CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`201655Orig1s000
`
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`

`

`h FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANESTHESIA AND ANALGESIA PRODUCTS
`
`Summary Review for Regulatory Action
`
`
`January 7, 2011
`Bob A. Rappaport, MD.
`Director
`
`Division of Anesthesia and Anal esia Products
`m__5—
`
`PDUFA Goal Date
`Proprietary Name /
`Established
`S ‘
`
`Name
`
`January 7, 2011
`W4)
`Ox :- o hone HCl extended-release tablets
`
`
`
`Dosage Forms / Strength
`
`Proposed Indication
`
`Extended-release tablets
`5 m, 7.5 m,10m,15 111,
`For the relief of moderate to severe pain in patients
`requiring continuous, around-the—clock opioid
`treatment for an extended eriod of time
`
`Comlete Resonse
`
`Reference ID: 2888730
`
`

`

`
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Clinical Review
`Statistical Review (supporting
`CSS)
`Preclinical Review
`CMC Review
`Microbiology Review
`Clinical Pharmacology Review
`Biopharmaceutics
`DSI
`CDTL Review
`OSE/DMEPA
`
`OSE/DRISK
`
`OSE/DEPI
`DDMAC
`Controlled Substance Staff
`
`N/A
`Ling Chen, Ph.D.; Stella Machado, Ph.D.
`
`Elizabeth Bolan, Ph.D.; Dan Mellon, Ph.D.
`Craig Bertha, Ph.D., Prasad Peri, Ph.D.
`James McVey, Ph.D.; Steven Langille, Ph.D.
`Srikanth Nallani, Ph.D., Suresh Doddapaneni, Ph.D.
`Sandra Suarez Sharp, Ph.D.; Patrick Marroum, Ph.D.
`John Kadavil, Ph.D.; Sam Haider, Ph.D.; Martin Yau, Ph.D.
`Ellen Fields, M.D., M.P.H.
`Tara Turner, Pharm.D.; Jibril Abdus-Samad, Pharm.D..; Todd
`Bridges, R.Ph.; Zachary Oleszczuk, Pharm.D.; Denise Toyer,
`Pharm.D.; Carol Holquist, R.Ph.
`Steve Morin, R.N., B.S.N., O.C.N.; Barbara Fuller, R.N., M.S.N.,
`Sharon Mills, B.S.N., R.N., C.C.R.P.; Marcia Britt, Ph.D.; Agnes
`Plante, B.S.N., R.N.; Megan Moncur, M.S.; Claudia Karwoski,
`Pharm.D.
`Rajdeep Gill, Pharm.D.; Laura Governale, Pharm.D., M.B.A.
`Twyla Thompson; Mathilda Fienkeng
`James Tolliver, Ph.D.; Silvia Calderon, Ph.D.; Michael Klein,
`Ph.D.
`
`
`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
`
`
`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,
` and to thereby
`reduce accidental misuse and deter certain specific methods of abuse. The support for
`the efficacy and safety of this new product is 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.
`
`
`
`Reference ID: 2888730
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`January 7, 2011
`
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`2. Background
`
`Based on our experience with a number of different purportedly abuse-deterrent opioid
`analgesic products, some approved and others still in development, and on the
`comments and conclusions on this topic received from the members of a joint meeting
`of the Anesthetic and Life Support and Drug Safety and Risk Management Advisory
`Committees in October of last year, we have determined that any reasonable, well-
`documented, even incremental change in the formulation of an abusable opioid that
`will possibly deter misuse and abuse is a positive step in dealing with the public health
`crisis of prescription opioid abuse in the United States. Both the members of the
`advisory committee and the Agency have also concluded that the available databases
`for determining whether these products actually reduce abuse in the communi
`are
`
`inad uate to track chan es over time at this pointb However, in order to provide as much
`patients, the labels will incorporate language describingb of
`
`information as possible regarding the advantages of these roducts to rescribers and
`
`the new formulation and the routes of abuse that they are intended to deter.
