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Safety of fluticasone propionate cream 0.05% for
the treatment of severe and extensive atopic
dermatitis in children as young as 3 months
S. F. Friedlander, MD,a A. A. Hebert, MD,b and D. B. Allen, MD,c for the Fluticasone Pediatrics Safety Study Group* San Diego, California, Houston, Texas, and Madison, Wisconsin Background: Topical corticosteroids are useful for the treatment of pediatric dermatoses. However,
concerns regarding possible systemic and topical toxicities have limited the use of moderate-potency
corticosteroids in children.
Objective: Our purpose was to characterize the safety of fluticasone propionate cream in children.
Methods: Children between 3 months and 5 years 11 months (n = 32) and 3 up to 6 years of age (n = 19)
with moderate to severe atopic dermatitis (≥ 35% body surface area; mean body surface area treated, 64%)
were treated with fluticasone propionate cream, 0.05% twice daily for 3 to 4 weeks. Serum cortisol
response, fluticasone levels, skin changes, and adverse events were analyzed.
Results: Mean cortisol levels were similar at baseline (13.76 ± 6.94 µg/dL prestimulation and 30.53 ± 7.23
µg/dL poststimulation) and at end of treatment (12.32 ± 6.92 µg/dL prestimulation and 28.84 ± 7.16 µg/dLpoststimulation). Only 2 of 43 children had end-treatment poststimulation values less than 18.0 µg/dL. Nosignificant adverse cutaneous effects were noted.
Conclusion: Fluticasone propionate cream 0.05% appears to be safe for the treatment of severe eczema
for up to 4 weeks in children 3 months of age and older. (J Am Acad Dermatol 2002;46:387-93.)
Atopic dermatitis affects approximately 5% to 20% of all children by 11 years of age,1 making it the most common skin disease of child- hood.2 Because of its chronic, recurrent nature, this form of eczema can have a considerable impact on the quality of life of patients and their families, including adverse effects on sleep patterns, behavior, family relationships, and financial stability.3 Topical corticosteroids are commonly used to treat eczema.4 HPLC: high-pressure liquid chromatography From the Department of Pediatrics and Medicine (Dermatology), University of California, San Diego School of Medicine and Children’s Hospitala; the Department of Dermatology, Universityof Texas Medical School, Houstonb; and the Department ofPediatrics, University of Wisconsin, Madison.c Their misuse, however, may lead to skin thinning and systemic complications such as reversible hypo- Accepted for publication April 30, 2001.
thalamic-pituitary-adrenal (HPA) axis suppression.
Reprint requests: Sheila Fallon Friedlander, MD, Department of Pediatrics and Medicine (Dermatology), University of California, The occurrence of HPA axis suppression is of partic- San Diego School of Medicine and Children’s Hospital, San ular concern in children because of the potential for Diego, 3030 Children’s Way, Suite 408, San Diego, CA 92123.
increased absorption caused by a higher ratio of skin *A complete list of the members of the Fluticasone Pediatrics Safety Group appears at the end of the article.
Topical formulations of fluticasone propionate Copyright 2002 by the American Academy of Dermatology, Inc.
