CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`22-272Orig1s014
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`Clinical Pharmacology Review
`IND: 29,038 SDN 693, 753
`Date Received: 9/17/2010, 9/4/2012
`Product Name: OxyContin Tablets
`Active Ingredient: Oxycodone HCl
`Sponsor: Purdue Pharma
`Type of Submission: Abuse Liability Clinical Study Reports
`Reviewer: Srikanth C. Nallani, Ph.D.
`
`Background:
`Purdue Pharma LP conducted five clinical studies to evaluate the abuse potential of their
`developmental tamper resistant formulation of oxycodone extended release tablets
`(OTR). These studies were submitted to IND 029038 on September 16, 2010.
`1. OTR-1016 entitled “A Randomized, Open-Label, Single-Dose, Crossover Study
`of the Effects of Various Tampering Methods on Exposure to Oxycodone in
`Fasting Healthy Subjects”.
`2. OTR-1018 entitled “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”.
`3. OTR-1019 entitled “Relative Attractiveness of Oxycodone TR: Comparative
`Assessment of Tampering Potential and Recreational Drug User Preferences for
`Different Opioid Formulations”.
`4. OTR-1021 entitled “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”.
`5. OTR-1022 entitled “Single-Center, Randomized, Cross-Over Study in
`Recreational Opioid Users to Evaluate the Safety of Crushed and Intranasally
`Administered OTR and OC Placebo Tablets”.
`Studies OTR-1016, OTR-1018 and OTR-1021 are reviewed in this memo with
`particular focus on pharmacokinetic disposition of oxycodone following administration
`of intact oxycodone extended release formulations (OxyContin tablets (OC) or tamper
`resistant tablets (OTR)) or administration of tablet contents following various methods of
`abuse (chewing, grinding followed by intranasal administration). Sponsor compares
`systemic exposure (Cmax and AUC) of oxycodone in blood following several treatments.
`
`
`
`
`Reference ID: 3190167
`
`1
`
`

`

`1. Study OTR-1016
`
`Study Title:
`A Randomized, Open-Label, Single-Dose, Crossover Study Of The Effects Of Various
`Tampering Methods On Exposure To Oxycodone In Fasting Healthy Subjects
`OBJECTIVES:
`The objectives of this study were as follows:
`Primary: To characterize the pharmacokinetic (PK) profiles and metrics for each
`treatment.
`Secondary: To assess the safety and tolerability of the oxycodone treatments
`administered under naltrexone blockade.
`METHODOLOGY:
`Part A: Randomized, open-label, single-dose, 8-treatment, 5-period, incomplete block,
`crossover study in fasting healthy adult male and female subjects.
`Parts B and C: Randomized, open-label, single-dose, 4-period, 2-treatment replicated
`design in fasting healthy adult male and female subjects.
`Part A: Subjects were randomized to a treatment sequence. All sequences included the
`immediate-release oxycodone reference solution. All treatments were administered orally
`with a total fluid volume of 240 mL in the fasted state.
`Test Treatments:
`Part A:
`Treatment A: OTR 40 mg tablet swallowed intact
`Treatment B: OTR 40 mg tablet chewed and swallowed
`Treatment C: OTR 40 mg tablet particle size reduced by crushing via mortar and pestle,
`and swallowed
`Treatment D: OTR 40 mg tablet particle size reduced by crushing via mortar and pestle,
`chewed, and swallowed
`Treatment E: OTR 40 mg tablet pre-softened in water, chewed, and swallowed
`Treatment F: OxyContin® 40 mg tablet (OC formulation) swallowed intact
`Treatment G: OxyContin® 40 mg tablet chewed and swallowed
`Reference Treatment:
`Treatment H: Immediate-release 40 mg oxycodone solution
`There were 5 Periods for Part A. Study drug was administered in each period according
`to the random allocation schedule (RAS).
`Part B:
`Treatment B: OTR 40 mg tablet chewed and swallowed
`
`
`
`Reference ID: 3190167
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`2
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`