`
`Endo’s product has demonstrated a minimal improvement in resistance to tampering by
`crushing, thereby limiting the likelihood of abuse b in estion and b insufflation
`snortin
`to some de ee.
`
`
`
`
`
`ren ring it rea y a usa e y mgestlon an intravenous
`injection, and possibly still by insufflation, although they have not tested whether the
`mo tablets can be snorted. Of more concern, when chewed—
`, the new formulation essentially dose dumps like an immediate-release
`formulation. While the label and MedGuide would certamly carry warnings against
`chewing, some concern exists that any language in the label noting the reduced
`crushability of this formulation could be misleading and result in health care
`practitioners or patients thinking that it is safer than the old formulation, and that it is
`safe to chew the product; or that it is safe to give the new product to a cognitively
`impaired patient who may chew the product if not adequately supervised.
`
`This application’s basis for establishing the safety and efficacy of the new formulation
`is entirely dependent upon two bioequivalence (BE) studies comparing the new and old
`formulations. Based on an inspection of the CRO site that performed those studies, the
`Division of Scientific Investigation (DSI) has determined that there were significant
`procedural flaws in the performance of Study EN3288-103 and they have
`recommended that the study not be accepted for use in this a
`lication. Study
`
`EN3288-103 evaluated the 40 mg strength tablets ofdpcompared to the 40 mg
`
`strength tablets of Opana ER in normal volunteers under fasting conditions and
`naltrexone blockade. DSI issued a 483 to the CRO on December 9, 2010, and DSI
`completed their review and final recommendations to the Division on December 20,
`2010. Endo was notified of this finding by the division via teleconference on
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`December 27, 2010, and a Discipline Review Letter was sent to the sponsor on
`December 28, 2010, documenting these concerns and their possible impact on
`approvability. The CRO sent in a response to the 483 cements on December 29,
`2010, and the response has been reviewed by DSI. Based on that review, DSI has
`maintained their recommendation to the division that we not use Study EN3288-103 in
`our assessment of the application’s approvability. While Study EN3288-105, a BB
`study of the 5 mg tablets, also demonstrated bioequivalence to the old formulation, the
`Office of Clinical Pharmacology cannot make a determination of bioequivalence for
`the higher strength tablets based on these findings as, in a BB study, the intent is to
`compare the formulations for rate and extent of drug absorption after release from a
`given type of formulation, and this is best done with the highest strength as, over a
`prolonged period of time, cm and AUC can be acquired with due consideration for
`analytical methods, duration of sampling, and duration of formulation passage in the
`gastrointestinal tract. Oflen the lowest strength formulations have plasma levels
`detectable for a shorter period of time, depending on the sensitivity of the analytical
`method.
`
`In addition, the DSI findings raise systemic concerns about the studies performed at the
`CRO in question.
`
`3. CMC
`
`The following has been reproduced from page 8 of Dr. Bertha’s review:
`
`
`
`I concur with the CMC review team that there are no outstanding issues that would
`impact approvability. The Oflice of Compliance issued an overall recommendation of
`Acceptable in regard to the facilities inspections on November 15, 2010.
`
`4. Nonclinical Pharmacology/Toxicology
`
`No new nonclinical pharmacology or toxicology data was submitted with this
`application. The excipients used in the new formulation have either been used in
`approved products or have been found to be acceptable by the review team. I concur
`with the pharmacology/toxicology review team that there are no outstanding issues that
`would impact approvability.
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`5. Clinical Pharmacology/Biopharmaceutics
`
`The following summary of the clinical pharmacology program for- has been
`reproduced from pages 3 through 8 of Dr. Fields’ review:
`
`Six pharmacokinetic studies were conducted in healthy volunteers to support the eflicacy,
`
`safetF- tablets as shown in the tables below from
`
`’s revrew.
`
`Dr. N
`
`Table 1: Studies establishing bioequival-ce o
`
`to Opana ER
`
`Study # EN3288-103: BE study comparing—40 mg compared to OPANA ER 40 mg in
`health sub'ects under fastin state and naltrexone blockade.
