CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`22-272Orig1s014
`
`SUMMARY REVIEW
`
`
`
`
`

`

`i “arm“
`a”
`
`°*
`
`a {6 DEPARTMENTOFHEALTH&HUMANSERVICES
`
`4‘
`
`PublicHealthService
`
`
`Foo an Drug ministration
`Rockville. MD 20857
`
`To:
`
`Douglas C. Throckmorton, MD
`Deputy Director for Regulatory Programs
`Center for Drug Evaluation and Research (CDER)
`Food and Drug Adminis ration (FDA)
`
`Janet Woodcock
`
` From:
`
`Director
`
`CDER, FDA
`
`Subject:
`
`of Reformulated OxyContin
`Abuse-Deterrent Properties
`hydrochloride) Extended-Release Tablets
`
`(oxycodone
`
`Date:
`
`April 16, 2013
`
`I have reviewed your memorandum (including the appended data summary tables)
`regarding (l) the CDER review of the labeling supplement for reformulated OxyContin
`(oxycodone hydrochloride) extended-release tablets (OCR) (NDA 22-272),
`including your
`recommendation about whether the labeling should be revised to include language describing
`abuse-deterrent properties of the new formulation, and (2) whether Purdue’s original formulation
`of OxyContin (oxycodone hydrochloride) extended-release tablets (0C) (NDA 20-533) should
`be determined to be withdrawn for reasons of safety or effectiveness.
`
`I concur with your analyses and recommendations and I conclude that:
`
`1. The labeling for OCR should be revised to include appropriate language describing
`the abuse-deterrent properties of the new formulation (along with relevant caveats);
`and
`
`2. OC was withdrawn for reasons of safety or effectiveness.
`
`Thank you for your leadership in this complex, multidisciplinary effort.
`
`Reference ID: 3294259
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LISA E BASHAM
`04/16/2013
`Entered into DARRTS on behalf of Dr. Janet Woodcock
`
`Reference ID: 3294259
`
`

`

` FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
` DIVISION OF ANESTHESIA, ANALGESIA, AND ADDICTION PRODUCTS
`HFD-170, 10903 New Hampshire Avenue, Silver Spring, MD, 20993
`
`
`
`
`
`
`
`Division Director Review, Addendum
`
`
`
`
`
`Drug Name: OxyContin Tablets, Reformulated (ORF)
`Sponsor: Purdue Pharma
`Date of Review: April 15, 2013
`Division Director: Bob A. Rappaport, M.D.
`
`In my capacity as Division Director of the Division of Anesthesia, Analgesia, and
`Addiction Products (DAAAP), I am writing this addendum to clarify the summary
`conclusions in my review dated February 6, 2013, regarding Purdue’s reformulated
`OxyContin (ORF) and potential abuse-deterrent properties.
`
`As noted in my original review, the appended DAAAP medical officer review was
`completed by Dr. Pamela Horn with oversight from Dr. Sharon Hertz, in November of
`2012, prior to Dr. Horn’s going on extended leave of absence. That review evaluated in
`vitro, pharmacokinetic and “drug liking” pharmacodynamic, clinical, and postmarketing
`data. The review was not filed at that time as Drs. Horn and Hertz were waiting for the
`epidemiology study reviews to be completed by another office within CDER, the
`Division of Epidemiology in the Office of Surveillance and Epidemiology (OSE). Those
`reviews by Drs. Trinidad and Dal Pan have since been completed. My views of the
`postmarketing data were summarized in my February 6th review and Dr. Horn’s appended
`review summarized the in vitro and pharmacokinetic/pharmacodynamic data. Based on
`these reviews, and the reviews provided by the Controlled Substances Staff and the
`Office of Surveillance and Epidemiology, we concluded that there were adequate data to
`support inclusion of the in vitro data and the “drug liking” data
`
` in the product labeling.
`
`
`In regard to the postmarketing data, as I noted in my original review, there were no major
`inconsistencies between DAAAP and OSE in our interpretation of the findings related to
`the traditional (“formal”) epidemiology studies. There were five investigations that were
`reasonably well designed and that contained sufficient data for review. These studies
`included NAVIPPRO, the Client Treatment Study, the National Survey of Drug Use and
`Health (NSDUH), the RADARS System Poison Control Center Program, and the
`National Poison Data System (NPDS) investigation. While some studies suggested a
`decline in ORF abuse via non-oral routes, other studies did not support such a finding.
`
`We in DAAAP also found that the non-traditional studies provided some support for the
`sponsor’s conclusion that the ORF product’s changes to the original formulation’s
`
`Reference ID: 3293880
`
`(b) (4)
`
`

