ADIS DRUG EVALUATION Am J Clin Dermatoi 2011; 12 (6): 407-420

1176O661/11/OOOMH07/S49.W/0
© 2011 Adis Data Informatian BV. All rights reserved.

Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel

A Review of its Use in the Treatment of Acne Vulgaris in Patients Aged >12 Years
Gillian M. Keating
Adis, a Wolters Kluwer Business, Auckland, New Zealand

Various sections of the manuscript reviewed by:

V. Bettoli, Department of Clinical and Experimental Medidne, Section of Dermatology, University of Ferrara, Ferrara, Italy; V.D. Callender,
Callender Skin and Laser Center, Glenn Dale, MD, USA; S.R. Feldman, Department of Dermatology, Wake Forest University School of
Medicine, Winston-Salem, NC, USA; C.L. Goh, National Skin Center, Singapore; L.E. Millikan, Department of Dermatology, Tulane
University School of Medicine, New Orleans, LA, USA; A.R. Shalita, Department of Dermatology, State University of New York Downstate
Medical Center, Brooklyn, NY, USA; L. Stein Gold, Henry Ford Hospital, Detroit, MI, USA; J.K.L. Tan, Department of Medicine, University of
Western Ontario, London, ON, Canada.

Data Selection
Sources: Medical literature (including published and unpublished data) on 'adapalene/benzoyi peroxide' was identified by searching databases since 1981 pnciuding MEDLiNE
and EMBASE and in-house AdisBase), bibliographies from published literature, clinicai trial registries/databases and websites (including those of regionai reguiatory agencies
and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE and AdisBase search terms were 'adapalene/benzoyi peroxide' or 'adapalene' plus 'benzoyi peroxide' or 'adapalene benzoyi peroxide' or
'adapalene-benzoyl peroxide'. Searches were last updated 6 September 2011.
Selection: Studies in patients with acne vuigaris who received adapaiene/benzoyi peroxide, 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 phannacokinetic data are aiso included.
index terms: Adapalene, benzoyi peroxide, acne vulgaris, pharmacodynamics, pharmacokinetics, therapeutic use, toierabiiity.

Contents

Abstract 4Qg
1. Introduction 408
2. Pharmacologie Properties 409
2.1 Pharmocodynamic Profile 409
2.2 Pharmacokinetlc Profile 409
2.3 Potentiol Drug Interactions 410
3. Therapeutic Efficacy 410
3.1 Compared with Adapalene Alone, Benzoyi Peroxide Aione. or Vehicle 410
3.1.1 Pooled Analyses 411
3.2 Compared with Ciindamycin 1%/Benzoyl Peroxide 5% Gel 412
3.3 In Combination with Oral Tetracyclines 413
3.3.1 Maintenance Therapy Study 414
3.4 Noncomparative Trials 414
3.4.1 Community-Based Study 414
3.4.2 Long-Term Treatment 415
4. Toierabiiity 415
4.1 Gênerai Tolerability Profile 415
4.2 Compared with Ciindamycin 1 %/Benzoyi Peroxide 5% Gei 416
4.3 Compared with Other Retinoids 416
4.4 In Combination with Oral Tetracyciines 416
5. Dosage and Administration 416
6. Piace of Adapalene 0.1%/Benzoyl Peroxide 2.5% Gei In the Treatment of Acne Vulgaris in Patients Aged ^12 Years 417
408 Keating

Abstract Adapalene 0.1%/benzoyl peroxide 2.5% gel (Epiduo™, Tactuo™) is the only fixed-dose combination
product available that combines a topical retinoid with benzoyl peroxide; it targets three of the four main
pathophysiologic factors in acne. This article reviews the therapeutic efficacy and tolerability of topical
adapalene 0.1%/benzoyl peroxide 2.5% gel in the treatment of patients aged >12 years with acne vulgaris, as
well as summarizing its pharmacologie properties.
In three 12-week trials in patients aged >12 years with moderate acne, success rates were significantly
higher with adapalene 0.1%/benzoyl peroxide 2.5% gel than with adapalene 0.1% gel or benzoyl peroxide
2.5% gel alone, and combination therapy had an earlier onset of action. In addition, significantly greater
reductions in total, inflammatory, and noninfiammatory lesion counts were seen in patients receiving
adapalene 0.1%/benzoyl peroxide 2.5% gel than in those receiving adapalene 0.1% gel or benzoyl peroxide
2.5% gel alone.
Adapalene 0.1%/benzoyl peroxide 2.5% gel did not significantly differ from cUndamycin 1%/benzoyl
peroxide 5% gel in terms of the reduction in the inflammatory, noninfiammatory, or total lesion counts in
patients with mild to moderate acne, according to the results of a 12-week trial.
Twelve-week studies showed that topical adapalene 0.1%/benzoyl peroxide 2.5% gel in combination with
oral lymecycline was more effective than oral lymecycline alone in patients with moderate to severe acne, and
topical adapalene 0.1%/benzoyl peroxide 2.5% gel in combination with oral doxycycline hyclate was more
effective than oral doxycycline hyclate alone in patients with severe acne.
In patients with severe acne who responded to 12 weeks' therapy with topical adapalene 0.1%/benzoyl
peroxide 2.5% gel plus oral doxycycline hyclate or oral doxycycline hyclate alone, an additional 6 months'
therapy with adapalene 0.1%/benzoyl peroxide 2.5% gel was more effective than vehicle gel at maintaining
response, with further improvement seen in adapalene 0.1%/benzoyl peroxide 2.5% gel recipients. A non-
comparative study also demonstrated the efficacy of 12 months' therapy with adapalene 0.1%/benzoyl
peroxide 2.5% gel in patients with acne vulgaris.
Topical adapalene 0.1%/benzoyl peroxide 2.5% gel was generally well tolerated in patients with acne.
In 12-week trials, the most commonly occurring treatment-related adverse events included erythema,
scaling, dryness, and stinging/burning; these dermatologie treatment-related adverse events were usually
of mild to moderate severity, occurred early in the course of treatment, and resolved without residual ef-
fects. Topical adapalene 0.1%/benzoyl peroxide 2.5% gel was generally well tolerated in the longer term,
with dry skin being the most commonly occurring treatment-related adverse event over 12 months of
treatment.
In conclusion, adapalene 0.1 %/benzoyl peroxide 2.5% gel is a valuable agent for the first-line treatment of
acne vulgaris.

1. Introduction Highly effective treatments are available for use in acne.'^'

Acne vulgaris affects =85% of adolescent boys and =80% of
adolescent girls,'*' persisting into adulthood in up to 20-40% of
patients.'^'^l If left untreated, acne can have serious physical and
psychologic consequences (e.g. permanent physical scarring,
social inhibition, depression, and anxiety).''^ Thus, acne war-
rants early and aggressive treatment, with ongoing mainte-
nance therapy often required.''*'
The pathogenesis of acne involves four main factors: abnor-
malities in the keratinization process; increased sebum pro-
duction by the sebaceous glands; colonization of the follicle
with Propionibacterium acnes; and release of inflammatory This article reviews the therapeutic efficacy and tolerability of
mediators into the
Given that multiple factors are involved in the pathogenesis of
acne, combining agents with complementary modes of action
and synergistic activity is a rational treatment approach.'"*"^'
Adapalene 0.1%/benzoyl peroxide 2.5% gel (Epiduo™,
Tactuo™) is the only fixed-dose combination product available
that combines a topical retinoid with benzoyl peroxide (each
gram of gel contains 1 mg of adapalene and 25 mg of benzoyl
peroxide).'*'^' Adapalene 0.1%/benzoyl peroxide 2.5% gel is
indicated for once-daily use in patients aged >12 years with acne
vulgaris.'^''°' The efficacy of monotherapy with adapalene in
acne is well established and has been reviewed previously.'"'
adapalene 0.1%/benzoyl peroxide 2.5% gel in the treatment of

© 2011 Adis Data information BV. Ali rights reserved. Am J Ciin Dermatol 2011; 12 (6)
Adapalene 0.1%/Ben2oyl Peroxide 2.5% Gel: A Review 409