`

`Treatment G: OxyContin® 40 mg tablet chewed and swallowed (Under vigorous
`chewing conditions as established in Part A)
`
`Part C:
`
`Treatment B: OTR 40 mg tablet chewed and swallowed
`
`Treatment G: OxyContin® 40 mg tablet chewed and swallowed (Under normal chewing
`conditions with duration times established in the chewing qualification session prior to
`Part C.)
`
`Reterence Treatment:
`
`Parts B and C: none
`
`Study drugs (OTR, 0C, and IR oxycodone solution) were prepared and
`administered as follows:
`
`1. For intact dosing (Part A), the OTR and OxyContin® tablets were swallowed whole
`with 240 mL of water.
`
`2. Particle size reduction of OTR tablets by crushing via mortar and pestle (Part A only)
`was performed per standardized procedures. Following particle size reduction, subjects
`directly swallowed or chewed and swallowed the tablet contents as described below.
`
`3. Pre-softening of OTR tablets (Part A only) was performed per standardized
`procedures. Following tablet softening in water, subjects chewed and swallowed the
`softened tablet as described below. Just prior to administration of the softened tablet, the
`water used to soften the tablet was administered, followed by administration of a rinse of
`the tablet softening container. Upon completion of chewing, subjects received the
`remaining volume of water.
`
`4. For each ‘chewed and swallowed’ treatment in Parts A and B, subjects were required
`to chew the administered intact tablet (0C or OTR), crushed tablet (OTR), or softened
`tablet (OTR) vigorously for up to
`ma). Chewing stopped once
`(mo
`
`whichever occurred first. During chewing, subjects were allowed to swallow accumulated
`saliva and small particulates ad libitlun.
`
`Subjects informed site staff upon completion of chewing/particle size reduction if this
`occurred prior to the end of the
`(m4) chewing period, and immediately after
`chewing stopped, the remaining dosing solution was administered.
`
`(mo and the remaining tablet or tablet
`Otherwise chewing stopped at the end of
`fragments were swallowed with the remaining dosing solution.
`
`For Part B, the duration of chewing in minutes and seconds following vigorous chewing
`for each subject was recorded.
`
`5. For each ‘chewed and swallowed’ treatment in Part C, subjects were required to chew
`the administered intact tablet (0C or OTR), using “normal” non-vigorous chewing
`techniques. Chewing duration data from the chewing qualification session was used to
`obtain the maximum duration of chewing (in minutes and seconds) for each subject for
`
`Reference ID: 3190167
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`

`

`Part C. Once the subject reached his/her maximum chewing duration time, they were
`instructed to swallow the dose followed by 240 mL of water.
`6. For immediate-release oxycodone solution administration (Part A only), subjects
`received study drug in the appropriate volume of the oxycodone oral solution, followed
`by dosing cup rinses with an additional quantity of water sufficient to bring the total
`volume administered to 240 mL.
`7. Study drug (test or reference treatment) was administered following a 10-h overnight
`fast. Subjects continued fasting from food for 4 h following dosing.
`8. Subjects were standing or in an upright sitting position while receiving their dose of
`study drug. Following dosing, subjects remained in an upright position for a minimum of
`4 h.
`Fasting was not required for non-dosing study days.
`Subjects received naltrexone HCl 50 mg tablets with 240 mL of water at -13, -1, 11, 23,
`and 35 h relative to each study drug dosing.
`Endpoints/Criteria for Evaluation:
`Pharmacokinetic:
`Plasma concentrations of oxycodone were analyzed to determine the following PK
`metrics: area under the plasma concentration-time curve from h 0 to the last measurable
`plasma concentration (AUCt), area under the plasma concentration-time curve
`extrapolated to infinity (AUCinf), maximum observed plasma concentration (Cmax),
`time to maximum plasma concentration (tmax), apparent plasma terminal phase half-life
`(t1/2Z), lag time was estimated as the timepoint immediately prior to the first measurable
`plasma concentration value (tlag), and apparent terminal phase rate constant (λZ).
`Safety:
`Safety was assessed using recorded adverse events (AEs), clinical laboratory test results,
`vital signs results, pulse oximetry, physical examinations, and electrocardiograms.
`Bioanalytical Methods:
`Plasma concentrations of oxycodone were quantified by using a validated liquid
`chromatography tandem mass spectrometric method (
` SOP TM.664,
` Report #
`4141.090806.1).
`Statistical Analysis:
`For Part A, oxycodone AUCt, AUCinf, and Cmax, a mixed-model analysis of variance
`(SAS PROC MIXED) was used to compare logarithmic-transformed (base e) values for
`each comparison. The 90% confidence intervals were estimated for the ratios
`(test/reference) of exponentiated LS means from all 28 pairwise treatment comparisons.
`Additionally, a secondary analysis on normalized metrics (indexed by subjects’ own
`metric values from the Immediate-release 40 mg oxycodone solution treatment) was also
`performed.
`
`
`
`Reference ID: 3190167
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`For Part B, the relative bioavailability of the controlled release oxycodone formulations
`(OTR 40 mg and OxyContin® 40 mg) following vigorous chewing (as conducted in Part
`A) was evaluated.
`For Part C, the relative bioavailability of the controlled release oxycodone formulations
`(OTR 40 mg and OxyContin® 40 mg) under “normal” non-vigorous chewing conditions
`was evaluated. This would attempt to determine release of oxycodone from the
`formulations following chewing in a manner that would be considered accidental or
`inadvertent.
`The analyses for Parts B and C were performed using a linear mixed model appropriate
`for a replicated crossover design.
`Pharmacokinetic Analysis Results:
`Mean Plasma Profile of Oxycodone following administration of different oxycodone
`treatments
`
`
`The following table describes the mean pharmacokinetic parameters of oxycodone
`following administration of treatments A – H in part A of the study.
`
`
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`Reference ID: 3190167
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`5
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`

