CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
`
`APPLICATION NUMBER:
`201655Orig1s000
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`
`PHARMACOLOGY REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`201-655
`000
`Submit date: July 7, 2010
`Received date: July 7, 2010
`Oxymorphone HCl
`Release Tablet
`
`Relief of moderate to severe pain in patients
`requiring continuous opioid therapy for an
`extended period of time
`
`Endo Pharmaceuticals
`Applicant:
`Division of Anesthesia and Analgesia Products
`Review Division:
`Elizabeth A. Bolan, Ph.D.
`Reviewer:
`R. Daniel Mellon, Ph.D.
`Supervisor/Team Leader:
`Bob Rappaport, M.D.
`Division Director:
`Lisa Basham
`Project Manager:
`Template Version: December 7, 2009
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 201-655 are owned by Endo Pharmaceuticals or are
`data for which Endo Pharmaceuticals has obtained a written right of reference.
`Any information or data necessary for approval of NDA 201-655 that Endo
`Pharmaceuticals does not own or have a written right to reference constitutes one of the
`following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for
`a listed drug, as described in the drug’s approved labeling. Any data or information
`described or referenced below from a previously approved application that Endo
`Pharmaceuticals does not own (or from FDA reviews or summaries of a previously
`approved application) is for descriptive purposes only and is not relied upon for approval
`of NDA 201-655.
`
`Extended-
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`1
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`(b) (4)
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`

`

`NDA 201-655
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 5
`1.1 RECOMMENDATIONS............................................................................................ 5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 9
`2 DRUG INFORMATION ............................................................................................ 9
`
`3 STUDIES SUBMITTED.......................................................................................... 16
`
`4 PHARMACOLOGY................................................................................................ 16
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 17
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 17
`SAFETY PHARMACOLOGY................................................................................... 17
`4.3
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 17
`5.1
`PK/ADME........................................................................................................ 17
`5.2
`TOXICOKINETICS ............................................................................................... 17
`6 GENERAL TOXICOLOGY..................................................................................... 17
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 17
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 17
`7 GENETIC TOXICOLOGY ...................................................................................... 17
`
`8 CARCINOGENICITY ............................................................................................. 17
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 17
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................... 18
`9.1
`9.2
`EMBRYONIC FETAL DEVELOPMENT ..................................................................... 18
`PRENATAL AND POSTNATAL DEVELOPMENT......................................................... 18
`9.3
`10
`SPECIAL TOXICOLOGY STUDIES................................................................... 18
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 18
`
`APPENDIX/ATTACHMENTS............................................................................. 18
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`

`NDA 201-655
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`Table of Tables
`
`Table 1 Labeling Review................................................................................................. 6
`Table 2 Relevant IND/s, NDA/s and DMF/s .................................................................. 10
`Table 3 Oxymorphone
` ER Formulation ................................................................... 11
`Table 4 Drug Substance Specifications: Oxymorphone HCl ......................................... 12
`Table 5 Drug Product Specifications: Oxymorphone HCl
` ER .................................. 15
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`NDA 201-655
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`Table of Figures
`
`Figure 1 Structure of Oxymorphone HCl ....................................................................... 10
`Figure 2 Structure of
`................................................................. 14
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`

`NDA 201-655
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`1
`
`Executive Summary
`
`1.1 Recommendations
`
`1.1.1 Approvability
`
`This NDA can be approved from a pharmacology/toxicology perspective.
`
`1.1.2 Additional Non Clinical Recommendations
`
`None
`
`1.1.3 Labeling
`
`The following recommendations are being proposed for the nonclinical sections of the
`label. For the final version of the label, please refer to the Action Letter. Note: The
`recommended changes from the proposed labeling in Table 1 are in red or strikeout
`font.
