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

`

`
`
`CLINICAL PHARMACOLOGY REVIEW
`
`Submission Date(s): 6/13/2011
`NDA: 201655 Resubmission
`OPANA ER
`Brand Name
`Oxymorphone HCl ER tablets
`Generic Name
`Clinical Pharmacology Reviewer Srikanth C. Nallani, Ph.D.
`Team Leader
`Yun Xu, Ph.D.
`OCP Division
`Division of Clinical Pharmacology II
`OND Division
`Anesthesia and Analgesia Products
`Sponsor
`Endo Pharmaceuticals
`Submission Type; Code
`Response to CR action
`Formulation; Strength(s)
`Extended release tablet;
`Indication
`Relief of moderate to severe pain in patients
`requiring continuous opioid therapy for an extended
`
`period of time
`Proposed Dosage Regimen
`Titrated to effect with a twice daily dosing.
`
`
`Recommendation: The proposed reanalysis of plasma samples is acceptable and the
`study results are acceptable from a clinical pharmacology perspective. The new
`formulation OPANA ER (EN3288) is bioequivalent to the previous formulation OPANA
`ER under fasting condition according to the resubmission result.
`Regulatory Background:
`Endo Pharmaceuticals Inc. (Endo) and its partner, Grünenthal GmbH (Aachen, Germany)
`have developed OPANA ER(505(b)(1) application), a new extended-release (ER)
`formulation of oxymorphone HCl for the relief of moderate to severe pain in subjects
`requiring continuous, around-the clock opioid therapy for an extended period of time.
`On January 7, 2011 Action Letter from Agency noted the following, “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 of your proposed product to the
`reference product”. Endo addressed the above-noted deficiency by using back-up
`samples from study EN3288-103 for sample reassay, and all samples had sufficient
`volume available for reassay. In the current submission, Endo submitted results of
`pivotal bioequivalence study (EN3288-103) results after reanalysis of all plasma samples
`with stability data to address various discrepancies noted by Division of Scientific
`Investigations’ audit in
`. All plasma samples were reanalyzed for oxymorphone and
`6-hydroxy (OH)-oxymorphone concentrations; and Division of Scientific Investigations
`recommends that the re-analyis results acceptable for review.
`
`
`
`
`Reference ID: 3039284
`
`1
`
`(b) (4)
`
`

`

`Division of Scientific Investigations memo SW and recommendation
`documented in Darrts on September 19, 2011:
`Following the audit ofthe analytical records ofstudy EN3288-103 (studV
`conducted after
`(m4) at
`(be)
`no Form FDA-483 was issued and there were
`
`no significant adversefindings.
`
`Following the above inspection, the Division ofBioequivalence and GLP
`Compliance concludes
`om) concerns
`raised
`(we) implementedfor the current study
`and recommends that the analytical data of
`study EN3288-103 be acceptedfor Agency review. (See memo attached)
`
`(I!) (4)
`
`Study EN3288-103: BE study of 40 mg tablets in healthy subjects under fasted state
`
`Study Design and Methods
`
`This study was an open-label, randomized, 2-sequence, 4—period, crossover, replicated
`dosing design. Subjects were randomly allocated to receive a single dose of EN3288 or
`OPANA ER during alternate treatment periods. Each treatment period was separated by
`at least a 7—day washout. In total, each subject received 2 single doses of EN3288 and 2
`single doses of OPANA ER.
`
`Subjects included in each study were healthy males or females, of any race, between 18
`and 45 years of age, inclusive. Plasma samples were obtained at 0 (predose, within 1
`hour prior to administration of oxymorphone), 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24,
`36, and 48 hours after administration of oxymorphone in each period. Phannacokinetic
`parameters were analyzed by a repeated measure ANOVA. Bioequivalence was
`demonstrated by 90% C1s for oxymorphone AUCO-t, AUCO-inf, and Cmax that were
`between 0.80 and 1.25.
`
`Subject Disposition and Demographics
`
`Three (3) out of 37 subjects who entered the study were administered naltrexone but not
`randomized to oxymorphone treatments, 2 because of an AB and 1 because the study
`panel was filled. Thirty-four (34) subjects were randomized. Three (3) subjects were
`administered only 1 dose of oxymorphone (1 each because of withdrawal of consent,
`physician decision, AE), so no data were available for pharmacokinetic analysis. All 3
`subjects had been administered OPANA ER. Phannacokinetic data were available from
`31 subjects. There are data from 2 doses of each oxymorphone formulation for 30
`subjects and data from 1 dose of each oxymorphone formulation for 1 subject.
`
`Reference ID: 3039284
`
`

