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					        The efficacy and safety of tacrolimus ointment:
                      A clinical review
                                                         Lisa A. Beck, MD
                                                       Baltimore, Maryland

     Topical tacrolimus ointment was approved for the treatment of atopic dermatitis in Japan in 1999, the
     United States in 2000, and Europe in 2001. The safety and efficacy of tacrolimus ointment was established in
     vehicle-controlled, randomized, 12-week clinical trials; 1-year open-label trials; and comparative studies
     with topical steroids. Although an extensive database exists on the safety and efficacy of tacrolimus
     ointment based on the global development program, clinicians desire additional information on the long-
     term safety and efficacy of this novel agent. In this supplement, additional studies are reported that extend
     the safety and efficacy profile of tacrolimus ointment in patients with atopic dermatitis, including long-term
     safety studies for up to 4 years. The studies presented in this supplement address important questions
     regarding the selection and use of tacrolimus ointment in the treatment of patients with atopic dermatitis.
     ( J Am Acad Dermatol 2005;53:S165-70.)

T       acrolimus ointment was introduced in Japan                   tioneassociated cytokine transcription. For example,
        in 1999, the United States in 2000, and Europe               after topical treatment, tacrolimus down-regulates the
        in 2001 for the treatment of moderate to                     enhanced expression of the high-affinity IgE recep-
severe atopic dermatitis (AD) in patients 2 years                    tor on cutaneous dendritic cells of patients with AD
and older. The introduction of tacrolimus ointment                   whereas topical steroids have no effect. Although the
marked the advent of a new, nonsteroidal drug class:                 precise relevance of this finding is unknown, these
topical immunomodulators for the management of                       studies suggest that the mechanism of action by
inflammatory dermatoses. These agents inhibit the                     which tacrolimus, and presumably other topical cal-
activity of calcineurin, an enzyme important for the                 cineurin inhibitors, leads to clinical improvement in
translocation of the pluripotent transcription factor,               AD differs from the mechanism by which topical
nuclear factor of activated T cell, from the cytoplasm               steroids act. Further studies are likely to shed light on
to the nucleus where it ‘‘turns on’’ a number of                     the precise mechanisms of these important thera-
proinflammatory cytokines associated with T-cell                      peutic agents, and clarify the critical pathways in the
activation. Hence, these agents have also been                       pathogenesis of AD that will ultimately lead to
referred to as topical calcineurin inhibitors.                       additional novel therapeutic agents.

PATHOGENESIS OF AD                                                   TACROLIMUS OINTMENT: CLINICAL
   Advances in the understanding of the pathogen-                    STUDY OVERVIEW
esis of AD are summarized in the accompanying                           The safety and efficacy of tacrolimus ointment in
review by Novak and Bieber.1 They not only high-                     the treatment of moderate to severe AD was evalu-
light the known role of T cells in the pathogenesis of               ated in vehicle-controlled, randomized 12-week
AD, but also discuss the role of dendritic cells. Their              clinical trials; 1-year open-label trials; and compara-
in vivo studies have demonstrated that tacrolimus                    tive studies with topical steroids. In addition, more
has inhibitory effects beyond that of T-cell activa-                 recent studies provide further support of the safety
                                                                     and efficacy profile in children 2 years and older. Key
From the Johns Hopkins Asthma and Allergy Center.                    studies are highlighted in Tables I and II and
Funding sources: None.                                               described below.
Disclosure: Dr Beck is on the speakers bureau of Astellas Pharma
   US, Inc. and Novartis Pharmaceuticals Corp.                       Twelve-week, randomized, double-blind
Reprint requests: Lisa A. Beck, MD, Johns Hopkins Asthma and         vehicle-controlled studies
   Allergy Center, 5501 Hopkins Bayview Circle, Unit Office 3A.62,
                                                                        In 3 randomized, double-blind, vehicle-con-
   Baltimore, MD 21224. E-mail:
                                                                     trolled 12-week studies—one pediatric (age 2-15
ª 2005 by the American Academy of Dermatology, Inc.                  years, N = 351)2 and two similarly designed adult
doi:10.1016/j.jaad.2005.04.059                                       (N = 632)3,4 trials—tacrolimus 0.03% and 0.1%