`
` ER)
` ER (OM
`The nonclinical sections of the proposed label for Oxymorphone
`are identical to the Applicant’s current draft of the PLR conversion for OPANA ER. The
`reviewer’s proposed changes to the label for this product are the same for the PLR
`conversion for OPANA ER. The current version of the OPANA ER label (approved
`February 29, 2008) and the proposed version for OM
` ER submitted with this NDA
`use several different human doses of oxymorphone for nonclinical exposure
`comparisons. These include 40 mg every 12 h,
` 260 mg/day. In order
`to avoid confusion for the prescribing physician, the human dose used for all nonclinical
`sections will be 40 mg every 12 h (80 mg/day). This dose was selected as the
`comparison dose for the nonclinical data because it is using the highest available
`strength for both the OM
` ER and OPANA ER products dosed every 12 h as
`indicated in the labeling. Comparisons will be made on a body surface area basis. An
`exception to the human/animal dose comparison of 40 mg every 12 h based on body
`surface area will be the AUC comparisons in the carcinogenicity section. In the current
`draft of the label, the human dose of 260 mg oxymorphone is used in the exposure
`comparison (AUC) for the mouse and rat carcinogenicity studies. This dose was
`selected during the original NDA labeling review of OPANA ER because it was the
`highest dose used in the clinical trials with AUC values available (refer to NDA 21-610
`review by Dr. Mamata De). The oxymorphone carcinogenicity studies for the OPANA
`ER NDA were the first dedicated opiate carcinogenicity assessments to be included in
`an opiate label. At the time of writing the original OPANA ER and OPANA IR product
`labels, it was thought to use the highest human dose with AUC values as a comparison
`because the population of patients taking oxymorphone chronically would be an opioid
`tolerant population taking theoretically very high doses. In this labeling review, based
`on the previous rationale it was decided that the 260 mg oxymorphone human AUC
`exposure comparison for the mouse and rat carcinogenicity studies should remain.
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`NBA 201 —655
`
`Elizabeth A. Bolan, Ph.D.
`
`Refer to Table 1 for the reviewer’s edits and rationale for the edits to the version of the
`
`label provided by the Applicant.
`
`Table 1 Labeling Review
`
`Applicant’s proposed labeling
`
`Reviewer’s proposed changes
`
`532:"? for
`
`(from highlights section)
`INDICATIONS AND USAGE
`
`(from highlights section)
`INDICATIONS AND USAGE
`
`o
`
`TRADEMARK is an opioid agonist
`indicated for the relief of moderate
`
`o
`
`TRADEMARK is an opioid agonist
`indicated for the relief of moderate
`
`No changes were
`made to this section.
`
`to severe pain in patients requiring
`continuous around-the-clock opioid
`treatment for an extended period of
`time. (1 )
`
`to severe pain in patients requiring
`continuous around-the-clock opioid
`treatment for an extended period of
`
`time. (1) 8 USE IN SPECIFIC POPULATIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`The safety of using oxymorphone in
`pregnancy has not been established with
`regard to possible adverse effects on fetal
`development. The use of TRADEMARK in
`pregnancy, in nursing mothers, or in women
`of child-bearing potential requires that the
`possible benefits of the drug be weighed
`against the possible hazards to the mother
`and the child.
`
`8.1 Pregnancy
`The safety of using oxymorphone in
`pregnancy has not been established with
`regard to possible adverse effects on fetal
`development. The use of TRADEMARK in
`pregnancy, in nursing mothers, or in women
`of child-bearing potential requires that the
`possible benefits of the drug be weighed
`against the possible hazards to the mother
`and the child.
`
`Teratogenic Effects
`
`Teratogenic Effects
`
`Pregnancy Categog C
`
`Pregnancy Categog C
`
`There are no adequate and well-controlled
`studies of oxymorphone in pregnant
`women.
`
`"’"4’
`
`There are no adequate and well—controlled
`studies of oxymorphone in pregnant
`women.
`
`"M”
`
` (I!)(4)
`
`TRADEMARK should be used during
`pregnancy only if the potential benefit
`justifies the potential risk to the fetus.
