CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`
`
`
`
`

`

`Cross Discipline Team Leader Review
`NDA 201655
`
`OPANA ER (oxymorphone ER)
`
`Second Cycle
`
`Cross—Discipline Team Leader Review
`
`
`
`Ellen Fields, M.D., M.P.H.
`From
`m_——
`
`13 June 2011
`Date of Submission
`
`PDUFA Goal Date
`13 December 2011
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Dosage forms / Strength
`
`Opana ER/ OxymOIphone HCl extended-release tablets
`
`Extended-release tablets/ 5 mg, 7.5 mg. 10 mg. 15 mg, 20
`m-, 30m,40 m
`
`Proposed Indication(s)
`
`The relief of moderate-to-severe pain in patients requiring
`continuous, around—the-clock opioid treatment for an
`
`extended period of time.
`A roval
`
`
`
`Recommended:
`
`Material Reviewed/Consulted
`
`0ND Action Packa ' e, includin- :
`
`CMC
`Clinical Pharmacology
`DDMAC
`
`Crai Bertha, Ph.D., Prasad Peri, PhD.
`Srikanth Nallani, Ph.D., Yun Xu, Ph.D.
`Pendin-
`
`Controlled Substance Staff
`
`Silvia Calderon, Ph.D., Michael Klein, Ph.D.
`
`OSI
`
`OSE/DIVIEPA
`
`OSE/DRISK (patient labeling)
`
`OSE/DRISK (REMS)
`
`Aiindam Dasgupta, Ph.D., Xikui Chen,
`Ph.D., Sam Haider, PhD.
`
`Jibril Abdus-Samad, Pharm.D., Kellie
`Ta lor, MPH, Carol Hol uist, RPh.
`
`Steve Morin, R.N., B.S.N., O.C.N., LaShawn
`Gn'ffiths, MSHS-PH, BNS, RN
`
`Megan Moncur, M.S., Danielle Smith,
`Phann.D., M.S., Claudia Karwoski,
`PhaImD.
`
`Pro'ect Mana- ement
`
`Lisa Basham, M.S., Parinda Jani
`
`1. Introduction and Background
`
`In accordance with 21 CRF 314 and Section 505(b)(1) of the Federal Food, Drug and Cosmetic
`Endo Pharmaceuticals Inc. submitted an Original New Drug Application for oxymorphone
`hydrochloride extended-release tablets as a 505(b)(l) application on July 7. 2010. A Complete
`Response (CR) Action Letter was issued on January 7, 2011. The current submission is a
`response to the CR action.
`
`The Applicant intended to base approval on establishing bioequivalence to OPANA ER (NDA
`21—610). which was approved by the Agency on June 22. 2006, and is owned by Endo. The
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`Page 1 of 8
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`Reference ID: 3052041
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`1
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`

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`Cross Discipline Team Leader Review Second Cycle
`NDA 201655
`OPANA ER (oxymorphone ER)
`proposed product is to be dosed twice daily and will be available in the same dosage strengths as
`OPANA ER (5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg).
`
`The CR letter noted the following clinical deficiency regarding the bioequivalence study that was
`to be the basis for approval for oxymorphone extended-release tablets:
`
`
`
`
`
`The Applicant chose to address the above-noted deficiency by using back-up samples from study
`EN3288-103 for sample reassay. In the current submission, Endo submitted results of
`bioequivalence study (EN3288-103) after reanalysis of all plasma samples with stability data
`to address various discrepancies noted by the Office of Scientific Investigations’ audit in
`2010. All plasma samples were reanalyzed for oxymorphone and 6-hydroxy (OH)-
`oxymorphone concentrations.
`
`The nonclinical pharmacology/toxicology portion of this NDA submission was reviewed
`during the first cycle, and the reader is referred to the those reviews for additional
`information.
`2. Chemistry, Manufacturing, and Controls
`The primary CMC review during both review cycles was conducted by Craig Bertha, Ph.D.,
`with secondary concurrence by Prasad Peri, Ph.D.
`
`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 data were
`provided for a single batch of 5 and 40 mg strengths
`
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`Page 2 of 8
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`Reference ID: 3052041
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`2
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`(b) (4)
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`

