Full text of DOI:10.2165/00128071-200203060-00006

Am J Clin Dermatol 2002; 3 (6): 435-438
1175-0561/02/0006-0435/$25.00/0
ADIS SPOTLIGHT
© Adis International Limited. All rights reserved.
Spotlight on Topical Pimecrolimus in
Atopic Dermatitis1
Keri Wellington and Blair Jarvis
Adis International Inc., Langhorne, Pennsylvania, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
1. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3.1 In Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3.2 In Infants Aged 3 to 23 Months . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
3.3 In Children Aged 2 to 17 Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and
has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and pediatric patients when applied
topically.
Abstract
Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing
symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3
to 23 months, children aged 2 to 17 years, and adults. The median reductions from baseline in the total EASI
score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were
47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks
resulted in significant decreases in mean EASI scores compared with vehicle.
The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with
pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by
intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty-one percent of
children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing
a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids
for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups
than in the vehicle groups.
Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were
no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis.
The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling
of warmth.
In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate
atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have
not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no
reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus has shown no potential for
skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Topical pimecrolimus
1.0% provides a promising and well tolerated treatment option in the management of infants, children and adults
with mild to moderate atopic dermatitis.
1 The full text of this article was published in Drugs 2002; 62 (5): 817-40.

436
Wellington & Jarvis
μg/L [78% of the concentrations were below the assay limit
of quantification (LoQ)]. The area under the whole-blood
concentration-time curve from 0 to 12 hours ranged from <0.5 to
11.4 μg • h/L.[8,10]
In 40 adult patients with extensive atopic dermatitis (up to
62% body surface area affected) treated with pimecrolimus cream
1.0% for 1 year, 98% of the blood samples collected provided
concentrations below the assay LoQ; the maximum concentration
measured was 0.8 μg/L.[10]
In 58 patients aged 3 months to 14 years with moderate to
severe atopic dermatitis (10 to 92% affected body surface area)
treated with pimecrolimus 1.0% twice daily for 3 weeks, 93% of
the blood concentrations of pimecrolimus were <2 μg/L. The con-
centrations were in a range similar to those measured in adult
patients.[9]
In a study examining the pharmacokinetics of single-dose
oral pimecrolimus,[11] healthy volunteers received 5, 15, 30 or
60mg under fasting conditions. The fall in concentrations after
maximum plasma concentrations had been reached involved
three disposition phases with an apparent terminal elimination
half-life of 30 to 40 hours. The mean apparent systemic clearance
among the pimecrolimus 30 and 60mg groups was 71 and 91 L/h,
and the apparent volume of distribution was 3452 and 4830L,
respectively. Proportionality between the dose of the drug and
maximum concentrations of pimecrolimus was observed.
Pimecrolimus is stable in the skin but, when taken up into the
circulation, it is metabolized by the liver cytochrome P450 3A4
pathway and excreted in the feces, as shown after oral adminis-
tration.[12,13]
1. Pharmacodynamic Properties
Pimecrolimus binds to macrophilin-12 (FKBP12) at nano-
molar concentrations (concentration required for 50% inhibition
= 1.8 nmol/L), and the resulting complex inhibits calcineurin,
causing a signal transduction blockade in target cells.[1] As a con-
sequence, the synthesis of inflammatory cytokines is blocked at
the level of gene transcription.[1] The release of T helper (Th)-1
and Th2 cytokines from a house dust mite-sensitive Th cell clone
was inhibited by pimecrolimus 0.2 to 0.42 nmol/L.[1]
Pimecrolimus dose-dependently inhibited the anti-immuno-
globulin E-induced release of the preformed pro-inflam-
matory mediators histamine and tryptase from activated human
dermal mast cells,[2] and β-hexosaminidase, serotonin and tumor
necrosis factor-α from activated rat basophilic leukemia 2H3
cells.[1,3] Furthermore, the up-regulation of co-receptors CD134
and CD137, which are implicated in the activation and expansion
of inflammatory effector T cells, was dose-dependently inhibited
by pimecrolimus (80% inhibition at 10 nmol/L in primary T
cells).[4]
Twice-daily topical pimecrolimus 1.0% showed no potential
for skin atrophy when applied for 6 days/week to normal skin in
a randomized, double-blind, vehicle-controlled 4-week study in
16 healthy volunteers.[5] Conversely, betamethasone-17-valerate
0.1% and triamcinolone acetonide 0.1% creams significantly re-
duced skin thickness (by 7.9 and 12.2%, respectively) compared
with baseline thickness.[5]
Symptoms of nickel-induced allergic contact dermatitis in 66
healthy volunteers were significantly reduced by twice-daily top-
ical pimecrolimus 0.6% for 12 days compared with vehicle.[6]
Furthermore, after 12 days, there was no significant between-
group difference in mean reductions of the total symptom score
for erythema, induration and vesiculation in patients treated
twice daily with topical pimecrolimus 0.6% or betamethasone-
17-valerate 0.1% (32% reduction for both).
3. Therapeutic Efficacy
Topical pimecrolimus 1.0% has been evaluated in random-
ized, double-blind, vehicle-controlled clinical trials in infants
(aged 3 to 23 months), children (aged 2 to 17 years) and adults
with mild to severe atopic dermatitis (the majority of patients had
moderate disease).[14-23] In clinical trials, the dosage of topical
pimecrolimus was 1.0% administered twice daily as a cream un-
less otherwise stated.
2. Pharmacokinetic Profile
Systemic absorption of topically applied pimecrolimus 1.0%
has been investigated in short-term (3 weeks) and long-term (up
to 12 months) studies in a total of 52 adults and 58 children (aged
≥3 months) with moderate to severe atopic dermatitis.[7-10] In all
these studies, blood concentrations of pimecrolimus were consis-
tently low, regardless of the extent of lesions treated (up to 92%
body surface area involved) or duration of therapy. No systemic
accumulation was observed over the treatment period.
3.1 In Adults
Twice daily administration of pimecrolimus 1.0% cream for
3 weeks was significantly more effective than once daily admin-
istration or vehicle at reducing symptoms of atopic dermatitis, as
measured by the Atopic Dermatitis Severity Index (ADSI), in 34
patients with disease of mild to moderate severity.[14] The group
that received pimecrolimus twice daily showed a 71.9% mean
reduction in the ADSI score at endpoint, compared with a mean
In 12 adult patients with moderate to severe atopic derma-
titis, blood concentrations of pimecrolimus during 3 weeks of
twice daily treatment with topical pimecrolimus 1.0% were ≤1.4
© Adis International Limited. All rights reserved.
Am J Clin Dermatol 2002; 3 (6)

Spotlight on Topical Pimecrolimus
437
reduction of 10.3% at the vehicle-treated sites. Furthermore,
pimecrolimus demonstrated a significant therapeutic effect by
day 2 compared with vehicle (a reduction in the ADSI score of
18.5% compared with a 1.5% increase, respectively). At sites
treated with pimecrolimus once daily, the mean percentage reduc-
tion from baseline in the ADSI total score was 37.7%, compared
with 6.2% at sites treated with vehicle.[14]
treated with corticosteroids (all patients were able to receive res-
cue medication in the form of emollients and/or medium potency
corticosteroids for eczematous flares not controlled by study
medication) was approximately twice as high as that in the
pimecrolimus group.[18]
3.3 In Children Aged 2 to 17 Years
In a dose-finding study involving 260 patients,[15] pimecro-
limus 0.2, 0.6 and 1.0% creams were significantly more effective
than vehicle at reducing total Eczema Area and Severity Index
(EASI) scores after 3 weeks of twice daily treatment. Among
patients randomized to pimecrolimus 1.0%, the median reduction
from baseline in EASI scores was 47%, compared with a 0%
reduction among vehicle recipients. Pimecrolimus 0.6 and 1.0%
were also associated with significant improvements in pruritus
compared with vehicle; at endpoint, the proportion of patients
with absent or mild pruritus increased to 52.4 from 11.9% at
baseline and to 46.7 from 6.7% at baseline for pimecrolimus 0.6
and 1.0%, respectively. In comparison, absent or mild pruritus
was present in 18.6 and 4.7% of vehicle recipients at endpoint
and baseline, respectively.[15]
In a study in 192 adults with mild to moderate atopic derma-
titis,[16] topical pimecrolimus 1.0% significantly reduced the in-
cidence of eczematous flares and the need for rescue treatment
with topical corticosteroids compared with vehicle. Among pa-
tients in the pimecrolimus group, 14.8% were treated with topical