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`Table: Summary of Mean Oxycodone Pharmacokinetic Metrics: Part A
`
`
`
`
`
`Reference ID: 3190167
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`6
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`Table: Summary of Mean Oxycodone Pharmacokinetic Metrics: Part B
`
`Table: Summary of Mean Oxycodone Pharmacokinetic Metrics: Part C
`
`
`
`
`
`
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`Reference ID: 3190167
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`7
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`

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`The sponsor utilized the immediate release oral tablet, treatment H, as reference in
`assessing/comparing the pharmacokinetic parameters of oxycodone following various
`methods of abuse. However, the proper reference is an intact OTR formulation
`(treatment A). 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, which
`produces a much rapid plasma levels of oxycodone, would confound the PK results of
`physical manipulation which may defeat the control release properties of Oxycontin TR
`(see table below). Hence, from a clinical pharmacology perspective, bioavailability
`comparisons are appropriate using Treatment A or the intact extended-release tablet as
`reference. Note that the OTR tablet (Treatment A) is bioequivalent to Oxycontin tablet
`(Treatment F) when swallowed intact.
`Summary of PK parameters of oxycodone compared to reference treatment A (OTR
`tablet swallowed intact): Part A results.
`LS Meana
`
`
`
`
`Test/Referenceb
`90% Confidence
`PK
`Test
`n
`n
`Reference
`Intervalc
`(%)
`Parameter
`(97.93 , 111.83)
`105
`41.1
`Cmax
`32
`35
`39.3
`(95.24 , 103.72)
`99.4
`453
`AUCt
`32
`35
`455
`(94.86 , 103.34)
`99.0
`455
`AUCinf
`32
`34
`459
`(160.08 , 183.60)
`171
`70.5
`41.1
`Cmax
`31
`32
`(89.72 , 97.99)
`93.8
`424
`AUCt
`31
`32
`453
`(89.65 , 97.90)
`93.7
`426
`AUCinf
`31
`32
`455
`(96.74 , 111.26)
`104
`42.7
`Cmax
`30
`32
`41.1
`(87.74 , 96.00)
`91.8
`415
`AUCt
`30
`32
`453
`(87.85 , 96.12)
`91.9
`418
`AUCinf
`30
`32
`455
`(158.03 , 181.78)
`169
`69.7
`41.1
`Cmax
`29
`32
`(87.37 , 95.61)
`91.4
`414
`AUCt
`29
`32
`453
`(87.31 , 95.57)
`91.3
`415
`AUCinf
`29
`32
`455
`(165.50 , 189.84)
`177
`72.9
`41.1
`Cmax
`31
`32
`(88.05 , 96.17)
`92.0
`417
`AUCt
`31
`32
`453
`(88.79 , 96.97)
`92.8
`422
`AUCinf
`31
`32
`455
`(182.97 , 209.93)
`196
`80.6
`41.1
`Cmax
`30
`32
`(93.21 , 101.82)
`97.4
`441
`AUCt
`30
`32
`453
`AUCinf
`30
`442
`32
`455
`97.3
`(93.08 , 101.66)
`a Least squares means from ANOVA, calculated by transforming the natural log (ln) means back to the
`linear scale, i.e., geometric means.
`b Ratio of metric means (expressed as a percent), transformed back to the linear scale.
`c 90% confidence interval for ratio of metric means (expressed as a percent), transformed back to the linear
`scale.
`Part A:
`Treatment A: OTR 40 mg tablet swallowed intact
`Treatment B: OTR 40 mg tablet chewed and swallowed
`Treatment C: OTR 40 mg tablet particle size reduced by crushing via mortar and pestle, and swallowed
`Treatment D: OTR 40 mg tablet particle size reduced by crushing via mortar and pestle, chewed, and
`swallowed
`Treatment E: OTR 40 mg tablet pre-softened in water, chewed, and swallowed
`Treatment F: OxyContin® 40 mg tablet swallowed intact
`Treatment G: OxyContin® 40 mg tablet chewed and swallowed
`
`
`Treatment
`Comparison
`A vs. F
`
`
`B vs. A
`
`
`C vs. A
`
`
`D vs. A
`
`
`E vs. A
`
`
`G vs. A
`
`
`
`
`
`Reference ID: 3190167
`
`8
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`