S166 Beck                                                                                         J AM ACAD DERMATOL
                                                                                                           AUGUST 2005

Table I. Randomized, blinded multicenter studies of tacrolimus ointment
Study                               Design                Population           Disease severity       N       follow-up
  Paller et al2              Double-blind             Pediatric (2-15 y)     Moderate to severe      351       12 wk
  Hanifin et al3 and Soter   Double-blind             Adult                  Moderate to severe      304       12 wk
    et al4 (study 1)
  Hanifin et al3 and Soter   Double-blind             Adult                  Moderate to severe      328       12 wk
    et al4 (study 2)
  Chapman et al19            Double-blind             Adult                  Mild to moderate        300        6 wk
  Chapman et al19            Double-blind             Pediatric (2-15 y)     Mild to moderate        317        6 wk
Active comparator
  Paller et al22             Investigator-blinded     Pediatric   (2-15 y)   Mild                    425        6 wk
  Paller et al22             Investigator-blinded     Pediatric   (2-15 y)   Moderate to severe      225        6 wk
  Paller et al22             Investigator-blinded     Adult                  Mild to severe          413        6 wk
  Reitamo et al7             Double-blind             Adult                  Moderate to severe      570        3 wk
  Reitamo et al8             Double-blind             Pediatric   (2-15 y)   Moderate to severe      560        3 wk
  Reitamo et al9             Double-blind             Pediatric   (2-15 y)   Moderate to severe      624        3 wk
  Reitamo et al11            Double-blind             Adult                  Moderate to severe      972        6 mo

ointment were evaluated for the treatment of mod-             studies, the most common adverse events were
erate to severe AD. As evaluated by the Physician’s           skin burning and pruritus. These events generally
Global Assessment, 37% and 28% of adults cleared or           occurred at the beginning of treatment and resolved
achieved at least 90% improvement from baseline               within the first few days of treatment, as the skin
with tacrolimus 0.1% and 0.03% ointment, respec-              began to heal; they rarely led to treatment discon-
tively, compared with 7% in the vehicle group (P \            tinuation.5,6
.001).3 In the pediatric trial, 41% and 36% of patients
cleared or achieved at least 90% improvement with             Tacrolimus and topical steroids: Comparative
tacrolimus 0.1% and 0.03% ointment, respectively,             trials
compared with 7% in the vehicle group (P \.001).2                Several short-term trials were conducted to com-
In addition, 73% and 62% of adults and 78% and 73%            pare the efficacy and safety of tacrolimus 0.03% and
of children treated with tacrolimus 0.1% and 0.03%            0.1% ointment with that of topical steroids. The first
ointment, respectively, achieved at least 50% im-             compared tacrolimus ointment and the midpotency
provement, compared with 20% of adults and 27% of             (class IV) topical steroid hydrocortisone butyrate
children treated with vehicle (P \.001).2,3                   0.1% ointment in 570 adults with moderate to severe
   The most common treatment-related adverse                  AD for 3 weeks.7 Tacrolimus 0.1% ointment and
events in these trials were application-site irritation       hydrocortisone butyrate 0.1% ointment had similar
reactions—the sensation of skin burning and pruri-            efficacy, with 76% and 70% of patients, respectively,
tus.2,4 These events were generally short-lived, oc-          achieving at least 75% improvement from baseline in
curring primarily at the beginning of therapy and             this short-term trial. Both of those agents were
resolving as the skin began to heal. Application-site         significantly more effective than tacrolimus 0.03%
adverse events rarely led to treatment discontinua-           ointment (58% of patients achieving at least 75%
tion in these 12-week studies.2,4                             improvement; P # .002). Skin burning and pruritus
                                                              were, again, the most common adverse events in the
Long-term (1-year) safety studies                             tacrolimus ointment groups. Similar to other tacroli-
   Two separate open-label, noncomparative 1-year             mus ointment clinical trials, these events were tran-
studies evaluated the use of tacrolimus 0.1% oint-            sient, occurred early in treatment, and decreased in
ment in adults (N = 316)5 and children (aged 2-15,            prevalence. For example, there was a 68% and an
N = 255)6 with moderate to severe AD. The efficacy            80% reduction in the prevalence of skin burning
and safety results of these studies reinforced those of       within the first and second weeks of treatment with
the 12-week trials. In the 1-year trials, improvement         tacrolimus 0.1% ointment, respectively.
began within 1 week of starting treatment and                    The second trial compared tacrolimus 0.03% and
continued throughout the study period, with no                0.1% ointment with hydrocortisone acetate 1%
loss of efficacy over time.5,6 As in the 12-week              ointment (class VII) for 3 weeks in 560 children
J AM ACAD DERMATOL                                                                                            Beck S167

