CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`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
`Office of Medication Error Prevention and Risk Management
`
`Addendum - Final Risk Evaluation and Mitigation Strategy (REMS) Review
`
`Date:
`
`November 30, 2011
`
`Danielle Smith, PharmD, M.S., Risk Management Analyst
`Reviewer(s):
`Division of Risk Management (DRISK)
`
`Megan Moncur, M.S.
`Team Leader:
`DRISK
`
`Claudia Karwoski, PharmD
`Division Director
`DRISK
`
`OPANA ER (oxymorphone hydrochloride extended release)
`Drug Name(s):
`Opioid Analgesic
`Therapeutic Class:
`Oral tablets
`Dosage and Route:
`Application Type/Number: NDA 201655
`Submission Number:
`Sequence Number 0032
`Applicant/sponsor:
`Endo Pharmaceutical, Inc.
`OSE RCM #:
`2010-1527
`
`
`
`
`
`
`
`
`
`
`
`*** This document contains proprietary and confidential information that should not be
`released to the public. ***
`
`
`
`Reference ID: 3051468
`
`

`

`CONTENTS
`
`1
`
`INTRODUCTION....................................................................................................... 1
`1.1
`Background......................................................................................................... 1
`1.2
`Regulatory History.............................................................................................. 2
`2 MATERIALS REVIEWED ........................................................................................ 2
`2.1
`Data and Information Sources ............................................................................ 2
`2.2
`Analysis Techniques ........................................................................................... 3
`3 RESULTS OF REVIEW OF PROPOSED OPANA ER RISK EVALUATION AND
`MITIGATION STRATEGY............................................................................................... 3
`3.1
`Goals ................................................................................................................... 3
`3.2
`REMS Elements.................................................................................................. 3
`3.3
`REMS Assessment Plan...................................................................................... 5
`4 DISCUSSION.............................................................................................................. 6
`5 CONCLUSION ........................................................................................................... 6
`6 RECOMMENDATIONS............................................................................................. 7
`ATTACHMENTS............................................................................................................... 7
`
`Reference ID: 3051468
`
`

`

`EXECUTIVE SUMMARY
`The purpose of this review is to amend the Division of Risk Management’s (DRISK)
`Final Review (Reviewer: Smith, dated October 3, 2011) of Endo Pharmaceuticals’
`proposed Risk Evaluation and Mitigation Strategy (REMS) for OPANA ER
`(oxymorphone hydrocholoride extended-release (ER) tablets). The Final Review is being
`amended to address two additional changes proposed by the sponsor, and to document
`DRISK’s verification that all recommended revisions have been incorporated.
`
`The OSE, DRISK finds the revisions acceptable and recommends approval of the
`OPANA ER REMS, submitted 21 November 2011.
`
`INTRODUCTION
`
` 1
`
`
`
`1.1 BACKGROUND
`OPANA ER (NDA 20-1655) is an opioid agonist, developed for the relief of moderate to
`severe pain in patients requiring continuous around-the-clock opioid treatment for an
`extended period of time.
`On September 23, 2011, via email communication through Ms. Lisa Basham, Regulatory
`Project Manager, Endo proposed two additional revisions (described below). Since the
`REMS Review was in the process of being finalized and these two items required further
`discussion with the Office of Compliance (OC), it was decided that these proposed
`revisions would be addressed in the addendum to the Final REMS Review:
`
`
`1. REMS document – Section II.c, Section II.e – Endo proposed the following
`change:
`
`To: “Endo will ensure that at least 3 weeks prior to first availability of
`OPANA® ER to healthcare professionals, a Dear Healthcare Professional
`letter will be mailed to HCPs…”
`Rationale: Endo believes that for the REMS information to have maximum
`value, it should be delivered in a close temporal relationship to the product
`availability to healthcare professionals. Therefore, we are proposing this
`modification to the timing of the distribution of the Dear Healthcare
`Professional letter.
`
`
`
`Reference ID: 3051468
`
`(b) (4)
`
`

