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

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA: 207154
`Brand Name
`Generic Name
`Primary Reviewer
`Secondary Reviewer
`OCP Division
`OND division
`Sponsor
`Submission Type; Code
`Formulation; Strength(s)
`Indication
`
`Table of Contents
`
`Submission Date(s): 4/28/2015
`Aczone Gel, 7.5%
`Dapsone
`Doanh Tran, Ph.D.
`Capt. E. Dennis Bashaw, Pharm.D.
`Division of Clinical Pharmacology 3
`Division of Dermatology and Dental Products
`Allergan
`Original NDA
`Gel, 7.5%
`Topical treatment of acne vulgaris in patients 12
`years of age and older
`
`1 Executive Summary ......................................................................................................2
`1.1 Recommendation....................................................................................................2
`1.2
`Phase IV Requirements and Commitments............................................................2
`1.3
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings..2
`2 Question-Based Review................................................................................................5
`2.1 General Attributes ..................................................................................................5
`2.2 General Clinical Pharmacology..............................................................................5
`2.3
`Intrinsic Factors......................................................................................................8
`2.4
`Extrinsic Factors.....................................................................................................8
`2.5 General Biopharmaceutics .....................................................................................9
`2.6 Analytical .............................................................................................................10
`3 Detailed Labeling Recommendations .........................................................................11
`4 Appendix.....................................................................................................................14
`4.1
`Individual Study Reviews ....................................................................................14
`
`Reference ID: 3871849
`
`1
`
`

`

`1 Executive Summary
`The applicant submitted an application for a new gel formulation of Aczone (dapsone)
`Gel, 7.5%, for topical treatment of acne vulgaris in patients 12 years of age and older.
`Dapsone is a synthetic sulfone with antimicrobial and anti-inflammatory properties.
`Dapsone is the same drug substance contained in Aczone (dapsone) Gel, 5% (NDA
`21794), which is currently approved for twice daily application for the topical treatment
`of acne vulgaris. The recommended dosage and administration of Aczone Gel, 7.5% will
`be to apply a thin layer to the entire face once daily. In addition, a thin layer may be
`applied to other affected areas once daily.
`
`The clinical development program comprised 2 pivotal phase 3 studies, and 4 phase 1
`studies including a pharmacokinetic (PK) study in patients with moderate acne vulgaris
`(Study 225678-004) and 3 dermal tolerability studies in healthy subjects. The
`development program was based on the target population of patients 12 years of age and
`older. The Division of Dermatology and Dental Products recommends that for the acne
`indication, the target age be 9 years of age and older. Therefore, a post marketing
`requirement to assess PK in subjects 9 years to 11 years 11 months is included in section
`1.2 of this review.
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 3 finds NDA
`207154 acceptable pending agreement on recommended labeling changes.
`
`1.2 Phase IV Requirements and Commitments
`
`The following post marketing requirement 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.
`
`1.3
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`
`Bioavailability:
`Study 225678-004 compared the PK of dapsone gel, 7.5% (formulation 11080X, to-be-
`marketed formulation) applied once-daily (QD) for 28 days with Aczone Gel, 5% applied
`twice-daily (BID) for 28 days in subjects (≥16 years of age) with acne vulgaris. Study
`medication was applied for 28 days to the skin of male and female patients with moderate
`acne vulgaris by the clinical site staff. For each application, study treatment (2 grams)
`was topically applied to the face, upper chest, upper back, and shoulders corresponding to
`a treatment area of approximately 1000 cm2.
`
`Reference ID: 3871849
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`2
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`