`

`
`Results: The summary of pharmacokinetic parameters of oxymorphone after each
`product administration in the study is provided in the table below (reanalysis results).
`
`The Geometric Least Square Meam 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 (EN3288-103), are provided in
`the table below. As indicated in the table below, the new formulation OPANA ER
`(EN3288) is bioequivalent to the previous formulation OPANA ER under fasting
`condition according to both original submission and resubmission results. The results
`from the two submissions are very similar.
`
`
`
`
`
`
`Reference ID: 3039284
`
`
`
`3
`
`

`

`Bioequivalence Analysis of Oxymorphone Pharmacokinetic Parameters After Single
`Oral Doses Administered to Fasted Healthy Subjects:
`Comparison of Original Submission and Resubmission
`
`Summary of Assay Validation
`The method (AP LC/MS/MS 374.100) for determining oxymorphone/6-OH-
`oxymorphone in human plasma has been validated with a detection range of
`0.02500/0.02500 to 10.00/10.00 ng/mL using an atmospheric pressure ionization (API)
`4000 liquid chromatography with tandem mass spectroscopy (LC/MS/MS) system.
`The stability of oxymorphone and 6-OH-oxymorphone in stock solutions, after
`extraction, and in plasma was established. Stock solutions of oxymorphone, 6-OH-
`oxymorphone, and internal standard were stable at room temperature for 6 hours and
`were stable refrigerated at 4°C±6°C for 21 days.
`Long Term Freezer Stability in HumanPlasma at -70°C ±20°C After 314 Days for
` Oxymorphone
` 6-β-Hydroxyoxymorphone
`
`
`
`
`
`Plasma samples of oxymorphone and 6-OH-oxymorphone were stable for at least 6
`freeze-thaw cycles and for at least 24 hours at room temperature. Extracted samples,
`reconstituted in preparation for injection, were stable at room temperature for 99 hours
`and were stable stored refrigerated (4°C±6°C) for 99 hours. Both analytes were stable in
`plasma stored at -70°C±20°C for at least 723 days.
`
`
`
`Reference ID: 3039284
`
`4
`
`Best Available
`Copy
`
`

`

`L Precision(%(‘.V)
`
`HQC
`MQC
`LQC
`HQC
`MQC
`LQC
`0.075 ng/mL 0.75 ng/mL 7.50 ng/mL 0.075 ng/mL 0.75 ng/mL 7.50 ng/mL
`
`Accuracy(%Blas)
`
`
`
`
`
`
`
`
`
`
` 66 EN3288-103 n = 66 n = 65 n = 66 n = 66 n= 65 n =
`
`
`
`
`
`
`
`7.6%
`
`6.3%
`
`-5.5%
`
`4.7%
`
`-l.8%
`
`Storage duration of plasma samples:
`
`Study
`
`EN3288-103
`
`EN3288-103 Resubmission
`
`First Sample
`Collected
`
`first Sample
`Assayed
`
`Last Sample Duration of Sample
`Assay-ed
`Storage
`
`20090728
`
`20090728
`
`20090913
`
`20110222
`
`20091009
`
`20110312
`
`73 days
`
`592 days
`
`Reanalysis of Study Samples
`
`Reasons for Sample Reassays
`Low Volume
`in Auto
`Injector Vial
`
`'
`
`Analyte
`
`Oxymorphone
`6~0H-
`
`oxymorphone
`
`EN3288-103
`
`EN3288-103
`
`Resubmission
`
`Very few samples had peak in pre—dose samples upon reanalysis and the concentration of
`drug upon integration of the noted peaks was very close to the detection limit.
`
`At least 5% of the study samples were reanalyzed (incurred sample reanalysis) to
`demonstrate reproducibility. Assay reproducibility was established if at least two—thirds
`of the samples had repeat results within 20% of the original values. The results are
`
`Reference ID: 3039284
`
`