`

`1.2 REGULATORY HISTORY
`Following are highlights of key regulatory actions and communications for Opana ER,
`following the Final REMS Review:
`
`Final REMS Review checked into DARRTS
`03 October 2011:
`REMS submission [via email]
`17 October 2011:
`Interim Comments provided to Sponsor [via email]
`28 October 2011:
`17 November 2011: REMS submission [via email]
`18 November 2011: Interim Comments provided to Sponsor [via email]
`21 November 2011: Submission of final agreed-upon REMS (Seq No. 0032)
`
` 2
`
` MATERIALS REVIEWED
`
`2.1 DATA AND INFORMATION SOURCES
`
`The following materials were reviewed:
`• OPANA ER proposed REMS, REMS Supporting Document, and REMS
`Website Draft Screen Shots, received November 21, 2011 (Seq No. 0032),
`including:
`o Dear Healthcare Professional (DHCP) Letter
`o Dear Pharmacist Letter
`o Healthcare Professional (HCP) Training Guide
`o OPANA ER REMS Education Confirmation Form
`
`
`The following materials were referenced:
`• Opana ER proposed REMS, REMS Supporting Document, and REMS
`Website Draft Screen Shots, received September 7, 2011 (Seq. No. 0027)
`including:
`o Dear Healthcare Professional (DHCP) Letter
`
`Reference ID: 3051468
`
` 2
`
`(b) (4)
`
`

`

`o Dear Pharmacist Letter
`o Healthcare Professional (HCP) Training Guide
`o Opana ER REMS Education Confirmation Form
`
`
`
`2.2 ANALYSIS TECHNIQUES
`Endo’s proposed REMS was reviewed for conformance with Title IX, Subtitle A, Section
`901 of the Food Drug Administration Amendments Act of 2007 (FDAAA), and to ensure
`that all comments communicated to the sponsor to date, were accurately incorporated.
`A comparison of the November 21, 2011 REMS submission was made to the September
`7, 2011 REMS submission to ensure that only the agreed upon revisions were made.
`
` 3
`
` RESULTS OF REVIEW OF PROPOSED OPANA ER RISK EVALUATION
`AND MITIGATION STRATEGY
`
`3.1 GOALS
`The goals of the OPANA ER REMS are:
`1. To inform patients and healthcare professionals about the potential for abuse,
`misuse, overdose and addiction associated with the use of OPANA ER
`2. To inform patients and healthcare professionals about the safe use of OPANA ER
`
`
`
`3.2 REMS ELEMENTS
`
`3.2.1 Medication Guide
`A Medication Guide will be dispensed with each OPANA ER prescription in
`accordance with 21 CFR 208.24.
`The Medication Guide is part of the REMS and is appended.
`
`3.2.2 Elements to Assure Safe Use
`
`3.2.2.1 Healthcare professionals (HCPs) who prescribe OPANA ER will receive
`training.
`a.
`Endo will ensure that training will be provided to HCPs who prescribe
`OPANA ER. Endo will ensure that each prescriber will be provided with
`the OPANA ER REMS educational material.
`
`b. The OPANA ER REMS training includes the following:
`
`
`
`i.
`Proper patient selection
`ii. Appropriate OPANA ER dosing and administration
`
`Reference ID: 3051468
`
` 3
`
`