`

`Cross Discipline Team Leader Review Second Cycle
`NDA 201655
`OPANA ER (oxymorphone ER)
`
` 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 Office of Compliance on November 15, 2010
`
`The information submitted was found acceptable by Dr. Bertha, who recommended approval
`of OPANA ER from the CMC perspective.
`3. Clinical Pharmacology/Biopharmaceutics
`The primary clinical pharmacology review during both review cycles was conducted by
`Srikanth Nallani, Ph.D., with secondary concurrence by Suresh Doddapaneni, Ph.D. during
`the first cycle, and Xu Yun, Ph.D. during the current review cycle.
`
`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 under a fasted state. 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.
`
`
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`Page 3 of 8
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`Reference ID: 3052041
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`3
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`(b) (4)
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`

`

`Cross Discipline Team Leader Review Second Cycle
`NDA 201655
`OPANA ER (oxymorphone ER)
`
`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.
`
`
`
`
`4. Other Relevant Regulatory Issues
`Office of Scientific Investigation (OSI) Consult
`During the first review cycle, OSI, (previously called DSI) was consulted to inspect the study
`site that conducted Study EN288-103, 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.
`
`The clinical portion of Study EN3288-103 was conducted at SeaView Research, Inc., Miami,
`FL. The analytical portion was conducted at
` While the
`inspection of the clinical site was found acceptable OSI hd concerns about the reliability of
`the BE/BA data generated by
`
`
`
`
`OSI concluded that:
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`Page 4 of 8
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`Reference ID: 3052041
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`4
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Cross Discipline Team Leader Review
`NDA 201 655
`
`OPANA ER (oxymorphone ER)
`
`
`Second Cycle
`
`tion
`
`OSI conducted a re-ins
`
`
`Following the audit of the
`
`
`analyitical records of the reanalyses, there were no significant adverse findings, and OSI
`concluded that suflicient corrective actions were implemented for the current study
`— and recommended that the analytical data be accepted for
`Agency review.
`
`Risk Evaluation and Mitigation Strategies
`As an extended-release Schedule II opioid, a REMS is required for the approval of this
`product to inform patients and providers about the potential for misuse, abuse, overdose, and
`addiction.
`The current REMS requirements for drugs in the class are a Medication Guide,
`an element to assure safe use (prescriber training), and a Timetable for REMS assessments.
`Oxymorphone ER will become part of the class-wide, long-acting opioid REMS when it
`ultimately takes efl'ect.
`
`The Applicant submitted a proposed REMS, REMS Supporting Document, and REMS
`Website Drafi Screen Shots on September 7, 2011, including a Dear Healthcare Professional
`Letter, a Dear Pharmacist Letter, a Healthcare Professional Training Guide, and an OPANA
`ER REMS Education Confirmation Form.
`
`As stated in the DRISK review dated September 30, 2011:
`
`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 Phamracist Letter, a Healthcare Professional Training
`Guide, an Education Confirmation Form, and REMS website.
`
`The DRISK Review Team found the proposed REMS and REMS materials for OPANA ER
`as submitted on September 7, 2011 to be acceptable pending verification of recommended
`revisions. The Applicant has subsequently made the appropriate changes to the REMS. The
`final REMS was submitted on November 21, 2011. See the DRISK reviews dated December
`9, 2010, August 31, 2011, and September 30, 2011, and November 30, 2011 for details
`regarding the REMS review.
`
`Page 5 of 8
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`Reference ID: 3052041
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`Cross Discipline Team Leader Review
`NDA 201 655
`
`OPANA ER (oxymorphone ER)
`
`5.Labeflng
`
`Second Cycle
`
`The Oflice of Surveillance and Epidemiology (OSE), Division of Medication Error
`Prevention and Analysis (DMEPA reviewed the to rie
`name OPANA ER and found it
`acce table for this
`roduct.
`
`
` However,
`
`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.
`
`DMEPA reviewed the carton and container labels and provided cements for the Applicant
`regarding diflerenfiafion 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 statedin their review from the original NDA submission dated 21 December 2010, CSS
`recommended that the label not include lan
`
` characteristics of the formulation are compromised by cutting, chewing or grinding.
`
`The label will also include instructions for the patient to take one tablet at a time, with
`enough water to ensure complete swallowing immediately after placing in the mouth, due to
`concerns regarding the potential choking and sticking resulting from the PEO in the
`formulation.
`
`6. Recommendations/Risk Benefit Assessment
`
`0 Recommended Regulatory Action
`Approval
`
`0 Risk Benefit Assessment (taken from original submission CDTL review dated
`December 22, 2010)
`The Applicant developed an extended-release formulation of
`oxymorphone HCl
`an is
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`Page 6 of 8
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`Reference ID: 3052041
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`