`
`TRADEMARK should be used during
`pregnancy only if the potential benefit
`justifies the potential risk to the fetus
`
`Oxymorphone hydrochloride administration
`did not cause malformations at any doses
`evaluated during developmental toxicity
`studies in rats (525 mglkglday) or rabbits
`(:50 mglkglday). These doses are ~3-fold
`and ~12—fold the human dose of 40 mg
`every 12 hours, based on body surface
`area. There were no developmental effects
`'
`'
`da or rabbits
`
`Oxymorphone hydrochloride administration
`did not cause malformations at any doses
`evaluated during developmental toxicity
`studies in rats (525 mglkg/day) or rabbits
`(s50 mglkg/day). These doses are ~3-fold
`and ~12—fold the human dose of 40 mg
`every 12 hours, based on body surface
`area. There were no developmental effects
`in rats treated with 5 moo/k da or rabbits
`
`

`

`NDA 201-655
`
`treated with 25 mg/kg/day. Fetal weights
`were reduced in rats and rabbits given
`doses of ≥10 mg/kg/day and 50 mg/kg/day,
`respectively. These doses are ∼1.2-fold
`and
`-fold the human dose of 40 mg every
`12 hours based on body surface area,
`respectively. There were no effects of
`oxymorphone hydrochloride on intrauterine
`survival in rats at doses ≤25 mg/kg/day, or
`rabbits at ≤50 mg/kg/day in these studies
`(see Non-teratogenic Effects, below). In a
`study that was conducted prior to the
`establishment of Good Laboratory Practices
`(GLP) and not according to current
`recommended methodology, a single
`subcutaneous injection of oxymorphone
`hydrochloride on gestation day 8 was
`reported to produce malformations in
`offspring of hamsters that received 15.5-fold
`the human dose of 40 mg every 12 hours
`based on body surface area. This dose
`also produced % maternal lethality.
`
`Non-teratogenic Effects
`
`Oxymorphone hydrochloride administration
`to female rats during gestation in a pre- and
`postnatal developmental toxicity study
`reduced mean litter size (18%) at a dose of
`25 mg/kg/day, attributed to an increased
`incidence of stillborn pups. An increase in
`neonatal death occurred at ≥5 mg/kg/day.
`Post-natal survival of the pups was reduced
`throughout weaning following treatment of
`the dams with 25 mg/kg/day. Low pup birth
`weight and decreased postnatal weight gain
`occurred in pups born to oxymorphone-
`treated
`rats given a dose of 25
`mg/kg/day. This dose is ∼3-fold higher than
`the human dose of 40 mg every 12 hours
`on a body surface area basis.
`
`Prolonged use of opioid analgesics during
`pregnancy may cause fetal-neonatal
`physical dependence. Neonatal withdrawal
`may occur. Symptoms usually appear
`during the first days of life and may include
`convulsions, irritability, excessive crying,
`tremors, hyperactive reflexes, fever,
`vomiting, diarrhea, sneezing, yawning, and
`increased respiratory rate.
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`Carcinogenesis
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`treated with 25 mg/kg/day. Fetal weights
`were reduced in rats and rabbits given
`doses of ≥10 mg/kg/day and 50 mg/kg/day,
`respectively. These doses are ∼1.2-fold
`and 12-fold the human dose of 40 mg
`every 12 hours based on body surface area,
`respectively. There were no effects of
`oxymorphone hydrochloride on intrauterine
`survival in rats at doses ≤25 mg/kg/day, or
`rabbits at ≤50 mg/kg/day in these studies
`(see Non-teratogenic Effects, below). In a
`study that was conducted prior to the
`establishment of Good Laboratory Practices
`(GLP) and not according to current
`recommended methodology, a single
`subcutaneous injection of oxymorphone
`hydrochloride on gestation day 8 was
`reported to produce malformations in
`offspring of hamsters that received 15.5-fold
`the human dose of 40 mg every 12 hours
`based on body surface area. This dose
`20% maternal lethality.