`Study # EN3288- 104: BE study comparing-0 mg compared to OPANA ER 40 mg in
`health sub'ects under fed state and naltrexone blockade.
`
`Study # EN3288-105: BE study comparin
`
`5 mg compared to OPANA ER 5 mg in
`
`health sub'ects under fastin and naltrexone blockade.
`taken intact and afier chewin- without naltrexone blockade.
`
`Table 2: PK studies conducted to evaluate dose dumping of
`
`after improper use
`
`Study # EN3288-107: Alcohol interaction study assessing relative bioavailability of-
`40 mg taken with or without an alcoholic beverage and naltrexone blockade.
`Study # EN3288-108: Relative bioavailability study comparing-40 mg taken intact and
`after h srcalt
`- ring cutting. crushin- and u 'din- and naltrexone blockade.
`
`Study # EN3288-109: Relative bioavailability and drug-liking study comparing-40 mg
`
`Additional in vitro studies were performed by the Applicant to address if different
`methods of tampering with controlled-release
`cts known to drug addicts would
`defeat the extended-release properties of
`These studies were reviewed by Drs
`Sharp and Tolliver and will be discussed ater m 5 review.
`
`Bioequivalc-ce of- to Opana ER was established with the highest dose, 40mg,
`and the lowest dose, 5mg, under fasting conditions. The adequacy of the in vitro
`dissolution profiles submitted in support of the biowaiver for the intermediate strengths
`was reviewed by Dr. Sharp and found acceptable. The table below from Sr. Nallani’s
`review shows the results of the BE studies. Note that - 40mg is also
`bioequivalent to Opana ER 40mg under fed conditions.
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`Table 3: Summary Table ofBE analyses of-f-compared to Opana ER
`
`Geometric Least S - uares \Ieans
`
`Ratio of \Ieans
`
`90%
`
`Parameter
`
`_
`E33288
`
`OPANA ER
`
`Confidence
`Interval
`
`EN3288-103: Sin 1e 40 1112 Oral Doses to Fasted Healthy Subjects“
`
`Cmax (110 mL)
`
`AUCO-t na-h/mL
`
`ENBZSS- 104: Sin e 40 Ill Oral Doses to Health Sub'ects with a High-Fat Meal
`
`
`
`AUC‘O-t ng-h/mL
`
`47.10
`
`48.43
`
`EN3288-105: Single 5 mg Oral Doses to Fasted Healthy Subjects
`
`0.360
`
`Acco-r n-me
`
`0.88102
`
`0.93-1.02
`
`0.93.103
`
`1.01-1.09
`
`Previously, during the review of OPANA ER in NDA 21-610, the Clinical Pharmacology
`reviewer noted a large food eflefl, such that the mean oxymorphone Cmax in the fed
`state was about 52% higher than the Cmax in fasted state. Since- and OPANA
`ER are bioequivalent under fasting and fed conditions, it can be assumed that-
`has the same degree of food effect as OPANA ER. Current dosing recommendations for
`OPANA ER indicate that the tablet should be dosed at least one hour
`'or to or two
`
`hours after eating. The same dosing recommendation will apply to
`
`Dr. Nallani discussed the extended-release profile of - under normal and
`improper use in his review. The Applicant conducted a study to evaluate alcohol drug
`interaction efi'ects of consuming 20% or 40% alcohol on the pharmacokinetic profile of
`The results indicated that similar to Opana ER, administration of beverages
`containing alcohol (20% and 40%) resulted in significant increase in peak plasma levels.
`On average, oxymorphone Cmax increased with the amount of ethanol consumed and
`was 1.14-fold and 1.80-fold higher with 20% and 40% ethanol, respectively. Noteworthy
`is the fact that in certain individuals maximum fold change in Cmax u to 2.5-fold or 5.5-
`fold were noted in 20% or 40% alcohol treatment groups compared toh alone.
