CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`207154Orig1s000
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`SUMMARY REVIEW
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`Decisional Memorandum to the File
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`
`Date:
`February 17, 2016
`From:
`Kendall A. Marcus, MD.
`
`Director, Division of Dermatolo 3 and Dental Products
`
`Summary and Recommendations
`Subj ect:
`NDA/BLA #:
`2071 54
`
`Aller an, Inc.
`
`Submission Date
`PDUFA Goal
`
`April 28, 2015
`Feb .
`28, 2016
`
`
`
`Proprietary /
`Generic (USAN)
`names
`
`Dosage forms /
`strength
`Proposed
`Indication s
`
`ACZONE (dapsone) Gel 7.5%
`
`Topical gel
`
`Treatment of acne vulgaris in patients 12 years of age and older
`
`1.
`
`Introduction/Background
`
`With this New Drug Application (NDA), the applicant seeks marketing approval for
`ACZONE (dapsone) Gel, 7.5%, applied once daily, for the treatment of acne vulgaris in
`patients 12 years of age and older. The active ingredient, dapsone, also known as
`diaminodiphenyl sulfone, has both anti—inflammatory and antimicrobial properties.
`Dapsone is currently marketed in the United States (US) in both topical and oral dosage
`forms. ACZONE Gel, 5%, applied twice daily, was approved in 2005 for the treatment of
`acne vulgaris in patients 12 years of age and older. Dapsone Tablets (25 mg and 100 mg)
`were approved in 1992 for the systemic treatment of dermatitis herpetiformis and leprosy.
`Various professional treatment guidelines also recommend the off-label use of Dapsone
`Tablets as an alternative for prevention and treatment of pneumocystis pneumonia (PCP)
`and as an alternative for prevention of toxoplasmosis encephalitis in HIV-infected
`patients.
`
`Acne vulgaris is a complex skin disorder involving multiple abnormalities of the
`pilosebaceous gland, including hyperkeratinization, increased sebum production,
`bacterial proliferation, and inflannnation. The face, anterior trunk, and upper back are the
`most commonly affected areas due to higher concentrations of these glands. Dapsone
`inhibits growth of certain species of bacteria through inhibition of folic acid synthesis,
`but the specific mechanism of action of dapsone for the treatment of acne vulgaris is not
`known. Current topical therapies approved for the treatment of acne include retinoids,
`antibiotics (including dapsone) and benzoyl peroxide while approved systemic therapies
`include antibiotics and hormonal therapy.
`
`This application includes letters from Allergan that authorize reference to data associated
`with NDA 21,794 and IND 54,440, for ACZONE (dapsone) Gel, 5%. The conditions of
`use of ACZONE Gel, 7.5%, including the volmne of product applied per treatment, the
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`Reference ID: 3888488
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`maximum area treated, and the patient population, will be similar to those associated with
`ACZONE Gel, 5%, with the exception that the 7.5% product will be labeled for once
`daily application as compared to twice daily application for the 5% product. Clinical use
`of ACZONE Gel, 7.5%, will generally include application of about 2 g of product
`containing 150 mg dapsone, while use of ACZONE Gel, 5%, will generally include twice
`daily application of a total of about 4 g of product containing 200 mg dapsone.
`
`The clinical development program for ACZONE Gel, 7.5% is composed of 2 pivotal
`Phase 3 trials, 4 Phase 1trials that include a pharmacokinetic (PK) trial in patients with
`moderate acne vulgaris and 3 dermal tolerability trials in healthy subjects.
`
`2. CMC
`
`For complete details, please refer to Office of Product Quality’s (OPQ) Integrated
`Quality Assessment completed by the Quality Review Team.
`
`Aczone Gel, 7.5% is an off-white to yellow aqueous gel with suspended dapsone
`particles for topical use. It is packaged in a
` airless pump container closure
`system. The
` airless pump container system consists of a
`polypropylene bottle with a high density polyethylene piston. Each gram of ACZONE
`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.
`
` was reviewed and found adequate to support the
`The Drug Master File (DMF)
`use of the drug substance in this application. The identity, strength, purity (including
`microbial limits) and quality of the drug product are deemed assured. The facility review
`team from the Office of Process and Facility has issued an “Approval” recommendation
`for the facilities submitted in support of this application.