`

`physiochemical properties are likely to reduce abuse to some degree. These abuse-
`deterrent features reduce the ability to snort crushed product and reduce drug-liking with
`administration by snorting. These features also render the product almost impossible to
`dissolve, syringe, and inject.
`
`While we found that the non-traditional epidemiology studies generally appear to suggest
`or support a trend of reduced abuse by these routes (i.e., intravenous and intranasal) in the
`community, we also recognized the limitations of both the non—traditional and the
`traditional epidemiology studies,
`(we)
`The results of the data
`
`collectively did, however, support inclusion of the physiochemical property studies and
`the drug-liking abuse liability studies data in the labeling.
`
`Reference ID: 3293880
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`04/16/2013
`
`Reference ID: 3293880
`
`

`

` FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
` DIVISION OF ANESTHESIA, ANALGESIA, AND ADDICTION PRODUCTS
`HFD-170, 10903 New Hampshire Avenue, Silver Spring, MD, 20993
`
`Division Director Review
`
`
`
`
`
`Drug Name: OxyContin Tablets, Reformulated (ORF)
`Sponsor: Purdue Pharma
`Date of Review: February 6, 2013
`Division Director: Bob A. Rappaport, M.D.
`
`The appended review was completed by Dr. Pamela Horn with oversight from Dr. Sharon
`Hertz, in November of 2012, prior to Dr. Horn’s going on extended leave of absence.
`The review was not filed at that time as Drs. Horn and Hertz were waiting for the
`epidemiology study reviews to be completed by the Division of Epidemiology in the
`Office of Surveillance and Epidemiology. Those reviews have since been completed and
`filed. There are no major inconsistencies between the two divisions in the findings
`related to the traditional epidemiology studies. However, DAAAP does find that the non-
`traditional studies provide some support for the sponsor’s conclusion that the ORF
`product’s changes to the original formulation’s physiochemical properties is likely to
`reduce abuse to some degree. These abuse-deterrent features are limited to a reduction in
`the ability to snort crushed product, an almost impossible ability to dissolve, syringe and
`inject the product for injection and some degree of reduced drug-liking with
`administration by snorting. While we find that the non-traditional epidemiology studies
`do appear to, for the most part, support a trend of reduced abuse by these routes in the
`community, we also recognize the limitations of both the non-traditional and the
`
`traditional epidemiology studies submitted in the application,
` They will, however, support inclusion of
`the physiochemical property studies and the drug-liking abuse liability studies data in the
`labeling.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3258740
`
`(b) (4)
`
`

