For this 505(b)(1) application, based on the data submitted from the six trials in the clinical development program, safety and efficacy of ACZONE ® (dapsone) Gel, 7.5% have been established for the topical treatment of acne vulgaris in patients 12 years of age and older.

A proposal for the PMR is as follows: Conduct an open-label study to assess safety, pharmacokinetics, and treatment effect of ACZONE® Gel, 7.5% in 100 pediatric subjects age 9 to 11 years 11 Reference ID: 3875816 Clinical Review Patricia C. Brown, MD

Formulations Brand Name Generic Name Owner moderate acne .35 mg Norgestlmate .025 mg/ ethinyl estradiol Orhto-Cyden Orhto Tri- cyclen Jansse" Pharms vulgaris in females at least 15 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche Compiled by reviewer from website “Drugs at FDA” accessed October 28, 2015 2.3 Availability of Proposed Active Ingredient in the United States ACZONE® (dapsone) Gel, 5% was approved July 7, 2005 (NDA 21794).

The site of Dr. Forsha was issued a Form FDA 483 noting deficiencies including a lack of adherence to the protocol, and inadequate documentation of adverse events (AEs), concomitant medications, informed consent or assent, and drug accountability.

17.6 ± 6.7 186 ± 71 379 ± 142 The clinical pharmacology reviewer explains that: “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.

Attention: Jeremy McCumber, MS Director, Global Regulatory Affairs 2525 Dupont Drive P.O.

This new drug application provides for the use of ACZONE (dapsone) Gel, 7.5% for the topical treatment of acne vulgaris in patients 12 years of age and older.

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

To do so, submit, in triplicate, a cover letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package insert, Medication Guide, and patient PI (as applicable) to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266

As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253.

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.

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).

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).

Dapsone had no effect on male fertility at dosages of 2 mg/kg/day or less (approximately 15 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 7.5%, based on AUC comparisons).

Use of benzoyl peroxide with ACZONE Gel, 7.5% at the same time may cause your skin or facial hair to temporarily turn yellow or orange at the site of application.

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.

ACZONE (dapsone) Gel, 7.5% The reader is referred to the comprehensive statistical review and evaluation by Matthew W Guerra, Ph.D. (Division of Biostatistics III) for a more complete discussion of the efficacy results (dated January 14, 2016).

Therefore, to fulfill the requirements of PREA, the applicant will need to conduct:  An open-label study to assess safety, pharmacokinetics, and treatment effect of ACZONE Gel, 7.5% applied once daily in 100 pediatric subjects age 9 to 11 years 11 months with acne vulgaris.

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.

ACZONE (dapsone) Gel, 7.5% The reader is referred to the comprehensive statistical review and evaluation by Matthew W Guerra, Ph.D. (Division of Biostatistics III) for a more complete discussion of the efficacy results (dated January 14, 2016).

Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) *** This document contains proprietary information that cannot be released to the public*** Date of This Review: July 8, 2015 Application Type and Number: NDA 207154 Product Name and Strength: Aczone (Dapsone) Gel, 7.5% Product Type: Single ingredient product Rx or OTC: Rx Applicant/Sponsor Name: Allergan Inc. Submission Date: April 28, 2015 Panorama #: 2015-411667 DMEPA Primary Reviewer: Carlos M Mena-Grillasca, RPh DMEPA Team Leader: Kendra Worthy, PharmD DMEPA Associate Director: Lubna Merchant, MS, PharmD Reference ID: 3789326

Intended Pronunciation: ak-zōn   Active Ingredient: dapsone Indication of Use: Topical treatment of acne vulgaris   Route of Administration: Topical  Dosage Form: Gel  Proposed Strength: 7.5% Currently Marketed: 5%  Proposed Dose and Frequency (7.5% strength): Apply approximately a pea-sized amount of ACZONE Gel, 7.5%, in a thin layer to the acne affected areas once daily.

Current Dose and Frequency (5% strength): Apply approximately a pea-sized amount of ACZONE Gel, 5%, in a thin layer to the acne affected areas twice daily.

If any of the proposed product characteristics as stated in your April 28, 2015 submission are altered prior to approval of the marketing application, the name must be resubmitted for review.

The database is designed to support the FDA's postmarket safety surveillance program for drug and therapeutic biologic products.

Aczone Dapsone Gel 7.5% Allergan, Inc. February 24, 2016 For topical treatment of acne vulgaris in patients 12 years of age and older.

This new drug application provides for the use of ACZONE (dapsone) Gel, 7.5% for the topical treatment of acne vulgaris in patients 12 years of age and older.

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable.

To do so, submit, in triplicate, a cover letter requesting advisory comments, the proposed materials in draft or mock-up form with annotated references, and the package insert, Medication Guide, and patient PI (as applicable) to: OPDP Regulatory Project Manager Food and Drug Administration Center for Drug Evaluation and Research Office of Prescription Drug Promotion 5901-B Ammendale Road Beltsville, MD 20705-1266

As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the package insert, at the time of initial dissemination or publication, accompanied by a Form FDA 2253.

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.

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%.

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.

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.

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.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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 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).

Dapsone had no effect on male fertility at dosages of 2 mg/kg/day or less (approximately 15 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 7.5%, based on AUC comparisons).

Cements and recommendations regarding the proposed dosage Providing the location of chemistry, manufacturing, and controls informtion previously submitted to NDA 21794 for ACZONE (dapsone) Ge], 5% and specifically referenced by this .

Therefore, from the OPQ perspective, this NDA is not ready for approval in its present form per 21 CFR 314.125(b)(6) until the aforementioned issues are satisfactorily resolved (See the List of Deficiencies on pp.

Ifthe drug product contains material sourcedfrom animals, what documentation is provided to assure a low risk of virus or prion contamination (causative agent of TSE) ?

The 30 g, 60 g and 90 g pump labels should be revised to include the following information: 0 Display “Lot” and “Exp:” 0 Display a barcode 0 Add the following statement in the storage condition description “[See USP Controlled Room Temperature]” 0 List ingredients as shown below: “Each gram of gel contains 75 mg of dapsone, diethylene glycol monoethyl ether, methyl paraben, acrylamide/sodium ac1yloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and purified water.” The 3 g sample tube labels should be revised to include the following information: 0 Display “Lot:” and “Exp:” 0 Add the following statement in the storage condition description “[See USP Controlled Room Temperature]” 2 Page(s) of Drafi Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

Satisfacto 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 ac1yloyldimethyl 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: