CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`207154Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NDA 2071 54
`
`ACZONE (dapsone) Gel, 7.5%
`
`Cross-Discipline Team Leader Review
`
`27, 2016
`Jan .
`Date
`
`From
`Gordana Diglisic, MD
`Sub'ect
`Cross-Disci 0 line Team Leader Review
`
`
`Applicant
`Allergan, Inc.
`Date of Submission
`Letter date: April 28, 2015
`CDER stam date: Aril 28, 2015
`
`PDUFA Goal Date
`February 28, 2016
`
`
`
`ACZONE/
`Proprietary Name /
`
`Established (USAN) names
`(dapsone)
`Dosa_e forms / Stren_ h
`Gel / 7.5%
`Proposed Indication(s)
`Topical treatment of acne vulgaris in patients 12 years of
`age and older
`A roval
`
`Recommended:
`
`1. Introduction
`
`ACZONE (dapsone) Gel, 7.5% is a topical drug product for which the applicant seeks
`approval under Section 505(b)(1) of the Federal Food Drug and Cosmetic Act for the treatment
`of acne vulgaris in patients 12 years of age and older. This application is for a new strength
`and dosing regimen of dapsone. The proposed dosing regimen is once daily.
`
`The active ingredient, dapsone, is synthetic sulfone which is currently marketed in the United
`States (US) in various topical dosage forms (tablets, gel) and is available since 1955. Dapsone
`Tablets for oral use (25 mg and 100 mg) is indicated for the treatment of dermatitis
`herpetifonnis and leprosy. The topical dosage form of dapsone, ACZONE (dapsone) Gel, 5%
`was approved on July 7, 2005, for the treatment of acne vulgaris in patients 12 years of age
`and older (NDA 021794; Allergan, Inc.). The approved dosing regimen is twice daily.
`
`This NDA, NDA 207154, and NDA 21794 were developed under IND 54,440. NDA 207154
`includes letters from Allergan that authorize reference to data associated with NDA 21794 and
`IND 54,440.
`
`This memo will summarize the findings of the multi—disciplinary review team and provide the
`rationale for my recommended action.
`
`Page 1 of 23
`
`Reference ID: 3900096
`
`1
`
`

`

`Cross Discipline Team Leader Review
`NBA 207 l 54
`
`ACZONE (dapsone) Gel, 7.5%
`
`2. Background
`
`ACZONE (dapsone) Gel, 7.5% was developed under IND 054440. During development
`program, the applicant interacted with the Agency at two milestone meetings [End of Phase 2
`Meeting (August 28, 2013) and Pre-NDA Meeting (November 19, 2014)].
`
`At the EOP2 Meeting, the following key points were discussed:
`The Division did not agree with the applicant’s
`The Division stated that
`0') (4)
`
`on»
`
`should be assessed because the proposed dapsone gel, 7.5% differs from the
`approved product, ACZONE Gel, 5%, in both concentration of the active ingredient as
`well as the excipients in the formulation.
`The applicant’s rationale (based on low plasma concentration, historical clinical use
`and relative bioavailability data to ACZONE Gel, 5%) seemed reasonable to support a
`waiver to conduct a thorough QT/QTc study for dapsone gel, 7.5%.
`
`For assessing efficacy for acne indication, the co—primary endpoints regarding the
`lesion counts recommended by the Division are the absolute change in inflammatory
`and non-inflammatory lesion counts from baseline. Facial counts should include
`lesions on the nose.
`
`The proposed secondary efficacy endpoints of percentage change in inflammatory and
`noninflammatory lesion counts from baseline to week 12 are acceptable.
`
`The Agency also provided comments regarding the handling missing data [e.g.
`recommended a more scientifically sound approach, such as multiple imputation or
`modeling approach, instead of the last observation carried forward (LOCF) approach].
`
`A Pre—NDA, the following key points of discussion were:
`The applicant proposed to integrate the two pivotal Phase 3 trials for the ISS and ISE.
