
`
`NDA 200-533 TSI 466
`
`
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`2011-921
`
`
`Date:
`To:
`
`Thru:
`
`From:
`
`Subject:
`
`Drug Name(s):
`
`Dosage
`Formulation:
`Submission
`Number:
`Application
`Type/Number:
`
`Applicant:
`OSE RCM #:
`
`
`
`Reference ID: 3005856
`
`

`

`1 PURPOSE
`
`The purpose of this review is to evaluate Ortho-McNeil-Janssen Pharmaceutical’s
`proposed Risk Evaluation and Mitigation Strategy (REMS) for Nucynta ER (tapentadol)
`extended-release tablets, NDA 200-533 submitted on February 28, 2011, as a Class 2
`resubmission, sequence number 0023.
`
` 2
`
`
`
`BACKGROUND
`
`
`Nucynta ER (tapentadol) extended-release is a CII, centrally-acting opioid analgesic.
`The proposed indication for Nucynta ER is 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. The drug entity, tapentadol hydrochloride, was
`approved in 2008 for use in an immediate-release formulation to treat moderate to
`severe pain.
`On November 20, 2009 Ortho-McNeil-Janssen Pharmaceuticals submitted the original
`application and proposed REMS for Nucynta ER (tapentadol) extended-release tablets.
`The original proposed REMS consisted of a Medication Guide, communication plan,
`and a timetable for assessment of the proposed REMS.
`On April 22, 2010, the sponsor received a Pre-Approval REMS notification that stated
`the proposed REMS must include elements to assure safe use, specifically training for
`healthcare providers as described under 505-1(f)(3)(A), to ensure that the benefits of the
`drug outweigh the risks of: abuse, misuse, addiction and overdose as well as the use of
`Nucynta ER in non-opioid tolerant individuals, and to prevent the occurrence of serious
`adverse events associated with those risks.
`The sponsor submitted an amendment for the proposed REMS and REMS supporting
`document on June 21, 2010, sequence 0014. DRISK evaluated this submission and
`posted a review in DARRTS on August 6, 2010. Comments to the sponsor included in
`the DRISK review were communicated to the sponsor. On October 1, 2010 the sponsor
`received a Complete Response (CR) because the proposed in vitro in vivo correlation
`models did not support the bridging of the clinical study batches to the to-be-marketed
`tamper resistant formulation.
`On February 28, 2011 the sponsor resubmitted their application as a Class 2,
`resubmission in response to the CR letter addressing the aforementioned issues with
`bioequivalency and in response to the Agency’s comments, revised the proposed REMS
`and REMS supporting documents.
`On April 18, 2011, the sponsor received a Pre-Approval REMS notification that stated
`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 extended-release and long-
`acting (ER/LA) opioid products. The Agency is currently working with all sponsors of
`ER/LA opioids to develop the single shared system. Ortho-McNeil-Janssen
`Pharmaceuticals, and other sponsors with pending approvals, have been instructed to
`
`
`
`Reference ID: 3005856
`
`2
`
`

`

`develop an interim REMS that will conform with agency standards for the other interim
`REMS for ER/LA opioids.
`
` 3
`
` METHODS AND MATERIALS
`
`
`The proposed REMS submission was reviewed for conformance with Title IX, Subtitle
`A, Section 901 of the Food Drug Administration Amendments Act of 2007 (FDAAA),
`the REMS notification letter, and consistency with REMS requirements for other long-
`acting and extended-release opioid analgesics. The following materials were reviewed:
`3.1 Materials Reviewed
`• Proposed REMS for Nucynta ER, received August 24, 2011 (Sequence 0041)
`• Proposed REMS and REMS supporting document, for Nucynta ER, received July
`29, 2011 (Sequence 0035)
`• Proposed REMS and REMS supporting document for Nucynta ER (tapentadol)
`extended-release tablets, received February 28, 2011.(Sequence 0023)
`• Screen shots for the Nucynta ER website and the Nucynta ER REMS website, dated
`May 25, 2011, sequence 0028.
`3.2 Materials Referenced
`• Proposed labeling for Nucynta ER, received August 23, 2011 (Sequence 0040)
`• Proposed labeling for Nucynta ER, provided on August 10, 2011 by Dominic
`Chiapperino, Regulatory Project Manager
`• Proposed labeling for Nucynta ER (tapentadol) extended-release tablets,
`provided on May 17, 2011 by Dominic Chiapperino, Regulatory Project
`Manager.
`• Interim REMS review, prepared by Cynthia LaCivita, Pharm.D., dated June 22,
`2011
`• REMS Pre-Approval Notifications, dated April 22, 2010 and April 18, 2011
`
`PROPOSED REMS FOR NUCYNTA ER (TAPENTADOL) EXTENDED-
`RELEASE TABLETS
`
`4
`
`
`Listed below are the goals of the proposed REMS and a summary of the elements.
`Appendix A contains the complete REMS.
`4.1 Goals
`The goals of the proposed REMS for Nucynta ER are:
`• To inform patients and healthcare professionals about the potential for abuse,
`misuse, overdose, and addiction to Nucynta ER.
`• To inform patients and healthcare professionals about the safe use of Nucynta ER.
`
`
`
`Reference ID: 3005856
`
`3
`
`