Table II. Open-label, noncomparative multicenter studies of tacrolimus ointment
Study                            Population                  Disease severity           N                   follow-up
Reitamo et al5*             Adults                         Moderate to severe           316          1y
Kang et al6*                Pediatric (2-15 y)             Moderate to severe           255          1y
Koo et al17*                Adult and pediatric            Mild to severe              7923          Median, 210 days
                              (2-15 y)                                                                 (range: 1-687 days)
Hanifin et al18*            Adult and pediatric            Mild to severe               799          Median, 982 days
                              (2-15 y)                                                                 (range: 1-1479 days)
Stiehm et al20y             Pediatric (2-12 y)             Moderate to severe            26          7 wk

*Primary study objective was assessment of safety.
  Primary study objective was assessment of B- and T-cell immunity including the primary antibody response to pneumococcal
polysaccharide vaccine.

with moderate to severe AD.8 In this study, both                    with a steroid ointment regimen in almost 1000
tacrolimus 0.1% and 0.03% ointment were signifi-                    adults with moderate to severe AD.11 In this 6-
cantly more effective than the low-potency topical                  month, multicenter double-blind trial, 487 patients
steroid hydrocortisone acetate 1% ointment (P \                     were treated with tacrolimus 0.1% ointment twice
.001). Tacrolimus 0.1% ointment was significantly                   daily on all affected body areas, and 485 patients
more effective than tacrolimus 0.03% ointment in                    were treated with hydrocortisone butyrate 0.1%
this pediatric trial (P = .006). The adverse event pro-             ointment (class IV) on the trunk and extremities
files observed were similar to those in the previ-                  and hydrocortisone acetate 1% ointment (class VII)
ous studies. No safety concerns were identified.                    on the head and neck. Withdrawals caused by
    The third trial compared once or twice daily                    lack of efficacy occurred significantly more often in
applications of tacrolimus 0.03% ointment with                      the corticosteroid treatment arm (26%) compared
twice daily applications of hydrocortisone acetate                  with the tacrolimus ointment treatment arm (11%;
1% ointment (class VII) in 624 pediatric patients                   P = .01). Tacrolimus ointment was shown to be
with moderate to severe AD for 3 weeks.9                            significantly more effective than the steroid regimen
Treatment with both once and twice daily applica-                   at ameliorating the signs and symptoms of AD
tions of tacrolimus 0.03% ointment significantly                    (based on reduction in the modified EASI score) at
decreased the modified Eczema Area and Severity                     all time points throughout this 6-month study (P \
Index (EASI) score* compared with treatment with                    .001). In addition, there was a higher percentage of
twice daily applications of hydrocortisone acetate                  patients who cleared or had excellent improve-
1% ointment (67% and 77% reduction vs 48%,                          ment ($90% improvement from baseline by the
respectively; P \ .001). The improvement in AD                      Physician’s Global Assessment) in the tacrolimus
by reduction in modified EASI score was also                        treatment group versus the corticosteroid treatment
significantly greater for patients applying tacrolimus              group at all time points (P \ .001). Both treatment
0.03% ointment twice daily versus those applying                    groups had similar incidence rates for the most
topical tacrolimus once daily (P = .007). This differ-              common (occurring at $10% incidence) adverse
ence between the twice and once daily tacrolimus                    events, with the exception of skin burning being
ointment treatment regimens was more pronounced                     reported at a higher incidence in the tacrolimus
in the patients with severe disease at baseline (76%                group compared with the corticosteroid group (P \
vs 54% reduction in modified EASI score, respec-                    .001). Similar to other reports, these local irritation
tively; P = .001). Although significantly more pa-                  reactions decreased in prevalence after treatment
tients experienced transient skin burning in the                    initiation.
tacrolimus ointment treatment groups than in the
hydrocortisone ointment treatment group (P = .03),                  Systemic exposure during topical
skin burning and pruritus at the application site                   tacrolimus treatment
were the most commonly reported adverse events                         Several pharmacokinetic studies in adult and
in all 3 treatment groups.                                          pediatric patients with AD have demonstrated
    A recent long-term study evaluated the efficacy                  minimal systemic absorption during tacrolimus oint-
and safety of tacrolimus ointment therapy compared                  ment therapy.12-15 After topical treatment, patients
                                                                    with AD generally have exposure that is approxi-
*The modified EASI score10 incorporates itch assessment.            mately 30- to 60-fold less than the exposure observed
S168 Beck                                                                                            J AM ACAD DERMATOL
                                                                                                             AUGUST 2005