`

`Mean Ctroughs 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 1.
`
`Relative to Aczone Gel, 5%, daily systemic exposure of dapsone, defined by the
`geometric mean ratio for maximum plasma concentration (Cmax) 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 Cmax and AUC0-24, these differences were statistically significant;
`however, the upper limit of 90% CI were close to 100% (93% for Cmax and 92% for
`AUC0-24) and therefore the statistically significantly lower systemic exposure may not
`be clinically meaningful.
`
`Table 1: Summary of plasma dapsone PK parameters
`PK parameter
`Dapsone Gel, 7.5% QD
`(TBM formulation 11080X)
`N=19
`
`Aczone Gel, 5% BID
`N=18
`
`Cmax (ng/mL)
`AUC0-12 (ng*h/mL)
`AUC0-24 (ng*h/mL)
`
`13.0 ± 6.8
`NA
`282 ± 146
`
`17.6 ± 6.7
`186 ± 71
`379 ± 142
`
`Drug-drug interactions:
`The sponsor proposed to omit information contained in section 7.3 of Aczone Gel, 5%
`label regarding potential interaction with oral dapsone and enzyme inducers such as
`rifampin, anticonvulsants, St. Johns’ wort or folic antagonist such as pyrimethamine that
`may lead to increased risk of hemolysis. Compared to oral dapsone, the risk of drug
`interactions is anticipated to be low due to much lower systemic concentration observed
`following topical dosing of Aczone Gel, 5% and 7.5%. However, because risk of
`methemoglobinemia has been reported following treatment with Aczone gel, 5% (Aczone
`Gel, 5% product label), such risk cannot be ruled out for dapsone gel, 7.5%. In addition,
`risk of hemolysis due to dapsone or its metabolites cannot be ruled out. Therefore, this
`reviewer concurs with the clinical team’s recommendation that the interactions potential
`as noted in section 7.3 of the Aczone Gel, 5% label should be included in the label for
`dapsone gel, 7.5%.
`
`Pediatrics:
`Pharmacokinetic trial 225678-004 included pediatrics ≥16 years of age (7 of 19 in
`dapsone gel, 7.5% group and 6 of 18 in Aczone Gel, 5% group). Aczone Gel, 5% label
`indicates that systemic exposure is pediatrics 12 – 15 years of age is similar to those 16
`years and older. Therefore, additional PK trial in subjects ages 12 -15 was not requested
`for dapsone gel, 7.5%.
`
`Because acne vulgaris do occur in children younger than 12 years of age, the Division of
`Dermatology and Dental Products recommends evaluation of subjects down to 9 years of
`age. As part of a post marketing requirement, the Applicant should evaluate the
`
`3
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`Reference ID: 3871849
`
`

`

`pharmacokinetic properties of dapsone gel, 7.5% in subjects 9 years to 11 years 11
`months of age with acne vulgaris under maximal use conditions. The plan was discussed
`with the pediatric review committee (PeRC) on 12/2/2015 and the PeRC agreed.
`
`Clinical vs. to-be-marketed formulation:
`The to-be-marketed dapsone gel, 7.5% formulation (11080X) was used in all clinical
`studies, including the 2 phase 3 trials and the 4 phase 1 studies.
`
`Method validation:
`Human plasma concentrations of dapsone, N-formyl dapsone (NFD), N-acetyl dapsone
`(NAD), and dapsone hydroxylamine (DHA) were measured using validated liquid
`chromatography tandem mass spectrometry methods (LC-MS/MS).
`
`Reference ID: 3871849
`
`4
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`

