CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`APPLICA TION NUMBER:
`
`PHARMACOLOGY REVIEW(S)
`PHARMACOLOGY REVIEWQS!
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`

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`Reviewer: Elizabeth A. Bolan, Ph.D.
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`NDA 22-272
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
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`NDA NUMBER:
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`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
`PRODUCT:
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`INTENDED CLINICAL POPULATION:
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`SPONSOR:
`DOCUMENTS REVIEWED:
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`REVIEW DIVISION:
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`PHARM/TOX REVIEWER:
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
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`PROJECT MANAGER:
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`Date of review submission to DARRTs:
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`22-272
`000
`March 30, 2009
`OxyContin reformulation
`For management of moderate to severe pain when
`a continuous, around-the-clock analgesic is needed
`for an extended period of time
`Purdue Pharma L.P.
`All nonclinical information in the above
`submission
`Division of Anesthesia, Analgesia, and
`Rheumatology Products (HFD 170)
`Elizabeth A. Bolan, Ph.D.
`R. Daniel Mellon, Ph.D.
`Bob Rappaport, M.D.
`Lisa Basham
`
`September 3, 2009
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`
`1
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`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
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`NDA 22-272
`
`EXECUTIVE SUMMARY
`
`
`I.
`
`
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`
`
`Recommendations
`
`A. Recommendation on approvability
`This NDA can be approved from a pharmacology/toxicology perspective.
`
`B. Recommendation for nonclinical studies
`None
`
`C. Recommendations on labeling
`The following recommendations are being proposed for the nonclinical
`sections of the label. Note that this second cycle review of the labeling takes
`into consideration the new data submitted by the Applicant in the second cycle.
`For the final version of the label, please refer to the Action Letter. Note: The
`recommended changes from the proposed labeling are in red or strikeout font.
`
`
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`Applicant’s proposed labeling
`8 USE IN SPECIFIC
`POPULATIONS
`
`8.1 Pregnancy
`
`Teratogenic Effects - Category B:
`
`The effect of oxycodone in human
`reproduction has not been adequately
`studied.
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`Non-Teratogenic Effects
`Oxycodone hydrochloride was
`administered orally to female rats during
`gestation and lactation in a pre- and
`postnatal toxicity study. There were no
`drug-related effects on reproductive
`performance in these females or any
`long-term developmental or
`reproductive effects in pups born to
`these rats. Decreased weight gain was
`found during lactation and the early
`post-weaning phase in pups nursed by
`mothers given the highest dose used (6
`mg/kg/day, equivalent to approximately
`2-times an adult human dose of 160
`mg/day, on a mg/kg basis). However,
`
`Rationale
`
`
`
`
`
`
`
`
`This section has been
`reworded for clarity
`and the exposure ratios
`were changed to the
`more appropriate
`comparison of mg/m2.
`
`
`Dose ratios are
`expressed on a body
`surface area basis.
`
`Reviewer’s proposed labeling
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Teratogenic Effects - Category B
`The effect of oxycodone in human
`reproduction has not been adequately
`studied.
`
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`
` Studies with oral doses of
`oxycodone hydrochloride in rats up to 8
`mg/kg/day and rabbits up to 125
`mg/kg/day, equivalent to 0.5 and 15
`times an adult human dose of 160
`mg/day, respectively on a mg/m2 basis,
`did not reveal evidence of harm to the
`fetus due to oxycodone.
`
`Non-Teratogenic Effects
`Oxycodone hydrochloride was
`administered orally to female rats during
`gestation and lactation in a pre- and
`postnatal toxicity study. There were no
`drug-related effects on reproductive
`performance in these females or any
`long-term developmental or reproductive
`effects in pups born to these rats.
`Decreased weight gain was found during
`lactation and the early post-weaning
`
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`
`2
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`(b) (4)
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`(b) (4)
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`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`body weight of these pups recovered.
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`NDA 22-272
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`
`Carcinogenesis:
`No animal studies to evaluate the
`carcinogenic potential of oxycodone
`have been conducted.