`

`provided in Table 5 and show that more than two-thirds (67%) reanalyzed samples had
`results within 20% of reported assay result.
`Reanalysis of Incurred Samples
`
`
`
`Conclusion: The proposed reanalysis of plasma samples is acceptable and the results of
`the study EN3288-103 establishing bioequivalence of previous OPANA ER product with
`new/reformulated OPANA ER are acceptable from a clinical pharmacology perspective.
`
`
`
`
`
`
`
`
`Reference ID: 3039284
`
`6
`
`3 pages has been withheld in full immediately
`following this page as a duplicate copy of the EIR
`Memo dated September 19, 2011 which is located in
`the "Other Review" Section
`
`

`

`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`
`XIKUI CHEN
`091’191201 1
`
`SAM H HAIDAR
`09120r‘201 1
`
`AR IN DAM DASGUPTA
`
`09r'20i'201 ‘1
`
`Reference ID' 3017275
`
`
`
`Reference ID: 3039284
`Reference ID: 3039284
`
`
`
`10
`1 0
`
`

`

`Addendum to Primary Clinical Pharmacology Review Dated 12/14/2010
`
`
`NDA:
`
`201-655
`
`Date Received:
`
`7/7/2010
`
`Product Name: -
`
`Active Ingredient:
`
`Oxymorphone HCl extended-release tablets
`
`S onsor:
`
`Reviewer:
`
`Endo Pharmaceuticals
`
`Srikanth C. Nallani, Ph.D.
`
`BACKGROUND:
`
`Tablets
`Endo Pharmaceuticals submitted a 505(b)(l) NDA 201-655 (on 7/7/2010) for
`with pharmacokinetic data showin bioe uivalence to their own currently mar ete product
`OPANA ER Tablets. Approval of
`is based on successful demonstration of its
`bioe uivalence (BE) to OPANA ER. Study EN3288-103 is the pivotal BE study comparing
`
`* 40 mg compared to OPANA ER 40 mg in healthy subjects under fasting conditions.
`
`This study forms the primary support for the NDA submission as the highest formulation
`strength of- was em 10 ed under fasting conditions in this stud . Other bioequivalence
`studies were conducted with
`40 mg under fed conditions andh 5 mg under
`
`fasting conditions with corresponding strengths of OPANA ER. Biowaiver was sought for the
`intermediate strengths. Clinical pharmacology review for this NDA was signed off on
`with comments that the inspection results of pivotal BE study EN3288-103 from
`D1v1sron 0 Scientific Investigations were pending. In his review of inspection results dated
`_, Dr. John Kadavil of DSI indicated the following observations 1 and 2 and
`conclusions on BE study EN3288-103:
`
`
`
`onc usion:
`
`Fallowing DSI's evaluation ofthe inspectionalfindings, DSI recommends thefollowing:
`
`- Stud EN3288—103 should not be acce ted or reviei-v at this time due to the
`
`
`
`BS] is currently awaiting
`response to the Form FDA-483 to determine what steps the
`firm will initiate to address t e inspectionalfindings.
`
`Reference ID: 2887880
`
`