`

`APPENDIX
`
`
`
`
`
`
`
`
`
`
`Medical Officer Review
`
`
`
`
`
`Drug Name: OxyContin Tablets, Reformulated (ORF)
`Sponsor: Purdue Pharma
`Date of Review: 11/14/12
`Reviewer: Pamela Horn, M.D.
`Team Leader: Sharon Hertz, M.D.
`
`Materials Reviewed:
`IND 29038
`• Abuse liability and pharmacokinetic studies
`o CSS reviews of studies OTR-1016, 1018, 1019, 1021, and 1022,
`DARRTS, 9/21/12
`o Statistical review of study OTR-1018, DARRTS, 8/20/12
`o Clinical Pharmacology review of studies OTR-1016, 1018, and 1021,
`DARRTS, 9/20/12
`o Study reports OTR-1016, 1018, 1019, 1021, and 1022, submitted to IND
`9/17/10
`o Pharmacy instruction manuals OTR-1018 and 1021
`
`NDA 22272:
`In vitro studies: CSS review of the following documents, DARRTS, 9/4/09
`•
`o Comprehensive In Vitro Testing of the Controlled-Release Properties of
`New OCR Tablets After Physical and Chemical Manipulation - Summary
`Report
`o Comprehensive in Vitro Testing of the Controlled-Release Properties of
`New OCR Tablets After Physical and Chemical Manipulation - Complete
`Dataset Appendix
`o Evaluation of the Resistance to Physical and Chemical Manipulation of
`Oxycodone HCl (10, 15, 20, 30, 40, 60 and 80 mg) TR Tablets Compared
`to Currently Marketed OxyContin (10, 15, 20, 30, 40, 60 and 80 mg)
`o Protocol for Creating Particle Size Fractions by Crushing and Milling
`Extended Release Oxycodone HCl Tablets - OxTR In Vitro Testing Plan -
`Experiments 2a, b and 5a, b, c
`o Protocol TTP-PMP-M0043.00 - "Simple Extraction: pH-Dependent API
`Release Study for Extended Release Oxycodone HCl Tablets"
`o Protocol for Smoking (Inhalation) Testing of Physically Manipulated
`Extended Release Tablets Containing Oxycodone HCl
`o Validation Protocol for Simple Extraction Testing of Physically
`Manipulated Extended Release Tablets Containing Oxycodone HCl
`
`
`
`Reference ID: 3258740
`
`2
`
`

`

`• Epidemiology studies
`o Division of Epidemiology review of “A Summary of the Findings of the
`Post-Marketing Epidemiology Study Program to Detect Changes in
`Patterns of Abuse and Misuse and their Consequences: Addiction,
`Overdose and Death (as of October 15, 2011)” DARRTS, 4/30/12
`o Statistical reviews of “Report on the Findings as of May 2012: Post-
`Marketing Epidemiology Study Program to Assess the Effects of
`Reformulated OxyContin on Patterns of Abuse and Misuse and their
`Consequences (Addiction, Overdose and Death), Patient Adverse Events,
`and Unintentional Exposures” DARRTS, Studies 1, 2, and 6: 11/5/12,
`Studies 3, 4, 5, and 11: 11/9/12
`o Report titled “Report on the Findings as of May 2012: Post-Marketing
`Epidemiology Study Program to Assess the Effects of Reformulated
`OxyContin on Patterns of Abuse and Misuse and their Consequences
`(Addiction, Overdose and Death), Patient Adverse Events, and
`Unintentional Exposures”, submitted to NDA 7/31/12
`• Report on media coverage, submitted to NDA 8/6/12
`• Report on information acquired from law enforcement officers, submitted to NDA
`8/6/12
`
`
`Issue
`Is there robust and meaningful evidence to conclude that reformulated OxyContin®
`(ORF) is abuse-deterrent?
`
`Summary of Evidence and Conclusions
`The physicochemical differences between ORF and OxyContin appear to make ORF
`more difficult to use by the intravenous and intranasal routes and, to a lesser extent, to
`overcome the controlled-release properties by the oral route. The controlled-release
`properties of ORF can be overcome with chewing and swallowing. The Sponsor
`concludes that the interim data from epidemiology studies indicates a trend towards less
`OxyContin abuse since the introduction of ORF. I generally agree that the currently
`available epidemiological data indicate a decrease in OxyContin abuse. The
`physicochemical properties of ORF may be responsible for these trends. There is some
`alignment between the in vitro, pharmacokinetic, and drug-liking data and the
`epidemiological data, in that the data indicate that the most robust evidence of tamper-
`resistance is for non-oral routes and abuse by non-oral routes has decreased more than for
`oral routes.
`
`The consult reviews of the various studies note several limitations and flaws in study
`design. Additionally, the epidemiologic data represent a small number of data points and
`much data still remain to be collected. However, these flaws and limitations do not
`negate the available evidence of a measure of abuse-deterrence. While the amount of
`data will continue to increase as the ongoing studies are completed, the current evidence
`is sufficient to draw a conclusion that can be used in making public health decisions.
`
`
`
`
`Reference ID: 3258740
`
`3
`
`

