CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`SUMMARY REVIEW
`
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`

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`h FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA, ANALGESIA AND ADDICTION PRODUCTS
`
`Summary Review for Regulatory Action
`
`
`December 9, 2011
`
`Bob A. Rappaport, MD.
`Director
`
`Division Of Anesthesia, Analgesia and Addiction
`
`Products
`
`20 165 5
`NDA #
`
`Endo Pharmaceuticals
`Applicant Name
`Date of Submission
`
`June 13, 2011
`
`Division Director Summa Review
`
`PDUFA Goal Date
`
`December 13, 2011
`
`Proprietary Name /
`Established
`S I
`
`Name
`
`Opana ER/
`Ox :- o shone HCl extended-release tablets
`
`Dosage Forms / Strength
`
`Extended-release tablets
`
`5 m, 7.5 m,10m,15m
`
`
`
`Proposed Indication
`
`For the relief Of moderate to severe pain in patients
`requiring continuous, around-the-clock opioid
`
`treatment for an extended period of time
`A roval
`
`Action:
`
`Reference ID: 3056615
`
`

`

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`
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`CDTL
`CMC
`Clinical Pharmacology
`Controlled Substance Staff
`OSI
`
`OSE/DMEPA
`
`OSE/DRISK (patient labeling)
`
`OSE/DRISK (REMS)
`
`Ellen Fields, M.D., M.P.H.
`Craig Bertha, Ph.D., Prasad Peri, Ph.D.
`Srikanth Nallani, Ph.D., Yun Xu, Ph.D.
`Silvia Calderon, Ph.D., Michael Klein, Ph.D.
`Arindam Dasgupta, Ph.D., Xikui Chen, Ph.D.,
`Sam Haider, Ph.D.
`Jibril Abdus-Samad, Pharm.D., Kellie Taylor,
`MPH, Carol Holquist, RPh.
`Steve Morin, R.N., B.S.N., O.C.N., LaShawn
`Griffiths, MSHS-PH, BNS, RN
`Megan Moncur, M.S., Danielle Smith, Pharm.D.,
`M.S., Claudia Karwoski, Pharm.D.
`Lisa Basham, M.S., Parinda Jani
`
`Project Management
`
`OND=Office of New Drugs
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DRISK=Division of Risk Management
`CDTL=Cross-Discipline Team Leader
`OSI=Office of Scientific Investigations (previously known as the Division of Scientific Investigations or DSI)
`
`1. Introduction
`
`Endo Pharmaceuticals has submitted this application for a reformulated version of their
`approved oxymorphone ER product, Opana ER. This new formulation, developed with
`their partner Grünenthal GmbH, was intended to
`
`reduce accidental misuse and deter certain specific methods of abuse. The support for
`the efficacy and safety of this new product was intended to be based entirely on
`bioequivalence to the previously approved product. The new formulation will be dosed
`on the same schedule as the old formulation and will be available in the same dosage
`strengths.
`
`On January 7, 2011, a Complete Response (CR) Letter was issued for the original
`application of NDA 201655. The current submission is the Applicant’s response to the
`CR Letter.
`
`
`
`
`
`Reference ID: 3056615
`
`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`Opana ER (New Formulation)
`December 9, 2011
`
`
`2
`
`(b) (4)
`
`

`

`2. Background
`
`The CR Letter defined a single deficiency that resulted in the Complete Response
`action and three possible methods of addressing this deficiency:
`
`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 cannot be relied upon to establish bioequivalence ofyour proposed
`drug product to the reference product.
`
`This deficiency may be addressed by doing one of the following:
`
`1. Provided adequate samples are available, rmalyze blood samples collected in
`bioequivalence study EN3288-103 and submit data establishing the
`bioequivalence of Oxymorphone Hydrochloride Extended-Release 40 mg tablets
`with OPANA ER 40 mg tablets. Ensure that the inspectional findings identified
`in the Agency’s audit of study EN3288-103 are properly addressed in the
`reanalysis of blood samples.
`
`OR
`
`2. Conduct another pharmacokinetic study and establish the bioequivalence of
`Oxymorphone Hydrochloride Extended-Release 40 mg tablets with OPANA ER
`40 mg tablets under fasting conditions using adequately validated analytical
`methodology.
`
`OR
`
`3. Conduct a clinical development program with clinical eflicacy and safety studies
`to support your product.
`
`The Applicant chose to address the deficiency by assaying back-up samples from
`Study EN3288-103. The data from these assays form the basis for this submission.
`My detailed first-cycle review and summary basis for the Complete Response action
`has been appended to this review. This review will only address the contents of the
`current submission and whether the Applicant has provided data to sufficiently address
`the deficiency noted above. The reader is referred to the Appendix and the primary and
`secondary reviews for additional detail and discussion of this application.
`
`Of note, durin the first c cle the review team determined that the data submitted to
`
`
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`formulation has demonstrated a minimal improvement in resistance to tampering by
`crushing, thereby limiting the likelihood of abuse by crushing followed by ingestion,
`and by insufflation snortin
`to some de ee, it can still be
`, cut
`rendering it readily abusable
`
`3
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`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`
`Opana ER (New Formulation)
`December 9, 2011
`
`Reference ID: 3056615
`
`