`The applicant stated that the four Phase 1 trials (three dermal tolerability studies and
`one PK study) will not be part of the integrated analysis because the design, treatment
`exposures, and objectives of those trials were different than the Phase 3 trials. The
`Agency stated that the proposed approach for the ISS and ISE appeared reasonable.
`In July of 2014, the applicant became aware of a site—specific issue concerning the
`Phase 3 trial, Clinical Study 225678-006, and Principal Investigator Dr. Ellen Marmur
`(Site 16078, located at Marmur Medical in New York City, New York). Allergan
`investigated the issue, which culminated in an on—site assessment 11-12 September
`2014, and confirmed the existence of Good Clinical Practice (GCP) compliance issues
`in the areas of Protocol Adherence and Clinical Study Management. Due to concerns
`over the overall data integrity for Dr. Marmur’s site, Allergan has made the decision to
`exclude all subjects randomized at the site (51 patients) from the Intent-to-Treat (ITT)
`analysis. All subjects seen at Dr. Marmur’s site will be included in the safety analysis
`for the NDA.
`
`Given the potential seriousness of the violations described, data from this investigative
`site should not be included in the primary efficacy analysis. In addition, the Agency
`
`Page 2 of 23
`
`Reference ID: 3900096
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`recommended that the statistical analysis should follow the randomization; therefore, as
`the randomization was stratified by gender and center, the Agency recommended the
`applicant conduct the analyses stratified by both factors with and without pooling.
`Line listings should be provided for any safety data collected at this site, but should not
`be included in analyses.
` The Agency agreed with the applicant proposal of using the gatekeeping approach
`without the Hochberg’s Step-up method when controlling for multiplicity after the
`applicant clarified that the testing would be done sequentially for total lesion counts
`followed by inflammatory and non-inflammatory lesion counts before testing the next
`secondary endpoints.
`
`During the development program, the applicant submitted an Initial Pediatric Study Plan
`(iPSP) on October 17, 2013 requesting a partial waiver of the requirement to perform pediatric
`studies in patients from birth to
` of age for the indication of acne vulgaris.
`The applicant stated that the reason for waiving pediatric studies is that “necessary studies are
`impossible or highly impractical (because, for example, the number of patients in that age
`group is so small or patients in that age group are geographically dispersed) (Section
`505B(a)(4)(B)(i) of the Act)”. The Division issued an Advice Letter confirming agreement
`with the initial agreed PSP on March 24, 2014.
`
`3. CMC/Device
`
`Drug substance:
`ACZONE (dapsone) Gel, 7.5% contains dapsone as the active ingredient. The drug substance,
`dapsone is chemically produced. The chemical name of dapsone is: 4-[(4-
`aminobenzene)sulfonyl]aniline. Dapsone is a white or slightly yellow-white, crystalline
`powder that has an empirical formula of C12H12N2O2S and a molecular weight of 248.30.
`Dapsone melts in the temperature range of 175 – 181°C and it is very slightly soluble in water,
`freely soluble in acetone, sparingly soluble in alcohol, and dissolves freely in dilute mineral
`acids. Detailed CMC information for dapsone is referred to DMF
` The DMF has been
`reviewed by CMC reviewer and found adequate in supporting the use of the drug substance in
`the NDA. (Review by Martin T. Haber, PhD.; Branch II; Division of New Drug API/ONDP;
`dated December, 18, 2015)
`
`Drug product:
`ACZONE (dapsone) Gel, 7.5%, is off-white to yellow gel with suspended dapsone particles.
`Each gram of ACZONE (dapsone) Gel, 7.5%, contains 75 mg of dapsone in a gel of diethylene
`glycol monoethyl ether, methylparaben, acrylamide/sodium acryloyldimethyl taurate
`copolymer, isohexadecane, polysorbate 80, and purified water.
`The composition of ACZONE (dapsone) Gel, 7.5% is described in the following table:
`
`Page 3 of 23
`
`Reference ID: 3900096
`
`3
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`
`ACZONE (dapsone) Gel, 7.5%
`
`Table 1: Composition of ACZONE (dapsone) Gel, 7.5%
`
`(9’. wlw)
`
`Quality
`Standard
`
`Concentration
`
`There are no novel excipients used in the drug roduct formulation. There is no overage of the
`API. All excipients are compendial exc
`t the
`. The CMC information is
`provided in DMF- . The DMF
`was reviewed on 12/14/2015 and found to be
`adequate.
