TheraD

II I
Topical clobetasol- 17-propionate:
its clinical efficacy and safety*
Review of
El i se A. Ol sen, M. D. , and Roger C. Comel l , M. D. Durham, NC, and La Jolla, CA
Clobetasol-17-propionate, the most potent of currently available topical
steroids as predicted by the vasoconstrictor assay, has just been approved in
the United States. In psoriasis, it has proved significantly more effective
than class II steroids and as or more effective than the only marketed class I
steroid. In the more steroid-responsive eczemas, the superior efficacy of
clobetasol is also apparent, but less striking. Clobetasol prolongs remission
rates, making intermittent treatment schedules feasible and minimizing inherent
potential steroid side effects. Clobetasol may also be useful in the treatment
of a myriad of other skin conditions. A review of the pharmacology, efficacy,
and side effects of this addition to our dermatologic armamentarium is
presented here. (J AM ACAD DERMATOL 15:246-255, t986.)
A successi on of i ncr easi ngl y pot ent topical ste-
roids has f ol l owed the i nt r oduct i on of topical hy-
drocort i sone by Sul zber ger and Wi t t en i n 1952.1
These agent s have pr oved i nval uabl e in t he treat-
ment of a wi de r ange of der mat oses, but enthu-
siasm for t hei r i mpr oved ef f i cacy has been tem-
pered by appreci at i on of an i ncr eased potential for
st eroi d-rel at ed si de effect s. The cur r ent l y mar-
ket ed topical st eroi ds can be di vi ded into classes
of rel at i ve pot ency (Table I) based on cl i ni cal ef-
ficacy. Based on t he vasoconst r i ct or t est , ? a
useful pr edi ct or of cl i ni cal pot ency, cl obet asol - 17-
propi onat e ( Temovat e; Gl axo I nc. , Resear ch Tri-
angle Park, NC) is gener al l y acknowl edged to be
the most pot ent t opi cal st eroi d available in this
country.
The maj or i t y of cl i ni cal trials of cl obet asol have
From the Division of Dermatology, Department of Medicine, Duke
University Medical Center, Durham, and the Division of Derma-
tology, Scripps Clinic and Research Foundation, La Jolla.
Reprint requests to: Dr. Elise A. Olsen, Box 3294, Duke University
Medical Center, Durham, NC 27710/919-684-6844.
*Publication No. 146 from the Division of Dermatology, Department
of Medieirte, Duke University Medical Center.
'~Comell RC, Stoughton RB: The use of topical steroids i n psoriasis.
Dermatol Clin 2:397-409, 1984.
been in the t wo most prevalent steroid-responsive
skin disorders, eczema and psoriasis. As eczema
is i nherent l y mor e steroid-responsive t han pso-
riasis, val i d assessment of effi cacy requires clear
separation of t hese two populations. In general,
studies have been short -t erm and wel l -cont rol l ed,
i nvol vi ng t reat ment of limited body surface areas.
Some studies wer e conduct ed with small popula-
tions of patients, and, therefore, t he power to de-
t ermi ne a significant di fference bet ween two ef-
fect i ve t reat ment s is limited. Several studies have
at t empt ed to answer the question of whet her an
intermittent schedul e of clobetasol application
over a l onger peri od of firr~e can be effect i ve whi l e
mi ni mi zi ng t he potential si de effect s of a potent
steroid.
A review of the pharmacol ogy, efficacy, and
safety profile of this new superpotent topical ste-
roid, clobetasol-17-propionate, is present ed here.
PHARMACOLOGY
Clobetasol- 17-propionate, an analog of prednis-
ol one, has an empi ri cal formul a of C25H32OsC1F,
a mol ecul ar wei ght of 467, and a chemi cal
structure as shown in Fig. 1. In rats, approxi-
mat el y 50% of radiolabeled clobetasol-17-pro-
246
Volume 15
Number 2, Part 1
August, 1986
Topical clobetasol-17-propionate 2 4 7
T a b l e I. Ranki ng of t opi cal steroids*'1"
Br and na me Generi c na me
I. Diprolene ointment
0.05%
Temovate cream
0.05%
Temovate ointment
0.05%
II. Cyclocort ointment
0.01%
Diprosone ointment
0.05%
Florone ointment
0.05%
Halog cream 0.1%
Lidex cream 0.05%
Lidex ointment 0.05%
Maxiflor ointment
0.05%
Topicort cream 0.25%
Topicort ointment
0.25%
Topsyn gel 0.05%
III. Aristocort cream (HP)
O.5%
Diprosone cream
0.05%
Florone cream 0.05%
Maxiflor cream 0.05%
Valisone ointment
0.1%
IV. Aristocort ointment
0.1%
Benisone ointment
0.025%
Cordran ointment
O.05%
Kenalog ointment
0.1%
Betamethasone dipro-
pionate in optimized
vehicle
Clobetasol-17-pro-
pionate
Clobetasol-17-pro-
pionate
Amcinonide
Betamethasone dipro-
pionate
Diflorasone diacetate
Halcinonide
Fluocinonide
Fluocinonide
Diflorasone diacetate
Desoximetasone
Desoximetasone
Fluocinonide
Triamcinolone
acetonide
Betamethasone dipro-
pionate
Diflorasone diacetate
Diflorasone diacetate
Betamethasone
valerate
Triamcinolone
acetonide
Betamethasone
benzoate
Flurandrenolide
Triamcinolone
acetonide
Brand name Generi c name
Synalar cream (HP)
0.2%
Synaiar ointment
O,O25%
Topicort LP cream
0,05%
Benisone cream
0 , 0 2 5 %
Cordran cream 0,05%
Diprosone lotion
0,02%
Kenalog cream 0. 1%
Kenalog lotion 0. 1%
Locoid cream 0. 1%
Synalar cream 0. 025%
Valisone cream 0. 1%
Valisone lotion 0. 1%
Westcort cream 0. 2%
VI. Tridesilon cream
0.05%
Locorten cream 0.03 %
Synalar solution
0.01%
VII. Topicals with hydro-
cortisone, dexa-
methasone, flu-
met hal one, prednis-
olone, and met hyl
prednisolone
Fluocinolone acetonide
Fluocinolone acetonide
Desoximetasone
Betamethasone
benzoate
Flurandreno!ide
Betamethasone dipro-
pionate
Triarncinolone
acetonide
Triamcinolone
acetonide
Hydrocortisone bu-
tyrate
Fluoeinolone acetonide
Betamethasone
valerate
Betamethasone
valerate
Hydrocortisone
valerate
Desonide
Flumethasone pivalate
Fluocinolone acetonide
*Modified from Comell RC, Stoughton RB: Dermatol Clini 2:397-409, 1984. The exact ranking of clobetasol as determined by Comell and
Stoughton has not been determined.