`

`iii. General opioid use including information about opioid abuse and
`how to identify patients who are at risk for addiction
`iv. The risks of abuse, misuse, overdose, and addiction from exposure
`to opioids, including OPANA ER
`v. Risks of OPANA ER, including:
`1. The risk of overdose caused by exposure to an essentially
`immediate-release form of oxymorphone by consuming
`broken, chewed, crushed or dissolved OPANA ER tablets
`2. The risk of addiction from exposure to OPANA ER
`Information to counsel patients on the need to store opioid
`analgesics safely out of the reach of children and household
`acquaintances
`vii. The importance of providing each patient with a Medication
`Guide, instructing the patient to read the Medication Guide and
`assisting the patient in understanding the content.
`
`vi.
`
`c.
`
`Endo will ensure that at least 3 weeks prior to first availability of OPANA
`ER to healthcare professionals, a Dear Healthcare Professional letter will
`be mailed to HCPs experienced in treating chronic pain with opioid
`agonists, including pain specialists and primary care physicians. This
`letter is designed to convey and reinforce the risks of abuse, misuse,
`overdose, and addiction of OPANA ER, as well as the need to complete
`the OPANA ER REMS prescriber training. The letter will be available on
`the OPANA ER REMS website (www.OPANAERrems.com) for 1 year
`from the date of mailing.
`
`d. The Dear Healthcare Professional letter mailing will include the following
`materials:
`
`i. Full Prescribing Information
`ii. Medication Guide
`iii. OPANA ER Healthcare Professional (HCP) Training Guide
`iv. OPANA ER REMS Education Confirmation Form
`
`e. Additional copies of the printed REMS materials will be available for
`download via the OPANA ER website (www.OPANAERrems.com) or by
`calling Endo’s toll-free phone number 1-800-462-3636.
`
`
`f.
`
`Endo will maintain a list of all prescribers who have completed the
`OPANA ER REMS training.
`
`Prescribers will be re-trained every two years or following substantial changes
`to the OPANA ER REMS. Substantial changes may include changed to the
`OPANA ER Full Prescribing Information or to the Medication Guide that
`require substantial modification of the REMS educational materials.
`
`
`
`
`
`
`
`
`
`Reference ID: 3051468
`
` 4
`
`

`

`The following materials are part of the REMS and are appended:
`• Medication Guide
`• Dear Healthcare Professional letter
`• OPANA ER Healthcare Professional (HCP) Training Guide
`• OPANA ER REMS Website
`• OPANA ER REMS Education Confirmation Form
`
`
`
`3.2.3 Implementation System
`Because OPANA ER can 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.
`
`3.2.4 Timetable for Submission of Assessments
`Endo 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. To facilitate
`inclusion of as much information as possible while allowing reasonable time to
`prepare the submission, the reporting interval covered by each assessment will
`conclude no earlier than 60 days before the submission date for that assessment
`time interval. Endo will submit each assessment so that it will be received by the
`FDA before or on the due date.
`
`
`
`3.3 REMS ASSESSMENT PLAN
`The following information needed for assessments is included in the REMS
`Supporting Document:
`1. An evaluation of patients’ understanding of the serious risks of OPANA ER.
`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. A report on the status of the training program for healthcare providers.
`5. An evaluation of healthcare providers’ awareness and understanding of the
`serious risks associated with OPANA ER (for example, through surveys of
`healthcare providers).
`6. Specification of measures that would be taken to increase awareness if
`surveys of healthcare providers indicate that healthcare provider awareness is
`not adequate.
`7. An analysis and summary of surveillance and monitoring activities for abuse,
`misuse, overdose, and addiction of OPANA ER and any intervention taken
`resulting from signals of abuse, misuse, overdose, and addiction.
`
`Reference ID: 3051468
`
` 5
`
`

`

`8. With respect to the REMS goals, an assessment of the extent to which the
`elements to assure safe use are meeting the goals or whether the goals or such
`elements should be modified
`
`4 DISCUSSION
`
`DRISK agreed that the timing of the distribution ofthe Dear Healthcare Professional
`Letter should be closely tied to first drug availability. However, in order to assess
`compliance with the REMS, and following discussion with DC, DRISK requested that
`the sponsor specify, in the REMS Supporting Document, a timeframe for when ‘first drug
`availability’ is to be expected. The sponsor replied by stating, “First availability of
`OPANA ER is anticipated to be around February 17, 2012.”
`
`
`
`5 CONCLUSION
`
`In conclusion, Endo’s proposed REMS for OPANA ER (oxymorphone hydrochloride
`extended-release, tablets 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg),
`submitted November 21, 2011, addresses the requirements stipulated by the FDA in the
`April 6, 2010 pre-NDA meeting via Teleconference, conforms to agency standards for
`other interim ER/LA opioid REMS, and incorporates all comments commlmicated to
`date. The proposed REMS includes a Medication Guide and Elements to Assure Safe
`Use, including a DHCP Letter, a Healthcare Professional Training Guide, an Education
`Confirmation Form, and REMS website.
`
`The OPANA ER REMS is acceptable to the Oflice of Surveillance and Epidemiology,
`the Division of Risk Management.
`
`Reference ID: 3051468
`
`

