Tacrolimus ointment: Its utilization patterns in children under 2 years old
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
13 March review/editing

Introduction

Atopic dermatitis (AD) is a common eczematous skin condition; as many as 10-17 percent of all children are affected by AD, and 35-60 percent of symptoms manifest 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 and liberal use of emollients after bathing. Also, antihistamines and antibiotics are frequently used as adjunctive therapy. 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 include skin atrophy, stria formation, telangiectasia, hypopigmentation, secondary infections, steroid acne, allergic contact dermatitis, and miliaria [4]. The pediatric population is also at an increased risk for systemic absorption because, in part, of the ratio of skin surface to body mass resulting in hypothalamic-pituitary-adrenal (HPA) axis suppression and ultimately growth retardation [4, 5]. Most topical and systemic corticosteroids have not been approved by the Food and Drug Administration (FDA) for use in children under 2 years old [4]. Moreover, conservative treatment often fails in this age group and frequently patients are treated with TCS, antibiotics, and antihistamines [1]

Tacrolimus is a recently approved drug for AD, which acts by inhibiting the phosphatase activity of calcineurin in T-cells [4, 6, 7] This process 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 have been implicated in the pathogenesis of AD [4, 8]. Currently, there are two FDA-approved concentrations of tacrolimus, 0.1 percent for use in patients 16 years and older and 0.03 percent for use in children 2 years and older. Recent studies of children 2 years and older demonstrated that both concentrations of tacrolimus are safe and effective for use in moderate to severe AD [4, 5] As compared to mid- and high-potency TCS, tacrolimus was found to be safe for use on the face, neck, and intertriginous areas without the common local side effects such as atrophy and telangiectasias [4, 5]. Also, it was not found to be significantly absorbed systemically, has not caused problems with growth retardation, and does not appear to induce systemic immunosuppression in studies [4, 5, 8]. It 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 on application [4, 5, ,9]. The present study was designed to evaluate the utilization patterns of tacrolimus ointment (0.1 % and 0.03 %) in AD patients under 2 years old and identify its safety and efficacy in this age group.

Materials and Methods

Patient charts were evaluated from the following dermatology centers: Wake Forest University School of Medicine in Winston-Salem (coordinating center); Oregon Health and Science University in Portland; and Yale University in New Haven. The study population consisted of all patients with a diagnosis of AD who had been treated between March 1 and September 1, 2001 with tacrolimus ointment (Protopic® 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 treated for AD with an extemporaneous formulation of tacrolimus ointment. 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 data entry and analysis. The following data points were collected for the baseline visit: age, gender, race, age at onset of AD, severity of AD (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 severity of AD, assessment of response to treatment, pruritus, and sleep, on a -1 to +2 scale for worse, no change or slightly better, moderate or marked improvement, and excellent improvement or cleared, were recorded on followup visits. All treatments were recorded, including treatment dates, adverse events as the result of treatment, and serum levels of tacrolimus, if available. All analyses were performed using SAS software (version 8.0; Cary).

Results

Of 38 patient charts reviewed, 1 was excluded from all data analyses because the child was over 2 years old at the baseline visit. Of the subjects, 15 of 37 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 were available only on six patients and ranged from 11 percent to 30 percent to 91 percent to 100 percent BSA involvement with a mean BSA of 51-90 percent. At baseline, half the patients were prescribed tacrolimus (0.1 %), the other half was prescribed tacrolimus (0.3 %), and 95 percent were applying TCS (table 1).

Data were available on 24 followup contacts from 15 patients; 23 were office visits; 1 was a telephone contact. At 42 percent of these visits, the patient was 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 one patient only had one of 4 visits with reported 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 Ð1 (worse) to +2 (excellent improvement or cleared). Pruritus assessment was available on seven followup visits with a mean score of 0 (± 0.8) ranging from -1 (worse) to +1 (moderate or 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 or slightly better. There were no reported adverse events at 87 percent of 23 visits, and other 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 equal to or less than 3 ng/mL.

Discussion

The findings from this multicenter retrospective chart review demonstrate that tacrolimus ointment is being utilized effectively in children under 2 years old with 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, or 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 lasting for 2 weeks.

The safety and efficacy of tacrolimus in children under 2 years old has far-reaching implications. Using tacrolimus in the treatment of AD can reduce the occurrence of adverse effects seen with the chronic use of TCS alone. Furthermore, in a chronic condition such as AD, which requires repeated applications, tacrolimus is advantageous owing to its self-regulatory properties. This drug may be appropriate for long-term use without apparent, severe systemic side effects such as HPA axis suppression [4, 5, 10]. The low occurrence of adverse effects in this very young, age group may suggest a superior safety profile for tacrolimus. In conclusion, tacrolimus ointment may be an effective and safe alternative for children under age 2 with AD.

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.

© 2004 Dermatology Online Journal