`

`Subsequently, after reviewing the written response submitted by—0n-
`to theissues identified1n Form FDA 483, Dr. Kadavil summarized his evaluationin an
`addendum date
`as follows.
`
`
`
`In summary, DSI has no basis to reverse our recommendation.
`
`RECOMJVIENDATION:
`
`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 deficiencies from a
`clinical pharmacology perspective should be conveyed to Endo Pharmaceuticals:
`
`Clinical Pharmacology
`
`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 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 samples collected in
`bioe uivalence study EN3288-103 and submit data establishing bioequivalence of
`
`i 40 mg tablets with OPANA ER 40 mg tablets. Ensure that the inspectional
`
`findings identified in Agency’s audit of study EN3288-103 are properly addressed in the
`reanalysis of blood samples.
`
`OR
`
`Conduct another pharmacokinetic study and establish bioequivalence of- 40 mg
`tablets with OPANA ER 40 mg tablets under fasting condition using adequately validated
`analytical methodology.
`
`Reference ID: 2887880
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SRIKANTH C NALLANI
`01/06/2011
`
`SURESH DODDAPANENI
`01/06/2011
`
`Reference ID: 2887880
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`NDA: 201655
`
`Brand Name
`
`Generic Name
`
`Submission Date(s): 07/07/2010
`
`mo
`
`Oxymorphone HCl Extended Release Tablets
`
`Clinical Pharmacology Reviewer Srikanth C. Nallani, PhD.
`
`Team Leader
`
`OCP Division
`
`0ND Division
`
`Sponsor
`
`Suresh Doddapaneni, Ph.D.
`
`Division of Clinical Pharmacology H
`
`Anesthesia and Analgesia Products
`
`Endo Pharmaceuticals Inc.
`
`Relevant lND(s)
`
`104,250
`
`Submission Type; Code
`
`Original NDA; New Formulation
`
`Formulation; Strength(s)
`
`5 , 7.5, 10, 15, 20, 30 and 40 mg
`
`Indication
`
`Relief of moderate to severe pain in patients
`requiring continuous opioid therapy for an extended
`period of time
`
`Proposed Dosage Regimen
`
`Titrated to effect with a twice daily dosing.
`
`Table of Contents
`
`1 Executive Summary ................................................................................................... 2
`1.1
`Recommendation .......................................................................................................................... 2
`1.2
`Phase IV Commitments................................................................................................................ 2
`
`1.3
`
`Summary of Clinical Pharmacology Findings ........................................................................... 2
`
`2 QBR ........................................................................................................................... 12
`2.1
`General Attributes ...................................................................................................................... 12
`
`2.2
`2.3
`2.4
`
`2.5
`2.6
`
`General Clinical Pharmacology................................................................................................. 12
`Intrinsic Factors.......................................................................................................................... 15
`Extrinsic Factors ......................................................................................................................... 15
`
`General Biopharmaceutics......................................................................................................... 27
`Analytical..................................................................................................................................... 30
`
`3 Labeling ..................................................................................................................... 33
`4 Appendix ................................................................................................................... 36
`4.1
`Proposed labeling........................................................................................................................ 36
`4.2
`Individual Study Reviews .......................................................................................................... 63
`4.2.1
`Study EN3288—103: BE study of 40 mg tablets in healthy subjects under fasted state. 63
`4.2.2
`Study EN3288—104: BE study of 40 mg tablets in healthy subjects under fed state ...... 67
`4.2.3
`Study EN3288—105: BE study of 5 mg tablets in healthy subjects under fasted state... 71
`4.2.4
`Study EN3288—107: Alcohol Interaction Study ................................................................ 75
`4.2.5
`Study EN3288-108: Effect of physical tampering on pharmacokinetics of
`(IN!)
`81
`4.2.6
`Study EN3288-109: Effects of Mastication on pharmacokinetics of
`09(4) .............. 86
`4.2.7
`OCP Filing Memo ............................................................................................................... 93
`
`Reference ID: 2877396
`
`1
`
`