`

`
`2 Question-Based Review
`
`2.1 General Attributes
`
`2.1.1 What is dapsone?
`Dapsone is a sulfone with anti-inflammatory and antimicrobial properties. Dapsone
`(Molecular formula: C12H12N2O2S; MW: 248.30) is a white to off-white fine crystalline
`powder with the following structural formula:
`
`Aczone Gel, 7.5% is an off-white to yellow aqueous gel with suspended drug particles for
`topical dermatologic use.
`
`2.1.2 What are the proposed indication and dosing regimen for dapsone gel, 7.5%?
`Aczone (dapsone) Gel, 7.5%, is indicated for the topical treatment of acne vulgaris in
`patients 12 years of age and older. The proposed dosing regimen is: after the skin is
`gently washed and patted dry, apply approximately a pea-sized amount of Aczone Gel,
`7.5%, in a thin layer to the entire face once daily. In addition, a thin layer may be applied
`to other affected areas once daily. Rub in Aczone Gel, 7.5%, gently and completely.
`
`2.1.3 What is acne vulgaris?
`Acne vulgaris is the most common dermatological disorder in the US. Acne vulgaris is a
`complex skin disorder involving multiple abnormalities of the pilosebaceous unit,
`including 1) hyperkeratinization, 2) increased sebum production, 3) bacterial proliferation,
`and 4) inflammation. The face, anterior trunk, and upper back are the most commonly
`affected areas due to a greater concentration of sebaceous glands in these areas. Clinically,
`acne is graded according to the number and types of lesions present: open and closed
`comedones, inflammatory papules, pustules, cysts, nodules, and even scarring may be
`seen. Current topical and systemic therapies recommended for the treatment of acne
`include dapsone, retinoids, benzoyl peroxide, antibiotics, and hormonal therapy.
`However, most anti-acne medications do not act against all of the pathophysiological
`features of acne, so combination therapy is often used.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What were the design features of the clinical pharmacology and clinical trials
`used to support dapsone gel, 7.5%?
`The clinical development program comprised 2 pivotal phase 3 studies (Studies 225678-
`006 and 225678-007), and 4 phase 1 studies including a pharmacokinetic study in
`patients with moderate acne vulgaris (Study 225678-004) and 3 dermal tolerability
`
`5
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`Reference ID: 3871849
`
`

`

`studies in healthy subjects (Studies 225678-009, 225678-010, and 225678-011). An
`overview of the clinical development program is shown in Table 2.
`
`Table 2: Clinical development program
`
`2.2.2 What is the systemic bioavailability of dapsone gel, 7.5% under maximal use
`conditions and what is the relative bioavailability compared to Aczone
`(dapsone) Gel, 5%?
`
`Study 225678-004 compared the PK of dapsone gel, 7.5% (formulation 11080X, to-be-
`marketed formulation) applied once-daily for 28 days with Aczone Gel, 5% applied
`twice-daily for 28 days in subjects (≥16 years of age) with acne vulgaris. Study
`medication was applied for 28 days to the skin of male and female patients with moderate
`acne vulgaris by the clinical site staff. For each application, study treatment (2 grams)
`was topically applied to the face, upper chest, upper back, and shoulders corresponding to
`a treatment area of approximately 1000 cm2.
`
`Mean Ctroughs 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 treatment with dapsone gel, 7.5% and Aczone Gel, 5% for 28 days are
`shown in Table 3 and the PK profile for dapsone gel, 7.5% is shown in Figure 1. PK
`parameters and PK profile for metabolites dapsone hydroxylamine (DHA) and N-acetyl
`dapsone (NAD) can be found in the Appendix. Plasma concentration of metabolite N-
`formyl dapsone (NFD) were measured but found to be below the lower limit of
`quantitation (0.100 ng/mL) for all subjects at all timepoints.
`
`6
`
`Reference ID: 3871849
`
`

`

`Relative to Aczone Gel, 5%, daily systemic exposure of dapsone, defined by the
`geometric mean ratio for maximum plasma concentration (Cmax) 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 Cmax and AUC0-24, these differences were statistically significant;
`however, the upper limit of 90% CI were close to 100% (93% for Cmax and 92% for
`AUC0-24) and therefore the statistically significantly lower systemic exposure may not
`be clinically meaningful.
`
`Table 3: Summary of plasma dapsone PK parameters following dosing on Day 28
`PK parameter
`Dapsone gel, 7.5% QD
`Aczone Gel, 5% BID
`(TBM formulation 11080X)
`N=18
`N=19
`
`Cmax (ng/mL)
`AUC0-12 (ng*h/mL)
`AUC0-24 (ng*h/mL)
`
`13.0 ± 6.8
`NA
`282 ± 146
`
`17.6 ± 6.7
`186 ± 71
`379 ± 142
`
`Figure 1: Mean Plasma Concentrations of Dapsone (ng/mL) on Day 28 Following
`Once Daily Topical Application of dapsone gel, 7.5% (Formulation 11080X)
`
`Note: This trial also include 2 additional treatment arms of other dapsone gel, 7.5%
`formulations, namely formulations 11078X and 11079X; however, these are pilot
`formulations that were not developed and they are not discussed further here. Please see
`Appendix for additional details.
`
`7
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`Reference ID: 3871849
`
`

