ADIS DRUG EVALUATION

Drugs 2004; 64 (13): 1465-1478 0012-6667/04/0013-1465/$34.00/0 2004 Adis Data Information BV. All rights reserved.

Adapalene
A Review of its Use in the Treatment of Acne Vulgaris
John Waugh, Stuart Noble and Lesley J. Scott
Adis International Limited, Auckland, New Zealand

Various sections of the manuscript reviewed by: N. Auffret, Hopital Europeen Georges Pompidou, Paris, France; S. Bershad, Department of Dermatology, The Mount Sinai School of Medicine, New York, New York, USA; P. Coates, Department of Dermatology, The General Infirmary at Leeds, Leeds, United Kingdom; B. Dreno, Clinique Dermatologique, Centre Hospitalier Regional University De Nantes, Nantes, France; A.M. Layton, Harrogate District Hospital, Harrogate, United Kingdom; J.C. Shaw, Division of Dermatology, University of Toronto, Toronto, Canada.

Data Selection Sources: medical literature published in any language since 1997 on adapalene, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: Medline search terms were adapalene or CD-271. EMBASE search terms were adapalene or CD 271. AdisBase search terms were adapalene or CD271. Searches were last updated 10 May 2004. Selection: Studies in patients with acne vulgaris who received adapalene. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Adapalene, acne vulgaris, pharmacodynamics, pharmacokinetics, therapeutic efficacy, tolerability.

Contents
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1466 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467 2. Pharmacological Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467 2.1 Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1467 2.2 Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1468 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1468 3.1 Comparison with Other Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1469 3.1.1 Comparison with Tretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1469 3.1.2 Comparison with Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1469 3.2 Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1471 3.2.1 Maintenance Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1472 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1472 4.1 General Tolerability Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473 4.2 Comparative Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473 4.2.1 Versus Tretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1473 4.2.2 Versus Tazarotene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1474 4.3 Adjunctive Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1475 6. Place of 0.1% Adapalene Gel in the Management of Acne Vulgaris . . . . . . . . . . . . . . . . . . . . . . . . . 1475

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Summary
Abstract

Adapalene (Differin) is a retinoid agent indicated for the topical treatment of acne vulgaris. In clinical trials, 0.1% adapalene gel has proved to be effective in this indication and was as effective as 0.025% tretinoin gel, 0.1% tretinoin microsphere gel, 0.05% tretinoin cream and 0.1% tazarotene gel once every two days; however, the drug was less effective than once-daily 0.1% tazarotene gel. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favourable tolerability profile compared with other retinoids. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the first-line treatment of acne vulgaris. Adapalene is a chemically stable derivative of naphthoic acid that binds selectively to the nuclear retinoic acid receptor (RAR) subtypes RAR (found mainly in the epidermis) and RAR (found in dermal fibroblasts), activating genes responsible for cellular differentiation; it does not bind to cytosolic retinoic acid binding proteins. Adapalene is thought to modulate keratinisation, differentiation and inflammation of follicular epithelial cells. This results in a reduction in microcomedones, the precursors of acne lesions. Absorption of 0.1% adapalene gel through human skin is low. Adapalene was not detected in plasma in volunteers after topical application of either the gel or cream, nor was it detected in urine, faeces or skin. In animals, metabolism is via O-demethylation, hydroxylation and conjugation, and excretion is primarily by the biliary route. There are no known interactions with other drugs and, because of the low absorption through the skin, interaction with systemic drugs is unlikely. Across several endpoints (including the mean percentage reduction in the number of inflammatory and noninflammatory lesions), 0.1% adapalene gel had similar efficacy to 0.025% tretinoin gel, 0.05% tretinoin cream and 0.05% isotretinoin cream as well as the newer 0.1% tretinoin microsphere gel formulation in the treatment of mild-to-moderate acne vulgaris. Data were from predominantly multicentre, randomised, single- or double-blind, parallel-group trials. After 812 weeks treatment, the percentage reductions in lesion counts were 4775% and 3873% for adapalene and 0.025% tretinoin gel treatment groups (inflammatory lesions), respectively, and 4683% and 33%83% (noninflammatory lesions). The similar efficacy of these two treatments was confirmed by two meta-analyses. The onset of action with 0.1% adapalene gel is rapid and generally appears to be similar to that with tretinoin formulations. In two randomised, double-blind, parallel-group studies, patients with mild-tomoderate acne vulgaris receiving 0.1% tazarotene gel once daily had significantly greater reductions in inflammatory and noninflammatory lesions than 0.1% adapalene recipients. The same dosage of 0.1% adapalene gel showed similar efficacy to that of 0.1% tazarotene gel once every two days (dosage reduced to improve tolerability) in another trial of the same design. Data indicate that 0.1% adapalene gel is effective in combination with topical clindamycin or benzoyl peroxide or oral cyclines (lymecycline, minocycline) in reducing the number of inflammatory and noninflammatory lesions in patients with mild-to-moderate or moderate to moderately severe acne vulgaris. Furthermore, 0.1% adapalene gel was effective as maintenance treatment following treatment with clindamycin plus adapalene.
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Pharmacological Properties

Therapeutic Efficacy

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Tolerability

Adapalene was generally better tolerated than comparators, particularly in the first 4 weeks of treatment. The most commonly reported adverse events in both adapalene and comparator recipients were erythema, dry skin, pruritus, desquamation and stinging/burning sensations. These were generally less severe in adapalene recipients than in the recipients of other topical retinoids. Several randomised, intraindividual patch studies in healthy volunteers found 0.1% adapalene gel was the least irritating acne treatment when compared with various concentrations of tretinoin gel, cream, the new formulation of tretinoin (0.1% and 0.04% tretinoin microsphere gel) or with tazarotene gel. When used as adjunctive therapy with topical clindamycin or oral lymecycline, 0.1% adapalene gel was generally well tolerated compared with gel vehicle plus the respective antibacterial agent. Overall, local cutaneous adverse events were mild in intensity.