`

`1
`
`Executive Summary
`
`1.1 Recommendation
`
`The submission is acceptable from a Clinical Pharmacology and Biopharmaceutics
`perspective provided that Division of Scientific Investigations finds data from pivotal BE
`study EN3288-103 a mutually satisfactory agreement can be reached between the
`applicant and the Agency regarding the language in the package insert.
`
`1.2 Phase IV Commitments
`
`None.
`
`1.3 Summary of Clinical Pharmacology Findings
`
`Endo Pharmaceuticals Inc. and its partner, Griinenthal GmbH (Aachen, Germany) have
`developed- (505(b)(l) application), a new extended-release 03R) formulation of
`oxymorphone HCl for the relief of moderate to severe pain in subjects requiring
`continuous, around-the clock opioid therapy for an extended period of time.
`
`- or EN3288, a new formulation of oxymo hone hydrochloride was developed to
`
`resrst accidental misuse and intentional abuse.
`tablet is characterized b a
`
`
`
`This product contains the same drug
`ceutrc s’ immediate-release GR) OPANA (NDA 21-
`su stance oun 1n En o P
`611) and extended release OPANA ER (NDA 21-610) oral formulations of oxymorphone
`HCl, which were both approved by the FDA on June 22, 2006. This application seeks to
`market 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg and 40 mg strengths of-
`tablets (same strengths as OPANA ER).
`
`The applicant submitted pharmacokinetic studies seeking approval of- by
`demonstrating bioequivalence to their own OPANA ER product. Pharmacokinetics and
`tamper resistance properties of- were evaluated under conditions ofnormal use
`and accidental misuse (i.e., breaking and/or crushing for patient convenience) and certain
`methods of intended abuse (i.e., crushing for snorting and/or injection, alcohol interaction
`and chewing).
`
`Six pharmacokinetic studies were conducted in healthy volunteers to support the efficacy,
`safety— of- tablets (See table below).
`
`1.3.1 Studies establishin_ bio nuivalence of
`
`to OPANA ER
`
`health sub'ects under fastin ; and naltrexone blockade.
`
`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- 40 mg compared to OPANA ER 40 mg in
`health sub'ects under fed state and naltrexone blockade.
`
`Study # EN3288-105: BE study comparing- 5 mg compared to OPANA ER 5 mg in
`
`Reference ID: 2877396
`
`2
`
`

`

`
`
`1.3.2 PK studies conducted to evaluate dose dum n in of
`
`after im n to 1 er use
`
`Study # EN3288-107: Alcohol interaction study assessing relative bioavailability of
`40 m taken with or without an alcoholic bevera . e and naltrexone blockade.
`
`«9(4) 40 mg taken intact and
`Study # EN3288-108: Relative bioavailability study comparing
`after physical tampering (cutting, crushing and grinding) and naltrexone blockade.
`
`taken intact and after chewin -, without naltrexone blockade.
`
`Study # EN3288—109: Relative bioavailability and drug-liking study comparing
`
`um 40 mg
`
`Additional in vitro studies were performed by the applicant to address if different
`methods of tampering with controlled release products known to drug addicts would
`defeat the extended release properties of
`"to These in vitro studies are reviewed by
`biopharmaceutics reviewer Dr. Sandra Suarez of Office of New Drug Quality Assurance
`and control substance staff reviewer Dr. James Tolliver.
`
`1.3.1 Studies establishing bioequivalence of
`
`“m to OPANA ER
`
`”m to OPANA ER was established with the highest (40 mg)
`Bioequivalence of
`strength
`mo and OPANA ER under fasting condition (Study # EN3288— 103) under
`fed condition(Study # EN3288—104). With regard to intermediate strengths (7.5— 30
`mg) of
`results of bioequivalence of the lowest (5 mg) tablet strength of
`com compared to OPANA ER under fasting condition (Study # EN3288- 105) along
`with similarity of intermediate tablet strengthin vitro dissolution profiles was provided to
`support biowaiver. Biopharmaceutics review by Dr. Sandra Suarez will address the
`adequacy of the dissolution data and biowaiver request of the intermediate strengths .
`
`The above described bioequivalence studies were generally open-label, randomized,
`single-dose, 2—sequence, 4-period, replicate, crossover studies in healthy subjects
`receiving naltrexone to block opioid effects of oxymorphone. In BE studies,
`«$0 or
`bioequivalence is concluded if the 90% CI of the geometric mean ratio (
`EN3288 over OPANA ER) for oxymorphone AUCM and Cmax fall within the limits of 0.8
`to 1.25.
`
`The results of the ANOVA comparison of geometric mean results of oxymorphone AUC
`and Cmax for the three BE studies are provided in the table below. As indicated in the
`table, the analysis confirms that the 5 mg and 40 mg
`one tablets are bioequivalent to
`5 mg and 40 mg OPANA ER, respectively under fasting condition. Additionally, 40 mg
`«no tabletis also bioequivalent to OPANA ER under fed condition.
`
`Reference ID: 2877396
`
`3
`
`