`
`- and OPANA ER are similar in their susceptibility to alcohol-related drug
`interaction. Interestingly, this interaction is not due to the failure of the extended-release
`characteristics of the formulation but is probably due to the alcohol efi'ect on the
`absorption of oxymorphone itself. For both OPANA ER and - in vitro
`dissohltion studies have demonstrated that these products do not release oxymorphone
`more rapidly in dissolution media containing alcohol.
`
`A study was conducted by the Applicant to evaluate dose dumping of oxymorphone
`under conditions of accidental or intentional misuse by breaking and/or crushing with
`difi‘erent methods.
`It was an open-label, randomized, 6-sequclce, 6-peirod crossover
`design with subjects randomized to the following treatments:
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`A EN3288 40 mg — intact tablet
`B EN3288 40 mg — tablet tampered with a commercial pill crusher
`C EN3288 40 mg — tablet cut
`m"
`”(9
`D EN3288 40 mg — tablet tampered
`E OPANA ER 40 mg — tablet tampered with a commercial pill crusher
`F OPANA 40 mg (4x 10 mg) — intact tablets
`
`The Applicant compared BE of- following physical manipulation (B, C, and D)
`with Treatment A (intact ER tablets) or Treatment F (40mg IR tablets). Since the goal of
`this study is to understand whether the extended-release product can withstand physical
`tampering, PK results from an intact extended-release product is the more appropriate
`reference. Using intact- as reference, peak plasma levels of oxymorphone failed
`bioequivalence and were significantly higher when- was consumed following
`grinding and cuttin indicating the loss of extended-release characteristics. However, the
`data indicates that
`resists physical crushing forces noted using a pill cnrsher
`(Treatrnent B) as demonstrated by bioequivalence to intact - with respect to
`Cmax. In terms of individual data, fold increases in Cmax as high as 4-fold were noted
`with cutting or grinding the tablet. The following figure from Dr. Nallani’s review
`illustrates the mean plasma oxymorphone profiles for the treatment groups.
`
`Figure: Mean plasma oxymorphone profiles
`over an initial 3 hour period with treatments as
`follows:
`
`0 Treatment A EN3288 40 mg - mtact tablet
`Cl Treatment 8' EN3388 40 mg —(commcrc1al pill crusher)
`A TreatmentC: EN3388 40mg - (tablet cut
`P“)
`0 Treatment D: E.\'3288 40 mg-
`_ “m
`I Treatment E‘ OPANAIZI ER ‘40 mg - tcommcrcral p1ll crusher)
`A Treatment F‘ OPANA 40 mg (4 - 10 mg) - intact tablets (reference product)
`
`Figure 1
`
`l.) 0
`
`0
`
`l
`
`2
`
`3
`
`The Applicant also conducted a study to evaluate the effect of mastication/chewing on
`the bioavailability of
`40mg. No specific instructions were given to the study
`
`subjects regarding therate or uration ofchewing; theywere instructed to completei and
`carefully chew the tablet for as long as possible. When compared to an intact
`tablet, there was a 22-fold increase in Cmax when- is consumed afier c ewm .
`In terms of individual data, up to 6-fold increases in Cmax were noted wheni
`was consumed after chewing.
`
`
`
`
`
`PlasmaConcentration(ng/mL)
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`Below are conclusions of the Clinical Pharmacology review team as stated in Dr.
`Nallani’s review.
`
`Overall Conclusions:
`
`1. -40 mg is bioequivalent to OPANA ER under fasted and fed conditions.
`At the time of uniting this review. inspection report fi'om DSI of study EN3288-
`103 is pending.
`2. -5 mg is bioequivalent to OPANA ER imder fasted condition.
`3. Similar to OPANA ER. alcohol-related interaction results in high peak plasma
`levels.
`
`4. Although-seems to resist cmshing by pill crusher. it is susceptible to
`defeat of extended-release characteristics b other methods of physical
`manipulation. Cutting and grinding
`resulted in a significant increase in
`peak plasma levels compared to intact product.