in systemic tacrolimus-treated solid organ trans-                     In summary, quantifiable tacrolimus blood con-
plant recipients.12,13y In addition, in the 3 random-              centrations were minimal during clinical trials; these
ized, double-blind, vehicle-controlled, 12-week                    were transient, isolated occurrences, observed early
studies of tacrolimus ointment, no detectable tacro-               in treatment and were not associated with any
limus blood concentration was observed for 80%                     adverse events during the course of these studies.
(815/1014) of the adult and for 90% (133/148) of the               These studies have demonstrated that after both
pediatric blood samples collected during treatment                 short- and long-term (1-year) topical treatment,
(level of quantification [LOQ] = 0.5 ng/mL).2,4 Blood              tacrolimus does not accumulate, either in the skin
tacrolimus concentrations greater than 5 ng/mL were                or systemically.
found in only 3/1014 adult samples (0.3%); when
detectable, these concentrations were transient (not               REINFORCING THE SAFETY AND
duplicated on further blood draws) and not associ-                 EFFICACY PROFILE: NEW DATA ON
ated with any adverse events.4 Of the samples, 100%                TACROLIMUS OINTMENT
were below 2 ng/mL in the pediatric patients in                        This supplement presents important new data
the tacrolimus 0.03% ointment treatment group                      supporting the safety and efficacy of tacrolimus
(n = 65).2 The variables that showed a statistically               ointment. Koo et al17 report the results of a large,
significant difference between those patients with                 long-term (#23 months) trial, involving almost 8000
and those without detectable tacrolimus blood                      patients, and Hanifin et al18 report the findings of a
levels were race (African American vs non-African                  trial that examined tacrolimus ointment use for up
American, P = .006), baseline edema score (P =                     to 4 years. More than 93% of patients in these two
.0035), percentage of body surface area affected at                studies were treated with tacrolimus 0.1% ointment
baseline (P = .0015), and total amount of ointment                 and 50% of the enrolled patients were children (age
used (P = .0008). There was no statistically signifi-              2-15 years). These studies together comprise the
cant difference in the incidence of adverse events                 largest long-term safety studies ever conducted for
between the patients with detectable versus non-                   patients with AD and provide valuable insight into
detectable tacrolimus blood levels. This suggests that             the long-term outcome of disease management.
these transient and low but detectable blood levels                These studies confirm that the safety with long-
are not likely to pose a safety concern (data on file,             term use of tacrolimus ointment for up to 4 years is
Astellas Pharma US, Inc). Subsequent pharmacoki-                   similar to the safety profile observed in the 1-year
netic studies have demonstrated similar profiles with              studies; no increase in adverse events, particularly
whole blood tacrolimus levels greater than 5 ng/mL                 infections, were noted in these open-label studies.
observed rarely (data on file, Astellas Pharma US,                 Although additional longer-term studies are needed
Inc). In the pediatric, randomized, double-blind,                  to confirm the safety of this class of agents over
steroid comparative 3-week trial, 98% of the patients              extended use, these two large studies suggest that
in the tacrolimus 0.03% ointment treatment group                   there is an excellent safety profile for patients with
(n = 188) continuously showed levels below 1 ng/                   AD treated intermittently for up to 4 years. In these
mL; the majority of the samples were below the                     studies, patients who predominantly had moderate
LOQ (LOQ = 0.025 ng/mL) with 2.75 ng/mL be-                        to severe disease and extensive body surface area
ing the maximum level reported in one patient.8,16                 involvement at study entry experienced continued
   Similar tacrolimus blood level profiles have been                improvement on tacrolimus monotherapy, with no
observed in a long-term study involving 316 patients               loss of efficacy of tacrolimus oinment.
applying tacrolimus 0.1% ointment and followed                         Although the above long-term studies focused on
for up to 1 year.5 In this study, only one patient had             patients with moderate to severe disease, Chapman
a maximum tacrolimus blood concentration above                     et al19 report the efficacy and safety of tacrolimus
5 ng/mL (5.75 ng/mL); this was transient and not                   ointment for the treatment of mild to moderate
associated with any adverse events. No measurable                  AD in both children and adults. In these 6-week,
tacrolimus blood concentration was observed for                    double-blind, randomized vehicle-controlled studies,
75% of the blood samples (LOQ = 0.025 ng/mL), and                  tacrolimus 0.03% ointment demonstrated superior
75% of all patients had maximum tacrolimus blood                   efficacy over vehicle. Overall, side effects were min-
levels lower than 1 ng/mL.5                                        imal. Reports of skin burning/stinging were compa-
                                                                   rable between treatment groups, and significantly
                                                                   more itching and erythema were reported in the
yTacrolimus trough concentrations, which correlate with systemic
  tacrolimus exposure and intentional immunosuppresion in          vehicle group compared with the tacrolimus group
  solid organ transplant recipients, are maintained between 5      (P # .03). Prior studies suggest that local application
  and 20 ng/mL.                                                    site reactions occurring during tacrolimus ointment
J AM ACAD DERMATOL                                                                                    Beck S169