patients aged >12 years with acne vulgaris, as well as summa- the mean number of propionibacteria recovered from the sur-
rizing its pharmacologie properties. face of the skin and from follicular casts after 2 days' applica-
tion in patients with acne.P^' Benzoyi peroxide also demonstrated
2. Pharmacologie Properties in vitro activity against antibiotic-resistant propionibacteria.^"'
Significant (p<0.001) reductions in P. acnes counts, includ-
2.1 Pharmacodynamic Profile ing antibiotic-resistant P. acnes counts, occurred in volunteers
with high levels of P. acnes at baseline who applied adapalene
Adapalene and benzoyi peroxide have complementary modes 0.1%/benzoyl peroxide 2.5% gel once daily for 28 days.^'l
of action and synergistic activity.f^"*''^] Adapalene and benzoyi peroxide had synergistic effects in
Adapalene is a naphthoic acid derivative with retinoid-like an ex vivo model.t^^ When biopsies from the inflammatory
properties.'^'-'' Retinoids regulate gene transcription and normalize skin lesions of patients with moderate acne were cultured with
the proliferation and differentiation of hyperproliferative fol- adapalene 1 nmol/L plus benzoyi peroxide lO^mol/L, expres-
licular epithelial cells.'^-^'*''^' Adapalene binds with high affinity sion of markers of proliferation (Ki67), adhesion and differ-
to the retinoic acid nuclear receptors RARß and RARy and entiation {a.2 and ag integrins), and innate immunity (TLR2,
with low affinity to RARtx, but does not bind to cytosolic ret- ß-defensin 4, and IL-8) was significantly (p<0.05) reduced,
inoic acid-binding proteins.t^^"'^' RARy is predominantly ex- compared with untreated skin. The downregulation of 0.2 in-
pressed in the epidermis.t'^1 tegrin and ß-defensin 4 with adapalene plus benzoyi peroxide
Adapalene has anticomedogenic, comedolytic, and anti- exceeded the sum of the effect of adapalene and benzoyi per-
inflammatory properties.t'^''^'^"' Given that the development of oxide alone, suggesting synergistic activity.t^'
microcomedones is the initial step in all acne lesions, the fact
that adapalene inhibits microcomedone formation leads to a 2.2 Pharmacokinetic Profile
reduction in both comedones and inflarmnatory lesions.t^'^'l
In vitro, adapalene had antiproliferative effects and modu- Systemic exposure to adapalene is low,t'°l refiecting its low
lated cell differentiation, as well as inhibiting transglutaminaseabsorption through human skin.P'''^^' When a radiolabeled
type I (an enzyme involved in the final stages of keratinocyte formulation of adapalene 0.1% gel was applied to human skin
differentiation).['''''^'2°l Adapalene also showed antiproliferative
in vitro, there was rapid penetration of adapalene into the
effects and comedolytic activity in animal models.'^^''*'^"' pilosebaceous unit, although only 0.01% of the applied dose
The anti-infiammatory activity of adapalene reflects inhibi- penetrated through the skin.I^^i
tion of chemotactic and chemokine responses in human poly- Of 24 patients with acne who had adapalene 0.1%/benzoyl
morphonuclear leukocytes, inhibition of lipoxygenase pathways, peroxide 2.5% gel or adapalene 0.1% gel applied once daily for
and inhibition of cyclo-oxygenase activity.t'''''^'^'" Adapalene 30 days, only two adapalene 0.1%/benzoyl peroxide 2.5% gel
also modulates the epidermal immune system, decreasing recipients and three adapalene 0.1% gel recipients had quanti-
the expression of the transcription factor AP-1, decreasing fiable plasma concentrations of adapalene (2 g of adapalene
Toll-like receptor-2 (TLR2) expression (/*. acnes triggers 0.1%^enzoyl peroxide 2.5% gel or adapalene 0.1% gel was
proinflammatory cytokine production by activating TLR2), applied to lOOOcm^ of acne-affected skin on the face, chest, and
increasing CD Id expression and decreasing interleukin (IL)-10 upper back).'^''"] The maximum adapalene plasma concentra-
expression by keratinocytes.P^'^'*' tion was 0.1-0.2 ng/mL and, in a patient receiving adapalene 0.1%/
Benzoyi peroxide is a lipophilic oxidizing agent that has benzoyi peroxide 2.5% gel, the area under the plasma concen-
antibacterial activity and some keratolytic effects; benzoyi tration-time curve from time 0 to 24 hours was 1.99 ng • h/mL.['°J
peroxide 2.5% gel had similar efficacy to benzoyi peroxide 5% The presence of benzoyi peroxide in the adapalene 0.1%/
gel and 10% gel in patients with acne, although benzoyi per- benzoyi peroxide 2.5% gel does not appear to affect the phar-
oxide 2.5% gel was better tolerated than benzoyi peroxide macokinetics of adapalene.['0'34] NQ adapalene accumulation
10% gel.['*'25.26] jjie antibacterial activity of benzoyi peroxidewas observed over time.t^'*'
is thought to arise from its generation of reactive oxygen No metabolites of adapalene were detected in an in vitro
species in the sebaceous follicle and reduction of the P. acnes study.P"*' Adapalene was essentially unchanged when the epi-
dermis was analyzed for drug content after application of
Indeed, benzoyi peroxide 5% had bactericidal activity adapalene 0.1% gel to human skin in vitroS^^^ Adapalene ap-
against P. acnes in vitro,^^^^ and significantly (p<0.01) reduced pears to be mainly excreted via the biliary
© 2011 Adis Dota information BV. Ail rights reserved. Am J Clin Dermatol 2011; 12 (6)
410
Benzoyl peroxide has low percutaneous penetration.t'"'
Following absorption, benzoyl peroxide is rapidly and com-
pletely converted (in the skin) to benzoic acid and excreted in
the
2.3 Potential Drug Interactions
Although no formal drug interaction studies have been con-
ducted with adapalene 0.1%/benzoyl peroxide 2.5% gel,P''°l
prior experience with adapalene and benzoyl peroxide indicates
that there are no known interactions between these agents and
other medicinal products that might be used topically at the
same time.t'°'
The UK summary of product characteristics states that
other retinoids, benzoyl peroxide, or other agents with a similar
mode of action should not be used concurrently with adapalene
0.1%/benzoyl peroxide 2.5% gel.[i°] The US prescribing infor-
mation notes that other topical acne therapies should be used
with caution in combination with adapalene 0.1%/benzoyl
peroxide 2.5% gel, given the potential for a cumulative irritancy
effect, particularly with the use of peeling, desquamating, or
abrasive agents.!^' Cosmetics with desquamative, irritant, or
drying effects may also produce additive irritant effects if used
concomitantly with adapalene 0.1 %/benzoyl peroxide 2.5% gel,
indicating the need for caution.t^^^
Given their pharmacokinetic properties (section 2.2), it is
unlikely that either adapalene or benzoyl peroxide would in-
teract with systemic medicinal products.t'^^
3. Therapeutic Etficacy
3.1 Compared Wrth Adapaiene Aione, Benzoyi Peroxide
Aione, or Vehicle
The efficacy of adapalene 0.1%/benzoyl peroxide 2.5% gel in
patients aged >12 years with acne vulgaris was compared with that
of adapalene 0.1% gel alone, benzoyl peroxide 2.5% gel alone, or
vehicle gel in large, randomized, double-blind, multicenter, 12-week
trials.f^^-'^l Patients either had an investigator's global assessment
scale of acne severity (IGA) score of 3 (corresponding to moderate
^'-'^ or the majority of patients (80%) had an IGA score of
All study drugs were applied once daily in the evening.P^^^l
Where specified, primary efficacy endpoints included the
success rate at endpoint (assessed using the IGA)'-'^'^*' and the
median percentage reductions from baseline in the total, in-
flammatory, and noninflammatory lesion counts.'^^' Efficacy
was assessed in the intent-to-treat (ITT) population, using last
observation carried forward (LOCF) analysis.t^*"^^]
© 2011 Adis Dafa informafion BV. Ali rigfifs reserved.
Keating
Adapalene 0.1%/benzoyl peroxide 2.5% gel was more effec-
tive than adapalene 0.1% gel alone, benzoyl peroxide 2.5% gel
alone, or vehicle gel in the treatment of moderate acne in
patients aged > 12 years. After 12 weeks' treatment, success rates
were significantly higher in patients receiving adapalene 0.1%/
benzoyl peroxide 2.5% gel (27.5-37.9%) than in patients re-
ceiving adapalene 0.1% gel alone (15.5-21.8%), benzoyl per-
oxide 2.5% gel alone (15.4-26.7%), or vehicle gel (9.9-17.9%)
[table I].[36-38]
Adapalene 0.1 %/benzoyl peroxide 2.5% gel had a more rapid
onset of action than adapalene 0.1 % gel or benzoyl peroxide
2.5% gel alone. In terms of the success rate, a significant (p < 0.05)
difference between adapalene 0.1%/benzoyl peroxide 2.5% gel
and adapalene 0.1 % gel or vehicle gel was seen from weeks 2,t^^'
4,t^^' or 8'^^' onwards, with significant (p< 0.001) differences
between adapalene 0.1%/benzoyl peroxide 2.5% gel and ben-
zoyl peroxide 2.5% gel seen from week 8 onwards.t^^"^^!
Median percentage reductions in total, inflammatory, and
noninflammatory lesion counts were also significantly greater
with adapalene 0.1%/benzoyl peroxide 2.5% gel than with
adapalene 0.1% gel alone, benzoyl peroxide 2.5% gel alone, or
vehicle gel (table I).[36-38] Significant (p<0.05) differences be-
tween adapalene 0.1%/benzoyl peroxide 2.5% gel and all three
comparators for the median percentage reduction in total and
inflammatory lesion counts were seen as early as week 1 .Pe-ss]
In terms of the median percentage reduction in the non-
inñammatory lesion count, significant (p<0.05) differences
between adapalene 0.1%/benzoyl peroxide 2.5% gel and all
three comparators were seen at weeks 1 [36.37] QJ. 4 [38] ^j^^jj ^jjg
exception of one study in which a significant (p < 0.05) differ-
ence between adapalene 0.1%/benzoyl peroxide 2.5% gel and
benzoyl peroxide 2.5% gel was seen at week 2.[361
In addition, rates of improvement, assessed using the IGA,
were significantly higher in patients receiving adapalene 0.1 %/
benzoyl peroxide 2.5% gel than in those receiving adapalene
0.1% gel alone, benzoyl peroxide 2.5% gel alone, or vehicle gel
(table I).[36,38] Rates of improvement, as assessed by patients,
were also significantly higher in patients receiving adapalene
0.1%/benzoyl peroxide 2.5% gel than in those receiving benzoyl
peroxide 2.5% gel alone or vehicle gel in all three studies,^^^'^^'
with a significantly higher improvement rate in patients re-
ceiving adapalene 0.1 %/benzoyl peroxide 2.5% gel than in those
receiving adapalene 0.1 % gel alone in two of the studies^^^'^^'
(table I).
The proportion of patients who were 'satisfied' or 'very
satisfied' with the effectiveness of treatment was 70%'^^' and
71%[36] ^itji adapalene 0.1%/benzoyl peroxide 2.5% gel,
and 62%[361 with adapalene 0.1% gel alone, 61%["] and
Am J Clin Dermafoi 2011.12 (6)
Adapalene 0.1%/Ben2oyl Peroxide 2.5% Gel: A Review 411

