CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`207154Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`207154
`DSN 1
`28-APR-2015
`28-APR-2015
`ACZONE® (dapsone) Gel, 7.5%
`Topical treatment of acne vulgaris in patients 12
`years of age or older.
`Allergan, Inc.
`Applicant:
`DDDP
`Review Division:
`Norman A. See, PhD
`Reviewer:
`Barbara Hill, PhD
`Supervisor/Team Leader:
`Kendall Marcus, MD
`Division Director:
`Strother Dixon, RPM
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of 207154 are owned by Allergan, Inc. or are data for which
`Allergan, Inc. has obtained a written right of reference. Any information or data
`necessary for approval of 207154 that Allergan, Inc. 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 reflected in the drug’s
`approved labeling. Any data or information described or referenced below from reviews
`or publicly available summaries of a previously approved application is for descriptive
`purposes only and is not relied upon for approval of 207154.
`
`Reference ID: 3846193
`
`1
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`TABLE OF CONTENTS
`
`1
`
`3
`
`EXECUTIVE SUMMARY...........................................................................................3
`1.1
`INTRODUCTION .....................................................................................................3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................3
`1.3
`RECOMMENDATIONS .............................................................................................5
`2 DRUG INFORMATION..............................................................................................7
`2.1
`DRUG ..................................................................................................................7
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS............................................................8
`2.3
`DRUG FORMULATION ............................................................................................8
`2.4
`COMMENTS ON NOVEL EXCIPIENTS........................................................................8
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN..........................................9
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.......................................9
`2.7
`REGULATORY BACKGROUND ...............................................................................10
`STUDIES SUBMITTED...........................................................................................10
`3.1
`STUDIES REVIEWED............................................................................................10
`3.2
`STUDIES NOT REVIEWED.....................................................................................10
`3.3
`PREVIOUS REVIEWS REFERENCED.......................................................................11
`PHARMACOLOGY .................................................................................................11
`4.1
`PRIMARY PHARMACOLOGY ..................................................................................11
`4.2
`SECONDARY PHARMACOLOGY .............................................................................11
`4.3
`SAFETY PHARMACOLOGY ....................................................................................11
`PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................11
`5.1
`PK/ADME .........................................................................................................11
`5.2
`TOXICOKINETICS.................................................................................................11
`6 GENERAL TOXICOLOGY......................................................................................11
`6.1
`SINGLE-DOSE TOXICITY ......................................................................................11
`6.2
`REPEAT-DOSE TOXICITY .....................................................................................11
`7 GENETIC TOXICOLOGY........................................................................................25
`8 CARCINOGENICITY...............................................................................................25
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................26
`10
`SPECIAL TOXICOLOGY STUDIES....................................................................27
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................27
`12
`APPENDIX/ATTACHMENTS ..............................................................................28
`
`4
`
`5
`
`Reference ID: 3846193
`
`2
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Executive Summary
`1
`Introduction
`1.1
`Topical use of dapsone in the treatment of acne vulgaris, involving twice daily
`application of ACZONE® (dapsone topical gel), 5%, has been found to be safe under
`NDA 21-794 (approved 07-JUL-2005). Under NDA 207154 the sponsor has proposed
`to market a 7.5% dapsone topical product (ACZONE® (dapsone topical gel), 7.5%).
`The conditions of use of the 7.5% product, including the volume of product applied per
`treatment, the maximum area treated, and the patient population, will be similar to those
`associated with 5% dapsone gel, with the exception that the 7.5% product will be
`labeled for once daily application (in comparison to two daily applications of the 5%
`product). The approved label of NDA 21-794, and the proposed label of 207154,
`discuss application of a “pea-sized” amount; a typical individual dose is estimated to
`approximate 2 g per application. Therefore, clinical use of ACZONE® Gel, 7.5%,
`typically involves application of approximately
`
`dapsone, while use of ACZONE® Gel, 5%, typically involves application of
`approximately
` dapsone.