treatment correlate with baseline disease severity of       of the key mechanism or mechanisms of tacrolimus
treated patients4; the lower incidence of application       ointment may help us understand more about the
site reactions in patients with mild to moderate AD         pathogenesis of AD. If tacrolimus ointment alters the
treated with tacrolimus ointment is consistent with         long-term outcome of patients with AD, will man-
these previously reported studies.                          agement of AD with topical immunomodulators
    Despite the absence of detectable blood levels of       prevent or retard progression of AD to airway
these topical immunomodulators in most patients             involvement (rhinitis or asthma) and/or decrease
and no evidence of systemic immunosuppression,              the severity of these respiratory diseases (ie, prevent
clinicians have been concerned about whether                the ‘‘allergic march’’)?23 Longer-term follow-up stud-
patients treated with topical calcineurin inhibitors        ies will be necessary to answer these questions, and
would have normal responses to routine childhood            to further address long-term safety issues. The stud-
immunizations. Stiehm et al20 examined immune               ies presented in this supplement provide additional
responses, including pneumococcal seroconversion            evidence demonstrating the efficacy and safety of
postvaccination with the 23-valent pneumococcal             tacrolimus ointment for the treatment of children and
polysaccharide vaccine, in pediatric patients with          adults with AD.
moderate to severe AD treated with tacrolimus 0.03%
ointment. In this study, all evaluable patients dem-        ADDENDUM
onstrated an increase in protective pneumococcal               After submission and acceptance of this editorial,
responses to serotypes present in the pneumococcal          the US Food and Drug Administration (FDA) con-
polysaccharide vaccine and no significant change            vened a pediatric advisory board to discuss risk
in other immunologic parameters (eg, lymphocyte             evaluation, labeling, risk communication, and dis-
subsets, immunoglobulin levels, antibody titers to          semination of information on potential cancer risk
tetanus and Haemophilus influenzae, and prolif-             among pediatric patients treated for AD with the
erative responses to tetanus toxoid). This study            topical calcineurin inhibitors, tacrolimus ointment
is particularly relevant because AD disproportion-          (Protopic), and pimecrolimus cream (Elidel). On
ately affects the pediatric population, a population        March 10, 2005, the FDA issued an alert for health
requiring frequent, routine immunizations. Interestingly,   care professionals, advising them to prescribe Elidel
previous studies have suggested that children with          and Protopic only as directed and only after other
AD treated with conventional therapy (emollients            eczema treatments had failed, because of a possible
and various classes of topical steroids) exhibit an         cancer risk. Both agents are recommended as sec-
impaired immune response to pneumococcal vacci-             ond-line treatments for AD for patients age 2 years
nation.21                                                   and older. The FDA cited information from animal
    Recently, Paller et al22 reported the results of        studies, case reports in a small number of patients,
several head-to-head studies that compared the              and the mechanism of action of these products in
safety and efficacy of tacrolimus ointment and              the pubic health advisory. The FDA is reviewing
pimecrolimus cream in more than 1000 children               the current product labeling for both Protopic and
and adults with AD of all severities. In these 6-week,      Elidel and will likely recommend changes, including
multicenter, randomized investigator-blinded stud-          addition of a black-box warning about the risk of
ies, tacrolimus ointment demonstrated superior effi-        malignancy.
cacy to pimecrolimus cream in achieving success                The sponsors of these products (Astellas Pharma
(clear or almost clear) and in ameliorating the signs       US, Inc and Novartis Pharma Inc) do not believe that
and symptoms of AD, including pruritus. In these            there is an increased risk of malignancy based on the
comparative studies, the adverse event profile for          small numbers of reported malignancies, the large
patients treated with tacrolimus and pimecrolimus           number of patients treated, and data from the clinical
was similar. Overall, the incidence of skin burning         development programs. More than 19,000 patients,
was 11% in the patients treated with tacrolimus             including approximately 7600 pediatric patients,
ointment (n = 530) and 10% for those treated with           participated in the tacrolimus ointment clinical
pimecrolimus cream (n = 533).                               development program, and an estimated 1.7 million
                                                            patients in the United States have been treated with
CONCLUSION                                                  Protopic since 2000. In the clinical studies and
   The studies discussed here further our under-            postmarketing experience, there has been no evi-
standing of the safety, efficacy, and role of tacrolimus     dence of an increased risk of lymphoma, lympho-
ointment in the management of AD. Although they             proliferative disorders, or skin cancers associated
answer many of our questions, there are still unan-         with the use of Protopic ointment. In transplant
swered issues. For example, further understanding           recipients exposed to sustained and higher levels of
S170 Beck                                                                                                        J AM ACAD DERMATOL
                                                                                                                             AUGUST 2005