`

`6 RECOMMENDATIONS
`The OSE, DRISK recommends approval of the OPANA ER REMS (submitted 21
`November 2011; Seq No. 0032).
`
`
`
`ATTACHMENTS
`REMS Document
`Dear Healthcare Professional Letter
`Healthcare Professional Training Guide
`OPANA ER REMS Website
`OPANA ER REMS Education Confirmation Form
`
`
`
`Reference ID: 3051468
`
` 7
`
`34 pages has been withheld in full as B(4) 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/
`----------------------------------------------------
`
`DANIELLE SMITH
`11/30/2011
`
`CLAUDIA B KARWOSKI
`11/30/2011
`concur
`
`Reference ID: 3051468
`
`

`

`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`DRISK REMS REVIEW
`
`September 30, 2011
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia and Addiction Products
`(DAAAP)
`
`Claudia Karwoski, Pharm.D, Director
`Division of Risk Management (DRISK)
`
`Danielle Smith, Pharm.D, M.S.
`Risk Management Analyst (RMA), DRISK
`
`Megan Moncur, MS
`Team Leader, Risk Management Analyst (RMA), DRISK
`
`
`
`
`
`Kate Heinrich
`Health Communications Analyst, DRISK
`
`Mathilda Fienkeng
`Regulatory Review Officer
`Division of Drug Marketing, Advertising and
`Communications (DDMAC)
`
`Marcia Britt Williams
`Consumer Safety Officer,
`Division of Risk Management and Surveillance
`Office of Compliance
`
`Review of Proposed Risk Evaluation and Mitigation
`Strategies (REMS)
`
`Opana® ER (Oxymorphone Hydrochloride, Extended-
`Release Tablets)
`
`Endo Pharmaceuticals Inc.
`
`2010-1527
`
`
`Date:
`
`To:
`
`
`
`
`Through:
`
`
`From:
`
`
`
`
`
`
`
`
`
`
`Review Team:
`
`
`
`
`
`Reference ID: 3023450
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Subject:
`
`
`
`
`Drug Name (Established
`Name):
`
`
`
`
`
`
`
`Application Type/Number: NDA 201655
`
`Applicant:
`
`OSE RCM #:
`
`

