CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`
`OTHER 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
`
`
`PATIENT LABELING REVIEW
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`October 03, 2011
`
`Bob Rappaport MD, Director
`Division of Anesthesia, Analgesia and Addiction Products
`(DAAAP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Acting Team Leader, Patient Labeling Reviewer
`Division of Risk Management (DRISK)
`Barbara Fuller, RN, MSN, CWOCN
`Acting Team Leader, Patient Labeling Reviewer
`Division of Risk Management
`
`Steve L. Morin, RN, BSN, OCN
`Patient Labeling Reviewer
`Division of Risk Management
`
`Subject:
`
`DRISK Review of Patient Labeling (Medication Guide)
`
`Drug Name (established
`name):
`Dosage Form and Route:
`
`OPANA ER (oxymorphone hydrochloride)
`
`Extended-Release tablets, CII
`
`Application Type/Number: NDA 201-655
`
`Endo Pharmaceuticals Inc.
`
`2011-2447
`
`Applicant:
`
`OSE RCM #:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3023753
`
`

`

`INTRODUCTION
`
`
`
` 1
`
`
`
`
`
`This review is written in response to a request by the Division of Anesthesia, Analgesia and
`Addiction Products (DAAAP) for the Division of Risk Management (DRISK) to review the
`Applicant’s proposed Medication Guide (MG) for OPANA ER (oxymorphone
`hydrochloride) Extended-Release tablets. The proposed indication for OPANA is for the
`relief of moderate to severe pain in patients requiring continuous, around-the-clock opioid
`treatment for an extended period of time.
`On July 7, 2010 Endo Pharmaceuticals submitted New Drug Application (NDA) 201-655
`for
` (oxymorphone hydrochloride) Extended-Release Tablets. . DRISK
`completed a review of the proposed Medication Guide on December 22, 2010. On January
`6 2011 Endo Pharmaceuticals
`
`submitted a request for the proposed proprietary tradename OPANA ER.
`On January 7, 2011 Endo received a Complete Response for bioequivalence study
`deficienciesOn June 13, 2011 Endo Pharmaceuticals submitted a Class 2 Resubmission for
`OPANA ER (oxymorphone hydrochloride) Extended-Release Tablets.
`The proposed REMS was reviewed by DRISK and submitted to DAAAP under separate
`cover on August 31, 2011.
`
` MATERIAL REVIEWED
`• Draft OPANA ER (oxymorphone hydrochloride) Extended-Release tablets Medication
`Guide (MG) received on June 13, 2011and sent to DRISK on September 19, 2011.
`• Draft OPANA ER (oxymorphone hydrochloride) Extended-Release tablets Prescribing
`Information (PI) received June 13, 2011 and sent to DRISK on September 19, 2011.
`
` 2
`
`
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th to 8th grade reading
`level, and have a reading ease score of at least 60%. A reading ease score of 60%
`corresponds to an 8th grade reading level. In our review of the MG the target reading level is
`at or below an 8th grade level.
`
`
`
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP)
`in collaboration with the American Foundation for the Blind (AFB) published Guidelines for
`Prescription Labeling and Consumer Medication Information for People with Vision Loss.
`The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make
`medical information more accessible for patients with vision loss. We have reformatted the
`MG document using the Verdana font, size 11.
`In our review of the MG we have:
`
`simplified wording and clarified concepts where possible
`ensured that the MG is consistent with the Prescribing Information (PI)
`
` •
`
`
`•
`
`
`
`
`
`Reference ID: 3023753
`
`(b) (4)
`
`(b) (4)
`
`

`

`•
`•
`•
`
`removed unnecessary or redundant information
`ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful
`Written Consumer Medication Information (published July 2006)
`
`
`4 CONCLUSIONS
`The MG is acceptable with our recommended changes.
`
`5 RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DRISK on the correspondence.
`• Our annotated versions of the MG are appended to this memo. Consult DRISK regarding
`any additional revisions made to the PI to determine if corresponding revisions need to be
`made to the MG.
` Please let us know if you have any questions.
`
`
`
`
`
`Reference ID: 3023753
`
`16 pages of draft labeling 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/
`----------------------------------------------------
`
`STEVE L MORIN
`10/03/2011
`
`LASHAWN M GRIFFITHS
`10/03/2011
`
`Reference ID: 3023753
`
`