corticosteroids, compared with 37.3% of patients in the vehicle
group. The mean number of disease flares over a 24 week study
period in patients who received pimecrolimus was 1.2, compared
with 2.6 in patients who received vehicle. Reductions in total
EASI scores and the severity of pruritus were also significantly
in favor of pimecrolimus.[16]
Combined results from two studies showed that pimecro-
limus 1.0% cream was significantly more effective than vehicle
at reducing symptoms of the disease in 403 children with mild to
moderate atopic dermatitis.[19-21] After 6 weeks, the median re-
duction of the EASI total score was 59% in the pimecrolimus
group, compared with 14% in the vehicle group. Treatment with
pimecrolimus was also associated with a significant improvement
in health-related quality-of-life scores based on a 28-point ques-
tionnaire filled out by the patients’ parents.
Compared with a conventional therapy, pimecrolimus 1.0%
cream significantly reduced the incidence of eczematous flares in
the first 6 months of a year-long study involving 713 patients with
predominantly moderate atopic dermatitis.[22,23] At month 6, 60%
of patients in the pimecrolimus group remained free of flares,
compared with 35% in the conventional therapy control group.
Over the course of the year, fewer patients in the pimecrolimus
group than patients in the control group were treated with corti-
costeroids (57 vs 32%).
4. Tolerability
Evidence to date indicates that topical pimecrolimus 1.0% is
well tolerated in patients of all age groups (infants aged 3 to 23
months, children aged 2 to 17 years, and adults) with atopic der-
matitis.[14-23]
The most frequently reported adverse events during treat-
ment with pimecrolimus 1.0% cream were application site reac-
tions, such as burning and a feeling of warmth, which occurred
in approximately 10% of patients aged 2 to 17 years, and in about
26% of adults.[13]
There were no significant between-group differences in the
incidence of adverse events among 192 adult patients with mod-
erate to severe atopic dermatitis who received pimecrolimus 1.0%
or vehicle twice daily according to need for up to 1 year.[16]
There are limited published data on the tolerability of
pimecrolimus 1.0% in infants and children because the five clin-
ical trials have, so far, been reported only as abstracts.[17-23] How-
ever, there were no reports of clinically relevant systemic adverse
events. The incidence of skin infections in 335 patients aged 2 to
17 years treated with pimecrolimus 1.0% cream was low
(≈5%).[13,20]
3.2 In Infants Aged 3 to 23 Months
In a study involving 186 infants with mild to moderate atopic
dermatitis,[17] treatment with pimecrolimus 1.0% cream for up to
6 weeks resulted in a significant reduction in EASI and Investi-
gators Global Assessment (IGA) scores, as well as in the severity
of pruritus.
Compared with a conventional therapy, pimecrolimus 1.0%
cream significantly reduced the incidence of eczematous flares in
the first 6 months of a 1-year study involving 251 infants with
mild to very severe atopic dermatitis (the majority of patients had
moderate disease).[18] 70.1% of patients in the pimecrolimus
group completed 6 months of treatment without experiencing a
flare, compared with 32.6% of patients in the control group. The
mean number of days that patients in the control group were
© Adis International Limited. All rights reserved.
Am J Clin Dermatol 2002; 3 (6)

438
Wellington & Jarvis
4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001;
144: 507-13
5. Dosage and Administration
6.