`also produced
`
`Non-teratogenic Effects
`
`Oxymorphone hydrochloride administration
`to female rats during gestation in a pre- and
`postnatal developmental toxicity study
`reduced mean litter size (18%) at a dose of
`25 mg/kg/day, attributed to an increased
`incidence of stillborn pups. An increase in
`neonatal death occurred at ≥5 mg/kg/day.
`Post-natal survival of the pups was reduced
`throughout weaning following treatment of
`the dams with 25 mg/kg/day. Low pup birth
`weight and decreased postnatal weight gain
`occurred in pups born to oxymorphone-
`rats given a dose
`treated female
`of 25 mg/kg/day. This dose is ∼3-fold
`higher than the human dose of 40 mg every
`12 hours on a body surface area basis.
`
`Prolonged use of opioid analgesics during
`pregnancy may cause fetal-neonatal
`physical dependence. Neonatal withdrawal
`may occur. Symptoms usually appear
`during the first days of life and may include
`convulsions, irritability, excessive crying,
`tremors, hyperactive reflexes, fever,
`vomiting, diarrhea, sneezing, yawning, and
`increased respiratory rate.
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`Carcinogenesis
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`NDA 201-655
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`Long-term studies have been completed to
`evaluate the carcinogenic potential of
`oxymorphone in both Sprague-Dawley rats
`and CD-1 mice. Oxymorphone HCl was
`administered to Sprague-Dawley rats (2.5,
`5, and 10 mg/kg/day in males and 5, 10,
`and 25 mg/kg/day in females) for 2 years by
`oral gavage. The systemic drug exposure
`(AUC ng•h/mL) at the 10 mg/kg/day in male
`rats was 0.34-fold and at the 25 mg/kg/day
`dose in female rats was 1.5-fold the human
`exposure at a dose of 260 mg/day. No
`evidence of carcinogenic potential was
`observed in rats. Oxymorphone was
`administered to CD-1 mice (10, 25, 75 and
`150 mg/kg/day) for 2 years by oral gavage.
`The systemic drug exposure (AUC ng•h/mL)
`at the 150 mg/kg/day dose in mice was
`14.5-fold (in males) and 17.3-fold (in
`females) times the human exposure at a
`dose of 260 mg/day. No evidence of
`carcinogenic potential was observed in
`mice.
`
`Mutagenesis
`Oxymorphone hydrochloride was not
`mutagenic when tested in the in vitro
`bacterial reverse mutation assay (Ames
`test) at concentrations of ≤5270 μg/plate, or
`in an in vitro mammalian cell chromosome
`aberration assay performed with human
`peripheral blood lymphocytes at
`concentrations ≤5000 μg/ml with or without
`metabolic activation. Oxymorphone
`hydrochloride tested positive in both the rat
`and mouse in vivo micronucleus assays.
`An increase in micronucleated
`polychromatic erythrocytes occurred in mice
`given doses ≥250 mg/kg and in rats given
`doses of 20 and 40 mg/kg. A subsequent
`study demonstrated that oxymorphone
`hydrochloride was not aneugenic in mice
`following administration of up to 500 mg/kg.
`Additional studies indicate that the
`increased incidence of micronucleated
`polychromatic erythrocytes in rats may be
`secondary to increased body temperature
`following oxymorphone administration.
`Doses associated with increased
`micronucleated polychromatic erythrocytes
`also produce a marked, rapid increase in
`body temperature. Pretreatment of animals
`with sodium salicylate minimized the
`increase in body temperature and
`prevented the increase in micronucleated
`polychromatic erythrocytes after
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`Long-term studies have been completed to
`evaluate the carcinogenic potential of
`oxymorphone in both Sprague-Dawley rats
`and CD-1 mice. Oxymorphone HCl was
`administered to Sprague-Dawley rats (2.5,
`5, and 10 mg/kg/day in males and 5, 10,
`and 25 mg/kg/day in females) for 2 years by
`oral gavage. The systemic drug exposure
`(AUC ng•h/mL) at the 10 mg/kg/day in male
`rats was 0.34-fold and at the 25 mg/kg/day
`dose in female rats was 1.5-fold the human
`exposure at a dose of 260 mg/day. No
`evidence of carcinogenic potential was
`observed in rats. Oxymorphone was
`administered to CD-1 mice (10, 25, 75 and
`150 mg/kg/day) for 2 years by oral gavage.
