Efficacy, Safety, and Subject Satisfaction of a Specified Skin Care Regimen to Cleanse, Medicate, Moisturize, and Protect the Skin of Patients Under Treatment for Acne
aJames Q. Del Rosso, DO, FAOCD; bMichael Gold, MD, PhD; cMaria José Rueda, MD; cStaci Brandt, PA-C; cWarren J. Winkelman, MD, PhD aLas Vegas Skin and Cancer Clinics/West Dermatology, LLC, Henderson, Nevada; bGold Skin Care Center, Nashville, Tennessee; cGalderma Laboratories, L.P., Fort Worth, Texas
Disclosure: Dr. Del Rosso is a consultant, serves on advisory boards, participates as a speaker, and conducts research for Galderma Laboratories, L.P. He also serves as a consultant, participates in advisory boards, is a speaker, and/or conducts research for several other companies who market medications for acne and/or skin care products and/or conduct research on such products including Allergan, Aqua, Dermira, Innocutis, Promius, PuraCap, Ranbaxy, Valeant, and Unilever. Dr. Gold was the principal investigator for Galderma Laboratories, L.P., on this study. Dr. Rueda, Ms. Brandt, and Dr. Winkelman are employees of Galderma Laboratories, L.P.
Optimal management of acne vulgaris requires incorporation of several components including patient education, selection of a rational therapeutic regimen, dedicated adherence with the program by the patient, and integration of proper skin care. Unfortunately, the latter component is often overlooked or not emphasized strongly enough to the patient. Proper skin care may reduce potential irritation that can be associated with topical acne medications and prevents the patient from unknowingly using skin care products that can actually sabotage their treatment. This article reviews the effectiveness, skin tolerability, safety, and patient satisfaction of an open label study in which a specified skin care regimen is used in combination with topical therapy. The study was designed to mirror “real world” management of facial acne vulgaris clinical practice. The skin care regimen used in this study included a brand foam wash and a brand moisturizer with SPF 30 photoprotection, both of which contain ingredients that are included to provide benefits for acne-prone and acne-affected skin. (J Clin Aesthet Dermatol. 2015;8(1):22–30.)
The availability of both prescription (Rx) medications, advanced over-the-counter (OTC) skin care formulations, and other OTC therapeutic and skin care options have allowed clinicians to select more complete treatment regimens that are better suited for patient-specific management of acne vulgaris (AV). However, the plethora of OTC options for AV that are available in pharmacies, retail stores, spas, and skin care centers, and via the internet are confounding to patients, as are the many skin care products promoted to the public. Without the professional knowledge provided by a dermatologist and their clinical staff, the patient is likely to choose a collection of products that will not adequately control their AV and/or reduce damage to the epidermal barrier that can cause signs and symptoms of skin irritation.
Importantly, the fundamental goal common to all patients when the clinician is devising a management plan for AV remains unchanged. That is, to provide optimal treatment outcomes for patients with AV through dedicated patient evaluation, rational selection of pharmacological therapy, and integration of an adjunctive skin care regimen that further supports a favorable therapeutic outcome and avoids skin tolerability reactions.
There are four major components of a complete AV management regimen based on the characteristics of acne-prone skin and acne-treated skin and current understanding of maintaining the structural and functional integrity of the epidermal barrier: 1) cleansing, 2) medicating, 3) moisturizing, and 4) photoprotection.[1–3]
Most dermatologists, and their extenders who work with them in dermatology practices, feel very well-versed at selecting Rx medications for AV; however, many do not consistently recommend a specified skin care regimen when treating patients with AV, thus allowing patients to select skin care products on their own or by others unknown to their physician. As a result, the skin care regimen selected by the patient or by someone other than the clinician treating their AV may not be appropriate for use in the management of AV, especially when the patient is utilizing acne medications.