`
`
`NDA 21-794 and NDA 207154 were developed under IND 54,440. NDA 207154
`includes letters from Allergan that authorize reference to data associated with NDA 21-
`794 and IND 54,440. I will refer to the CDER nonclinical reviews of NDA 21-794, as
`well as IND 54,440, for summary and interpretation of the nonclinical data.
`1.2 Brief Discussion of Nonclinical Findings
`Dapsone has been evaluated in a battery of nonclinical studies that included evaluation
`of pharmacology, pharmacokinetics, general (repeated-dose) toxicology, genetic
`toxicology, carcinogenicity, reproductive toxicology, and special toxicity studies. Please
`see reviews of NDA 21-794 for detailed analysis of those data. For convenience, the
`pivotal data will be summarized below.
`
`Pharmacology: Dapsone inhibits growth of certain species of bacteria through inhibition
`of folic acid synthesis. The mechanism through which dapsone ameliorates acne is
`unclear, although reducing the bacterial count may reduce the size and quantity of
`lesions by reducing inflammation.
`
`ADME: Approximately 10% to 25% of a topically applied dose of dapsone was
`systemically absorbed by rats and rabbits. In humans, less than 1% of a topically
`applied dose of dapsone is systemically absorbed. Dapsone is rapidly metabolized to
`N-acetyl dapsone and hydroxylamine dapsone. Dapsone is primarily excreted in the
`urine.
`
`General toxicology: Substantial toxicity was not observed in chronic toxicology studies
`in which dapsone topical gel was dermally applied. No adverse effects were observed
`in female rats treated daily for six months, although the mean RBC, HGB, and HCT
`values of male dapsone-treated animals were slightly, but significantly, reduced, and the
`mean weight of the spleen was significantly increased, in male rats that received
`
`Reference ID: 3846193
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`dapsone gel. No effects were observed in male or female rabbits treated topically for
`nine months.
`
`In rats that were orally dosed for 90 days, treatment-related findings observed at 30
`mg/kg/day included cyanosis of the skin, hyperactivity, increased WBC count,
`decreased RBC count, hemoglobin concentration and hematocrit, increased
`prothrombin time, splenomegaly, mild splenic "congestion", and mild pigmentation of the
`spleen. These effects and more were observed at 100 mg/kg/day. 3 mg/kg/day was an
`apparent no-adverse-effect-level (NOAEL) in that study.
`
`Genetic toxicology: Dapsone was negative in an Ames assay (both with and without
`metabolic activation) and in a micronucleus assay. However, dapsone induced
`chromosomal aberrations in cultured CHO cells, suggesting that it is a clastogen.
`
`Carcinogenicity: Dapsone was evaluated for carcinogenicity in a two-year oral (gavage)
`rat study at dose levels up to 15 mg/kg/day, and in a Tg.AC mouse study. Both studies
`were judged by the exec-CAC to be acceptable. No evidence of carcinogenicity was
`obtained in either study.
`
`Reproductive toxicology: Dapsone impaired fertility of male rats, as evidenced by a
`reduction in the fertility index (number of rats pregnant/number of rats mated), reduced
`sperm motility (percentage of observed sperm that were motile), and reduced numbers
`of implantations and viable embryos in the females that did become pregnant.
`Statistically significant reductions in percentage of motile sperm were observed at
`exposures of 3 mg/kg/day and above. The mean numbers of embryo implantations and
`viable embryos were significantly reduced in untreated females mated with males that
`had been dosed at 12 mg/kg/day or greater, presumably due to reduced numbers or
`effectiveness of sperm, indicating impairment of fertility. 2 mg/kg/day was an apparent
`NOAEL for effects on male fertility.
`
`When administered to female rats at a dosage of 75 mg/kg/day for 15 days prior to
`mating and for 17 days thereafter, dapsone reduced the mean number of implantations,
`increased the mean early resorption rate, and reduced the mean litter size. These
`effects were probably secondary to maternal toxicity. No effects on the incidence of
`external, visceral or skeletal malformations or variations were observed. Under the
`conditions of this study, the NOAEL for dapsone was 12 mg/kg/day.