`
`Mutagenesis:
`
`
`
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`
`
`Oxycodone was not mutagenic in the
`following assays; Ames Salmonella and
`E. coli test with and without metabolic
`activation at doses of up to 5000
`μg/plate, chromosomal aberration test in
`human lymphocytes (in the absence of
`metabolic activation) at doses of up to
`1500 μg/mL, and with activation after
`48 hours of exposure at doses of up to
`5000 μg/mL, and in the in vivo bone
`marrow micronucleus assay in mice (at
`plasma levels of up to 48 μg/mL).
`Mutagenic results occurred in the
`presence of metabolic activation in one
`human chromosomal aberration test at
`greater than or equal to 1250 μg/mL at
`24 but not 48 hours of exposure.
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`Impairment of fertility: In a study of
`reproductive performance,
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`phase in pups nursed by mothers given
`the highest dose used (6 mg/kg/day,
`equivalent to approximately 0.4-times an
`adult human dose of 160 mg/day, on a
`mg/m2 basis). However, body weight of
`these pups recovered.
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`
`Carcinogenesis: No animal studies to
`evaluate the carcinogenic potential of
`oxycodone have been conducted.
`
`Mutagenesis:
`
`
`
`
`
`
`
`Oxycodone was genotoxic in the
`mouse lymphoma assay at concentrations
`of 50 µg/mL or greater with metabolic
`activation and at 400 µg/mL or greater
`without metabolic activation.
`Clastogenicity was observed with
`oxycodone in the presence of metabolic
`activation in one chromosomal
`aberration assay in human lymphocytes
`at concentrations greater than or equal to
`1250 µg/mL at 24 but not 48 hours of
`exposure. In a second chromosomal
`aberration assay with human
`lymphocytes, no structural clastogenicity
`was observed either with or without
`metabolic activation. However, in the
`absence of metabolic activation,
`oxycodone increased numerical
`chromosomal aberrations (polyploidy).
`Oxycodone was not genotoxic in the
`following assays: Ames S. typhimurium
`and E. coli test with and without
`metabolic activation at concentrations up
`to 5000 µg/plate, chromosomal
`aberration test in human lymphocytes (in
`the absence of metabolic activation) at
`concentrations up to 1500 µg/mL, and
`with activation after 48 hours of
`exposure at concentrations up to 5000
`µg/mL, and in the in vivo bone marrow
`micronucleus assay in mice (at plasma
`levels up to 48 µg/mL).
`
`Impairment of fertility: In a study of
`reproductive performance, rats were
`administered a once daily gavage dose of
`the vehicle or oxycodone hydrochloride
`
`3
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`The suggestion of a
` has
`
`been removed.
`
`The order of the data
`presentation has been
`changed from the
`previous version of the
`label. The positive
`genotoxic findings
`with oxycodone are
`now presented before
`the negative findings
`
`Results from newly
`submitted
`Chromosomal
`Aberration study are
`described here. The
`finding of polyploidy
`was included.
`
`
`
`
` was
`The word
`replaced by more
`accurate word
`“concentration.”
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

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`NDA 22-272
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
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`(0.5, 2, and 8 mg/kg). Male rats were
`dosed for 28 days before cohabitation
`with females, during the cohabitation and
`until necropsy (2-3 weeks post-
`cohabitation). Females were dosed for
`14 days before cohabitation with males,
`during cohabitation and up to gestation
`day 6. Oxycodone hydrochloride did not
`affect reproductive function in male or
`female rats at any dose tested (≤8
`mg/kg/day).
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`II.
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`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`In this cycle, the Applicant submitted one genetic toxicology study to
`support a proposed labeling change. An in vitro chromosomal aberration
`assay in human peripheral blood lymphocytes was conducted with
`oxycodone. The study showed that oxycodone did not produce
`clastogenicity. However, increased levels of polyploid cells were
`observed in cultures treated with oxycodone. The findings from this study
`will be described in the product label.
`
`
`4
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`(b) (4)
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
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`NDA 22-272
`
`The specification set by the Applicant for residual solvent levels of
` in the
` excipient exceeded ICH Q3C
`guideline thresholds. The Applicant provided toxicologic justification of
`the proposed levels of this solvent. The Applicant’s justification has been
`found adequate and the proposed specification of
` for the
`residual solvent level of
` in the
` is acceptable.
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`B. Nonclinical safety issues relevant to clinical use
`No new nonclinical safety issues were identified.