Many Rx treatments, despite their effectiveness for AV, can cause epidermal barrier impairment as evidenced by increased transepidermal water loss (TEWL) and decreased stratum corneum (SC) water content (hydration), which can induce inflammation and may increase skin sensitivity when facial skin is exposed to personal hygiene products, certain cosmetics, and topical medications., To add, acne-affected skin may be associated with inherent SC abnormalities, especially with greater severity of AV. Another important factor that influences skin care needs is that some therapies for AV predispose patients to photosensitivity (i.e., tetracyclines), even when exposed to lower levels of ultraviolet (UV) light, with official labeling approved by the United States Food and Drug Administration (FDA) for Rx products containing benzoyl peroxide and/or topical retinoids including recommendations to use sunscreens and to avoid sun and sunlamp exposure.[6–11] In some cases, certain OTC products and cosmetics and some facial skin beauty treatments can cause skin irritation, exacerbate AV, and/or induce acneiform eruptions, thus countering the positive effects of Rx therapy for AV., Collectively, the potential adverse consequences of improper concomitant skin care may be problematic for some patients, compromising adherence, overall therapeutic outcomes, and patient satisfaction with their treatment, and in some cases their physician. Unfortunately, prospectively captured data are limited on the combined use of designated skin care and Rx therapy in patients with active AV.[2–4] The following study provides data on the concomitant use of a specific skin care regimen (i.e., cleanser, moisturizer with sunscreen) designed for acne-prone and acne-treated skin in patients treated topically for AV.,[14–16]
This open-phase, single-arm, observational, eight-week study evaluated an AV management regimen consisting of an Rx fixed combination topical gel containing adapalene 0.1% and benzoyl peroxide 2.5% (A-BPO) applied once daily in subjects (N=81) with facial AV. As A-BPO has been shown to be efficacious and well-tolerated, and is FDA-approved for treatment of AV in subjects greater than nine years of age, the inclusion criteria allowed for enrollment of study subjects nine years of age and older with facial AV rated as mild or moderate in severity.[17–21] All enrolled subjects were treated with A-BPO once daily in combination with two specified skin care products designed for acne-prone skin—a foaming skin cleanser (Cetaphil® DermaControl™ Foam Wash, Galderma Laboratories L.P., Fort Worth, Texas) and a moisturizer with broad-spectrum sun protection factor 30 (SPF 30) sunscreen (Cetaphil® DermaControl™ Moisturizer SPF 30, Galderma Laboratories L.P.), referred to as the CoMMPlete Regimen. Efficacy, skin tolerability, safety, and patient satisfaction were evaluated in all subjects. This article reports the results of this study, discusses clinical relevance, and reviews the importance of a practical and convenient comprehensive management plan when treating patients with AV.
The primary objective of this study was to assess total AV lesion counts after eight weeks of use of A-BPO gel once daily in conjunction with an acne-specific foam wash twice daily and moisturizer with SPF 30 (broad spectrum). Other objectives included evaluation of changes in the following parameters:
• Total AV lesion counts at Week 2 and Week 4
• Change in inflammatory lesion counts (papules, pustules)
• Change in noninflammatory lesion counts (comedones)
• Cutaneous irritation after two weeks, four weeks, and eight weeks
• Quantitative change in facial skin shininess (Canfield photographic system)
• Quantitative change in skin texture (Canfield photographic system)
• Quantitative changes in Propionibacterium acnes porphyrin fluorescence (Canfield photographic system) • Subject questionnaire at Baseline and Week 8
• Investigator questionnaire at Week 8. Methodology.
An open-label, multicenter study of subjects ?9 years of age with mild or moderate AV who met other inclusion/exclusion criteria and were appropriately consented to being enrolled. The study, conducted in the United States, examined the change in AV lesion counts in study subjects using A-BP0 gel, applied once daily, in conjunction with a designated foam wash twice daily, and designated moisturizer SPF 30, once daily, in the morning.
There were five (5) visits over the course of the study: screening, visit 1 (Baseline), visit 2 (Week 2), visit 3 (Week 4) and visit 4 (Week 8, study endpoint). Subjects used only the provided study products as directed for facial AV over a duration of eight weeks. In the event of a premature termination, exit study procedures were performed as soon as possible.