`

`Summary table indicating BE analysis of
`
` compared to OPANA ER
`
`Geometric Least Squares Means Ratio of Means
`EN3288
`
`90%
`Confidence
`Interval
`
`Parameter
`
`OPANA ER
`EN3288-103: Single 40 mg Oral Doses to Fasted Healthy Subjects*
`Cmax (ng/mL)
`AUC0-t (ng•h/mL)
`EN3288-104: Single 40 mg Oral Doses to Healthy Subjects with a High-Fat Meal
`Cmax (ng/mL)
`5.24
`5.55
`0.94
`0.88-1.02
`AUC0-t (ng•h/mL)
`47.10
`48.43
`0.97
`0.93-1.02
`EN3288-105: Single 5 mg Oral Doses to Fasted Healthy Subjects
`Cmax (ng/mL)
`0.352
`0.360
`0.98
`AUC0-t (ng•h/mL)
`5.04
`4.82
`1.05
`*Pending Division of Scientific Investigations inspection report
`Previously, during the review of OPANA ER in NDA 21-610, Clinical Pharmacology
`reviewer Dr. David Lee noted that the mean oxymorphone Cmax in the fed state (4.25
`ng/mL) was about 52% higher than the Cmax in fasted state (2.79 ng/mL). 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 prior to or two hours after eating. No change in dosing recommendation is needed
`taking into consideration the safety and efficacy of OPANA ER and bioequivalence of
` to OPANA ER under fasting and fed condition.
`1.3.2 PK studies conducted to evaluate safety of
`improper use
` is characterized by lower plasma levels and delayed
`Extended release profile of
`time to peak plasma levels when compared to equal dose of immediate release product in
`the same dosing interval. Peak plasma levels of 40 mg
` taken intact under
`fasting condition are ~ 1/4th (~ 2 ng/mL) of that noted with 4 X 10 mg dose of OPANA
`IR (~8 ng/mL). Time to peak plasma levels is ~ 5 hours with
` compared to ~ 0.5
`hour with immediate release product. Hence, extended release profile of
` under
`normal use or improper use is discussed with particular attention to peak plasma levels in
`the clinical pharmacology summary. Over all systemic profile is discussed later in the
`QBR section of the review and individual study reviews.
`Alcohol Interaction Study: PK study # EN3288-107 was conducted to evaluate alcohol-
`drug interaction effect of consuming 20% alcohol or 40% alcohol on PK of
`
`Results indicate that, similar to OPANA ER, administration of
` with alcohol
`contained beverages (20% or 40%) will result in significant increase in peak plasma
`
`0.93-1.03
`1.01-1.09
`
` taken intact or after
`
`
`Reference ID: 2877396
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`levels. The study was not powered to establish bioequivalence, but rather provide
`relative bioavailability adequate to allow clinical interpretation. Eighteen (18) subjects
`were to be randomized to ensure that 12 subjects had evaluable pharmacokinetic data
`from 12 of the ethanol treatment arms and the water treatment arm.
`
`Table: Oxymorphone pharmacokinetic parameters after each treatment (with or
`without alcohol) administration are provided in the table below.
`
`E83288 40 mg
`Administered with
`240 ml) 40% Ethanol
`
`EN3288 40 mg
`EN3288 40 mg
`Administered with 240 ml. Administered with
`20% Ethanol
`240 ml. Water
`
`Parametera
`
`(N=l4)
`
`(N=l7)
`
`(N=l7)
`
`AUCW-(ngoh mL)"
`
`3161:1189] (39.0)
`
`29.99Ls.9o9 (29.9)
`
`31.03L9913 (31.3)
`
`
`
`0.083L0.0372(44.8)
`
`0.072L0.0413(57.9)
`
`921128049)
`
`lO.7:‘3.48(32.5)
`
`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 upto 25-fold or 5.5-
`fold were noted in 20% or 40% alcohol treatment groups compared to
`no) alone
`(see figure below).
`
`one with 40%
`Figure: Fold increase in Cmax following administration of
`alcohol (A) or 20% alcohol (B) compared to water (C, not shown) in individual
`subjects.
`
`
`
`FoldincreaseinCmax
`
`A: Cmax with Treatment A
`Cmax with Treatment C
`B: Cmax with Treatment B
`Cmax with Treatment C
`
`Water (reference)
`
`Treatment A: 40 mg,
`40% ethanol
`
`one + 240 mL
`
`Treatment B: 40 mg,
`20% ethanol
`
`«to + 240 mL
`
`Treatment C: 40 mg,
`
`"‘9 + 240 mL
`
`Reference ID: 2877396
`
`5
`
`