`

`4.2 Elements of the Proposed Interim REMS
`Below is a summary of the sponsor’s proposed REMS.
`4.2.1 The Medication Guide
`The Medication Guide will be dispensed with each Nucynta ER prescription in
`accordance with 21 CFR 208.24.
`4.2.2 Elements to Assure Safe Use
`The elements to assure safe use include a training program for healthcare providers that
`prescribe Nucynta ER. Three weeks prior to the availability of Nucynta ER a Dear
`Healthcare letter will be mailed to prescribers most experienced in treating chronic pain
`with opioids agonists.
`The training program includes educational information about: proper patient selection;
`appropriate dosing and administration; general principles of safe opioid use, including
`information about opioid abuse and how to identify patients who are at risk for
`addiction; potential misuse; and overdose with opioids including Nucynta ER.
`The training program includes specific information about the potential for an overdose
`caused by exposure to an essentially immediate-release form of tapentadol by
`consuming tablets that are broken, chewed, crushed, dissolved or injected; and the risk
`of overdose in patients who have not developed tolerance to the sedating or respiratory-
`depressant effects of opioids, especially when the initial dose of Nucynta ER exceeds 50
`mg twice daily.
`Prescribers will receive training on the need to counsel patients to store opioid
`analgesics safely out of the reach of children and household acquaintances; to properly
`dispose of unused drugs when no longer needed by the patient; to not share drugs with
`anyone for any reason; and the importance of dispensers providing each patient a
`Medication Guide with each prescription, and instructing the patient to read it.
`Prescribers will be re-trained every two years or following substantial changes to the
`NUCYNTA® ER REMS. The following materials are part of the REMS.
`• Dear Healthcare Professional Letter
`• Prescribing Nucynta ER Healthcare Professional Education Program: A Guide for
`Healthcare Professionals Who Intend to Prescribe NUCYNTA® ER
`• Nucynta ER Education Confirmation Form
`• Nucynta ER REMS website
`A copy of the full Prescribing Information (PI) will be included with the training
`materials. All REMS materials will be available on the Nucynta ER REMS website
`(NUCYNTAERREMS.COM)
`4.2.3 Implementation System
`Because Nucynta ER could be approved without the elements to assure safe use
`described under FDCA 505-1(f)(3)(B), (C), and (D) of the Act, an implementation
`system is not required.
`
`
`
`Reference ID: 3005856
`
`4
`
`

`

`4.2.4 Timetable for Submission of Assessments
`The sponsor will submit REMS Assessments to the FDA every 6 months for the first year
`from the date of approval of the REMS, and annually thereafter.
`
`CONCLUSIONS
`
`The interim REMS for Nucynta ER will be implemented by the sponsor, and will be in
`effect until the single-shared REMS for all long-acting and extended-release opioid
`products is approved and implemented. The DRISK Review Team finds the proposed
`interim REMS for Nucynta ER, as submitted on August 24, 2011 and attached to this
`review, to be acceptable.
`
`
`
` 5
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3005856
`
`5
`
`39 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DORIS A AUTH
`08/24/2011
`
`CLAUDIA B KARWOSKI
`08/24/2011
`concur
`
`Reference ID: 3005856
`
`