AV lesion counts and cutaneous tolerability assessments were completed at all study visits with a study treatment questionnaire completed by the investigator at Week 4 and at end of the study. Photographic evaluation for facial skin shininess, skin texture, and P. acnes porphyrin fluorescence were completed at all study visits. Adverse event assessments were conducted at every visit; compliance assessments were also completed.
All efficacy analyses and questionnaires were completed based on the intent-to-treat (ITT) population, which included all subjects who had at least one post-treatment administration evaluation. Last observation carried forward (LOCF) was used to impute missing efficacy data for this population excluding data collected at exit. Completed subject questionnaires were analyzed additionally using “as observed” population, which was defined as all subjects who were enrolled and received at least one dose of any study product. Missing data was excluded from the analysis. The safety population was inclusive of all subjects who used at least one application of study products.
Subject inclusion criteria.
• Men and women aged nine years and older
• Agreed to be photographed at each visit
• Diagnosed with AV of mild or moderate severity (see below) by a board-certified dermatologist and eligible for treatment with A-BPO gel per the package insert
• Women of childbearing potential must have had a negative urine pregnancy test at the clinic at Baseline/visit 1 and must have agreed to abstinence or, if sexually active, practiced two forms of effective birth control methods accepted as defined by the study protocol for the duration of the study
• Agreed to use the provided study products as their only AV treatment, facial wash and facial moisturizer, for the duration of the study
• Agreed to refrain from temporary and permanent tattoos, paint, or other facial art (including, but not limited to piercings), cosmetic procedures, and devices (including, but not limited to facial peels, microdermabrasion, and Clarisonic®) on the face for the duration of the study
• Apprised of Health Insurance Portability and Accountability Act (HIPAA) requirements and applicable state Bill of Rights
• Able to follow instructions, study procedures, and likely to complete all required visits
• Patients aged 9 to 17 years who were able and willing to read and provide written consent through an assent form in conjunction with a parent/legally authorized representative who was able and willing to read and provide written consent prior to any study-related procedure or patients aged 18 and older who were able and willing to read and provide written informed consent prior to any study-related procedures.
Subject exclusion criteria.
• Presence of facial nodules and “cysts”
• Female patients who were pregnant, nursing or planning a pregnancy during the study • Facial hair, a degree of skin pigmentation, abnormal pigmented vascular skin lesions, abnormal skin pigmentation, or body art (tattoos, permanent or temporary) on the face, which could interfere with subsequent study evaluations
• Any systemic or dermatological disorder, a known history of allergies or other medical conditions, which in the opinion of the investigator could interfere with the conduct of the study, interpretation of results, or increase the risk of adverse reactions
• Any known allergies to any of the ingredients listed on the study product labels (refer to the study drug approved package insert)
• Participated in another interventional, investigational drug or device research study within 30 days of enrollment • Study site staff or sponsor staff, relatives of site staff or sponsor, or other individuals who had access to the clinical study protocol
• Patients with a washout period less than one week for OTC topical AV treatments (with active ingredients, such as benzoyl peroxide, salicylic acid, sulfur, and resorcinol), prescription topical AV treatments, topical corticosteroids, and use of cosmetic devices (such as Clarisonic® or similar devices), or less than four weeks for topical retinoids
• Washout period less than four weeks for systemic Rx treatment for AV and systemic corticosteroids and less than 24 weeks for oral retinoids
• Presence of sunburn, eczema, atopic dermatitis, perioral dermatitis, rosacea, or other skin conditions on the area to be treated
• Patients at risk in terms of precautions, warnings, and contraindications (refer to the study drug package insert)
• Patients who anticipate unprotected and intense UV exposure during the study (mountain sports, UV radiation, sunbathing, etc.)