Table I. Efficacy of adapalene 0.1%/benzoyl peroxide 2.5% gel (ADA/BPO) vs adapaiene 0.1% gel alone (ADA), benzoyl peroxide 2.5% gel alone (BPO), or
vehicle gel (VEH) in patients (pts) with acne vulgaris. Results of randomized, doubie-blind, muiticenter, 12 wk trials in pts aged ^12 y with moderate acne.** Efficacy
was assessed in the intent-to-treat (ITT) population using last observation canned forward analysis. All study drugs were applied once daily in the evening
Study Treatment Success rate"^ Median percentage reduction in lesion count Percentage of pts with
[no. of ITT pts] (% of pts) [median baseline count] improvement
total inflammatory noninflammatory IGA"^ pt assessment^
Gollnick et al.l^ei ADA/BPO [419] 37.9""«' 65.4""** [76.0] 70.3""** [26.0] 6 2 . 2 " " * [45.0] 75""** 50*"**
ADA [418] 21.8' 52.3 [77.5] 57.1 [27.0] 50.4 [46.0] 63 44
BPO [415] 26.7' 48.2 [74.0] 61.9 [26.0] 48.8 [45.0] 59 39
VEH [418] 17.9' 37.1 [76.0] 45.5 [26.0] 36.7 [46.0] 53 26
Stein Gold et al.i^^ ADA/BPO [415] 30.1 •** 5 6 * ^ [76] 62.r^[27] 53.8*** [44] 73.5"*
ADA [420] 19.8 499 [79] 50.0 [27] 49.1 [47] 65.6
BPO [415] 22.2 48a [76] 55.6 [27] 44.1 [46] 66.7
VEH [418] 11.3 299 [76] 34.3 [27] 29.5 [46] 55.0
Thiboutot et al.i^i ADA/BPO [149] 27.5'^' 51.0""**'[78] 62.9""**' [27] 51.2""**'[44] 70.5""** 42.5^
ADA [148] 15.5' 35.4' [75] 45.7' [28] 33.3' [45] 54.1 34.8
BPO [149] 15.4' 35.6' [74] 43.6' [28] 36.4' [43] 53.7 30.6
VEH [71] 9.9' 31.0'[78] 37.8' [29] 37.5' [46] 47.9 14.5
a Mean pt age was 16.4 y.l^si 18.2 y.l^^i and 19.0 y.^si

b Moderate acne was defined as having 20-50 infiammatory iesions,!^«-^^! 30-100 noninflammatory lesionsi^^-as] and an IGA score of ß^^-^^ pts could have
no more than
h one nodule,'^^'^^
d l ' ^ ^ ^ ^ no nodules,'^'
' ^ ' and/or no cysts.'' ^ ' ^ '
c Success was defined as the percentage of pts rated 'clear' or 'almost clear' on the IGA. The IGA ranged from 0 (clear) to 4 (severe)'^«'^^ or from 0 (clear) to
5 (very severe).'^'
d R s rated 'clear', 'almost clear', or 'miid' on the IGA.
e R s with 'complete improvement' or 'marked improvement''^^'^) or 'complete improvement', 'marked improvement', or 'moderate improvement'jl^^ the pt
assessment scale ranged from 0 (complete improvement) to 5 (worse).
f Primary endpoint.
g Vaiue estimated from graph.
IGA=investigator's global assessment scale of acne severity; * p < 0.05, " p < 0.001 vs ADA alone; t p < 0.05, t+ p < 0.001 vs BPO alone; tp< 0.05,4:^: p < 0.001
vs VEH alone.

with benzoyl peroxide 2.5% gel alone, and
with vehicle gel.
3.1.1 Pooled Analyses
Pooled analyses of the three previously discussed
were conducted in the overall population (n = 3855),'^' in ado-
lescents aged 12-17 years (n = 2453),[^'l and according to the
baseline lesion count (n = 3853).''"^] Efficacy was assessed in the
ITT population,'^-39.'«i] using LOCF analysis.'^^-^] Two of these
analyses'^'-'^l also assessed synergy (i.e. synergy shown if, rela-
tive to vehicle gel, the benefit of adapalene 0.1 %/benzoyl per-
oxide 2.5% gel was greater than the sum of the benefits of
adapalene 0.1 % gel alone and benzoyl peroxide 2.5% gel alone).
Overall Population
In keeping with the results of the individual studies, the
pooled analysis demonstrated that adapalene 0.1%/benzoyl
and peroxide 2.5% gel reduced total, inflammatory, and non-
inflammatory lesion counts to a significantly greater extent than
adapalene 0.1% gel alone, benzoyl peroxide 2.5% gel alone, or
vehicle gel in the overall patient population (table II).'''! More-
over, the success rate was significantly higher with adapalene
0.1%/benzoyl peroxide 2.5% gel than with adapalene 0.1% gel
alone, benzoyl peroxide 2.5% gel alone, or vehicle gel (table 11).'^
Synergy was observed up to week 8 for the reductions in the
total and noninflammatory lesion counts, up to week 4 for the
reduction in the inflammatory lesion count, and at weeks 1,4,8,
and 12 for the success rate.'^'
Subgroup Analysis in Adolescents Aged 12-17 Years
Adapalene 0.1%/benzoyl peroxide 2.5% gel reduced total,
inflammatory, and noninflammatory lesion counts to a sig-
nificantly greater extent than adapalene 0.1 % gel alone, benzoyl
peroxide 2.5% gel alone, or vehicle gel in adolescents aged

© 2011 Adb Data information BV. Aii rigtits reserved. Am J Ciin Dermatol 2011; 12 (6)
412 Keating

Table IL Pooled analyses examining the efficacy of adapalene 0.1 %/benzoyl peroxide 2.5% gel (ADA/BPO) in patients (pts) with acne vulgaris. Pooled results
of three randomized, double-blind, multicenter, 12wk trials'^^^' in pts aged >12y with moderate acne. Trials compared ADA/BPO with adapalene 0.1%
gel alone (ADA), benzoyi peroxide 2.5% gel alone (BPO), or vehicle gel (VEH). Results are for either the entire population'^ or for adolescents aged 12-17 y
(mean age

Study Treatment Median percentage reduction in lesion count Success rate°

[no. of pts] [median baseline count] (% of pts)
total inflammatory noninflammatory
Overall population
Tan et al.f^ ADA/BPO [983] 59*« [80.8] 66**"« [29.2] 58*** [51.6] 33.1*+*
ADA [986] 47 [81.5] 52 [29.4] 48 [52.2] 20
BPO [979] 46 [80.0] 57 [29.4] 45 [50.6] 23.1
VEH [907] 33 [80.9] 38 [29.4] 38 [51.5] 14.2
Adolescents aged 12-17 y
Eichenfield et al.i^^i ADA/BPO [619] 56*^ [82.5] 63*^ [30.0] 55*** [52.5] 30.9*^
ADA [636] 44 [83.8] 51 [30.0] 45 [53.9] 17.8
BPO [633] 44 [83.0] 53 [30.2] 41 [52.9] 21.3
VEH [565] 31 [84.0] 37 [30.1] 29 [53.9] 12.1
a Success was defined as the percentage of pts¡ rated 'clear' or 'almost clear' on the IGA. The IGA ranged from 0 (clear) to 4 (severe).
IGA=investigator's global assessment scale of acne severity; * p<0.05, ** p<0.001 vs ADA; t p<0.05. f t p< 0.001 v s B P O ; t p < 0 . 0 5 , i:ip<0.001 vsVEH.

12-17 years (table II).'3^1 Moreover, the success rate was sig-
nificantly higher with adapalene 0.1%/benzoyl peroxide 2.5%
gel than with adapalene 0.1% gel alone, benzoyi peroxide 2.5%
gel alone, or vehicle gel (table II).'3^1
Synergy was seen for the success rate at weeks 1,4,8, and 12,
for the reduction in the total lesion count at weeks 1,2,4, and 8,
and for the reduction in the inflammatory and noninflamma-
tory lesion counts at weeks 1, 2, and 4.'3^1
Subgroup Analysis by Lesion Count
Another analysis was designed to determine if the benefit
associated with adapalene 0.1%/benzoyl peroxide 2.5% gel
varied according to the baseline lesion count.'''^' Patients were
classified as having low (<23 inflammatory lesions, <36 non-
inflammatory lesions, <63 total lesions [n = 972]), medium
(24-33 inflammatory lesions, 37-61 noninflammatory lesions,
64-93 total lesions [n=1899]), or high (>34 inflammatory le-
sions, >62 noninflammatory lesions, >94 total lesions [n = 982])
lesion counts at baseline.''**''
Although significant (p<0.05) benefit was seen with ada-
palene 0.1%/benzoyl peroxide 2.5% gel versus vehicle gel in all
lesion count subgroups, the benefit was greatest in patients with
a high lesion count at baseline.''*^! In terms of the median per-
centage reduction in lesion count, the absolute benefit for
adapalene 0.1%/benzoyl peroxide 2.5% gel versus vehicle in
patients with low, medium, or high lesion counts at baseline was
19.4%, 26.4%, and 29.1%, respectively, for the total lesion
count, 18.2%, 27.9%, and 30.3%, respectively, for the in-
© 2011 Adis Data intormation BV. Aii rights reserved.
flammatory lesion count, and 21.8%, 24.6%, and 26.8%, re-
spectively, for the noninflammatory lesion count.''*"'
3.2 Compared with Ciindamycin 1 %/Benzoyi Peroxide
5% Gel
The efficacy of adapalene 0.1 %/benzoyl peroxide 2.5% gel in
patients with mild to moderate acne vulgaris was compared
with that of ciindamycin 1 %/benzoyl peroxide 5% gel in a
randomized, investigator-blind, multicenter, 12-week trial.''*''
The ciindamycin 1 %/benzoyl peroxide 5% gel formulation used
in this study contains hydrating excipients. Patients included in
this study were aged 12-45 years.''*''
The primary endpoint was the mean percentage change from
baseline in the inflammatory lesion count after 12 weeks' ther-
apy.''*'' Efficacy was assessed in the ITT population, using
LOCF analysis.''*''
The mean reduction from baseline in the inflammatory,
noninflammatory, or total lesion count did not significantly
differ between patients with mild to moderate acne vulgaris
receiving adapalene 0.1%/benzoyl peroxide 2.5% gel and those
receiving ciindamycin 1 %/benzoyl peroxide 5% gel (table III).''*''
Rapid improvements in lesion counts occurred with both
adapalene 0.1%/benzoyl peroxide 2.5% gel and ciindamycin
1 %/benzoyl peroxide 5% gel, with pronounced reductions seen
within the first 2 weeks of treatment.''*'' The percentage re-
duction in lesion counts did not significantly differ between
Am J Clin Dermatoi 2011; 12 (6)
Adapalene D.l%/Benzoyl Peroxide 2.5% Gel: A Review 413

