J. K. L. Tan, MD, FRCPC
Department of Medicine, University of Western Ontario, London, ON, Canada
Topical products commonly used to treat acne include retinoids and antimicrobials, due to their effects on different components of pathogenesis. Accordingly, a fixed combination of adapalene 0.1% and benzoyl peroxide (BPO) 2.5% was developed (Epiduo™, Galderma) and was approved by the US FDA in December 2008 for the treatment of acne. The superior efficacy of this combination was demonstrated in 2 large randomized controlled trials. This paper reviews the evidence for efficacy and tolerability of the combination of the retinoid adapalene 0.1% and BPO 2.5%, a once-daily gel formulation for the treatment of acne.
acne; adapalene; antibiotics; benzoyl peroxide; retinoids
Adapalene, a receptor-selective naphthoic acid derivative with retinoid-like properties, has comedolytic, anticomedogenic, and anti-inflammatory effects. Benzoyl peroxide (BPO) is a highly lipophilic oxidizing agent with bacteriocidal and keratolytic effects. The addition of adapalene with BPO does not result in chemical or photo-instability of the combined product. Retinoids are considered first line therapy for mild comedonal and inflammatory acne.1 In dermatological practice, topical retinoids are the class of agents most commonly used as topical monotherapy for acne. When 2 topical agents are used, the agents most frequently selected are retinoids and BPO, either alone or with antibiotics.2 In view of the primary role of these 2 classes of topical agents, a single formulation comprising both is rational and may increase adherence and improve overall efficacy.
Review of Clinical Studies
Individually, topical retinoids and BPO are potentially irritating agents and a combination product may increase this potential. In an irritancy study3 comparing adapalene 0.1% gel, tazarotene cream 0.05%, and tretinoin microsphere gel 0.04% used in combination with 2 different clindamycin/BPO products under occlusion, the adapalene 0.1% gel was reported to be the least irritating. This 3-week randomized, controlled intraindividual study involved test site applications at the back under occlusion. The tolerability of 2 different combination clindamycin/BPO topical products followed 8 hrs later by adapalene 0.1% gel, tazarotene cream 0.05%, and tretinoin microsphere gel 0.04% was evaluated. Regardless of the type of clindamycin/BPO combination, the mean cumulative irritancy index and erythema scores were significantly lower for sites involving adapalene gel. The combination of adapalene 0.1% and BPO 2.5% was selected for further development based on a cutaneous tolerability study4 evaluating adapalene 0.1% combined with either BPO 2.5% or 5%. In that study, 60 healthy subjects were randomized into a 3 week split-face trial with daily application of adapalene 0.1% + BPO 2.5%, adapalene 0.1% + BPO 5%, BPO 2.5% or 5%. This study showed that irritation scores (total sum score comprising erythema, dryness, pruritus, and stinging/burning) for adapalene 0.1% + BPO 2.5% were lower than for the combination product containing BPO 5%, and similar to BPO 5% alone.
Randomized-Controlled Trials (See Table 1)
A Phase II/III randomized, double-blind, parallel group study5 of adapalene 0.1% + BPO 2.5% gel, adapalene 0.1% gel,
BPO 2.5% gel, or vehicle gel used nightly for 12 weeks involved 517 acne patients enrolled in a 2:2:2:1 ratio, respectively. The combination arm was significantly more
effective in achieving a facial acne global grade of clear/almost
clear (i.e., 28% vs. 16% vs. 15% vs. 10%, respectively). The differences were significant against the BPO (P=0.003) and vehicle (P=0.02) arms, and borderline for adapalene itself (P=0.08). Significant improvements in the lesion counts were observed for the combination compared with monotherapy and vehicle arms. Total acne lesions were reduced by 51% (median 78 at baseline to 40 at end of study), inflammatory lesions by 63% (27 to 17), and noninflammatory lesions by 51% (44 to 22). Overall local tolerability of the combination was similar to that for adapalene alone, with a somewhat higher percentage of subjects in the combination group having erythema, dryness, and/or stinging/burning. Mean tolerability scores, based on erythema, scaling, dryness, and stinging/burning, peaked at the first week and declined thereafter. Mean symptom scores were mild or less for all treatment arms.