`

`
`M E M O R A N D U M
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`
`Subject:
`
`September 30, 2011
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia, and Addiction Products (DAAAP)
`
`Michael Klein, Ph.D., Director
`Silvia Calderon, Ph.D., Team Leader
`Controlled Substance Staff
`
`James M. Tolliver, Ph.D., Pharmacologist
`Controlled Substance Staff
`
`NDA 201-655, OPANA ER (oxymorphone HCl) Extended-Release Tablets
`Indication: Relief of moderate to severe pain in patients requiring continuous
`around-the-clock opioid treatment for an extended period of time.
`Dosages: 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg
`Oxymorphone HCl
`Sponsor: Endo Pharmaceuticals Inc.
`
`
`Materials reviewed: Label for OPANA ER (oxymorphone HCl) Extended-Release Tablets (NDA
`201-655) (Module 1.14.1.3)
`
`
`
`
`I.
`
`Table of Contents
`SUMMARY ........................................................................................................................................................1
`A. BACKGROUND..................................................................................................................................................1
`B. CONCLUSIONS:.................................................................................................................................................2
`C. RECOMMENDATIONS:.......................................................................................................................................2
`
`
`I. Summary
`A. Background
`This memorandum is in response to a consult request dated July 5, 2011, from the Division of
`Anesthesia, Analgesia and Addiction Products (DAAAP) requesting that CSS review and
`comment on the labeling for OPANA ER (oxymorphone) Extended Release Tablets (NDA 201-
`655), to ensure that the current language is the same as was agreed upon during the first review
`cycle. CSS has reviewed the labeling with respect to abuse and dependence.
`OPANA ER (Oxymorphone HCl) Extended Release Tablets are formulated to contain 5 mg, 7.5
`mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg oxymorphone HCl. The product is intended for
`
`N201-655_OPANA ER_093011
`
`
`
`1 of 2
`
`Reference ID: 3023107
`
`

`

`
`
`twice daily dosing (q12h) for treatment of moderate to severe pain in patients requiring
`continuous, around-the-clock opioid treatment for an extended period of time. Tablets are an
` formulation of oxymorphone HCl.
`
`
`Endo Pharmaceuticals, Inc. received a CR letter January 7, 2011, regarding NDA 201-655 for
` noting a deficiency pertaining to issues with the bioequivalence analytical site. The
`labeling for the product was thoroughly reviewed and considered adequate during the first
`review cycle. The Sponsor subsequently provided a resubmission for OPANA ER
`(oxymorphone HCl) Extended Release Tablets addressing the deficiencies mentioned in the CR
`letter.
`
`
`CSS reviewed the following sections of the OPANA ER label: Boxed Warning, section "2.
`DOSAGE AND ADMINISTRATION", section "5. WARNINGS AND PRECAUTIONS", and
`section "9. DRUG ABUSE AND DEPENDENCE."
`
`
`B. Conclusions:
`1. The sections of the OPANA ER label conveying information related to abuse and
`misuse are consistent with the sections of the label agreed during the first cycle
`(EDR, NDA 20655, Submission dated 1/6/2011).
`
`C. Recommendations:
`1. CSS does not recommend any additional changes to the proposed label.
`
`
`
`
`
`
`N201-655_OPANA ER_093011
`
`
`
`2 of 2
`
`Reference ID: 3023107
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SILVIA N CALDERON
`09/30/2011
`
`MICHAEL KLEIN
`09/30/2011
`
`Reference ID: 3023107
`
`