`
`When administered at a dosage of 150 mg/kg/day to rabbits on days 6-18 of gestation,
`dapsone significantly increased the incidence of early resorptions. Two does at this
`dosage delivered prematurely and seven does resorbed all fetuses. These effects were
`probably secondary to maternal toxicity. No effects on the incidence of external,
`visceral or skeletal malformations or variations were observed. Under the conditions of
`this study, the NOAEL for dapsone was 30 mg/kg/day.
`
`Little toxicity was observed in a two-generation study in which F0 females were
`administered the test articles daily from gestation day 7 through day 27 postpartum at
`
`Reference ID: 3846193
`
`4
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`

`

`NDA 207154
`
`Norman A. See, PhD
`
`exposures of 3, 12, and 30 mg/kg/day dapsone. The mean number of stillborn pups per
`litter was slightly, but statistically significantly, higher in high-dose dapsone litters than in
`control litters. No effects were observed on pup viability, physical development,
`behavior, learning ability, or reproduction.
`
`Special toxicology: Dapsone topical gel is not an irritant of skin or eyes, is not
`phototoxic, and is nonsensitizing.
`
`1.3 Recommendations
`1.3.1 Approvability
`The product is approvable with respect to nonclinical concerns.
`1.3.2 Additional Non Clinical Recommendations
`None.
`Labeling
`1.3.3
`It is recommended that section 8.1 (Pregnancy), section 12.1 (Mechanism of Action),
`and section 13.1 (Carcinogenesis, Mutagenesis, Impairment of Fertility) of the draft
`label be modified to the statements indicated below. Other portions of the draft label
`are acceptable in regard to nonclinical issues. The “dose-multiples” (systemic exposure
`comparisons) stated in the draft label reflect the following exposure estimates, which in
`some instances were calculated through extrapolation.
`
`Summary of systemic exposure values, as referenced in the draft label:
`Study Type
`Dose of Interest Estimated AUC (ng∙hr/mL)
`
`AUC Ratio*
`
`1. Section 8.1:
`
`“8.1 Pregnancy
`
`Reference ID: 3846193
`
`5
`
`(b) (4)
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Teratogenic Effects: Pregnancy Category C
`There are no adequate and well controlled studies in pregnant women. ACZONE® Gel,
`7.5%, should be used during pregnancy only if the potential benefit justifies the potential
`risk to the fetus. Dapsone has been shown to have an embryocidal effect in rats and
`rabbits when administered orally during the period of organogenesis in doses of 75
`mg/kg/day and 150 mg/kg/day, respectively (approximately 1400 and 425 times,
`respectively, the systemic exposure that is associated with the maximum recommended
`human dose (MRHD) of ACZONE® Gel, 7.5%, based on AUC comparisons). These
`effects may have been secondary to maternal toxicity.”
`
`2. Section 12.1:
`
`“12.1 Mechanism of Action
`The mechanism of action of dapsone gel in treating acne vulgaris is not known.”
`
`3. Section 13.1:
`
`“13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Dapsone was not carcinogenic to rats when orally administered for a lifetime at dose
`levels up to 15 mg/kg/day (approximately 340 times the systemic exposure that is
`associated with the MRHD of ACZONE® Gel, 7.5%, based on AUC comparisons).
`
`No evidence of potential to induce carcinogenicity was obtained in a dermal study in
`which dapsone gel was topically applied to Tg.AC transgenic mice for approximately 26
`weeks. Dapsone concentrations of 3%, 5%, and 10% were evaluated; 3% material was
`judged to be the maximum tolerated dosage.
`
`Topical gels that contained dapsone at concentrations up to 5% did not increase the
`rate of formation of ultraviolet light-induced skin tumors when topically applied to
`hairless mice in a 12-month photocarcinogenicity study.
`
`Dapsone was not mutagenic in a bacterial reverse mutation assay (Ames test) using S.
`typhimurium and E. coli, with and without metabolic activation, and was negative in a
`micronucleus assay conducted in mice. Dapsone increased both numerical and
`structural aberrations in a chromosome aberration assay conducted with Chinese
`hamster ovary (CHO) cells.
