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Adapalene

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 Drugs 2004; 64 (13): 1465-1478
ADIS DRUG EVALUATION 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Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.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
1466 Waugh et al.

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 inflamma-
tory 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.

Pharmacological Adapalene is a chemically stable derivative of naphthoic acid that binds selective-
Properties ly to the nuclear retinoic acid receptor (RAR) subtypes RARγ (found mainly in the
epidermis) and RARβ (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.

Therapeutic Efficacy
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 8–12
weeks’ treatment, the percentage reductions in lesion counts were 47–75% and
38–73% for adapalene and 0.025% tretinoin gel treatment groups (inflammatory
lesions), respectively, and 46–83% 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-to-
moderate 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. Further-
more, 0.1% adapalene gel was effective as maintenance treatment following
treatment with clindamycin plus adapalene.

 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (13)
Adapalene: A Review of its Use in the Treatment of Acne Vulgaris 1467

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, desqua-
mation 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 Tretinoin was the first retinoid used in the treat-

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 devel-
opment of acne are excessive sebum secretion, ab-
normal keratinisation and desquamation of seba-
ceous-follicle epithelium (comedogenesis), prolifer-
ation 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 corneo-
cytes.[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 treat-
ment. 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 pre-
scribed.[6] Although definitive data are lacking, clin-
ical experience suggests that early treatment of com-
edones reduces scarring and may prevent progres-
sion to the more severe inflammatory acne.[2,4]
ment of acne.[3] It is generally effective and widely
used, but its relatively high incidence of adverse
events may militate against adequate patient com-
pliance 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 ker-
atoses 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 differ-
entiation.[9,10] It shows greatest affinity for subtypes
RARγ, found mainly in the epidermis, and RARβ
which, in the skin, is found principally in dermal
fibroblasts.[9,11]

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

 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (13)
1468 Waugh et al.

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 Treatment Limit of Resultsa
participants detection
(ng/mL)
Caron et al.[14] 8 A single topical application of 5g of 0.1% [14C]ADA gel (n = 4) or a NR ADA not detected
single topical application of 5g of 0.1% [14C]ADA gel following 2wk
non-labelled ADA 0.1% gel treatment (n = 4)
Galderma 6 2g of 0.1% ADA cream applied to 1000 cm2 of acne-affected skin 0.35 ADA not detected
Laboratories[13] once daily for 5d
Medsafe[15] NR A full tube (30g) of 0.1% ADA gel applied all over the body each 0.15 ADA not detected
day for 7d
Medsafe[15] 6 Daily application of 0.1% ADA gel for 3mo 0.15 ADA not detected
a 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
Absorption of adapalene through human skin is
low. In several absorption studies,[13-15] adapalene
was not detected in plasma following topical appli-
cation of 0.1% adapalene gel or cream (table I). Five
of six female volunteers showed no sign of adapa-
lene 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 volun-
teers.[14]
The metabolism of adapalene in human volun-
teers or patients has not been examined; however, in
animals, metabolism is via O-demethylation, hy-
droxylation and conjugation,[15] and excretion is pri-
marily 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% tazaro-
tene 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 double-
blind[22,25,27,28] and parallel group in design. In addi-
tion, the use of 0.1% adapalene gel as adjunctive
therapy in combination with antibacterial
agents[29-32] or benzoyl peroxide[33] has been evalu-
ated 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 11–40 years
(mean age 17–22 years) and had mild-to-moderate
(or moderate-to-severe in some of the combined
therapy trials[29,32,34]) facial acne vulgaris graded 1–5
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 in-
flammatory (mean range at baseline 19–43) and ten