`

`
`
`
`FROM:
`
`
`
`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` PUBLIC HEALTH SERVICE
`
`
`
`
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`September 19, 2011
`DATE:
`
`TO:
`Bob A. Rappaport, M.D.
`Director, Division of Anesthesia, Analgesia, and
`Addiction Products (DAAAP)
`Arindam Dasgupta, Ph.D. and
`Xikui Chen, Ph.D.
`Bioequivalence Investigations Branch
`Division of Bioequivalence and GLP Compliance (DBGC)
`Office of Scientific Investigations (OSI)
`
`THROUGH: Sam H. Haidar, Ph.D., R.Ph.
`Chief, Bioequivalence Investigations Branch
`Division of Bioequivalence and GLP Compliance (DBGC)
`Office of Scientific Investigations (OSI)
`
`SUBJECT: Review of EIR Covering NDA 201-655, OPANA (Oxymorphone
`HCl) Extended Release Tablets, 40 mg, Sponsored by
`Endo Pharmaceuticals, Inc., and
`
`At the request of DAAAP, Division of Bioequivalence and GLP
`Compliance audited the analytical portion of the following study:
`
`Study Number: EN3288-103
`
`Study Title: An Open-Label, Randomized, Single-Dose, Four-
`Period, Replicate, Crossover Study to Determine
`the Bioequivalence of EN3288 (Oxymorphone HCl
`Extended-Release
` Formulation) 40
`mg Compared to Opana® ER (Oxymorphone HCl
`Extended-Release) 40 mg in Healthy Subjects Under
`Fasted Conditions
`
`Analytical Site:
`
`
` corrective
`The inspection was conducted to verify
`actions to concerns raised
`following two previous FDA
`inspections in
` OSI had concerns about reliability of
`
`
`
`
`Reference ID: 3017275
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`Page 2 - NDA 201-655, OPANA (Oxymorphone HCl) Extended Release
`Tablets, 40 mg
`
`BE/BA data generated by
` for the following reasons:
`
`
`
`
`
`Following the audit of the analytical records of study EN3288-
`103
` at
`
` no Form FDA-
`483 was issued and there were no significant adverse findings.
`
`
`Conclusions:
`
`Following the above inspection, the Division of Bioequivalence
`and GLP Compliance concludes that sufficient corrective actions
`to the concerns raised
` were implemented
`for the current study
` and recommends
`that the analytical data of study EN3288-103 be accepted for
`Agency review.
`
`After you have reviewed this transmittal memo, please append it
`to the original NDA submission.
`
`
`
`
`Arindam Dasgupta, Ph.D.
`
`
`
`Xikui Chen, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sam H. Haidar, Ph.D.,R.Ph.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3017275
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` – NAI (Analytical)
`
`Page 3 - NDA 201-655, OPANA (Oxymorphone HCl) Extended Release
`Tablets, 40 mg
`Final Classification:
`
`
`cc:
`CDER DSI PM TRACK
`OC/Ball/Moreno
`OC/OSI/DBGC/Salewski/Haidar/Dasgupta/Chen/Skelly/Dejernett
`ORA/DAL-DO/Gatica
`ORAORO/DDFI/NES/McClure
`OND/ODEII/DAAAP/Lisa Basham
`OTS/OCP/DCPII/Yun Xu
`
`Draft: XC 9/19/2011
`Edit: MFS 9/19/2011; SHH 9/19/2011
`OSI: 6225; O:\BE\EIRCOVER\201655end.oxy.doc
`FACTS
`
`
`
`Reference ID: 3017275
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`XIKUI CHEN
`09/19/2011
`
`SAM H HAIDAR
`09/20/2011
`
`ARINDAM DASGUPTA
`09/20/2011
`
`Reference ID: 3017275
`
`

`

`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
`
`Label and Labeling Review
`
`Date:
`
`September 2, 2011
`
`Reviewer(s):
`
`Team Leader
`
`Division Director
`
`Drug Name:
`
`Jibril Abdus-Samad, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`Todd Bridges, RPh, Team Leader
`Division of Medication Error Prevention and Analysis
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`Opana ER (Oxymorphone) Extended-release Tablets
`
`5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg
`
`Application Type/Number: NDA 201655
`Applicant:
`Endo Pharmaceuticals Inc.
`OSE RCM #:
`2011-2446
`
`*** This document contains proprietary and confidential information that should not be
`released to the public.***
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3009981
`
`1
`
`