adapalene 0.1%/benzoyl peroxide 2.5% gel recipients and clin-
damycin 1%/benzoyl peroxide 5% gel recipients at individual
time points, apart from the percentage reduction in the inflam-
matory lesion count at week 4, which significantly (p = 0.021)
favored clindamycin 1%/benzoyl peroxide 5% gel recipients
(-63.9% vs -58.0%). The time to achieve a 50% reduction in
inflammatory, noninflammatory, and total lesion counts did
not significantly differ between adapalene 0.1%/benzoyl per-
oxide 2.5% gel recipients and clindamycin 1%/benzoyl peroxide
5% gel recipients.''*''
The success rate, assessed using the IGA, was significantly
higher in patients receiving clindamycin 1 %/benzoyl peroxide
5% gel than in those receiving adapalene 0.1 %/benzoyl peroxide
2.5% gel (table III), and the time to treatment success was signif-
icantly (p = 0.035) shorter with clindamycin 1%/betizoyl peroxide
5% gel than with adapalene 0.1%/benzoyl peroxide 2.5% gel.t"*'' It
should be noted that during the first 4 weeks of treatment, the
number of tnissed applications was almost 3-fold higher with
adapalene 0.1%/benzoyl peroxide 2.5% gel than with clindamycin
1%/benzoyl peroxide 5% gel (429 vs 150 missed applications).'''"
3.3 In Combination with Oral Tetracyclines
The efficacy of adapalene 0.1%/benzoyl peroxide 2.5% gel in
combination with oral lymecycline''*^' or doxycycline hyclate''*^'
was examined in randomized, double-blind, multicenter, 12-week
trials in patients with moderate to severe'"*^' or severef*^' acne
vulgaris. Patients were aged 12-35 years.'''^''*-''
The primary endpoint was the median percentage change
from baseline in the total lesion count at 12 weeks.''*^'''^' Efficacy
was assessed in the ITT population, using LOCF analysis.''*^-'*^'
Adapalene 0.1%/benzoyl peroxide 2.5% gel in combination
with oral lymecycline'''^' or doxycycline hyclate'''^' was more
effective than oral lymecycline'''^' or doxycycline hyclate^^'
alone in patients with moderate to severe'''^' or severe'''^' acne.
Median percentage reductions in total lesion counts were
significantly greater in patients receiving adapalene 0.1 %/betizoyl
peroxide 2.5% gel plus lymecycline'"^' or doxycycline hyclate'"''
than in those receiving lymecycline'"^' or doxycycline hyclate'"^'
alone (table IV). Inflammatory and noninflammatory lesion
counts were also reduced to a significantly greater extent with
adapalene 0.1%/benzoyl peroxide 2.5% gel plus lymecyclinet"^'
or doxycycline hyclate'"^' than with lymecycline'"-^' or doxy-
cycline hyclate'"^' alone (table IV).
Adapalene 0.1 %/benzoyl peroxide 2.5% gel plus lymecycline'"^'
or doxycycline hyclate'"^' had a more rapid onset of action than
lymecycline'"^' or doxycycline hyclate'"'' alone, with a signif-
icant (p<0.01) between-group difference seen in the total and
noninflammatory lesion counts from week 2'"^"'' and in the
inflammatory lesion count from weeks 2'"'' or 4.'"^'
In addition, success rates were significantly higher with
adapalene 0.1%/benzoyl peroxide 2.5% gel plus lymecycline'"^'
or doxycycline hyclate'"'' than with lymecycline'"^' or doxy-
cycline hyclate'"" alone (table IV).
Significantly more patients receiving adapalene 0.1%/benzoyl
peroxide 2.5% gel plus lymecycline than lymecychne alone
were 'very satisfied' overall with treatment (38.9% vs 26.1%;
p=0.031).'"^' IVIoreover, the overall rate of treatment satisfaction
was significantly higher in patients receiving adapalene 0.1%/
benzoyl peroxide 2.5% gel plus doxycycline hyclate than in
those receiving doxycycline hyclate alone (76.3% vs 50.3%;
p< 0.001).'""
The reduction in P. acnes was documented with digital UV
fluorescence photography in a subset of patients (n = 38) from
one of the trials.'"'' Mean percentage reductions in the total
spot area at weeks 4 and 12 were 60% and 74% in patients

Table III. Efficacy of adapalene 0.1 %/benzoyl peroxide 2.5% gel (ADA/BPO) compared with clindamycin 1 %/ben2oyl peroxide 5% gel with hydrating excipients
(CLI/BPO) in patients (pts) with mild to moderate acne vulgaris.^ Results of a randomized, investigator-blind, multicenter, 12 wk trial in pts aged 12-45 y (mean
age 20.9y).l''^l ADA/BPO and CLI/BPO were applied once daily in the evening. Efficacy was assessed in the intent-to-treat (ITT) population using last
observation carried forward analysis
1 reatment [no. ot ITT pts] Mean percentage reduction in lesion count [mean baseline count] Success rate" (% of pts)
inflammatory noninflammatory total
ADA/BPO [192] 72.2° [40.8] 61.5 [51.1] 67.1 [92.0] 21.8
CLI/BPO [190] 76.8° [39.0] 62.2 [52.7] 69.1 [91.7] 30.5*
a Rs had 25-80 inflammatory lesions (including the nose), 12-100 noninflammatory lesions (excluding the nose), and no facial nodular or cystic lesions. At
baseline, 29% of pts had mild acne, 68% of pts had moderate acne, and 3% of pts had severe acne.
b Success was defined as an improvement of ^ grades on the IGA scale. The IGA ranged from 0 (clear) to 5 (severe).
c Primary endpoint.
IGA=investigator's global assessment scale of acne severity; • p<0.05 vs ADA/BPO.

© 2011 Adis Data information BV. Aiirightsreserved. Am J Ciin Demnatol 2011; 12 (6)
414 Keating

Table IV. Efficacy of adapalene 0.1 %/benzoyl peroxide 2.5% gel (ADA/BPO) in combination wifh oral lymecycline (LYM)!''^] or doxycycline hyclate (DOX)!""'
in pafienfs (pts) with acne vulgaris.* Results of randomized, double-blind, mulficenfer, 12wk trials in pfs aged 12-35y.'' Rs had moderate fo severe'''^) or
severe'"^! acne. Efficacy was assessed In the intenf-fo-freat (ITT) population using last observation carried forward analysis
Study Treatment" Median percentage reduction in lesion counf Success rate**
[no. of ITT pts] [mean baseline count] (% of pfs)
total® inflammatory noninflammatory
Dreno et al.l''^) ADA/BPO+ LYM [191] 74.1** [110.3] 81.7* [37.9] 71.7** [72.4] 47.6*
VEH + LYM[187] 56.8 [105.8] 71.0 [38.4] 52.5 [67.4] 33.7
Sfein Gold et al.!""! ADA/BPO + DOX [232] 64** [101.0] 72** [37.4] 61** [63.3] 31.5**
VEH + DOX [227] 41 [99.5] 48 [37.5] 40 [62.0] 8.4
a Pfs had >20 inflammafory lesions, 30-120 noninflammatory lesions, and <3 nodulocystic lesions, with an IGA score of 3 or 4 (i.e. moderate fo severe
acne)!"*^' or 4 (i.e. severe acne).'*''
b Mean age 18.9 y'-'^i and 18.4 y.l-^l
c ADA/BPO and VEH were applied once daily in fhe evening. Oral LYM 300 mg'^^l and DOX 100 mg''^i were administered once daily in fhe morning.
d Success was defined as fhe percentage of pfs rated 'clear' or 'almost clear' (i.e. an IGA score of 0 or 1). The IGA ranged from 0 (clear) to 5 (very severe).
e Primary endpoinf.
IGA=investigafor's global assessment scale of acne severity; VEH=vehicle gel; * p<0.01, ** p<0.001 vs comparator.

receiving adapalene 0.1%/benzoyl peroxide 2.5% gel plus
doxycycline hyclate and 22% and 14% in patients receiving
doxycycline hyclate
3.3.7 Maintenance Therapy Study
Results are also available from a study examining the effi-
cacy of adapalene 0.1 %/benzoyl peroxide 2.5% gel in maintain-
ing response.''**' Patients from the trial''*^' comparing adapalene
0.1%/benzoyl peroxide 2.5% gel plus doxycycline hyclate with
doxycycline hyclate alone who had >50% global improvement
were re-randomized to receive adapalene 0.1%/benzoyl per-
oxide 2.5% gel (n = 123) or vehicle gel (n = 120) once daily in the
evening for a further 24 weeks. The maintenance therapy study
examined the lesion maintenance success rate, defined as the
proportion of patients having >50% of improvement in lesion
counts obtained in previous therapy, and the IGA maintenance
success rate, defined as the proportion of patients with the
same or better IGA score versus baseline (i.e. the time of re-
randomization).''*'*'
Six months of maintenance therapy with adapalene 0.1%/
benzoyi peroxide 2.5% gel not only maintained response in pa-
tients with severe acne who had responded to prior treatment
with adapalene 0.1%/benzoyl peroxide 2.5% gel plus doxy-
cycline hyclate or doxycycline hyclate alone, but was also
associated with further reductions in lesion counts and improve-
ments in the success rate.''**'
At week 24, lesion maintenanee success rates were signif-
icantly (p< 0.001) higher in patients receiving adapalene 0.1%/
benzoyi peroxide 2.5% gel than in patients receiving vehicle gel
© 2011 Adis Data Intormation BV. Ali lights reserved.
for total lesions (78.9% vs 45.8%), inflammatory lesions (78.0%
vs 48.3%), and noninfiammatory lesions (78.0% vs 43.3%).''**'
The IGA maintenance success rate was also significantly
(p<0.001) higher with adapalene 0.1%/benzoyl peroxide 2.5%
gel than with vehicle gel (70.7% vs 34.2%).'*^'
Significant (p<0.01) differences were also seen between pa-
tients receiving adapalene 0.1%/benzoyl peroxide 2.5% gel and
those receiving vehicle gel in the change from re-randomization
until study end in total lesion count (-26.0% vs -H46.3%), in-
flammatory lesion count (-21.2% vs -1-28.6%), and noninflam-
matory lesion count (-31.0% vs -1-45.0%).''*^' After 24 weeks of
maintenance therapy, the IGA success rate (proportion of
patients rated 'clear' or 'almost clear') increased from 26.8% to
45.7% in adapalene 0.1%/benzoyl peroxide 2.5% gel recipients
and decreased from 37.5% to 25.6% in vehicle gel recipients
(p<0.01 ).'*'*'
Among patients with Fitzpatrick skin types IV-VI, post-
inflammatory hyperpigmentation was significantly improved
from baseline in recipients of adapalene 0.1%/benzoyl peroxide
2.5% gel versus recipients of the vehicle gel (-13.2% vs +28.1%;
p^O.02).'''^'
Overall, the study was completed by 75.3% of patients, in-
dicating good adherence.''*'*'
3.4 Noncomparative Trials
3.4.7 Community-Based Study
A noncomparative, multicenter study examined the use of
adapalene 0.1%/benzoyl peroxide 2.5% gel in a 'real world'
Am J Ciin Dermatol 2011:12 (6)
Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel: A Review
setting in patients with mild to moderate acne vulgaris
(n = 91).t''^l Patients were aged >15 years (mean age 19.9 years)
and had 20-50 inflammatory lesions and 30-100 noninflam-
matory lesions. Patients applied adapalene 0.1%/benzoyl per-
oxide 2.5% gel once daily in the evening for 12 weeks.'''^!
Following 12 weeks' treatment with adapalene 0.1 %/benzoyl
peroxide 2.5% gel, patients had significant (p< 0.001) mean
reductions from baseline in the inflammatory lesion count of
80.6% and in the noninflammatory lesion count of 69.3%.[''^1
The mean IGA scale score was significantly (p < 0.001) reduced
from 2.9 at baseline to 1.1 at study end. According to the IGA
score, 73% of patients had moderate acne at baseline, versus
12% at study end. The proportion of patients rated 'clear' or
'almost clear' at study end was 67%.'''^!
At study end, 94% of adapalene 0. l%^enzoyl peroxide 2.5%
gel recipients rated effectiveness as 'good' or 'very good', 87.5%
rated tolerability as 'good' or 'very good', and overall, 94% of
patients were 'satisfied' or 'very satisfied' with treatment.'''^'
3.4.2 Long-Term Tteatmenf
A noncomparative, multicenter study examined the long-
term efficacy of adapalene 0.1%/benzoyl peroxide 2.5% gel in
452 patients with acne vulgaris.'''^' Patients were aged >12 years
(mean age 18.3 years) and had 20-50 inflammatory lesions,
30-100 noninflammatory lesions, and no active nodules or
cysts. Patients applied adapalene 0.1%/benzoyl peroxide 2.5%
gel once daily for up to 12 months (mean extent of exposure of
294.6 days). Efficacy was assessed in the ITT population, using
LOCF analysis, and in the 327 patients who completed 12 months
of treatment (observed cases).'''^1
After 12 months' treatment with adapalene 0.1%/benzoyl
peroxide 2.5% gel, the median percentage reduction in the total,
inflammatory, and noninfiammatory lesion counts was 64.9%,
69.5%, and 65.7%, respectively, in the ITT population, and 70.8%,
76%, and 70%, respectively, among observed cases (median lesion
counts of 72.0 [total], 27.0 [inflammatory], and 42.0 [nonin-
flammatory] at baseline).'''^'
Of the 411 évaluable adapalene 0.1%/benzoyl peroxide 2.5%
gel recipients at study end, a moderate, marked, or complete
improvement was reported in 80.3%, a minimal improvement
was reported in 10:9%, and no change or worsening was re-
ported in 8.8%.'"^!
4. Toierabiiity
Data concerning the tolerability of adapalene 0.1%/benzoyl
peroxide 2.5% gel were obtained from the clinical trials dis-
cussed in section 3, as well as from additional trials specifically
© 2011 Adis Dafa informafion BV. Ail rigfifs reserved.
415
designed to examine tolerability.'"^-"^! Unless specified other-
wise, the dermatologie adverse events of erythema, scaling, dry-
ness, and stinging/burning were scored on a scale ranging from
0 (none) to 3 (severe).'36-38,42,43]
An early split-face trial'^"' in healthy participants found that
adapalene 0.1%/benzoyl peroxide 2.5% gel had a better der-
matologie tolerability profile than adapalene 0.1%/benzoyl
peroxide 5% gel, with the adapalene 0.1%/benzoyl peroxide
2.5% formulation selected for further evaluation. Results of this
are not discussed further.
4.1 General Toierabiiity Profiie
Topical adapalene 0.1%/benzoyl peroxide 2.5% gel was
generally well tolerated in patients aged >12 years with mod-
erate acne, according to the results of 12-week trials.'^^38] where
reported, treatment-related adverse events occurred in 17%'3*]
and 31%'3^1 of adapalene 0.1%/benzoyl peroxide 2.5% gel re-
cipients, 20%'^*] and 19%[^^1 of adapalene 0.1% gel recipients,
and 13%^^' of benzoyl peroxide 2.5% gel recipients, and
and 8%'^^! of vehicle recipients. The majority of these
treatment-related adverse events were dermatologie in nature,
of mild to moderate severity, occurred early in the course of
treatment, and resolved without residual effects.'^^"^*!
The most commonly occurring dermatologie treatment-
related adverse events were erythema, scaling, dryness, and
stinging/burning.'3ö-38] Throughout the 12 weeks of treatment,
mean scores for erythema, scaling, dryness, and stinging/burning
were <1 (i.e. mild irritation).'3^-3^] Dry skin was the most com-
monly reported dermatologie treatment-related adverse event,
occurring in 9.4%'381 and 21.2%[361 of adapalene 0.1%/benzoyl
peroxide 2.5% gel recipients, 10.1%'^^] and 14.1%'^^ of adapalene
0.1% gel recipients, 2.0%'^^' and 8.4%'3^ of benzoyl peroxide 2.5%
gel recipients, and 1.4%P8] and 5.3%'3^ of vehicle recipients.
Over 12 months' treatment, at least one treatment-related
adverse event occurred in 147 of 452 (32.5%) patients receiving
adapalene 0.1%/benzoyl peroxide 2.5% gel.'"^] The majority of
adverse events were of mild to moderate severity, and the most
commonly occurring treatment-related adverse event was dry
skin, affecting 17.3% of patients. Throughout the study, mean
scores for erythema, scaling, dryness, and stinging/burning
None of the serious adverse events reported in the short-
term'^^>3*] or longer-term'''^' studies were considered to be re-
lated to treatment.
A retrospective meta-analysis'"''! of data from the three
12-week trials'3^"3^1 found that in adapalene 0.1%/benzoyl per-
oxide 2.5% gel recipients (n=909), the distribution of dryness.
Am J Ciin Dermafoi 2011:12 (6)
416
scaling, and stinging/burning did not significantly differ be-
tween patients with Fitzpatrick skin types I-III and those with
Fitzpatrick skin types IV-VI in the combined analysis. However,
there was a significant (p< 0.001) difference in the distribution
of erythema severity, with no erythema and mild erythema re-
ported in 59% and 30% of patients with Fitzpatrick skin types
IV-VI and in 45% and 40% of patients with Fitzpatrick skin
types I-III.''*'']
4.2 Compared Wñh Clindamycin 1%/Benzoyl Peroxide
5% Gel
In a 12-week trial in which patients with acne received ada-
palene 0.1%/benzoyl peroxide 2.5% gel or clindamycin 1%/
benzoyl peroxide 5% gel, most patients experienced either no
dermatologie adverse events or dermatologie adverse events
(e.g. erythema, drying, peeling, pruritus, burning/stinging) of
mild severity (i.e. grade 0 or 1 [rated on a 5-point scale where
O = none and 4=severe]).''*'' However, with regard to these
dermatologie adverse events, elindamyein 1%/betizoyl peroxide
5% gel (with hydrating exeipients) was signifieantly (p < 0.05)
better tolerated than adapalene 0.1 %/benzoyl peroxide 2.5% gel
from week 1 onwards.''*''
Treatment-related adverse events occurred in 78.6% of