`
`3. Nonclinical Pharmacology/Toxicology
`
`Please refer to the review prepared by Norman See, PhD, the Pharmacology/Toxicology
`reviewer, for full details. This NDA is considered approvable from a pharm/tox
`perspective. The NDA was considered to be a 505(b)(1) NDA because the sponsor owns
`all the necessary nonclinical data for ACZONE (dapsone) Gel, 5% to support the
`ACZONE (dapsone) Gel, 7.5% application.
`
`Substantial toxicity was not observed in chronic toxicology studies in which dapsone
`topical gel was dermally applied. No effects were observed in male or female rabbits
`treated topically for nine months. Dapsone topical gel is not an irritant of skin or eyes, is
`not phototoxic, and is non-sensitizing.
`
`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,
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`Reference ID: 3888488
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`splenomegaly, mild splenic "congestion" and mild pigmentation of the spleen. These
`effects and more were observed at 100 mg/kg/day. The dose of 3 mg/kg/day was an
`apparent no-adverse-effect-level (NOAEL) in that study.
`
`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. 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 Executive Carcinogenicity Committee to
`be acceptable. No evidence of carcinogenicity was observed in either study.
`
`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. The dose of 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. Findings were similar in rabbit
`reproductive studies, except that the NOAEL for dapsone was 30 mg/kg/day.
`
`4. Clinical Pharmacology
`
`Please refer to the review by Doanh Tran, Ph.D., the clinical pharmacology reviewer
`from the Office of Clinical Pharmacology/DCP III for full details. The clinical
`pharmacology review team considers this NDA approvable.
`
`A PK trial compared the PK of ACZONE (dapsone) Gel, 7.5%, the to-be-marketed
`formulation, applied once-daily (QD) for 28 days to ACZONE Gel, 5% applied twice-
`daily (BID) for 28 days to subjects at least 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 which
`corresponded to a treatment area of approximately 1000 cm2. Mean trough concentrations
`for plasma dapsone were similar for Days 7 – 28, suggesting steady state PK was
`achieved by Day 7 and maintained until Day 28.
`
`Relative to ACZONE Gel, 5%, the daily systemic exposure of dapsone achieved by once
`daily application of the 7.5% gel, defined by the geometric mean ratio for maximum
`plasma concentration (Cmax) and area under the concentration-time curve from time 0 to
`24 hours post-dose (AUC0-24), was about 28.6% and 28.7% lower, respectively. Based
`on the 90% CIs for Cmax and AUC0-24, these differences were statistically significant;
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`however, the upper limit of the 90% CIs were close to 100% (93% for Cmax and 92% for
`AUC0-24); therefore, the statistically significantly lower systemic exposure may not be
`clinically meaningful.
`
`5. Microbiology
`
`No microbiologic studies were conducted in support of this application.
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`6. Clinical/Statistical
`
`Please refer to the reviews completed by Patricia Brown, M.D., the clinical reviewer, and
`Matthew Guerra, Ph.D., the biostatistical reviewer, for full details of the efficacy review.
`They consider this NDA approvable from an efficacy perspective.
`
`In support of the efficacy of ACZONE Gel, 7.5%, the applicant submitted data from two
`identically-designed, randomized, multicenter, vehicle-controlled, parallel-group, Phase 3
`trials (Trials 006 and 007). For enrollment, the protocol specified the following key
`inclusion criteria: 12 years of age or older, a Global Acne Assessment Score (GAAS) of 3
`(moderate), 20-50 inflammatory lesions (papules and pustules) on the face, and 30-100
`non-inflammatory lesions (open comedones and closed comedones) on the face. The
`protocol-specified co-primary efficacy endpoints were the proportion of subjects
`achieving a GAAS score of 0 (none) or 1 (minimal) at Week 12 and the absolute change
`in inflammatory and non-inflammatory lesion counts from baseline to Week 12.
`Secondary efficacy endpoints included percent change in inflammatory and non-
`inflammatory lesion counts from baseline to Week 12.