`

`1
`INTRODUCTION
`This review evaluates the proposed container label and insert labeling for Opana ER
`(NDA 201655) for areas of vulnerability that can lead to medication errors. Endo
`Pharmaceuticals Inc. submitted the proposed labels and labeling on June 13, 2011.
`1.1 REGULATORY HISTORY
`Opana ER (Oxymorphone) extended-release tablets (NDA 021610) was approved on
`June 22, 2006. The Applicant submitted NDA 201655 on July 7, 2010 to propose an
`abuse-deterrent formulation of oxymorphone extended-release tablets. The Applicant
`intends to replace the currently marketed formulation approved under NDA 021610 with
`the new formulation in NDA 201655 and therefore, proposes to continue using the
`Opana ER proprietary name per agreement with DAAAP during an Endo/FDA
`teleconference held January 5, 2011. On January 7, 2011, NDA 201655 received a
`Complete Response due inability to establish bioequivalence of the proposed product to
`the reference product (NDA 021610). The Applicant proposes to establish
`bioequivalence in this submission.
`1.2 PRODUCT INFORMATION
`Opana ER is the relief of moderate to severe pain in patients requiring continuous,
`around-the-clock opioid treatment for an extended period of time. Opana ER tablets are
`to be swallowed whole and not to be broken, chewed, dissolved, or crushed. Opana ER is
`to be administered every 12 hours with the following dose recommendations:
`• Opioid naive patients - 5 mg every 12 hours
`• Conversion from Opana to Opana ER – half the patient's total daily oral
`Opana dose as Opana ER, every 12 hours.
`• Conversion from parenteral - administer 10 times the patient’s total daily
`parenteral oxymorphone dose as Opana ER in two equally divided doses
`[(intravenous dose x 10) divided by 2].
`• Conversion from other oral opioids – follow Dose Conversion table in insert
`labeling.
`Opana ER is available as 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg tablets
`in bottles of 100 tablets. Opana ER should be stored at 25°C (77°F); excursions
`permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. The
`Applicant designed the proposed formulation to be physically harder than the referenced
`formulation to serve as an abuse deterrent.
`
`
`
`
`
`Reference ID: 3009981
`
`2
`
`

`

`2
`
`NIETHODS AND MATERIALS REVIEWED
`
`Using Failure Mode and Effects Analysis1 and postmarketing medication error data, the
`Division of Medication Error Prevention and Analysis (DMEPA) evaluated the
`following:
`
`0 Container Labels submitted June 13, 2011 (Appendix A)
`
`0
`
`Insert Labeling submitted June 13, 2011 (no image)
`
`Additionally, since Opana ER is currently marketed, DMEPA searched the FDA Adverse
`Event Reporting System (AERS) database to identify medication errors involving Opana
`ER. The AERS search conducted on August 19, 2011 used the following search terms:
`active ingredient “Oxymorphone”, trade name “Opana ER”, and verbatim terms
`“Opana%” with selection of extended-release formulation only and “Oxymor%”. The
`reaction terms used were the MedDRA High Level Group Terms (HLGT) “Medication
`Errors” and “Product Quality Issues”. The time frame was limited from previous OSE
`Review 2010—2081 date of the AERS search, October 4, 2010, until present.
`
`The reports were manually reviewed to determine if a medication error occurred.
`Duplicate reports were combined into cases. The cases that described a medication error
`were categorized by type of error. We reviewed the cases within each category to
`identify factors that contributed to the medication errors. Ifa root cause was associated
`with the label or labeling of the product, the case was considered pertinent to this review.
`Reports excluded from the case series include those that involved intentional overdoses,
`drug diversion, manipulation of Opana ER for abuse, patient self-adjusting their doses or
`cases that did not describe a medication error.
`
`Following exclusions, there were zero cases relevant to this review. Additionally, there
`were no cases involving drug name confusion.
`
`3
`
`DISCUSSION
`
`TheAnlicantis rosin-
`
`
`
`Additionally, in OSE Review 2010—1651, we provided recommendations to the container
`label and carton labeling to minimize the potential for medication errors. The Applicant
`addressed DMEPA’s label and labeling recommendations from both OSE Reviews 2010-
`2081 and 2010—1651. However, we have identified a few other revisions that should be
`completed before approval.
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. II-I[:2004.
`
`Reference ID: 3009981
`
`

