Dermatology Online Journal

Tacrolimus ointment: Utilization patterns in children under age 2 years
Tamara Salam Housman MD¹, Amy B Norton¹, Steven R Feldman MD PhD¹, Alan B Fleischer Jr MD¹, Eric L Simpson MD², Jon M Hanifin MD², and Richard J Antaya MD³
Dermatology Online Journal 10 (1): 2

Departments of Dermatology, Wake Forest University School of Medicine, Winston-Salem, North Carolina¹; Oregon Health and Sciences University, Portland, Oregon²; Yale University, New Haven, Connecticut³. afleisch@wfubmc.edu

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Abstract

Atopic dermatitis (AD) is a common eczematous skin condition; as many as 10-17 percent of all children are affected, and 35-60 percent of affected patients manifest symptoms manifest during the first year of life. Treatment principles for AD in young children involve conservative measures such as avoidance of hot water and environmental irritants, combined with liberal use of emollients after bathing. Low potency topical corticosteroids (TCS) are the current standard of therapy for AD in young children, reserving mid- and high-potency TCS for severe disease. However, complications of long-term use of TCS include skin atrophy, stria formation, telangiectasia, hypopigmentation, secondary infections, steroid acne, allergic contact dermatitis, and miliaria. The pediatric population is also at increased risk for systemic absorption because of their high ratio of skin surface to body mass. Systemic absorption may result in hypothalamic-pituitary-adrenal axis suppression and ultimately growth retardation. Although most topical and systemic corticosteroids are not approved by the Food and Drug Administration for use in children less than 2 years of age, conservative treatment often fails in this age group and frequently patients are treated with TCS, antibiotics, and antihistamines. Tacrolimus ointment is a safe and effective treatment for AD, indicated for children over age 2. This retrospective, multi-center chart review evaluated the utilization patterns (age, sex, response to therapy) of tacrolimus ointment (0.03 % and 0.1 %) in children less than 2-years old with AD seen during a 6-month period at three university-based dermatology practices. Of 38 patient charts reviewed, 37 met inclusion criteria. Fifty-four percent (20/37) were White, 27 percent (10/37) were Black, 8 percent (3/37) were Asian, and 11 percent (4/37) reported other race. Followup visits occurred with 15 patients and all patients (15/15) improved at 1 or more of 23 followup visits. Both concentrations of tacrolimus were effective, and adverse events were uncommon. Tacrolimus ointment appears to be effective and safe for children with AD under age 2.

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Introduction

Atopic dermatitis (AD) is a common eczematous skin condition; as many as 10 to 17 percent of all children are affected by AD, and 35 to 60 percent of affected patients manifest symptoms during the first year of life [1, 2, 3]. Treatment principles for AD in young children involve conservative measures such as avoidance of hot water and environmental irritants as well as liberal use of emollients after bathing. Low potency topical corticosteroids (TCS) are the current standard of therapy for AD in young children, reserving mid- and high-potency TCS for severe disease [4, 5]. However, complications of long-term use of TCS may occur and include skin atrophy, stria formation, telangiectasia, hypopigmentation, secondary infections, steroid acne, allergic contact dermatitis, and miliaria [4]. The pediatric population is also at increased risk for systemic absorption owing to the high ratio of skin surface to body mass; this may result in hypothalamic-pituitary-adrenal (HPA) axis suppression and ultimately growth retardation [4, 5] Although most topical and systemic corticosteroids have not been approved by the Food and Drug Administration (FDA) for use in children less than age 2 [4], conservative treatment often fails and frequently patients are treated with TCS, antibiotics, and antihistamines [1].

Tacrolimus is a recently approved drug for AD; it acts by inhibiting the phosphatase activity of calcineurin in T-cells [4, 6, 7]. This in turn inhibits the transcription of several genes encoding various interleukins, tumor necrosis factor α, interferon γ, and granulocyte-macrophage colony-stimulating factor, all of which are implicated in the pathogenesis of AD [4, 8]. Currently, there are two FDA-approved concentrations of tacrolimus, 0.1 percent for use in patients over age 16, and 0.03 percent for use in children over age 2. Recent studies of children over age 2 demonstrated that both concentrations of tacrolimus are safe and effective for use in moderate to severe AD [4, 5]. Compared to mid and high potency TCS, tacrolimus was found to be safe for use on the face, neck, and intertriginous areas, and was not associated with common local side effects such as atrophy and telangiectasia [4, 5]. Furthermore, systemic absorption was insignificant and there were no problems with growth retardation or systemic immunosuppression [4, 5, 8]. Tacrolimus may also exhibit a self-regulatory property, in that its high molecular weight prevents its absorption into the skin as inflammation decreases [9]. Only mild and transient adverse effects have been reported, such as burning and stinging upon application [4, 5, 9]. The present study was designed to evaluate the utilization patterns, safety, and efficacy of tacrolimus ointment (0.1 % and 0.03 %) in AD patients under age 2.