`

`Despite the significant role OxyContin has played in prescription opioid abuse, because
`of the availability of other opioids, ORF’s abuse-deterrent properties or the introduction
`of any single opioid product with abuse-deterrent properties alone should not be expected
`to affect the total incidence or prevalence of opioid abuse or dependence in the U.S.
`
`There is robust evidence that the new formulation of OxyContin has abuse-deterrent
`features that have translated into a measurable effect on non-oral abuse of OxyContin.
`This measured effect on OxyContin abuse is meaningful in the context of the current
`levels of prescription opioid abuse in the U.S.
`
`Background
`Purdue Pharma reformulated OxyContin with the goal of making it more difficult to
`abuse. Although labeling reflecting properties of the new formulation was not requested
`at the time of the application review, the Sponsor now wants to include language in the
`OxyContin product labeling describing the abuse-deterrent features of the product.
`Purdue Pharma submitted a citizen’s petition requesting that the Agency require that
`sponsors who reference ORF (NDA 22,272) demonstrate the abuse-deterrent properties
`of their formulation in order to receive ANDA marketing approval.
`
`The Agency is in the process of writing a guidance on abuse-deterrent formulations and
`there is currently no published standard setting the level of evidence required for a
`formulation to be considered abuse-deterrent.
`
`The Agency approved the NDA for ORF in April 2010. The NDA contained the reports
`of in vitro studies designed to evaluate the abuse-deterrent physicochemical properties of
`the formulation. The Controlled Substance Staff reviewed these studies and concluded
`that the new formulation had abuse-deterrent properties and had demonstrated an
`advantage over the previous OxyContin formulation by showing that the tablets are
`considerably more difficult to chew or crush and more difficult to convert to an aqueous
`solution suitable for intravenous injection.
`
`As a condition of approval, the Agency issued a postmarketing requirement for the
`Sponsor to conduct epidemiological studies to assess whether the changes made to the
`OxyContin Tablets formulation result in a decrease in misuse, abuse, addiction, overdose,
`and death.
`
`The Sponsor submitted an interim report on these studies in December 2011. The
`Division of Epidemiology reviewed the report in April 2012 and concluded that the
`interim findings are optimistic regarding an implicit claim of route-specific abuse-
`deterrence.
`
`Oral and non-oral abuse of OxyContin were significant problems prior to ORF
`introduction. Data from the ASI-MV® Connect NAVIPPROTM system indicate that 12%
`of prescription opioid abusers used OxyContin by the oral route and 18% used
`OxyContin by non-oral routes from June 2009 to August 2010.1 However, it appears
`
`1 ORF Epidemiology Study Program Update July 2012, p. 36
`
`
`
`Reference ID: 3258740
`
`4
`
`