`

`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`June 22, 2011
`Bob A. Rappaport, M.D., Director
`Division of Anesthesia and Analgesia Products (DAAP)
`Claudia Karwoski, Pharm.D., Director
`Division of Risk Management (DRISK)
`
`DRISK Scientific Lead
`Cynthia LaCivita, Pharm.D., Drug Risk Management Analyst (RMA)
`
`DRISK Review Team
`Megan Moncur, M.S., RMA, Team Leader
`Kate Heinrich, M.A., Health Education Reviewer
`Jodi Duckhorn, MA, Social Scientist
`Sharon Mills, Patient Labeling Reviewer
`
`Division of Drug Marketing, Advertising and Communications
`(DDMAC)
`Mathilda Fienkeng, Regulatory Review Officer
`
`Office of Compliance
`Marcia Britt Williams, Ph.D., Consumer Safety Officer
`
`Interim Review of the Proposed Risk Evaluation and Mitigation Strategy
`(REMS) for Nucynta ER (tapentadol) extended-release tablets
`
`Nucynta®ER (tapentadol) Extended-Release tablets
`
`
`50, 100, 150, 200, 250 mg tablets
`
`Resubmission Class 2, Sequence 0023
`
`NDA 200-533 TSI 466
`
`
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`
`2011-921
`
`
`Date:
`To:
`
`Thru:
`
`From:
`
`Subject:
`
`Drug Name(s):
`
`Dosage
`Formulation:
`Submission
`Number:
`Application
`Type/Number:
`
`Applicant:
`
`OSE RCM #:
`
`
`
`Reference ID: 2964281
`
`

`

`1 PURPOSE
`
`The purpose of this review is to evaluate Ortho-McNeil-Janssen Pharmaceutical’s
`proposed Risk Evaluation and Mitigation Strategy (REMS) for Nucynta ER (tapentadol)
`extended-release tablets, NDA 200-533 submitted on February 28, 2011, as a Class 2
`resubmission, sequence number 0023. The Medication Guide review will be provided
`under a separate cover.
`
` 2
`
`
`
`BACKGROUND
`
`
`Nucynta ER (tapentadol) extended-release is a CII, centrally-acting opioid analgesic.
`The proposed indication for Nucynta ER is the management of moderate to severe
`chronic pain in patients 18 years of age or older when a continuous, around-the-clock
`opioid analgesic is needed for an extended period of time. The drug entity, tapentadol
`hydrochloride, was approved in 2008 for use in an immediate-release formulation to
`treat moderate to severe pain.
`On November 20, 2009 Ortho-McNeil-Janssen Pharmaceuticals submitted the original
`application and proposed REMS for Nucynta ER (tapentadol) extended-release tablets.
`The original proposed REMS consisted of a Medication Guide, communication plan,
`and a timetable for assessment of the proposed REMS.
`On April 22, 2010, the sponsor received a Pre-Approval REMS notification that stated
`the proposed REMS must include elements to assure safe use, specifically training for
`healthcare providers as described under 505-1(f)(3)(A), to ensure that the benefits of the
`drug outweigh the risks of: abuse, misuse, addiction and overdose as well as the use of
`Nucynta ER in non-opioid tolerant individuals, and to prevent the occurrence of serious
`adverse events associated with those risks.
`The sponsor submitted an amendment for the proposed REMS and REMS supporting
`document on June 21, 2010, sequence 0014. DRISK evaluated this submission and
`posted a review in DARRTS on August 6, 2010. Comments to the sponsor included in
`the DRISK review were communicated to the sponsor. On October 1, 2010 the sponsor
`received a Complete Response (CR) because the proposed in vitro in vivo correlation
`models did not support the bridging of the clinical study batches to the to-be-marketed
`tamper resistant formulation.
`On February 28, 2011 the sponsor resubmitted their application as a Class 2,
`resubmission in response to the CR letter addressing the aforementioned issues with
`bioequivalency and in response to the Agency’s comments, revised the proposed REMS
`and REMS supporting documents.
`On April 18, 2011, the sponsor received a Pre-Approval REMS notification that stated
`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 long-acting and extended-
`release opioid products. Implementation of the single, shared REMS is not in the
`imminent future. If the REMS is the only outstanding requirement for drug approval,
`
`
`
`Reference ID: 2964281
`
`2
`
`