1. Introduction Acne is a chronic, inflammatory disorder of the pilosebaceous unit that affects almost everyone at some stage between the ages of 12 and 24 years.[1] It is related to neither hygiene nor diet, though there appears to be a genetic predisposition in severe cases.[2] It is a multifactorial disease; the main pathophysiological factors that influence the development of acne are excessive sebum secretion, abnormal keratinisation and desquamation of sebaceous-follicle epithelium (comedogenesis), proliferation of Propionibacterium acnes in the pilosebaceous duct and inflammation.[3,4] Treatments for acne address the various factors responsible for it. They include estrogens and antiandrogens to reduce the impact of androgens, antibacterial agents to reduce P. acnes colonisation of the pilosebaceous unit, and retinoids to reduce hyperproliferation and keratosis of ductal corneocytes.[3,4] Choice of treatment is dependent on the type and severity of the disorder.[5] If the acne is mainly comedonal, retinoids are the first-line treatment. In the case of inflammatory acne, topical and/ or systemic antimicrobial agents may be used in addition to retinoids. In cases that fail to respond to such treatment, oral isotretinoin may be prescribed.[6] Although definitive data are lacking, clinical experience suggests that early treatment of comedones reduces scarring and may prevent progression to the more severe inflammatory acne.[2,4]
1

Tretinoin was the first retinoid used in the treatment of acne.[3] It is generally effective and widely used, but its relatively high incidence of adverse events may militate against adequate patient compliance and, therefore, efficacy. Adapalene is one of the newer retinoids. Although adapalene cream and solution are available in the US, the 0.1% adapalene gel (Differin)1 is the focus of this review, which evaluates the efficacy and tolerability of 0.1% adapalene gel compared with 0.025% tretinoin gel or newer formulations of tretinoin or tazarotene in the treatment of acne vulgaris. Adapalene has also been investigated in the treatment of actinic keratoses and lentigines;[7] however, these indications fall outside the scope of this review. 2. Pharmacological Properties
2.1 Pharmacodynamic Properties

The pharmacodynamic properties of adapalene have been reviewed previously in Drugs[8] and are briefly overviewed here. Adapalene, a chemically stable derivative of naphthoic acid, binds selectively to specific nuclear retinoic acid receptors (RARs) but not to cytosolic retinoic acid binding proteins, thus activating genes responsible for cellular differentiation.[9,10] It shows greatest affinity for subtypes RAR, found mainly in the epidermis, and RAR which, in the skin, is found principally in dermal fibroblasts.[9,11]

The use of trade names is for product identification purposes only and does not imply endorsement.

2004 Adis Data Information BV. All rights reserved.

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Table I. Plasma adapalene (ADA) concentrations following topical application of the 0.1% gel or cream in healthy volunteers[14,15] or in patients with acne[13] Study No. of participants 8 Treatment Limit of detection (ng/mL) Resultsa

Caron et al.[14]

A single topical application of 5g of 0.1% [14C]ADA gel (n = 4) or a NR single topical application of 5g of 0.1% [14C]ADA gel following 2wk non-labelled ADA 0.1% gel treatment (n = 4) 2g of 0.1% ADA cream applied to 1000 cm2 of acne-affected skin once daily for 5d A full tube (30g) of 0.1% ADA gel applied all over the body each day for 7d 0.35 0.15 0.15

ADA not detected

Galderma Laboratories[13] Medsafe[15] Medsafe[15] a

6 NR

ADA not detected ADA not detected ADA not detected

6 Daily application of 0.1% ADA gel for 3mo Time of sample collection not stated.

NR = not reported.

Adapalene shows similar activity in inhibiting epithelial cell proliferation to tretinoin.[8] The mode of action is unclear, but topical application is thought to modulate keratinisation, inflammation and differentiation of follicular epithelial cells.[10,11] This results in a reduction in the formation of microcomedones and of the inflammatory lesions associated with acne vulgaris.[12] In vitro and in vivo studies in the rhino mouse strain reported in the previous review found that both comedogenesis and inflammation were reduced after topical application of 0.1% adapalene gel.[8]
2.2 Pharmacokinetic Properties

droxylation and conjugation,[15] and excretion is primarily by the biliary route.[10] There are no known interactions with other drugs; however, drugs with similar modes of action should not be used concurrently with adapalene.[10] Absorption through the skin is low, so interaction with systemic drugs is unlikely. 3. Therapeutic Efficacy The efficacy of 0.1% adapalene gel has been compared with that of 0.025% tretinoin gel,[16-22] 0.05% tretinoin cream[23] or 0.05% isotretinoin gel,[24] or the newer 0.1% tretinoin microsphere gel formulation[25,26] (section 3.1.1), and 0.1% tazarotene gel[27,28] (section 3.1.2) in the treatment of acne vulgaris. These studies were randomised, short-term (8- to 12-week), single-[16-21,23,24,26] or doubleblind[22,25,27,28] and parallel group in design. In addition, the use of 0.1% adapalene gel as adjunctive therapy in combination with antibacterial agents[29-32] or benzoyl peroxide[33] has been evaluated in 12- or 24-week, multicentre, randomised, investigator-blind[29,30,34] or nonblind[32,33] trials in patients with acne vulgaris. Patients for all studies were aged 1140 years (mean age 1722 years) and had mild-to-moderate (or moderate-to-severe in some of the combined therapy trials[29,32,34]) facial acne vulgaris graded 15 on the global facial acne scale devised by Burke and Cunliffe (a higher score indicates worse acne).[35] All treatments were applied to a clean, dry face in the evening before retiring. A minimum of ten inflammatory (mean range at baseline 1943) and ten
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Absorption of adapalene through human skin is low. In several absorption studies,[13-15] adapalene was not detected in plasma following topical application of 0.1% adapalene gel or cream (table I). Five of six female volunteers showed no sign of adapalene in adipose tissue (limit of detection 1 ng/g) after 3 months of daily topical treatment with 0.1% adapalene gel.[15] The other volunteer had mean concentrations of adapalene at three sites of 1.1, 1.3 and 5.5 ng/g. Adapalene concentrations were below the limit of detection in this individual 1 month after cessation of treatment.[15] In addition, topical 0.1% [14C]adapalene gel was undetectable in urine, faeces and skin strip samples from eight healthy volunteers.[14] The metabolism of adapalene in human volunteers or patients has not been examined; however, in animals, metabolism is via O-demethylation, hy 2004 Adis Data Information BV. All rights reserved.