• Any visible skin condition or facial hair that would interfere with the evaluations
• Patients taking or planning to take topical or systemic medications to treat AV during the course of the trial
• Patients taking other medications, supplements, or non-prescription treatments that, in the opinion of the investigator could interfere with study results including any regimen of steroidal/nonsteroidal anti-inflammatory drugs, antihistamines, or anabolic steroids
• Under treatment for asthma or diabetes (insulin-dependent only)
• Surgical or cosmetic procedures planned or completed during the course of the trial
• History of facial procedures within the last 90 days (cosmetic surgery, microdermabrasion, chemical peels, intense pulsed light, fillers, botulinum toxins [i.e., Botox®], lasers, photodynamic therapy, red and blue light therapy, etc.). Acne severity. Mild-to-moderate facial AV severity rating.
• 20 to 50 inflammatory facial lesions (papules and/or pustules excluding the nose)
• 30 to 100 noninflammatory facial lesions (open comedones and/or closed comedones excluding the nose). Daily regimen (CoMMPlete Regimen). Adapalene 0.1%/benzoyl peroxide 2.5% gel (Epiduo® Gel, Galderma Laboratories L.P.) applied once daily; specified foam wash (Cetaphil® DermaControl™ Foam Wash) used twice daily; specified moisturizer SPF 30 (Cetaphil® DermaControl™ Moisturizer SPF 30) applied once daily. Epiduo® Gel Pump, Cetaphil® DermaControl™ Foam Wash (twice daily) and Cetaphil® DermaControl™ Moisturizer SPF 30 (once daily) were provided to each enrolled patient with instructions to use only these products for facial AV over the entire study duration. Study duration. Eight weeks. Study assessments.
• Lesion counts (total, inflammatory, noninflammatory)
• Photographic evaluations using designated Canfield system (skin shininess, skin texture, P. acnes porphyrin fluorescence)
• Cutaneous tolerability scores (stinging/burning, erythema, scaling, dryness)
• Adverse events (AEs)
• Subject questionnaires
• Investigator questionnaire.
Treatment compliance. Adherence with the study treatment regimen by the subject was based on the questioning of the subject at each visit and the weight of study products at dispensation and end of study. Subjects were considered compliant with the treatment regimen if they utilized at least 80 percent, but no more than 120 percent, of the expected doses during participation in the study.
Study discontinuations. Any study patient was free to discontinue participation in the study at any time for any reason, specified or unspecified. Those who discontinued the study prematurely were fully evaluated whenever possible. The reason for premature discontinuation was carefully documented by the investigator on the exit form, and, if applicable, on the AE form. When applicable, the investigator was to ensure that subjects who discontinued prematurely received appropriate therapy for their condition.
For all efficacy variables, descriptive statistics were computed based on the nature of the variable (continuous or categorical). Subject disposition, demographics, baseline characteristics, previous therapies, concomitant therapies, and treatment duration were summarized by descriptive statistics. The change and percent change from baseline in total lesion counts was analyzed by t-tests and signed rank tests for the mean and median, respectively.
AEs were tabulated in frequency tables by treatment, system organ class (SOC), and preferred term (PT) based on the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. AE summary tables were based on the number of subjects who experienced an AE. For a given AE, subjects were counted once even if they experienced multiple episodes for that particular AE.
Study demographics. The study demographics and baseline characteristics of enrolled subjects are depicted in Table 1. The demographic and baseline characteristics for the ITT population (n=77) were similar to the safety population (N=81). The majority of study subjects were Caucasian or Black/African American with a mean age of 19.1 years and a mean duration of AV of 4.4 years. Study disposition. The disposition of study subjects is outlined in Table 2.