`

`by ingestion and intravenous injection, and possibly still by insufflation; although
`whether
`tablets can be snorted was not studied. Of more concern, when
`chewed
`the new formulation essentially dose dumps
`like an immediate-release formulation. While the label and MedGuide could certainly
`c
`warnin s a ainst chewin , we remain concerned that an lan
`
`e in the label
`
`3. CMC
`
`The following summary of the CMC information in the current submission has been
`reproduced from pages 2 and 3 of Dr. Fields’ review:
`
`There were no CMC-related issues pending at the time of the Complete Response action
`in January, 2011. The resubmission of June 13, 2011, included updated stability data and
`a proposed extension of the expiration dating period for the drug product to 36 months,
`with storage at controlled room temperature.
`In addition, update drug product stability
`datawere
`videdforas'
`ebatchof5and40
`strengths
`. The original application had
`contained stability data for both 60 and 100 count bottle presentations, but the labeling
`had only been presented for the latter. This resubmission included bottle labels for both
`the 60 and 100 count bottles.
`
`The manufacturing facilities received an overall “Acceptable” cGMP recommendation
`from the Oflice of Compliance on November 15, 2010
`
`The information submitted was found acceptable by Dr. Bertha, who recommended
`approval of OPANA ER from the CMC paspective.
`
`I concur with the review team that there are no outstanding CMC issues that would
`impact approvability.
`
`4. Nonclinical Pharmacology/Toxicology
`
`No new nonclinical pharmacology or toxicology data were submitted with this
`application.
`
`5. Clinical PharmacologyIBiopharmaceutics
`
`The following summary of the new clinical pharmacology data in this submission has
`been reproduced from pages 3 and 4 of Dr. Fields’ review:
`
`Dr. Nallani’s current review focuses on the reanalysis of samples from study EN3288-
`103: A bioequivalence study of 40 mg tablets in healthy subjects lmder a fasted state.
`
`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`
`Opana ER (New Formulation)
`December 9, 201 1
`
`Reference ID: 3056615
`
`

`

`Details regarding review of all clinical pharmacology data submitted during the first
`review cycle may be found in Dr. Nallani’s prior review, dated January 6, 2011.
`
`Bioequivalence of EN3288 to OPANA ER was established with the highest dose, 40 mg.
`The table below from Dr. Nallani’s review of the reanalysis shows the results of the BE
`studies.
`
`
`Table 3: Summary Table of BE reanalyses of EN3288 40 mg compared to Opana ER 40 mg
`
`Source: Dr. Nallani’s review, p. 3
`
`
`Additionally, the following table from Dr. Nallani’s review compares the results of Study
`EN3288-103 from the original analysis and the current reanalysis. The Geometric Least
`Square Mean ratios and their 90% CIs of AUC and Cmax of oxymorphone, from the
`original analysis and reanalysis of plasma samples from the single oral 40 mg doses
`administered to fasted subjects are provided in the table below. As indicated, the new
`formulation of oxymorphone ER is bioequivalent to the previous formulation of OPANA
`ER under fasting conditions according to both the original and resubmission results.
`
`
`Bioequivalence Analysis of Oxymorphone Pharmacokinetic Parameters After Single Oral Doses
`Administered to Fasted Healthy Subjects:
`Comparison of Original Submission and Resubmission
`
`
`
`
`
`Source: Dr. Nallani’s review, p. 4
`
`
`The Clinical Pharmacology team has concluded that the results of Study EN3288-103
`establishing bioequivalence of OPANA ER with the new formulation are acceptable. I
`concur with the review team.
`
`6. Clinical Microbiology
`
`
`
`
`Reference ID: 3056615
`
`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`Opana ER (New Formulation)
`December 9, 2011
`
`
`5
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`