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noninflammatory (mean range at baseline 4088) lesions were required for inclusion.[16-30,32,33] Patients with drug-induced or severe acne, such as acne conglobata or fulminans, or those who had taken systemic retinoids within the previous 612 months were excluded from some trials,[20,25] as were those who had taken systemic antibacterial agents or other anti-acne treatments within 26 weeks of commencement of all trials.[16-20,22-30,33,34] The efficacy parameter common to most studies was the reduction in the number of inflammatory and noninflammatory lesions (sections 3.1.1, 3.1.2 and 3.2). Other reported endpoints included the mean percentage improvement in global severity scale scores[17-19,27,28,30,32] (assessed using the Burke and Cunliffe scale in some trials[17-19]) and the percentage of patients showing improvement.[16-19,23,24,27-29] The reduction in lesion count was the primary endpoint in several studies;[16,17,19,26,34] the remaining studies did not specify if endpoints were primary or secondary efficacy measures. In general, baseline characteristics were similar between treatment groups within trials, with one exception[25] where there was a significant difference in the number of noninflammatory lesions between groups (48.6 vs 40.5; p < 0.05 vs 0.1% tretinoin microsphere gel). Most analyses were carried out on a per-protocol basis; however, some[23,29,30] used an intention-to-treat design. Recent noncomparative[36] and single-blind, placebo-controlled[37] studies showed that 0.1% adapalene gel was more effective than placebo in the treatment of mild-to-moderate acne vulgaris. These studies are not discussed further in this section.
3.1 Comparison with Other Retinoids

3.1.1 Comparison with Tretinoin

The efficacy of 0.1% adapalene gel is similar to that of 0.025% tretinoin gel in the treatment of mildto-moderate acne vulgaris.[16-22] Adapalene and tretinoin reduced the number of inflammatory lesions at the end of treatment by 4775% and 3873%, and the number of noninflammatory lesions by 4683% and 3383% in randomised trials.[16-22] Severity scale improvements with adapalene (3980%) were also similar to those for tretinoin (3972%) in sever 2004 Adis Data Information BV. All rights reserved.

al trials.[17-19] These data were confirmed by two meta-analyses.[38,39] In addition, 0.1% adapalene gel had similar efficacy to other formulations of tretinoin (0.1% tretinoin microsphere gel,[25,26] 0.05% tretinoin cream[23] and 0.05% isotretinoin gel,[24]) in patients with mildto-moderate acne vulgaris, as measured by mean percentage reduction in the number of inflammatory or noninflammatory lesions[23-26] and percentage of patients showing improvement[23-25] (table II).[23-25] Recipients of all treatments showed improvements in total lesion counts from baseline;[23-25] however, the statistical significance of this difference from baseline was generally not reported (table II). Adapalene has a rapid onset of action (within 1 week),[18,24] which appears generally similar to that of tretinoin,[17,18,20-22,25,26,38,40,41] although significant differences between treatments have been reported at individual early timepoints in some small trials.[18,24] In two recent, randomised, nonblind[24] or singleblind[18] trials, 0.1% adapalene gel provided a significantly faster onset of action than 0.025% tretinoin gel (32% vs 17% reduction in inflammatory lesions at week 1; p = 0.001)[18] or than 0.05% isotretinoin gel (23% vs 9% reduction in inflammatory lesions at week 2; p 0.05; 52% vs 36% reduction in noninflammatory lesions at week 4; p 0.05)[24]. Conversely, a double-blind study indicated that 0.1% tretinoin microsphere gel provided a significantly faster (p < 0.05) onset of action at week 4, with a 9% reduction in inflammatory lesions compared with a 4% increase in the adapalene group.[25] Nonetheless, a meta-analysis[38] based on published and unpublished 12-week, randomised, single-blind, multicentre trials with the same primary endpoint that used intention-to-treat analyses showed a more rapid onset of action at week 1 with adapalene than with tretinoin (28% vs 22% reduction in total lesion numbers; p < 0.05). There were no significant between-group differences at other timepoints (2, 4, 8 and 12 weeks).[38] Whether this statistically significant between-group difference in the onset of action is clinically relevant remains to be determined.
3.1.2 Comparison with Tazarotene

Although 0.1% adapalene gel once daily showed similar efficacy to 0.1% tazarotene gel once every 2
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Table II. Comparative efficacy of adapalene (ADA) versus tretinoin. Summary of randomised, parallel-group, multicentre trials in which 0.1% adapalene gel and various formulations of tretinoin were compared in the treatment of patients with mild-to-moderate acne vulgaris. All trials were of 12 weeks duration except Tu et al.[16] (8 weeks) and Cunliffe et al.[23] (10 weeks). Treatments were applied topically once daily in the evening. All endpoints were investigator assessed and analyses were on-treatment unless stated otherwise Study Drug No. of evaluable patients 30 30 131 128 111 126 48 46 149 139 72 67 24 24 Mean reduction in no. of inflammatory/noninflammatory lesions (%) 69/77 73/81 64/70 63/67 47/57 50/54 53c/54c 65c/67c 48/46 38/33 75/70 72/70 69/83 50/83 70 56 Reduction in mean grade for global severity scale (%)a 80 70 56 59 39* 39* 56 72 Patients showing improvement (%)b

Compared with 0.025% tretinoin gel (TRE-G) Alirezai et al.[20] Cunliffe et al.[19] Ellis et al.[17] Grosshans et al.[18] Shalita et al.[21] Tu et al.[16] Verschoore et al.[22] ADA TRE-G ADA TRE-G ADA TRE-G ADA TRE-G ADA TRE-G ADA TRE-G ADA TRE-G 90 93 72 75 88.4 89.6 >90 >90 29 18 75 73

Compared with 0.1% tretinoin microsphere gel (TRE-M) Nyirady et al.[25] Thiboutot et al.[26] ADA TRE-M ADA TRE-M Compared with 0.05% tretinoin cream (TRE-C) Cunliffe et al.[23] ADA TRE-C Compared with 0.05% isotretinoin gel (I-TRE) Ioannides et al.[24] a b ADA I-TRE 36 31 62/74 57/68 97 90 384de 28/45 33/50 59.6 57.7 84 82 161d 27c/44c 26c/46c 35c/37c 32c/44c 83 73

Assessed using the Burke and Cunliffe scale. Improvement was variously described as either a 50% reduction in total lesions,[20] showing some improvement,[17] showing excellent improvement,[21] showing clearance or marked or moderate improvement,[16] or showing good or excellent improvement.[24] Data estimated from a graph. Total population; patient numbers were not reported separately for individual treatment groups. Intention-to-treat analysis.

c d e

* p < 0.001 vs baseline;

p < 0.05 vs TRE-G.