`

`PURPOSE
`
`1
`
`This purpose of this review, performed at the request of the Division of Analgesia,
`Anesthesia and Addiction Products (DAAAP), is to evaluate Endo Pharmaceuticals’
`proposed Risk Evaluation and Mitigation Strategy (REMS) for Opana ER (oxymorphone
`hydrocholoride (HCl) extended-release (ER) tablets), submitted 07 September 2011.
`
` 2
`
`
`
`INTRODUCTION
`
`
`Opana ER (NDA 20-1655) is an opioid agonist, developed for the relief of moderate to
`severe pain in patients requiring continuous around-the-clock opioid treatment for an
`extended period of time. It is formulated as a hard tablet designed to withstand crushing.
`In standardized studies, oxymorphone HCl ER was shown to resist crushing forces in
`excess of
` however the clinical significance of this property and the impact
`on abuse liability has not been established.
`
`This product contains the same drug substance found in the immediate-release (IR;
`OPANA®, NDA 21-611) oral formulation of oxymorphone HCl, which was approved by
`the Food and Drug Administration (FDA) on June 22, 2006.
`
`In pre-NDA meeting communications (teleconference, 06 April 2010), FDA confirmed
`for Endo that an interim REMS would be required, pending approval of the class-wide
`Opioid REMS, to inform patients and providers about the potential for misuse, abuse,
`overdose, and addiction. Endo was informed that the REMS must include a Medication
`Guide and Elements to Assure Safe Use.
`
`On 07 July 2010, Endo submitted an Original NDA for Opana ER; the REMS included in
`this submission was consistent with the requirements conveyed by FDA.
`
`On December 10, 2010, comments from the first review of the proposed REMS and
`REMS materials [Interim REMS Review: Comment Set #1] were sent to the Sponsor. On
`December 17, 2010, the sponsor submitted the revised REMS documents incorporating
`the Agency’s comments. On December 30, 2010, additional REMS comments were
`provided to the sponsor via email correspondence through Ms. Lisa Basham, FDA Senior
`Regulatory Health Project Manager. The sponsor submitted the revised REMS document
`and REMS Supporting Document on January 6, 2011 (Seq. No. 0021).
`
`Subsequently, an audit performed by the Agency of the bioequivalence study EN3288-
`103 identified deficiencies in the methods used at the analytical site. Because of these
`deficiencies, the bioequivalence study could not be relied upon to establish
`bioequivalence of the proposed drug product. Therefore, NDA 201655 received a
`Complete Response (CR) Action Letter from the Agency on January 7, 2011. Due to the
`CR Action Letter, no comments were provided to the Sponsor on the REMS amendment
`submitted on January 6, 2011.
`
`In April 2011, the sponsors of all extended-release and long-acting (ER/LA) opioid
`products received a Pre-Approval REMS notification letter that stated in the interest of
`
`Reference ID: 3023450
`
`(b) (4)
`
`

`

`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 opioid products. The Agency is
`currently working with all sponsors of ER/LA opioids to develop the single shared
`system. Endo, and other sponsors with pending approvals, have been instructed to each
`develop an interim REMS that will conform with agency standards for approved interim
`REMS for other ER/LA opioid products.
`
`On June 13, 2011 (Seq. No. 0025), the sponsor submitted a Complete Response to the
`January 7, 2011 Action Letter. On August 31, 2011, comments on the proposed REMS
`were sent to the sponsor via email correspondence through Ms. Lisa Basham. On
`September 7, 2011, the sponsor submitted an amendment to the proposed REMS
`document and REMS Supporting Document (Seq. No. 0027). The proposed REMS,
`submitted on July 7, 2010 and amended on January 6, 2011, June 13, 2011, and
`September 7, 2011, is the subject of this review.
`
`
`MATERIALS REVIEWED OR REFERENCED
`
` 2
`
`
`
`
`The materials reviewed included:
`
`
`• Opana ER proposed REMS, REMS Supporting Document, and REMS
`Website Draft Screen Shots, received September 7, 2011 (Seq. No. 0027),
`including:
`o Dear Healthcare Professional (DHCP) Letter
`o Dear Pharmacist Letter
`o Healthcare Professional (HCP) Training Guide
`o Opana ER REMS Education Confirmation Form
`
`
`The materials referenced included:
`
`
`• DRISK Interim REMS Review: Comment Set #2. Reviewer: Smith, D., dated
`August 31, 2011.
`• Opana ER REMS Website Draft Screen Shots, received June 13, 2011 (Seq.
`No. 0025)
`• Pre-Approval REMS Notification Leter, dated April 18, 2011.
`• Opana ER proposed REMS and REMS Supporting Document, received
`January 06, 2011 (Seq. No. 0021), including:
`o Dear Healthcare Professional (DHCP) Letter
`o Dear Pharmacist Letter
`o Healthcare Professional (HCP) Training Guide
`o Opana ER REMS Education Confirmation Form
`• DRISK Interim REMS Review: Comment Set #1. Reviewer: Moncur, M.,
`dated December 9, 2010
`
`Reference ID: 3023450
`
`