`

`2.3
`
`Intrinsic Factors
`
`2.3.1 What is the systemic exposure of dapsone gel, 7.5% in pediatrics?
`Pharmacokinetic trial 225678-004 included pediatrics ≥16 years of age (7 of 19 in
`dapsone gel, 7.5% group and 6 of 18 in Aczone Gel, 5% group). The data showed similar
`systemic exposure to dapsone and its metabolites DHA and NAD between subjects 16-
`<18 years of age and those ≥18 years of age (Figure 2). In addition, Aczone Gel, 5% label
`indicates that systemic exposure is pediatrics 12 – 15 years of age is similar to those 16
`years and older. Therefore, additional PK trial in subjects ages 12 -15 was not requested
`for dapsone gel, 7.5%.
`
`Figure 2: Comparison of Plasma Concentrations of Dapsone, Dapsone
`Hydroxylamine, and N-Acetyl Dapsone (ng/mL) on Day 28 in subjects ≥18 years of
`age and subjects 16-17 years of age (all treatment groups combined)
`
`Because acne vulgaris do occur in children younger than 12 years of age, the Division of
`Dermatology and Dental Products recommends evaluation of subjects down to 9 years of
`age. As part of a post marketing requirement, the Applicant should evaluate the
`pharmacokinetic properties of dapsone gel, 7.5% in subjects 9 years to 11 years 11
`months of age with acne vulgaris under maximal use conditions. The plan was discussed
`with the pediatric review committee (PeRC) on 12/2/2015 and the PeRC agreed.
`
`2.3.2 What is the effect of sex on the systemic exposure of dapsone gel, 7.5%?
`A comparison of the systemic exposure of dapsone and its metabolites DHA and NAD
`for all treatment arms combined showed that there was similar systemic exposure in male
`and females (Figure 3). This is consistent with the findings noted in the current label for
`Aczone Gel, 5%.
`
`Figure 3: Comparison of Plasma Concentrations of Dapsone, Dapsone
`Hydroxylamine, and N-Acetyl Dapsone (ng/mL) on Day 28 in males and females (all
`treatment groups combined)
`
`Reference ID: 3871849
`
`8
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`

`

`2.4 Extrinsic Factors
`The applicant did not provide any information on the effect of extrinsic factors on the PK
`of dapsone gel, 7.5%. Because the systemic bioavailability of dapsone gel, 7.5% is
`similar to approved Aczone Gel, 5%, a request for additional studies is not warranted.
`
`Drug-drug interactions:
`The sponsor proposed to omit information contained in section 7.3 of Aczone Gel, 5%
`label regarding potential interaction with oral dapsone and enzyme inducers such as
`rifampin, anticonvulsants, St. Johns’ wort or folic antagonist such as pyrimethamine that
`may lead to increased risk of hemolysis. Compared to oral dapsone, the risk of drug
`interactions is anticipated to be low due to much lower systemic concentration observed
`following topical dosing of Aczone Gel, 5% and 7.5%. However, because risk of
`methemoglobinemia has been reported following treatment with Aczone gel, 5% (Aczone
`Gel, 5% product label), such risk cannot be ruled out for dapsone gel, 7.5%. In addition,
`risk of hemolysis due to dapsone or its metabolites cannot be ruled out. Therefore, this
`reviewer concurs with the clinical team’s recommendation that the interactions potential
`as noted in section 7.3 of the Aczone Gel, 5% label should be included in the label for
`dapsone gel, 7.5%.
`
`2.5 General Biopharmaceutics
`
`2.5.1 What is the formulation composition of dapsone gel, 7.5%?
`Aczone Gel, 7.5% (11080X) is an off-white to yellow gel with suspended dapsone
`particles. The Aczone Gel, 7.5% formulation is packaged in an airless pump container
`closure system and provided in 30 g, 60 g, 90 g,
` fill sizes and 3 g professional
`sample tube. The composition is shown in Table 4.
`
`Reference ID: 3871849
`
`9
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`(b) (4)
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`

