CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`022272Orig1s027
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`

`

`
`
`CLINICAL PHARMACOLOGY REVIEW
`NDA: 022272 S-027, SDN322,
`Submission Date(s): 12/10/2014, 5/11/2015,
`SDN325,
`5/14/2015
`Brand Name
`Oxycontin
`Generic Name
`Oxycodone Extended Release Tablets
`Srikanth C. Nallani, Ph.D.
`Clinical Pharmacology Reviewer
`Srikanth C. Nallani, Ph.D.
`Pharmacometrics Reviewer
`Kevin Krudys, Ph.D.
`Pharmacometrics Team Leader
`Team Leader
`Yun Xu, Ph.D.
`OCP Division
`Division of Clinical Pharmacology II
`OND Division
`Anesthesia, Analgesia and Addiction Products
`Sponsor
`Purdue Pharma LP
`Submission Type
`Pediatric Efficacy Supplement
`Formulation; Strength(s)
`Extended Release Tablet; 10 -80 mg
`Indication
`Chronic Pain Management
`Proposed Dosage Regimen
`Twice daily dosing based on efficacy and
`tolerability.
`
`
`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
`1.4
`General Biopharmaceutics .............................................................................................................. 7
`1.5
`Analytical ..................................................................................................................................... 10
`Labeling ................................................................................................................................................ 11
`2
`3 Appendix .............................................................................................................................................. 12
`3.1
`Proposed labeling ......................................................................................................................... 12
`3.2
`Individual Study Reviews ............................................................................................................. 41
`3.2.1
`Bioanalytical Method (Long term stability, Fifteen Freeze Thaw cycle stability) &
`OXNSR06-022-1 report synopsis. ........................................................................................................ 41
`3.2.2
`Population PK Analysis of OxyContin and Immediate Release Oxycodone. ....................... 47
`3.2.3
`Synopsis of Pediatric Patient Study OC96-0602 .................................................................. 60
`3.2.4
`Synopsis of Study OXP3003 Pediatric age group 5 – 16 yrs. ............................................... 63
`3.2.5
`Synopsis of Study OTR3001, Pediatric Study of OxyContin (ORF) in 6 – 16 yrs. .............. 69
`3.2.6
`Synopsis of Pediatric Study in 6 – 16 yrs. age (OXP3004): ................................................. 76
`3.2.7
`Synopsis of Pediatric Study with patient’s age birth to 4 yrs. (OXP1005): .......................... 82
`3.2.8
`Synopsis of Pediatric Study of OxyContin (ORF) in age group 6 – 16 yrs. (OTR1020). ..... 87
`3.2.9
`Synopsis of bioavailability study comparing IR oxycodone and original OxyContin in adults
`(OC94-0101). ....................................................................................................................................... 94
`
`
`
`
`
`
`Reference ID: 3757009
`
`1
`
`

`

`
`
`1 Executive Summary
`1.1 Recommendation
`The submission is acceptable provided that a mutually acceptable agreement is arrived on
`the product label.
`1.2 Phase IV Commitments
`None.
`1.3 Summary of Clinical Pharmacology Findings
`Purdue Pharma LP submitted a response to the Pediatric Written Request issued by the
`Agency. In addition, the sponsor has also submitted Oxycontin product label with
`changes to the Dosage and Administration (Section 2), Specific Populations, Pediatrics
`(Section 8); Clinical Pharmacology, Pharmacokinetics, Special Populations (Section
`12.3). Data from five multiple dose and one single dose pediatric pharmacokinetic
`studies, and two single dose BA/BE studies in adults were submitted (listed below in the
`table) to support meeting the exclusivity requirements and the labeling changes proposed.
`The sponsor also refers to a previously completed safety, PK study (OC96-0602 from
`1998) that evaluated relative bioavailability of Oxycontin (original formulation)
`compared to oral immediate release tablet in pediatric patients on other opioid
`medications. Additional reference is made to relative bioavailability study of Oxycontin
`(old and new formulations) with IR oxycodone solution/tablet for bridging PK
`information (OTR1001 (previously reviewed in 2010), OC94-0101 in attached synopsis,
`OTR1005, and OTR1502 in table below).
` Table: Studies Submitted to support pediatric population PK analysis.
`
`
`
`Reference ID: 3757009
`
`
`
`2
`
`