`

`Cross Discipline Team Leader Review
`NDA 201 655
`
`Second Cycle
`
`OPANA ER (oxymorphone ER)
`intended to reduce accidental misuse and to deter certain methods
`
`They planned to base the approval on
`of intended abuse.
`establishing bioequivalence to Opana ER. The proposed product
`is intended to be dosed twice-daily and will be available in the
`same dosage strengths as OPANA ER (5 mg, 7.5 mg, 10 mg, 15
`mg, 20 mg, 30 mg, 40 mg), and have the same indication.
`
`was shown to be bioequivalent to Opana ER in two
`Phase 1 studies that demonstrated bioequivalence of the 5mg and
`40 mg doses. A biowaiver was granted for the intermediate doses
`based on dissolution profile comparisons.
`
`Safety data was obtained from the pharmacokinetic studies,
`however since most of the subjects received naltrexone blockade,
`the data is of minimal use. However, no new safety signals
`compared to those labeled for Opana ER were detected. As the
`Applicant relied on the Agency’s revious findings of safety and
`efficacy for Opana ER, and
`was
`shown to be
`bioequivalent to Opana ER, no additional safety or eflicacy
`studies were required.
`
`
`an? abuse liability
`Reviews of the‘
`characteristics of- by the clinical pharmacology team and
`the Controlled Substance Stafl' showed that althou
`’71}
`
`characteristics
`
`of
`
`the
`
`formulation
`
`i e
`are
`
`appears resistant
`extended-release
`
`co
`
`romisedb chewin cuttin and
`
`' din .
`
`
`
`There is a potential safety concern regarding the polyethylene
`oxide (PEO) in the formulation. Postmarketing adverse events
`that
`include choking and sticking have been observed with
`another extended-release opioid that contains PEO. These events
`were not observed during the development of- however
`the tablets were taken under controlled conditions. The Division
`
`has determined that if the label includes patient instructions to
`take the tablets one at a time with suflicient water, and a
`postmarketing requirement of enhanced pharmacovigilance is put
`in place, this safety issue will not preclude approval.
`
`A Complete Response action was taken on January 7, 2011, due to the deficiencies noted at
`the analytic site for the bioequivalence study that was the key factor in determining approval.
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`Page 7 of 8
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`Reference ID: 3052041
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`Cross Discipline Team Leader Review Second Cycle
`NDA 201655
`OPANA ER (oxymorphone ER)
`The Applicant conducted a reanalysis of the plasma samples at the site following correction
`of the deficiencies, and an inspection by DSI confirmed that the results of the reanalysis were
`acceptable for review by the Division. These results confirmed that the new formulation of
`OPAPA ER is bioequivalent to the original formulation.
`
`Therefore, the benefits of OPANA ER outweigh the risks at this time, with inclusion of the
`REMS as part of the approval.
`
`Although there have been reports of choking and tablets sticking in the gastrointestinal tract
`in patients taking a different opioid product that contains polyethylene oxide (PEO), there
`have been none reported for OPANA ER. At this time, the Division has determined that
`enhanced reporting of adverse events related to the GI tract will be sufficient to monitor this
`potential problem. If over time, there are reports of adverse events possibly related to PEO in
`the formulation, additional actions may be taken. The following language will be included in
`the Approval letter:
`
`“In addition to the standard reporting requirements for an approved NDA, we request that
`you submit as 15-day expedited reports, all post-marketing and clinical trial cases of choking,
`gagging, sticking, and gastrointestinal obstruction, regardless of whether these reports are
`classified as serious or unexpected, and that you provide analyses of clinical trial and
`postmarketing reports of these adverse events of special interest in your periodic safety
`update reports.”
`
`
`• Recommendation for Postmarketing Risk Management Activities
`
`
`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.
`
`
`• Recommendation for other Postmarketing Study Commitments
`
`None
`
`
`None
`
`• Recommended Comments to Applicant
`
`Page 8 of 8
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`Reference ID: 3052041
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELLEN W FIELDS
`11/30/2011
`
`Reference ID: 3052041
`
`