`

`Sponsor’s choice of Reference Treatment:
`Treatment H: Immediate-release 40 mg oxycodone solution
`Comparison of OTR formulation and Oxycontin under rigorous conditions of abuse
`(Chewing) indicates that the rate and extent of oxycodone released and absorbed is
`bioequivalent (See table below).
`Table - Statistical Results of Oxycodone Pharmacokinetic Metrics (Treatment
`Comparison): Part B
`
`
`
`Note: Under vigorous chewing conditions: Treatment B = OTR 40 mg tablet chewed and swallowed;
`Treatment G = OxyContin® 40 mg tablet (OC formulation) chewed and swallowed.
`Reviewer’s comments: Bioequivalence of oxycodone systemic exposure indicates that
`under rigorous chewing condition, the OTR formulation did not show better tamper-
`resistant performance compared to the OxyContin® 40 mg tablet (OC formulation) based
`on PK data.
`Comparison of OTR formulation and Oxycontin under normal non-rigorous conditions of
`abuse (Chewing) indicates that the extent of oxycodone released and absorbed, as seen by
`Cmax, was lower with OTR formulation (See table below).
`Table - Statistical Results of Oxycodone Pharmacokinetic Metrics (Treatment
`Comparison): Part C
`
`
`
`Note: Under "normal" non-vigorous chewing conditions: Treatment B = OTR 40 mg
`tablet chewed and swallowed; Treatment G = OxyContin® 40 mg tablet chewed and
`swallowed.
`Reviewer’s comments: Under "normal" non-vigorous chewing conditions, Cmax of the
`OTR formulation does not meet the bioequivalent criteria to that of the OxyContin®
`tablet (OC formulation), but it is only about 23.6% lower.
`Conclusions:
`Part A:
`Utilizing intact Oxycontin extended release (OTR) as reference under fasting conditions:
` OTR 40 mg is bioequivalent to OC 40 mg when swallowed intact
`
`Immediate release oxycodone 40 mg oral treatment results in highest Cmax
` Chewing OTR 40 mg or OC 40 mg results in disruption of the extended release
`characteristics of both the products with early peak plasma concentrations noted
`compared to intact OTR or OC treatments.
`
`
`
`Reference ID: 3190167
`
`9
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`