`

`
`
`.
`dune-pencil.
`
`GOSSOVH
`
`0C96-0602
`(United States)
`
`To compare the relative
`bioavailabihnes following Single
`“s" “m ”Fm” ”'4 °C “1
`
`Single-Caner. rundown-cl
`open—label two-way crossover.
`5“!ng
`
`0C 10 mg tablet po
`[CC C3 5]
`lmrmdnte Release 5 mg. po
`[IR Oxycodone 961438]
`
`13 011061;)
`pmm
`My (6 m 12))
`
`oequinlence of om
`relative to OC
`
`OTR 40 mgtablets. po [CB-200648]
`0C 40 mg tablets. po [WMGI]
`
`'
`
`92 (611.18“)
`fluidly adult subjects
`wider fisnng and under
`nalmone blockade.
`31y (18.4930
`
`nce o
`andbioequlvale
`f0'l'R(UK)
`and 0C tablets
`
`.
`
`0TR(UK).OTR(US)Ind0C80mg
`.
`.
`Healthy mm subjects
`whim. p0
`WNW“,
`[01R(UK) 80mg imam
`bloclmk.
`[O'l'R (US) 80 mg: P513374].
`31); (19453')
`[0C 80 mg: PN3350]
`PM: IRWHn’A: Mantle: 0C= original Monti: Tablet: (”Rahal-dam! OxyContin Tabhl: with akin-datumW: ”(War
`W o: (by with); qllhmuy 12 but; WR-Inimnqut. y-yun.
`‘ muzmmmsmyomonmm “Madam 34-“: panel FoIPIoducllIkplaaxmullCSRO'IRJOOl.
`
`Clinical pharmacology of OxyContin: Pharmacokinetic properties of oxycodone
`following single and multiple dose administration (10 — 80 mg) of OxyContin
`(reformulated product approved in 2010) have been fairly well investigated in adults.
`Dose proportionality has been established for OxyContin 10 mg — 80 mg tablet strengths
`for both peak plasma concentrations (Cmax) and extent of absorption (AUC). Given the
`short elimination t1/2 of oxycodone (~5 hours), steady-state plasma concentrations of
`oxycodone are achieved within 24—36 hours of initiation of dosing with OxyContin.
`Oxycodone is extensively metabolized by multiple metabolic pathways to produce
`noroxycodone, oxymorphone and noroxymorphone, which are subsequently
`glucuronidated. Noroxycodone and noroxymorphone are the major circulating
`metabolites. CYP3A mediated N—demethylation to noroxycodone is the primary
`metabolic pathway of oxycodone with a lower contribution from CYP2D6 mediated O-
`demethylation to oxymorphone.
`
`Pediatric Studies with OxyContin and Immediate release Oxycodone formulations:
`
`It is important to note most of the pediatric OxyContin studies (in the table above)
`conducted in support of this supplement recruited pediatric patients with moderate to
`severe pain who were already receiving oxycodone or other opiates for pain management
`and could be considered opioid tolerant. These patients were administered OxyContin
`only if they required at least 10 mg twice daily. Patients requiring less than 10 mg twice
`daily were not included in the study.
`
`Pharmacokinetics and safety of an age—appropriate oral formulation of immediate release
`oxycodone solution in opioid-naive hospitalized patients from birth up to < 4 years of age
`were evaluated in Study OXP1005 and PK of oxycodone in opioid-naive hospitalized
`pediatric patients 6 — 16 yrs. of age in Study OXP3003.
`
`(m4)
`. Therefore, this review
`is focused on the use of OxyContin in pediatric patients and is not intended to provide
`dosing recommendations of this immediate release formulation in the pediatric
`population.
`
`Pediatric Bioavailability Study OC96—0602:
`
`In Study OC96-0602, pharmacokinetics of oxycodone following crossover administration
`of OxyContin (10 mg original formulation) was compared with IR oxycodone (5 mg
`tablet). Pediatric patients (N=13) were previously receiving opiates other than
`
`Reference ID: 3757009
`
`

`

`
`
`oxycodone to qualify for this study. In this study, pediatric patients in the 6-12 yrs. age
`group receiving 10 mg OxyContin had a Cmax or peak plasma concentration of
`oxycodone ~22 ng/mL; where as adults receiving the same dose would have a Cmax of ~
`11 ng/mL. OxyContin label indicates that a single 10 mg dose produces oxycodone AUC
`of about 136 ng.hr/mL.
`Table: Summary of PK Parameters from Study OC96-0602
`
`
`
`
`Figure: Box-Plot comparing Cmax (left figure) and AUC (right figure) of oxycodone in
`pediatric patients of 6 -12 yrs. age following administration of OxyContin 10 mg or IR
`oxycodone 5 mg (tablet) doses. Horizontal reference lines are label indicated mean
`Cmax (left figure) and mean AUC (right figure) of 10 mg OxyContin (bottom) and 20 mg
`OxyContin (top) in adults.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3757009
`
`4
`
`