`

`Previously, OPANA ER also exhibited highly variable but significant alcohol—drug
`interaction. Following concomitant administration of 240 mL of 40% ethanol the Cmax
`increased on average by 70% and up to 270% in individual subjects. Following the
`concomitant administration of 240 mL of 20% ethanol, the Cmax increased on average
`by 31% and up to 260% in individual subjects. As noted with OPANA ER previously, a
`slight increase (15% increase) in AUC is noted when
`mg is taken with alcohol (20
`or 40%, data not shown). Hence,
`cm and OPANA ER are similar in their
`susceptibility to alcohol-related drug interaction. It should be noted that this interaction
`is not due to the failure of the extended release characteristics of the formulation but is
`
`probably due to the alcohol effect on the absorption of oxymorphone itself. For both
`OPANA ER and
`”(a in vitro dissolution studies have demonstrated that these
`
`products do not release oxymorphone more rapidly in dissolution media containing
`alcohol.
`
`Accidental misuse study: Pharmacokinetic study # EN3288-108 was conducted to
`evaluate dose dumping of
`mo under conditions of accidental or intentional misuse
`by breaking and/or crushing with different methods. This study was an open-label,
`randomized, 6-sequence, 6-period, crossover design. Subjects were randomized to
`receive the following treatments:
`
`A EN3288 40 mg — intact tablet
`B EN3288 40 mg — tablet tampered with a commercial pill crusher
`C EN3288 40 mg — tablet cut
`9""
`(m4)
`D EN3288 40 mg — tablet tampered
`E OPANA ER 40 mg — tablet tampered with a commercial pill crusher
`F OPANA 40 mg (4><10 mg) — intact tablets
`
`«)0 following physical
`The applicant compared bioavailability (Cmax and AUC) of
`0(4) tablet) or
`manipulation (Treatments B, C and D) with Treatment A (intact
`Treatment F (40 mg immediate release tablets). The plasma concentration measurements
`(timing and assay range), sample size (29 subjects) were designed to accurately
`characterize the measures of systemic exposure to oxymorphone that provided evidence
`of bioequivalence.
`
`The first step in misusing or abusing opioid drug products involves methods that would
`destroy the extended-release characteristics of drug product, followed later by oral
`consumption or nasal administration (snorting; not evaluated) or IV injection (not
`evaluated). Hence, phannacokinetic analyses are conducted to understand the change in
`extended-release characteristics of drug products by comparing Cmax and AUC noted
`when the product is consmned under different conditions. Bioequivalence was concluded
`if the 90% CI of the geometric mean ratio of a treatment compared to appropriate
`reference for oxymorphone AUCM and Cm fall within the limits of 0.8 to 1.25.
`
`Reference ID: 2877396
`
`6
`
`