Queille-Roussel C, Graeber M, Thurston M. SDZ ASM 981 is the first non-steroid
that suppresses established nickel contact dermatitis elicited by allergen
challenge. Contact Dermatitis 2000; 42: 349-50
Harper J, Green A, Scott G, et al. First experience of topical SDZ ASM 981 in
children with atopic dermatitis. Br J Dermatol 2001; 144: 781-7
Van Leent EJM, Ebelin M-E, Burtin P, et al. Low systemic exposure after repeated
topical application of pimecrolimus (Elidel, SDZ ASM 981) in patients with
atopic dermatitis. Dermatology 2002; 204: 63-8
Pimecrolimus 1.0% has been approved in the US for the
short-term and intermittent long-term treatment of mild to mod-
erate atopic dermatitis in non-immunocompromised patients
aged ≥2 years who do not respond well to, or may have adverse
effects with, conventional treatments.[13]
Pimecrolimus 1.0% cream is applied twice daily to all af-
fected skin areas as a thin layer and rubbed in gently and com-
pletely. The drug should be used as long as signs and symptoms
persist. If disease resolution occurs, treatment should be stopped;
if symptoms persist beyond 6 weeks, the patient should be re-
evaluated.[13]
A change in dosage is not required in patients with renal or
hepatic insufficiency. Pimecrolimus should not be applied to
areas of active cutaneous viral infection. Furthermore, because
pimecrolimus may be associated with an increased risk of vari-
cella zoster virus infection, herpes simplex virus infection or ec-
zema herpeticum, the use of the drug in the presence of these
infections is cautioned.[13]
7.
8.
9.
Harper J, Lakhanpaul M, Wahn U, et al. Pimecrolimus (Elidel, SDZ ASM 981
cream 1%) blood levels are consistently low in children with extensive atopic
eczema [abstract]. J Eur Acad Dermatol Venereol 2001; 15 (Suppl. 2): S109
10. Van Leent EJM, De Vries H, Scott G, et al. Low blood concentrations of pimecrolimus
(Elidel, SDZ ASM 981) after topical treatment of adults with atopic dermatitis
[abstract]. J Eur Acad Dermatol Venereol 2001; 15 (Suppl. 2): S109
11. Greig G, Burtin P, Scott G, et al. Oral SDZ ASM981: pharmacokinetic profile in
humans; summary in 2 parts (Part A) [abstract no. 513 (plus poster)]. 59th
Annual Meeting of the American Academy of Dermatology; 2001 Mar 2-6;
Washington, DC
12. Novartis Pharma. 2002 (Data on file)
13. Novartis Pharma GmbH. Elidel (pimecrolimus) cream 1%: prescribing informa-
tion [online]. Available from URL: http://www.pharma.us.novartis.com/prod-
uct/pi/pdf/elidel.pdf [Accessed 2001 Jan 30]
14. Van Leent EJM, Gräber M, Thurston M, et al. Effectiveness of the ascomycin
macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch
Dermatol 1998; 134: 805-9
15. Luger T, van Leent EJM, Graeber M, et al. SDZ ASM 981: an emerging safe and
effective treatment for atopic dermatitis. Br J Dermatol 2001; 144: 788-94
16. Meurer M, Bräutigam M. Pimecrolimus (SDZ ASM 981) cream reduces the need
for corticosteroids in the long-term management of atopic dermatitis in adults
[abstract (plus poster no, 108)]. 60th Annual Meeting of theAmericanAcademy
of Dermatology; 2002 Feb 23-27; New Orleans (LA)
17. Ho V, Halbert A, Takaoka R, et al. Pimecrolimus (Elidel, SDZ ASM 981) cream
1% is effective and safe in infants aged 3-23 months with atopic dermatitis
[abstract]. J Eur Acad Dermatol Venereol 2001; 15 (Suppl. 2): S110
18. Kapp A, Bingham A, De Moor A, et al. Pimecrolimus (Elidel, SDZ ASM 981)
cream 1%: a new approach to long-term management of atopic dermatitis in
infants 3 to 23 months of age [abstract]. J Eur Acad Dermatol Venereol 2001;
15 (Suppl. 2): S111
Acknowledgments
The full text article in Drugs 2002; 62 (5): 817-840 was reviewed by: B.R.