`The systemic drug exposure (AUC ng•h/mL)
`at the 150 mg/kg/day dose in mice was
`14.5-fold (in males) and 17.3-fold (in
`females) times the human exposure at a
`dose of 260 mg/day. No evidence of
`carcinogenic potential was observed in
`mice.
`
`Mutagenesis
`Oxymorphone hydrochloride was not
`mutagenic when tested in the in vitro
`bacterial reverse mutation assay (Ames
`test) at concentrations of ≤5270 μg/plate, or
`in an in vitro mammalian cell chromosome
`aberration assay performed with human
`peripheral blood lymphocytes at
`concentrations ≤5000 μg/ml with or without
`metabolic activation. Oxymorphone
`hydrochloride tested positive in both the rat
`and mouse in vivo micronucleus assays.
`An increase in micronucleated
`polychromatic erythrocytes occurred in mice
`given doses ≥250 mg/kg and in rats given
`doses of 20 and 40 mg/kg. A subsequent
`study demonstrated that oxymorphone
`hydrochloride was not aneugenic in mice
`following administration of up to 500 mg/kg.
`Additional studies indicate that the
`increased incidence of micronucleated
`polychromatic erythrocytes in rats may be
`secondary to increased body temperature
`following oxymorphone administration.
`Doses associated with increased
`micronucleated polychromatic erythrocytes
`also produce a marked, rapid increase in
`body temperature. Pretreatment of animals
`with sodium salicylate minimized the
`increase in body temperature and
`prevented the increase in micronucleated
`polychromatic erythrocytes after
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`NDA 201-655
`
`administration of 40 mg/kg oxymorphone.
`
`Impairment of fertility
`Oxymorphone hydrochloride did not affect
`reproductive function or sperm parameters
`in male rats at any dose tested (≤50
`mg/kg/day). In female rats, an increase in
`the length of the estrus cycle and decrease
`in the mean number of viable embryos,
`implantation sites and corpora lutea were
`observed at doses of oxymorphone
`≥10 mg/kg/day. The dose of oxymorphone
`associated with reproductive findings in
`female rats is 1.2-fold the human dose of 40
`mg every 12 hours based on a body surface
`area. The dose of oxymorphone that
`produced no adverse effects on
`reproductive findings in female rats is 0.6-
`fold the human dose of 40 mg every 12
`hours on a body surface area basis.
`
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`
`
`
`
`
`
`
`
`The exposure
`comparison for males
`was added.
`
`
`
`
`
`administration of 40 mg/kg oxymorphone.
`
`Impairment of fertility
`Oxymorphone hydrochloride did not affect
`reproductive function or sperm parameters
`in male rats at any dose tested (≤50
`mg/kg/day). The highest dose tested is ∼6-
`fold the human dose of 40 mg every 12
`hours, based on body surface area. In
`female rats, an increase in the length of the
`estrus cycle and decrease in the mean
`number of viable embryos, implantation
`sites and corpora lutea were observed at
`doses of oxymorphone ≥10 mg/kg/day. The
`dose of oxymorphone associated with
`reproductive findings in female rats is 1.2-
`fold the human dose of 40 mg every 12
`hours based on a body surface area. The
`dose of oxymorphone that produced no
`adverse effects on reproductive findings in
`female rats is 0.6-fold the human dose of 40
`mg every 12 hours on a body surface area
`basis.