`

`The observed increase in exposure of oxycodone following OxyContin administration in
`the 6 -12 year age group is possibly due to decreased metabolic clearance in these
`patients with lower body weight.
`
`In another pediatric safety study (OTR3001) where OxyContin safety and PK was
`evaluated in 6 -16 year old patients, it was observed that for any given dose of OxyContin
`(10 — 30 mg) patients in 6 — 12 yr. age group had higher Cmax compared to 13 -16 yr. old
`patients (See appended results for OTR3001). The higher Cmax appeared to be a more
`consistent observation in pediatric patients < 60 kg bodyweight compared to >60 kg
`bodyweight (See figure below). Very limited number of subjects received doses 240 mg
`OxyContin; hence a comparison could not be made. These findings are consistent with
`the population pharmacokinetic analysis which demonstrated that body weight is an
`important covariate for the volume of distribution and clearance of oxycodone. A dose-
`proportional increase in Cmax and AUC was noted in pediatric patients in each age group
`or body weight group.
`
`It is important to note most of the pediatric studies conducted in support of this
`supplement (including study OTR3001) recruited pediatric patients who were already
`receiving oxycodone or other opiates for pain management and could be considered
`opioid tolerant. Hence, the observed difference in Cmax in pediatric patients with lower
`age/bodyweight becomes clinically relevant when considering 10 mg OxyContin for
`opioid naive patients. In fact, pediatric patients in the age range of 6 — 12 yrs., especially
`those with lower body weight, might benefit from a 5 mg OxyContin formulation.
`
`mm)
`
`. It is noteworthy that pediatric patients 12 — 17 yrs. Old have similar
`exposure to oxycodone compared to adults receiving similar dose of OxyContin.
`
`Figure: Box-Plot comparing Cmax (first dose) of oxycodone in pediatric patients (Study
`OTR3001) of bodyweight <60 kg vs. >60 kg bodyweight following administration of
`different OxyContin doses. Horizontal reference lines are label indicated mean Cmax of
`10 mg OxyContin (bottom) and 20 mg OxyContin (top) in adults.
`70
`
`
`
`Cmax(ng.mL)
`
`
`
`
`
`Cmax 20 mg ORF in adJIts
`
`Cmax10 mg ORF in adJIts
`
`10,
`10,
`15,
`15,
`20,
`20,
`30,
`30,
`40,
`40,
`60,
`<60 >60 <60 >60 <60 >60 <60 >60 <60 >60 <60
`
`k9
`n=25
`
`kg
`n=22
`
`k9
`n:8
`
`k9
`n=3
`
`k9
`n=13
`
`kg
`n:12
`
`kg
`n=7
`
`k9
`n=3
`
`kg
`n=1
`
`kg
`n=3
`
`kg
`n=1
`
`Note: Limited number of patients received doses 240 mg of OxyContin; hence a comparison could not be
`made.
`
`Reference ID: 3757009
`
`

`

`
`
`Data from several adult and pediatric studies (as indicated above) were combined in a
`population PK analysis to characterize the population pharmacokinetics of oxycodone in
`adult and pediatric subjects and to estimate the effects of individual-specific covariate
`factors, in particular, age and weight on the variability in pharmacokinetics. Full review
`of the population PK analysis is appended to this memo. The main conclusions of the
`analysis are discussed below. The final model identified weight as a predictor of
`variability in clearance (CL/F) and volume of distribution (V/F) and age as a predictor of
`variability in CL/F in patients less than one year of age. No other covariates investigated
`demonstrated any relationship in the graphical evaluation of unexplained variability in
`oxycodone PK.
`Figure: A plot of oxycodone clearance against bodyweight of pediatric patients and
`healthy subjects (Based on final model).
`
`
`The table below describes clearance and volume of distribution for oxycodone in
`different bodyweight groups.
`Table: Summary statistics of clearance and volume of distribution of oxycodone based
`on bodyweight groups from all studies.
`Weight
`Variable N Mean SD Median Variable N Mean SD
`Group
`CL/F
`43
`8.4
`4.8
`7.2 V/F
`43
`45.8
`26.4
`<10 kg
`CL/F
`23
`31.2
`11.4
`31.9 V/F
`23
`127.4
`55.6
`11-20 kg
`CL/F
`138
`66.8
`25.2
`64.8 V/F
`138
`388.9
`156.6
`21-60 kg
`>60 kg
`CL/F
`168
`96.7
`31.5
`91.8 V/F
`168
`590.4
`151.5
`These results provide further support that a 10 mg dose in lighter patients (i.e., less than
`10 years of age) would result in higher exposure than the same dose in the adult
`population. Therefore, pediatric patients would benefit from a 5 mg OxyContin
`formulation.
`We also note that the Sponsor’s pharmacokinetic model has adequately characterized the
`pharmacokinetics of oxycodone throughout the entire pediatric population. Therefore,
`this model could potentially be used to derive pediatric dosing regimens of immediate
`release oxycodone formulation that would match the exposure in adults at dosing regimen
`of FDA-approved oxycodone products.
`
`Median
`37.6
`117.9
`369.6
`584.1
`
`
`
`Reference ID: 3757009
`
`6
`
`