0190-9622/2002/$35.00 + 0 16/1/118337
(Cutivate, Glaxo Wellcome, Research Triangle Park, NC), a corticosteroid,5 are indicated for the relief of 388 Friedlander, Hebert, and Allen
the inflammatory and pruritic manifestations of cor- cant disease other than the study disease; any gross ticosteroid-responsive dermatoses. Both the cream physical impairment that would affect the outcome and ointment formulations have shown minimal of or interfere with participation in the trial; any effects on HPA axis function in adults, as determined unstable concomitant disease other than the condi- by measuring morning serum or plasma cortisol con- tion to be treated in the study; and known hypersen- centrations.6-9 Any fluticasone propionate that is sitivity to fluticasone propionate, its cream vehicle, or absorbed systemically is rapidly metabolized by the cosyntropin (Cortrosyn, Organon Inc, West Orange, liver. The major metabolite of fluticasone propionate NJ). Use or anticipated use of the following therapies has no significant anti-inflammatory activity or gluco- also resulted in exclusion from the study: topical or corticoid activity, contributing to its low potential for inhaled corticosteroids within 1 week of study entry; HPA axis suppression.10-12 These unique pharmaco- long-term therapy (>4 weeks continuously) such as logic characteristics suggest that fluticasone propi- cyclosporine, methotrexate, psoralen and ultraviolet onate may be appropriate for use in pediatric light (PUVA), or topical products for skin lesions patients with extensive eczema in whom more within 4 weeks; systemic corticosteroids within 6 potent corticosteroids are needed to suppress flares, months; systemic retinoids; or any other topical or but for whom HPA axis suppression is of concern.
systemic therapy for the study disease other than Although the adrenal response to stimulation bland emollients, such as moisturizers, in untreated with cosyntropin (Cortrosyn; CST) has been tested areas, with the exception of therapies known to have in children after treatment with topical mometasone no effect on cortisol values and HPA axis function.
furoate,13 no study in children has assessed the Patients who had engaged in certain recent activities adrenal response to stimulation with cosyntropin (eg, the use of tanning booths, sunbathing, or UV after extensive treatment with topical fluticasone light treatments) or who had potentially interfering propionate. This information is important, given the personality characteristics or habits (subject or par- recurrent nature of the disease and the need for safe, ent/guardian) during the study were also excluded.
effective therapies for severe eczema in children.
Participation in another investigational drug study Thus the purpose of the present study was to evalu- within 4 weeks before the start of the study was not ate the effects of fluticasone propionate cream 0.05% on HPA axis function using CST testing and to evalu-ate its effect on other safety variables in pediatric Study design
patients with moderate to severe eczema.
This phase IV open-label safety study was con- ducted at 10 centers in the United States. This study MATERIALS AND METHODS
was approved by the Institutional Review Board at Subjects
each center. Subjects were screened up to 6 days Pediatric patients between the ages of 3 months before baseline. After the baseline visit (day 1), visits and 5 years 11 months with extensive moderate to occurred weekly for 3 to 4 weeks. At baseline and at severe psoriasis or eczema (excluding acute self- the end of treatment visit, HPA axis function was limiting eczema) were considered for enrollment.
determined by the response to CST, and blood was Their condition must have been stable or worsening collected for clinical laboratory tests (serum chem- and must have involved at least 35% of body surface istry, hematology, and assay of plasma fluticasone area (BSA) (not counting lesions in the diaper area propionate concentrations). Proactive monitoring for subjects who wore diapers; also excluding lesions for adverse events, signs of skin atrophy, and skin on the eyelids, in the perioral area, in the nostrils, pigmentation changes was conducted weekly.
and in areas where corticosteroid treatment was con- Subjects who had abnormal CST results, other labo- traindicated). The total severity score was required to ratory abnormalities, or adverse events that required equal at least 6.0 for any 3 of 8 potential signs and follow-up were seen 1 or 2 weeks after the end of symptoms (erythema, pruritus, papulation, indura- tion, oozing/crusting, scaling, excoriation, lichenifica- Fluticasone propionate cream 0.05% was applied tion), for which each sign/symptom was rated on a twice daily to all lesions, including facial lesions, but scale of 0.0 (absent) to 3.0 (severe).14 BSA was esti- not including those in the diaper area, eyelids, peri- mated using the “rule of nines.”15 Subjects were strat- oral area, nostrils, and areas in which corticosteroid ified into 2 age groups: (1) 3 months to less than 3 treatment was contraindicated, such as those show- years (younger group) and (2) 3 years to less than 6 ing signs of atrophy. The amount necessary to cover years (older group). Written informed consent was the lesions was based on the fingertip unit, a ribbon obtained from the parent or guardian of all patients of cream the length of the tip of the guardian’s index before study entry. Exclusion criteria included signifi- finger (second phalanx).16 The investigator was Friedlander, Hebert, and Allen 389
expected to estimate the amount of cream that phy (HPLC) only in subjects 2 years of age and older, would make up the guardian’s fingertip unit and to to minimize the amount of blood drawn from chil- demonstrate to the guardian how much cream to dren younger than 2 years of age. For poststimula- apply based on the extent of BSA to be treated.