`
`5. As demonstrated by significant increase in eak lasma levels compared to intact
`
`product. extended-release characteristics of‘iwere defeated when chewed
`
`and consumed.
`
`and
`dissolution methods
`team reviewed the
`0NDQA-Biopharmaceutics
`The
`specification, the biowaiver request for intermediate doses based on the dissolution
`profile comparisons, and the in vitro alcohol interaction study.
`
`Dr. Sharp noted in her review that the dissohition method and proposed specifications for
`all strengths of the - tablets are acceptable. The dissolution profiles of all
`strengths in three difierent media were determined, and were similar. Therefore the
`waiver request of the in vivo BE requirements for the intermediate tablet strengths
`between 5mg and 40mg was granted.
`
`Wh- 40% ethanol was added to the dissolution media, dissolution rates of the 40mg
`tablets were slower, and there was no change in dissolution rates when 5% ethanol was
`added. These results are in contrast to the in vivo alcohol interaction study discussed
`earlier in this section.
`
`Several in vitro studies were conducted to assess the tamper-resistant characteristics of
`- The results of these studies are discussed in the review co
`leted by the
`Controlled Substance Staff. However, Dr. Sharp notes in her review that
`does
`not show good resistance to tampering employed by recreational or experienced abusers,
`as evidenced by a 60% increase in the dissolution in one hour for tablets
`0-)“)
`compared to intact tablets.
`
`Upon receiving the final recommendation from DSI, the Clinical Pharmacology team
`reassessed their own recommendations and filed an amendment to their review. The
`
`following has been reproduced from page 2 of that amended review written by Dr.
`Nallani:
`
`Based on the deficiencies identified in the DSI review, the BE study EN3288-103 data
`cannot be accepted. The following deficiencies and remedial actions to address the
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`deficiencies from a clinical pharmacology perspective should be conveyed to Endo
`Pharmaceuticals:
`An audit performed by the Agency of the bioequivalence study EN3288-103 identifi
`ed
`deficiencies in the
` methods used at the analytical site. Because of these deficiencies, the
`bioequivalence study cannot be relied upon to establish bioequivalence of your proposed
`
`drug product to the reference product.
`This deficiency may be addressed by doing the following:
`Provided adequate samples are available, reanalyze blood sam
`ples collected in
`bioequivalence study EN3288-103 and submit data establis
`hing bioequivalence of
` 40 mg tablets with OPANA ER 40 mg tablets. Ensure that the inspect
`ional
`findings identified in Agency’s audit of study EN3288-103 are properly addressed i
`n the
`reanalysis of blood samples.
`OR
`Cond
` 40 mg
`uct another pharmacokinetic study and establish bioequivalence of
`tablets with
` OPANA ER 40 mg tablets under fasting conditions using adequately
`validated analytical methodology.
`
`pplication.
`
`l Safety which included safety data from The Applicant submitted a Summary of Clinica
`
`240 subjects who received study drug in the pharmacokinetic and tampering studies. In
`six PK studies, subjects received naltrexone blockade, so the interpretation of the safety
`data in these studies is limited, as opioid associated adverse events would be blocked, and
`naltrexone could be the cause of the AEs…
`
`Overall, adverse events reported with EN3288
`were not different from those reported for
`PANA ER. No deaths were reported during the development program, and there were
`o SAEs reported in subjects receiving any formulation of oxymorphone. The most
`frequently occurring events related to EN3288 were vomiting, nausea, dizziness,
`abdominal pain, and headache, all of which have been reported in the Opana ER label.
`No new safety signals were detected in the Applicant’s studies.
`
`On
`
`6. Clinical Microbiology
`
`is application.
`There are no clinical microbiology concerns for th
`
`Clinical/Statistical-Efficacy
`
`No efficacy studies were submitted in this a
`
`Safety
`
`The followi
`ng summary of the safety data submitted in this application has been
`reproduced from page 8 of Dr. Fields’ review:
`
`
`7.
`
`8.