`

`4
`CONCLUSIONS AND RECOMMENDATIONS
`DMEPA concludes that the proposed container labels introduce vulnerability that can
`lead to medication errors because the proprietary name appears as one word and the
`strength presentation lacks prominence. To minimize these problems, we recommend the
`following:
`A.
`Container Label
`1. Revise the presentation of the proprietary name to title case to appear as
`Opana ER. Additionally, add more space between Opana and ER.
`Currently, Opana ER looks like one word instead of the root name,
`Opana, and modifier, ER.
`2. Increase the prominence of the strength presentation, x mg, by increasing
`the font size.
`3. Submit container labels for the 100 tablet count bottle after completing the
`above revisions.
`If you have further questions or need clarifications, please contact Danyal Chaudhry,
`OSE project manager, at 301-796-3813.
`
`
`
`
`
`Reference ID: 3009981
`
`4
`
`

`

`5
`
`REFERENCES
`1. Abdus-Samad, J. OSE Review 2010-1651: DMEPA Label and Labeling
`Review for
` December 16, 2010
`2. Abdus-Samad, J. OSE Review 2010-2081: DMEPA Medication Review for
`Opana ER, October 28, 2010
`
`
`
`
`
`Reference ID: 3009981
`
`5
`
`(b) (4)
`
`1 page of draft labeling has been withheld in full as
`B(4) CCI/TS immediately following this page
`
`

`

`Appendix B: ISR numbers from AERS database search
`
`ISR numbers
`7050431
`7266095
`7392010
`7298687
`7374265
`7380552
`7085797
`7371730
`7308176
`7265643
`7430159
`7493851
`7570108
`7653585
`7451714
`7374061
`7085145
`7293485
`7307408
`7461562
`7554056
`7114246
`7135428
`7097735
`7097736
`7051382
`7638090
`7369577
`7420174
`7568946
`
`
`
`
`
`7554055
`7101147
`7570107
`7406346
`7417569
`7423561
`7614396
`7597904
`7642520
`7635541
`7539693
`7101898
`7074543
`7132425
`7374233
`7472735
`7465132
`7155803
`7326356
`7245419
`7429307
`7315115
`7286095
`7556608
`7570929
`7069251
`7084165
`7114569
`7209107
`7568954
`7623579
`
`
`
`
`
`Reference ID: 3009981
`
`7
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JIBRIL ABDUS-SAMAD
`09/02/2011
`
`CAROL A HOLQUIST
`09/02/2011
`
`Reference ID: 3009981
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`MEMORANDUM
`
`
`PUBLIC HEALTH SERVICE
`
`
`
`
`
`FOOD AND DRUG ADMINISTRATION
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`___________________________________________________________
`
`DATE:
`
`TO:
`
`January 5, 2010
`
`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia and Analgesia Products
`(DAAP)
`
`
`FROM:
`
`John A. Kadavil, Ph.D.
`Division of Scientific Investigations (HFD-48)
`
`
`THROUGH: Sam H. Haidar, Ph.D., R.Ph. ____________
`
`
`Acting Branch Chief,
`
`
`GLP and Bioequivalence Investigation Branch
`
`
`Division of Scientific Investigations
`
`
`
`Martin K. Yau, Ph.D. _______
`Acting Team Leader (Bioequivalence)
`Division of Scientific Investigations (DSI)
`
`
`
`
`SUBJECT: Addendum to the Review of EIRs Covering NDA 201-
`655,
` (Oxymorphone HCl) Extended-Release
`Tablets 5, 7.5, 10, 15, 20, 30, 40 mg, Sponsored
`by Endo Pharmaceuticals
`
`
`At the request of DAAP, the Division of Scientific
`Investigations conducted an audit of the clinical and
`analytical portions of the following bioequivalence study
`supporting NDA 201-655:
`
`Study Number:
`
`Study Title:
`
`EN3288-103
`
`“An open-label, randomized, single-
`dose, four-period, replicate, crossover
`study to determine the bioequivalence
`of EN3288 (Oxymorphone HCl extended-
`release
` formulation)
`40 mg compared to OPANA® ER (Oxymorphone
`HCl extended-release) 40 mg in healthy
`subjects under fasted conditions”
`
`
`
`
`
`
`
`Reference ID: 2887289
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 2 - NDA 201-655,
`Release Tablets
`
` (Oxymorphone HCl) Extended-
`
`DSI inspection summary memo for the above study was sent to
`DAAP on
`. DSI recommended that the study
`not be accepted for review at that time
`
`
`
` (analytical site)
`On
`submitted their written response to the Form FDA 483. Our
`evaluation of the firm’s written response is summarized
`below:
`
`
`
`
`
`Conclusion:
`
`Based on (1) the allegations mentioned in our cover memo
`submitted to you on
`, (2) unsolved issues from
` previous inspection in
`
`
`
`Reference ID: 2887289
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Page 3 - NDA 201-655,
`Release Tablets
`
` (Oxymorphone HCl) Extended-
`
`
`In summary, DSI’s recommendation provided in the previous
`EIR cover memo
` remains unchanged.
`
`After you have reviewed this transmittal memo, please
`append it to the original NDA submission.
`
`
`
`
`
`
`
`John A. Kadavil, Ph.D.
`Pharmacologist
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Final Classification:
`
`
` – OAI
`Seaview Research, Miami, FL - NAI
`
`
`
`cc:
`OC DSI/Ball/Haidar/Yau/Viswanathan/Kadavil/Dejernett/CF
`OND ODEII DAAP/Basham
`OTS OCP DCPII/Nallani
`Draft: JAK 1/5/10
`Edit: MKY 1/5/10
`Edit: SHH 1/5/10
`DSI: 6111; O:\BE\EIRCover\201655end.rev.addeundum.doc
`FACTS 1203792
`
`
`
`Reference ID: 2887289
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN A KADAVIL
`01/05/2011
`
`MARTIN K YAU
`01/05/2011
`
`SAM H HAIDAR
`01/05/2011
`
`Reference ID: 2887289
`
`