`

`1.4 General Biopharmaceutics
`
`OxyContin (reformulated) product 10 — 80 mg strengths were used in pediatric patients
`and adult PK studies. For Studies OXPlOOS and OXP3003 an oral (20 mg/ml) solution
`was diluted to the appropriate strength with cherry syrup. This diluted solution was
`administered to patients orally using a 1 cc syringe.
`
`Table: Composition of the pediatric oxycodone IR solution used in the clinical studies
`OXP1005 and OXP3003.
`
`.........
`
`‘3”)ng “Cl USP P». Eu‘
`
`0 l
`
`(b) (4)
`
`
`curiaurliléguihiigiifigx aim-2m
`3'1an
`1 v.) "IL
`La! um
`LL'L'U'J.‘ t
`
`I
`
`Slugg-
`
`DEA Hamilton No.
`Annual 5|;th
`
`landauuvov
`
`M'mcfl ma )3 crrcca :t- In
`
`”m
`111,: mL
`Lug.» Fame-pm: L L' aunt-Jed :1; Lara).-
`Lhym'a LL' 4:: :a MOIth-v Rt) Nat-rte, NY
`“14.72
`
`(b) (4)
`
`Pediatric study OC96-0602, which was conducted in 1998, employed original
`formulation of OxyContin and an immediate release 5 mg tablet of oxycodone.
`
`Relative bioavailability study OC94-0101 compared original formulation of OxyContin
`with 2 X 5 mg tablets of oxycodone by Boots Labs (Endone, lot AV4522), and
`immediate release solution of oxycodone by Roxane laboratories (Lot 940729).
`
`Bioavailability Study OC94—0101
`
`A variety of different formulations were evaluated in pediatric patients over a period of
`15 years by Purdue Pharma. Results of study OC94-0101, originally conducted in
`support of the original NDA 20553 for Oxycontin, were resubmitted to support bridging
`of bioavailability of different formulations used. In this study bioavailability of old
`OxyContin formulation 10 mg of Purdue Pharma L.P. was compared with immediate-
`release oxycodone tablets (IR Oxy 2 X 5mg tablet, Endone, The Boots Company) and
`immediate—release oxycodone moxicodone, 10 mg oral solution, Roxane Laboratories).
`Following oral administration in the fasted state, the 0C 10 mg tablet was equally
`bioavailable to IR oxycodone 2x5 tablets and to IR oxycodone 10 mL oral solution with
`respect to the extent (AUC) but not the rate of absorption (neither Cmax or Tmax were
`similar). The Cmax of the controlled-release tablet was approximately one-third of that
`observed with the IR products. Minor differences were noted in the two IR products (See
`appended results of Study OC94—0101).
`
`(hm)
`
`Reference ID: 3757009
`
`

`

`
`
`
`
`
`
`Reference ID: 3757009
`Reference ID: 3757009
`
`8
`
`(b) (4)
`
`

`

`
`
`Reference ID: 3757009
`
`

`

`(b) (4)
`
`(b) (4)
`
`The sponsor did not specifically
`provide any information bridging pediatric oxycodone solution product used in clinical
`trials and marketed oxycodone products. However, the sponsor generally indicates that
`alternative sources of a formulation suitable for younger children are commercially
`available in the US. Glenmark Pharma, Lannett Holdings Inc, Lehigh Valley Tech,
`Mallinckrodt, Roxane, Midlothian Labs, and Vistapharm market a 20 mg/mL oral
`solution of oxycodone HCl. Glenmark Pharma, Lehigh Valley Tech, Mallinckrodt,
`Roxane, and Vistapharm also market a 5 mg/SmL oral solution. All these are available by
`prescription.
`
`1.5 Analytical
`
`During routine investigation of one clinical site for 0XP1005 and OXP3003, OSI
`investigators noted “The temperature log for the freezer did not include temperature
`records for the first nine of the total 15 months of PK blood sample storage.” The
`bioanalytical method of oxycodone and its metabolites had been reviewed several times
`over the past decades for this NDA. However, the reason for inclusion of PK data from
`the pediatric studies is docmnented in the Bioanalytical methodology report (see attached
`Appendix 3.2.1), with specific emphasis on long-term stability of oxycodone &
`metabolite samples in human plasma for an extended period of time. In conclusion, the
`stability data showed that oxycodone and its metabolites, noroxycodone and
`oxymorphone, were stable in human plasma for up to 22 months. The stability data also
`showed that oxycodone and its metabolites, noroxycodone and oxymorphone, were stable
`in 1:1 MeOH/H2O stock and spiking solutions for up to 4 months.
`
`Reference ID: 3757009
`
`10
`
`