`

`Part B and C:
`
`It should be noted that chewing disrupts ER characteristics of OTR and OC
`treatments (Part A)
` Upon chewing vigorously (part B), OTR and OC products are bioequivalent with
`respect to oxycodone Cmax and AUC.
` Upon chewing normally (part C), OTR formulation resulted in a lower Cmax
`(76.4%) compared to chewed OC formulation
`Reviewer’s comments:
`Use of intact oxycodone extended release formulation is indicated in the product label
`(OC or OTR formulation). Hence, pharmacokinetic profile of the approved extended
`release product serves as a reference for subsequent manufacturing changes as well as
`approval of generic drugs. Since the goal of the PK study is to understand whether the
`extended-release product can withstand physical tampering, PK results from an intact
`oxycodone extended-release product should be used as reference. However, the Sponsor
`used the IR formulation as reference in study OTR-1016. Use of IR formulation as a
`reference, which produces a much rapid plasma levels of oxycodone, would confound the
`PK results of physical manipulation which may defeat the control release properties of
`Oxycontin OTR. Hence, from a clinical pharmacology perspective, bioavailability
`comparisons are appropriate using the intact extended-release tablet as reference instead
`of IR formulation after oral administration.
`After oral administration, the extents of drug absorption (in term of AUC) are comparable
`among different formulations (OTR, OC and IR solution formulations) with different
`chewing methods including swallowing intact. However, the rates of absorption (in term
`of Cmax and Tmax) are different. Disrupted ER characteristics of the OTR or OC
`formulation after several chewing methods can be characterized by shorter Tmax and
`higher Cmax compared to swallowing intact.
`The sponsor tested various chewing methods for the OTR formulation before swallowing.
`Only Treatment C (particle size reduced by crushing via mortar and pestle, and
`swallowed) showed comparable Tmax and Cmax to Treatment A (swallowing intact).
`The ER characteristics of the OTR formulation was mostly disrupted for the rest of the
`chewing methods, including Treatment B (chewed and swallowed), Treatment D (particle
`size reduced by crushing via mortar and pestle, chewed, and swallowed), and Treatment
`E (tablet pre-softened in water, chewed, and swallowed). This was demonstrated by
`shorter Tmax and higher Cmax compared to swallowing intact OTR tablet, and
`comparable Tmax and Cmax to the IR oxycodone solution.
`There is no substantial evidence that the OTR formulation demonstrated better tamper-
`resistant characteristics than the OC formulation after chewing and swallowing based on
`PK data. The Cmax value met the bioequivalence criteria between the two formulations
`after vigorously chewing, while the Cmax value for OTR is only about 23.6% lower than
`that of OC formulation after "normal" non-vigorous chewing conditions.
`
`
`
`Reference ID: 3190167
`
`10
`
`

`

`2. Study OTR-1018
`Study Title:
`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
`Objectives:
`Qualification Phase
`To ensure that subjects with self-reported recreational opioid experience including
`intranasal administration, were also able to report positive subjective effects of the drugs
`in a controlled laboratory setting.
`To ensure that no safety issues arose, if subjects needed to receive an opioid antagonist
`rescue during the study.
`Treatment Phase
`To evaluate intranasal abuse potential and pharmacodynamic effects of coarsely and
`finely crushed OTR compared to OC, oxycodone Active Pharmaceutical Ingredient
`(API), and OC placebo in healthy, adult recreational opioid users with a history of
`intranasal abuse.
`To evaluate the safety and tolerability of intranasally administered crushed OTR in
`healthy, adult recreational opioid users with a history of intranasal abuse.
`To determine the comparative pharmacokinetics of intranasally administered crushed
`OTR compared to OC and Oxy API.
`Study Design
`This was a randomized, double-blind, placebo-controlled crossover study to evaluate the
`relative pharmacodynamic, pharmacokinetic, and safety profile of intranasally
`administered crushed OTR tablets (fine powder [OTRF] and coarse powder [OTRC])
`compared to crushed OC tablets (fine powder), Oxy API powder, and OC placebo (fine
`powder) in recreational opioid users with a history of intranasal use. The procedures for
`crushing to “coarse” and/or “fine” powder for OTR and for OC were standardized, and
`particle size distributions were assessed.
`The study design is summarized below. The study consisted of 4 phases: Screening,
`Qualification, Treatment, and Follow-up.
`Treatments administered
`During the double-blind Qualification Phase, the following single intranasal doses were
`administered to each subject:
` 30 mg Oxy API powder
`
`lactose powder placebo
`During the double-blind Treatment Phase, the following single intranasal doses were
`administered to each subject in a randomized, full crossover manner:
`
`
`
`Reference ID: 3190167
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`11
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`