`

`that, historically, the vast majority of the deaths associated with OxyContin were related
`to oral consumption. DEA medical examiner data from 2002 indicated that 2% of deaths
`linked to OxyContin were associated with the presence of a recent “injection site” and
`0.2% were associated with snorting the drug.2
`
`Evidence of Abuse-deterrence: In vitro physicochemical testing
`
`As part of the NDA 22,272 review, the Controlled Substance Staff reviewed seven in
`vitro studies (named individually under “Materials Reviewed” above) and found that:
`• ORF tablets are considerably more difficult to chew or crush compared to the
`original OxyContin; ORF is less susceptible to immediate release of a high dose
`of oxycodone.
`• ORF can still be crushed to a fine powder using a coffee grinder.
` percent of oxycodone can be extracted from ground ORF using water
`•
`compared to
` in the original OxyContin;
` of oxycodone can be extracted
`from intact ORF.
`• The percentage of oxycodone extracted from ORF using other solvents and
`different pH levels is less than the original OxyContin.
`It is more difficult to prepare a solution for intravenous injection using ORF than
`original OxyContin as a result of the inclusion of the excipient polyethylene
`oxide.
`• Obtaining oxycodone free base that could be inhaled from ORF took three times
`as long as from original OxyContin.
`
`•
`
`
`Reviewer Comment: DAAAP found that the results of these studies provided
`evidence of an incremental improvement in the formulation’s resistance to
`manipulation and approved the new formulation for marketing. In the NDA
`Summary Review for Regulatory Action, the division noted that the product is not
`completely resistant to manipulation and that a postmarketing epidemiology study
`(or studies) would be required to determine the effect of the new formulation on the
`misuse and abuse of OxyContin.
`
`As a clinical study of the effects of the new formulation on intravenous abuse is not
`ethically feasible, it is necessary to rely on the in vitro data. The in vitro testing
`demonstrated a substantial increase in difficulty in attempting to prepare a solution
`for injection from ORF compared to the original formulation.
`
`The findings from these studies regarding chewing were not supported by the in
`vivo pharmacokinetic study OTR-1016 (reviewed below), but are otherwise
`generally in alignment with the findings of studies that were subsequently
`submitted, reviewed and discussed below.
`
`Evidence of Abuse Potential
`
`
`
`2 http://www.deadiversion.usdoj.gov/drugs_concern/oxycodone/oxycontin7 htm
`
`
`
`Reference ID: 3258740
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Purdue completed five studies designed to evaluate the abuse potential of ORF. The
`Controlled Substance Staff, Clinical Pharmacology, and Statistical teams completed
`reviews of these studies. The following summary comes from the individual study
`reports that Purdue submitted to 1ND 29,038. Overall, these studies indicate that the
`controlled-release properties of ORF can be overcome when chewed vigorously and
`swallowed, but the controlled-release properties of ORF were slightly less susceptible to
`compromise than OxyContin when chewed normally. The ORF formulation scored
`lower on drug—liking and had a lower Cmax and a longer tmax than OxyContin when
`taken intranasally, and was less attractive to recreational drug users than OxyContin.
`ORF created mild irritation and may have less predictable effects than OxyContin when
`used intranasally.
`
`OTR31016 “A Randomized, Open—Label, Single-Dose, Crossover Study of the Effects
`of Various Tampering Methods on Exposure to Oxycodone in Fasting Healthy Subjects”
`
`0 Objective: Characterize PK profile of chewed and crushed ORF
`o Treatments:
`
`Part A
`
`o ORF 40 mg swallowed intact
`o ORF 40 mg tablet chewed4 and swallowed
`ORF 40 mg tablet particle size reduced by crushing via mortar and pestle,
`and swallowed
`
`ORF 40 mg tablet particle size reduced by crushing via mortar and pestle,
`chewed, and swallowed
`ORF 40 mg tablet pre-softened in water, chewed, and swallowed
`OxyContin 40 mg tablet swallowed intact
`OxyContin 40 mg tablet chewed and swallowed
`Reference: immediate-release 40 mg oxycodone solution
`
`O 0
`
`000
`
`PartB
`
`o ORF 40 mg vigorously chewed and swallowed
`o OxyContin 40 mg vigorously chewed and swallowed
`Part C
`
`o ORF 40 mg normally chewed and swallowed
`o OxyContin 40 mg normally chewed and swallowed
`
`0 Comparisons
`0 Part A: Each ORF and OxyContin condition AUC and Cmax compared to
`reference
`
`0 Part B: Bioavailability of vigorously chewed ORF and OxyContin 40 mg
`0 Part C: Bioavailability of normally chewed ORF and OxyContin 40 mg
`0 Results
`
`0 vigorous chewing overcame the controlled-release properties of ORF and
`OxyContin, but swallowing after crushing ORF with a mortar and pestle
`did not (Part A in figure below)
`
`3 Purdue referred to reformulated OxyContin as oxycodone tamper resistant tablets or OTR in these studies
`4 chewing in Part A was vigorous chewing
`(I!)(4)
`
`Reference ID: 3258740
`
`