tGroup I is the most potent, and potency descends with each group to Group VII, which is least potent. Within each group the compounds are
arranged alphabetically.
pi onat e ( subsequent l y t o be cal l ed cl obet asol ) is
syst emi cal l y absorbed. * Syst emi c absorpt i on f r om
the skin is sl ow; peak pl as ma levels do not occur
until 48 hour s post appl i cat i on of cl obet asol , and
*Data on file: Glaxo Inc., Research Triangle Park, NC,
r adi oact i vi t y .is still pr es ent i n t he rat ski n aft er
168 hours, wi t h a r et ur n t o negl i gi bl e levels by
240 hours (10 days). Al t hough i n rats t he percu=
t aneous absorpt i on is gr eat er wi t h t he oi nt ment
t han the cr eam, i n ma n a compar abl e absorpt i on
of cl obet asol is obser ved f r om each pr epar at i on.
248 Olsen and Cornell
J our nal of t he
Ame r i c a n Ac a d e my of
De r ma t ol ogy
C H 2 C I
I
C=0
, , , , 3 " . . . . 0 . C 0 . C 2 H 5
~ ......
0 .
Fig. 1. S tmctural formula for clobet asol- 17-propionate.
Absorpt i on peaks in normal human skin fol l owi ng
application of 25 gm of clobetasol are 5 and 15
hours with oi nt ment and 11 hours with cream, wi t h
peak pl asma clobetasol levels of 0. 6 to 0. 7 ~g/ dl .
A single application of 25 gm of clobetasol oint-
ment to t wel ve patients with eczema or psoriasis
resul t ed in a rapid rise in pl asma levels during t he
first 3 hours mad peak levels bet ween 0. 6 and 15.8
ng/ ml in ni ne pat i ent s (3 had no detectable clo-
betasol levels) with return to zero baseline levels
by 96 hours. 2 Absorpt i on is i ncreased consi derabl y
wi t h occl usi on, especi al l y wi t h cream.
The skin bl anchi ng effect of ethanolic extracts
of corticosteroid preparat i ons reflects the intrinsic
pot ency of the steroid mo l e c u l e : In some vaso-
constriction tests, t he pot ency of clobetasol has
been demonst rat ed to be 1, 800 times greater t han
that of hydrocort i sone and consi derabl y more po-
t ent than all hi gh-pot ency corticosteroids now
commerci al l y available. The vasoconstriction as-
says of mar ket ed topical corticosteroid prepara-
tions reflect not onl y the pot ency of t he steroid
mol ecul e but also t he topical activity and bio-
availability f r om the particular f or mul at i on: Table
II illustrates the superior ski n bl anchi ng results of
Temovat e versus Di prol ene, Li dex, and Bet novat e
in sixteen normal subjects.
EFFICACY OF CLOBETASOL PROPIONATE
Ps or i as i s
Co mp a r a t i v e st udi es. Clobetasol propi onat e
was, as expect ed, mor e effect i ve than mi d-st rengt h
(Class III-V) topical steroids i n short-term studies
of ps or i as i s : 7 In addi t i on, patients wi t h psoriasis
treated wi t h clobetasol oi nt ment had remi ssi ons 1
to 2 weeks l onger than patients similarly treated
wi t h class III 0. 1% bet amet hasone valerate oint-
Tabl e H. Topical activity of four
commeri cal l y available corticosteroid
ointments as assessed by skin bl anchi ng*' t
Oi nt me nt
Ave r age bl anchi ng s c o r e
(scale of 1 to 4)
Temovate 3.40:~
Diprolene 3.12
Lidex 2.57
Betnovate 2.52
*Using modified skin-blanching test of Christie and Moore-Robin-
son. 4
t Dat a on file: Glaxo Inc., Research Triangle Park, NC.
~:Significanfly greater than Diprolene (p = 0.01), Lidex
(p = 0. 00t ), and Betnovate (p = 0.001).