`
`The identity, strength, purity including microbial limits, and quality of the drug product are
`deemed assured by the drug product specification.
`
`
`
`Container Closure System:
`ACZONE ( . sone Gel, 7.5%, is nackaged in a non-metered airless pump container closure
`system. The
`airless p u . container
`
`em consrsts of . 1‘! o ylene
`
`
`
`
`The details on this container
`
`
`
`c osure system are prov1 ‘ a in DMF
`. A letter of authorization for
`
`this DMF was provided. The product will be available in fllree differentsizes (30 fi 60
`
`. Additionally, 3 gram professional samples packaged in an
`are also available.
`
`and 90
`
`The extractable and leachable study demonstrated that there is virtually no risk of leachables
`
`from the airless
`
`s stem. The container closure s stem is a uateg
`
`ting
`The expiration
`period of 24 months is recommended for the drug product when stored at controlled room
`temperature based on the 12-month long-term and 6-month accelerated stability data obtained
`from 3 registration batches of the drug product.
`
`Special Product Quality Labeling Recommendations: Protect from freezing.
`
`The CMC reviewer concluded that the applicant has submitted suflicient information to assure
`the identity, strength, purity, and quality of the drug product.
`
`Page 4 of 23
`
`Reference ID: 3900096
`
`4
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`The facility review team from the Office of Process and Facility has issued an “Approval”
`recommendation for the facilities involved in this application.
`
`The reader is referred to the comprehensive reviews by Hitesh Shroff, Ph.D.; Branch V;
`Division of New Drug Products II/ONDP/OPQ dated December 18, 2015; Yuesheng Ye,
`Ph.D.; Branch VIII; Division of Process Assessment III/OPF; Sherry (Xiaohui) Shen, CSO;
`Branch III; Division of Inspection Assessment/OPF, dated January 4, 2016; Vidula Kolhatkar,
`Ph.D., Branch II, Division of Biopharmaceutics/ONDP dated January 5, 2016; and Elizabeth
`Bearr, PhD. BranchI, Division of Microbiology Assessment/OPF dated January 5, 2016;
`
`Label/Labeling recommendation:
`
`Immediate container labels:
`The 30 g, 60 g and 90 g pump labels should be revised to include the following information:
` Display “Lot:” and “Exp:”
` Display a barcode
` Add the following statement in the storage condition description
` “[See USP Controlled Room Temperature]”
` List ingredients as shown below:
`“Each gram of gel contains 75 mg of dapsone, diethylene glycol monoethyl ether,
`methyl paraben, acrylamide/sodium acryloyldimethyl taurate copolymer,
`isohexadecane, polysorbate 80 and purified water.”
`
`The 3 g sample tube labels should be revised to include the following information:
` Display “Lot:” and “Exp:”
` Add the following statement in the storage condition description
`“[See USP Controlled Room Temperature]”
`Include “Manufactured for: and by:” same as pump labels.
`
`
`
`Carton labels:
`The 8 x 3 g sample tubes, 30 g, 60 g and 90 g carton labels should be revised to include the
`following information:
` Add the following statement in the storage condition description
`“[See USP Controlled Room Temperature]”
` List ingredients as shown below:
`“Each gram of gel contains 75 mg of dapsone, diethylene glycol monoethyl ether,
`methyl paraben, acrylamide/sodium acryloyldimethyl taurate copolymer,
`isohexadecane, polysorbate 80 and purified water.”