adapalene 0.1%/benzoyl peroxide 2.5% gel reeipients and in
48.4% of elindamyein 1 %/benzoyl peroxide 5% gel reeipients,
with severe adverse events reported in 21.4% and 7.4% of pa-
tients in the eorresponding treatment groups.''*'' Although eom-
parisons aeross trials should be made with eaution, it is worth
noting that the incidence of treatment-related adverse events re-
ported in recipients of adapalene 0.1%/benzoyl peroxide 2.5% gel
in this trial''*'' was 2.5- to 4.6-fold greater than the incidence re-
ported in the larger, vehiele-controlled trials'^^'^*' (section 4.1).
4.3 Compared Wúh Other Retinoids
The irritation potential of adapalene 0.1%/benzoyl peroxide
2.5% gel was compared with that of tazarotene 0.1% gel, ada-
palene 0.1% gel, benzoyl peroxide 2.5% or 10% gel, or vehicle
gel''*^' or a mierosphere tretinoin 0.04% gel formulation''*^' in
healthy volunteers (n = 25''*^' and HO'"*^') enrolled in two ran-
domized, investigator-blind, single-eenter studies.
The mean eumulative irritaney index (which reflected er-
ythema) did not signifieantly differ between adapalene 0.1%/
benzoyl peroxide 2.5% gel and adapalene 0.1% gel, benzoyl
peroxide 2.5% or 10% gel, or vehicle gel (0.046 vs 0.017, 0.043,
0.026, and 0.011).'"*^' However, the mean cumulative irritaney
index for tazarotene 0.1 % gel (0.616) was significantly (p < 0.05)
© 2011 Adis Data information BV. All rigtits reserved.
Keating
higher than that for eaeh of the comparators. Over 65% of
volunteers experieneed no erythema with adapalene 0.1 %/benzoyl
peroxide 2.5% gel, and there were no cases of severe erythema,
whereas >95% of volunteers experienced erythema with tazar-
otene 0.1% gel, with 33% of volunteers experiencing severe
erythema.''**'
Compared with adapalene 0.1%/benzoyl peroxide 2.5% gel,
the mierosphere tretinoin 0.04% gel formulation was associated
with signifieantly (p<0.05) less investigator-rated erythema
and dryness and patient-rated burning/stinging and itehing,
aeeording to the results of a split-faee study.''*^'
4.4 In Combination with Oral Tetracyclines
Adapalene 0.1%/benzoyl peroxide 2.5% gel had generally
good tolerability when administered in eombination with oral
lymeeyeline''*^' or doxyeycline hyclate,''*^' according to the re-
sults of 12-week studies.
Throughout 12 weeks of treatment, mean scores for erythe-
ma, scaling, dryness, and stinging/burning were <1 in patients
receiving adapalene 0.1%/benzoyl peroxide 2.5% gel in eombi-
nation with lymeeyeline''*^' or doxyeycline hyelate''*^' and in
those reeeiving lymeeyeline alone'''^' or doxycycline hyelate
alone.''*^' In one of the trials, most patients did not experience
worsening from baseline in erythema, sealing, or dryness, al-
though stinging/burning peaked in adapalene 0.1%/benzoyl
peroxide 2.5% gel plus doxyeyeline hyelate reeipients at week 2,
before returning to near-baseline levels.''*^'
Treatment-related adverse events oeeurred in 8.4% of pa-
tients reeeiving adapalene 0.1%/benzoyl peroxide 2.5% gel plus
lymeeyeline versus 8.0% of patients reeeiving lymeeyeline alone''*^'
and in 11.2% of patients reeeiving adapalene 0.1%/benzoyl
peroxide 2.5% gel plus doxycycline hyclate versus 12.3% of
patients receiving doxycycline hyclate alone.''*^' In one of the
trials, treatment-related adverse events mainly reflected doxy-
eyeline hyclate administration (e.g. gastrointestinal disorders).^'*^'
5. Dosage and Administration
Adapalene 0.1%/benzoyl peroxide 2.5% gel is approved for
the topical treatment of aene vulgaris.'^''"' The US prescribing
information specifies that adapalene 0.1%/benzoyl peroxide
2.5% gel is approved for use in patients aged >12 years of age'^'
and the UK summary of product characteristies specifies that
adapalene 0.1%/benzoyl peroxide 2.5% gel is indieated for use
when comedones, papules, and pustules are present and notes
that effieaey and safety data are not available in children aged
<12 years.""'
Am J Ciin Dermatoi 2011; 12 (6)
Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel: A Review
A thin film of adapalene 0.1%/benzoyl peroxide 2.5% gel
should be applied to affected areas on the face and/or trunk
once daily after washing;'^''"' the UK summary of product
characteristics recommends application in the evening.''"' A
pea-sized amount of the gel should be used for each area of the
face (i.e. the forehead, chin, and each cheek), avoiding the eyes,
lips, and mucous membranes.'^''"' The UK summary of product
characteristics states that the duration of treatment should be
determined by the physician, based on the clinical condition.''"'
The US prescribing information states that topical adapa-
lene 0.1 %/benzoyl peroxide 2.5% gel should only be used during
pregnancy if the potential benefit justifies the risk to the fetus
(pregnancy category C),''' whereas the UK summary of prod-
uct characteristics states that adapalene 0.1%/benzoyl peroxide
2.5% gel should not be used during pregnancy and that appli-
cation to the chest should be avoided if used during breast-
feeding, to avoid contact exposure of the infant.''"'
Local prescribing information should be consulted for
contraindications, warnings, and precautions for use relating to
adapalene 0.1%/benzoyl peroxide 2.5% gel.
6. Place of Adapalene 0.1 %/Benzoyi Peroxide
2.5% Gel in the Treatment ot Acne Vulgaris in
Patients Aged >12 Years
Guidelines from the Global Alliance to Improve Outcomes
in Acne state that combination therapy with a topical retinoid
and an antibacterial agent is the preferred first-line treatment
approach in most patients with acne (i.e. in all but the most
severe cases of acne).''*'
In terms of selecting an antibacterial agent, the use of anti-
biotics should be limited (in terms of both frequency and du-
ration) and they should not be used as monotherapy, given the
global rise in antibiotic resistance.''*' The advantage of using
benzoyi peroxide as an antibacterial agent is that it has bac-
tericidal activity (section 2.1), but does not create selective
pressure for antibiotic resistance.''*' Indeed, concomitant ad-
ministration of benzoyi peroxide with an antibiotic minimizes
the risk of antibiotic resistance developing.''*'
Poor adherence to therapy is the main patient-related factor
associated with a lack of treatment success.'*'^'' Historically,
combination therapy comprising a topical retinoid and an anti-
bacterial agent has involved the administration of two separate
agents, which may impact on patient adherence. Fixed-dose
combination products provide improved patient convenience,
which may result in better adherence.''*-^'
Given these factors (i.e. no selective pressure for antibiotic
resistance with benzoyi peroxide and the potential for improved
© 2011 Adb i^ata information BV. Aiirightsreserved.
417
comphance with fixed-dose combination products), treatment
guidelines state that, theoretically, products combining a reti-
noid with benzoyi peroxide may be the most desirable.''*'
Topical combination therapy is generally indicated in
patients who have mild to moderate acne with an inflammatory
component.''*' Adapalene is the only topical retinoid currently
available in a fixed-dose combination product with benzoyi
peroxide.''*'^' Adapalene 0.1%/benzoyl peroxide 2.5% gel does
not need to be refrigerated and remains stable for up to 6 months
after the tube has been opened.'^^' Topical tretinoin is available
in combination with the antibiotics ciindamycin and erythro-
mycin, but it is not stable when combined with benzoyi per-
oxide.''*-*' Tazarotene is not currently formulated with either
an antibiotic or benzoyi peroxide in a fixed-dose, topical
formulation.''*'
The key features of adapalene 0.1%/benzoyl peroxide 2.5%
gel are summarized in table V. For example, adapalene
0.1%/benzoyl peroxide 2.5% gel targets three of the four main
pathophysiologic factors in acne (abnormal keratinization,
P. acnes colonization of the follicle, and inflammation) [section 2.1].
Results of three well designed clinical trials demonstrated the
greater efficacy of adapalene 0.1%/benzoyl peroxide 2.5% gel
versus treatment with the component monotherapies in pa-
tients aged >12 years with moderate acne. Success rates were
significantly higher with adapalene 0.1%/benzoyl peroxide
2.5% gel than with adapalene 0.1% gel or benzoyi peroxide 2.5%
gel alone, and combination therapy had an earlier onset of action
(section 3.1). In addition, significantly greater reductions in
total, inflammatory, and noninflammatory lesion counts were
seen in patients receiving adapalene 0.1%/benzoyl peroxide
2.5% gel than in those receiving adapalene 0.1% gel or benzoyi
peroxide 2.5% gel alone (section 3.1). Moreover, =70% of pa-
tients were 'satisfied' or 'very satisfied' with the effectiveness of
Table V. Adapalene 0.1%/benzoyl peroxide 2.5% gel in acne vulgaris:
a summary
Only fixed-dose product combining a topicai retinoid with benzoyi peroxide
Compiementary modes of action and synergistic activity targets muitipie
pathophysioiogic factors
Benzoyi peroxide does not create selective pressure for antibiotic resistance
More effective than adapaiene or benzoyi peroxide aione
Can be used in combination with orai antibiotics in severe acne
Suitabie for use as iong-term maintenance therapy
Once-daily, fixed-dose combination product has the potentiai to improve
patient adherence
Generaliy weii toierated, with dryness being the most commoniy occurring
dermatologie treatment-reiated adverse event
Am J Clin Dermatoi 2011; 12 (6)
418
adapalene 0.1%/benzoyl peroxide 2.5% gel (section 3.1). Good
patient satisfaction has been shown to have an independent