Ointment formulation of betamethasone valerate marketed i n United
Kingdom.
me n t : Although one early study found no statis-
tically significant difference bet ween pai red pso-
riatic lesions treated with either the class II 0. 1%
halcinonide cream or clobetasol cream, a a mor e
recent study employing a larger patient popul at i on
found clobetasol to be superior. 9 At the end of t he
t wo study weeks of this doubl e-bl i nd compari son
study of seventy patients wi t h psoriasis, 42. 9% of
the clobetasol-treated sides had >75% cl eari ng
versus only 15.8% of the hal ci noni de-t reat ed sides
(p < 0.001). Of sixty-two psoriasis patients ex-
ami ned 2 weeks off treatment, 62. 9% rel apsed first
on the halcinonide-treated side versus 3.2% on t he
clobetasol-treated side.
Well-controlled studies of clobetasol versus
fluocinonide (class II) also demonstrated t he su-
peri or effectiveness of clobetasol. In two large
multicenter double-blind parallel group studies of
patients with moderate to severe psoriasis, t hree
times daily application of 0. 05% clobetasol cr eam
or oi nt ment was compared with 0. 05% fl uoci no-
nide in its comparative vehi cl e. Cream formul a-
tions of both drugs were compared in 114 pa-
tients,~ and ointment formul at i ons were compar ed
in 110 patients.* In both studies, t he i nvest i ga-
tors' assessment of "mar kedl y i mpr oved" and
"cl ear ed" were grouped into the cat egory " r e-
sol ved. " Significantly mor e patients were j udge d
to be resolved with clobetasol cream compar ed
with fluocinonide cream at the end of the first st udy
week (.66% vs 46%; p < 0. 05). By the end of t he
*Data on file: Glaxo Inc., Research Triangle Park, NC.
Volume 15
Number 2, Part 1
August, 1986
Topical clobetasol-17-propionate 249
second study week, 82% of these patients treated
with clobetasol cream had resolved, but no further
improvement was noted in those patients treated
with fluocinonide cream. The difference in re-
sponse was even more marked with the ointment
formulations as 95% of patients in the clobetasol
ointment group versus 64% of those in the fluo-
cinonide ointment group were resolved on or prior
to completion of the two study weeks. This re-
sponse was more lasting in the clobetasol ointment
group; 89% of the clobetasol group versus 41%
of the fluocinonide group were still resolved 1
week posttreatment (p ~< 0.001). In another dou-
ble-blind comparison study of twice-daily 0.05%
clobetasol ointment versus 0.025% fluocinolone
acetonide ointment it was found that resolution
lasted longer and relapses, when they occurred,
were less severe on the sides treated with clobe-
tasol ointment. 1t
Betamethasone dipropionate in an optimized
ointment base (Diprolene; Schering Corp., Ken-
ilworth, NJ) is currently the only other class I
topical steroid besides clobetasol marketed in the
United States, One 2-week double-blind parallel
group study comparing twice-daily application of
optimized betamethasone dipropionate ointment
(for purposes of brevity, referred to as Diprolene)
versus 0.05% clobetasol ointment to selected le-
sions of forty-two psoriasis patients found almost
complete resolution of the signs and symptoms in
both groups of patients, i2 A second, larger study
compared twice-daily Diprolene to clobetasol oint-
ment in a randomized multicenter double-blind bi-
lateral comparison trial of 124 patients. 13 At com-
pletion of the 2-week study, 70% of the patients
treated with clobetasol had at least 75% reduction
in the overall severity of their disease versus 50%
of those treated with Diprolene (p < 0.001). The
investigators concluded that 41% of the patients
responded better to clobetasol versus 8% respond-
ing better to Diprolene (p < 0.001). Approxi-
mately hal f of the psoriasis patients responded
equally well to either medication. Remission time
may be greater for clobetasol than for Diprolene:
41/72 relapses occurred first on the Diprolene-
treated side versus only 7/72 on the clobetasol-
treated side.
Only one study focused on the use of clobetaso!
in the treatment of scalp psoriasis, and this study
also showed a potential l engt heni ng of remission
with clobetasol. Of eighteen patients treated with
0. 05% clobetasol in an alcoholic solution applied
twice daily for up to 25 days, fifteen of eighteen
patients had a complete response. 14 Three patients
wi t h a partial relapse 30 days after the end of
treatment were gi ven a second cycle of once-a-
day topical applications to clearing (~<8 days). At
examination at least 60 days after t he end of t he
initial study, only one of eighteen patients had any
si gn of relapse.
Appl i cat i on schedul e. Three studies compared
various application schedules for clobetasol in pso-
riasis. 15.~7 In one study, twenty-three patients wi t h
steroid-resistant plaque psoriasis were treated with
three times daily applications of clobetasol cream
on days 1 through 4, 7, 11, and 13.15 At the end
of 2 weeks of therapy, scaling and induration had
cleared in sixteen of twenty-three (70%) patients.
In a double-blind 3-week compari son study of
twenty patients wi t h psoriasis, Van der Harst
et a116 found no significant difference between a
continuous twice-daily versus a twice daily 3 days
a week treatment schedule with clobetasol. In per-
haps the most definitive study, 334 patients with
plaque psoriasis were treated in an open multicen-
ter trial with three different regimens of clobeta-
sol. i7 Eighteen patients were treated for 14 days
wi t h twice-daily applications of either clobetasol
cream or ointment, 252 patients with twice-daily
applications of clobetasol cream on days 1 through
4, 8, 9, 12, and 14, and sixty-four patients with
three times daily application of clobetasol ointment
on the same intermittent schedule. A complete re-
sponse was acknowl edged if all infiltration and
scale had disappeared despite residual erythema.