`

`waiting for implementation of the shared system could cause a significant delay in the
`availability of this drug. Therefore, the proposed REMS and REMS supporting
`documents under review are for an interim REMS that is consistent with agency
`standards for the other interim REMS for long-acting extended-release opioids.
`
` 3
`
` METHODS AND MATERIALS
`
`
`The proposed REMS submission was reviewed for conformance with Title IX, Subtitle
`A, Section 901 of the Food Drug Administration Amendments Act of 2007 (FDAAA),
`the REMS notification letter, and consistency with REMS requirements for other long-
`acting and extended-release opioid analgesics. The following materials were reviewed:
`3.1 Materials Reviewed
`• Proposed REMS and REMS supporting document for Nucynta ER (tapentadol)
`extended-release tablets, received February 28, 2011.
`• Proposed labeling for Nucynta ER (tapentadol) extended-release tablets, provided
`on May 17, 2011 by Dominic Chiapperino, Regulatory Project Manager.
`• Screen shots for the Nucynta ER website and the Nucynta ER REMS website, dated
`May 25, 2011, sequence 0028.
`3.2 Materials Referenced
`• REMS Pre-Approval Notifications, dated April 22, 2010 and April 18, 2011
`
`PROPOSED REMS FOR NUCYNTA ER (TAPENTADOL) EXTENDED-
`RELEASE TABLETS
`
`4
`
`
`Listed below are the goals of the proposed REMS and a summary of the elements.
`Appendix A contains the complete REMS with DRISK edits in track changes.
`4.1 Goals
`The goals of the proposed REMS for Nucynta ER are:
`• To inform patients and providers about the potential for abuse, misuse, overdose,
`and addiction to Nucynta ER.
`• To inform patients and healthcare professionals about the safe use of Nucynta ER.
`4.2 Elements of the Proposed Interim REMS
`Below is a summary of the sponsor’s proposed REMS. Please refer to the REMS
`document (Appendix A) for DRISK edits using track changes.
`4.2.1 The Medication Guide
`The Medication Guide will be dispensed with each Nucynta ER prescription in
`accordance with Federal law 21 CFR 208.24.
`
`
`
`Reference ID: 2964281
`
`3
`
`

`

`4.2.2 Elements to Assure Safe Use
`The elements to assure safe use include a training program for healthcare providers that
`prescribe Nucynta ER. Three weeks prior to the availability of Nucynta ER a Dear
`Healthcare letter will be mailed to prescribers most experienced in treating chronic pain
`with opioids agonists.
`The training program includes educational information about: proper patient selection;
`appropriate dosing and administration; general principles of safe opioid use, including
`information about opioid abuse and how to identify patients who are at risk for
`addiction; potential misuse; and overdose with opioids including Nucynta ER.
`The training program includes specific information about the potential for an overdose
`caused by exposure to an essentially immediate-release form of tapentadol by
`consuming tablets that are broken, chewed, crushed, dissolved or injected; and the risk
`of overdose in patients who have not developed tolerance to the sedating or respiratory-
`depressant effects of opioids, especially when the initial dose of Nucynta ER exceeds 50
`mg twice daily.
`Prescribers will receive training on the need to counsel patients to store opioid
`analgesics safely out of the reach of children and household acquaintances; to properly
`dispose of unused drugs when no longer needed by the patient; to not share drugs with
`anyone for any reason; and the importance of dispensers providing each patient a
`Medication Guide with each prescription, and instructing the patient to read it.
`Prescribers will be offered training every two years or following substantial changes to
`the NUCYNTA® ER REMS. The following materials are part of the REMS.
`• Dear Healthcare Professional Letter
`• Nucynta ER Medication Guide
`• Prescribing Nucynta ER Healthcare Professional Education Program: A Guide for
`Healthcare Professionals Who Intend to Prescribe NUCYNTA® ER
`• Nucynta ER Education Confirmation Form
`A copy of the full Prescribing Information (PI) will be included with the training
`materials. All REMS materials will be available on the Nucynta ER REMS website
`(NUCYNTAERREMS.COM)
`4.2.3 Implementation System
`Because Nucynta ER could be approved without the elements to assure safe use
`described under FDCA 505-1(f)(3)(B), (C), and (D) of the Act, an implementation
`system is not required.
`4.2.4 Timetable for Submission of Assessments
`The sponsor will submit REMS Assessments to the FDA every 6 months for the first year
`from the date of approval of the REMS, and annually thereafter.
`
`
`
`
`Reference ID: 2964281
`
`4
`
`