`
`
`
`
`
`
`
`
`
`Reference ID: 2888730
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`January 7, 2011
`
`
`9
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`9. Advisory Committee Meeting
`
`This application was not taken to an advisory committee meeting as there were no
`unusual concerns regarding the eflicacy 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 lmder the
`Pediatric Research Equity Act.
`
`1 1 . Other Relevant Regulatory Issues
`
`The following summary of the concerns regarding Study EN288-103 has been
`reproduced from page 9 of Dr. Fields’ review:
`
`Division of Scientific Investigation 1281} Consult
`DSI was consulted in order to inspect the study site that conducted Study EN288-103, An
`open-label, randomized, single dose, four-period, replicate, crossover
`to detamine
`
`the bioequivalence of EN3288 (Oxymorphone HCl extended-releasih
`
`fornmlation) 40 mg compared to OPANA ER (Oxymorphone HCl exten
`mg in healthy subjects under fasted conditions.
`
`-re ease 40
`
`The clinical portion of Study EN3288-103 was conducted at SeaView Research, Inc.,
`Miami, FL. The analytical portion was conducted at
`
`
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`Reference ID: 2888730
`
`January 7, 201 l
`
`

`

`This is an approvability issue, since this study is one of two key studies establishing
`bioequivalence with Opana ER.
`If the firm responds acceptably to the DSI findings
`within the time period allotted by DSI, these inspection results may not preclude
`approval, however if not, this NDA will not be approved.
`
`As noted in Section 2, the CRO sent in a response to the 483 comments on December
`29, 2010, and that response was reviewed by DSI. Based on their review, DSI retained
`their recommendation to the division that we not use Study EN3288—103 in our
`assessment of the application’s approvability.
`
`The following conclusions and recommendations from the CSS team have been
`reproduced from pages 2 through 4 of Dr. Tolliver’s review:
`
`2. CONCLUSIONS
`
`We reviewed the in vitro manipulation and chemical extraction studies, a clinical
`pharmacokinetic (bioavailability) study (EN3288-108), human abuse potential studies
`(EN3288-109), and two bench top attractiveness studies (EN3288-901 and EN3288-902),
`and have the following conclusions regarding- tablets.
`
`0
`
`a use.
`. In
`or grin
`oxymorphone.
`
`provides limited resistance to physical and chemical manipulation for
`extended release mechanism can be overcome by cutting, chewing,
`e of
`with food or alcohol increases blood levels of
`ets provide some resistance to crushing
`
`0
`
`33 tablets can
`The Sponsor did not conduct studies to demonstrate that
`the difliculty in crushiTg- tablets-
`—as observed in the in vitro studies makes it less
`likely that, relative to OPANA ER, individuals will intranasally abuse
`manipulated using these tools. The bench top study
`3288-902 demonstrated the
`difficul
`in forming an intranasal preparation with
`However, the in vitro studies and study EN3288-902 did not address the
`grinding of- tablets for possible abuse by intranasal administration.
`
`0 - tablets are more diffith to cut than are OPANA ER tablets. !mismg
`
`Revopan tablets can be cut
`extended release properties 0
`
`e
`
`compro
`
`e
`
`0 An in vitro study conducted by the Sponsor shows that it might be easier to prepare a
`solution for injection when using
`than when usin OPANA ER.
`sure
`
`of a crushed Revopan 40 mg tablet
`
`of the label claim of extracted
`oxymorphone HCl. However, the bench top manipulation study, Study EN3288-
`
`901, showed that both forrmrlations behaved similarly.
`
`
`0 Grinding the? tablets severely compromises the controlled release of
`
`oxymorphone HC , as demonstrated
`the hi
`es of label claim of
`o
`hone HCl
`
`represent extraction evels
`These
`
`of oxymorp one. Consrdering that at
`ranging from
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`1 1
`
`Reference ID: 2888730
`
`January 7, 201 1
`
`

`

`equianalgesic doses, oral oxymorphoneis” morepotent than
`
`oral oxycodone when physiological opioi e ects m10s1s, ypotension, analgesia)
`are compared, the extracted amounts of oxymorphone are equivalent in its opioid
`effects of analgesia, miosis, and respiratory depression to— oforal
`oxycodone respectively.