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`5
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
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`NDA 22-272
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`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`
`
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`
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`2.6.1 INTRODUCTION AND DRUG HISTORY
`
`NDA number: 22-272
`Review number: 2
`Sequence number/date/type of submission: 000/March 30, 2009/second cycle NDA
`submission
`Information to sponsor: Yes ( ) No (X)
`Sponsor and/or agent: Purdue Pharma, L.P. Stamford, CT 06901
`Manufacturer for drug substance:
`
`Reviewer name: Elizabeth A. Bolan, Ph.D.
`Division name: Division of Anesthesia, Analgesia, and Rheumatology Products
`HFD #: 170
`
`Review completion date: May 22, 2009
`
`Drug:
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`Trade name: OxyContin
`Generic name: oxycodone hydrochloride
`
`Code name: N/A
`
`Chemical name: 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one
`hydrochloride.
`CAS registry number: 124-90-3
`Molecular formula/molecular weight: C18 H21 NO4 • HCl; MW 351.83 g/mol
`Structure:
`
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`6
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`(b) (4)
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`NDA 22-272
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`Background Pharmacology/Toxicology had recommended approval for NDA 22-272 in
`the first review cycle. The NDA was not approved due to CSS and Clinical issues. In the
`second cycle, the Applicant submitted one genetic toxicology study (Study # 778436) to
`support a proposed labeling change. Also in the second cycle, Dr. Craig Bertha
`(ONDQA) submitted an information request to the Applicant requesting justification of
`levels of the residual solvent
` in the
` excipient. The
`Applicant provided toxicologic justification of the levels of this solvent (Amendment
`0031). This second cycle review contains the review of the new genetic toxicology
`study, the assessment of the adequacy of the Applicant’s justification regarding the
` specification and updated edits to the product label.
`
`
`Studies reviewed within this submission:
`• Study # 778436: Oxycodone Hydrochloride Injection 50 mg/mL Containing
` and Oxycodone Hydrochloride Injection 50 mg/mL Reference
`Formulation (OH-Form) Chromosomal Aberrations Assay with Human Peripheral
`Lymphocytes Cultures in vitro
`
` •
`
`
`
` Amendment 0031: Applicant’s response to ONDQA information request
`regarding toxicologic justification of residual solvent levels of
`
`
`
`Refer to the pharmacology/toxicology review of the original OxyContin NDA
`(Purdue Pharma; NDA 20-553) by BeLinda Hayes, Ph.D. dated August 21, 1995 and
`the pharmacology/toxicology review of the first cycle of NDA 22-272 by Elizabeth
`Bolan, Ph.D dated May 1, 2008.
`
`
`Studies not reviewed within this submission: none
`
`
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`7
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

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`NDA 22-272
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`
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`
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`Study title: Oxycodone Hydrochloride Injection 50 mg/mL Containing
` and Oxycodone Hydrochloride Injection 50 mg/mL Reference Formulation
`(OH-Form) Chromosomal Aberrations Assay with Human Peripheral Lymphocytes
`Cultures in vitro
`
`Key findings: It is concluded that oxycodone and
` are not clastogenic
`in an in vitro chromosome aberration assay with human peripheral blood lymphocytes
`under conditions of the assays conducted. However, increased levels of polyploid cells
`were observed in cultures treated with oxycodone at concentrations of 2500 and 3750
`mcg/mL and
` at concentrations of 1250, 2500 and 3750 mcg/mL.
`
`Study no.: 778436
`Volume #, and page #: Module 4.2.3.3.1.1
`Conducting laboratory and location:
`
`Date of study initiation: January 24, 2007
`GLP compliance: Yes
`QA reports: yes (X) no ( )
`Drug, lot #, and % purity: Oxycodone hydrochloride, Batch # RM3015; purity:
`>94.3%;
` Batch # PN2969; purity: not specified;
`content: 0.68%
`
`The objective of this study as stated in the study report was to determine whether or not
`the presence of the
` a potential oxycodone (OXY) impurity,
`would alter the potential of oxycodone alone to induce chromosomal aberrations in
`human peripheral lymphocyte cultures. Oxycodone and oxycodone with a given
`were tested individually in this in vitro chromosomal
`concentration of the
`aberration assay.