`
`
`1.2 Brief Discussion of Nonclinical Findings
`
` ER (Endo Pharmaceuticals) is being submitted
`NDA 201-655 for Oxymorphone HCl
`via the 505(b)(1) regulatory pathway. Cross-reference is made to the nonclinical
`pharmacology, ADME, and toxicology information for oxymorphone provided in NDA 21-
`610 (OPANA ER) which is also owned by Endo Pharmaceuticals. The applicant also
`references the rat and mouse carcinogenicity studies submitted to IND 56,919
`(Oxymorphone HCl
`; Endo Pharmaceuticals). These studies are described in the
`current versions of the both OPANA IR and OPANA ER labels and will be described in
`the label for this product.
`
`No nonclinical studies were conducted for this NDA. There are no unique nonclinical
`issues with this product as compared to OPANA ER or other approved oxymorphone
`products. The impurities/degradants are controlled at acceptable levels in both the drug
`substance and drug product. The excipients used in this formulation can be found in
`previously approved products and do not pose any unique toxicologic concerns. There
`are no outstanding pharmacology or toxicology issues for NDA 201-655 and the
`recommendation from the Pharmacology/Toxicology perspective is approval.
`
`2 Drug Information
`
`2.1 Drug
`
`9
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`
`
`Elizabeth A. Bolan, Ph.D.
`
` Extended-Release Tablet
`
`NDA 201-655
`
`Oxymorphone Hydrochloride
`
`2.1.1 CAS Registry Number
`
`357-07-03
`
`2.1.2 Generic Name
`
`Oxymorphone hydrochloride
`
`2.1.3 Code Name
`
`EN3288
`
`2.1.4 Chemical Name
`
`4,5 α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one hydrochloride
`
`2.1.5 Molecular Formula/Molecular Weight
`
`.HCl; MW= 337.80
`
`C17H19NO4
`
`2.1.6 Structure
`
`Figure 1 Structure of Oxymorphone HCl
`
`
`2.1.7 Pharmacologic class
`
`Opioid agonist
`
`2.2 Relevant IND/s, NDA/s, and DMF/s
`
`Table 2 Relevant IND/s, NDA/s and DMF/s
`IND/NDA/DMF
`drug/compound
`sponsor
`IND 104,250
`Oxymorphone
` ER
`Endo
`NDA 21-611
`OPANA IR
`Endo
`NDA 22-610
`OPANA ER
`Endo
`
`division
`DAAP
`DAAP
`DAAP
`
`status
`active
`approved
`approved
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`

`NDA 201-655
`
`Elizabeth A. Bolan, Ph.D.
`
`IND 58,602
`
`DMF-
`
`Oxymorphone HCI
`
`IND 56,919 —
`
`ONDQA
`
`reviewed by Dr.
`Julia Pinto
`2010
`
`2.3 Clinical Formulation
`
`formulation with properties purported by the
`extended release oxymorp one
`applicant to reduce accidental misuse (i.e. by breakage or crushing) and to deter certain
`methods of intended abuse i. e. intentional crushin for snortin or in ection .
`
`The Oxymorphone HCIm Extended-Release tablet (0M I ER) is an
`
`
`The tablet"Is
`
`roduced b
`
`The indication proposed for the OM I ER tablet is the relief of moderate to severe pain
`in adult patients requiring continuous, around-the-clock opioid treatment for an extended
`period of time. The product will be labeled for twice daily administration and will be
`available in 5, 7.5, 10, 15, 20, 30, and 40 mg tablets. The amounts of each excipient
`per 40 mg tablet and at the maximum theoretical daily dose of 0M are listed in Table 3.
`Refer to discussion of the MTDD of OM in Section 2.4. Levels of all excipients in the
`formulation when the product is used at the MTDD of OM are acceptable; refer to
`Section 2.3.2 for discussion.
`
`Table 3 Oxymorphone I ER Formulation
`
`.
`
`.
`
`t T” '" a".°”',°'d
`olerant patient (mg)
`
`Ingredient
`
`per 40 mg
`
`tablet
`m
`
`.