`
`The 8 x 3 g sample tube carton labels should be revised to include the following information:
` Display “Lot:” and “Exp:”
`
`Page 5 of 23
`
`Reference ID: 3900096
`
`5
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`Physician Insert
`“Highlights” Section
`This section should be revised as follows:
` Display the drug product title as shown below:
`ACZONE (dapsone) gel, for topical use
` Delete the following statement:
`“Each gram of ACZONE Gel, 7.5% contains 75 mg of dapsone in an off-white to
`yellow gel”
`
`3 “Dosage Forms and Strength” Section
`This section should be revised as follows:
` Revise the dosage form description as shown below:
`“Each gram of ACZONE Gel, 7.5% contains 75 mg of dapsone in an off-white to
`yellow gel with suspended particles.”
`
`11 “Description”
`This section should be revised as follows:
` Revise the drug product title as shown below:
`ACZONE (dapsone) gel, 7.5%
` Replace the chemical name with the following IUPAC name:
`4-[(4-aminobenzene)sulfonyl] aniline
` The molecular weight of dapsone should be revised to “248.30”
`
`16 “How supplied/storage and handling”
`This section should be revised as follows:
` The following drug product and container closure description should be added.
`“ACZONE gel is an off-white to yellow gel with suspended particles It is supplied
`in airless pumps containing polypropylene bottles with high density polyethylene
`pistons.”
` The following statement should be added to the storage condition
`“[See USP Controlled Room Temperature]”
`
`4. Nonclinical Pharmacology/Toxicology
`
`Dapsone has been evaluated in a battery of nonclinical studies that included evaluation of
`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. These studies have been reviewed under NDA 21794 (refer to the
`
`Page 6 of 23
`
`Reference ID: 3900096
`
`6
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`CDER nonclinical reviews of NDA 21794 and IND 54440 for summary and interpretation of
`the nonclinical data). This application includes letters from Allergan that authorize reference to
`data associated with NDA 21794 and IND 54440.
`
`In addition, the Study “AGN-225678: 3-Month Dermal Toxicity Study in Rats” (study No.
`20053240) was conducted to assess ACZONE® (dapsone) Gel, 7.5% for potential to induce
`toxicity when topically applied to the skin of rats.
`
`The pharmacology-toxicology reviewer, Norman A See, Ph.D. summarized the pivotal data
`reviewed under NDA 21794:
`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 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
`
`Page 7 of 23
`
`Reference ID: 3900096
`
`7
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`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
`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.
`
`Per pharmacology-toxicology reviewer, key findings from the Study AGN-225678 (3-Month
`Dermal Toxicity Study in Rats) are summarized:
`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 body weights 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
`increased mean thyroid weight in males and females, increased mean splenic weight in
`males, and decreased mean thymus weight in females. The primary microscopic
`
`Page 8 of 23
`
`Reference ID: 3900096
`
`8
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`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.
`
`Impurities/Excipients
`The proposed specifications for organic impurities of the drug product are acceptable; 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 0.2% of the label strength of
`the API). The product contains no novel excipients.
`
`The reader is referred to the comprehensive review by Norman A See, Ph.D. dated November
`12, 2015.
`
`There are no outstanding pharmacology-toxicology issues.
`
`The pharmacology-toxicology reviewer, Norman A See, Ph.D., recommended Approval of this
`application (review dated November 12, 2015).
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The applicant conducted one pharmacokinetic (PK) trial , Study 225678-004, to compare the
`PK of ACZONE (dapsone) Gel, 7.5% (formulation 11080X, to-be-marketed formulation)
`applied once-daily (QD) for 28 days with ACZONE (dapsone) Gel, 5% applied twice-daily
`(BID) for 28 days in subjects (≥16 years of age) with moderate acne vulgaris (sore of 3 on
`GAAS). For each application, study product (2 grams) was topically applied (by study staff) to
`the face, upper chest, upper back, and shoulders corresponding to a treatment area of
`approximately 1000 cm2.
`
`Plasma concentrations of dapsone, its metabolites N-acetyl dapsone (NAD) and dapsone
`hydroxylamine (DHA), and N-formyl dapsone (NFD) were collected prior to administration of
`the morning dose on days 1, 7, 14, 18, 21, 26, 27, on day 28 (pre-dose, 1, 2, 4, 6, 8, 10, and 12
`hours post-dose), on days 29 to 32 (24, 30, 36, 48, 72, and 96 hours after the last dose), on day
`35 (168 hours after the last dose), and early exit (if applicable), and were determined using
`validated liquid chromatography- tandem mass spectrometry (LC-MS/MS) methods.