days (frequency of application was reduced to improve tolerability [section 4]),[27] the drug was less effective than once-daily tazarotene (standard regimen) in a randomised double-blind trial.[28] Oncedaily 0.1% tazarotene gel recipients with mild-tomoderate acne vulgaris had significantly greater reductions in inflammatory and noninflammatory lesions than 0.1% adapalene gel recipients, with sig 2004 Adis Data Information BV. All rights reserved.

nificantly more patients achieving 50% improvement in their acne (p 0.01 in all comparisons) [table III].[28] An analysis of 145 patients treated with 0.1% adapalene gel (n = 73) or 0.1% tazarotene gel (n = 72) once daily in a multicentre, double-blind trial in the US found that the cost per treatment
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success for adapalene was $US107.88 versus $US79.95 for tazarotene.[28]

3.2 Adjunctive Therapy

Adapalene has been found to be effective as an adjunctive treatment to topical clindamycin,[30,32] oral antibacterial medications[29,34] and benzoyl peroxide[33] in the treatment of acne vulgaris (table IV). When combined with 1% clindamycin topical lotion twice daily,[30] 0.1% adapalene gel once daily led to a significantly greater reduction in acne lesions than the antibacterial agent plus adapalene gel vehicle (hereafter referred to as gel vehicle) in patients with mild-to-moderate acne vulgaris (table IV). Furthermore, clindamycin plus 0.1% adapalene gel recipients showed significantly greater improvement in global severity grade than clindamycin plus gel vehicle recipients at weeks 8 (p = 0.006) and 12 and (p <0.001).[30] These results were supported by those of Zhang et al.[32] who found 1% clindamycin topical solution twice daily plus 0.1% adapalene gel once daily significantly more effective than clindamycin alone in patients with moderate to moderately severe acne vulgaris. Significant improvements in lesion counts (table IV), global severity scale (p < 0.05) and global assessment of improvement (p < 0.05) were observed in patients adjunctively treated versus those who received clindamycin alone.[32] Combination with lymecycline also proved effective in patients with moderate-to-moderately severe acne vulgaris.[29,34] Patients showed significantly greater percentage reductions in mean total lesion

count, mean inflammatory lesion count and mean noninflammatory lesion count at week 12 when treated with lymecycline plus 0.1% adapalene gel versus lymecycline plus gel vehicle (table IV). Significantly more patients receiving lymecycline plus adapalene showed marked improvement or were almost clear of facial lesions at week 12 than patients receiving lymecycline plus gel vehicle (75.5% vs 51.8%, p < 0.001; global improvement based on total lesion count and global severity grade).[29] This was supported by results from a comparative study, reported as a poster,[34] in patients with moderate or moderately severe acne vulgaris who received oral lymecycline 300 mg/day or oral minocycline 100 mg/day concomitantly with 0.1% adapalene gel. Patients showed reductions from baseline in the mean percentage total lesions (the primary endpoint); reduction in lesion count was high with both treatment combinations but significantly favoured combination therapy with lymecycline compared with minocycline (table IV). There were no significant differences between the two treatment groups in the percentage reduction of inflammatory lesions or inflammatory lesion count, but a significant difference in the percentage reduction of total lesions (p < 0.001) and noninflammatory lesions (p-value not stated) favouring lymecycline plus adapalene recipients was found at the end of the trial.[34] Combination therapy with 0.1% adapalene gel and benzoyl peroxide was as effective as adapalene alone in a nonblind trial in 150 Chinese patients with mild-to-moderate acne vulgaris reported in an abstract (table IV).[33]

Table III. Comparative efficacy of 0.1% adapalene gel (ADA) versus 0.1% tazarotene gel (TAZ). Results at week 12[28] or 15[27] in randomised, multicentre, double-blind, parallel-group trials in patients with mild-to-moderate acne vulgaris. All endpoints were investigator assessed and analyses were on-treatment Study Treatment regimen ADA od TAZ q2db Webster et al.[28] a b c ADA od TAZ od No. of Mean reduction in no. of evaluable inflammatory/noninflammatory patients lesions (%) 74 74 73 72 62/69 61/63 55c/48c 70*c/71**c Reduction in mean grade for Patients showing 50% global severity scale (%)a global improvement (%) 30 31 24 44** 73 74 52 78*

Leyden et al.[27]

Assessed using the Burke and Cunliffe scale. Patients received placebo on the non-treatment day. Median values.

od = once daily; q2d = once every two days; * p 0.01, ** p 0.001 vs ADA.

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Table IV. Efficacy of topical 0.1% adapalene gel (ADA) as adjunctive therapy. Percentage reduction in the number of lesions in patients with mild-to-moderate[30,33] or moderate to moderately severe acne vulgaris[29,34] after 12[29,30,32,33] or 24[34] weeks combination therapy in randomised, multicentre trials. Endpoints were investigator assessed at the end of treatment and trials were investigator-blinded unless otherwise indicated Study Study design No. of evaluable patients 118 124 Fang et al.[33]a Campo et al.[34]a OT, nb OT 150b 64 Treatment regimen Meanreduction in Mean reduction in no. of inflammatory no. of lesions (%) noninflammatory lesions (%) 60.3** 45.6 56.6* 47.6 Mean reduction in total no. of lesions (%) 58.7** 47.9 81.3d 68.9d 77e 77**

Cunliffe et al.[29]

ITT

LMC 300mg od + ADA od LMC 300mg od + V BP od + ADA odc ADA od LMC 300mg od + ADA od for 2 weeks followed by LMC 150mg od for 22 weeks + ADA od MNC od + ADA od CLM bid + ADA odf CLM bid + V odf CLM bid + ADA odf CLM bid + V odf

58 Wolf et al.[30] Zhang et al.[32] a b c d e f Abstract. ITT ITT 125 124 150 150

64 55* 44.2 75.2** 67.8 42.5** 16.3 75.5** 62.2

67 46.7** 25.5 75.1* 64.9

Total evaluable population; patient numbers were not reported separately for individual treatment groups. BP was applied in the morning and ADA in the evening. Percentage of people experiencing >60% reduction in lesion count. Significant difference vs MNC + ADA (p-value not given). ADA or V applied in the evening and CLM applied in the morning and evening.

bid = twice daily; BP = 5% benzoyl peroxide; CLM = 1% clindamycin lotion; ITT = intention-to-treat; LMC = oral lymecycline; MNC = oral minocycline 100mg; nb = nonblind; od = once daily; OT = on-treatment; V = adapalene gel vehicle; * p 0.05, ** p 0.01 vs comparator.