`
`Pol eth lene oxide Citric acid, anh drous
`
`*Total daily intake based on the maximum theoretical daily dose (MTDD) of
`oxymorphone in an opioid tolerant patient of 1 g/day (refer to Section 2.4 for
`discussion of MTDD)
`
`2.3.1 Drug Formulation
`
`See Section 2.3
`
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`

`NDA 201-655
`
`2.3.2 Comments on Novel Excipients
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
` ER formulation are found in approved drug products
`All of the excipients in the OM
`and are listed in the FDA Inactive Ingredients Guide (IIG; Table 3). However, two of the
`excipients in the OM
` ER drug product will exceed levels in previously approved
`drugs when the MTDD of OM is consumed. Polyethylene oxide (PEO) is found in OM
` ER at a total daily dose of
` when the highest strength tablet is consumed
`at the MTDD of OM. Polyethylene oxide is found in the FDA approved product
`OxyContin at a level of
` when the product is used at the MTDD of oxycodone.
`Therefore, the levels of PEO in the OM
` ER product are considered acceptable. The
`levels of α-tocopherol (Vitamin E;
` in OM ER, when the highest strength
`tablet is used at the MTDD of OM, exceed the values listed in the IIG. However, the
`upper safe limit of Vitamin E established by the Food and Nutrition Board of the Institute
`of Medicine is 1000 mg daily. Therefore, the levels of α-tocopherol in the OM ER
`product are considered acceptable.
`
` ER when used at the MTDD of OM
`Levels of all excipients in the formulation of OM
`are considered acceptable from the pharmacology/toxicology perspective and do not
`pose any unique toxicologic concerns.
`
`2.3.3 Comments on Impurities/Degradants of Concern
`
`Drug Substance Impurities
`
` for the OM drug substance. The
`The applicant is referencing DMF
`qualification threshold according to the ICH Q3A (R2) guidance for impurities in the drug
`substance for a maximum daily dose (MDD) of < 2 g/day is 0.15% or 1 mg/day intake,
`whichever is lower. The applicant has set the specifications for drug substance
`impurities at NMT
` unless otherwise noted (Table 4; see discussion of specific
`exceptions below). For a MDD of
` of OM with a specification of
` the TDI of the
`impurity would be
`, which exceeds the 1 mg/day maximum as stated in ICH
`Q3A (R2). Although these OM drug substance specifications do not technically meet
`ICH Q3A (R2) guidelines, several products have been approved by FDA and are
`currently marketed using the same drug substance DMF. No safety signals have arisen
`and the proposed drug substance specifications of NMT
`, although slightly
`exceeding ICH Q3A (R2) thresholds, are considered to be of no toxicologic concern.
`
`Table 4 Drug Substance Specifications: Oxymorphone HCl
`Acceptance
`Specification
`
`Impurity
`
`Acceptable?
`Yes
`Yes
`Yes
`Yes: FDA approved compound
`Yes
`Yes: ICSAS comp tox report
`
`
`
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`NDA 201-655
`
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`Drug Product Impurities/Degradants
`The qualification threshold according to the ICH Q3B (R2) guidance for
`impurities/degradants in the drug product for the MDD of the drug substance
`administered per day between
` (MDD of OM is
`) is
` or
`TDI, whichever is lower. The Applicant has set the stability specifications for
`impurities/degradation products at
` and no further qualification will be necessary
`(Table 5).
`
`
`
`Table 5 Drug Product Specifications: Oxymorphone HCl
`Impurity
`Acceptance Criteria
`
`
`
`
` ER
`Acceptable?
`Yes
`Yes
`Yes
`Yes
`
`2.4 Proposed Clinical Population and Dosing Regimen
`
` ER) is
`Extended-Release tablet (OM
`The Oxymorphone HCl
`proposed to be indicated for the relief of moderate to severe pain in adult patients
`requiring continuous, around-the-clock opioid treatment for an extended period of time.
`The product will be labeled to be administered twice daily and will be available in 5, 7.5,
`10, 15, 20, 30, and 40 mg tablets.