At the end of the 2-week study, 94% of those
treated with clobetasol every day had a complete
response compared with 75% of those treated in-
termittently three times a day and 59% of those
treated intermittently twice a day. Clearly, the con-
tinuous twice-daily schedule was best at initiating
a complete response.
Intermittent treatment of heal ed psoriatic lesions
wi t h clobetasol, however, can lead to a prolonged
remission. Eight of twelve psoriasis patients who
applied clobetasol cream three times a day, once
weekl y to any lingering eryt hema, remained clear
for a mean observation period of 21 weeks, ts Sire-
250 Olsen and Cornell
Journal of the
Ameri can Academy of
Dermatology
ilarly, 75% of 132 patients in remission who re-
n'mined on twice-weekly clobetasol remained clear
during the average observation period of 3.8
months. ~7 The mean time to relapse was 2.2 to 3.3
months.
Van Scott* treated twenty-five patients with
moderate to severe psoriasis with twice-daily clo-
betasoI (up to 50 gm/wk) for three 2-week courses
of therapy in an open label study. A rest period
of at least 1 week was required between treatment
periods. With each repeated course of therapy,
there was continued improvement in lesion sever-
ity and, in many cases, a reduction in the overall
percentage of body surface area requiring treat-
ment. By the end of the third treatment course,
67% of patients had a final overall severity score
of ~< 1 (on a scale of 9). Prolonged remissions of
5 to 15 weeks following clobetasol treatment were
achieved by four patients.
Adj unct i ve t herapy. Clobetasol has also been
used as adjunctive therapy with ultraviolet light in
the treatment of psoriasis. In one double-blind
Swedish study, twenty patients received intermit-
tent 0.05% clobetasol cream and ultraviolet B
(UVB), twenty-three patients received vehicle and
UVB, and twenty-six patients received only in-
termittent clobetasol.~8 Psoriasis improved sooner
with the addition of clobetasol to UVB, but there
was no significant difference in the percent of in-
dividuals healed or in the time to healing. As has
been noted with other topical steroids, the addition
ofclobetasol to UVB decreased the time to relapse.
Those patients treated with intermittent clobetasol
alone showed faster improvement than the vehicle/
UVB group, but a lower percentage of healing and
a shorter time to recurrence.
In a second double-blind bilateral comparison
study sixteen patients with chronic plaque psoriasis
were treated. Clobetasol ointment was applied
twice daily to one plaque and vehicle to a sym-
metric plaque on the opposite side of the body for
1 week prior to instituting psoralens plus ultravi-
olet A (PUVA) for a median of 10 weeks, t9 Fifteen
of sixteen patients had a more rapid and/or greater
response on the lesion pretreated with clobetasol.
*Van Scott E: Scientific exhibit presented at the 44th Annual Meeting
of the American Academy of Derrmuology, Las Vegas, N V , De-
cember, I985.
In the eight patients in whom bot h lesions healed,
the mean number of PUVA treatments to achieve
healing was 7.2 on the clobetasol-treated lesion
compared to 13.5 on the vehicle-treated lesion.
Eczema
Compar at i ve studies. In t he more steroid-re-
sponsive eczematous dermatoses, hi gh-pot ency
steroids are less likely than in psoriasis to reveal
a therapeutic difference. Not surprisingly, small
comparative studies of 0. 05% clobetasol in its
equivalent vehicle with 0.05% betamethasone di-
proprionate cream, 2 0. 1% halcinonide cream, 8
and optimized betamethasone diproprionate oint-
ment ~2 showed no statistically significant differ-
ences. A large multicenter comparison study of
0.05% clobetasol cream versus 0.05% fluocino-
nide cream in 113 patients with eczema, however,
did demonstrate enhanced therapeutic effect i ve-
ness for clobetasol.~ In this randomi zed trial of
three times a day application of either cream f or
2 weeks (maxi mum, 50 gm/ wk), "mar kedl y i m-
pr oved" and "cl ear ed" were once again grouped
as ' ~resolved." Seventy-one percent of the patients
treated with clobetasol resolved within 3 days ver-
sus 42% of the fluocinonide-treated group (p <
0.001). By the end of week 2, both groups had a
very good response (89% resolution in t he cl o-
betasol group versus 70% resolution in the fluo-
cinonide group). Eighty-one percent of t he 0, 05%
clobetasol-treated groups versus only 54% of t he
0.05% fluocinonide-treated group retained this
good response 1 week after treatment. Al t hough
they responded as well as other forms of eczema
to the 2-week treatment course, patients wi t h
chronic hand/foot eczema were the only ones on
clobetasol to have relapses.
Application schedul e. One major Swedi sh
multicenter study focused exclusively on hand
eczema and minimization of application to prevent
tachyphylaxis. Sixty-one patients with chroni c
(more than 6 months) hand eczema were treated
in an open-phase study with twice-daily 0. 05%
clobetasol cream for up to 21 days. 2~ Ei ght y-t wo
percent healed (slight or no redness and dryness)
within 14 days and 90% healed within 3 weeks.
The fifty-five healed patients continued in a
double-blind randomized bilateral comparison of
0.05% clobetasol cream versus fluprednidene
Vol ume 15
Number 2, Par t 1
August , 1986
Topical clobetasol-17-propionate 251
acetate cream (Corticoderm; Merck, Sharp &
Dohme, Rahway, NJ) applied twice a week in a
maintenance regi men for a mean of 138 days (55-
193 days). Of the forty-six patients who completed
the maintenance trial, 70% of the clobetasol-
treated eczematous hands did not show relapse of
the eczema versus a relapse in 30% of those treated
with fluprednidene (p < 0.05). Of those who did
have relapses, the mean time to relapse was 66
days among t he clobetasol-treated eczematous
hands and 36 days among the fluprednidene-
treated eczematous hands.