`
`Mean C troughs for plasma dapsone were similar for Days 7 - 28 suggesting steady state
`PK was achieved by Day 7 and maintained until Day 28. PK parameters for plasma dapsone
`following 28 days of dosing are shown in Table 2.
`
`Page 9 of 23
`
`Reference ID: 3900096
`
`9
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`Table 2: Summary of plasma dapsone PK parameters following dosing on Day 28
`PK parameter
`Dapsone Gel, 7.5% QD
`ACZONE Gel, 5%
`(TBM formulation 11080X)
`BID N=18
`N=19
`
`C max (ng/mL)
`AUC0-12 (ng*h/mL)
`AUC0-24 (ng*h/mL)
`Source Clinical Pharmacology Review (p.7, Table 3)
`
`13.0 ± 6.8
`NA
`282 ± 146
`
`17.6 ± 6.7
`186 ± 71
`379 ± 142
`
`The Clinical Pharmacology reviewer concluded the following:
`“Relative to Aczone Gel, 5%, daily systemic exposure of dapsone, defined by the geometric
`mean ratio for maximum plasma concentration (C max) and area under the concentration-time
`curve from time 0 to 24 hours postdose (AUC0-24), was approximately 28.6% and 28.7%
`lower for formulation 11080X, respectively. Based on the 90% CIs for C max and AUC0-24,
`these differences were statistically significant; however, the upper limit of 90% CI were close
`to 100% (93% for C max and 92% for AUC0-24) and therefore the statistically significantly
`lower systemic exposure may not be clinically meaningful.”
`
`Trial 225678-004 included pediatric subjects ≥16 years of age (7/19 in ACZONE Gel, 7.5%
`group and 6 /18 in ACZONE Gel, 5% group). The data showed similar systemic exposure to
`dapsone and its metabolites DHA and NAD between subjects 16 to <18 years of age and those
`≥18 years of age. In addition, because systemic exposure of dapsone in patients 12 – 15 years
`of age is similar to those 16 years and older (per ACZONE Gel, 5% labeling), additional PK
`trial in subjects ages 12 -15 years was not requested for ACZONE Gel, 7.5%.
`Long-term safety study was not conducted with ACZONE Gel, 7.5%. However, in a long-term
`safety study of ACZONE Gel, 5%, periodic blood samples were collected up to 12 months to
`determine systemic exposure of dapsone and its metabolites. Based on the measurable dapsone
`concentrations from 408 subjects, neither gender nor race appeared to affect the
`pharmacokinetics of dapsone. Exposure to dapsone were approximately the same between the
`12-15 years (N=155) and >16 years (N=253) age groups. Additionally, there was no evidence
`of increasing systemic exposure to dapsone over the time.
`
`Clinical Pharmacology Team Labeling Recommendations:
`
`
`The following changes are recommended for sections 5, 7 and 12 of the label. Deletions
`are noted as strikethrough and additions are noted as double underline.
`5 WARNINGS AND PRECAUTIONS
`5.1 Hema
`Oral dapsone treatment has produced dose-related hemolysis and hemolytic anemia.
`Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are more prone to
`
`Page 10 of 23
`
`Reference ID: 3900096
`
`10
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NBA 207154
`
`ACZONE (dapsone) Gel, 7.5%
`
`hemolysis with the use of certain drugs. G6PD deficiency is most prevalent in populations
`of African, South Asian, Middle Eastern, and Mediterranean ancestry.
`
`In clinical studies, there was no evidence of clinically relevant hemolysis or hemolytic
`anemia in patients treated with topical dapsone. Some patients with GGPD deficiency using
`twice dail
`sone el 5% develo
`laborato
`chan es s
`estive of mild hemol sis.
`
`
`
`
`
`
`
`Combination of topical dapsone with trimethoprim/sulfamethoxazole (TMP/SMX) may
`increase the likelihood of hemolysis in patients with G6PD deficiency.