`
`Determination of the maximum theoretical daily dose (MTDD) of oxymorphone
`The maximal dosing information for OM is relevant to this review in that the ICH
`specifications for impurity levels for the drug substance and the drug product as well as
`the acceptable levels of total amount of inactive ingredients are based on the total daily
`dose of the drug substance.
`
`The development of tolerance to the effects of an opioid precludes easily defining a
`maximum daily dose. The reduced effectiveness as a result of tolerance necessitates
`
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`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 201-655
`
`increased dosing in order to maintain the desired therapeutic effect. Therefore, in an
`opioid tolerant individual, very high daily doses are theoretically possible. Because the
`dosing is tailored to the individual needs of the patient it not possible to set a maximum
`daily dose that fits all patients. Based on potency comparisons with morphine, the
`clinicians in DAAP have determined that a reasonable maximum theoretical daily dose
`(MTDD) of OM in an opioid tolerant individual is
`.
`
`
`2.5 Regulatory Background
`
`NDA 201-655 (Endo Pharmaceuticals) is being submitted via the 505(b)(1) regulatory
`pathway. Cross-reference is made to the nonclinical pharmacology, ADME, and
`toxicology information for oxymorphone provided in NDA 21-610 (OPANA ER) which is
`also owned by Endo Pharmaceuticals. The applicant also references the rat and mouse
`carcinogenicity studies submitted to IND 56,919 (OPANA ER). These studies are
`described in the current versions of the both OPANA IR and OPANA ER labels. No
`nonclinical studies were conducted for this NDA.
`
`3
`
`Studies Submitted
`
`3.1 Studies Reviewed
`
`No studies were submitted with this NDA.
`
`3.2 Studies Not Reviewed
`
`3.3 Previous Reviews Referenced
`
`Refer to the combined pharmacology toxicology review for OPANA IR and OPANA ER
`(NDAs 21-611 and 21-610, respectively) by Dr. R. Daniel Mellon dated October 15 2003
`for the first cycle review and by Dr. Mamata De dated June 16, 2006 for the second
`cycle review. The rat and mouse carcinogenicity studies were submitted to IND 56,919
`and were reviewed in the NDA review mentioned above by Dr. Mamata De.
`
`Pharmacology
`4
`Oxymorphone is a semi-synthetic mu opioid receptor agonist with a long history of safe
`use. The pharmacology has been well characterized and is described in the NDA
`review of OPANA ER (22-610). The applicant owns and is cross-referencing NDA 22-
`610 to support approval of this NDA. No new pharmacology studies were submitted
`with this NDA.
`
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`
`
`Elizabeth A. Bolan, Ph.D.
`
`NDA 201-655
`
`4.1 Primary Pharmacology
`
`4.2 Secondary Pharmacology
`
`4.3 Safety Pharmacology
`
`Pharmacokinetics/ADME/Toxicokinetics
`5
`No new studies were submitted. Refer to review of NDA 22-610 for discussion.
`
`5.1 PK/ADME
`
`5.2 Toxicokinetics
`
`6 General Toxicology
`No new studies were submitted. Refer to review of NDA 22-610 for discussion.
`
`6.1 Single-Dose Toxicity
`
`6.2 Repeat-Dose Toxicity
`
`7 Genetic Toxicology
`No new studies were submitted. Refer to review of NDA 22-610 for discussion.
`
`8 Carcinogenicity
`No new studies were submitted. Refer to review of NDA 22-610 for discussion.
`
`9 Reproductive and Developmental Toxicology
`No new studies were submitted. Refer to review of NDA 22-610 for discussion.
`
`17
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`

`NDA 201-655
`
`9.1 Fertility and Early Embryonic Development
`
`
`
`Elizabeth A. Bolan, Ph.D.
`
`9.2 Embryonic Fetal Development
`
`9.3 Prenatal and Postnatal Development
`
`10 Special Toxicology Studies
`No new studies were submitted.
`
`Integrated Summary and Safety Evaluation
`11
`There ar