immunosuppressive regimes, lymphoproliferative                        10. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte S, Graeber
disorders, particularly posttransplant lymphoproli-                       M, et al. The eczema and area severity index (EASI): assess-
                                                                          ment of reliability in atopic dermatitis. Exp Dermatol 2001;10:
ferative disease, and nonmelanoma skin cancer are                         11-8.
increased. Similarly, in preclinical studies, animals                 11. Reitamo S, Ortonne JP, Sand C, Cambazard F, Bieber T, Folster-
with sustained tacrolimus exposure at levels higher                       Holst R, et al. A multicenter, randomized, double-blind,
than generally observed after topical application                         controlled study of long-term treatment with 0.1% tacrolimus
developed systemic malignancy.                                            ointment in adults with moderate to severe atopic dermatitis.
                                                                          Br J Dermatol (in press).
   Astellas Pharma US, Inc will continue to evaluate                  12. Harper J, Smith C, Rubins A, Green A, Jackson K, Zigure S, et al.
long-term safety, including the risk of malignancy, in                    A multicenter study of the pharmocokinetics of tacrolimus
pediatric patients with AD who have been treated                          ointment after first and repeated application to children with
with Protopic and is enrolling patients in a multi-                       atopic dermatitis. J Invest Dermatol 2005;124:695-9.
national, registry study, A Prospective Pediatric                     13. Rubins A, Gutmane R, Valdmane N, Stevenson P, Foster C,
                                                                          Undre N. Pharmacokinetics of 0.1% tacrolimus ointment after
Longitudinal Evaluation Study.                                            first and repeated application to adults with moderate to
                                                                          severe atopic dermatitis. J Invest Dermatol 2005 (in press).
                                                                      14. Alaiti A, Kang S, Fiedler VC, Ellis CN, Spurlin DV, Fader D, et al.
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