`
`The Applicant (Purdue Pharma LP) submitted this study in support of a statement added
`to the proposed label of reformulated OxyContin (NDA 22-272). The addition to the
`label explains that although some positive results were seen with a prior in vitro
`chromosomal aberration assay, this study demonstrates that structural aberrations were
`not seen with OXY treatment. Refer to the suggested labeling section under Conclusions
`for the proposed wording from the Applicant and the edits recommended by the reviewer.
`
`Methods
`Strains/species/cell line: Human peripheral blood lymphocytes
`
`Doses used in definitive studies: See Table 1 (Assay 2)
`
`
`Basis of dose selection: In the first assay, for each test article the Applicant used nine
`concentrations between 20 and 5000 mcg/mL in the presence or absence of S9 activation
`with harvest after 29 hours. In the second assay, the concentration range was narrowed
`and cells were incubated in the presence or absence of S9 activation with harvest after 29
`
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`8
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`Table 1. Assay parameters
`treatment
`time to
`with test
`harvest, h
`article, h
`5
`29
`5
`29
`5
`29
`5
`29
`5
`29
`25
`29
`5
`29
`25
`29
`25
`53
`25
`53
`
`20, 39, 78, 156, 313,
`625, 1250, 2500, 5000
`
`625, 1250, 2500, 3750,
`5000
`
`156, 313, 625, 1250,
`2500, 3750, 5000
`
`5000
`>5000
`>2500
`5000
`>5000
`>3750
`>3750
`>3750
`5000
`>3750
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`NDA 22-272
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`hours or in the absence of S9 activation with harvest after 53 hours. In the presence or
`absence of S9 activation with a 29 hour harvest, the vehicle or test article was incubated
`with the cells for 5 hours. In the absence on S9 with the 53 hour harvest, the cells were
`incubated with the vehicle or test article for 25 hours. Water for injection was used as the
`vehicle as well as the diluent. In both assays, the highest concentrations selected for
`chromosomal aberration analysis were limited by cytotoxicity and reductions in mitotic
`activity. The assay parameters and concentrations at which cytotoxicity was observed are
`described in Table 1.
`
`
`
`Assay
`
`test article S9
`
`concentration, mcg/mL
`
`cytotoxicity
`
`OXY
`
`OXY
`
`1
`
`2,
`part I
`
`OXY
`
`+
`-
`+
`-
`+
`-
`+
`-
`-
`-
`
`2,
`part II
`
`The Applicant states that the procedures and assay design comply with the
`recommendations of the OECD guideline 473, European Commissions Annex V BIO,
`ICH guidelines, and Test Method B10.
`
`
`Negative controls: The negative control was water for injection.
`
`Positive controls: Mitomycin C (MMC) was used as the positive control at 0.1-0.8
`mcg/mL in the presence of S9 activation and cyclophosphamide (CPH) was used at 10-20
`mcg/mL in the absence of S9 activation.
`
`Incubation and sampling times: See Table 1.
`
`Three concentrations of test article not exhibiting cytotoxicity were selected for
`assessment of chromosomal aberrations. From two to four slides per culture, a total of
`100 metaphase cells per were examined. The number of chromosomes in each metaphase
`cell and all abnormalities, using the nomenclature of Gebhart et al., was recorded
`(Gebhart E, 1970).
`
`Assessment of polyploidy was also conducted. For this assessment, approximately 300
`metaphase cells were examined and deemed to be either diploid, polyploid,
`
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`9
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`(b) (4)
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`(b) (4)
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`NDA 22-272
`
`1. Lesions per cell
`2. Percentage of aberrant cells including cells with gaps only
`3. Percentage of aberrant cells excluding cells with gaps only
`4. Percentage of aneuploid cells
`5. Percentage of polyploid cells (normal and endoreduplicated) from additional
`assessment of polyploidy
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`endoreduplicated. Polyploidy was only assessed in the absence of S9 at the 53 h harvest
`time point.
`
`Cytotoxicity:
`Mitotic indices were calculated by dividing the number of metaphase cells by the total
`number of metaphase plus interphase cells (approximately 1000 interphase cells were
`counted where possible). These were then compared with the mitotic indices of the
`vehicle control cultures. The Applicant considered a concentration to be cytotoxic if the
`mitotic indices were <50% of the mean vehicle control values. The Applicant also states
`that if mitotic indices are >50% the concentration can still be considered toxic if there are
`consistent changes to cellular morphology.