`
`The effects of dapsone on fertility and general reproduction performance were assessed
`in male and female rats following oral (gavage) dosing. Dapsone reduced sperm motility
`at dosages of 3 mg/kg/day or greater (approximately 22 times the systemic exposure
`that is associated with the MRHD of ACZONE® Gel, 7.5%, based on AUC
`comparisons). The mean numbers of embryo implantations and viable embryos were
`significantly reduced in untreated females mated with males that had been dosed at 12
`mg/kg/day or greater (approximately 187 times the systemic exposure that is associated
`with the MRHD of ACZONE® Gel, 7.5%, based on AUC comparisons), presumably due
`to reduced numbers or effectiveness of sperm, indicating impairment of fertility.
`
`Reference ID: 3846193
`
`6
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Dapsone had no effect on male fertility at dosages of 2 mglkg/day or less
`(approximately 15 times the systemic exposure that is associated with the MRHD of
`ACZONE® Gel, 7.5%, based on AUC comparisons). When administered to female rats
`at a dosage of 75 mg/kg/day (approximately 1400 times the systemic exposure that is
`associated with the MRHD of ACZONE® Gel, 7.5%, based on AUC comparisons) for 15
`days prior to mating and for 17 days thereafter, dapsone reduced the mean number of
`implantations, increased the mean early resorption rate, and reduced the mean litter
`size. These effects may have been secondary to maternal toxicity.
`
`Dapsone was assessed for effects on perinatal/postnatal pup development and
`postnatal maternal behavior and function in a study in which dapsone was orally
`administered to female rats daily beginning on the seventh day of gestation and
`continuing until the twenty-seventh day postpartum. Maternal toxicity (decreased body
`weight and food consumption) and developmental effects (increase in stillborn pups and
`decreased pup weight) were seen at a dapsone dose of 30 mglkg/day (approximately
`560 times the systemic exposure that is associated with the MRHD of ACZONE® Gel,
`7.5%, based on AUC comparisons). No effects were observed on the viability, physical
`development, behavior, learning ability, or reproductive function of surviving pups.”
`
`2
`
`Drug Information
`
`2.1
`
`Drug
`
`CAS Registry Number
`80—08-0
`
`Generic Name
`
`Dapsone
`
`Code Name(s)
`AGN-225678
`
`Chemical Name(s)
`4-[(4-aminobenzene)sulfonyl]aniline; 4,4'-Sulfonylbisbenzeneamine
`
`Molecular Formula/Molecular Weight
`C12H12N2028/24830
`
`Structure or Biochemical Description
`
`0 |
`
`|3 I
`
`I0
`
`Pharmacologic Class
`Antimicrobial
`
`Reference ID: 3846193
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`NDA 10-039 (Avlosulfon tablets, Wyeth-Ayerst, approved 8/11/55); NDA 21-794
`(ACZONE® (dapsone) gel, 5%, a
`roved 07-JUL-2005 ; IND 54,440; DMF-
`(dapsone drug substance); DMF
`
`2.3 Drug Formulation
`
`Quality
`
`Concentration
`
`N—on-compendial
`
`——=_
`
`Note: “MP” in the formulation refers to "methylparaben”.
`
`2.4 Comments on Novel Excipients
`
`The roduct contains no novel exci
`
`ients.
`
`
`
`Reference ID: 3846193
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`M“)
`
`2.5 Comments on Impurities/Degradants of Concern
`
`2.5.1 Impurities Associated with Drug Substance (API)
`“m
`The API under NDA 207154 (dapsone, USP, produced by
`in association with DMF m”) is the same API (with the same specifications) that is
`associated with ACZONE‘!9 (dapsone topical gel), 5% (approved under NDA 21-794).
`The prospective patient population and maximum duration of exposure to the API are
`identical under NDA 207154 and NDA 21-794. The daily exposure to the API, and
`therefore impurities associated with the API, under NDA 207154 is lower than the
`exposure under NDA 21-794. Therefore, the exposures to impurities of the API in
`association with NDA 207154 are considered to be qualified by the clinical and
`nonclinical data that supported approval of NDA 21-794, as well as by the history of
`safe use of ACZONE® (dapsone topical gel), 5%, that has accrued post-approval of
`NDA 21 -794.