`

`
`
`
`
`PlasmaConcentration(ng/mL)
`
`Figure: Mean plasma oxymorphone profiles
`over an initial 3 hour period with treatments as
`follows:
`
`0 Treatment A: EN3288 40 mg - intact tablet
`[3 Treatment B: EN3288 40 mg - (commercial pill crusher)
`A Treatment C: EN3288 40 mg - (tablet cut
`(m4)
`“M"
`0 Treatment D: EN3388 40 mg -
`I Treatment E: 0P1~\NA(R)ER 40 mg -(commerc1al pill crusher)
`A Treatment F: OPANA 40 mg (4 , 10 mg) - intact tablets (reference product)
`
`I'd
`
`0
`
`l
`
`2
`
`3
`
`Classically, immediate release (IR) tablets produce peak plasma levels that are higher
`than extended-release drug products containing the same dose upon single dose
`administration. Use of such high Cmax values noted with OPANA IR tablets (See figure
`above) as reference would indicate a decrease in peak plasma levels to 0.4 — 0.7-fold
`when
`«M: is consumed intact or under any condition ofphysical manipulation (See
`table below).
`
`Table: Change in Cmax, with respect to OPANA IR 40 mg, when
`consumed intact or following physical manipulation
`
`mo 40 mg is
`
`Treatment N
`
`Geometric Ratio of
`Least
`Least
`
`Lower
`90% CI
`
`Upper
`90% CI
`
`_-_--__
`
`Squares
`Mean
`
`Squares
`Mean
`
`E--_--__
`
`_-_--__
`_-_-IE-IE-
`
`Since the goal of this PK study is to understand whether the extended-release product can
`withstand physical tampering, PK results from an intact extended-release product should
`be used as reference. Use of IR tablets as a reference is masking the effects of physical
`manipulation which are obviously defeating the control release properties of
`(no)
`(see table below). Hence, from a clinical pharmacology perspective, bioavailability
`comparisons are appropriate using Treatment A or the intact extended-release tablet as
`reference. Using intact
`mo (Treatment A) as reference, peak plasma levels of
`oxymorphone failed bioequivalence and were significantly higher when
`one was
`consumed following grinding and cutting
`mo indicating loss of extended-
`release characteristics. However, data indicates that
`one resists physical crushing
`
`Reference ID: 2877396
`
`7
`
`

`

`forces noted using a pill crusher as demonstrated by bioequivalence to intact
`with respect to Cmax (see table below) and AUC (not shown)
`
`0(4)
`
`Table: Change in Cmax when
`manipulation, with respect to intact
`
`one 40 mg is consumed following physical
`”a, 40mg.
`
`_-_-___
`
`Treatment
`
`Geometric
`Least
`
`Ratio of
`Least
`
`Lower Upper
`90%
`90%
`
`Squares
`Mean
`
`Squares
`Mean
`
`CI
`
`CI
`
`I3-
`
`mo 40 mg— intact tablet
`A
`om 40 mg — tablet tampered with a commercial pill crusher
`B
`«no 40 mg — tablet cut
`(m4)
`C
`M4)
`mo 40 mg — tablet tampered
`D
`E OPANA ER 40 mg — tablet tampered with a commercial pill crusher
`F OPANA 40 mg (4><10 mg) — intact tablets
`
`When considering individual data, fold increase in Cmax as high as 4—fold were noted
`with cutting (Treatment C) and grinding (Treatment D) (See figure below). Fold change
`in Cmax for each individual were calculated by dividing Cmax noted for each treatment
`with Cmax noted with reference treatment A (
`mo 40 mg intact). As indicated
`previously, bioequivalence was noted for Treatment B indicating no significant change
`compared to Treatment A.
`With regard to AUC, bioequivalence was demonstrated between different methods of
`physical manipulation irrespective of the reference used (data not shown).
`Change in Peak Plasma Levels with Tampering
`when Compared to Intact
`W“)
`
`0)“)
`
`(9(4)
`
`tablets
`
`Treatments
`
`mo 40 mg
`A = Intact tablet
`B
`C
`
`Opana ER 40 mg
`E =
`
`5
`
`g 4
`5
`5
`53
`
`§ §
`
`2
`
`F = 4X10 mg, OPANA IR (intact)
`
`Reference ID: 2877396
`
`8
`
`

`

`Study ofintentional abuse by chewing: Pharmacokinetic study # EN3288-109 was
`conducted to evaluate the effect of mastication on bioavailability of
`«no 40 mg.
`This was a randomized, double-blind, double-dummy, 4—period, 4—sequence, single-dose,
`crossover study in healthy, nondependent, recreational oral prescription opioid users
`experienced in mastication of ER opioid formulations. Unlike the previous
`bioavailability studies, subjects did not receive naltrexone to block opioid effects. The
`treatment arms in this PK study were as follows:
`A EN3288 40 mg — intact tablet
`B EN3288 40 mg — tablet ingested afier mastication
`C OPANA ER 40 mg — tablet ingested after mastication
`D OPANA 10 mg (4X10 mg) — intact tablets
`
`No specific instructions with regard to rate of chewing or duration of chewing were
`given to the subjects. The subjects were instructed to “completely and carefully”