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`Table 4: Composition of dapsone gel, 7.5%
`
`2.5.2 Was the to-be-marketed formulation used in the clinical trials?
`
`Yes. The to-be-marketed dapsone gel 7.5% formulation (11080X) was used in all clinical
`studies, including the 2 phase 3 trials and the 4 phase 1 studies.
`
`2.6 Analytical
`
`2.6.1 What bioanalytical methods were used to assess dapsone and its metabolites
`N-acetyl dapsone, N-hydroxy dapsone and N-formyl dapsone and were they
`adequately validated?
`Human plasma concentrations of dapsone, N-formyl dapsone (NFD), N-acetyl dapsone
`(NAD), and dapsone hydroxylamine (DHA) were measured using adequately validated
`liquid chromatography tandem mass spectrometry methods (LC-MS/MS). A summary of
`selected assay validation results are shown in Table 5.
`
`Table 5: Summary of assay performance
`N-formyl
`N-hydroxy
`Parameter
`Dapsone
`N-acetyl
`dapsone
`dapsone
`dapsone
`100 – 20,000
`100 – 25,000
`50 – 25,000
`50 – 25,000
`pg/mL
`pg/mL
`pg/mL
`pg/mL
`0.907 to 4.01% 0.602 to 7.32% 0.534 to 7.24% 1.47 to 8.38%
`
`Assay range
`
`Intra-run
`precision
`Intra-run
`accuracy
`Inter-run
`precision
`Inter-run
`accuracy
`Long term
`storage
`stability
`
`0.733 to 4.89% -7.67 to -0.111
`
`-7.78 to -1.68% -3.68 to -2.06%
`
`3.38 to 4.83%
`
`1.68 to 5.45%
`
`0.939 to 6.07% 2.15 to 7.04%
`
`-3.36 to 2.96% -4.81 to 0.500% -5.76 to -2.92% -2.07 to -3.38%
`
`563 days at -
`80°C
`
`563 days at -
`80ºC and 475
`days at -20°C
`
`97 days at -80ºC
`and -20°C
`
`563 days at -
`80°C
`(required wider
`75% -125%
`threshold to
`pass stability)
`
`10
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`Reference ID: 3871849
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`(b) (4
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`(b) (4)
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`