`

`o vigorously chewed ORF and OxyContin had similar overall bioavailability
`(Part B below)
`o normally chewed ORF had lower Cmax and higher tmax than OxyContin
`(Part C below)
`
`Source: Harris, S. et al., Effects of Various Tampering Methods on Exposure to Oxycodone in Healthy
`Subjects, 74th Annual Scientific Meeting of the College on Problems of Drug Dependence, Abstract #
`242 and Poster # 78 (presented June 12, 2012), Figure 3
`
` CSS review conclusion
`o Assuming that across studies there is a similar correlation of oxycodone
`plasma concentrations to drug liking scores on the Drug Liking VAS, it is
`predicted that vigorous chewing followed by ingestion of either an ORF
`40 mg tablet, a crushed (mortar and pestle) ORF 40 mg tablet, or a pre-
`softened ORF 40 mg tablet will produce significant levels of drug liking
`indicative of positive subjective reinforcing effects.
`• Clinical Pharmacology review conclusions
`o Part A: Chewing ORF 40 mg or OxyContin (OC) 40 mg results in
`disruption of the extended-release characteristics of both products with
`early peak plasma concentrations noted compared to intact ORF or OC
`treatments.
`
` •
`
`
`
`Reference ID: 3258740
`
`7
`
`Copyright Material
`
`

`

`o Part B and C:
`• Upon chewing vigorously, OFR and OC products are
`bioequivalent with respect to oxycodone Cmax and AUC.
`• Upon chewing normally, ORF formulation resulted in a lower
`Cmax (76.4%) compared to chewed OC formulation
`
`
`Reviewer Comment: Swallowed ORF retains some of its controlled-release
`properties even after it is crushed with a mortar and pestle, less so after it is chewed
`normally, and not at all if it is chewed vigorously. This represents a minor
`advantage over OxyContin.
`
`OTR1018 “A Single-Center, Double-Blind Study in Recreational Opioid Users to
`Evaluate the Abuse Potential, Pharmacokinetics, and Safety of Crushed and Intranasally
`Administered Oxycodone HCl Tamper Resistant Tablets”
`• Objective: evaluate intranasal abuse potential of ORF compared to OxyContin
`• Treatments:
`o ORF 30 mg coarsely crushed (ORFC)5
`o ORF 30 mg finely crushed (ORFF)6
`o OxyContin 30 mg finely crushed7
`o Oxy API powder
`o placebo finely crushed
`• Results
`o ORFF and ORFC produced drug liking scores that were lower than crushed
`OxyContin and Oxy API and higher than placebo
`o Both ORF peak effects were slower (1-2 hrs post-dose) compared to
`OxyContin and Oxy API (0.5 hrs post dose)
`o Both ORF outcomes were more variable than OxyContin and Oxy API
`o Both ORFs were rated higher on intranasal irritation than OxyContin and
`Oxy API
`o Mean AUC values were similar across treatment groups and mean Cmax
`values were higher for OxyContin and Oxy API than for both ORFs
`o ORF PK was more variable than OxyContin and Oxy API and the coarsely
`crushed ORF was more variable than the finely crushed
`
`
`5 cut into
` using razor blade
`6 prepared using coffee mill
`7 prepared using mortar and pestle
`
`
`
`Reference ID: 3258740
`
`8
`
`(b) (4)
`
`