3.2.1 Maintenance Treatment

Adapalene was effective as maintenance treatment in an open-label, follow-on study after successful treatment with clindamycin plus 0.1% adapalene gel.[32] Patients who had shown at least a moderate improvement with a 12-week 1% clindamycin topical solution twice daily plus 0.1% adapalene gel once daily treatment regimen were randomised to receive 0.1% adapalene gel once daily or no treatment. By week 24, noninflammatory, inflammatory and total, lesion counts were all significantly lower in adapalene recipients (40.8% vs +87.7%; 41.7% vs +97.1%; 41.6% vs +92.1%; all p < 0.01).[32] In addition, global improvement was greater (67.2% vs 4.2%; p < 0.01) and global severity scale was significantly lower (p < 0.01) in this group. 4. Tolerability Data for this section are primarily derived from studies comparing 0.1% adapalene gel with other
2004 Adis Data Information BV. All rights reserved.

retinoid agents,[16-19,23-28,42-44] studies in which adapalene was part of an adjunctive therapy regimen[30,32] oral antibacterial medications[29] (see section 3 for trial design details) and a meta-analysis[38] of data from five, randomised, 12-week, parallelgroup trials (n = 900).[20,21,45-47] Tolerability data from trials discussed in section 3 and the meta-analysis are supplemented by those from a large, noncomparative study,[48] a study in African patients,[36] several studies in healthy volunteers[49-54] and two studies evaluating adjunctive therapy that included 0.1% adapalene gel.[33,34] These investigator-assessed tolerability data relate to similar endpoints in most studies, but the way they are presented differs considerably. Some trials employed a 03 severity scale (0 = none, 1 = mild, 2 = moderate, 3 = severe);[18,19,24,25] others used a 9-[23,26] or 10-point[43] scale. Some reported the frequency but not the severity of adverse events[17,24] and one used a percentage scale of patients experiencing adverse events.[17] This diversity of data
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presentation precluded tabulation or comparative analysis across trials. The tolerability parameters assessed in some studies were erythema, desquamation, pruritus, dryness and burning/stinging sensations.[18,19,23,25,26] In one trial these were scored separately for immediate or persistent effects.[18]
4.1 General Tolerability Profile

were classified as mildly, moderately or severely irritating.

4.2.1 Versus Tretinoin

Adapalene was generally well tolerated. In a noncomparative study in 2545 patients with mild-tomoderate acne vulgaris, treatment-related adverse events were reported in 3.7% of 0.1% adapalene gel recipients; the majority of these involved skin irritations (2.2%).[48] However, according to the prescribing information, adverse effects such as erythema, scaling, dryness, pruritus and burning, are expected in 1040% of patients treated with 0.1% adapalene gel.[10] A transient exacerbation of acne symptoms may occur in approximately 1% of patients.[23] No additional adverse events were observed with longterm use of 0.1% adapalene gel in a 24 week followon study.[32] In addition, hyperpigmentation did not occur in African patients receiving 0.1% adapalene gel and two-thirds of the patients within this group experienced a reduction in both the number and the density of pigmented macules.[55]
4.2 Comparative Studies

In general, 0.1% adapalene was better tolerated than 0.025% tretinoin gel in clinical trials.[16-21,45,46,57] The incidence of patients experiencing erythema, dryness, scaling or stinging/burning were generally lower in these trials, particularly during the first 4 weeks of administration.[16-21,45,46] In several studies of 1215 weeks duration, there were significant (p < 0.05) differences favouring adapalene for at least one tolerability parameter and at least one timepoint.[16-19] A large meta-analysis based on five randomised, multicentre, investigatorblinded trials[38] confirmed the better tolerability profile of 0.1% adapalene gel versus 0.025% tretinoin gel (figure 1).[38] The most marked difference was for immediate burning/stinging, which was approximately 5-fold more common in 0.025% tretinoin gel recipients.[38] Adverse events were of moderate-to-severe intensity.[38] In addition, 0.1% adapalene gel generally showed better tolerability than several newer formulations of tretinoin in numerous, randomised trials of 412 weeks duration.[23-26,42-44] As with the gel formulation of tretinoin,[16-18,20,21,45,46,51,57] this differ40 35 30 Patients (%) 25 20 15 10 5 0
at io n I in mm g/ e st di in at g e bu rn P ing in er g/ si st st in en gi t n Pe g rs i pr st ur en it t Im us m pr edi ur ate itu s bu rn
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ADA TRE-G

Adverse effects such as erythema, dry skin, pruritus, desquamation and stinging/burning sensations are common to all topical retinoids, but were experienced significantly less frequently and with milder severity in adapalene recipients than in recipients of other retinoids (sections 4.2.1 and 4.2.2).[16-19,23-26,28,38,43,44] In addition, 0.1% adapalene gel showed the lowest irritancy of all active treatments (active comparators were 0.01%, 0.025%, and 0.05% tretinoin gel, 0.025%, 0.05% and 0.1% tretinoin cream, and 0.1% and 0.04% tretinoin microsphere gel and 0.5% and 0.1% tazarotene gel and benzoyl peroxide) in 3week, randomised, single-blind[49-51,53,54] or doubleblind[46,52,56] intra-individual patch studies in healthy volunteers. In all studies, adapalene showed the lowest irritancy which was similar to the gel vehicle or white petroleum and was classified as non-irritant, whereas tretinoin and tazarotene formulations
2004 Adis Data Information BV. All rights reserved.

***

**

***

***

ss

ry

he m yt D es

ne

a qu a

Fig. 1. Comparative tolerability of 0.1% adapalene gel (ADA) and 0.025% tretinoin gel (TRE-G) in patients with mild-to-moderate acne vulgaris. Incidence of adverse events of moderate-to-severe intensity reported in a meta-analysis[38] of five[20,21,45-47] randomised, 12-week, single-blind, parallel-group trials in 900 patients receiving once-daily treatment. * p < 0.05, ** p = 0.005, *** p < 0.001 vs TREG.