`Note: assay for N-hydroxy dapsone (aka dapsone hydroxylamine) used more relaxed
`criteria of accuracy within ±25% at each QC and ±30% at LLOQ due to the unstable
`nature of the analyte.
`
`Storage stability:
`Study samples from Study 225678-004 were analyzed within the demonstrated long-term
`sample stability duration for each analyte. Samples were stored at -70ºC for up to 80 days
`before analysis for dapsone, NAD, and DHA concentrations. Long-term stability has
`been established for dapsone, NAD, and DHA in human plasma for 563 days at -70ºC. In
`addition, samples from Study 225678-004 were stored at -70ºC for up to 97 days before
`analysis for NFD concentrations, and long-term stability has been established for NFD in
`human plasma for 97 days at -70ºC.
`
`3 Detailed 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.
`
`WARNINGS AND PRECAUTIONS
`5
`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 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 G6PD deficiency
`using twice daily dapsone gel, 5%, developed laboratory changes suggestive of mild
`hemolysis
`
`
`
`Combination of topical dapsone with trimethoprim/sulfamethoxazole (TMP/SMX) may
`increase the likelihood of hemolysis in patients with G6PD deficiency.
`
`If signs and symptoms suggestive of hemolytic anemia
`
`
`
`
`
` occur,
`
`ACZONE® Gel, 7.5%
` in patients who are taking oral dapsone or
`antimalarial medications because of the potential for
` hemolytic
`reactions.
`
`7
`
`DRUG INTERACTIONS
`
`Reference ID: 3871849
`
`11
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`No formal drug-drug interaction studies were conducted with ACZONE® Gel, 7.5%.
`
`Trimethoprim-Sulfamethoxazole
`7.1
`A drug-drug interaction study evaluated the effect of the use of dapsone gel, 5% in
`combination with double strength (160 mg/800 mg) trimethoprim-sulfamethoxazole
`(TMP/SMX). 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 ACZONE® 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.
`
`Drug Interactions with Oral Dapsone
`7.3
`Certain concomitant medications (such as rifampin, anticonvulsants, St. John’s wort) may
`increase the formation of dapsone hydroxylamine, a metabolite of dapsone associated
`with hemolysis. With oral dapsone treatment, folic acid antagonists such as
`pyrimethamine have been noted to possibly increase the likelihood of hematologic
`reactions.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`
`is not known.
`
` The mechanism of action of dapsone gel in treating acne vulgaris
`
`Pharmacokinetics
`12.3
`In a pharmacokinetic study, male and female subjects 16 years of age or older with acne
` received 2 grams of ACZONE Gel,
`vulgaris (N=19)
`7.5%, topically to the
` face, upper chest, upper back and shoulders once daily for 28
`days
`
` Steady state for dapsone was reached within 7 days of dosing
`. On Day 28, the mean dapsone maximum plasma
`concentration (Cmax) and area under the concentration-time curve from 0-24 hours post
` 282 ± 146 ng∙h/mL, respectively
`
`dose (AUC0-24h) were 13.0 ± 6.8 ng/mL and
`
`Reference ID: 3871849
`
`12
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
`(4)
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`(b) (4)
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`