`

`• Oxymorphone HCl ER proposed REMS and REMS Supporting Document,
`received July 07, 2010 (Seq. No. 0000), including:
`o Dear Healthcare Professional (DHCP) Letter,
`o Dear Pharmacist Letter,
`o Healthcare Professional (HCP) Training Guide
`• Opana ER proposed Prescribing Information, received June 13, 2011 (Seq.
`No. 0025)
`• REMS Memorandum, dated January 10, 2011.
`• Opana ER proposed Prescribing Information and Medication Guide, received
`January 06, 2011 (Seq. No. 0021)
`• OxyContin REMS (Initial Approval 04/2010; Most Recent Modification
`11/2010) and Prescribing Information
`• Exalgo REMS (Initial Approval 03/01/2010; Most Recent Modification
`03/24/2010)
`
`REVIEW OF PROPOSED REMS
`
` 3
`
`
`
`
`Following is a list of the documents reviewed and an overview of the proposed Opana ER
`REMS:
`• Opana ER REMS document
`• Opana ER REMS Supporting Document
`• Dear Healthcare Professional (DHCP) Letter
`• Dear Pharmacist Letter
`• Healthcare Professional (HCP) Training Guide
`• REMS Website Screen Shots
`
`
`3.1 Goals
`1. To inform patients and healthcare professionals about the potential for
`abuse, misuse, overdose and addiction associated with the use of OPANA
`ER
`2. To inform patients and healthcare professionals about the safe use of
`OPANA ER
`
`
`3.2
`
`REMS Elements
`
`3.2.1 Medication Guide
`A Medication Guide will be dispensed with each OPANA ER prescription in
`accordance with 21 CFR 208.24.
`
`
`
`Reference ID: 3023450
`
`

`

`3.2.2
`
`Elements to Assure Safe Use
`
`1. Healthcare professionals (HCP) who prescribe OPANA ER will receive
`training.
`
`a.
`
`ii.
`
`iii.
`
`iv.
`
`vi.
`
`vii.
`
`Endo will ensure that training will be provided to HCPs who prescribe
`OPANA ER. Endo will ensure that each prescriber will be provided
`with the OPANA ER REMS educational material.
`
`The OPANA ER REMS training includes the following:
`
`Proper patient selection
`Appropriate OPANA ER dosing and administration
`General opioid use including information about opioid abuse and
`how to identify patients who are at risk for addiction
`The risks of abuse, misuse, overdose, and addiction from exposure
`to opioids, including OPANA ER
`Risk of OPANA ER, including:
`1. The risk of overdose caused by exposure to an essentially
`immediate—release form of oxymorphone by consuming
`broken, chewed, crushed or dissolved OPANA ER tablets
`2. The risk of addiction from exposure to OPANA ER
`Information to counsel patients on the need to store opioid
`analgesics safely out of the reach of children and household
`acquaintances
`The importance of providing each patient with a Medication
`Guide, instructing the patient to read the Medication Guide and
`assisting the patient in understanding the content.
`
`C.
`
`Endo will ensure that
`
`(no)
`
`, a Dear Healthcare Professional letter will be mailed to HCPs
`experienced in treating chronic pain with opioid agonists, including
`pain specialists and primary care physicians. This letter is designed to
`convey and reinforce the risks of abuse, misuse, overdose, and
`addiction of OPANA ER, as well as the need to complete the OPANA
`ER REMS prescriber training. The letter will be available on the
`OPANA ER REMS website (www.0PANAERrems.com) for 1 year
`from the date of mailing.
`
`The Dear Healthcare Professional letter mailing will include the
`following materials:
`
`i. Full Prescribing Information
`ii. Medication Guide
`
`iii. OPANA ER Healthcare Professional (HCP) Training Guide
`iv. OPANA ER REMS Education Confirmation Form
`
`(II) (4)
`
`Reference ID: 3023450
`
`