Er

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ence tended to be more marked in the first 4 weeks.[23-26,42-44] Three of these trials[42-44] employed a split-face design where patients applied one treatment to one side of their face and the other treatment to the other side once daily. A fully published 4-week trial showed better tolerability scores for 0.1% adapalene gel compared with 0.025% tretinoin cream in three out of four tolerability parameters assessed (figure 2).[43] Conversely, a 6-week trial[44] showed similar tolerability in both treatment groups at study end; however, fewer 0.1% adapalene gel than 0.025% tretinoin cream recipients reported burning/stinging at 3 days (7% vs 27%; p = 0.02).[44] Differences in tolerability favouring 0.1% adapalene gel were also observed in three trials that compared it with 0.1% tretinoin microsphere gel.[25,26,42] For example, a randomised, multicentre study[26] showed significant differences in mean scores (9-point scale) between adapalene and tretinoin treatment groups for erythema (0.6 vs 1.0), pruritus (0.2 vs 0.4), stinging/burning (0.3 vs 0.4), dryness (0.6 vs 1.1) and desquamation (0.4 vs 1.2) [p < 0.05 for all comparisons] at week 12 (data estimated from graph). Tolerability (assessed using a 3-point scale for erythema, scaling or burningpruritus at 12 weeks) was significantly better with
2.5 ADA TRE-C

0.1% adapalene gel (p < 0.05) than that with 0.05% isotretinoin gel in a small, nonblind trial.[24] Adapalene was favoured over several tretinoin formulations in 4- to 12-week trials that assessed patient preference.[22,42,43] In a 4-week randomised, single-blind, split-face trial,[43] significantly more patients responded in favour of 0.1% adapalene gel than of 0.025% tretinoin cream to five of six patient preference questions: which product spread more easily? (81% vs 19%; p < 0.001); which product had the best smell? (77% vs 24%; p < 0.001); which product felt the best? (74% vs 26%; p < 0.001); which product felt greasier? (40% vs 60%; p < 0.05); which product do you prefer? (65% vs 35%; p < 0.01). There was no significant difference between treatment groups in answers to the question about which product was absorbed the quickest. Similar results were reported in another trial of the same design.[42]
4.2.2 Versus Tazarotene

Mean assessment score

2.0

*
1.5

*
1.0

0.5

0.0

Erythema

Dryness

Burning/ stinging

Desquamation

Fig. 2. Comparative tolerability of 0.1% adapalene gel (ADA) versus 0.025% tretinoin cream (TRE-C).[43] Tolerability scores (based on a 10-point scale where 0 = none and 79 = severe) at endpoint in a 4-week, randomised, single-blind trial comparing ADA with TRE-C in 100 patients with mild-to-moderate acne vulgaris.[43] Patients aged 1330 years (mean age 18.5 years) applied one treatment to one side of their face and the other treatment to the other side once daily. * p < 0.05 vs TRE-C.

Adapalene 0.1% gel was generally better tolerated, in particular during the first few weeks, than 0.1% tazarotene gel once daily[28] or 0.1% tazarotene gel once every 2 days[27] in randomised, doubleblind trials. Adverse events were generally mild or moderate in severity in all three studies.[27,28] No patients in either treatment group discontinued treatment as a result of an adverse event in one of these trials[28] and in another, one person in each treatment group discontinued treatment.[27] Generally, tolerability differences between the drugs were greater during the first 24 weeks of treatment, with differences decreasing thereafter.[27,28] For example, in a 12-week, double-blind trial comparing 0.1% adapalene gel once daily with 0.1% tazarotene gel once daily using a 5-point scale,[28] there was no significant difference between the treatments at week 12; however, at week 4, scores for four endpoints showed significant differences favouring adapalene (erythema 0.8 vs 1.3, pruritus 0.6 vs 1.0, burning 0.5 vs 1.0 and peeling 0.8 vs 1.6; all p 0.05 vs tazarotene). In a 15-week, double-blind trial, a similar trend was seen when the dosage of tazarotene was reduced (once every 2 days) to improve the tolerability profile of the drug.[27] For example, mean cumulative dryness scores assessed using a 5-point scale were
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significantly lower in the adapalene group than in the tazarotene group for the first 6 weeks (1.0 vs 1.4 at week 3, 0.8 vs 1.2 at week 6; p 0.05 both comparisons), but there were no significant differences during the remaining 9 weeks of this study.[27]
4.3 Adjunctive Therapy

When used as adjunctive therapy with 1% clindamycin lotion[30,32] or oral lymecycline 300 mg/ day,[29,34] 0.1% adapalene gel was generally well tolerated in patients with acne vulgaris. There were no statistically significant differences in the overall incidence of adverse events for 0.1% adapalene gel plus an antibacterial agent compared with gel vehicle plus an antibacterial agent (30.4% vs 21.8% in patients receiving combined therapy with clindamycin[30] and 29.9% versus 28.2% in patients receiving combined therapy with lymecycline[29]). In addition, dermatological adverse events were reported by a similar proportion of patients receiving clindamycin plus 0.1% adapalene gel to those receiving clindamycin plus gel vehicle (10.4% and 9.7%).[30] Although numerically more patients receiving adjunctive 0.1% adapalene gel than gel vehicle experienced scaling, dryness and stinging/burning sensations in both trials,[29,30] differences between treatments were only statistically significant (p < 0.05) in one clindamycin trial,[30] and then only in those with moderate-to-severe irritation. In most cases, local cutaneous symptoms were mild in intensity.[29,30,32] Furthermore, abstract reports suggest that 0.1% adapalene gel used as adjunctive therapy with minocycline[34] or benzoyl peroxide[33] may be well tolerated in patients with acne vulgaris, although quantitative data are not available. 5. Dosage and Administration Adapalene 0.1% gel is widely approved for the topical treatment of acne vulgaris.[10] A cream formulation[13] and a solution[58] are also approved in the US. Administration is similar for all three formulations; however, information presented in this section is focused specifically on 0.1% adapalene gel. Adapalene should be applied once daily at night before retiring, after washing and drying the affected areas. A thin film should be applied to lightly
2004 Adis Data Information BV. All rights reserved.