`

`
`
`2 Labeling
`Discussion is still ongoing regarding what specific pediatric PK information should be
`included in the final product label. Refer to the approved label for details.
`Pediatric PK information for 6 to 11 yrs. age group may imply established safety or
`efficacy and hence such may not be included.
`
`Section 12.3 Pharmacokinetics
`…
`Pediatrics
`In the pediatric age group of 11 years and older systemic exposure of oxycodone is
`expected to be similar to adults at any given dose of OxyContin.
`
`
`
`
`
`
`Reference ID: 3757009
`
`11
`
`29 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`
`
`3.2
`
`Individual Study Reviews
`
`3.2.1 Bioanalytical Method (Long term stability, Fifteen Freeze Thaw cycle stability) &
`OXNSR06-022-1 report synopsis.
`In Study OXP3003, The first set of samples was collected January 31, 2003 and was
`received on March 11, 2003. The last batch of samples was analyzed on June 29, 2004
`for Oxycodone, Noroxycodone, and Oxymorphone; the last batch of samples was
`analyzed on May 6, 2005 for Morphine. The maximum storage duration for the study
`samples from collection to extraction was 348 days for Oxycodone, Noroxycodone, and
`Oxymorphone, and 700 days for Morphine.
`In Study OXP1005, the first set of samples was collected March 31, 2003, and was
`received on May 1, 2003. The last batch of samples was analyzed on February 27, 2004.
`The maximum storage duration for the study samples from collection to extraction was
`234 days.
`Frozen storage stability of oxycodone and its metabolites, noroxycodone and
`oxymorphone, in human plasma stored at approximately -20°C was demonstrated for up
`to 22 months. Stability of stock solutions of oxycodone and its metabolites,
`noroxycodone and oxymorphone stored at 5ºC was demonstrated for up to 4 months.
`Frozen storage stability of morphine in human plasma stored at approximately -20°C was
`demonstrated for up to five and a half months. Stability of stock solutions of morphine
`stored at 1-8ºC was demonstrated for up to 26 days.This report describes the results of the
`long-term stability of oxycodone and its metabolites, noroxycodone and oxymorphone, in
`human plasma based on method OXYMR00-004:1, “Quantitation of Oxycodone and
`Metabolites in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry
`(LC-MS/MS).” The full validation results were also reported in the validation report
`OXYVR00-017:1.
`Long-Term Stability in Human Plasma
`
`The long-term storage stability of oxycodone and its metabolites, noroxycodone and
`oxymorphone, in human plasma stored at approximately –20 °C was assessed at 2, 3, 7
`and 22 months. The results are shown in Tables 6.1 A-C.
`Long-Term Stability in Stock and Spike Solution
`
`The long-term storage stability of oxycodone and its metabolites, noroxycodone and
`oxymorphone, in the specific solvent defined in the method OXYMR00-004:1(draft) was
`assessed using the highest concentration stock solution and two spiking solutions (high
`and low) stored at 5 °C for 4 months. The results are shown in Tables 6.2 A-C.
`
`
`
`Reference ID: 3757009
`
`41
`
`