`
`Structural and Numerical Chromosomal Aberrations:
`For the analysis of chromosomal aberrations, five parameters were calculated and judged
`as negative, suspicious or positive. The parameters are listed below:
`
`
`
`
`
`
`
`
`The Applicant’s criteria for a negative, positive or inconclusive determination of
`clastogenicity are reproduced verbatim below:
`
`
`The results for test item and positive control treated cultures are evaluated
`by comparison with the concurrent vehicle control cultures and with
`historical negative control data. A negative response was recorded if
`responses from the test item treated cultures are within the 95%
`confidence limits for the historical negative control data.
`The response at a single dose was classified as significant if the percent of
`aberrant cells is consistently greater than the 99% confidence limits for the
`historical negative control data or greater than double the frequency of an
`elevated vehicle or untreated control culture if appropriate.
`
` A
`
` test was positive if the response in at least one acceptable dose level is
`significant by the criterion described above.
`
` A
`
` test item was positive if Test 1 was positive, as described above or if
`one of the tests was positive and the other test gave indications of activity.
`These indications may be suspicious levels of aberrant cells (between 95%
`and 99% confidence limits).
`
`Experiments that met in part the criteria for a positive response, or
`marginally met all the criteria, were classed as inconclusive.
`
`
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`10
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`

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`NDA 22-272
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`Results
`Study validity: This study is valid. It utilizes appropriate replicates and cell
`counting/viability methodology. The vehicles and positive controls for the S9-activated
`and non-activated groups are within the range of the historical data set. The positive
`controls are higher than vehicle controls for all groups. No historical controls for the
`positive controls were provided.
`
` are not clastogenic in vitro with
`Study outcome: It is concluded that OXY and
`human peripheral blood lymphocytes under conditions of the assays conducted.
`However, increased levels of polyploid cells were found in cultures treated with OXY at
`concentrations of 2500 and 3750 mcg/mL and
` at concentrations of 1250, 2500
`and 3750 mcg/mL.
`
`OXY Results
`In the presence of S9, cultures treated with OXY and harvested at 29 h showed mean
`mitotic indices below 50% at 5000 mcg/mL in Assay 1 (40%; Table 2) but not Assay 2
`(58%; Table 3). In the absence of S9, cultures treated with OXY and harvested at 29 h
`showed a mean mitotic index of 82% at 5000 mcg/mL in Assay 1 (Table 2) and 45% at
`3750 mcg/mL in Assay 2 (Table 3). In the absence of S9, cultures treated with OXY and
`harvested at 53 h showed a mean mitotic index of 0% at 5000 mcg/mL with no
`metaphase cells present for evaluation and consistent changes to cellular morphology. At
`3750 mcg/mL the mean mitotic index was 67% (Table 4). Structural and numerical
`aberrations (aneuploidy) were evaluated in cultures with at least three of the cultures
`having concentrations showing >50% reduction in the mean mitotic index. No
`precipitate or significant effects on osmolality or pH were observed at any dose. In
`cultures treated with OXY, no structural aberrations or changes in aneuploidy greater
`than control values were observed for any condition (Tables 2, 3, and 4). In the absence
`of S9 with a 53 h harvest the number of cells with polyploidy was further evaluated
`(Table 4). In OXY-treated cultures concentration-dependent increases in polyploidy
`were observed. The vehicle and untreated control showed 0.2% and 0% polyploid cells,
`respectively. Cultures treated with concentrations of OXY (1250, 2500, and 3750
`mcg/mL) showed 0.5%, 1.8%, and 3.9% polyploid cells (not including endoreduplicated
`cells), respectively (Table 4). The positive controls were not evaluated for changes in
`ploidy. The historical negative control mean for polyploid cells including
`endoreduplicated cells was 0.20 +/- 0.28. The concentrations of 2500 and 3750 were
`judged as positive for polyploidy because the number of polyploidy cells fell outside the
`>99% confidence level. Historical negative control data are presented in Table 8.
`Statistical analyses were not conducted.