`

` Treatment A: finely crushed OC placebo
` Treatment B: 30 mg Oxy API powder
` Treatment C: 30 mg finely crushed OTR tablets
` Treatment D: 30 mg coarsely crushed OTR tablets
` Treatment E: 30 mg finely crushed OC tablets
`
`
`
`
`
`Sponsor indicates that insufflation was incomplete for OTRF and OTRC for
`approximately one-third of subjects (10 out of 30). This may have been due to the
`inability to completely insufflate OTR when crushed into a coarse or fine powder.
`Incomplete dosing was more likely to occur with OTRF (10 subjects) and OTRC (9
`subjects) compared with OC (2 subjects), Oxy API (0 subjects), and placebo (3 subjects),
`due to granules falling from the subjects’ nostrils.
`Study Endpoints
`Pharmacodynamic Endpoints (results are discussed by Dr. James Tolliver of the
`Controlled Substances Staff)
`For the purpose of study validation, the primary pharmacodynamic measures were Drug
`Liking VAS, Overall Drug Liking VAS, Subjective Drug Value, and ARCI MBG.
`Measurements were carried out at 6 and 23 hours post-dose for the Qualification Phase
`and at 8 and 24 hours post-dose for the Treatment Phase.
`Safety Endpoints
`The safety endpoints of this study were as follows:
` Concomitant medications
` Type, incidence, and severity of AEs
` Vital signs (blood pressure, heart rate, respiratory rate, and oxygen saturation)
` 12-lead ECG (heart rate and PR, QRS, QT, and QTc intervals)
` Clinical laboratory tests (haematology, chemistry, and urinalysis)
` Physical examination
`
`
`
`
`
`
`Reference ID: 3190167
`
`12
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`

`

`Pharmacokinetic Endpoints
`
`Blood samples were collected at 0, 0.25, 0.5, l, 2, 3, 4, 6, 8 and 24 hours post dose. The
`plasma samples were analyzed by
`(I'm
`using validated methods "’"" SOP TM.664, "'"" Report # 3351.0615052). The limit of
`quantification was 0.100 ng/mL. Plasma concentration data for oxycodone were listed
`for each subject and time point, and summarized using descriptive statistics at each time
`point. Pharmacokinetic parameters were calculated using non—compartmental methods
`and summarized by treatment.
`
`The pharmacokinetic endpoints of this study were as follows:
`
`Cmax: maximum plasma concentration
`
`Tmax: time to maximum plasma concentration
`AUClmz area under the concentration time curve from time zero to last assessment
`
`AUCM: area under the concentration time curve from time zero to infinity
`
`Plasma concentrations over time for oxycodone
`
`Pharmacokinetic Results:
`
`Range of PK parameters following Complete and Incomplete Dosing of OTR
`
`Range (Minimum — Maximum)
`
`Cmax
`
`AUClast
`
`OTRF
`
`Incomplete (n=10)
`
`Complete (n=l9)
`
`OTRC
`
`(nglmL)
`
`(nglmL*h)
`
`20.0 — 34.8
`
`141 — 432
`
`19.1 — 44.9
`
`162 — 534
`
`Incomplete (n=9)
`
`6.93 — 46.2
`
`41.2 — 427
`
`Complete (n=l9)
`
`12.7 — 55.6
`
`131 — 726
`
`Mean Oxycodone Plasma Concentration Curves (nglmL)
`5U
`
`
`
`
`
`NeanPlasmaConcentration(ngImL)
`
`Mwx:-t:t:t:
`
`
`
`Scheduled Timepoint (hr)
`
`l—I—I OTRCoarse A—A- —A— 00 Fine
`O-—-O—~-+ 0TH Fine
`4—4—4 OXMPI
`
`
`Reference ID: 3190167
`
`13
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`