`
`The mean age was 20.3 years and 20.2 years (range of 12 to 63 years) for the ACZONE
`Gel and the Vehicle groups, respectively. Adolescents (ages 12 to 17 years) comprised
`49.5% and Caucasians comprised 57.4% of trial subjects. The median total dose used
`was 41.4 grams in the ACZONE Gel group and 42.3 grams in the Vehicle group. The
`duration of exposure and average daily use of study product were similar between
`treatment arms within each trial and between the two trials.
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`Table 1 presents the results of the co-primary efficacy endpoints and the secondary
`efficacy endpoints of percent change in inflammatory and inflammatory lesion counts
`from baseline to Week 12. In both trials, ACZONE Gel, 7.5% was statistically superior
`(p-values ≤ 0.004) to vehicle gel for all endpoints presented in Table 1.
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`Of note, for the assessment of GAAS, the interpretation of a “few” or “no” lesions
`seemed to vary from investigator to investigator. Some subjects counted as successes
`under the GAAS seemed to have relatively high lesion counts for the definition of “none”
`(no evidence of facial acne vulgaris) or “minimal” (a few non-inflammatory lesions
`(comedones) are present; a few inflammatory lesions (papules/pustules) may be present).
`Subjects scored as 0 (none) had as many as 10 inflammatory lesions or 45 non-
`inflammatory lesions. Subjects scored as 1 (minimal) had as many as 57 inflammatory
`lesions or 102 non-inflammatory lesions.
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`7. Clinical/Safety
`
`Please refer to the review completed by Patricia Brown, M.D., the clinical reviewer, for
`full details of the safety review. This NDA is considered approvable from a safety
`perspective.
`
`The applicant submitted data from the Phase 3 Trials 006 and 007 to establish the safety
`of their product applied once daily for 12 weeks in the topical treatment of acne vulgaris.
`Additional safety data are available from PK Trial 004 and dermal safety studies. All of
`the trials were conducted with the final-to-be-marketed formulation.
`
`The pooled safety database includes 4336 subjects exposed to study drugs; 2161 to
`ACZONE Gel, 7.5% and 2175 to Vehicle. Safety was assessed by adverse events, local
`tolerability (at baseline and at Weeks 1, 2, 4, 8, and 12) and vital signs (at screening and
`at the Week 12/early exit visit). The local dermal tolerability assessment for the face was
`performed by the investigators or appropriately trained designee and by the patient.
`Assessments included dryness, scaling, and erythema (assessed by the investigator) and
`stinging/burning (assessed by the patient). Each assessment used 4-point scales: 0 = none,
`1 = mild, 2 = moderate, 3 = severe.
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`A few subjects in either treatment arm discontinued from the trials due to adverse events
`considered related to treatment. Three subjects in the ACZONE Gel arm discontinued for
`the events of application site acne and dermatitis; application site vesicles, swelling and
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`pruritus; and application site discomfort. In the Vehicle arm 2 subjects discontinued for
`mild application site pain and 1 subject discontinued for application site acne.
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`The frequency of application site treatment-emergent adverse events (TEAEs) was
`similar between ACZONE Gel-treated and Vehicle-treated subjects. The most common
`application site TEAEs occurring in ≥1% of subjects in any treatment group were:
`application site dryness (1.2% in the ACZONE Gel group versus 1.0% in the Vehicle
`group), application site pruritus (1.1% versus 0.6%), and application site pain (0.5%
`versus 1.5%). The proportion of subjects experiencing TEAEs was similar among those
`aged 12 to 17 years of age as compared with those subjects > 18 years of age and among
`males and females.
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`Treatment-related TEAEs, or adverse drug reactions (ADRs), were reported in 3.5%
`(75/2161) of subjects in the ACZONE Gel treatment arm and 3.4% (73/2175) of subjects
`in the Vehicle treatment arm. The most common ADRs occurring at a rate greater than
`vehicle were application site dryness (1.1% in the ACZONE Gel group versus 1.0% in
`the Vehicle group) and application site pruritus (0.9% versus 0.5%).
`
`Approved labeling for ACZONE Gel, 5%, includes warnings and precautions for
`methemoglobinemia, hematologic effects, peripheral neuropathy and serious skin
`reactions. The Warning and Precautions section of labeling for ACZONE Gel, 7.5% will
`contain language similar to the current approved labeling for ACZONE Gel, 5%.