`
`
` Results
` showed mean mitotic indices below
`In the presence of S9, cultures treated with
`50% at 2500 mcg/mL in Assay 1 (40%; Table 5). In Assay 2, although the mean mitotic
`indices for 3750 and 5000 mcg/mL were >50% (60% and 91%, respectively; data not
`shown) changes to cellular morphology consistent with toxicity as well as insufficient
`numbers of metaphase cells were present. The highest concentration assessed for
`
`
`
`
`11
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`NDA 22-272
`
`
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`chromosomal aberrations was 2500 mcg/mL which showed a mean mitotic index of 88%
`(Table 6). In the absence of S9, cultures treated with
` showed a mean mitotic
`index of 40% at 5000 mcg/mL in Assay 1 (Table 6) and 46% at 3750 mcg/mL in Assay 2
`(Table 7). In the absence of S9, cultures treated with
` and harvested at 53 h
`showed a mean mitotic index of 48% at 3750 mcg/mL. All
`-treated conditions
`with the exception of cultures in the absence of S9 at 29 and 53 h to harvest were
`evaluated for structural and numerical aberrations (aneuploidy) at three concentrations
`showing >50% reduction in the mean mitotic index. The two conditions in the absence
`of S9 (Tables 6 and 7) had only two concentrations each where the mean mitotic index
`was >50%, although the third concentration was very close to 50% in both cases. No
`precipitate or significant effects on osmolality or pH were observed at any dose. In
`cultures treated with
`, no structural aberrations or changes in aneuploidy greater
`than vehicle controls were observed for any condition (Tables 5, 6, and 7). In the
`absence of S9 with a 53 h harvest the number of cells with polyploidy was further
`evaluated (Table 7). In
`-treated cultures concentration-dependent increases in
`polyploidy were observed. The vehicle and untreated control showed
` and 0%
`polyploid cells (not including endoreduplicated cells), respectively. Cultures treated with
`concentrations of
` (1250, 2500, and 3750 mcg/mL) showed
` and
` polyploid cells, respectively (Table 7). The positive controls were not evaluated for
`changes in ploidy. The historical negative control mean for polyploid cells plus
`endoreduplicated cells was 0.20 +/- 0.28. The concentrations of 2500 and 3750 were
`judged as positive by the Applicant for polyploidy because the number of polyploidy
`cells fell outside the >99% confidence level. The concentration of 1250 mcg/mL was
`considered “suspicious” by the Applicant because it fell within the >95-99% confidence
`level. Historical negative control data are presented in Table 8. Statistical analyses were
`not conducted.
`
`Reviewer’s comment:
`If a cutoff of >95% confidence levels is used as the criterion for a positive response
`(instead of >99% as used by the Applicant), all three concentrations tested with
`would be considered positive for inducing polyploidy. This reviewer considers
`treated cultures at 1250, 2500 and 3750 mcg/mL to be positive for inducing polyploidy.
`
`Conclusions
`No increases above control values were seen for structural aberrations or aneuploidy in
`any condition with either OXY or
` It is concluded that OXY and
` are not
`clastogenic in vitro with human peripheral blood lymphocytes under conditions of the
`assays conducted. However, increased levels of polyploid cells were found in cultures
`treated with OXY at concentrations of 2500 and 3750 mcg/mL and
`at
`concentrations of 1250, 2500, and 3750 mcg/mL.
`
`The proposed wording for the label by the Applicant and the reviewer is detailed in the
`suggested labeling section under Conclusions. This study is being used by the Applicant
`to support the addition of the following statement (underlined) to the reformulated
`OxyContin label:
`
`
`
`
`
`
`
`
`
`
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`NDA 22-272
`
`
`
`
`
`
`
`
`
`
`
`
`Oxycodone was cytotoxic at several concentrations tested which were lower than 5000
`mcg/mL and therefore those concentrations are not appropriate for evaluation of
`structural aberrations (Tables 2, 3, and 4). The concentration will be removed from the
`draft labeling (see suggested labeling under Conclusions). Although no structural
`aberrations were observed in cultures treated with OXY, concentration-dependent
`increases in numerical aberrations (specifically polyploidy) were seen. The additional
`wording is proposed to be added to the label:
`
`
`
`Refer to suggested labeling section under Conclusions for edits to the Applicant’s
`proposed label.
`
`
`
`Concentration,
`mcg/mL
`
`S9
`
`Mean Mitotic
`Index, %
`
`Aneuploid Cells,
`%
`
`Table 2. Oxycodone: Mean chromosomal and numerical aberrations and
`mitotic indices, 29 hour harvest (Assay 1)
`Mean Aberrant
`Cell Frequency,
`% (excluding
`gaps)
`0
`0
`0
`0
`0.5
`2
`10
`0
`0
`0
`0
`0
`0
`7
`5
`0
`
`Vehicle
`625
`1250
`2500
`5000
`CPH, 10
`CPH, 20
`untreated
`Vehicle
`625
`1250
`2500
`5000
`MMC, 0.7
`MMC, 0.8
`untreated
`
`+
`+
`+
`+
`+
`+
`+
`+
`-
`-
`-
`-
`-
`-
`-
`-
`
`100
`89
`84
`63
`40
`NC
`NC
`100
`100
`92
`96
`84
`82
`NC
`NC
`97
`
`0.5
`0
`1
`0.5
`0.5
`1
`1
`0
`2.5
`1
`1.5
`4
`2
`7
`5
`1
`
`
`
`
`13
`
`(b) (4)
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
` NC: not calculated
`
`
`
`
`
`
`
`
`
`
`
`NDA 22-272
`
`S9
`
`+
`+
`+
`+
`+
`+
`+
`-
`-
`-
`-
`-
`-
`-
`-
`
`Aneuploid
`Cells, %
`0.5
`0.5
`0
`0.5
`0
`0
`0.5
`0
`0
`0
`0
`0
`0
`0
`0
`
`Table 3. Oxycodone: Mean chromosomal and numerical aberrations and
`mitotic indices, 29 hour harvest (Assay 2, part I)
`Mean
`Mean Aberrant Cell
`Concentration,
`Mitotic
`Frequency, %
`mcg/mL
`Index, %
`(excluding gaps)
`Vehicle
`0
`100
`1250
`0
`80
`3750
`0
`80
`5000
`0.5
`58
`CPH, 10
`5
`NC
`CPH, 20
`8
`NC
`untreated
`0
`104
`Vehicle
`0
`100
`625
`0
`99
`1250
`0
`93
`2500
`0
`62
`3750
`0
`45
`MMC, 0.15
`4
`NC
`MMC, 0.5
`8
`NC
`untreated
`0
`107
` NC: not calculated
`
`
`
`Table 4. Oxycodone: Mean chromosomal and numerical aberrations and mitotic
`indices in the absence of metabolic activation, 53 hour harvest (Assay 2, part II)
`Mean Aberrant Cell
`Mean
`Concentration,
`Aneuploid
`Polyploid Cells, %
`Frequency, %
`Mitotic
`mcg/mL
`Cells, %
`(negative or positive)
`(excluding gaps)
`Index, %
`Vehicle
`0
`100
`0
`0.2 (neg)
`1250
`0.5
`90
`1
`0.5 (neg)
`2500
`0
`92
`0.5
`1.8 (pos)
`3750
`0.5
`67
`0
`3.9 (pos)
`MMC, 0.1
`7
`NC
`0
`NC
`MMC, 0.15
`14
`NC
`0
`NC
`untreated
`0.5
`96
`0.5
`0 (neg)
`NC: not calculated
`
`
`
`
`
`
`
`
`14
`
`

`

`
`
`
`
`
`
`
`
`NDA 22-272
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`
`
`
`
`S9
`
`+
`+
`+
`+
`+
`+
`+
`+
`-
`-
`-
`-
`-
`-
`-
`-
`
`: Mean chromosomal and numerical
`Table 5.
`aberrations and mitotic indices, 29 hour harvest (Assay 1)
`Mean
`Mean Aberrant Cell
`Aneuploid
`Concentration,
`Mitotic
`Frequency, %
`Cells, %
`mcg/mL
`Index, %
`(excluding gaps)
`Vehicle
`0
`100
`0.5
`313
`0.5
`90
`0.5
`625
`1
`72
`0.5
`1250
`0.5
`78
`1.5
`2500
`0
`40
`0.5
`CPH, 10
`2
`NC
`1
`CPH, 20
`10
`NC
`1
`untreated
`0
`97
`0
`Vehicle
`0
`100
`2.5
`625
`0
`88
`1
`1250
`0.5
`82
`0.5
`2500
`0
`55
`3
`5000
`0
`40
`2.5
`MMC, 0.7
`7
`NC
`7
`MMC, 0.8
`5
`NC
`5
`untreated
`0
`104
`1
` NC: not calculated
`
`
`: Mean chromosomal and numerical
`Table 6.