 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (13)
Adapalene: A Review of its Use in the Treatment of Acne Vulgaris
noninflammatory (mean range at baseline 40–88)
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 6–12
months were excluded from some trials,[20,25] as
were those who had taken systemic antibacterial
agents or other anti-acne treatments within 2–6
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 per-
centage of patients showing improve-
ment.[16-19,23,24,27-29] The reduction in lesion count
was the primary endpoint in several stud-
ies;[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 dif-
ference 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 car-
ried 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 mild-
to-moderate acne vulgaris.[16-22] Adapalene and treti-
noin reduced the number of inflammatory lesions at
the end of treatment by 47–75% and 38–73%, and
the number of noninflammatory lesions by 46–83%
and 33–83% in randomised trials.[16-22] Severity
scale improvements with adapalene (39–80%) were
also similar to those for tretinoin (39–72%) in sever-
 2004 Adis Data Information BV. All rights reserved.
1469
al trials.[17-19] These data were confirmed by two
meta-analyses.[38,39]
In addition, 0.1% adapalene gel had similar effi-
cacy to other formulations of tretinoin (0.1% treti-
noin microsphere gel,[25,26] 0.05% tretinoin cream[23]
and 0.05% isotretinoin gel,[24]) in patients with mild-
to-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 single-
blind[18] trials, 0.1% adapalene gel provided a signif-
icantly 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 nonin-
flammatory lesions at week 4; p ≤ 0.05)[24]. Con-
versely, 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 unpub-
lished 12-week, randomised, single-blind, multicen-
tre trials with the same primary endpoint that used
intention-to-treat analyses showed a more rapid on-
set 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 be-
tween-group differences at other timepoints (2, 4, 8
and 12 weeks).[38] Whether this statistically signif-
icant 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
Drugs 2004; 64 (13)
1470 Waugh et al.

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 Mean reduction in no. of Reduction in mean Patients showing
evaluable inflammatory/noninflammatory grade for global improvement (%)b
patients lesions (%) severity scale (%)a
Compared with 0.025% tretinoin gel (TRE-G)
Alirezai et al.[20] ADA 30 69/77 80 90
TRE-G 30 73/81 70 93
Cunliffe et al.[19] ADA 131 64/70 56 72
TRE-G 128 63/67 59 75
Ellis et al.[17] ADA 111 47/57 39* 88.4
TRE-G 126 50/54 39* 89.6
Grosshans et al.[18] ADA 48 53c/54c 56 >90
TRE-G 46 65c/67c 72 >90
Shalita et al.[21] ADA 149 48/46† 29†
TRE-G 139 38/33 18
Tu et al.[16] ADA 72 75/70 75
TRE-G 67 72/70 73
Verschoore et al.[22] ADA 24 69†/83 70
TRE-G 24 50/83 56
Compared with 0.1% tretinoin microsphere gel (TRE-M)
Nyirady et al.[25] ADA 84 27c/44c 83
TRE-M 82 26c/46c 73
Thiboutot et al.[26] ADA 161d 35c/37c
TRE-M 32c/44c
Compared with 0.05% tretinoin cream (TRE-C)
Cunliffe et al.[23] ADA 384de 28/45 59.6
TRE-C 33/50 57.7
Compared with 0.05% isotretinoin gel (I-TRE)
Ioannides et al.[24] ADA 36 62/74 97
I-TRE 31 57/68 90
a Assessed using the Burke and Cunliffe scale.
b 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]
c Data estimated from a graph.
d Total population; patient numbers were not reported separately for individual treatment groups.
e Intention-to-treat analysis.
* p < 0.001 vs baseline; † p < 0.05 vs TRE-G.

days (frequency of application was reduced to im-
prove tolerability [section 4]),[27] the drug was less
effective than once-daily tazarotene (standard regi-
men) in a randomised double-blind trial.[28] Once-
daily 0.1% tazarotene gel recipients with mild-to-
moderate acne vulgaris had significantly greater re-
ductions in inflammatory and noninflammatory le-
sions than 0.1% adapalene gel recipients, with sig-
nificantly more patients achieving ≥50% improve-
ment 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