In another study an attempt was made to deter-
mine whet her application of clobetasol ointment
once daily was as effective as twice-daily appli-
cation for acute atopic dermatitis. 22 Thirty children
with atopie dermatitis were assigned to apply
clobetasol oi nt ment once daily to one side of their
body versus twice daily to the other side. After 1
to 5 weeks of observation, 37% of patients had
more i mprovement on the twice-daily clobetasol-
treated side versus the side treated once daily.
Other derrnatologie disorders
Certainly, there are other less common derma-
toses that are somewhat resistant to topical steroids
but in whi ch clobetasol, by virtue of its superior
potency, may play an important therapeutic role.
In general, studies performed to date on skin dis-
orders other than psoriasis and eczema have been
poorly controlled and often anecdotal. These pre-
liminary reports, however, may offer a treatment
suggestion for uncommon, and, typically, unre-
sponsive skin disorders and may suggest areas re-
quiring further controlled study.
Three studies suggest that clobetasol may be
useful in the treatment of vitiligo, especially in
dark-skinned patients. 2325 Continuous treatment
was necessary beyond the current recommended
2-week time period, however, and repigmentation
was often incompletel Similarly, although a lotion
formulation of 0. 05% clobetasol has been used to
treat seborrheic demaatitis successfully, 26 use of
clobetasol on the face and for periods up to a month
of continuous use (as was necessary to clear some
patients) is not recommended.
In a double-blind controlled trial, clobetasol or
its vehicle was applied immediately after cryo-
therapy to the sites of treated basal cell carcinomas
or war t s) 7 There was a marked diminution in er-
ythema, pain, and degree of inflammatory swelling
for the clobetasol-treated sites compared with ve-
hicle-treated sites when assessed 24 hours after
cryotherapy.
Several case reports noting successful use of
0.05% clobetasol for other skin disorders have
been published. One patient with active nail dis-
ease secondary to Hal l opeau' s acrodermatitis, un-
responsive to 0.1% bet amet hasone valerate/3% io-
dochlorhydroxyquin, silver nitrate soaks, antibiot-
ics, and topical nitrogen mustard, showed dramatic
improvement with a mixture of 0.05% clobet-
asol cream with 0. 5% neomyci n and 100,000 U
nystatin/gm applied locally twice per day with
overnight occlusion. 28 One patient with granuloma
annulare and necrobiosis lipoidica 29 and another
with necrobiosis lipoidica alone had reduction of
lesion infiltration with application of 0.05% clo-
betasol cream. 3 A patient with actinic reticuloid 3t
and another with pemphi gus vegetans, ~2 both
poorly responsive to systemic and/ or other topical
steroids, were controlled with clobetasol. Clobet-
asol has also been not ed to be an effective adjunct
when applied to glabrous or mucosal surfaces in
the treatment of pemphi gus and pemphigoid. 33
Topical clobetasol was successfully used after top-
ical and/or systemic antibiotic failure in several
elderly female patients with erosive pustular der-
matosis of the scalp. 34 The potential usefulness of
topical clobetasol has also been noted in discoid
lupus erythematosus,* parapsoriasis,* palmoplan-
tar keratoderma,'~ mycosis fungoides,*"r and li-
chen sclerosus et at rophi cus, t but well-controlled
studies have not been reported in these disorders.
SAFETY
Hypothalamus-pituitary-adrenal axis
suppression
It is well document ed that topically applied glu-
cocorticosteroids can be absorbed in sufficient
quantities to suppress the hypothalamus-pituitary-
adrenal (HPA) axis function. Virtually any topical
*Bopp C, Peres M, Schmidt I: Final report on the therapeutic effect
of Dermovate in some cutaneous complaints. Folha Med 71:497-
498, 1975.
tAmblard P, Jerome P: Clinical trials of a new topical corticosteroid:
Clobetasol propionate. Rev Med Alpes Fr 9:47-49, 1980.
252 Olsen and Cornell
Journal of the
American Academy of
Dermatology
steroid can cause suppression if enough is applied,
a large surface area is covered, occlusion is used,
or areas of the treated skin are thin or diseased.
The more inherently potent a steroid, the more
likely it is to suppress the HPA axis. The more
potent compounds such as halcinonide and desoxi-
metasone, when applied to psoriatic skin, have
been reported to depress plasma cortisol levels
even when used without occlusive dressings. 35,36
Therefore, a study to first evaluate the potential of
topical clobetasol propionate to depress cortisol
secretion when applied without occlusion was un-
dertaken.