Eighty-one subjects 12 years of age or older, with mild-to-moderate AV were enrolled with data from 77 subjects eligible for efficacy analysis and data from 81 subjects available for safety analysis. Most subjects were Caucasian or Black/African American with a mean age of 19.1 years and a mean duration of AV of 4.4 years. Lesion counts. At Baseline, the mean number of total AV lesions was 76.7 (range 52.0—145.0), the mean number of inflammatory lesions was 27.3 (range 20.0—48.0), and the mean number of noninflammatory (comedonal) lesions was 49.4 (range 30.5—100.0). The studied management regimen demonstrated an early onset of therapeutic effect with lesion reductions noted at two weeks, and with continued progressive reductions in AV lesion counts noted throughout the eight-week study. Mean percent change from baseline in total AV lesion counts are shown in Figure 1, with a 30.6 percent reduction at Week 2, 35.9 percent at Week 4, and 44.0 percent reduction at Week 8 (p<0.001). The mean percent change from baseline in inflammatory lesion counts are shown in Figure 2, with reductions of 35.9, 42.5, and 48.1 percent at Weeks 2, 4, and 8, respectively (p<0.001). Mean percent change from baseline in non-inflammatory lesion counts are shown in Figure 3, with reductions of 27.5, 31.8, and 41.8 percent at a Weeks 2, 4, and 8, respectively (p<0.001).
Photographic documentation of skin shininess scores and P. acnes scores (assessed through photographic demonstration of fluorescence) using a designated Canfield photographic system also showed reductions. Mean skin shininess scores decreased when compared to baseline at Week 2 (-1.5), Week 4 (-3.4), and Week 8 (-3.2), with these decreases statistically significant at Week 4 and at Week 8 (p<.05). Mean P. acnes porphyrin fluorescence scores decreased significantly at Weeks 2, 4, and 8 when compared to baseline with reductions of -53.4, -51.8, and -48.1 percent, respectively (p<0.05). No significant changes in skin texture were observed throughout the study.
Questionnaire results.Data from Subject Questionnaires are shown in Figure 4. Results indicated that most subjects noted seeing a positive difference in the appearance of their skin and marked improvement in their acne. In addition, the majority of subjects felt the treatment regimen was easy to use, were satisfied with the treatment regimen, and would continue to use it. Interestingly, at baseline, 15.8 and 18.4 percent stated that use of a moisturizer with sunscreen was “very important” or “important,” respectively (Figure 5). At the end of the study (Week 8), 29.7 percent of patients noted they “strongly agree” and 40.5 percent of patients noted that they “agree” that a moisturizer with sunscreen made specifically for acne-prone skin is important to them (Figure 6). With regard to the Investigator End of Study Questionnaire, all five investigators agreed or strongly agreed that recommending a regimen formulated specifically for patients with AV is important, that they were satisfied with this regimen in treating patients with AV, that they would recommend this regimen to patients with AV, and that recommending a skin care regimen that includes a moisturizer with sunscreen (SPF) specifically made for acne-prone skin is important to them.
Tolerability/safety data.Most subjects did not experience cutaneous irritation (erythema, scaling, dryness, stinging/burning) at sites of use and/or application of the studied products and no subjects experienced severe skin irritation (Table 3; Table 4). Overall, a decrease in signs and symptoms of skin irritation were noted when the worst post-baseline scores from this study (n=77) were compared to the Phase 2 and Phase 3 studies that evaluated A-BPO gel once daily (N=533) by Week 8 in a similar patient population of subjects with AV except that the latter enrolled subjects 12 years of age or older (Table 4).17–19 In the current study, a total of 13 subjects reported 18 AEs, with 17 considered by the investigator to be related to the three-component regimen (CoMMPlete Regimen). No subjects discontinued use of the complete three-component regimen due to AEs and no serious AEs were reported during the study.
Compliance assessment. Seventy-six study subjects (93.8%) were considered compliant with the entire treatment regimen. Four subjects were not fully compliant with use of A-BPO gel or the foam wash treatment and five subjects were not fully compliant with moisturizer SPF 30 treatment.