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`No clinical microbiology data were necessary for this application.
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`7. Clinical/Statistical-Efficacy
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`No efficacy studies were submitted in this application.
`
`8. Safety
`
`No new safety data were included in this submission.
`9. Advisory Committee Meeting
`
`This application was not taken to an advisory committee meeting as there were no
`unusual concerns regarding the efficacy or safety of this reformulated opioid product.
`10. Pediatrics
`
`Pediatric studies were not required for this application as a new formulation of an
`approved drug is not one of the types of applications requiring pediatric data under the
`Pediatric Research Equity Act.
`
`11. Other Relevant Regulatory Issues
`
`The following discussion of the OSI re-inspection has been reproduced from page 5 of
`Dr. Fields’ review:
`
`
`
`OSI conducted a re-inspection of
`in order verify the corrective actions regarding the above concerns. Following the audit
`of the analyitical records of the reanalyses, there were no significant adverse findings,
`and OSI concluded that sufficient corrective actions were implemented for the current
`study
` and recommended that the analytical data be accepted
`for Agency review.
`
`
`There were no clinical studies conducted in support of this application and, therefore,
`no financial disclosure was required.
`12. Labeling
`
`The following summary of the key labeling issues for this application has been
`reproduced from page 6 of Dr. Fields’ review:
`
`
`The Office of Surveillance and Epidemiology (OSE), Division of Medication Error
`Prevention and Analysis (DMEPA) reviewed the proprietary name OPANA ER, and
`found it acceptable for this product.
`
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`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`Opana ER (New Formulation)
`December 9, 2011
`
`
`6
`
`Reference ID: 3056615
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`

`

`et
`e curren y
`e
`to rep
`e App cant now into-
`However,
`orm tron approved under NDA 21-610 with the new formulation in NDA 201655 and
`therefore, proposes to continue using the OPANA ER proprietary name per agreement
`with the Division during an Endo/FDA teleconference held January 5, 2011.
`
`DIVIEPA reviewed the carton and container labels and provided comm-ts for the
`Applicant regarding difiamfiafim from the OPANA labels, which were adequately
`addressed.
`
`The Medication Guide was reviewed by the DRISK patient labeling team who provided
`comments to the Applicant that have been adequately addressed.
`
`DDMAC has reviewed the label and Medication Guide and have provided comments to
`the Applicant that have been adequately addressed.
`
`Due to the marked food effect associated with OPANA ER the label will state that
`
`OPANA ER must be taken on an empty stomach, at least one hour prior to or two hours
`after eating.
`
`As stated in their review from the original NDA submission dated 21 December 2010,
`C88 recommended that the label not include language asserting that OPANA ER
`
`provides resistance to crushing smce neex Wn-reeasec ...
`
`w »
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`cutting,
`
`chewingorgrinding.
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`The label will also include instructions for the patient to take one tablet at a time, with
`enough water to ensure complete swallowing immediately afier placing in the mouth, due
`to concerns regarding the potential choking and sticking resulting from the PEO in the
`formulation.
`
`1 3. Decision/ActionIRisk Benefit Assessment
`
`0 Regulatory Action
`
`Approval
`
`0 Risk Benefit Assessment
`
`The Applicant has addressed the single deficiency noted in the CR Letter issued to the
`original application. This new formulation of Opana ER has been determined to be
`bioequivalent to the old formulation and, therefore, the application may be approved
`with the agreed upon product labeling and REMS.
`
`0 Required Postmarketing Risk Evaluation and Mitigation Strategy
`
`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`
`Opana ER (New Formulation)
`December 9, 2011
`
`Reference ID: 3056615
`
`

`

`The following summary of the review team’s assessment of the Applicant’s proposed
`REMS has been reproduced from page 8 of Dr. Fields’ review:
`
`
`As an extended-release opioid, a REMS is required for approval. The REMS must
`include a Medication Guide, an element to assure safe use (prescriber training), and a
`Timetable for Assessments. The Applicant has submitted a proposed REMS including
`the required elements, and the Division and DRISK have agreed that the REMS is
`acceptable with inclusion of the modifications put forth by DRISK. When the opioid
`class REMS is finalized, it will replace the REMS being approved with this application.
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`Reference ID: 3056615
`
`Division Director’s Review and Summary Basis for Approval Action
`NDA 201655
`Opana ER (New Formulation)
`December 9, 2011
`
`
`8
`
`14 has been withheld as a duplicate copy of the “Complete Response Summary Review” dated January 7, 2011
`which is located in the “Medical Review” Section of this NDA approval package.
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOB A RAPPAPORT
`12/09/2011
`
`Reference ID: 3056615
`
`