Allen, Department of Dermatology, Queen’s Medical Centre, Nottingham,
England; J. Berth-Jones, Department of Dermatology, Walsgrave Hospitals,
Walsgrave, Coventry, England; J.D. Bos, Academic Medical Centre, Depart-
ment of Dermatology, Universiteit van Amsterdam, Amsterdam, The Nether-
lands; A. Gottlieb, Department of Medicine and Clinical Research Center,
UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jer-
sey, USA; K. Landow, University of Southern California School of Medicine,
Los Angeles, California, USA; A.M. Oakley, Tristram Clinic, Hamilton, New
Zealand; A.S. Paller, Department of Pediatrics, Northwestern University
Medical School, Chicago, Illinois, USA; S. Reitamo, Department of Derma-
tology, Hospital for Skin and Allergic Diseases, Helsinki University Central
Hospital, Helsinki, Finland; A.K. Silverman, Dallas, Texas, USA.
19. Lucky A, Marshall K, Bush C, et al. SDZ ASM 981 cream 1% is effective and
safe in children and adolescents with atopic dermatitis [abstract]. Clin Exp
Dermatol 2001; 26: 214
20. Boguniewicz M, Eichenfield L, Honig P, et al. Pimecrolimus (Elidel, SDZ ASM
981) cream 1% is safe in the long-term management of atopic dermatitis [ab-
stract]. J Eur Acad Dermatol Venereol 2001; 15 (Suppl. 2): S110
21. Whalley D, McKenna S, Huels J, et al. The benefit of pimecrolimus (Elidel, SDZ
ASM 981) on quality of life in the treatment of pediatric atopic dermatitis: results
of two 6-week randomized double-blind vehicle-controlled clinical trials in the
US [abstract]. J Eur Acad Dermatol Venereol 2001; 15 (Suppl. 2): S112
22. Wahn U, Molloy S, Graeber M, et al. SDZ ASM 981 cream 1%: a new approach
to long-term management of atopic dermatitis [abstract no. 863]. J Invest
Dermatol 2001; 117 (2): 533
23. de Prost Y, Wahn U, Bos JD, et al. Pimecrolimus (SDZ ASM 981) cream reduces
the number of flares and the need for topical corticosteroids in children with
atopic dermatitis: a 12-month, double-blind, controlled study [abstract (plus
poster no. 95)]. 60th Annual Meeting of the American Academy of Dermatol-
ogy; 2002 Feb 23-27; New Orleans (LA)
References
1.
2.
Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug, SDZ
ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J
Dermatol 1999; 141: 264-73
Zuberbier T, Chong SU, Grunow K, et al. The ascomycin macrolactam
pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release
from human dermal mast cells and peripheral blood basophils. J Allergy Clin
Immunol 2001 Aug; 108 (2 Pt 1): 275-80
Hultsch T, Müller KD, Meingassner JG, et al. Ascomycin macrolactam derivative
SDZ ASM 981 inhibits the release of granule-associated mediators and of
newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-de-
pendent manner. Arch Dermatol Res 1998; 290: 501-7
3.
4.
5.
KalthoffE,ChungJ,GrassbergerM,etal.SDZASM981potentlyinhibitstheinduction
of coreceptors involved in the accessory cell-dependent activation of inflammation-
mediating T cells [abstract no. 305]. J Invest Dermatol 2001; 117 (2): 440
Queille-Roussel C, Paul C, Duteil L, et al. The new topical ascomycin derivative
SDZ ASM 981 does not induce skin atrophy when applied to normal skin for
Correspondence: Keri Wellington, Adis International Inc., 860 Town Center
Drive, Langhorne, PA 19047, USA.
E-mail: demail@adis.com
© Adis International Limited. All rights reserved.
Am J Clin Dermatol 2002; 3 (6)