`

`
`
`Date:
`
`
`To:
`
`
`Subject:
`
`
`
`
`From:
`Mathilda Fienkeng – Regulatory Review Officer
`
` Division of Drug Marketing, Advertising, and Communications (DDMAC)
`
`DDMAC draft labeling comments
`NDA 201655
` (oxymorphone hydrochloride) Extended-Release
`tablets C-II
`
`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`
`**PRE-DECISIONAL AGENCY MEMO**
`
`December 22, 2010
`
`Lisa Basham – Senior Regulatory Health Project Manager
`Division of Anesthesia, and Analgesia Products (DAAP)
`
`
`
`
`
`
`
` (oxymorphone
`DDMAC has reviewed the proposed product labeling (PI), for
`hydrochloride) Extended-Release tablets C-II (
` submitted for DDMAC review on July
`13, 2010.
`
`The following comments are provided using the draft PI sent via email by Lisa Basham on
`December 21, 2010. If you have any questions about DDMAC’s comments, please do not
`hesitate to contact me. DDMAC will provide comments on the proposed Medication Guide
`under separate cover.
`
`
`
`
`
`
`1
`
`Reference ID: 2882812
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`22 Page(s) of Draft Labeling have 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/
`----------------------------------------------------
`
`MATHILDA K FIENKENG
`12/22/2010
`
`Reference ID: 2882812
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`PATIENT LABELING REVIEW
`
`December 22, 2010
`Bob Rappaport MD, Director
`Division of Anesthesia and Analgesia Products (DAAP)
`
`Sharon Mills, BSN, RN, CCRP
`Senior Patient Labeling Reviewer
`Division of Risk Management (DRISK)
`Barbara Fuller, RN, MSN, CWOCN
`Patient Labeling Reviewer
`Division of Risk Management
`
`Steve L. Morin, RN, BSN, OCN
`Patient Labeling Reviewer
`Division of Risk Management
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`
`DRISK Review of Patient Labeling (Medication Guide)
`
` (Oxymorphone hydrochloride), CII
`
`Drug Name (established
`
`name):
`Extended-Release tablets
`Dosage Form and Route:
`Application Type/Number: NDA 201655
`Therapeutic Class:
`Opioid Analgesic
`Applicant:
`Endo Pharmaceuticals Inc.
`
`2010-1527
`
`OSE RCM #:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 2882348
`
`
`
`(b) (4)
`
`