positive effect on adherence to acne therapy.'^^' Other factors
having a positive effect on adherence include good clinical im-
provement as evaluated by the physician and the use of topical
treatment only.'^^'
Results of a pharmacodynamic study (section 2.1) and
pooled analyses of three clinical trials (section 3.1) suggest that
adapalene 0.1%/benzoyl peroxide 2.5% gel may have synergistic,
rather than just additive, effects in patients with acne. One
possible explanation for this finding is that since both adapa-
lene and benzoyl peroxide have keratolytic activity (section
2.1), they may act synergistically to increase skin permeability,
with greater absorption and penetration into the pilosebaceous
unit, resulting in improved efficacy.'^' Adapalene also has an-
ticomedogenic and immunomodulatory activity, and a syner-
gistic effect between adapalene and benzoyl peroxide was seen
for a marker of innate immunity (section 2.1).
Adapalene 0.1%/benzoyl peroxide 2.5% gel did not signif-
icantly differ from clindamycin 1%/benzoyl peroxide 5% gel in
terms of the reduction in inflammatory, noninflatnmatory, or
total lesion counts in patients with mild to moderate acne, al-
though the IGA success rate was significantly higher with
clindamycin 1%/benzoyl peroxide 5% gel than with adapalene
0.1%/benzoyl peroxide 2.5% gel, according to the results of
a 12-week trial (section 3.2). It has been suggested that the
between-group difference in success rate may reflect physician
perception of improved appearance with clindamycin \%ñxnzoy\
peroxide 5% gel versus adapalene 0.1%/benzoyl peroxide 2.5%
gel, arising from less erythema and peeling in patients receiving
clindamycin 1%/benzoyl peroxide 5% gel.'"'' Although com-
parisons across trials should be made with caution, the success
rate reported in adapalene 0.1%/benzoyl peroxide 2.5% gel re-
cipients in this trial'"'' appeared lower (22%) than the success rates
reported in other trials (28-38%) [section 3.1].""«' It should be
noted that the definition of success differed between this trial (an
improvement of >2 grades on the IGA)'"'' and other trials (per-
centage of patients rated 'clear' or 'almost dear' on the IGA).''"*'
Moreover, patients in the trial'"'' comparing adapalene 0.1%/
betizoyl peroxide 2.5% gel with clindamycin 1%/benzoyl peroxide
5% gel had less severe acne than patients in the other trials.
Oral antibiotics are indicated for use in patients with mod-
erate to severe acne, usually in combination with a topical
retinoid with or without benzoyl peroxide.'"'^'^'' Oral anti-
biotics should not be used as monotherapy and although they
should ideally be used for 3 months, the response to treatment
should be assessed after 6-8 weeks of therapy.'"' Twelve-week
studies showed that adapalene 0.1%/benzoyl peroxide 2.5% gel
® 2011 Adis Data information BV. Aii rights reserved.
Keating
in combination with oral lymecycline was more effective than
oral lymecycline alone in patients with moderate to severe acne,
and adapalene 0.1%/benzoyl peroxide 2.5% gel in combination
with oral doxycycline hyclate was more effective than oral doxy-
cycline hyclate alone in patients with severe acne (section 3.3).
In many patients, acne has a prolonged course characterized
by recurrences and relapses, and should be regarded as a chronic
disease.'"' After initial successful treatment, the use of main-
tenance therapy will minimize the risk of relapse.'"' Topical
retinoids are recommended for use as maintenance therapy,
either alone or in combination with benzoyl peroxide.'"'^'
Benzoyl peroxide is a good option for use in combination with a
topical retinoid in long-term maintenance therapy, given that
longer-term use of antibiotics should be avoided because of
concerns over antibiotic resistance.'"' In patients with severe
acne who responded to 12 weeks' therapy with adapalene 0.1%/
benzoyl peroxide 2.5% gel plus oral doxycycline hyclate or oral
doxycycline hyclate alone, not only was an additional 6 months'
therapy with adapalene 0.1%/benzoyl peroxide 2.5% gel more
effective than vehicle gel at maintaining response, further im-
provement was seen in adapalene 0.1%/benzoyl peroxide 2.5%
gel recipients (section 3.3.1). A noncomparative study also
demonstrated the efficacy of 12 months' therapy with adapa-
lene 0.1%^enzoyl peroxide 2.5% gel in patients with acne vul-
garis (section 3.4.2).
Topical adapalene 0.1%/benzoyl peroxide 2.5% gel was
generally well tolerated in patients with acne. In 12-week trials,
the most commonly occurring treatment-related adverse events
were dermatologie in nature and included erythema, scaling,
dryness, and stinging/burning (section 4.1). These dermatologie
treatment-related adverse events were usually of mild to mod-
erate severity, occurred early in the course of treatment, and
resolved without residual effects. Topical adapalene 0.1 %/benzoyl
peroxide 2.5% gel was generally well tolerated in the longer term,
with dry skin being the most commonly occurring treatment-
related adverse event over 12 months of treatment (section 4.1).
When starting treatment with adapalene 0.1 %/benzoyl per-
oxide 2.5% gel, patient education regarding the concomitant
daily use of a noncomedogenic moisturizer may help avoid the
development of dermatologie adverse events, such as dry
skin.''^'"^' In patients experiencing skin irritation, options in-
clude applying noncomedogenic moisturizers, using adapalene
0.1 %/benzoyl peroxide 2.5% gel less frequently (e.g. every other
day), or discontinuing treatment temporarily or permanently.'^''^'
In order to miminize dermatologie adverse events, patients should
be advised not to apply adapalene 0.1 %/benzoyl peroxide 2.5% gel
to cuts, abrasions, or eczematous or sunburned skin and to avoid
potentially irritating topical products (section 2.3).'^'
Am J Ciin Dermatoi 2011:12 (6)
Adapalene 0.1%/Benzoyl Peroxide 2.5% Gel: A Review
Monotherapy with topical adapalene has a generally better
tolerability profile than topical tazarotene or tretinoin,'"' al-
though newer formulations of tretinoin have been developed
(e.g. microsphere'^' and polymerized'^^ tretinoin formulations)
with a view to improving its tolerability. Indeed, a microsphere
tretinoin 0.04% gel formulation had better cutaneous tolerability
than adapalene 0.1%/ben2oyl peroxide 2.5% gel in one study,
whereas adapalene 0.1%/benzoyl peroxide 2.5% gel was better
tolerated than tazarotene 0.1% gel in another study (section 4.3).
Unlike tretinoin, adapalene is photostable.''^' Still, exposure
to sunlight should be minimized during use of adapalene 0.1%/
benzoyi peroxide 2.5% gel; use of sunscreen products and pro-
tective apparel are recommended if exposure cannot be avoided.'^'
Oral isotretinoin is a teratogen.'''^^' However, no teratogenic
effects were seen in rats administered oral doses of adapalene
that were up to 25 times the maximum recommended human
dose of adapalene 0.1%/benzoyl peroxide 2.5% gel (2g), al-
though teratogenic changes were seen in rats and rabbits ad-
ministered oral doses of adapalene that were 123 and 246 times,
respectively, the maximum recommended human dose.'^' The
US prescribing information states that topical adapalene
0.1%/benzoyl peroxide 2.5% gel should only be used during
pregnancy if the potential benefit justifies the risk to the fetus
(pregnancy category C),'^' whereas the UK summary of prod-
uct characteristics states that adapalene 0.1 %/benzoyl peroxide
2.5% gel should not be used during pregnancy''"' (section 5).
In conclusion, the once-daily, fixed-dose combination of
adapalene 0.1%/benzoyl peroxide 2.5% gel is effective and
generally well tolerated in the treatment of acne vulgaris.
Adapalene 0.1%/benzoyl peroxide 2.5% gel targets three of the
four main pathophysiologic factors in acne and is more effec-
tive than adapalene 0.1% gel or benzoyi peroxide 2.5% gel
alone, with an earlier onset of action. Maintenance therapy
with adapalene 0.1%/benzoyl peroxide 2.5% gel maintains
response and is associated with further improvement in patients
with acne, as well as improving postinflammatory hyper-
pigmentation among darker skinned patients. In addition, the
fixed-dose combination of adapalene 0.1%/benzoyl peroxide
2.5% gel has the potential to improve patient adherence to
treatment. Thus, adapalene 0.1 %/benzoyl peroxide 2.5% gel is a
valuable agent for the first-line treatment of acne vulgaris.
Disclosure
The preparation of this review was not supported by any external
funding. During the peer review process, the manufacturer of the agent
under review was offered an opportunity to comment on this article.
Changes resulting from comments received were made by the Adis author
on the basis of scientific and editorial merit
© 2011 Adis Data inforrrration BV. Aii rights reserved.
419
References
1. GollnickH. Current concepts ofthepathogenesis of acne: implications for drug
treatment. Drugs 2003; 63 (15): 1579-96
2. Yentzer BA, Hick J, Reese EL, ct al. Acne vulgaris in the United States:
a descriptive epidemiology. Cutis 2010 Aug; 86 (2): 94-9
3. Gollnick HPM, Finlay AY, Shear N. Can we define acne as a chronic disease? If
so, how and when? Am J Clin Dermatol 2008; 9 (5): 279-84
4. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of
acne: an update from the Global Alliance to Improve Outcomes in Acne
group. J Am Acad Dermatol 2009 May; 60 (5 Suppl.): S1-50
5. Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne
management. Pediatrics 2006 Sep; 118 (3): 1188-99
6. Zuliani T, Khammari A, Chaussy H, et al. Ex vivo demonstration of a syner-
gistic effect of adapalene and benzoyi peroxide on inflammatory acne lesions.
Exp Dermatol. Epub 2011 Jul 2