`
`Oral dapsone treatment has produced dose-related hemolysis and hemolytic anemia,
`peripheral neuropathy (motor loss and muscle weakness) and serious skin reactions (toxic
`epidermal necrolysis, erythema multiforme, morbilliform and scarlatiniform reactions,
`bullous and exfoliative dermatitis, erythema nodosum, and urticaria). These types of skin
`reactions were not observed in topical ACZONE Gel, 5% clinical trials or in the
`ACZONE Gel, 7.5% development program.
`
`Labeling for ACZONE Gel, 5% was modified in July 2015 to include the information
`that cases of methemoglobinemia, with resultant hospitalization, have been reported
`postmarketing in association with the use of ACZONE Gel, 5%. In the ACZONE Gel,
`7.5% development program, two events were reported in two subjects (of note, the
`subjects were a parent and child) in a Phase 1 dermal safety trial that were considered
`potentially related to methemoglobinemia. Both subjects reported possible cyanosis,
`which is usually the first presenting symptom of methemoglobinemia, and tremor. The
`events resolved within one hour of removal of test patches containing the dapsone gel,
`which is inconsistent with the Tmax and the half-life of dapsone. For this and other
`reasons, the two cases are not considered definitive regarding an association between the
`use of ACZONE Gel, 7.5% and the occurrence of methemoglobinemia.
`
`Clinically significant changes in methemoglobin levels over the course of PK Trial 004
`were not seen. Mean methemoglobin levels at baseline were 0.76%, and 0.74% in the
`ACZONE Gel, 7.5%, and ACZONE Gel, 5% gel groups, respectively. At Day 28, the
`mean change from baseline was -0.02, and -0.02 in each group, respectively.
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`Similarly, clinically significant changes in other hematologic parameters were not seen.
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`8. Advisory Committee Meeting
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`No regulatory issues were identified during the review of this application that required
`input from an advisory committee.
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`9. Pediatrics
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`Because necessary studies are impossible or highly impractical, a partial waiver for the
`study of acne in pediatric patients ages 0 to 9 years will be granted. Prior to this NDA
`submission, the Agency agreed with the proposed iPSP and study of pediatric patients
`down to an age of 12 years; however, review of the literature indicates that acne vulgaris
`is increasing in prevalence in younger children. As a result, a deferral of pediatric study
`of patients 9 years to 11 years 11 months will be granted and the applicant will be
`required 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.
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`10. Other Relevant Regulatory Issues
`
`No issues related to financial disclosures, GCP issues, or patent issues were identified in
`the review of the application. GMP inspections received an “Acceptable” determination
`from the Office of Process and Facilities.
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`11. Labeling
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`The ACZONE Gel, 7.5% product will have a separate label from the existing ACZONE
`Gel, 5% product at the applicant’s request. Review of the proposed label was based on
`evaluation of clinical trial data and DMEPA, DRISK, and OPDP reviews.
`
`Because this product is not a new molecular entity, changes to the label consistent with
`the Pregnancy and Lactation Labeling Rule (PLLR) will be deferred to a later time.
`Proposed labeling will mirror that of the currently approved ACZONE Gel, 5% product.
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`Product labeling appears adequate to communicate safety information to prescribers.
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`12. Decision/Action/Risk Benefit Assessment
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`Regulatory Action: Approval
`
`I concur with the recommendations of the multi-disciplinary review team to approve
`NDA 207154 ACZONE (dapsone) Gel, 7.5% for the treatment of acne vulgaris in
`patients 12 years of age and older.
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`Reference ID: 3888488
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`Risk-benefit assessment: Efficacy of ACZONE (dapsone) Gel, 7.5% was established in
`two adequate and well-controlled clinical trials. Safety of the product is demonstrated
`through data from the clinical development program as well as extensive postmarketing
`experience with the 5% gel formulation.
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`Postmarketing Risk Evaluation and Management Strategies: Prescription status, routine
`pharmacovigilance, and professional and patient labeling are adequate risk management
`measures for the product. A Risk Evaluation and Mitigation Strategy (REMS) is not
`required.
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`Postmarketing requirements (PMR): 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 postmarketing trial to assess PK in subjects 9 years to 11 years 11 months
`will be required.
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`Reference ID: 3888488
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KENDALL A MARCUS
`02/17/2016
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`Reference ID: 3888488
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