`

`
`
`Source: Purdue Pharma Citizen Petition, Exhibit 18, 7/13/12
`• Sponsor’s conclusions
`o Intranasal ORF has lower abuse potential than OxyContin or Oxy API
`• CSS review conclusions
`o There is some evidence that ORF may be less susceptible to intranasal
`abuse than OC, but on some measures both finely and coarsely crushed
`ORF scored higher (indicating higher abuse potential) than placebo
`• Statistical review conclusions
`o Median responses to ORF were significantly lower than active
`comparators on analyses of the Drug Liking VAS.
`• Clinical Pharmacology review conclusions
`o ORF subjects were more likely to have incomplete insufflation than other
`treatments
`o ORF had higher variability in PK than the other treatments
`
`Reviewer Comment: The variability in ORF PK and drug liking could make it less
`desirable to intranasal users. It could also increase the risk of overdose due to lack
`of predictability in the effect a given dose will have. While the difficulty with
`insufflation in the ORF groups may make the study results more challenging to
`interpret, it is indicative of the difficulty associated with using the product
`intranasally, and is consistent with the CSS conclusion that ORF has lower
`intranasal abuse potential than OxyContin.
`
`OTR1019 “Relative Attractiveness of Oxycodone TR: Comparative Assessment of
`Tampering Potential and Recreational Drug User Preferences for Different
`Opioid Formulations”
`• Objective: compare attractiveness for abuse and tampering with ORF, OxyContin
`and other oxycodone products
`• Methods: recreational opioid users were given information cards about ORF,
`OxyContin and other oxycodone products and were interviewed about the
`attractiveness of the formulations
`• Sponsor’s conclusions
`
`
`
`Reference ID: 3258740
`
`9
`
`

`

`o ORF was less attractive than OxyContin and other oxycodone products
`and more attractive than a hypothetical oxycodone/naltrexone product
`• CSS review conclusions
`o Part 1 of the study, which asked subjects to evaluate attractiveness was
`poorly designed
`o Part 2 indicates that OFR is less susceptible to physical manipulation than
`OxyContin using a hammer, pill crusher, mortar and pestle, or X-Acto
`knife
`
`
`Reviewer Comment: The study is consistent with the findings of the in vitro studies
`reviewed as part of original NDA 22272.
`
`OTR1021 “A Randomized, Single-Blind, 3-Way Crossover Study Evaluating the Safety,
`Tolerability, and Pharmacokinetics of Crushed Intranasal Oxycodone Tamper Resistant
`Tablets (OTR) and Oxycontin® In Healthy Adults”
`• Objective: compare PK of 10 mg of intranasal finely crushed ORF8, coarsely
`crushed ORF9 and finely crushed OxyContin10
`• Results
`o 90% CI of AUC was within 80-125% for all comparisons
`o Cmax was lower and tmax was longer for ORF compared to OxyContin
`(Tmax 1 hr for finely crushed OxyContin, 2 hrs for finely crushed ORF,
`and 3 hrs for coarsely crushed ORF)
`
`Source: Purdue Pharma Citizen Petition, Exhibit 19, 7/13/12
`
`
`
`
`• CSS review conclusions
`o PK results indicate that ORF may be less susceptible to intranasal abuse
`o The Cmax values compared to those in OTR-1018 indicate that the doses
`used (10 mg) are unlikely to result in sufficient drug liking
`o The intranasal tolerability study indicates that nasal irritation will not be a
`deterrent to intranasal abuse
`• Clinical Pharmacology conclusions
`
`
`8 prepared using coffee mill
`9 cut into
` using razor blade
`10 prepared using mortar and pestle
`
`
`
`Reference ID: 3258740
`
`10
`
`Best Available Copy
`
`(b) (4)
`
`