7. Tan J, Gollnick HP, Loesche C, ct al. Synergistic efficacy of adapalene 0.1%-
benzoyl peroxide 2.5% in the treatment of 3855 acne vulgaris patients.
J Dermatolog Treat 2011 Aug; 22 (4): 197-205
8. Ghali F, Kang S, Leyden J, et al. Changing the face of acne therapy. Cutis 2009
Feb; 83 (2 Suppl.): 4-15
9. Galderma Laboratories. Epiduo® (adapalene and benzoyi peroxide) gel 0.1%/
2.5% for topical use: US prescribing information [online]. Available from
URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/O22320s0011bl.
pdf [Accessed 2011 Jun 14]
10. Galderma (UK) Ltd. Epiduo 0.1%/2.5% gel: UK summary of product char-
acteristics [online]. Available from URL: http://www.medicines.org.uk/
EMC/medicine/22679/SPC/Epiduo+0.1-H-2.5++Gel/ [Accessed 2011 Jun 14]
11. Waugh J, Noble S, Scott LJ. Adapalene: a review of its use in the treatment of
acne vulgaris. Drugs 2004; 64 (13): 1465-78
12. Layton AM, Eady EA. Benzoyi peroxide and adapalene fixed combination:
a novel agent for acne. Br J Dermatol 2009 Nov; 161 (5): 971-6
13. Tan JKL. Adapalene 0.1% and benzoyi peroxide 2.5%: a novel combination for
treatment of acne vulgaris. Skin Therapy Lett 2009 Jul/Aug; 14 (6): 4-5
14. Bikowski JB. Mechanisms of the comedolytic and anti-inflammatory proper-
ties of topical retinoids. J Drugs Dermatol 2005 Jan/Feb; 4 (1): 41-7
15. Millikan LE. The rationale for using a topical retinoid for inflammatory acne.
Am J Clin Dermatol 2003; 4 (2): 75-80
16. Asselineau D, Cavey M-T, Shroot B, et al. Control of epidermal differentiation
by a retinoid analogue unable to bind to cytosolic retinoic acid-binding
proteins (CRABP). J Invest Dennatol 1992 Feb; 98 (2): 128-34
17. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad
Dennatol 1997 Jun; 36 (6 Pt 2): S96-103
18. Shroot B. Pharmacodynamics and pharmacokinetics of topical adapalene.
J Am Acad Dermatol 1998 Aug; 39 (2 Pt 3): SI 7-24
19. Czemielewski J, Michel S, Bouclier M, et al. Adapalene biochemistry and the
evolution of a new topical retinoid for treatment of acne. J Eur Acad Der-
matol Venereol 2001; 15 Suppl. 3: 5-12
20. Shroot B, Michel S, Allée J, et al. A new concept of drug delivery for acne.
Dermatology 1998; 196 (1): 165-70
21. Imahiyerobo-Ip JI, Dinulos JG. Changing the topography of acne with topical
medications. Curr Opin Pediatr 2011; 23 (1): 121-5
22. Tenaud I, Khammari A, Dreno B. In vitro modulation of TLR-2, CDld and
IL-10 by adapalene on normal human skin and acne inflammatory lesions.
Exp Dennatol 2007 Jun; 16 (6): 500-6
23. Vega B, Jomard A, Michel S. Regulation of human monocyte Toll-like receptor
2 (TLR2) expression by adapalene [abstract no. Pl-39]. J Bur Acad Dermatol
Venerol 2002 Oct; 16 Suppl. 1: 123-4
24. Michel S, Jomard A, Démarchez M. Pharmacology of adapalene. Br J Der-
matol 1998 Oct; 139 Suppl. 52: 3-7
Am J Clin Dermatol 2011; 12 (6)
420
25. Center for Drug Evaluation and Research. Application number: 22-320:
pharmacology review(s) [online]. Available from URL: http://www.access
data.fda.gov/drugsatfda_docs/nda/2008/022320s000_PharmR.pdf [Accessed
2011 Jun 14]
26. Mills OH, Kligman AM, Pochi P, et al. Comparing 2.5%, 5%, and 10% benzoyl
peroxide on inflammatory acne vulgaris. Int J Dermatoi 1986 Dec; 25 (10):
664-7
27. Krautheim A, Gollnick H. Transdermal penetration of topical drugs used in
the treatment of acne. Clin Pharmacokinet 2003; 42 (14): 1287-304
28. Cove JH, Holland KT. The effect of benzoyl peroxide on cutaneous micro-
organisms in vitro. J Appl Bacteriol 1983 Jun; 54 (3): 379-82
29. Bojar RA, Cunliffe WJ, Holland KT. The short-term treatment of acne vulgaris
with benzoyl peroxide: effects on the surface and follicular cutaneous mi-
croflora. Br J Dermatoi 1995 Feb; 132 (2): 204-8
30. Farmery MR, Jones CE, Eady EA, et al. In vitro activity of azelaic acid,
benzoyl peroxide and zinc acetate against antibiotic-resistant propionibac-
teria from acne patients. J Dermatoi Treat 1994; 5 (2): 63-5
31. Leyden JJ, Preston N, Osbom C, et al. In-vivo effectiveness of adapalene
0.1%/benzoyl peroxide 2.5% gel on antibiotic-sensitive and resistant Propio-
nibacterium acnes. J Clin Aesthet Dermatoi 2011 May; 4 (5): 22-6
32. Caron D, Clucas A, Dunsire JP, et al. Radiolabelled adapalene is poorly ab-
sorbed after topical application of adapelene 0.1% gel [abstract no. P384].
J Eur Acad Dermatoi Venerol 1998 Sep; 11 Suppl. 2: S275-6
33. Allée J, Chatelus A, Wagner N. Skin distribution and pharmaceutical aspects
of adapalene gel. J Am Acad Dermatoi 1997 Jun; 36 (6 Pt 2): SI 19-125
34. Center for Drug Evaluation and Research. Application number 22-320: clinical
pharmacology and biopharmaceutics review(s) [online]. Available from URL:
http://www.accessda ta.fda.gov/drugsa tfda_docs/nda/2008/022320s000_Clin
PharmR.pdf [Accessed 2011 Jun 14]
35. Nacht S, Yeung D, Beasley JN, et al. Benzoyl peroxide: percutaneous pene-
tration and metabolic disposition. J Am Acad Dermatoi 1981 Jan; 4 (1): 31-7
36. Gollnick HPM, Draelos Z, Glenn MJ, et al. Adapalene-benzoyl peroxide, a
unique fixed-dose combination topical gel for the treatment of acne vulgaris:
a transatlantic, randomized, double-blind, controlled study in 1670 patients.
Br J Dermatoi 2009 Nov; 161 (5): 1180-9
37. Stein Gold L, Tan J, Cruz-Santana A, et al. A North American study of
adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis
2009 Aug; 84 (2): 110-6
38. Thiboutot DM, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixed-
dose combination for the treatment of acne vulgaris: results of a multicenter,
randomized double-blind, controlled study. J Am Acad Dermatoi 2007 Nov;
57 (5): 791-9
39. Eichenfield LF, Jorizzo JL, Dirschka T, et al. Treatment of 2,453 acne vulgaris
patients aged 12-17 years with the fixed-dose adapalene-benzoyl peroxide
combination topical gel: efficacy and safety. J Drugs Dermatoi 2010 Nov;
9(11): 1395-401
40. Feldman SR, Tan J, Pouhn Y, et al. The efficacy of adapalene-benzoyl peroxide
combination increases with nimiber of acne lesions. J Am Acad Dermatoi
2011 Jun; 64 (6): 1085-91
41. Zouboulis CC, Fischer TC, Wohlrab J, et al. Study of the efficacy, tolerability,
and safety of 2 fixed-dose combination gels in the management of acne vul-
garis. Cutis 2009 Oct; 84 (4): 223-9
© 2011 Adis Data informafion BV. Aiirigfifsreserved.
Keating
42. Dreno B, Kaufmann R, Talarico S, et al. Combination therapy with adapalene-
benzoyl peroxide and oral lymecycline in the treatment of moderate to severe
acne vulgaris: a multicenter, randomised, double-blind controlled study. Br
J Dermatoi 2011 Aug; 165 (2): 383-90
43. Stein Gold L, Cruz A, Eichenfield L, et al. Effective and safe combination
therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-
bhnd study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination
gel with doxycycUne hyclate 100 mg. Cutis 2010 Feb; 85 (2): 94-104
44. Poulin Y, Sanchez NP, Bucko A, et al. A 6-month maintenance therapy with
adapalene-benzoyl peroxide gel prevents relapse and continuously improves
efficacy among patients with severe acne vulgaris: results of a randomized
controlled trial. Br J Dermatoi 2011 Jun; 164 (6): 1376-82
45. TroieUi PA, Asis B, Bermejo A, et al. Community study of fixed-combination
adapalene 0.1% and benzoyl peroxide 2.5% in acne. Skinmed 2010 Jan/Feb;
8(1): 17-22
46. Pariser DM, Westmoreland P, Morris A, et al. Long-term safety and efficacy of a
unique fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5%
for the treatment of acne vulgaris. J Drugs Dermatoi 2007 Sep; 6 (9): 899-905
47. Callender VD, Preston N, Osbom C, et al. A meta-analysis to investigate the
relation between Fitzpatdck skin types and tolerability of adapalene-benzoyl
peroxide topical gel in subjects with mild or moderate acne. J Clin Aesthet
Dermatoi 2010 Aug; 3 (8): 15-9
48. Loesche C, Pemin C, Poncet M. 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. Eur J Dermatoi 2008 Sep-Oct; 18 (5):
524-6
49. Leyden JJ, Nighland M, Rossi AB, et al. Irritation potential of tretinoin gel
microsphere pump versus adapalene plus benzoyl peroxide gel. J Drugs
Dermatoi 2010 Aug; 9 (8): 998-1003
50. Andres P, Pemin C, Poncet M. Adapalene-benzoyl peroxide once-daily, fixed-
dose combination gel for the treatment of acne vulgaris: a randomized, bi-
lateral (split-face), dose-assessment study of cutaneous tolerability in healthy
participants. Cutis 2008 Mar; 81 (3): 278-84
51. Webster GF. Evidence-based review: fixed-combination therapy and topical
retinoids in the treatment of acne. J Drugs Dermatoi 2011 Jun; 10 (6): 636-44
52. Dreno B, Thiboutot D, Gollniek H, et al. Large-scale worldwide observational
study of adherence with acne therapy. Int J Dermatoi 2010 Apr; 49 (4): 448-56
53. Strauss JS, Krowchuk DP, Leyden JJ, ct al. Guidelines of care for acne vulgaris
management. J Am Acad Dermatoi 2007 Apr; 56 (4): 651-63
54. Ortho Dermatologies. Retin-A Micro® (tretinoin) gel microsphere 0.1% and
0.04%: US prescribing information [online]. Available from URL: http://
www.retinamicro.com/sites/default/files/RetinAMicro.pdf#zoom=200 [Ac-
cessed 2011 Jun 17]
55. Mylan Pharmaceuticals Inc. Avita® (tretinoin) gel 0.025%: US prescribing
information [online]. Available from URL: http://www.drugs.com/pro/avita.
html?printable=l [Accessed 2011 Jun 21]
Correspondence: Gillian M. Keating, Adis, a Wolters Kluwer Business, 41
Centodan Drive, Private Bag 65901, Mairangi Bay, North Shore 0754,
Auckland, New Zealand.
E-mail: demail@adis.co.nz
Am J Ciin Dermafoi 2011; 12 (6)
Copyright of American Journal of Clinical Dermatology is the property of ADIS International Limited and its
content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for individual use.