`
`t be diflicult,
`
`tablets or OPANA ER tablets mi
`
`Clinical abuse liability study EN3288-109 demonstrates that mastication of-
`40 mg tablets compromises the controlled release mechanism of-
`
`Based on the results ofphaimacokinetic study EN3288-108 and abuse liability study
`EN3288-109 it is like
`that the '
`stion of a
`.40 mg tablet cut
`
`produce substantial and
`
`statistically significant sub'ective reinforcing effects above those produced by the
`ingestion of intact
`40 mg tablets. In addition, food increases the absorption
`of oxymorphone, thus increasing the likeability of oxymorphone containing
`products, including-
`
`3. RECOMluENDATIONS
`
`Based on our review ofthe relevant studies concerning- Tablets submitted under
`NDA 201,655 and the above conclusions, we recommend the following:
`
` assertin that vides resistance to
`The product label not inchlde Ian
`
`
`
`
`could be administered intranasally,
`Conduct a study to determine if ground
`study15 relevant considering that the
`if such a study can be conducted safely.
`intranasal route seems to be the most prominent route of abuse of OPANA ER,
`followed by the oral and intravenous routes as reported by adult individuals (18 years
`or older) entering treatrn-t (Addiction Severity Index-Multimedia Version (ASI-
`MV) 2009- Data presented at the FDA joint meeting of the Anesthetic and Life
`Support Drugs and Drug Safety and Risk Management Advisory Committee held
`October 21-22, 2010 in Gaithersburg, Maryland).
`
`12. Labeling
`
`The review team has provided preliminary recommendations regarding changes to the
`applicant’s proposed labeling. However, final labeling discussions will not occur until
`the applicant addresses the concerns raised during this review cycle in a resubmission.
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`12
`
`Reference ID: 2888730
`
`January 7, 201 l
`
`

`

`1 3. Decision/Actioanisk Benefit Assessment
`
`0 Regulatory Action
`
`Complete Response
`
`0 Risk Benefit Assessment
`
`While the applicant has provided data that support the bioequivalence of their
`reformulated oxymorphone product to Opana ER, the data on the higher-strength
`tablets were obtained in a study that has been found to be unacceptable upon inspection
`and review by DSI. Therefore, until the sponsor has either resolved the concerns raised
`by that review or completed a new BE study, the application cannot be approved.
`
`”“tamper-resistant
`Additional concerns have been raised regarding the
`features of this product’s formulation. While some resistance to crushin
`
`“is inherent in this new formulation, the product can still be
`
`(”cut or
`
`c ewe to provide rapid release of oxymorphone. It may provide an incremental
`improvement in tamper resistance for those wishing to snort the drug, and a similarly
`incremental improvement in preventing overdosage in a patient who attempts to crush
`the pills in spite of the warnings or when a health care practitioner overlooks the
`labeled admonition not to crush the pills when administering the product to a atient.
`
`However, the roduct can be
`m» c
`
`
`Perhaps most importantly, afler chewing
`
`
`e pro uct acts like an immediate-release oxymorp one p
`an
`s p aces certain
`patient populations, particularly the elderly and/or cognitively impaired, at high risk of
`overdose. While the latter risk can probably be addressed with adequate warnings in
`product label, we are concerned that any reference to the product’s incremental
`improvement in tamper resistance could be misleadin to health care ractitioners and
`atients, considerin the risks noted above.
`
`0 Required Postmarketing Risk Evaluation and Mitigation Strategy
`
`As a member of the class of long-acting and extended-release opioid analgesic drug
`products,- is required to have a REMS consistent with the approved class-wide
`REMS for these products. As with the other approved products in this class, we have
`accepted an interim REMS while the Agency finalizes our criteria for the class REMS.