`

` The systemic exposure from
`ACZONE® Gel, 7.5% is expected to be about 1% of that from a 100 mg oral dose.
`
`Long-term safety studies were not conducted with ACZONE® Gel, 7.5%, however, in a
`long-term clinical study of
` dapsone gel, 5%, periodic blood samples were
`collected up to 12 months to determine systemic exposure of dapsone and its metabolites
`in approximately 500
`. Based on the measurable dapsone concentrations from 408
`patients (M=192, F=216), obtained at month 3, neither gender nor race appeared to affect
`the pharmacokinetics of dapsone. Similarly, dapsone exposures were approximately the
`same between the age groups of 12-15 years (N=155) and those greater than or equal to
`16 years (N=253). There was no evidence of increasing systemic exposure to dapsone
`over the study year in these
`.
`
`Reference ID: 3871849
`
`13
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`4 Appendix
`
`4.1
`
`Individual Study Reviews
`
`Maximal use PK Trial 225678-004
`Title:
`Safety, Tolerability, and Pharmacokinetics of Dapsone Dermal Formulations in Subjects
`with Acne Vulgaris
`
`Study Centers:
`There were a total of 2 study sites in the United States (US).
`
`Study period:
`Study Initiation Date (First Subject Enrolled): 21 January 2013
`Study Completion Date (Last Subject Completed): 13 May 2013
`
`Objectives:
`To evaluate the safety and tolerability of 3 dapsone 7.5% gel formulations dosed once
`daily, and dapsone 5% gel (ACZONE® 5% Gel) dosed twice daily following 28 days
`repeat topical administration in male and female subjects with moderate acne vulgaris.
`
`To evaluate the pharmacokinetics of dapsone and dapsone metabolites following 28 days
`repeat topical administration of 3 dapsone 7.5% gel formulations dosed once daily, and
`ACZONE 5% Gel dosed twice daily in male and female subjects with moderate acne
`vulgaris.
`
`To explore efficacy measures.
`
`Design:
`This study was a multicenter, randomized, investigator-blinded, active-controlled,
`multiple-dose, parallel-group study that evaluated the safety, tolerability, and
`pharmacokinetics of 3 dapsone 7.5% gel formulations (dosed once daily) and ACZONE
`5% gel (dosed twice daily) in male and female subjects with moderate acne vulgaris.
`Eligible subjects were randomized to 1 of the 4 treatment groups (in a 1:1:1:1 allocation
`ratio) to receive 1 of 3 dapsone 7.5% formulations, or ACZONE 5% gel; subjects were
`stratified by gender and age group. Study medication was applied to the subject’s entire
`face, upper chest, upper back, and shoulders. The total surface area covered by the study
`medication was approximately 1000 cm2 for each study medication application
`administered by the drug administrator (or designee). Subjects were to be administered
`study medication on days 1 to 28, were scheduled for daily clinic visits for study
`procedures on days 29 to 34 (during which they received no study medication), and
`exited the study on day 35.
`
`Number of subjects:
`Approximately 72 subjects were planned for this study. A total of 77 subjects (41 males
`and 36 females) were enrolled.
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`Reference ID: 3871849
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`Inclusion criteria:
`Adolescent and adult male and female subjects who were 16 to 35 years of age; subjects
`with a minimum weight of 35 kg, and a body mass index (BMI) of ≥ 15 and ≤ 30 kg/m2
`(if BMI was > 30 to ≤ 35 kg/m2, waist circumference must have been below 40 inches for
`male and 35 inches for female); subjects with a minimum of 20 but not more than 50
`inflammatory lesions (papules and pustules) on the face (excluding the nose); subjects
`with a minimum of 30 but not more than 100 noninflammatory lesions (open comedones
`and closed comedones) on the face (excluding the nose); and subjects with a score of 3
`(moderate) on the Global Acne Assessment Scale (GAAS).
`
`Test Product, Dose and Mode of Administration, Batch Number:
`Dapsone 7.5% gel, 2 g applied topically; formulation number 11078X, batch ENB-C
`(herein referred to as DAP-11078)
`
`Dapsone 7.5% gel, 2 g applied topically; formulation number 11079X, batch ENC-1C
`(herein referred to as DAP-11079)
`
`Dapsone 7.5% gel, 2 g applied topically; formulation number 11080X, batch ENA-1C
`(herein referred to as DAP-11080)
`
`Reference Therapy, Dose and Mode of Administration, Batch Number:
`ACZONE (dapsone 5% gel), 2 g applied topically; batch END-C
`
`Duration of Treatment: 28 days
`
`Pharmacokinetic assessment:
`Plasma concentrations of dapsone, its metabolites (NAD and DHA), and NFD were
`collected prior to administration of the morning dose on days 1, 7, 14, 18, 21, 26, 27, on
`day 28 (predose, 1, 2, 4, 6, 8, 10, and 12 hours postdose), 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.
`
`Assay method validation: See section 2.6 of this review.
`
`Results:
`
`Subject disposition:
`A total of 77 subjects were enrolled and randomized into 1 of 4 treatment groups: DAP-