`

`RECOMMENDATIONS
`
`5
`
`The interim REMS for Nucynta ER will be implemented by the sponsor, and will be in
`effect until the single-shared REMS for all long-acting and extended-release opioid
`products is approved and implemented. The DRISK Review Team finds the proposed
`interim REMS for Nucynta ER to be acceptable, provided the sponsor addresses all
`comments in the OCC-cleared REMS document, as well as comments listed below in
`Section 5.1 Comments for the Sponsor and the accompanying appendices. DRISK will
`perform a review of the final REMS to ensure it addresses all the identified deficiencies.
`
`The “comments to the sponsor” are listed below. Please convey the comments provided
`below to the sponsor and copy DRISK on the correspondence.
`
`The following comments and appendices address the necessary revisions for the proposed
`REMS and REMS Supporting Document submitted for Nucynta ER, NDA 200533.
`5.1 Comments for the Sponsor
`1. REMS Document
`Appendix A contains the necessary revisions to the REMS document in track changes.
`The following materials are part of the REMS and must be appended to the REMS:
`o Medication Guide
`o Dear Healthcare Professional Letter
`o Prescribing Nucynta ER Healthcare Professional Education Program: A Guide for
`Healthcare Professionals Who Intend to Prescribe Nucynta ER
`o Nucynta ER Education Confirmation Form
`o Nucynta ER REMS website (screen shots of the web pages)
`2. Dear Healthcare Professional Letter
`Appendix B contains the necessary revisions to the document in track changes.
`3. Healthcare Professionals Educational Program: A Guide for Healthcare
`Professionals Who Prescribe or Dispense Nucynta ER
`Appendix C contains the necessary revisions to the document in track changes.
`4. Education Confirmation Form
`Appendix D contains the necessary revisions to the form in track changes.
`5. REMS Website
`Make the necessary changes on the landing page of the Nucynta ER REMS website.
`Second paragraph
`
`
`
`Reference ID: 2964281
`
`5
`
`(b) (4)
`
`

`

`Third paragraph,
` Provide the content for “click here”.
`The REMS program is designed to inform patients and healthcare professionals
`(HCPs) about the risks of NUCYNTA ER. To lean more about the serious risks,
`including potential for abuse, overdose and addiction, click here.
`
`Under step one and the REMS materials - Use the correct the name of the training
`program, Prescribing NUCYNTA® ER Healthcare Professional Education Program.
`Provide a hyperlink in step one to the program.
`
`Include the full indication, including the limitations to the indication, and full boxed
`warning on the REMS website.
`
`6. REMS Supporting Document
`a. All changes in the REMS and Prescribing Information (PI) should also be reflected in
`the REMS Supporting Document.
`b. In the section titled “Background” remove reference to a reduced risk for abuse with
`regard to crushing or destroying the extended release property.
`c. Correct the URL for the website for a Nucynta ER REMS.com
`d. Assessments and Surveys
`o Add an assessment of the mailing of the Dear Healthcare Professional (HCP)
`Letters to your Information Needed for Assessment: including the number of
`mailings sent; the targeted specialties that received the Dear HCP Letter, the
`number of returned mailings, the date of the mailing
`o The six-month survey should include an implementation survey that identifies
`timelines and/or milestones identified during the initial six months after the
`approval of the REMS.
`o Please also refer to comments previously provided in the advice letter dated Sept
`21, 2010, regarding assessments and survey methodology.
`
`
`
`
`
`
`
`Reference ID: 2964281
`
`6
`
`(b) (4)
`
`