`

`Summary of PK parameters for OTR coarse, OTR fine, OC fine, oxycodone API
`Geometric
`CI
`Mean
`SD
`Mean
`90%Lower
`Coarsely crushed OTR tablet
`376.4
`182.4
`320.4
`328.4
`151.8
`285.0
`29.8
`12.2
`27.0
`3.1
`1.9
`2.4
`Finely crushed OTR tablet
`339.2
`101.2
`323.3
`311.5
`86.6
`299.1
`29.4
`7.7
`28.4
`2.1
`1.1
`1.9
`Finely crushed Oxycontin tablet
`384.6
`101.8
`371.6
`374.2
`93.2
`362.7
`59.6
`16.2
`57.5
`1.3
`1.0
`0.9
`Oxycodone API powder
`350.2
`69.6
`343.4
`342.1
`67.0
`335.6
`52.1
`13.0
`50.6
`1.2
`1.2
`0.8
`
`231.8
`228.1
`30.0
`-0.8
`
`468.7
`456.1
`74.2
`3.2
`
`Parameter
`
`AUCINF
`AUCLAST
`CMAX
`TMAX
`
`AUCINF
`AUCLAST
`CMAX
`TMAX
`
`AUCINF
`AUCLAST
`CMAX
`TMAX
`
`N
`
`27
`28
`28
`28
`
`29
`29
`29
`29
`
`28
`28
`28
`28
`
`Nobs
`
`28
`28
`28
`28
`
`29
`29
`29
`29
`
`28
`28
`28
`28
`
`CI
`90%Upper
`
`687.4
`587.0
`50.5
`6.2
`
`511.4
`458.9
`42.5
`3.9
`
`558.0
`532.9
`87.3
`3.0
`
`65.3
`69.7
`9.1
`-0.1
`
`167.1
`164.1
`16.3
`0.2
`
`211.2
`215.5
`32.0
`-0.4
`
`29
`29
`29
`29
`
`29
`29
`29
`29
`
`AUCINF
`AUCLAST
`CMAX
`TMAX
`Conclusions:
`
`Insufflation was incomplete for finely ground OTRF and coarsely ground OTRC
`for approximately one-third of subjects.
` Higher variability is noted in the pharmacokinetics of oxycodone following
`intranasal administration of OTR coarse/fine treatments.
` Without the intact tablet as reference and because of incomplete insufflation in
`OTR treatment arms, the PK comparison of the various treatments via intranasal
`administration has limited utility.
`Reviewer’s comments
`
`The Cmax value for Treatment C (Finely Crushed 30 mg OTR) and Treatment D
`(Coarsely Crushed 30 mg OTR) is approximately 40-50% lower than that of Treatment A
`(30 mg Oxy API powder) and Treatment E (30 mg finely crushed OC tablets). If the
`Drug Liking VAS score measured in the study also favors the OTR formulation, the
`results may be used to support that the OTR formulation has a better tamper-resistant
`characteristics compared to the OC and API formulation by nasal administration after
`crushing. In addition, the reason for incomplete insufflation of the coarse or fine OTR
`powder is not clear. Hence, input from CSS will be necessary to conclude if incomplete
`insufflation is in itself a valid advantage.
`
`
`
`Reference ID: 3190167
`
`14
`
`