When devising a management plan for AV, it is important to achieve four primary fundamental goals: cleansing, medicating, moisturizing, and protecting against the adverse effects of sunlight and UV exposure. These four important goals are inherent to a complete regimen that serves to optimize therapeutic outcomes for the patient, primarily by mitigating impairment of the epidermal barrier and its associated skin sensitivity that may be caused by climatic factors (i.e., low humidity), topical medications, and a variety of OTC skin products.[3–5] Some important considerations when selecting a complete treatment regimen that incorporates adjunctive skin care are the onset of therapeutic effect, impact on skin tolerability and irritation, moisturizer tolerability, sunscreen tolerability, overall patient satisfaction with the therapeutic outcome, and patient satisfaction with the skin care products themselves. Use of a moisturizer with sunscreen is an important recommendation for patients with AV. This is especially true in those using topical AV therapy and in those treated with oral antibiotics associated with increased risk of photosensitivity. The moisturizer component assists in mitigating epidermal barrier impairment and its related skin sensitivity and irritation.[1–5] Both the moisturizer and sunscreen components can assist in prevention of residual hyperpigmentation, which can result from skin irritation and inflammation, especially in individuals with darker skin. The sunscreen component may also protect against photosensitivity induced by UV radiation in patients using certain Rx medications for AV.6–11 It is important to recognize that many sunscreens can induce skin irritation and some moisturizers and sunscreens can be acnegenic and comedogenic in a subset of patients.2,12,14–16 The specific moisturizer SPF 30 formulation used in this study as part of the complete three-component regimen incorporates its sunscreen ingredients in a vehicle technology that allows for a broad-spectrum SPF 30 rating using a markedly lower concentration of sunscreens as compared to many other commercially available OTC moisturizer products with sunscreen, thus lowering the potential for irritant skin reactions.1,14,16 To add, the same specific moisturizer SPF 30 formulation has been shown not to be acnegenic or comedogenic and did not exacerbate or worsen AV with continued use, including in subjects using a variety of Rx products for AV.16 Additional characteristics of the specific foam cleanser and the moisturizer SPF 30 and study data with these formulations have been published elsewhere.,, Ultimately, it is prudent for the clinician to use medications for the AV patient that are well-studied, effective, and safe, and to incorporate a concomitant skin care regimen shown to provide adjunctive benefits that optimize the potential for positive therapeutic outcomes.
Another important factor when treating AV is to recommend a management regimen that minimizes factors that are likely to diminish patient satisfaction and adherence (such as inadequate or slow response to therapy, too complicated, too many products, inconvenient, increased risk of skin irritation or other side effects, etc)., An early onset of therapeutic effect is very favorable from the perspective of the patient as it reflects that the treatment regimen is working. In addition, use of a complete management program that is associated with a low risk of cutaneous irritation is important as it reduces the likelihood that a patient will stop treatment due to signs and symptoms of skin irritation that can be associated with topical acne therapy. If a patient is forced to stop applying their acne medication because of skin irritation, the result of interrupted treatment is a marked delay in improvement which is frustrating for both the patient and the clinician. From the perspective of the clinician, it is important to devise a management program for AV treatment that is convenient and efficacious, produces both early and sustained visible therapeutic effects, and is well-tolerated in order to enhance patient adherence and overall satisfaction.,,
The results of this eight-week study support the use of a complete management approach that incorporates an acne-specific skin care regimen (specified foam wash and moisturizer SPF 30) and a single fixed-dose combination Rx topical gel containing adapalene 0.1% and benzoyl peroxide 2.5% that is applied once daily for patients with mild or moderate AV. Outcome data demonstrated effective AV treatment with an early onset of therapeutic benefit; good skin tolerability with broad-spectrum SPF 30 photoprotection; safe use in patients 12 years of age or older; use of specific skin care products that do not exacerbate, worsen, or induce AV and do not interfere with medication efficacy; a convenient and complete regimen with one topical Rx product, a specific facial cleanser used twice daily, and a single moisturizer SPF 30 product applied once daily; and a high degree of overall patient satisfaction. The outcomes of this study support that this three-component topical regimen may provide many adult and pediatric patients affected by mild-to- moderate AV with a complete management program that is convenient, easy to use, effective, well-tolerated, and likely to produce a high level of patient satisfaction.
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