`

`
`
`TABLE BAA. Oxycodone Long-Term Stahllfly In Human Plasma
`
`Calculated Concentration lngmL]
`
`Nominal Concentration
`
`0020
`0.294
`0.329
`
`2 months 3 months 7 months 22 months
`0.353
`0.327
`0.204
`0.290
`0.310
`0.309
`0.200
`0.290
`
`0.202
`0.200
`0.320
`0.200
`0.250
`0.271
`0.292
`0.300
`0.207
`0.277
`0.207
`0.273
`0.310
`0.310
`0.310
`0.271
`0.293
`0.310
`I131 a
`[3.306
`0
`0
`0
`0
`0
`n
`0.201
`0.201
`0.314
`0.313
`0.290
`mean
`SD
`0.0255
`0.0245
`0.00312
`0.0141
`0.0142
`CV {00}
`0.95
`7.01
`2.59
`5.01
`5.06
`
`11.0171
`N10
`5.50
`0.70
`.527
`.014
`30.0
`35.3
`35.0
`33.0
`37.9
`30.0
`35.3
`30.0
`33.7
`34.5
`30.7
`30.0
`33.1
`35.0
`31.4
`39.1
`30.5
`30.5
`30.1
`35.7
`55.0
`34.4
`33.9
`34.0
`30.0
`30.0
`33.9
`35.0
`34.2
`55.0
`0
`0
`0
`0
`0
`30.9
`30.5
`35.1
`34.7
`35.2
`1.11
`1.34
`1.30
`0.973
`2.15
`3.00
`5.04
`3.72
`2.30
`6.15
`NJA
`.124
`5.13
`.590
`4.73
`
`(fi'ég‘figfi
`
`00 High-QC c
`40.0
`
`n
`mean
`SD
`CV [96}
`10001
`
`
`
`TABLE 0.10. Nomxycodane Long-Term 5100111111r In Human Plasma
`
`Nominal Concentration
`00 Low-QC A
`0.303 nglrnL
`
`11
`mean
`00
`01.11%}
`9013111
`
`cc High-DC c
`40.4 rugtmL
`
`[1
`mean
`so
`av {90;
`00001
`
`Calculated Concentration [ngIle
`
`Day: I]
`0.205
`0.207
`0.243
`0.230
`0.203
`0.2590
`0.201
`0.0221
`0.40
`N74
`30.5
`37.0
`30.0
`39.2
`40.3
`37.0
`0
`39.7
`0.940
`2.44
`Ne’A
`
`2 months 3 months 1 months 22 months
`0.320
`0.296
`0.239
`0.203
`0.320
`0.304
`0.251
`0.250
`0.330
`0.309
`0.290
`0.200
`0.253
`0.290
`0.300
`0.285
`0.297
`0.232
`0.236
`0.200
`0.305
`0.3041
`[3.286
`0.2040
`0
`6
`5
`0.312
`0.299
`U23?
`0.200
`0.0140
`0.00944
`0.0033
`0.0100
`4.74
`3.15
`1.15
`3.79
`19.7
`14.6
`9.17
`1.30
`40.1
`40.6
`3?.9
`30.1
`39.9
`40.3
`38.0
`30.0
`39.0
`37.3
`33.0
`34.7
`40.2
`42.5
`38.9
`30.7
`40.2
`40.0
`36.3
`30.5
`38.9
`3?.3
`35.0
`40.50
`6
`6
`0
`40.1
`40.0
`3?.6
`30.0
`0.300
`i .71"?
`1.02
`0.007
`0.704
`4.43
`2.47
`2.?1
`3.00
`3.35
`4.00
`-7.10
`
`TABLE 6.11:. Oxymorphane LungATerm Stabirity In Human Plasma
`Calculated Concentration
`mL
`
`Nominal Concentration
`
`$3931.33:
`
`11
`mean
`513
`CV (90]
`560i“
`
`2 months 3 months 7 months 22 months
`0020
`0.200
`0.013
`0.290
`0.270
`0.270
`0.255
`0.308
`0.2?”
`0.221"
`0.2741
`0.2?6
`0.300
`D280
`0.245
`0.231
`0 251
`0.332
`0.260
`0.254
`0.250
`0.252
`0.252
`0.266
`0.274
`D.266
`0.232
`0.286
`0.282
`0.247
`0.261
`6
`5
`5
`5
`6
`0.260
`0.299
`0.276
`0.253
`0.259
`0.0193
`0.03341
`0.0135
`0.0!“
`0.0162
`T313
`9.15
`41.86
`6.90
`6 2'."
`0.5“
`15.5
`8.89
`12.38
`MA
`3.60
`3.90
`3.”
`3.1?
`41 11
`3.05
`4.00
`3.03
`3.07
`3.90
`3.38
`3.90
`3.51
`3.21
`41.00
`00 HighAOC C
`180
`4.05
`3.3?
`3.84
`3.46
`3.60
`3.70
`3.02
`3.73
`3.71
`3.54
`
`__
`3.5.5
`9.5.3
`3.117
`31-2-14
`9.9?
`n
`6
`6
`6
`6
`6
`mean
`3.96
`3.53
`3.81
`3.55
`3.2?
`SD
`0.120
`0.124
`0.100
`0.104
`0.240
`CV(%I
`3.15
`3.51
`4.90
`5.17
`1.53
`00010
`NA
`-11.1
`6.97
`40.41
`-1?.5
`
`
`
`
`
`
`
`
`
`
`
`Reference ID:
`3757009
`Reference ID: 3757009
`
`42
`
`

`

`
`
`Excerpt from bioanalytical report TM-543 indicating stability of oxycodone in plasma or
`solutions following different storage conditions (with focus on 15 cycles of
`Freeze/Thaw).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3757009
`
`43
`
`