`

`(I!)(4)
`
`f. Additional copies of the printed REMS materials will be available for
`download via the OPANA ER website www.0PANAERrems.com or
`
`by calling Endo’s toll-free phone number 1—800-462-3636.
`
`g. Endo will maintain a list of all prescribers who have completed the
`OPANA ER REMS training.
`
`Prescribers will be re-trained every two years or following substantial changes to
`the OPANA ER REMS. Substantial changes may include changed to the
`OPANA ER Full Prescribing Information or to the Medication Guide that require
`substantial modification of the REMS educational materials.
`
`The following materials are part of the REMS and are appended:
`
`Medication Guide
`
`Dear Healthcare Professional letter
`
`OPANA ER Healthcare Professional gflCP! Training Guide
`(I!) (4)
`
`OPANA ER REMS Website
`
`OPANA ER REMS Education Confirmation Foun
`
`3.3
`
`REMS Assessment Plan
`
`Endo 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.
`
`The following information needed for assessments is included in the REMS Supporting
`Document:
`
`1. An evaluation of patients’ understanding of the serious risks of OPANA ER.
`
`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. A report on the status of the training program for healthcare providers.
`
`5. An evaluation of healthcare providers’ awareness and understanding of the
`serious risks associated with OPANA ER (for example, through surveys of
`healthcare providers).
`
`6. Specification of measures that would be taken to increase awareness if surveys of
`healthcare providers indicate that healthcare provider awareness is not adequate.
`
`Reference ID: 3023450
`
`

`

`7. An analysis and summary of surveillance and monitoring activities for abuse,
`misuse, overdose, and addiction of OPANA ER and any intervention taken
`resulting from signals of abuse, misuse, overdose, and addiction.
`8. With respect to the REMS goals, an assessment of the extent to which the
`elements to assure safe use are meeting the goals or whether the goals or such
`elements should be modified.
`
`
`
`DISCUSSION AND RECOMMENDATIONS
`
`4
`
`Endo’s proposed REMS for OPANA ER (submitted Sept. 7, 2011) addresses the
`requirements stipulated by the FDA in the April 6, 2010 pre-NDA meeting via
`teleconference and conforms to agency standards for other interim ER/LA opioid REMS.
`The proposed REMS includes a Medication Guide and Elements to Assure Safe Use,
`including a DHCP Letter, a Dear Pharmacist Letter, a Healthcare Professional Training
`Guide, an Education Confirmation Form, and REMS website.
`
`One additional recommendation was communicated to the sponsor via email
`correspondence on Sept. 21, 2011 (through the Regulatory Project Manager, Ms. Lisa
`Basham), and is described below:
`
`
`• Please modify the goals of your REMS to read as follows:
`
`
`
`I. GOAL(S):
`
`The goals of the OPANA ER REMS are:
`
`1. To inform patients and healthcare professionals about the potential for abuse,
`misuse, overdose and addiction associated with the use of OPANA ER
`2. To inform patients and healthcare professionals about the safe use of OPANA
`ER
`
`CONCLUSION
`
` 5
`
`
`
`
`The DRISK Review Team finds the proposed REMS and REMS materials for OPANA
`ER, as submitted September 7, 2011 (and appended to this review) to be acceptable
`(pending DRISK’s verification of the recommended revisions).
`
`Reference ID: 3023450
`
`50 pages has been withheld in full as B(4) 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/
`----------------------------------------------------
`
`DANIELLE SMITH
`09/30/2011
`
`CLAUDIA B KARWOSKI
`10/03/2011
`concur
`
`Reference ID: 3023450
`
`

`

`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`DRISK INTERIM REMS REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`August 31, 2011
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia and Analgesia Products (DAAP)
`
`Claudia Karwoski, Pharm.D, Director
`Division of Risk Management (DRISK)
`
`Danielle Smith, Pharm.D, M.S.
`Risk Management Analyst (RMA), DRISK
`
`Megan Moncur, MS
`Team Leader, Risk Management Analyst (RMA), DRISK
`
`
`
`
`
`Kate Heinrich
`Health Communications Analyst, DRISK
`
`Mathilda Fienkeng
`Regulatory Review Officer
`Division of Drug Marketing, Advertising and
`Communications (DDMAC)
`
`Agnes Plante, BSN, RN
`Consumer Safety Officer,
`Division of Risk Management and Surveillance
`Office of Compliance
`
`Interim REMS Review Comment Set # 2
`
`Opana® ER (Oxymorphone Hydrochloride, Extended-
`Release Tablets)
`
`Endo Pharmaceuticals
`
`2010-1527
`
`
`Date:
`
`To:
`
`
`
`
`Through:
`
`
`From:
`
`
`
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`
`
`
`
`
`
`Review Team:
`
`
`
`
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`
`
`Reference ID: 3008927
`
`Subject:
`
`Drug Name (Established
`Name):
`
`
`
`
`
`
`
`Application Type/Number: NDA 201655
`
`Applicant:
`
`OSE RCM #:
`
`
`