Materials and Methods

Patient charts were evaluated from the following dermatology centers: Wake Forest University School of Medicine in Winston-Salem, NC (coordinating center); Oregon Health & Science University in Portland, OR; and Yale University in New Haven, CT. The study population consisted of all patients with a diagnosis of AD who had been treated between 3/1/2001 and 9/1/2001 with tacrolimus ointment (Protopic&tm; 0.03 % or 0.1 %), prior to their second birthday. Patients were excluded if tacrolimus ointment was given for a condition other than AD or if tacrolimus was used in an extemporaneous formulation. Clinical charts meeting the inclusion and exclusion criteria were reviewed, and each center extracted the outcome data from each chart and mailed the anonymous, completed data collection forms to the coordinating center for entry and analysis. The following data points were collected for the baseline visit: age, sex, race, age at onset,, severity, (1-3 scale for mild, moderate, and severe), concentration of tacrolimus prescribed, percent of body surface area (BSA) affected, and concomitant medications. In addition to noting the severity of AD, an assessments of response to treatment, pruritus, and sleep (on a -1 to +2 scale for worse, no change/slightly better, moderate/marked improvement, and excellent improvement/cleared) were recorded on follow-up visits. All treatments were recorded, including treatment dates, adverse events associated with treatment, and serum levels of tacrolimus, if available. All analyses were performed using SAS software (version 8.0; Cary, NC).

Results

Table 1: Frequency of medication use at baseline and followup visits

Drug	Percent of baseline visits	Percent of followup visits
Tacrolimus Ointment (0.1 %)	50% (18/36)	42% (10/24)
Tacrolimus Ointment (0.03 %)	50% (18/36)	58% (14/24)
Topical corticosteroids	95 % (35/37)	83% (20/24)
Antihistamines	57% (21/37)	54% (13/24)
Topical Emollients	97% (36/37)	96% (23/24)
Systemic Antibiotics	19% (7/37)	8% (2/24)
Systemic corticosteroids	3% (1/37)	4% (1/24)
Other	3% (1/37)	17% (4/24)

A total of 38 patient charts were reviewed, and 1 was excluded from all data analyses because the child was over age 2 at the baseline visit. Of the 37 subjects, 15 had documented followup visits within the 6-month inclusion window. There were 20 boys and 17 girls with a mean age (±SD) at baseline visit of 14 months (±6); ages ranged from 4 to 24 months. Fifty-four percent (20/37) were White, 27 percent (10/37) were Black, 8 percent (3/37) were Asian, and 11 percent (4/37) reported other race. Average patient age (±SD) at the onset of AD was 3 months (±4). The mean baseline severity score was available on 11 patients and was 2.5 (±0.7) with scores ranging from 1 (mild) to 3 (severe). Baseline BSA data was only available on six patients and ranged from 11-30 percent to 91-100 percent BSA involvement with a mean BSA of 51-90 percent. At baseline, 95 percent were applying TCS. Half of the patients were prescribed 0.1 percent and the other half were prescribed 0.03 percent tacrolimus (table 1).

Table 2: Frequency of adverse events at followup visits (n=23)

Adverse Event	Number of followup visits (%)
None	20    (87 %)
Pain	0
Burning	2     (9 %)
Stinging	1     (4 %)
Itch	1     (4 %)
Other	0
Note: Totals do not add up to 23 visits or 100 percent because more than one adverse event was reported at some visits.

Data was available on 24 followup contacts from 15 patients; 23 contacts were office visits and 1 was a telephone visit. At 42 percent of these visits, the patients were using the 0.1 percent concentration, and at most visits, patients were also using TCS (table 1). All patients (15/15) improved at one or more of 23 followup visits, but 1 patient only had one of 4 visits that documented disease improvement. For 17 of these visits, the mean followup severity score (±SD) was 2.0 (±0.7) for 9 patients. The mean response to treatment score (±SD) from 23 visits was 0.8 (±1.0) ranging from -1 (worse) to +2 (excellent improvement/cleared). Pruritus assessment was available on seven follow-up visits with a mean score of 0 (±0.8) ranging from -1 (worse) to +1 (moderate/marked improvement). Sleep assessment was available on three followup visits with a mean score of 0 (±1.0) equivalent to a response of "no change/slightly better." There were no reported adverse events at 87 percent of 23 visits, and adverse events were uncommon (table 2). At 22 of 23 followup visits, tacrolimus therapy was continued. Serum tacrolimus levels were collected at four visits, and all trough levels were less than 3ng/mL.

Discussion

The findings from this multicenter retrospective chart review demonstrate that tacrolimus ointment is being utilized effectively in children under age 2 who have mostly moderate to severe AD. No patients had to discontinue tacrolimus therapy because of an adverse event. Furthermore, adverse events such as burning, pain, stinging, and itching at the application site were uncommon. Although our findings suggest that TCS were used with tacrolimus, it is important to note that TCS use was usually suggested for a limited amount of time, generally for two weeks. Improvement was seen for both 0.1 percent and 0.03 percent tacrolimus. Because this was a retrospective chart review, it was difficult to determine if both concentrations had similar efficacy.

The safety and efficacy of tacrolimus in children under age 2 has far-reaching implications. Using tacrolimus in the treatment of AD can reduce the chronic use of TCS and their associated adverse effects. Furthermore, in a chronic condition such as AD, which requires long-term treatment, tacrolimus is advantageous because of its self-regulatory properties. This drug may be appropriate for long-term use and severe systemic side effects have not been documented [4, 5,10]. The low occurrence of adverse effects in this very young age group suggests a superior safety profile for tacrolimus. In conclusion, tacrolimus ointment appears to be safe and effective for children with AD under age 2.

Disclaimer:The Wake Forest University School of Medicine, Dept. of Dermatology has and is currently receiving research grant funding and gifts from Fujisawa Healthcare, Inc. Yale University and Oregon Health and Sciences University have received research grants and unrestricted educational grants from Fujisawa Healthcare, Inc. Dr. Alan Fleischer and Dr. Richard Antaya are on the Speaker's Bureau for Fujisawa Healthcare, Inc. This study was not directly funded by Fujisawa Healthcare, Inc.

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