Although 45 gm/week of clobetasol applied to
the skin of normal subjects has not suppressed the
HPA axis, 37 this is not the case with patients who
have eczema or psoriasis. Applications of 2 gm,
3.5 gm, or 7 gm a day of 0.5% clobetasol pro-
pionate cream or ointment, covering at least 30%
of the body surface area, were made for 1 week
to twenty-two hospitalized patients with psoriasis
or atopic dermatitis.* All patients had a normally
functioning HPA axis as determined by normal
8:00 A.M. plasma cortisol levels and 24-hour uri-
nary excretion of free cortisol. Patients were ex-
cluded from the study if they had used topical
corticosteroids within the previous 2 weeks or sys-
temic corticosteroids within the previous 3 months
or were female and taking estrogen therapy. All
three dosages of clobetasol demonstrated the po-
tential to depress cortisol secretion during treat-
ment, but the incidence of depressed A.M. cortisol
levels below 5 Ixg/dl was dose-related. Three of
four patients receiving 7 gm/day, two of nine pa-
tients receiving 3.5 gm/ day, and one of nine pa-
tients receiving 2 gm/day of topical clobetasol
demonstrated end-treatment A.M. plasma cortisol
levels below 5 ~g/dl. Thus, some patients receiv-
ing less than the currently recommended maximum
dosage of 50 gm/week demonstrated marked
depressions in cortisol secretion during treatment.
Recovery of A.M. cortisol secretion was observed
in all patients within 2 to 3 days of discontinuing
therapy. Further, a normal posttreatment response
to the single dose overnight metyrapone test was
achieved in four of the six patients who agreed to
evaluation. A similar return to baseline cortisol
within 96 hours of stopping clobetasol, along with
the concomitant decrease in plasma clobetasol
levels, was also found in Hehir et al's studyJ No
clinical adverse events were reported for any of
the patients. Pre- and posttreatment monitoring of
selected blood chemistries, hematology, and uri-
nalysis revealed only an occasional change" con-
sistent with systemic glucocorticosteroid effect.
The effect of topically applied clobetasol cream
or ointment on A.M. plasma cortisol levels was
also monitored in outpatient studies where up to
50 gm/week of cream or ointment was dispensed
for the treatment of psoriasis and chronic eczem-
atous dermatoses. The incidence of posttreatment
A.M. cortisol measurements below 5 p~g/dl in pa-
tients treated with clobetasol cream or ointment
was compared with patients treated with 0.05%
fluocinonide cream or ointment. 10., Patients did not
necessarily use 50 gm/week, but this was the max-
imum allowable. Treatment periods were limited
to two consecutive weeks and frequency of appli-
cation was two to three times per day. All patients
had a normal baseline cortisol. Seven of 113
(6.2%) psoriasis and eczema patients thus treated
with clobetasol cream had A.M. cortisol levels be-
low normal. 10 Of forty psoriasis patients who were
treated with clobetasol ointment, two (5%) had
A.M. cortisol levels below 5 ~g/dl.* The incidence
of suppression with fluocinonide cream or oint-
ment control was lower and ranged from 0% to
0.9%. All patients with HPA suppression at the
end of therapy in the clobetasol or fluocinonide
groups returned to normal when the A.M. plasma
cortisol was retested 7 days after treatment was
discontinued.
One 3-week study of less than or equal to 49
gm/wk of clobetasol ointment versus optimized
betamethasone propionate ointment in the treat-
ment of twenty patients with psoriasis saw no sub-
normal plasma cortisol levels in either group. 12 In
a second study by these same investigators, four
of ten patients treated with clobetasol versus one
of ten treated with optimized betamethasone di-
propionate ointment had subnormal cortisols at
least once during a 2-week treatment period.12 In
*Comell RC, Stoughton RB. Unpublished data. *Data on file: Glaxo Inc., Research Triangle Park, NC.
Volume 15
Number 2, Part 1
August, 1986
Topical clobetasol-17-propionate 253
bot h s t udi es , it was appar ent t hat pat i ent s t r eat ed
wi t h cl obet as ol ha d t he gr eat es t decr ease i n me a n
cor t i sol l evel on t he t hi r d t r e a t me nt day ver s us
bet ween t he s e c ond and t hi r d t r eat ment we e k f or
opt i mi zed b e t a me t h a s o n e di pr opi onat e oi nt ment . 12
Thr ee of t he f our pat i ent s t r eat ed wi t h cl obet asol
who had s u b n o r ma l cor t i sol l evel s on day 3 r e-
t u me d to n o r ma l by day 14 whi l e on c ont i nue d
t herapy. ~'- Thi s ear l y di p i n cor t i sol and r et ur n t o
nor mal whi l e o n t r e a t me nt has be e n o b s e r v e d pr e-
vi ous l y as wel l . ~5 Wi t h r epet i t i ve t r eat ment cour ses
of cl obet asol s epar at ed by we e k- l ong dr ug- f r ee pe-
ri ods, p l a s ma cor t i s ol r et ur ns t o basel i ne wi t hi n a
week aft er s t o p p i n g t r e a t me nt . *
I f pr ol onge d t he r a py wi t h cl obet asol is consi d-
er ed, f r e que nt eval uat i on of t he pat i ent , i ncl udi ng
i nt er r upt i on o f t r e a t me nt f or HPA axis as s es s ment ,
is war r ant ed. Th e r e c e nt r e por t of a case o f Cush-
i ng' s s y n d r o me as s oci at ed wi t h gr eat er t han 5
year s' appl i cat i on o f a ppr oxi ma t e l y 30 g m/ we e k
of cl obet asol t o f l exur al areas of a psor i at i c pat i ent
wi t h l i ver di s eas e s uppor t s t hi s poi nt . 38
LOCAL SI DE EFFECTS
Few l ocal si de ef f ect s have been r epor t ed dur i ng
shor t - t er m ( ~ 3 we e ks ) appl i cat i on o f t opi cal cl o-
bet asol pr opi ona t e des pi t e its cl i ni cal pot ency. I n
t he pr evi ous l y de s c r i be d st udi es o f t opi cal cl o-
bet asol wi t hout oc c l us i on i n whi ch si de ef f ect s
wer e reported,8'l'12'~4'~7'2'2~'l" t went y- f our of 926
pat i ent s had adver s e l ocal si de effect s. Tr ansi ent
bur ni ng, s t i ngi ng, or t i ngl i ng was r epor t ed i n t en
pat i ent s and pr ur i t us , i n f our pat i ent s. Thr e e pa-
t i ent s de ve l ope d pyoder ma/ f ol l i cul i t i s , t wo pa-
t i ent s de ve l ope d br i t t l e ski n a nd/ or " c r a c k i n g , "
and one pat i ent e a c h de ve l ope d areas of der mat i t i s,
t el angi ect asi a, or st ri ae. Two pat i ent s us i ng cl o-
bet asol de ve l ope d at r ophy i n t he t reat ed areas, one
r el at ed to oc c l us i on by a r ubber kne e cap. Wi t h
l onger t r eat ment , at r ophy was mor e c o mmo n but
no di f f er ent f r o m t hat s een wi t h me d i u m- p o t e n c y
t opi cal st er oi ds. 24
No cut aneous t oxi ci t y of cl obet asol has been
*Van Scott E: Scientific exhibit presented at the 44th Annual Meeting
of the American Academy of Dermatology, Las Vegas, NV, De-
cember, 1985.