`11078 (20 subjects), DAP-11079 (19 subjects), DAP-11080 (19 subjects), and ACZONE
`(19 subjects), and had at least 1 study medication administration. All 77 subjects had at
`least 1 application of study medication; therefore all subjects were included in the safety
`population. Five subjects aged between 12 and 15 years old were discontinued from the
`study following Protocol Amendment 2 which excluded subjects 12 to 15 years old. The
`remaining 72 subjects completed the study as scheduled.
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`Two subjects were excluded from the PP population; 1 subject missed more than 20% of
`the study visits (Subject 1002-1597, DAP-11078 treatment arm) and the second subject
`had taken prohibited medication for 15 days during the treatment period (subject 1002-
`1552, Dapsone 5% gel treatment arm). Therefore, 70 subjects were included in the PP
`population. However, both subjects were included in the PK population. Subject 1002-
`1552 had AUC0-24 of 394 ng*hr/mL and Cmax of 18 ng/mL, which were similar to the
`means for Dapsone 5% gel arm, suggesting that its inclusion would not alter the results.
`Subject 1002-1597 had AUC0-24 of 164 ng*hr/mL, which was lower than the mean of
`235 ng*hr/mL for the DAP-1078 treatment arm and may lower the group mean by
`several units; this was not followed up further because DAP-1078 is not the proposed to-
`be-marketed formulation.
`
`The mean percentage BSA treated was similar among all four treatment groups: 5.5% in
`the DAP-11079 treatment group, 5.7% in the DAP-11078 and ACZONE treatment
`groups, and 5.8% in the DAP-11080 treatment group.
`
`Subject disposition and demographic information are shown in Tables 6 and 7,
`respectively. Note that data in Table 7 includes the 5 pediatric subjects 12 – 15 years of
`age that were discontinued due to a change in protocol. Of relevant to the current NDA,
`the Aczone 5% gel arm had 1 subject discontinued; therefore the number of pediatric
`subjects in the PK population was 6 instead of the 7 listed in that table. No subjects were
`discontinued in the to-be-marketed formulation DAP-11080 treatment arm.
`
`Table 6: Subject disposition (Safety population)
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`Reference ID: 3871849
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`Table 7: Demographic and baseline characteristics (Safety population)
`
`Pharmacokinetics:
`
`Plasma concentration of dapsone and its metabolites NAD and DHA were measurable
`and their PK properties are described below. PK parameters estimates are shown in Table
`9 and mean concentration versus time profiles are shown in Figures 4 – 6. Plasma
`concentrations of metabolite NFD were found to be below the lower limit of quantitation
`(0.100 ng/mL) for all subjects at all timepoints.
`
`Relative to ACZONE 5% gel, the mean systemic exposures of dapsone was
`approximately 25% to 40% lower for the 3 dapsone 7.5% gel formulations. Among the
`dapsone 7.5% gel formulations, the highest exposure of dapsone in terms of AUC was
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`observed with the to-be-marketed formulation (DAP-11080), with respective mean Cmax
`and AUC0-24 being approximately 28.6% and 28.7% lower relative to ACZONE 5% gel
`(Table 9).
`
`Mean Tmax for dapsone and its metabolites (NAD and DHA) was similar between each
`treatment group, with values ranging from 10.3 to 16.1 hours. Plasma concentrations of
`dapsone and its metabolites declined slowly after the last administration on day 28 for
`each treatment group, with mean terminal T1/2 values ranging from 39.2 to 54.7 hours
`(Table 9). Base on assessment of Ctroughs, steady-state for all 3 analytes appeared to be
`reached within 7 days of dosing in all 4 treatment groups (data not shown). Ctrough
`values for dapsone were similar across Days 7 – 28 suggesting that the PK parameter
`estimates on Day 28 is representative of steady state (Table 8).
`
`Mean plasma concentrations of dapsone, NAD, and DHA following once daily
`administration of the 3 dapsone 7.5% gel formulations (DAP-11078, DAP-11079, and
`DAP-11080) were lower than those following twice daily administration of ACZONE
`5% gel. Relative to ACZONE 5% gel given twice daily, daily systemic exposure of
`dapsone, as defined by the geometric mean ratio for Cmax and AUC0-24, was
`approximately 36.1% and 40.4% lower for DAP-11078, 25.4% and 31.9% lower for
`DAP-11079, and 28.6% and 28.7% lower for DAP-11080, respectively. Based on the
`90% CIs for Cmax and AUC0-24, these differences were statistically significant;
`however, the upper limit of 90% CI were close to 100% (93% for Cmax and 92% for
`AUC0-24 of to-be-marketed formulation DAP-11080, Table 9) and therefore the
`statistically significantly lower systemic exposure may not be clinically meaningful.
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`Reference ID: 3871849
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`Table 8: Mean Plasma Concentrations of Dapsone (ng/mL) Following Once