`
`
`
`IfSi? andfltoms suiiestiveofhemolfi'c anemia_ occur,
`
`ACZONE“ Gel, 7.5%— in patients who are takin oral dapsone or
`antimalarial medications because ofthe potential for‘ hemolytic
`
`reactions.
`
`7
`
`DRUG INTERACTIONS
`
`
`
`Noformaldrug-druginteractionstudieswereconductedwithACZONEIGel,7.5%.
`
`
`
`Trimethoprim—Sulfamethoxazole
`7.1
`A drug-drug interaction study evaluated the efl'ect of the use of dapsone gel, 5% in
`combination with double strength (160 mg/800 mg) trimethoprim-sulfamethoxazole
`('I'MP/SMIQ. During co—administration, systemic levels of TMP and SMX were essentially
`unchanged, however, levels of dapsone and its metabolites increased in the presence of
`TMP/SMX. The systemic exposure from ACZONE0 Gel, 7.5% is expected to be about 1%
`of that from the 100 mg oral dose, even when co-administered with TMP/SMX.
`
`Topical Benzoyl Peroxide
`7.2
`Topical application of dapsone gel followed by benzoyl peroxide in patients with acne
`vulgaris may result in a temporary local yellow or orange discoloration of the skin and
`facial hair.
`
`7.3
`
`Drug Interactions with Oral Dagsone
`
`Page 11 of23
`
`Reference ID: 3900096
`
`11
`
`

`

`Cross Discipline Team Leader Review
`NBA 207154
`
`ACZONE (dapsone) Gel, 7.5%
`
`Certain concomitant medications (such as rifm‘, anticonvulsants, St. John’s wort) may
`increase the formation of
`sone h dro
`lamine a metabolite of da sone associated
`
`with hemolxsis. With oral dapsone treatment, folic acid antagonists such as
`m‘ethamine have been noted to Essiblx increase the likelihood of hematolog'c
`reactions.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`- The mechanism of action of dapsone gel in treating acne vulgaris is not known.
`
`12.3
`
`Pharmacokinetics
`
`In a pharmacokinetic stu ,male and female sub'ects 16 years of age or older with acne
`
`
`-r_eceived 2 grams of ACZONE Gel,
`
`
`
`
`
`-. On Day 28, the mean dapsone maximum plasma
`
`concentration Cmax and area under the concentration-time curve from 0-24 hours u
`
`
`dose iAUCo_24h! were 13.0 i 6.8 anL and
`
`282 i 146 ngh/mL,eresgtivelx
`
`
`
`
` _rhe systemic exposes sens
`
`ACZONE." Gel, 7.5% is expected to be about 1% of that from a 100 mg oral dose.
`
`The applicant proposed to omit section 7.3 and 7.4 of ACZONE Gel, 5% labeling regarding
`concomitant use with drugs that induce methemoglobinemia. As per clinical pharmacology
`reviewer, based on the 90% C1s for C m and AUCO-24, these differences were statistically
`significant; however, the upper limit of 90% CI were close to 100% (93% for C m and 92%
`for AUCO-24). The statistically significantly lower systemic exposure may therefore not be
`clinically meaningful and a caution regarding concomitant use of drugs that induce
`methemoglobinemia that is pertinent for ACZONE Gel, 5% is also understood to be pertinent
`for ACZONE Gel, 7.5%. Therefore, information from Section 7.3 and Section 7.4 for
`ACZONE Gel, 5% labeling will be included into the labeling for ACZONE Gel, 7.5%.
`
`7.4 Concomitant Use with Drugs that Induce Methemoglobinemia
`Concomitant use of ACZOQE’ Gel, 7.5% with drug; that induce methemoglobinemia such as
`sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chlorogu_m'e, dapsone,
`naphthalene, nitrates and nitrites, nitrofurantoin, nitroglyceg, nitrogrusside, 2%111118,
`
`Page 12 of 23
`
`Reference ID: 3900096
`
`12
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`para‐aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine may
`
`increase the risk for developing methemoglobinemia [see Warnings and Precautions (5.1)].