`

`1
`
`INTRODUCTION
`
`This review is written in response to a request by the Division of Anesthesia and Analgesia
`Products (DAAP) for the Division ofRisk Management (DRISK) to review the Applicant’s
`proposed Medication Guide (MG) for
`0"
`(oxymorphone hydrochloride) Extended-
`Release tablets. The Applicant submitted New Drug Application, NDA 201655, on July 7,
`2010 for
`no (ox
`orphone hydrochloride) Extended-Release tablets. The proposed
`indication for
`o)
`is for the relief of moderate to severe pain in patients requiring
`continuous, around-the-clock opioid treatment for an extended period of time.
`
`DRISK’s review of the proposed interim REMS was sent to DAAP under separate cover
`dated Month December 10, 2010.
`
`2 MATERIAL REVIEWED
`
`mo (oxymorphone hydrochloride) Extended-Release tablets Medication
`o Drafi
`Guide (MG) received on July 7, 2010, and revised by the review division throughout the
`review cycle, and sent to DRISK on December 14, 2010.
`
`mu (oxymorphone hydrochloride) Extended-Release tablets prescribing
`0 Draft
`information (PI) received July 7, 2010, and revised by the Review Division throughout
`the current review cycle, and received by DRISK on December 14, 2010.
`
`3
`
`REVIEW METHODS
`
`To enhance patient comprehension, materials should be written at a 6‘ll to 8"1 grade reading
`level, and have a reading ease score of at least 60%. A reading ease score of 60%
`corresponds to an 8tll grade reading level. In our review of the MG the target reading level is
`at or below an 8‘ll grade level.
`
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP)
`in collaboration with the American Foundation for the Blind (AFB) published Guidelinesfor
`Prescription Labeling and Consumer Medication Informationfor People with Vision Loss.
`The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make
`medical information more accessible for patients with vision loss. We have reformatted the
`MG document using the Verdana font, size 11.
`
`In our review of the MG we have:
`
`0
`
`0
`
`0
`
`o
`
`0
`
`simplified wording and clarified concepts where possible
`
`ensured that the MG is consistent with the prescribing information (PI)
`
`removed unnecessary or redundant information
`
`ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`
`ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful
`Written Consumer Medication Information (published July 2006)
`
`4
`
`CONCLUSIONS
`
`The MG is acceptable with our recommended changes.
`
`Reference ID: 2882348
`
`

`

`5 RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DRISK on the correspondence.
`• Our annotated versions of the MG are appended to this memo. Consult DRISK regarding
`any additional revisions made to the PI to determine if corresponding revisions need to be
`made to the MG.
` Please let us know if you have any questions.
`
`
`
`Reference ID: 2882348
`
`17 pages of draft labeling 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/
`----------------------------------------------------
`
`BARBARA A FULLER
`12/22/2010
`
`SHARON R MILLS
`12/22/2010
`I concur.
`
`Reference ID: 2882348
`
`

`

`
`
`
`
`
`
`
`Date:
`
`To:
`
`
`
`
`From:
`
`
`Subject:
`
`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`
`**PRE-DECISIONAL AGENCY MEMO**
`
`
`
`December 22, 2010
`
`Lisa Basham – Senior Regulatory Health Project Manager
`Division of Anesthesia, and Analgesia Products (DAAP)
`
`Twyla Thompson – Regulatory Review Officer
`Division of Drug Marketing, Advertising, and Communications (DDMAC)
`
`DDMAC draft labeling comments
`NDA 201655
` (oxymorphone hydrochloride) Extended-
`Release tablets C-II
`
`
` (oxymorphone
`DDMAC has reviewed the proposed Medication Guide, for
`hydrochloride) Extended-Release tablets C-II (
` submitted for DDMAC review
`on July 13, 2010.
`
`The following comments are provided using the draft Medication Guide sent via email
`by Lisa Basham on December 22, 2010. If you have any questions about DDMAC’s
`comments, please do not hesitate to contact me. Comments on the proposed product
`labeling (PI) were provided under separate cover by Mathilda Fienkeng.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
`
`Reference ID: 2882866
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`6 pages of draft labeling 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/
`----------------------------------------------------
`
`TWYLA N THOMPSON
`12/22/2010
`
`Reference ID: 2882866
`
`

`

`M E M O R A N D U M
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Date:
`
`December 21, 2010
`
`To:
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia and Analgesia Products
`
`Through:
`
`Michael Klein, Ph.D., Director
`Silvia Ca