`

`
`
`
`
`
`
`
`
`
`TABLE 6.2A. Oxycodone Long-Term Stability in Solution - 4months
`
`
`
`
`
`Std Spk ’I F — Low
`
`
`
`
`
`Mean
`
`SD
`
`
`CV {‘16}
`Final Concentration
`
`
`
`(ngme)
`
`
`Adjusted Mean PA
`9-6001
`
`
`IS
`
`
`Solution
`Area
`IS Area
`Area
`PAR
`Area
`PAR
`
`
`
`
`
`
`
`
`
`814100 - Old
`1214100- New
`
`
`
`
`MA
`MA
`
`
`MA
`
`
`MA
`
`
`MA
`
`
`MA
`
`
`MA
`
`
`MA
`
`
`
`
`
`
`13??)
`1583
`
`1561
`
`1 542
`
`1 585
`
`1 51 0
`
`1611
`
`135
`
`
`
`8.36
`
`MA
`MA
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`1511
`1401
`
`1422
`
`145?
`
`1386
`
`1407'
`
`1431
`
`45.6
`
`
`3.19
`
`MA
`MA
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`
`
`
`
`
`
`
`
`
`
`
`MA
`
`
`
`
`
`
`
`Std Spk 'I D — High
`
`
`
`
`1 .00
`
`1611
`12 . 6
`
`
`
`133060
`133863
`
`136510
`
`1346 84
`
`133195
`
`133702
`
`
`
`135002
`2281
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`MA
`
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`MA
`
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1 .00
`
`1431
`MA
`
`
`131534
`135323
`1 33956
`1 33545
`133316
`131491
`
`133194
`14??
`
`
`
`
`1.11
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`MA
`
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`MA
`
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1.69
`
`
`
`100
`
`1350
`1.36
`
`
`2493023
`
`2595994
`
`261 97136
`
`263?286
`
`264 T3 61
`
`2670466
`
`261 0656
`
`
`62684
`
`
`
`2.41
`
`
`1 .00
`
`2610656
`-1 .45
`
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`MA
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`MA
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`100
`
`1332
`MA
`
`
`MA
`MA
`MA
`
`2559340 MA
`
`2635478 MA
`
`264821 6 MA
`
`2635625 MA
`
`2701425 MA
`
`2730491 MA
`
`2651 846 MA
`
`
`
`
`59418
`
`2.24
`
`MA
`
`MA
`
`
`MA
`1 .00
`
`264913? MA
`MA
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MA
`MA
`MA
`
`MA
`MA
`MA
`MA
`MA
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`MA
`MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`44
`44
`
`
`
`
`
`Reference ID: 3757009
`Reference ID: 3757009
`
`Mean
`
`SD
`
`
`CV 11%}
`Final Concentration
`
`
`
`(ngme)
`
`
`Adjusted Mean PAR
`9-5Diff
`
`
`
`
`Stock Solution - Std 1A
`
`
`
`
`
`
`
`Mean
`
`SD
`
`
`CV {36}
`Final Concentration
`
`
`
`(ugme)
`
`
`Adjusted Mean PA
`9-6D1'ff
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`TABLE 0.23. Noroxycodone Long-Term Stability in Solution - 4 months
`
`
`
`
`
`
`
`Solution
`
`
`
`
`
`Std Spk 2F — Low
`
`
`
`
`
`Mean
`
`SD
`
`
`cu 1%)
`
`Final Concentration
`
`010’le
`
`
`Adjusted Mean PAR
`95Diff
`
`
`
`
`
`
`
`
`
`
`Std Spk 2o — High
`
`
`
`Mean
`
`SD
`
`
`CV 11%)
`Final Concentration
`
`
`{ngi'mLJ
`
`
`Adjusted Mean PA
`9»'bDiff
`
`
`
`
`
`
`Stock Solution - Std
`
`
`
`2A
`
`
`
`
`Mean
`
`SD
`
`
`CV [Ea-13)
`
`Final Concentration
`
`{Udu’mLi
`
`
`Adjusted Mean PA
`AbDiff
`
`
`
`
`
`
`Reference ID: 3757009
`Reference ID: 3757009
`
`IS
`IS
`
`
`
`Area
`Area
`Area
`PAR
`Area
`PAR
`
`
`
`
`
`
`314100 - Old
`1214100 - New
`
`MA
`MA
`
`
`
`"1'59
`MA
`MA
`
`
`
`":55
`MA
`MA
`
`
`
`7'53
`MA
`MA
`
`
`
`WE
`MA
`MA
`
`
`
`T94
`MA
`MA
`
`
`
`H'B
`MA
`MA
`
`
`
`23.5
`MA
`MA
`
`
`
`3.134
`MA
`MA
`
`
`
`
`T95
`902
`020
`519
`1'88
`
`859
`
`1185
`
`
`
`
`
`
`
`
`18.0
`
`
`155
`
`819
`
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`
`
`569
`
`1.00
`
`
`11.9
`
`
`T1834
`
`T25 05
`
`T0323
`
`59224
`
`59623
`
`59359
`
`T0495
`
`
`2.00
`
`
`1410
`
`100
`
`T05
`
`
`
`1.35
`
`
`2526 ?25
`
`2549 903
`
`2?00 930
`
`2?53 935
`
`2?3? 825
`
`2?82 393
`
`2?09 591r
`
`
`
`60919
`
`2.25
`
`
`1.00
`
`21’0859?r
`
`-1 .45
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`1.00
`
`NIB
`
`MA
`
`
`T0809
`
`7"0135]Ir
`
`59419
`
`as 344
`
`58449
`
`59100
`
`59 55?r
`
`
`999
`
`1.42
`
`
`100
`
`595
`
`MA
`
`
`2521386
`
`259 92?8
`
`2109 9092
`
`2??20B2
`
`2815021
`
`28054319
`
`21'51 390
`
`T3445
`
`
`2.5?
`
`
`1.00
`
`2T48041
`MA
`
`
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`MA
`
`
`MA
`
`MA
`
`MA
`
`
`
`
`45
`45
`
`