tData on file: Glaxo Inc., Research Triangle Park, NC.
f o u n d wi t h t h e use o f t he mu l t i p l e i ns ul t i r r i t at i on
t es t i n ani mal subj ect s or t he ma x i mi z a t i o n t es t o f
Kl i g ma n i n h u ma n v o l u n t e e r s . *
DI SCUSSI ON
Cl obe t a s ol - 17- pr opi ona t e ( Te mova t e ) is a n e w
t opi cal cor t i cos t er oi d o f e xt r a or di na r y p o t e n c y as
de t e r mi ne d by t he v a s o c o n s t r i c t o r assay. Wh e t h e r
mo r e pot ent i s bet t er d e p e n d s o n wha t di s eas e pr o-
ces s is bei ng t r eat ed a nd wh a t sacr i f i ce one pa ys
f or i ncr eased s t r engt h. I n ve r y s t e r oi d- r e s pons i ve
e c z e ma t ous d e r ma t o s e s or mi l d cas es o f psor i asi s,
cl obet as ol has p r o v e d as, or mo r e ef f ect i ve t ha n,
ot he r hi gh- pot e nc y t opi cal s t er oi ds i n cl ear i ng cl i n-
i cal l esi ons. 8,to.2o In t he mo r e s t er oi d- r es i s t ant eases
o f mode r a t e t o sever e ps or i as i s , cl obet as ol c r e a m
a n d oi nt me nt ha ve p r o v e d mo r e ef f i caci ous t han
cl ass II f l uoc i noni de i n e q u i v a l e n t vehi cl es. 10,, I n
a l ar ge wel l - cont r ol l ed s t u d y o f 126 ps or i as i s pa-
t i ent s, t hose t r eat ed wi t h c l o b e t a s o l oi nt me nt al so
r e s p o n d e d f as t er and s t ayed c l e a r l onge r t han t hos e
t r eat ed wi t h Di p r o l e n e . ~3 A t wi c e - da i l y s chedul e
o f cl obet asol appl i cat i on ove r a 2 - we e k pe r i od
doe s s e e m mo r e e f f e c t i ve i n br i ngi ng psor i asi s or
e c z e ma u n d e r c ont r ol t han a onc e - da i l y or i nt er -
mi t t e nt s c he dul e o f a ppl i c a t i on. 17.22
One o f t he ma n y a dva nt a ge s o f el obet as ol i s a
mo r e r api d a n d p r o l o n g e d r e s p o n s e r el at i ve t o
ot he r pot ent cl ass I a n d cl ass I I t opi cal s t er oi ds . 10.u
Pr ol onga t i on o f t i me t o r e l a ps e i s i mpor t a nt as i t
al l ows e f f e c t i ve i nt r oduc t i on of i nt e r mi t t e nt ma i n-
t enance t r eat ment s c he dul e s t hat c a n mi n i mi z e po-
t ent i al st er oi d si de ef f ect s . On c e - or t wi c e - we e kl y
appl i cat i ons o f cl obet as ol t o r e ma i n i n g e r y t h e ma
has l ed t o p r o l o n g e d cl ear i ng i n 66% t o 75% of
pat i ent s wi t h ps or i as i s or e c z e ma . 15,~7.21 Wh e n u s e d
as adj unct i ve t her apy wi t h PUVA, cl obet as ol has
accel er at ed t he rate o f he a l i ng r el at i ve t o t he ul -
t r avi ol et l i ght t her apy alone.19
Mu c h c onc e r n has be e n e x p r e s s e d a bout t he i n-
cr eas ed pot ent i al f o r s t e r oi d s i de ef f ect s i mpl i ci t
wi t h i ncr eas ed pot ency. Cl o b e t a s o l can caus e HPA
axi s s uppr es s i on e ve n wh e n t h e r e c o mme n d e d
ma x i mu m of 5 0 g m/ we e k i s obs er ved. ' ~ In s hor t
*Data on file: Glaxo Inc., Research Triangle Park, NC.
~'Comell RC, Stoughton RB: The use of topical steroids in psoriasis.
Dermatol Clin 2:397-409, 1984.