`
`2.5.2 Impurities that are Degradation Products in the Drug Product
`The proposed specifications for organic impurities of the drug product are acceptable; it
`is noted that no specified or individual unspecified dapsone-related impurities of the
`drug product exceed the qualification limit under the ICH Q3B document (the
`qualification threshold for degradation products that are associated with dapsone under
`NDA 207154 is ““’% of the label strength of the API).
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`The product is proposed for the topical treatment of acne vulgaris in patients 12 years of
`age and older. The proposed labeling states:
`
`(5) (4)
`
`-
`
`Apply approximately a pea-sized amount of ACZONE® Gel, 7.5%, in a thin layer
`to the entire face. A thin layer
`"M" be applied to other affected areas.
`(5)“)
`
`lb) (4)
`
`2.7 Regulatory Background
`
`Dapsone tablets for oral administration were originally approved under NDA 10-039
`(Avlosulfon tablets, Wyeth-Ayerst, approved 8/11/55). Topical use of dapsone in the
`treatment of acne vulgaris, involving twice daily application of ACZONE® (dapsone
`topical gel), 5%, has been found to be safe under NDA 21-794 (approved 07-JUL-
`2005). Under NDA 207154 the sponsor has proposed to market a 7.5% dapsone
`topical product (ACZONE® (dapsone topical gel), 7.5%). ACZONE® (dapsone topical
`gel) 5% and 7.5% products were developed by Allergan under IND 54,440. NDA
`
`Reference ID: 3846193
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`207154 includes letters from Allergan that authorize reference to data associated with
`NDA 21-794 and IND 54,440, which are owned by Allergan.
`3
`Studies Submitted
`3.1
`Studies Reviewed
`A battery of nonclinical studies, which adequately qualifies topical use of dapsone within
`the context of NDA 207154, has been reviewed in association with NDA 21-794. The
`studies include assessment of dapsone in regard to pharmacology, pharmacokinetics,
`pharmacodynamics, safety pharmacology, single and repeated-dose general toxicity
`(involving both oral and topical dermal administration), genetic toxicology, reproductive
`toxicology (assessment of potential to impact fertility/reproductive success of male and
`female rodents, developmental toxicity of rats and rabbits, and prenatal and postnatal
`development, including maternal function, of rodents), carcinogenicity, and special
`toxicology issues. See reviews of NDA 21-794 for details concerning these studies.
`Data obtained in these studies are summarized in section 1.2 of this review. In addition,
`the following study was conducted to assess ACZONE® (dapsone topical gel), 7.5%,
`and related formulations, for potential to induce toxicity when topically applied to the
`skin of rats:
`
`1. AGN-225678: 3-Month Dermal Toxicity Study in Rats, study No. 20053240 (Sponsor
`Reference No. TX14006-TX).
`
`Studies Not Reviewed
`3.2
`The submission contained the reports of several nonclinical studies that were judged to
`add no useful information to the database that is associated with topical dapsone under
`NDA 21-794, including the study:
`
`Dapsone/adapalene: A 3-month study by dermal administration in minipigs with a 14-
`day interim and a 1-month recovery period, study No. TX11018.
`
`This study involved topical application of various formulations that contained 5%
`dapsone and/or 0.3% adapalene. These studies will not be further commented upon in
`this review.
`3.3
`Previous Reviews Referenced
`NDA 21-794 - Nonclinical reviews
`IND 54,440 - Nonclinical reviews
`
`Note: NDA 207154 includes letters from Allergan that authorize reference to data
`associated with NDA 21-794 and IND 54,440.
`
`Reference ID: 3846193
`
`10
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`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Pharmacology
`4
`Primary Pharmacology
`4.1
`See nonclinical reviews of NDA 21-794.
`4.2
`Secondary Pharmacology
`See nonclinical reviews of NDA 21-794.
`4.3
`Safety Pharmacology
`See nonclinical reviews of NDA 21-794.