cover the affected areas, avoiding lips, eyes and mucous membranes.[10] Adapalene should not be used in association with other potentially irritating, topically applied products, including medicated or abrasive soaps, cosmetics that have a strong drying effect and products with high concentrations of alcohol, astringents, spices or lime.[10] Patients may experience increased susceptibility to sunburn and are advised to minimise exposure to sunlight or artificial sources of ultraviolet radiation during treatment with adapalene. Patients with sunburn should not use adapalene until fully recovered, and adapalene should not be applied to skin with cuts, abrasions or eczema. The safety and efficacy of adapalene have not been established in children <12 years of age. Adapalene should be used in pregnancy only if the potential benefits outweigh potential risks to the foetus. Caution is advised with the use of adapalene in breast-feeding mothers.[10] 6. Place of 0.1% Adapalene Gel in the Management of Acne Vulgaris Acne vulgaris affects almost all people in the age group 1224 years, at least occasionally and, in some cases, persistently.[1,4,5,59] Frequency and severity tend to be greater in boys; however, acne persists into adulthood more commonly in women.[59] Acne is so common that it is sometimes regarded as a natural part of human development and the question arises as to whether it should be treated at all.[60] It lacks the medical urgency of many more debilitating and, sometimes, life-threatening disorders. However, the psychosocial sequelae of this condition can be far reaching and may have an impact on academic performance, social functioning and employment success.[1] It is also one of the most common reasons for young people to consult a medical practitioner.[60] Acne scarring can cause long-term trauma and, particularly in men, may be a risk factor for suicide.[61] Successful treatment is associated with improved psychological well being.[62] Available treatments for acne are very effective and could prevent scarring in many cases if
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employed early enough, as well as reducing the overall impact of this condition.[2,60,63] Choice of treatment depends on the pathophysiology of the acne. In mild-to-moderate acne, where there are mainly noninflammatory lesions, the firstline treatments are the comedolytic agents.[4] These include the retinoids (tretinoin, adapalene and tazarotene).[4] In mild-to-moderate inflammatory acne, combination therapy with a topical or oral antibacterial plus a retinoid is the preferred treatment. Thus, early treatment, which addresses the pathophysiological factors leading to inflammatory lesions, can prevent development of inflammation with its associated risk of scarring.[41,64] The emergence of antibacterial resistance in P. acnes has led to treatment plans that recommend earlier intervention with comedolytic agents, such as the retinoids.[60] In patients with mild-to-moderate acne vulgaris, 0.1% adapalene gel showed similar efficacy to several formulations of tretinoin (the gold standard agent in the treatment of acne[1]), but was less effective than standard dosages of tazarotene. Notably, adapalene was generally better tolerated than all other retinoids with which it was compared (section 4). Cost-effectiveness and/or benefit/risk analyses would be useful in establishing the position of adapalene relative to other retinoid agents for the treatment of mild-to-moderate acne vulgaris. Early formulations of tretinoin were not well tolerated and caused excessive skin irritation.[59] Lower concentration formulations (0.025%) were produced to improve tolerability. Adapalene has similar efficacy (section 3.1.1) but generally better tolerability (section 4.2.1) than 0.025% tretinoin gel. Recent formulations (tretinoin cream and tretinoin microsphere gel) have been designed to be slower releasing and less penetrating, thus improving tolerability; nonetheless, 0.1% adapalene gel proved to be better tolerated than these formulations, especially in the first 4 weeks, in several comparative trials (section 4.2.1). Tazarotene 0.1% gel once daily showed better efficacy (section 3.1.2) but was not as well tolerated (section 4.2.2) as 0.1% adapalene gel, particularly during the first 24 weeks of treatment. However, adapalene was as effective as, and initially better tolerated than, a lower dosage of tazarotene (0.01%
2004 Adis Data Information BV. All rights reserved.

tazarotene gel once every 2 days), a regimen designed to improve the tolerability profile of tazarotene, in a double-blind trial.[27] Adapalene provided effective adjunctive treatment with topical clindamycin,[30,32] oral antibacterials[29,34] or benzoyl peroxide[33] in patients with inflammatory acne. Poor compliance is considered to be one of the main reasons for treatment failure in patients with acne.[23,38] Clinical observation suggests that patients are more likely to comply with treatments that demonstrate good tolerability than with those that are more irritating.[18,23,42] In addition, individuals within this population of mainly adolescent patients are particularly prone to discontinue any treatment that does not rapidly resolve their condition.[42] Adapalene combines good tolerability and rapid onset of action; these features may potentially positively affect patient compliance[18,23,42] and, therefore, treatment success,[38] and are reflected in the overall patient satisfaction with this drug (section 4.2.1). In conclusion, 0.1% adapalene gel has proved to be an effective retinoid treatment for acne vulgaris, a disease that affects almost everyone at some time in their lives. It can be used alone in mild acne or in combination with antimicrobials in inflammatory acne, and has proved efficacious as maintenance treatment. Adapalene has a rapid onset of action and a particularly favourable tolerability profile. These attributes can potentially promote patient compliance, an important factor in treatment success. Adapalene is, therefore, assured of a role in the firstline treatment of acne vulgaris. References
1. Bergfeld WF. Topical retinoids in the management of acne vulgaris. J Drug Dev Clin Pract 1996 Dec; 8: 151-60 2. Strasburger VC. Acne: what every pediatrician should know about treatment. Pediatr Clin North Am 1997; 44 (6): 1505-23 3. Gollnick H. Current concepts of the pathogenesis of acne: implications for drug treatment. Drugs 2003; 63 (15): 1579-96 4. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a global alliance to improve outcomes in acne. J Am Acad Dermatol. 2003 Jul; 49 (1): S1-38 5. Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 2003 Sep; 49 (3): S200-10 6. Webster GF. Acne vulgaris. BMJ 2002; 325: 475-8 7. Kang S, Goldfarb MT, Weiss JS, et al. Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: a randomized trial. J Am Acad Dermatol 2003 Jul; 49 (1): 83-90