`

`3: Study OTR-1021 Synopis:
`Study Title:
`A Randomized, Single-Blind, Single-Dose, Single-Center, 3-Treatment, 3-Period
`Crossover Study In Fasted Healthy Adult Subjects.
`Objective:
`The objective of this study was to compare the safety, tolerability, and PK of Finely
`Crushed OTR, Coarsely Crushed OTR, and Finely Crushed OC tablets administered as
`10 mg intranasally.
`Study Design:
`Single intranasal doses of the following study drugs were administered in a randomized,
`single-blinded, 3-way crossover study:
` Treatment A: Finely Crushed 10 mg OTR
` Treatment B: Coarsely Crushed 10 mg OTR
` Treatment C: Finely Crushed 10 mg OC
`Treatments were administered in alternating nares (left-right-left) and were separated by
`a 48-hour washout. Detailed procedures for crushing the OTR (coarse and fine crush) and
`OC (fine crush) tablets were described in the Pharmacy Manual.
`Treatment Sequences
`
`
`
`Subjects were healthy men and women aged 18 to 55 years, inclusive, with no clinically
`significant medical history, who were deemed suitable to participate in this clinical study
`by the PI. The washout period separating dose administrations was 48 hours. When a
`subject prematurely discontinued from the study, an additional subject may have been
`enrolled following Sponsor (or designee) approval to ensure that up to approximately 20
`subjects completed the study. Additional subjects were assigned the next sequential
`randomization number.
`Blood samples for determining oxycodone plasma concentrations were obtained for each
`subject predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 28,
`32, 36, and 48 hours post study-drug administration during each of the study periods. The
`first 48-hour samples may have been obtained up to 10 minutes early and served as the
`predose samples for the remaining treatments. Plasma concentrations of oxycodone were
`quantified by a validated liquid chromatography tandem mass spectrometric method. The
`
`
`
`Reference ID: 3190167
`
`15
`
`

`

`PK metrics used in this study were those typically used to assess rate and extent of drug
`absorption (ie, bioavailability). Assessments of bioavailability were based on
`comparisons of area under the plasma concentration-time curve from hour 0 to the last
`measurable plasma concentration (AUCt), area under the plasma concentration-time
`curve extrapolated to infinity (AUCinf), and maximum observed plasma concentration
`(Cmax). Other standard PK metrics (time to maximum plasma concentration [tmax],
`apparent terminal phase rate constant [λZ], and apparent plasma terminal phase half-life
`[t1/2Z]) were estimated and presented as mean ± standard deviation.
`Summary of Mean Oxycodone Pharmacokinetic Metrics: Full Analysis Population
`
`
`Mean Plasma Concentrations of Oxycodone following intranasal administration of
`different oxycodone formulations
`
`
`
`Reference ID: 3190167
`
`
`
`16
`
`

`

`The 90% CIs for oxycodone Cmax for the comparison of Finely Crushed 10 mg OTR
`versus Finely Crushed 10 mg OC and Coarsely Crushed 10 mg OTR versus Finely
`Crushed 10 mg OTR were not entirely contained within the 80 to 125% range, while the
`90% CI for oxycodone Cmax for the comparison of Coarsely Crushed 10 mg OTR versus
`Finely Crushed 10 mg OC was entirely outside of the 80 to 125% range (See table
`below).
`Table: Statistical Results of Oxycodone Pharmacokinetic Metrics (Treatment
`Comparison): Full Analysis Population
`
`
`
`a Least squares means from ANOVA, calculated by transforming the natural log (ln)
`means back to the linear scale, ie, geometric means.
`b Ratio of metric means (expressed as a percent), transformed back to the linear scale.
`c 90% confidence interval for ratio of metric means (expressed as a percent), transformed
`back to the linear scale.
`d Intersubject variability, intrasubject variability, and intrasubject coefficient of variation
`(expressed as a percent) for ln-transformed metric from ANOVA. They are same for all
`treatment comparisons (by metric).
`These results demonstrate that the 3 treatments were not equivalent with regard to
`oxycodone Cmax. In contrast, the 90% CIs for oxycodone AUCt and AUCinf were
`entirely contained within the 80 to 125% range for all treatment comparisons, indicating
`bioequivalence.
`
`Reviewer’s comments
`The Cmax value for both Treatment A (Finely Crushed 10 mg OTR) and Treatment B
`(Coarsely Crushed 10 mg OTR) is lower that of Treatment C (Finely Crushed 10 mg
`OC), which are 22.4% and 33% lower, respectively. This trend is consistent with the PK
`results from Study OTR-1018. However, without Drug Liking VAS score measured, it is
`difficult to make a conclusion whether the 22.4% and 33% lower Cmax for the OTR
`formulation can be interpreted as better tamper-resistant characteristics by nasal
`administration after crushing.
`
`
`
`Reference ID: 3190167
`
`17
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`09/19/2012
`
`YUN XU
`09/20/2012
`
`Reference ID: 3190167
`
`