 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (13)
Adapalene: A Review of its Use in the Treatment of Acne Vulgaris
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 per-
oxide[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 le-
sions than the antibacterial agent plus adapalene gel
vehicle (hereafter referred to as gel vehicle) in pa-
tients with mild-to-moderate acne vulgaris (table
IV). Furthermore, clindamycin plus 0.1% adapalene
gel recipients showed significantly greater improve-
ment 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 ef-
fective in patients with moderate-to-moderately se-
vere acne vulgaris.[29,34] Patients showed significant-
ly greater percentage reductions in mean total lesion
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 No. of Mean reduction in no. of
regimen evaluable inflammatory/noninflammatory
patients lesions (%)
Leyden et al.[27] ADA od 74 62/69
TAZ q2db 74 61/63
Webster et al.[28] ADA od 73 55c/48c
TAZ od 72 70*c/71**c
a Assessed using the Burke and Cunliffe scale.
b Patients received placebo on the non-treatment day.
c Median values.
od = once daily; q2d = once every two days; * p ≤ 0.01, ** p ≤ 0.001 vs ADA.
 2004 Adis Data Information BV. All rights reserved.
1471
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). Sig-
nificantly more patients receiving lymecycline plus
adapalene showed marked improvement or were
almost clear of facial lesions at week 12 than pa-
tients 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 compara-
tive study, reported as a poster,[34] in patients with
moderate or moderately severe acne vulgaris who
received oral lymecycline 300 mg/day or oral mino-
cycline 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 signifi-
cantly favoured combination therapy with lyme-
cycline 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 reduc-
tion of total lesions (p < 0.001) and noninflamma-
tory lesions (p-value not stated) favouring lyme-
cycline 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 ab-
stract (table IV).[33]
Reduction in mean grade for Patients showing ≥50%
global severity scale (%)a global improvement (%)
30 73
31 74
24 52
44** 78*
Drugs 2004; 64 (13)
1472 Waugh et al.

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 No. of Treatment regimen Meanreduction in Mean reduction in Mean reduction
design evaluable no. of inflammatory no. of in total no. of
patients lesions (%) noninflammatory lesions (%)
lesions (%)
Cunliffe et al.[29] ITT 118 LMC 300mg od + ADA od 60.3** 56.6* 58.7**
124 LMC 300mg od + V 45.6 47.6 47.9
Fang et al.[33]a OT, nb 150b BP od + ADA odc 81.3d
ADA od 68.9d
Campo et al.[34]a OT 64 LMC 300mg od + ADA od for 2 77e 77**
weeks followed by LMC 150mg
od for 22 weeks + ADA od
58 MNC od + ADA od 64 67
Wolf et al.[30] ITT 125 CLM bid + ADA odf 55* 42.5** 46.7**
124 CLM bid + V odf 44.2 16.3 25.5
Zhang et al.[32] ITT 150 CLM bid + ADA odf 75.2** 75.5** 75.1*
150 CLM bid + V odf 67.8 62.2 64.9
a Abstract.
b Total evaluable population; patient numbers were not reported separately for individual treatment groups.
c BP was applied in the morning and ADA in the evening.
d Percentage of people experiencing >60% reduction in lesion count.
e Significant difference vs MNC + ADA (p-value not given).
f 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 retinoid agents,[16-19,23-28,42-44] studies in which

Adapalene was effective as maintenance treat-
ment in an open-label, follow-on study after suc-
cessful treatment with clindamycin plus 0.1%
adapalene gel.[32] Patients who had shown at least a
moderate improvement with a 12-week 1% clinda-
mycin 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, noninflamma-
tory, 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
adapalene was part of an adjunctive therapy regi-
men[30,32] oral antibacterial medications[29] (see sec-
tion 3 for trial design details) and a meta-analysis[38]
of data from five, randomised, 12-week, parallel-
group 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 volun-
teers[49-54] and two studies evaluating adjunctive
therapy that included 0.1% adapalene gel.[33,34]
These investigator-assessed tolerability data re-
late to similar endpoints in most studies, but the way
they are presented differs considerably. Some trials
employed a 0–3 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 fre-
quency but not the severity of adverse events[17,24]
and one used a percentage scale of patients exper-
iencing adverse events.[17] This diversity of data