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8. Brogden RN, Goa KL. Adapalene: a review of its pharmacological properties and clinical potential in the management of mild to moderate acne. Drugs 1997 Mar; 53 (3): 511-9 9. Shroot B. Pharmacodynamics and pharmacokinetics of topical adapalene. J Am Acad Dermatol 1998 Aug; 39 (2 Pt 3): S17-24 10. Galderma Laboratories. Differin (adapalene) gel, 0.1%. Product insert information, United States [online]. Available from URL: http://www.differin.com/about/insertadapalenegel. shtml [Accessed 2004 May 4] 11. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol 1997; 36 (6 Suppl.): S96-103 12. Anonymous. Adapalene for acne. Med Lett Drugs Ther 1997; 39 (995): 19-20 13. Galderma Laboratories. Differin (adapalene) cream 0.1% product insert information, United States [online]. Available from URL: http://www.differin.com/about/insertadapalene cream.shtml [Accessed 2004 May 4] 14. Caron D, Clucas A, Dunsire JP, et al. Radiolabelled adapalene is poorly absorbed after topical application of adapalene 0.1% gel. J Eur Acad Dermatol Venerol 1998 Sep; 11 Suppl. 2: 275-6 15. Medsafe. Information for Health Professionals: data sheet. Differen adapalene 0.1% [online]. Available from URL: http:// www.medsafe.govt.nz/Profs/Datasheet/d/Differingel.htm [Accessed 2004 May 28] 16. Tu P, Li GQ, Zhu XJ, et al. A comparison of adapalene gel 0.1% vs. tretinoin gel 0.025% in the treatment of acne vulgaris in China. J Eur Acad Dermatol Venereol 2001; 15 Suppl. 3: 31-6 17. Ellis CN, Millikan LE, Smith EB, et al. Comparison of adapalene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol 1998 Oct; 139 Suppl. 52: 41-7 18. Grosshans E, Marks R, Mascaro JM, et al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life. Br J Dermatol 1998 Oct; 139 Suppl. 52: 26-33 19. Cunliffe WJ, Caputo R, Dreno B, et al. Efficacy and safety comparison of adapalene (CD271) gel and tretinoin gel in the topical treatment of acne vulgaris: a European multicentre trial. J Dermatol Treat 1997; 8 (3): 173-8 20. Alirezai M, Meynadier J, Jablonska S, et al. Efficacy and safety comparison study of 0.1% and 0.03% adapalene gels and tretinoin gel in the topical treatment of acne [in French]. Ann Dermatol Venereol 1996; 123 (3): 165-70 21. Shalita A, Weiss J, Chalker D, et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol 1996 Mar; 34 (3): 482-5 22. Verschoore M, Langner A, Wolska H, et al. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol 1991 Apr; 124: 368-71 23. Cunliffe WJ, Danby FW, Dunlap F, et al. Randomised, controlled trial of the efficacy and safety of adapalene gel 0.1% and tretinoin cream 0.05% in patients with acne vulgaris. Eur J Dermatol 2002; 12 (4): 350-4 24. Ioannides D, Rigopoulos D, Katsambas A. Topical adapalene gel 0.1% vs. isotretinoin gel 0.05% in the treatment of acne vulgaris: a randomized open-label clinical trial. Br J Dermatol 2002 Sep; 147 (3): 523-7 25. Nyirady J, Grossman RM, Nighland M, et al. A comparative trial of two retinoids commonly used in the treatment of acne vulgaris. J Dermatolog Treat 2001 Sep; 12 (3): 149-57 26. Thiboutot D, Gold MH, Jarratt MT, et al. Randomized controlled trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001 Oct; 68 (4 Suppl.): 10-9

27. Leyden J, Lowe N, Kakita L, et al. Comparison of treatment of acne vulgaris with alternate-day applications of tazarotene 0.1% gel and once-daily applications of adapalene 0.1% gel: a randomized trial. Cutis 2001 Jun; 67 (6 Suppl.): 10-6 28. Webster G, Guenther L, Poulin YP, et al. A multicenter, double-blind, randomized comparison of the efficacy and tolerability of treating facial acne vulgaris once daily with tazarotene 0.1% gel or adapalne 0.1% gel. Cutis 2002; 69: 4-11 29. Cunliffe WJ, Meynadier J, Alirezai M, et al. Is combined oral and topical therapy better than oral therapy alone in patients with moderate to moderately severe acne vulgaris? A comparison of the efficacy and safety of lymecycline plus adapalene gel 0.1%, versus lymecycline plus gel vehicle. J Am Acad Dermatol 2003 Sep; 49 (3 Suppl.): S218-26 30. Wolf Jr JE, Kaplan D, Kraus SJ, et al. Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized, investigatorblinded study. J Am Acad Dermatol 2003 Sep; 49 (3 Suppl.): S211-7 31. Campo M, Zuluaga A, Escobar P, et al. A comparative study on the effectiveness of lymecicline and adapalene versus minocicline and adapalene in the treatment of acne vulgaris. Ann Dermatol Venereol 2002 Jul; 129 (Suppl.): 371 32. Zhang J, Feng LL, Teng TY, et al. The maintenance effect of a treatment with adapalene gel 0.1% in patients with acne vulgaris previously treated with clindamycin topical solution, 1% alone or in combination with adapalene gel, 0.1% [poster]. The American Academy Of Dermatology 62nd Annual Meeting; 2004 Feb 6-11; Washington, DC 33. Fang L, Fu W, Gu J, et al. Efficacy and safety of benzoyl peroxide gel, 5% combined with adapalene gel, 0.1% in Chinese patients with acne vulgaris [abstract no. P0020]. Ann Dermatol Venereol 2002 Jul; 129 Suppl.: 374 34. Campo MH, Zuluaga A, Escobar P, et al. Efficacy and safety comparison of lymecycline associated with adapalene and minocycline associated with adapalene in the treatment of acne vulgaris [poster]. 20th World Congress of Dermatology; 2002 Jul 1-5; Paris 35. Burke BM, Cunliffe WJ. The assessment of acne vulgaris: the Leeds technique. Br J Dermatol 1984 Jul; 111(1): 83-92 36. Jacyk WK. Adapalene in the treatment of African patients. J Eur Acad Dermatol Venereol 2001; 15 Suppl. 3: 37-42 37. Miyachi Y, Kawashima M, Harada S. Efficacy and safety of 0.1% and 0.03% adapalene gel or vehicle in Japanese subjects with acne [abstract no. P0049]. Ann Dermatol Venereol 2002 Jul; 129 Suppl.: S380 38. Cunliffe WJ, Poncet M, Loesche C, et al. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol 1998 Oct; 139 Suppl. 52: 48-56 39. Cunliffe WJ, Caputo R, Dreno B, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials. J Am Acad Dermatol 1997 Jun; 36 (6 Pt 2): S126-34 40. Cunliffe WJ, Orfanos C, Caputo R, et al. Comparison of clinical safety and efficacy of adapalene gel and tretinoin gel in the treatment of acne vulgaris [abstract no. P139]. J Eur Acad Dermatol Venereol 1995 Oct; 5 Suppl. 1: S152 41. Cunliffe WJ, Gollnick H. Currents concepts in the treatment of acne vulgaris [abstract]. European Academy of Dermatology and Venereology Annual Meeting; 2000 Oct 11-15; Geneva 42. Egan N, Loesche MC, Baker MM. Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001 Oct; 68 (4 Suppl.): 20-4

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Correspondence: John Waugh, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 1311, New Zealand. E-mail: demail@adis.co.nz

2004 Adis Data Information BV. All rights reserved.

Drugs 2004; 64 (13)