`

`7. General Comments
`REMS materials are not appropriate for use in a promotional manner.
`All REMS materials and the REMS Supporting Document should be revised to reflect
`the content in the final product labeling.
`Submit revisions for the proposed REMS with appended materials and the REMS
`Supporting Document and all other materials in WORD format. It is preferable that the
`entire REMS and appended materials be a single WORD document. If certain
`documents such as enrollment forms are only in PDF format, they may be submitted as
`such. The preference is to include as many as possible be in a single WORD document.
`Please provide a track changes and clean version of all revised materials and
`documents.
`
`Appendix A - REMS Document
`Appendix B - Dear Healthcare Provider Letter
`Appendix C - Prescribing NUCYNTA® ER Healthcare Professional Education Program
`Appendix D - NUCYNTA® ER Education Confirmation Form
`
`
`
`Reference ID: 2964281
`
`7
`
`32 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CYNTHIA L LACIVITA
`06/22/2011
`
`CLAUDIA B KARWOSKI
`06/22/2011
`concur
`
`Reference ID: 2964281
`
`

`

`NDAs 6034. 19516. 19813. 19977. 20616. 21610. 22324. 200533. 201655. 20553. 21044
`
`~29V
`
`E1
`
`.w
`"a'
`‘6
`\f
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA, ANALGESIA, AND ADDICTION PRODUCTS
`
`
`
`MEMORANDUM
`
`DATE:
`
`April 18, 2011
`
`TO:
`
`File,
`
`Tradename
`
`Established Name
`
`19516
`
`19813
`
`19977
`
`20616
`
`21610
`
`21260
`
`Dolophine Tablets
`
`MS CONTIN Tablets
`
`DURAGESIC
`
`Oramorph SR Tablets
`
`KADIAN Capsules
`
`OPANA ER Tablets
`
`AVINZA Capsules
`
`(methadone hydrochloride) 5 mg and
`8 ?
`
`(morphine sulfate controlled-release)
`15, 30, 60, 100, 200 mo
`(fentanyl transdermal system) 1.25,
`2.5, 5, 7.5, 10 mo
`(morphine sulfate sustained-release)
`15, 30, 60, 100 mo
`(morphine sulfate extended-release)
`10, 20, 30, 50, 60, 80, 100, 200 m-
`(oxymorphone hydrochloride
`extended-release) 5, 7.5, 10, 15, 20,
`30, 40 mo
`(morphine sulfate extended-release)
`30, 45, 60, 75, 90, 120 m .
`Oxycodone Hydrochloride Extended-
`Release, 5, 10, 20, 30 and 40 m
`
`(Tapentadol Extended-Release) 50,
`100, 150, 200, 250 m
`Oxymorphone HCI Extended-Release
`Tablets, 5, 7.5, 10, 15, 20, 20, 40
`
`(oxycodone hydrochloride controlled-
`release
`
`(hydromorphone hydrochloride
`extended-release 12, 16, 24, 32 mo
`
`PALLADONE Capsules
`
`22324 (pending)
`
`REMOXY Capsules
`
`200533 (pending)
`
`Nucynta ER Tablets
`
`201 655
`
`(between cycles)
`
`tradename pending
`
`20553 (discontinued)
`
`OxyContin Tablets
`
`21044 (discontinued)
`
`From:
`
`Through:
`
`Laura Govemale, Pharm.D., MBA
`Acting Deputy Director for Safety
`
`Bob Rappaport, MD.
`Division Director
`
`RE:
`
`Risk Evaluation and Mitigation Strategy (REMS) Requirements
`
`Reference ID: 2935041
`
`