`aberrations and mitotic indices, 29 hour harvest (Assay 2, part I)
`Mean Aberrant Cell
`Mean
`Concentration,
`Aneuploid
`Frequency, %
`Mitotic
`mcg/mL
`Cells, %
`(excluding gaps)
`Index, %
`Vehicle
`0
`100
`0.5
`625
`0
`88
`0.5
`1250
`0.5
`91
`0
`2500
`0
`88
`0
`CPH, 10
`5
`NC
`0
`CPH, 20
`8
`NC
`0
`untreated
`0
`104
`0.5
`Vehicle
`0
`100
`0
`1250
`0
`101
`0
`2500
`0
`60
`0
`3750
`0.5
`46
`0
`
`S9
`
`+
`+
`+
`+
`+
`+
`+
`-
`-
`-
`-
`
`
`
`
`15
`
`(b) (4)
`
`(b) (4)
`
`

`

`MMC, 0.15
`MMC, 0.5
`untreated
` NC: not calculated
`
`: Mean chromosomal and numerical aberrations and mitotic
`Table 7.
`indices in the absence of metabolic activation, 53 hour harvest (Assay 2, part II)
`Mean
`Mean Aberrant
`Mitotic
`Cell Frequency, %
`Index,
`(excluding gaps)
`%
`0
`100
`0
`79
`0
`84
`0
`48
`7
`NC
`14
`NC
`0.5
`96
`
`
`
`
`
`
`
`
`
`NDA 22-272
`
`4
`8
`0
`
`NC
`NC
`107
`
`0
`0
`0
`
`Aneuploid
`Cells, %
`
`Polyploid Cells, %
`(negative or positive)
`
`0
`0
`0
`0
`0
`0
`0.5
`
`0.2 (neg)
`0.8 (pos)
`1.5 (pos)
`3.7 (pos)
`NC
`NC
`0 (neg)
`
`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`-
`-
`-
`
`Concentration,
`mcg/mL
`
`Vehicle
`1250
`2500
`3750
`MMC, 0.1
`MMC, 0.15
`untreated
` NC: not calculated
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`16
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`
`
`
`
`Table 8. Historical Negative Control Data (reproduced from NDA submission)
`
`
`
`
`NDA 22-272
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`17
`
`
`
`
`(b) (4)
`
`

`

`Reviewer: Elizabeth A. Bolan, Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`NDA 22-272
`
`Evaluation of Amendment 0031: Applicant’s response to FDA Comment/Request
`Question #2 (May 1, 2009)
`
`Dr. Craig Bertha (ONDQA reviewer) noted in his Chemistry Review dated April 28,
`2009 that since the review of the original application, the Applicant has added limits for
` in the excipient
` The Applicant
` at the level for a Class 3 solvent as designated by
`has set the specification for
`ICH Q3 guidelines. This specification is
`ppm. As Dr. Bertha notes in his review,
` is not included as a Class 3 solvent in ICH Q3C. Both the USP <467> general
`chapter and ICH Q3C include specific requirements for
`, which is an isomer of
` is considered a class 3 solvent by both the USP and the ICH.
` are structurally similar and may have similar toxicologic profiles.
`Dr. Bertha submitted an information request to the Applicant requesting justification of
`the
` ppm limit for
`. The Applicant provided a summary of the nonclinical
`toxicology literature of
` in support of their justification of the
`proposed specification for
`. The question submitted to the Applicant as well as
`my evaluation of the adequacy of the Applicant’s justification are below.
`
`The following information request was submitted to the Applicant:
`
`
`Provide the data or other supporting information in justification of the limit of
`
`not more than
`ppm that is applied to residual
`in the
` excipient, which makes up the bulk of each formulated
`strength of the drug product. Neither ICH Q3C nor USP<467> include limits
`for this isomer of
` only for
`. A