A subsequent larger Phase III double-blind, randomized-controlled trial6 (RCT) with similar trial design involving 1668 patients randomized into the same 4 treatment arms in a 1:1:1:1 ratio was performed. Results demonstrated that the combination was more effective in achieving clear/almost clear global scores (30% vs. 20% for adapalene 0.1% gel , 22% for BPO 2.5% gel and 10% for vehicle gel), and in reducing acne counts. Total acne counts were reduced by 56% (median 76 at baseline to 35 at end of study), inflammatory lesions by 62% (27 to 11), and noninflammatory lesions by 54% (44 to 20). A significant reduction in all lesion counts were noted within the first week of treatment compared with vehicle. Local intolerability adverse events were mild-to-moderate
in all treatment arms and peaked during the first week. However, more patients in the adapalene + BPO combination group experienced signs and symptoms of local intolerability compared with the other treatment groups. The number of patients with adverse events leading to discontinuation was slightly higher with the combination compared with adapalene monotherapy, BPO monotherapy, and vehicle groups: 11 (2.7%) vs. 4 (1.0%), 5 (1.2%), and 2 (0.5%), respectively. The most frequent treatment-related adverse event was dry skin, which was higher in the combination and adapalene groups than in the BPO monotherapy and vehicle groups (i.e., 6.0%, 4.3%, 1.9%, and 2.2% respectively).
in Vehicle Gel
in Vehicle Gel
|Thiboutot, et al.5||number of patients||149||148||149||71|
|success rate (%)||28||16||15||10|
|P-value (vs. Epiduo™)||0.008||0.003||0.002|
|total lesions (median % change)||-51||-35*||-36*||-31*|
|Stein-Gold et al.6||number of patients||415||420||415||418|
|success rate (%)||30||20||22||11|
|P-value (vs. Epiduo™)||<0.001||0.006||<0.001|
|total lesions (median % change)||-56||-47**||-48**||-28**|
|Pooled outcomes||number of patients||564||568||564||489|
|success rate (%)||28||18||19||10|
|Table 1: Efficacy of Epiduo™ and its components on success rate and lesion reduction in acne (success defined as investigator global scores of clear or almost clear).|
* P <0.001; ** P < 0.017
Long-term Safety and Efficacy
The long-term tolerability and safety of adapalene 0.1% + BPO 2.5% gel was evaluated in 452 acne subjects over 12 months.7 Of these, 327 completed the study (72%). No subjects discontinued due to lack of efficacy, while discontinuation due to adverse events was 2%. Overall, treatment was well tolerated with mean scores for local intolerance (comprising erythema, dryness, scaling, and burning/stinging) reported as mild or less in all study visits. The mean worst scores of subjects were consistent with mild irritation. The highest irritation scores were recorded at the first week and subsequently declined thereafter. The most common adverse event was dry skin (17%). Efficacy, based on the intent to treat population with last observation carried forward, was 65% reduction in total, 70% in inflammatory, and 66% in noninflammatory lesion counts.
The combination of adapalene 0.1% + BPO 2.5% gel in a single formulation is a novel topical agent for the treatment of mild-to-moderate inflammatory acne. The clinical efficacy and tolerability of this fixed dose combination over 12 weeks has been shown in 2 large high quality RCTs. Furthermore, long-term tolerability and ongoing efficacy has been demonstrated in a 12-month study.
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- Tan J, Balagurusamy M, Fung K. et al. The effect of QoL impact and clinical severity on adherence to topical acne treatment. J Cutan Med Surg. In press (2009 Feb).
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- Andres P, Pernin C, Poncet M. Adapalene-benzoyl peroxide once-daily, fixed dose combination gel for the treatment of acne vulgaris: a randomized, bilateral (split-face, dose-assessment study of cutaneous tolerability in healthy participants. Cutis 81(3):278-84 (2008 Mar).
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- Stein-Gold L, Tan J, Werschler W et al. Adapalene-benzoyl peroxide, a unique fixed dose combination gel for the treatment of acne: A North American, multicenter, randomized, double-blind, controlled, Phase III trial in 1,668 patients. Cutis. In press (2009 Apr).
- Pariser D, Westmoreland P, Morris A, et al. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1%. J Drugs Dermatol 6(9):899-905 (2007 Sep).