`

`NDAs 6034, 19516, 19813, 19977, 20616, 21610, 22324, 200533, 201655, 20553, 21044
`
`
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of
`2007 (FDAAA) amends the Federal Food, Drug, and Cosmetic Act (FDCA) to authorize
`FDA to require the submission of a Risk Evaluation and Mitigation Strategy (REMS) if
`FDA determines that such a strategy is necessary to ensure that the benefits of the drug
`outweigh the risks (section 505-1(a)(1)). Section 505-1(a)(1) provides the following
`factors:
`
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the
`drug and the background incidence of such events in the population likely to use the
`drug;
`(F) Whether the drug is a new molecular entity.
`
`
`The use of prescription opioid drug products has nearly doubled in the past decade, and
`with that increase in use, there has been a concordant rise in the abuse and misuse of
`prescription opioid drug products, resulting in increased reports of serious adverse
`outcomes such as death, overdose and addiction. The spectrum of behaviors contributing
`to these problems include inappropriate prescribing such as improper dosing, patient
`selection, and patient counseling, as well as inappropriate patient behaviors such as
`improper use, storage and disposal of prescription drug opioid products.1 Extended-release
`(ER) and long-acting (LA) opioid products pose unique risks to patients due to their
`pharmacokinetic properties, duration of use, and the amount of active ingredient contained
`in the drug product in comparison to their immediate-release opioid counterparts. The
`amount of opioid contained in an extended-release tablet can be much more than the
`amount of opioid contained in an immediate-release tablet because extended-release tablets
`are designed to release the opioid over a longer period of time. Long-acting opioids can
`take many hours to be cleared out of the body. Improper use of any opioid can result in
`serious side effects including overdose and death and this risk is magnified with long-
`acting and extended-release opioids. As it is important that these products are prescribed
`and used safely among the intended population, FDA has determined that a REMS is
`necessary to address the issues of unintentional overdose, addiction, and death resulting
`from inappropriate prescribing, misuse and abuse of ER and LA opioid drug products.
`
`After consultations with the Office of New Drugs, the Office of Surveillance and
`Epidemiology, and members of the Anesthetic and Life Support Drugs and Drug Safety
`and Risk Management committees on July 2010, we have determined that a class-wide
`REMS is necessary to ensure that the benefits of ER and LA opioid drug products outweigh
`their risks. In reaching this determination, we considered the following:
`
`
`
`1http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCo
`mmittee/UCM217510.pdf
`
`
`
`Reference ID: 2935041
`
`2
`
`

`

`NDAs 6034, 19516, 19813, 19977, 20616, 21610, 22324, 200533, 201655, 20553, 21044
`
`A. Approximately 24-33% of Americans suffer from chronic, non-cancer pain such as
`arthritis, lower back pain, and fibromyalgia.2 In year 2009, an estimated
`
`unique patients received a dispensed prescription for an ER/LA opioid product from
`outpatient retail pharmacies.3
`
`B. ER and LA opioid products are indicated for the management of moderate to severe
`pain when a continuous, around-the-clock opioid analgesic is needed for an
`extended period of time. The majority of use for ER/LA opioid products is
`associated with “diseases of the musculoskeletal system and connective tissue”
`(ICD-9 codes 710-739) which include chronic pain conditions such as arthritis and
`back pain.4
`
`
`C. ER and LA opioid products are an important part of the armamentarium of drugs
`used to treat chronic pain. Some advantages of these types of formulations over the
`short-acting opioids are: 1) less frequent dosing; 2) better control of pain achieved
`through more stable drug levels; 3) improved patient compliance; and 4) less opioid
`side-effects.5 It is important to note that patients respond differently to different
`opioid drug substances and some patients develop tolerance to an opioid after
`chronic exposure. Physicians use a technique known as “opioid rotation” whereby
`they switch patients from one opioid to another if patients develop tolerance and
`cannot get adequate pain relief from any given opioid. Therefore, having different
`opioids available as modified-release formulations provides important pain relief
`options for these patients.
`
`
`D. The expected duration of treatment with ER and LA opioids will be from weeks to
`months or longer. Data from outpatient prescription claims databases suggest that
`ER and LA opioid products are typically prescribed for approximately 30-days at a
`time, whereas immediate-release opioid products are prescribed for 13-21 days at a
`time.6
`
`
`E. ER and LA opioid drug products such as OxyContin have distinguished themselves
`among the class of opioid pain medications with their disproportionately high rate
`of serious adverse outcomes including deaths, unintentional overdose and addiction,
`in comparison to immediate-release opioid products.1 The goal of the REMS would
`be to reduce serious adverse outcomes resulting from inappropriate prescribing,
`misuse and abuse of ER and LA opioids while maintaining patient access to these
`medications. Serious adverse outcomes of concern including addiction,
`unintentional overdose, and death have been reported for each of the currently
`marketed products listed in the table above and in association with approved
`formulations of the drug substances in the products under review.
`
`
`
`
`2 Nelson, R. Lancet 362(9390); 1129, 2003.
`3 SDI, Total Patient Tracker. Year 2009, Extracted, June 2010.
`4SDI, Physician Drug and Diagnosis Audit, Year 2009, Extracted June 2010
`5 Balch RJ,