 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (13)
Adapalene: A Review of its Use in the Treatment of Acne Vulgaris 1473

presentation precluded tabulation or comparative were classified as mildly, moderately or severely

analysis across trials. The tolerability parameters
assessed in some studies were erythema, desquama-
tion, pruritus, dryness and burning/stinging sensa-
tions.[18,19,23,25,26] In one trial these were scored sepa-
rately for immediate or persistent effects.[18]
4.1 General Tolerability Profile
Adapalene was generally well tolerated. In a
noncomparative study in 2545 patients with mild-to-
moderate acne vulgaris, treatment-related adverse
events were reported in 3.7% of 0.1% adapalene gel
recipients; the majority of these involved skin irrita-
tions (2.2%).[48] However, according to the prescrib-
ing information, adverse effects such as erythema,
scaling, dryness, pruritus and burning, are expected
in 10–40% 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 long-
term use of 0.1% adapalene gel in a 24 week follow-
on 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
Adverse effects such as erythema, dry skin, pruri-
tus, desquamation and stinging/burning sensations
irritating.
4.2.1 Versus Tretinoin
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 exper-
iencing erythema, dryness, scaling or stinging/burn-
ing were generally lower in these trials, particularly
during the first 4 weeks of administration.[16-21,45,46]
In several studies of 12–15 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, investigator-
blinded trials[38] confirmed the better tolerability
profile of 0.1% adapalene gel versus 0.025% treti-
noin gel (figure 1).[38] The most marked difference
was for immediate burning/stinging, which was ap-
proximately 5-fold more common in 0.025% treti-
noin gel recipients.[38] Adverse events were of mod-
erate-to-severe intensity.[38]
In addition, 0.1% adapalene gel generally show-
ed better tolerability than several newer formula-
tions of tretinoin in numerous, randomised trials of
4–12 weeks’ duration.[23-26,42-44] As with the gel for-
mulation of tretinoin,[16-18,20,21,45,46,51,57] this differ-
40 ADA
TRE-G
35
30
Patients (%)

are common to all topical retinoids, but were experi- 25

enced significantly less frequently and with milder 20 *** **
***
severity in adapalene recipients than in recipi- 15
ents of other retinoids (sections 4.2.1 and
10
4.2.2).[16-19,23-26,28,38,43,44] *** *
5 *
In addition, 0.1% adapalene gel showed the low-
est irritancy of all active treatments (active compara- 0
tors were 0.01%, 0.025%, and 0.05% tretinoin gel,
ss

g e

gi t

it t

ur ate
in en

ur en
m

io

in at
ne

rn P ing

Pe g

Im us

s
at
he

st di

st st

pr ist

pr edi
itu
n

0.025%, 0.05% and 0.1% tretinoin cream, and 0.1%

ry

g/ e

g/ si

rs
yt

m
in er
D

a
Er

qu

Im

and 0.04% tretinoin microsphere gel and 0.5% and

es

in
D

rn

0.1% tazarotene gel and benzoyl peroxide) in 3-

bu

bu

week, randomised, single-blind[49-51,53,54] or double-
blind[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-irri-
tant, whereas tretinoin and tazarotene formulations
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 TRE-
G.