`The company has submitted an interim REMS that is consistent with the requirements
`set forth by the Agency and with their approved Opana ER product’s interim REMS. It
`consists of a Medication Guide, elements to assure safe use, an implementation system,
`and a timetable for submission of assessments of the REMS.
`
`Division Director’s Review and Summary Basis for Complete Response Action
`NDA 201655
`
`l 3
`
`Reference ID: 2888730
`
`January 7, 2011
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`01/07/2011
`
`Reference ID: 2888730
`
`

`

`Cross Discipline Team Leader Review
`NDA 201655
`
`(51(4) (oxymorphone ER)
`
`Cross—Discipline Team Leader Review
`
`
`Date
`December 22, 2010
`
`Ellen Fields, M.D., M.P.H.
`From
`m_ Cross-Disci line Team Leader Review
`NDA/BLA #
`201655
`
`Endo Phalmaceuticals
`
`Date of Submission
`July 7, 2010
`
`PDUFA Goal Date
`January 7, 2011
`
`om Oxymorphone HCl extended-release tablets
`
`Extended-release tablets/ 5 mg, 7.5 mg, 10 mg, 15 mg, 20
`m, 30 111, 40111
`
`The relief of moderate-to—severe pain in patients requiring
`continuous, around-the—clock opioid treatment for an
`extended eriod of time.
`
`Proprietary Name /
`Established
`S ‘
`
`names
`
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`Recommended:
`
`Material Reviewed/Consulted
`
`0ND Action Packa - e, includin :
`
`Pharmacolo 3 Toxicolo 3 Reviews
`
`Elizabeth Bolan, Ph.D., Dan Mellon, Ph.D.
`
`
`
`CMC Reviews
`
`Clinical Pharmacology
`
`Biopharmaceutics
`
`OSE/DMEPA
`
`Crai. Bertha, Ph.D., Prasad Peri, Ph.D.
`
`Srikanth Nallani, Ph.D., Suresh Doddapaneni,
`Ph.D.
`
`Sandra Suarez Sharp, Ph.D., Patrick
`Marroum, Ph.D.
`
`John Kadavil, Ph.D., Sam Haider, Ph.D.,
`
`Martin Yau, Ph.D.
`
`Tara Turner, Phann.D., Zachary Oleszczuk,
`Pharm.D., Denise Toyer, Pharm.D., Carol
`H01 uist, R.Ph.
`
`Fuller, R.N., M.S.N., Sharon Mills, B.S.N.,
`
`R.N., C.C.R.P.
`
`R.N., Megan Moncur, M.S., Claudia
`Karwoski, PharmD.
`
`James Tolliver Ph.D., Silvia Calderon, Ph.D.
`
`Biometrics su. ortin. CSS
`
`Lin Chen, Ph.D., Stella Machado, Ph.D.
`
`ReferencePlB:12:882834
`
`1
`
`

`

`Cross Discipline Team Leader Review
`NDA 201655
` (oxymorphone ER)
`1. Introduction
`In accordance with 21 CRF 314 and Section 505(b)(1) of the Federal Food, Drug and Cosmetic
`Endo Pharmaceuticals Inc. has submitted an Original New Drug Application for oxymorphone
`hydrochloride
`extended-release tablets as a 505(b)(1) application.
`
`Endo Pharmaceuticals Inc. and its partner Grünenthal GmbH (Aachen, Germany) have developed
`an extended-release formulation of oxymorphone HCl that
` is
`intended to reduce accidental misuse (i.e., breaking, and/or crushing for patient convenience) and
`to deter certain methods of intended abuse (i.e., crushing for snorting and/or injection).
`
`The Applicant intends 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 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).
`2. Background
`Oxymorphone is a semisynthetic opioid analgesic, first approved in 1959 as Opana
`(oxymorphone 1mg/mL), a parenteral formulation indicated for the relief of moderate-to-
`severe pain, preoperative medication, support of anesthesia, obstetrical analgesia, and for relief
`of anxiety in patients with dyspnea associat