Adapalene 0.1% and benzoyl peroxide 2.5% as a fixed-dose combination gel is as well tolerated as the individual components alone in terms of cumulative irritancy

ARTICLE

Auteur(s) : Christian Loesche, Colette Pernin, Michel Poncet

Galderma Research & Development, 2400 route des Colles, 06410 Biot, France

accepté le 16 Avril 2008

There is no single topical anti-acne medication which acts on all the different major pathophysiological features of acne. Because of this, the combination of acne treatments with different modes of action has the potential to produce better patient outcomes than monotherapy.

Retinoids (e.g. adapalene and tazarotene) and benzoyl peroxide (BPO) have complementary mechanisms of actions; adapalene 0.1% is a well-tolerated and efficacious topical retinoid with anticomedogenic, comedolytic, and anti-inflammatory properties [1-4], whilst BPO is a well established antimicrobial agent which is more effective than topical antibiotics against Propionibacterium acnes [5].

A 12-week randomised study comparing adapalene/BPO gel with adapalene 0.1% gel and BPO 2.5% gel found the combination was significantly more effective than corresponding monotherapies, with significant differences in total lesion counts observed as early as Week 1 [6].

In a 12-month, open label, continuous-use study of a new fixed-dose combination of adapalene 0.1% and BPO 2.5% (hereafter, “adapalene/BPO gel”), early and sustained reductions in inflammatory and non-inflammatory lesions were observed, with clinically significant lesion reductions from Week 1 [7].

In addition to advantages in terms of efficacy, combining adapalene 0.1% and BPO 2.5% may decrease the incidence of epidermal bacterial resistance relative to antibiotics because neither retinoids nor BPO are known to induce resistance [8, 9]. Fixed-dose combination products also offer advantages in terms of ease of use, which can improve the patient’s adherence to treatment, in turn improving the treatment outcomes.

The choice of treatments and dosages in this fixed dose combination offers specific advantages. The retinoid adapalene is stable when combined with BPO in the presence or absence of light, which is not the case for tretinoin [10]. The choice of strength of BPO 2.5% is justified as it has been shown to be as effective as higher concentrations (BPO 5% and 10%) whilst causing fewer side effects [11, 12].

The safety of this new combination product was compared to that of the products used alone and to other marketed products in terms of specific safety parameters. The results of a study assessing cumulative irritancy are reported here.

Materials and methods

This single centre, controlled, randomized, investigator-masked, intra-individual study was conducted in May and June 2002. The objective of the study was to compare, on healthy subjects, the cumulative irritancy of adapalene/BPO gel (Epiduo™, Galderma) with that of adapalene 0.1% gel, BPO 2.5% gel, BPO 10% gel (Cutacnyl^®), a negative control (vehicle) and a positive control (tazarotene 0.1% gel, Zorac^®). Tazarotene 0.1% gel is a retinoid which is approved for use as an acne treatment in the US and so was considered to be a relevant comparator.

Six 2 cm × 2 cm zones were selected on the upper back of each subject and the product to be applied to each zone was determined by a randomization list. Study personnel other than the investigator applied 25 μL of each product under semi-occlusive conditions five times a week (weekdays only) for three weeks, i.e. a total of 15 applications. Treatments were left on for approximately 24 hours, except for the Friday treatment, which remained on over the weekend (approximately 72 hours).

Skin assessments were conducted by the investigator 24 hours after product application (72 hours following application on a Friday), immediately before the next product application. Erythema was graded on a 5-point scale (0 = no reaction, 0.5 = erythema barely visible, 1 = mild erythema, 2 = moderate erythema, 3 = severe erythema) and oedema was graded on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). Other local reactions such as papules, pustules, vesicles, blisters, hyperpigmentation, weeping or oozing of the application site or spreading of any reaction beyond the test area were reported individually. Adverse events were recorded at each visit. In case an application had to be discontinued due to severe irritation (erythema score of 3), the score was carried forward from the day following the last application until the end of the study.

A Cumulative Irritancy Index (CII) for each product and each subject was calculated by dividing the sum of all erythema scores across readings (Day 1 to Day 21) by the number of readings. Individual CIIs were submitted to analysis of variance for Latin square design, with effects for subject, zone and product, followed by the Tukey multiple comparison test comparing all products, at the 5% significance level. The primary safety variable was the Mean Cumulative Irritancy Index (MCII) which was calculated for each product by averaging individual CIIs across subjects. The worst scores for erythema were summarized in a frequency table.