254 Ol sen and Cornel l
Journal of the
American Academy of
Dermatology
t r e a t me nt pe r i ods o f no g r e a t e r t han 2 we e ks , t hi s
s u p p r e s s i o n is r e a di l y r e v e r s e d wi t hi n a f e w days
of f me di c a t i on. Mo r e o v e r , ut i l i zat i on of a n i nt er -
mi t t e nt s c h e d u l e o f c l o b e t a s o l appl i cat i on ma y
c i r c u mv e n t HPA s uppr e s s i on. '5,~7,* Be c a us e o f
pot e nt i a l l y s er i ous c o mp l i c a t i o n s s e c onda r y to
c hr oni c a b s o r p t i o n of e x o g e n o u s st er oi ds, cont i n-
uous dai l y us e o f c l obe t a s ol f or l onge r t han 2
we e k s is not r e c o mme n d e d . Fr e que nt eval uat i on
o f t he pa t i e nt on p r o l o n g e d i nt e r mi t t e nt t her apy is
i ndi cat ed.
Lo c a l s i de e f f e c t s h a v e b e e n mi n i ma l wh e n
c l obe t a s ol ha s b e e n u s e d f or s hor t pe r i ods of t i me
( < 3 we e k s ) , t r ans i ent b u r n i n g and pr ur i t us bei ng
mo s t p r o mi n e n t . At r o p h y is a pot ent i al p r o b l e m
wi t h c ont i nuous l o n g - t e r m u s e of cl obet as ol as
wi t h ot her pot e nt s t er oi ds , but , agai n, i nt er mi t t ent
t he r a py s e e ms t o be he l pf ul i n mi ni mi z i ng t hi s
t r o u b l e s o me ef f ect . ~7
Cl o b e t a s o l - 1 7 - p r o p i o n a t e i s a powe r f ul addi t i on
t o our t opi c a l s t er oi d p h a r ma c o p e i a . Re s pons i bl e
us e o f c l o b e t a s o l i nc l ude s o b s e r v a n c e of t he f ol -
l owi ng gui de l i ne s as mo d i f i e d f r o m t hos e o f Par i s h
et a139:
1. Use dai l y f or short courses of ~ 2 weeks and
restrict dosage to < 5 0 g m per week.
2. Do not use on the f ace, axillae, genitalia, or peri-
anal region.
3. Avoid use in chi l dren or pregnant women.
4. Aft er 2 weeks or upon cl eari ng of lesions, change
to i nt ermi t t ent t herapy or consi der substituting a weaker
steroid.
5. Wi t h chroni c i nt ermi t t ent use, assess HPA axis
integrity peri odi cal l y.
6. Speci al caution shoul d be exerci sed if liver i m-
pai rment is present .
7. Do not use under occl usi on.
8. Avoid i ssui ng repeat prescri pt i ons.
*Van Scott E: Scientific exhibit presented at the 44th Annual Meeting
of the Arnerican Academy of Dermatology, Las Vegas, NV, De-
cember, 1985.
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Volume 15
Number 2, Part 1
August, 1986
Topi c al c l o b e t a s o l - 1 7 - p r o p i o n a t e 2 5 5
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ABSTRACTS
Anti-lymphocyte antibodies in systemic lupus
erythematosus
Winfield JB: Clin Rheum Dis 11:523-549, 1985
Antilymphocyte antibodies Occur naturally in systemic luPUs er-
ythematosus, usually increasing when the disease is active. Are the
antibodies important in causing some components of the disease, or
are they only a secondary product of Uttle importance? No one knows
yet.
Philip C. Anderson, M.D.
Lupus pregnancy
Loekshin MD: Clin Rheum Dis 11:611-632, 1985
As the author notes, patients with lupus erythematosus often are
told that pregnancy is wholly safe, or at least they claim they have
been told that. Such advice is not indicated, and the patient's chart
should show that they were warned of risk if they choose to become
pregnant. Major problems for mother and infant may develop. Co-
operation between the various specialists is important and each patient
must be followed with care.
Philip C. Anderson, M.D.
Primary cutaneous cryptococcosis
Baes H, Van Cutsem J: Dermatologica 171:357-361, 1985
No surprise; an elderly asthmatic who was on chronic systemic
steroids and who handled pigeons developed cutaneous cryptococ-
coses on the wrist. Ketaconazole cured him.
Philip C. Anderso n, M.D.
Therapeutic and clinico-pathological factors in the
survival of 1,469 patients with primary cutaneous
malignant melanoma in clinical Stage I. A multivariate
regression analysis
Sondergaard K, Schou G: Virehows Arch 408:149-158,
1985
Repetitiously, and reliably, in these oncologic studies physicians
are taught that many factors do not affect survivat in patients with
melanoma; these include the margin of resection, diagnostic biopsy,
removal of deep fascia, or age at surgery. Tell your surgeons. The
major factor in forecasting an outcome is the thickness of the tumor.
Other lesser but possibly related factors discussed in this article are
ulceration, lymphocytic reaction, sex, mitotic rate, and anatomic
level. The number of patients was 1,469, all with Stage I melanoma.
Philip C. Anderson, M.D.
Posttherapeutic allergy to benzoyl peroxide in patients
with leg ulcers (German text)
Bandmann H-J, Agathos M: Hautarzt 36:670-674, 1985
Benzoyl peroxide has a high sensitization risk; therefore, it is not
recommended for the treatment of leg ulcers. In contrast, it has no
adverse effect in the treatment of acne vulgaris.
Alfred Hollander, M.D.