`5
`Pharmacokinetics/ADME/Toxicokinetics
`5.1
`PK/ADME
`See nonclinical reviews of NDA 21-794.
`5.2
`Toxicokinetics
`See nonclinical reviews of NDA 21-794.
`6
`General Toxicology
`6.1
`Single-Dose Toxicity
`See nonclinical reviews of NDA 21-794.
`6.2 Repeat-Dose Toxicity
`See nonclinical reviews of NDA 21-794 for additional information.
`
`6.2.1 3-Month Topical Rat study
`Study title: AGN-225678: 3-Month Dermal Toxicity Study in Rats
`
`Reference ID: 3846193
`
`11
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Study no.: 20053240 (Sponsor Reference No.
`TX14006-TX)
`Study report location: NDA 207154, DSN 1
`Conducting laboratory and location:
`Date of study initiation: 06-MAR-2014
`GLP compliance: Yes
`QA statement: Yes
`Drug, lot #, and % purity: Formulations containing various
`concentrations of dapsone (AGN-225678)
`in the vehicle of the clinical (to-be-
`marketed) product; one formulation also
`contained
`
`a potential impurity of dapsone):
`
`Identification: Vehicle (0% AGN-225678)
`Batch (Lot) No.: AN14007-020314-01
`
`Identification: 3.75% AGN-225678
`Batch (Lot) No.: AN14007-020414-01
`
`Identification: 7.5% AGN-225678
`Batch (Lot) No.: AN14007-020514-01
`
`Identification: 7.5% AGN-225678 with
`%
`Batch (Lot) No.: AN14007-020614-02
`
`Identification: 15% AGN-225678
`Batch (Lot) No.: AN14007-020614-01
`
`The test articles were manufactured by Allergan using bulk AGN-225678 (lot no.
`2319968) and
`(lot no. 0776/01). The test articles were presumed to be
`100% pure.
`
`Key Study Findings
`Formulations containing dapsone at concentrations ranging from 3.75% to 15% w/w
`were topically applied to rats once daily for approximately 92 days (1 or 2 mL/kg per
`application). In addition, a group of rats received a formulation that contained both
`dapsone and
` No treatment-related deaths occurred, and no dermal
`irritation at the treatment site was observed. Exposure to dapsone trended to correlate
`with reduced mean BW in both genders. Erythrocytic parameters (e.g., RBC, HGB,
`HCT) tended to be reduced in animals exposed to dapsone, particularly males.
`Reticulocyte counts were increased in these animals. Methemoglobinemia was
`observed in treatment groups. Treatment-related effects on mean organ weight
`included trends (which achieved statistical significance in some instances) toward
`
`Reference ID: 3846193
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`increased mean thyroid weight in males and females, increased mean splenic weight in
`males, and decreased mean thymus weight in females. The primary microscopic
`lesions appeared to be related to increased erythrocyte turnover, which was presumably
`secondary to dapsone-induced oxidative damage to erythrocytes. Those changes
`included increased hematopoiesis/erythropoiesis in the bone marrow, spleen, and liver,
`increased iron in the liver, spleen and kidney, pigmentation in the kidneys, and
`congestion in the spleen.
`
`Methods
`
`Reference ID: 3846193
`
`13
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`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Doses:
`
`2 mng of the assigned test article, containing
`either 0% (vehicle control), 3.75%, 7.5%, or 15%
`w/w dapsone (AGN-225678), or 7.5% dapsone
`plus
`(b)(4)%
`(m4)
`mm)
`was topically applied once daily to approximately
`10% of the BSA (an area of shaved dorsal skin).
`The materials were applied for approximately 90
`consecutive days. Beginning on Day 7, the dose
`volume and level of animals that were receiving
`either 15% dapsone or 7.5% dapsone plus
`(”""%
`"M (groups 5 and 6) were
`reduced to 1 mL/kg/day due to adverse clinical
`signs.