`

`o Consistent with the results of OTR-1018, the Cmax of finely crushed and
`coarsely crushed ORF are lower than finely crushed OxyContin. There
`are no drug-liking measures to correlate to the PK findings.
`
`
`Reviewer Comment: The study design, which used lower doses and did not include
`an evaluation of drug-liking, is less informative than OTR-1018, but the PK results
`of this study are consistent with the results of OTR-1018. Therefore, the study adds
`little to the overall conclusions regarding this formulation.
`
`OTR1022 “Single-Center, Randomized, Cross-Over Study in Recreational Opioid Users
`to Evaluate the Safety of Crushed and Intranasally Administered OTR and OC Placebo
`Tablets”
`• Objective: Assess subjective and administration site tolerability of intranasal ORF
`and OxyContin
`• Results
`o all formulations caused mild congestion and irritation
`there was residual powder in the nasal cavity with ORF but not OxyContin
`o
`placebo
`• CSS review conclusions
`o The effects of ORF and OxyContin non-active components are not
`expected to be a deterrent to intranasal abuse
`
`Reviewer Comment: Any observed decrease in intranasal use of ORF would not be
`expected to be due to irritants in the formulation.
`
`Evidence of Public Health Impact of ORF
`
`Purdue has conducted six epidemiology studies to fulfill the postmarketing requirement
`and five additional epidemiology studies. The Division of Epidemiology (DEPI)
`reviewed an interim report on these studies and concluded that the preliminary results
`were optimistic in demonstrating route-specific abuse-deterrence, but the findings were
`not mature enough to support an abuse-deterrent claim because there were no formal
`statistical analyses yet reported and none of the studies had completed the recommended
`follow-up period of 3-5 years. Purdue submitted an update on these studies on 7/31/12.
`DEPI is in the process of reviewing it, but the review has not been completed. Purdue
`concludes that replacing original OxyContin with ORF has resulted in a decrease in
`misuse and abuse of OxyContin, including a decrease in abuse overall, and abuse by
`injection, snorting, and smoking, a decrease in diversion, and a decrease in intentional
`and unintentional poisonings and adverse events. Purdue’s findings in the 7/31/12 update
`are overall slightly less encouraging than those reviewed by DEPI in 4/12, but appear to
`be generally indicative of a decline in OxyContin abuse, including by non-oral routes,
`while there was evidence of an increase in abuse of other opioids.
`
`In the update report, Purdue numbered the studies and summarized the data sources and
`endpoints addressed in the studies (reproduced below).
`
`
`
`
`Reference ID: 3258740
`
`11
`
`

`

`Source: ORF Epidemiology Study Program Update July 2012, p. 7
`
`
`
`
`Source: ORF Epidemiology Study Program Update July 2012, p. 7
`
`Division of Epidemiology review
`In the April 2012 review, DEPI considered studies 1, 2, 3, and 11 (see tables 1 and 2
`above for data source and endpoints) to be pivotal to understanding ORF’s effect on
`OxyContin abuse and the other seven studies to provide additional context to the societal,
`
`
`
`
`
`Reference ID: 3258740
`
`12
`
`

`

`behavioral, and clinical aspects of OxyContin abuse. Below are the key findings from the
`DEPI review.
`• Overall OxyContin abuse and desirability
`o In study 1, prevalence of past-month abuse per all individuals entering
`substance abuse treatment decreased by
` after the introduction of
`ORF. Similarly, in study 11, intentional-abuse exposures per quarter-
`years as reported to poison control centers decreased by
`.
`o In study 5, both drug diversion cases and average street price of
`OxyContin decreased after the introduction of ORF.
`o Studies 3 and 7 had mixed results,
`• OxyContin compared to other opioids
`o Studies 2, 5, and 8 found a decrease in OxyContin abuse or drug diversion
`and an increase in abuse or diversion of IR oxycodone.
`o Studies 1 and 8 found a reduction in OxyContin abuse and an increase in
`oxymorphone abuse.
`• OxyContin abuse by routes of administration
` decrease in the prevalence of oral routes of
`o Study 1 found a
`OxyContin abuse and a 70% decrease in non-oral routes of abuse among
`all individuals entering substance abuse treatment.
`o Study 3 found a decline in injection and inhalation routes following
`introduction of ORF, but the number of non-oral exposures was small.
`
`
`Purdue’s July 2012 update
`
`Study 1: Routes and Rates of OxyContin Abuse Among Patients in Substance Abuse
`Treatment Programs in the ASI-MV® Connect NAVIPPRO™ System
`
`Objective: Characterize routes of administration patterns and abuse associated with ORF.
`Data Source: NAVIPPRO Addiction Severity Index-Multimedia Version (ASI-MV
`Connect)
`Design: A prospective observational surveillance study
`Methods: Data collected from a sample of substance abuse treatment centers in the
`United States using the NAVIPPRO Addiction Severity Index- Multimedia Version
`(ASI-MV) Connect system.
`Population: Male and female adult substance abuse patients at substance abuse treatment
`centers.
`Outcomes: Past 30-day abuse and past 30-da