`

`
`
`CONCLUSION
`The stability data showed that oxycodone and its metabolites, noroxycodone and
`oxymorphone, were stable in human plasma for up to 22 months. The stability data also
`showed that oxycodone and its metabolites, noroxycodone and oxymorphone, were stable
`in 1:1 MeOH/H2O stock and spiking solutions for up to 4 months.
`
`
`
`
`
`Reference ID: 3757009
`
`46
`
`

`

`
`
`3.2.2 Population PK Analysis of OxyContin and Immediate Release Oxycodone.
`Population Pharmacokinetics in Pediatric Patients and Healthy Adult Subjects:
`The sponsor conducted a rather comprehensive pharmacokinetic data analysis strategy
`involving population pharmacokinetics modeling based on nonlinear mixed-effects
`modeling (NONMEM). The population PK analysis was conducted with a qualified
`installation of the nonlinear mixed effects modeling (NONMEM) software, Version 7,
`Level 2.0 (ICON Development Solutions, Hanover, MD). A covariate modeling
`approach emphasizing parameter estimation rather than stepwise hypothesis testing was
`implemented for this population PK analysis. Predefined covariate-parameter
`relationships were identified based on exploratory graphics, scientific and clinical
`interest, and mechanistic plausibility of prior knowledge; a full model was then
`constructed with care to avoid correlation or collinearity in predictors.
`This involved pooling of all available plasma oxycodone concentrations (intensive and
`sparse) from single- and multiple-dose PK studies. The pooled data represented
`oxycodone concentrations across a range of formulations [oral immediate release from
`liquid and tablet, extended release original OxyContin (OC) and reformulated OxyContin
`(OTR or ORF)] in pediatric patients and representative oral OxyContin data in adult
`subjects for the population pharmacokinetic (POPPK) dataset. A total of 5 Phase 1 and
`three Phase 3 clinical studies were included in the POPPK modeling of oxycodone in
`pediatric patients and adult subjects.
`Table: Studies included in final population pharmacokinetic analysis of oxycodone
`and the different formulations, doses, and demographics of patients/subjects
`employed.
`
`
`Reference: Table 1 from Purdue Pharma’s Report on Population Pharmacokinetic Modeling of Oxycodone
`in Pediatric and Adult subjects.
`The final oxycodone POP PK dataset consisted of 5567 oxycodone concentrations from
`370 subjects from 8 studies (see Table below). There were 255 pediatric patients (< 18
`years), with weights ranging from 2.4 to 112 kg. The final dataset contained 184 pediatric
`
`
`
`Reference ID: 3757009
`
`47
`
`

`

`
`
`patients between the ages of 6 and 16 years, of which 43 (23%) were > 6 to < 12 years
`old and 141 (77%) were ≥ 12 to ≤ 16 years old. Clinical PK experience with IR
`oxycodone formulations accounted for the rest of the pediatric patients.
`Weight and age were positively correlated with a correlation coefficient of 0.76 and an
`obvious trend evident in scatter plots (bottom left).
`
`
`
`Reference: Figure 1 and Figure 2 from Purdue Pharma’s Report on Population Pharmacokinetic Modeling
`of Oxycodone in Pediatric and Adult subjects.
`
`Distributions of continuous covariates (top right) were similar for pediatric subjects in
`both sexes. In adult subjects, age was similar across sexes but weight demonstrated the
`typical dependency on sex, with males having a higher median weight and overall range
`than females. Weight, age and sex were considered as potential covariates in the model
`(table below)
`
`
`Reference: Table 2 from Purdue Pharma’s Report on Population Pharmacokinetic Modeling of Oxycodone
`in Pediatric and Adult subjects.
`
`
`
`
`
`Reference ID: 3757009
`
`48
`
`

`

`
`
`The population PK of oxycodone in pediatric patients and adult subjects was described
`by a one-compartment model with first-order absorption and elimination. The model was
`parameterized in terms of apparent (oral) clearance (CL/F), apparent (oral) volume of
`distribution (V/F), relative bioavailability (F) and first-order absorption rate constant
`(Ka). Separate relative F terms and absorption models were included to model each oral
`oxycodone formulation. A single first-order absorption model described the absorption of
`the IR liquid, IR solid, and ORF, while a parallel first-order absorption model described
`the absor