`
`The reader is referred to the comprehensive review by Doanh C Tran, PhD. for a full
`discussion of the clinical pharmacology data (dated January 11, 2016).
`
`The clinical pharmacology reviewer, Doanh C Tran, PhD., Office of Clinical Pharmacology/
`Division of Clinical Pharmacology 3, recommended Approval of this application pending
`agreement on recommended labeling changes.
`
`The following post marketing requirement (PMR) is recommended:
`An open-label study to assess safety, pharmacokinetics, and treatment effect of
`ACZONE Gel, 7.5% in 100 pediatric subjects age 9 years to 11 years 11 months with
`acne vulgaris. Pharmacokinetic assessments will be done in at least 16 evaluable
`subjects under maximal use conditions.
`
`6. Clinical Microbiology
`
`The applicant did not conduct microbiologic studies.
`
`7. Clinical/Statistical- Efficacy
`
`The applicant submitted data from pivotal trials, 225678-006 (Trial 006) and 225678-007
`(Trial 007), to establish the effectiveness of their product, ACZONE (dapsone) Gel, 7.5%,
`applied once daily for 12 weeks in the treatment of acne vulgaris.
`
`The Trial 006 and Trial 007 were identically-designed, double-blind, randomized, multicenter,
`vehicle- controlled, parallel-group, Phase 3 trials. The population enrolled was subjects 12
`years of age or older with moderate acne vulgaris defined as sore of 3 (moderate) on a Global
`Acne Assessment Score (GAAS) scale, 20-50 inflammatory lesions (papules and pustules) and
`30-100 non-inflammatory lesions (open comedones and closed comedones) on the face. Each
`trial was designed to enroll and randomize approximately 2180 subjects. Eligible subjects were
`randomized to one of the following treatment in a 1:1 ratio: ACZONE Gel, 7.5% or Vehicle
`Gel. Randomization was stratified by gender and center. Subjects applied study product once
`daily for 12 weeks. Subjects were evaluated at the following study visits: screening, baseline
`(Day 1) and Weeks 1, 2, 4, 8, and 12. An overview of the trials is presented in Table 3.
`
`Page 13 of 23
`
`Reference ID: 3900096
`
`13
`
`

`

`Cross Discipline Team Leader Review
`NDA 207154
`ACZONE (dapsone) Gel, 7.5%
`
`Table 3: Clinical Study Overview
`
`Trial
`
`006
`
`007
`
`Treatment Arms
`Study Population
`Location
`ACZONE Gel, 7.5%
`U.S. (96 centers) &
`Aged 12 years and older,
`Canada (9 centers)
`GAAS of 3 (moderate), 20
`Vehicle Gel
`to 50 inflammatory lesions,
`ACZONE Gel, 7.5%
`U.S. (93 centers) &
`and 30 to 100 non-
`Canada (10 centers)
`inflammatory lesions
`Vehicle Gel
`*Excluding subjects from center 16078 (25 on ACZONE Gel, 7.5% and 26 on Vehicle Gel).
`Source: Statistical Review (p.5, Table 2)
`
`Number of
`Subjects
`1044*
`1058*
`1118
`1120
`
`Dates
`11/27/2013 –
`10/28/2014
`11/27/2013 –
`10/21/2014
`
`Trial 006 enrolled and randomized a total (excluding center 16078) of 2102 subjects (1044 to
`ACZONE Gel and 1058 to Vehicle) from 105 centers (96 in U.S. and 9 in Canada). Trial 007
`enrolled and randomized a total of 2238 subjects (1118 to ACZONE Gel and 1120 to Vehicle)
`from 103 centers (93 in U.S. and 10 in Canada). The demographics and baseline disease
`characteristics were generally balanced across the treatment arms within each trial and similar
`between each trial. The mean age was 20 years in the both treatment arms. The majority of the
`subjects were White (> 54%). Slightly more subjects were female (>55%). All subjects had
`baseline disease severity “moderate” (GAAS 3) with exception of one subject in Trial 006 who
`had a GAAS of 4