 2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (13)
1474
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 treat-
ment 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] Con-
versely, 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 treti-
noin 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 burning-
pruritus at 12 weeks) was significantly better with
2.5
2.0
Mean assessment score
* Generally, tolerability differences between the
1.5
* treatment, with differences decreasing there-
1.0
0.5
*
0.0
Erythema Dryness Burning/ Desquamation
stinging
Fig. 2. Comparative tolerability of 0.1% adapalene gel (ADA) ver-
sus 0.025% tretinoin cream (TRE-C).[43] Tolerability scores (based
on a 10-point scale where 0 = none and 7–9 = 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] Pa-
tients aged 13–30 years (mean age 18.5 years) applied one treat-
ment to one side of their face and the other treatment to the other
side once daily. * p < 0.05 vs TRE-C.
 2004 Adis Data Information BV. All rights reserved.
Waugh et al.
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
Adapalene 0.1% gel was generally better tolerat-
ed, in particular during the first few weeks, than
0.1% tazarotene gel once daily[28] or 0.1% tazaro-
tene gel once every 2 days[27] in randomised, double-
blind trials. Adverse events were generally mild or
moderate in severity in all three studies.[27,28] No
patients in either treatment group discontinued treat-
ADA ment as a result of an adverse event in one of these
TRE-C trials[28] and in another, one person in each treatment
group discontinued treatment.[27]
drugs were greater during the first 2–4 weeks of
after.[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 differ-
ences 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 pro-
file of the drug.[27] For example, mean cumulative
dryness scores assessed using a 5-point scale were
Drugs 2004; 64 (13)
Adapalene: A Review of its Use in the Treatment of Acne Vulgaris
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 differ-
ences during the remaining 9 weeks of this study.[27]
4.3 Adjunctive Therapy
When used as adjunctive therapy with 1% clinda-
mycin 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 veh-
icle plus an antibacterial agent (30.4% vs 21.8% in
patients receiving combined therapy with clindamy-
cin[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 clinda-
mycin plus gel vehicle (10.4% and 9.7%).[30] Al-
though numerically more patients receiving adjunc-
tive 0.1% adapalene gel than gel vehicle experi-
enced 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 inten-
sity.[29,30,32]
Furthermore, abstract reports suggest that 0.1%
adapalene gel used as adjunctive therapy with mino-
cycline[34] or benzoyl peroxide[33] may be well toler-
ated in patients with acne vulgaris, although quanti-
tative 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 for-
mulation[13] and a solution[58] are also approved in
the US. Administration is similar for all three formu-
lations; however, information presented in this sec-
tion is focused specifically on 0.1% adapalene gel.
Adapalene should be applied once daily at night
before retiring, after washing and drying the affect-
ed areas. A thin film should be applied to lightly
 2004 Adis Data Information BV. All rights reserved.
1475
cover the affected areas, avoiding lips, eyes and
mucous membranes.[10]
Adapalene should not be used in association with
other potentially irritating, topically applied prod-
ucts, including medicated or abrasive soaps, cosmet-
ics 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 sun-
burn 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 12–24 years, at least occasionally and, in
some cases, persistently.[1,4,5,59] Frequency and se-
verity 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 disor-
ders. 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 be-
ing.[62] Available treatments for acne are very effec-
tive and could prevent scarring in many cases if
Drugs 2004; 64 (13)
1476
employed early enough, as well as reducing the
overall impact of this condition.[2,60,63]
Choice of treatment depends on the pathophysio-
logy of the acne. In mild-to-moderate acne, where
there are mainly noninflammatory lesions, the first-
line treatments are the comedolytic agents.[4] These
include the retinoids (tretinoin, adapalene and ta-
zarotene).[4] In mild-to-moderate inflammatory ac-
ne, combination therapy with a topical or oral anti-
bacterial plus a retinoid is the preferred treatment.
Thus, early treatment, which addresses the patho-
physiological factors leading to inflammatory le-
sions, can prevent development of inflammation
with its associated risk of scarring.[41,64] The emer-
gence of antibacterial resistance in P. acnes has led
to treatment plans that recommend earlier interven-
tion with comedolytic agents, such as the reti-
noids.[60]
In patients with mild-to-moderate acne vulgaris,
0.1% adapalene gel showed similar efficacy to sev-
eral formulations of tretinoin (the gold standard
agent in the treatment of acne[1]), but was less effec-
tive 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 toler-
ability; nonetheless, 0.1% adapalene gel proved to
be better tolerated than these formulations, especial-
ly 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 2–4 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.
Waugh et al.
tazarotene gel once every 2 days), a regimen de-
signed to improve the tolerability profile of tazaro-
tene, in a double-blind trial.[27]
Adapalene provided effective adjunctive treat-
ment with topical clindamycin,[30,32] oral antibac-
terials[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 pa-
tients 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 on-
set of action; these features may potentially positive-
ly 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 com-
pliance, an important factor in treatment success.
Adapalene is, therefore, assured of a role in the first-
line treatment of acne vulgaris.
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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
Drugs 2004; 64 (13)