`In addition, a similar group of animals
`was shaved and sham operated but received no
`test article (untreated control group). Residual
`control or test articles remained on the skin until
`
`removed with a moistened gauze immediately
`prior to the next dose application. These
`exposures equate to approximately 0, 75, and
`150 mg/kg/day in animals that received 2 mng
`of 0%, 3.75%, and 7.5% w/w dapsone,
`respectively. However, it is unknown what
`portion of each applied dose was subsequently
`removed when the site was wiped clean.
`
`Frequency of dosing:
`Route of administration:
`
`Dose volume:
`
`FormulationNehicle:
`
`Once daily for 91/92 days
`Topical to skin
`2 mng (dose volume of groups 5 and 6
`reduced to 1 mL/kg/day beginning day 7)
`Gel formulation containing DGME,
`, methylparaben, and water
`
`(I!) (4)
`
`1b) (4)
`
`Species/Strain:
`Number/Sex/Group:
`Age:
`Weight:
`
`Satellite groups:
`
`Unique study design:
`
`Rat/Sprague Dawley
`10/sex/group in main study
`Approx. 9 weeks
`Males: Approx. 280 9; Females: Approx. 210 g
`at initiation of dosing
`Yes, 7 additional animals/sex/group used for
`toxicokinetic analysis. Additional 5lsex in
`vehicle control group and 5/sex in groups 5 and
`6 maintained without treatment for 2 weeks
`
`following treatment period prior to sacrifice
`(recovery animals).
`NA
`
`Deviation from study protocol:
`
`In regard to the reduction of dosages for groups
`
`Reference ID: 3846193
`
`14
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`5 and 6, beginning on day 7: Quoting the study
`report, with editing: “AGN-225678-related clinical
`signs were observed at 2 75 mg/kg/day early in
`the study prior to dose level reduction on Day 7
`and included self-injurious behavior of varying
`severity in toxicology study animals, with
`females more affected than males...The skin
`
`lesions were associated with excessive
`
`scratching and the scabs were considered
`secondary to the self-injurious behavior; skin
`lesions were outside the dose administration
`
`sites. In general, the incidence of self-injurious
`behavior was non-dose—dependent but the
`severity of the findings was greater in Groups 5
`and 6 (150/75 mg/kg/day AGN-225678 with
`"m mg/kg/day
`m” and 300/150
`mg/kg/day AGN-225678, respectively). These
`findings correlated with increased activity
`observed at 2 150/75 mg/kg/day AGN-225678,
`which showed a greater incidence in females.
`The increased activity and self-injurious behavior
`necessitated a dose volume reduction from 2
`
`mng to 1 mng for the 150/75 mg/kg/dav
`AGN;)2%5678 with
`"M mg/kg/day m"
`and 300/150 mg/kg/day AGN-225678
`dose groups on Day 7. The self-injurious
`behavior and increased activity resolved by
`Study Day 22.”
`
`Study overview:
`
`AGN-ZZWS
`
`
`
`3. 75".AGN—225678
`75'. AGN—225678
`
`7.5'.@AgN-L‘Sflsmwnh
`
`=Ma1e. F= Fexnale
`'MAnixnalswueeudianizedonDays 92'93
`h AnimalswexeendianizedonDay 106.
`a
`I'KsaxnpleswuetollettedonDays L28 aid90atpredose.l~.--..4— 8— and24—haxxpostdoseimaxals
`BeginningomDayT thedosexuhmeandkwlofooupsSmdiwemdnteddxumthnitdngntwsisfing
`ofselfiinjmiousbdiavimandassotianedfinding:
`
`Observations and Results
`
`Mortality
`
`Reference ID: 38461 93
`
`15
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`Observations. Twice daily.
`
`
`Results. No treatment-related deaths occurred. One high-dose group animal was
`euthanized on day 91 due to a limb fracture, secondary to trauma. Three toxicokinetic
`animals were euthanized during the study due to apparent complications from blood
`collection procedures. None of these deaths were ascribed to treatment with the test
`article. All other animals survived to scheduled sacrifice.
`
`Clinical Signs
`Observations. Weekly.