Results

The MCII for adapalene/BPO was low (0.046) and was comparable to all test products (0.043 for BPO 2.5%, 0.017 for adapalene 0.1%, 0.026 for BPO 10% and 0.011 for the vehicle) with the exception of tazarotene 0.1% gel which had a significantly greater MCII than all other products (0.616, p < 0.05) (figure 1).

Adapalene/BPO and its individual components were all well tolerated in terms of erythema and other cutaneous reactions.

For each treatment, the number of subjects assigned a worst erythema score ranging from 0 to 3 is displayed in table 2. With adapalene/BPO gel, over 65% of subjects experienced no erythema with no subjects experiencing severe erythema. The incidence and severity of erythema with adapalene/BPO gel was similar to that of the individual components. In contrast, over 95% of subjects experienced erythema with tazarotene and 33% of subjects experienced severe erythema. In addition, three subjects suffered from severe irritation to tazarotene leading to product discontinuation on Day 17 for one subject and Day 18 for two subjects.

One subject had an oedema score of mild severity on the tazarotene-treated zone at Days 14, 15 and 17. All other oedema scores were zero.

The number of subjects experiencing reactions other than erythema or oedema with the test products ranged from 0/24 (gel vehicle) to 8/24 (33%) with the fixed-dose combination (table 3), while all subjects (24/24, 100%) experienced other reactions to tazarotene (including papules, vesiculation and hyperpigmentation).

There were no serious adverse events and no adverse events leading to treatment discontinuation. Ten subjects experienced a total of 11 non-serious adverse events, two of which were dermatological (papulo-pustular acne and Tinea versicolor, both on the back) and none of which were treatment-related. No allergic reactions were reported.
Table 1 Baseline characteristics of subjects

Table 3 Number of subjects who experienced a reaction other than erythema or œdema

Discussion

The study reported here showed that adapalene/BPO as a fixed-dose combination gel was as well tolerated as adapalene gel and BPO gel alone in terms of cumulative irritation. The study demonstrated that the addition of adapalene at a concentration of 0.1% does not significantly modify the cumulative irritation profile of BPO 2.5% gel. Indeed, under the semi occlusive conditions of this study, the numbers of skin reactions including erythema were low for all products, except the active control (tazarotene 0.1% gel) which was significantly more irritating than any of the other treatments tested.

The results of this study are in line with results from the 12-month continuous-use study during which most adverse events and symptoms of skin irritation were mild-to-moderate, occurred early in the study, and were transient [7].

In conclusion, the results of the study presented here demonstrate that the fixed-dose combination of adapalene/BPO gel is well tolerated, and that cumulative irritancy of BPO is not increased by the addition of adapalene.

Acknowledgements

References

2 Tenaud I, Khammari A, Dreno B. In vitro modulation of TLR-2, CD1d and IL-10 by adapalene on normal human skin and acne inflammatory lesions. Exp Dermatol 2007; 16(6): 500-6.

3 Thiboutot DM, Gollnick HP. Treatment considerations for inflammatory acne: clinical evidence for adapalene 0.1% in combination therapies. J Drugs Dermatol 2006; 5(8): 785-94; [Review. Erratum in: J Drugs Dermatol. 2007 Jan; 6 (1): table of contents].

4 Waugh J, Noble S, Scott LJ. Adapalene: a review of its use in the treatment of acne vulgaris. Drugs 2004; 64: 1465-78.

5 Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol 2001; 15(Suppl 3): 51-5.

6 Thiboutot DM, Bucko A, Eichenfield L, et al. Adapalene-benzoyl peroxide, a new fixed-dose combination for the treatment of acne vulgaris: results of a randomized, multi-centre, double-blind, controlled study. J Am Acad Dermatol 2007; 57(5): 791-9; (Epub 2007 Jul 26).

7 Pariser DM, Westmoreland P, Morris A, Gold MH, Liu Y, Graeber M. Long-term safety and efficacy of a new fixed-dose combination of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol 2007; 6(9): 899-905.

8 Harkaway KS, McGinley KJ, Foglia AN, et al. Antibiotic resistance patterns in coagulase-negative staphylococci after treatment with topical erythromycin, benzoyl peroxide, and combination therapy. Br J Dermatol 1992; 126(6): 586-90.

9 Thielitz A, Krautheim A, Gollnick H. Update in retinoid therapy of acne. Dermatol Ther 2006; 19(5): 272-9.

10 Martin B, Meunier C, Montels D, Watts O. Chemical stability of adapalene and tretinoin when combined with benzoyl peroxide in presence and in absence of visible light and ultraviolet radiation. Br J Dermatol 1998; 139(Suppl 52): 8-11.

11 Mills Jr. OH, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 1986; 25: 664-7.

12 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 2008; 81: 278-84.