`

`INTRODUCTION
`
`1
`
`The purpose of this interim review is to provide recommendations on Endo’s proposed
`REMS for Opana ER (Oxymorphone Hydrocholoride (HCl) Extended-Release (ER)
`tablets), submitted 06 January 2011. The review includes recommendations to the review
`division and letter-ready comments for the applicant.
`
` 2
`
`
`
`
`The materials reviewed included:
`
`
`MATERIALS REVIEWED OR REFERENCED
`
`• Opana ER REMS Website Draft Screen Shots, received June 13, 2011 (Seq.
`No. 0025)
`
`• Opana ER proposed REMS and REMS Supporting Document, received
`January 06, 2011 (Seq. No. 0021), including:
`o Dear Healthcare Professional (DHCP) Letter,
`o Dear Pharmacist Letter,
`o Healthcare Professional (HCP) Training Guide
`o Opana ER REMS Education Confirmation Form
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3008927
`
`
`The materials referenced included:
`
`
`• DRISK Interim REMS Review: Comment Set #1. Reviewer: Moncur, M.,
`dated December 9, 2010
`
`• DDMAC Internal Consult for Opana ER REMS Materials, received August
`10, 2011. Reviewer: Mathilda Fienkeng
`
` •
`
` Oxymorphone HCl ER proposed REMS and REMS Supporting Document,
`received July 07, 2010 (Seq. No. 0000), including:
`o Dear Healthcare Professional (DHCP) Letter,
`o Dear Pharmacist Letter,
`o Healthcare Professional (HCP) Training Guide
`
`
`• Opana ER proposed Prescribing Information, received June 13, 2011 (Seq.
`No. 0025)
`
` •
`
` Opana ER proposed Prescribing Information and Medication Guide, received
`January 06, 2011 (Seq. No. 0021)
`
`• OxyContin REMS (Initial Approval 04/2010; Most Recent Modification
`11/2010) and Prescribing Information
`
`

`

`• Exalgo REMS (Initial Approval 03/01/2010; Most Recent Modification
`03/24/2010)
`
`BACKGROUND
`
` 3
`
`
`
`
`Opana ER (NDA 20-1655) is an opioid agonist, developed for the relief of moderate to
`severe pain in patients requiring continuous around-the-clock opioid treatment for an
`extended period of time. It is formulated as a hard tablet designed to withstand crushing.
`In standardized studies, oxymorphone HCl ER was shown to resist crushing forces in
`; however the clinical significance of this property and the impact
`on abuse liability has not been established.
`
`This product contains the same drug substance found in the immediate-release (IR;
`OPANA®, NDA 21-611) oral formulation of oxymorphone HCl, which was approved by
`the Food and Drug Administration (FDA) on June 22, 2006.
`
`An audit performed by the Agency of the bioequivalence study EN3288-103 identified
`deficiencies in the methods used at the analytical site. Because of these deficiencies, the
`bioequivalence study could not be relied upon to establish bioequivalence of the proposed
`drug product. Therefore, NDA 20-1655 received a Complete Response (CR) Action letter
`from the Agency on January 7, 2011.
`
`On June 13, 2011, NDA 20-1655 was resubmitted.
`
`REMS SUMMARY
`
` 4
`
`
`
`
`In pre-NDA meeting communications (teleconference, 06 April 2010), FDA confirmed
`for Endo that an interim REMS would be re