`
`
`Results. As noted above, “self-injurious behavior” and increased activity, that appeared
`to be related to treatment, were observed, particularly in groups 5 and 6, resulting in
`reduction of the dosages beginning day 7. This behavior resolved by study Day 22. No
`other remarkable observations.
`
`Dermal Irritation
`
`Observations. Daily from days 2 to 7, and 3 times weekly thereafter throughout the
`dosing and recovery periods, according to the method of Draize.
`
`
`Results. Animals that received dapsone (the active formulations) were comparable to
`vehicle-treatment animals in regard to evidence of dermal irritation (primarily graded 0
`or 1).
`
`Body Weights
`Observations. Once weekly, and at termination (animals fasted prior to terminal
`weighing).
`
`
`Results. Exposure to dapsone tended to correlate with reduced mean BW and mean
`BW change (gain) in both genders.
`
`Mean BW data on da 91 mean1SD, o
`
`:
`
`Group
`Material A lied
`
`Males
`% of Vehicle Control
`
`Females
`% of Vehicle Control
`
`1 Control
`61301644 (104)
`31351210 (100)
`
`(None)
`2 Control
`(Vehicle)
`3 Low-Dose
`3.75% Daosone
`
`58961541 (NA)
`
`312.71188 (NA)
`
`
`
`
`
`544.41353 (92.3%)
`
`27591194 (88.2%)***
`
`4 Mid-Dose
`(7.5% Dapsone)
`5 Dapsone;
`(7.5%;
`"'""%)
`6 High-Dose
`15% Da sone
`
`483.3150.5 (82.0%)*** 24521155 (78.4%)***
`
`"M" 50771486 (86.1%)*** 276.61189 (88.5%)***
`
`493.1141.9 (83.6%)*** 24081182 (77.0%)***
`
`Reference ID: 38461 93
`
`16
`
`

`

`NDA 207154
`
`Norman A. See, PhD
`
`***p<0.001 in comparison to group 2. Dosage volume of groups 5 and 6 was reduced
`starting day 7.
`
`Mean bod weiht chane, da 30-91 mean18D, .
`
`:
`
`Group
`(Material Applied)
`1 Control
`None
`
`Males
`(% of Vehicle Control)
`33131624 (109)
`
`Females
`(% of Vehicle Control)
`10451160 (104)
`
`
`
`2 Control
`Vehicle
`
`30531442 (NA)
`
`100.4113.4 (NA)
`
`25931312 (84.9%)*
`
`66.01171 (65.7%)***
`
`20221493 (66.2%)*** 35.11187 (35.0%)***
`
`3 Low—Dose
`(3.75% Dapsone)
`4 Mid-Dose
`(7.5% Dapsone)
`5 Dapsone)
`(7.5%;
`"’""%
`6 High-Dose
`(15% Dapsone)
`*p<0.05 in comparison to group 2. ***p<0.001 in comparison to group 2. Dosage
`volume of groups 5 and 6 was reduced starting day 7.
`
`"'"" 226.0145.6 (74.0%)*** 65.01189 (64.7%)***
`
`210.1139.6 (68.8%)*** 34.11170 (34.0%)***
`
`
`
`Mean BW tended to recover slightly during the 2-week non-dosing period, in “recovery”
`animals.
`
`Feed Consumption
`Observations. Weekly.
`
`
`Results. Treatment-related decreases in mean food consumption were noted in males
`of all treatment groups over Days 1 to 8. Food consumption was comparable in all
`groups during the remainder of the study.
`
`Ophthalmoscopy
`Observations. At baseline and week of termination.
`
`
`Results. No remarkable observations.
`
`Hematology
`Observations. Blood samples collected on day 6 (5/sex/group), day 92/93 (all main-
`study animals), and day 106 (recovery animals), at sacrifice, for hematological analysis.
`Methemoglobin analysis performed at terminal sacrifices only.
`
`
`Results. Erythrocytic parameters (e.g., RBC, HGB, HCT) tended to be reduced in
`animals exposed to dapsone, particularly males. Reticulocyte counts were increased in
`these animals. Methemoglobinemia was observed in treatment groups. These
`observations were consistent with the known effec