tion CST results, the lower limit of normal for serum Maximum drug exposure conditions were main- cortisol level was 18 µg/dL for FPIA and 14.5 µg/dL tained by treating twice daily (fluticasone propionate for HPLC. The minimal value detectable of cortisol 0.05% is currently approved for once- or twice-daily was 1.0 µg/dL for the FPIA method and 0.5 µg/dL for application in the treatment of atopic dermatitis) and continuing treatment for 1 week after subjects’ The primary indicator of a normal adrenal lesional areas were assessed as cleared or for a max- response was defined as a poststimulation cortisol imum of 4 weeks. Clearing was defined as loss of peak value of more than 18.0 µg/dL by FPIA. The signs or symptoms of disease and no residual ery- FPIA was chosen as the primary indicator of normal thema. A minimum of 35% BSA was treated regard- adrenal response because FPIA results were avail- less of healing for 3 to 4 weeks to maintain adequate able to investigator sites within 24 hours of receipt.
conditions for testing the effects of systemic absorp- In addition, given the need to restrict HPLC analy- tion of the drug and evaluation of local side effects.
ses to the older age group because of blood volume At each weekly visit, signs and symptoms of disease concerns for the younger group, only FPIA values (eg, erythema, pruritus, papulation, induration, ooz- were available for all subjects. Of note is the corre- ing/crusting, scaling, excoriation, and lichenification) lation (>0.577 and >0.85 at 1 of 4 and 3 of 4 time were evaluated to monitor compliance and to assess points, respectively) between the cortisol data gen- the extent of exposure to study drug. Healed skin erated by the FPIA assay and HPLC assay (P < .001) would be expected to absorb less study drug than at each time point as determined by the Spearman diseased skin, although recently cleared lesional correlation coefficient. Thus, had there been both areas continue to exhibit less than normal barrier FPIA and HPLC cortisol data for all subjects, data function.17 In an effort to monitor compliance, all from either assay could have been used to evaluate returned medication tubes were weighed.
To assess consistency and to evaluate marginal Safety assessments
responses, other criteria stated in the product infor- Safety parameters included adrenal response to mation for CST were also examined, specifically, a CST, signs of skin atrophy and pigmentation changes, prestimulation to poststimulation increase in corti- changes in hematology and serum chemistries, and sol of approximately 2-fold (provided the prestimu- occurrence of adverse events. Plasma fluticasone val- lation value did not exceed the normal range) or an ues were measured only in subjects 2 years of age and increase of 7 µg/dL or more. CST results were also older because of the limited amount of blood that reviewed by a pediatric endocrinologist (D. B. A.).
could be drawn from younger subjects. A fasting Skin thinning and other signs associated with blood sample was obtained for analysis of serum cor- atrophy were assessed by 2× magnification and tisol and clinical laboratory tests. Covance Central included telangiectasia, loss of elasticity, purpura, Laboratory Services, Inc, Princeton, New Jersey, per- dusky erythema, and striae. These signs were scored formed all serum chemistries, hematology values, and according to severity. Any pigmentation change not considered to represent a normal healing process For the CST analyses, the baseline blood draw was reported as an adverse event. Treated skin was occurred on the morning of day 1, and the end- assessed by the investigator at each visit. Baseline treatment blood draw occurred on day 22 or 29.
and end-of-treatment analyses of serum chemistries Prestimulation blood samples were obtained at 8 AM.
were performed for concentrations of alkaline phos- CST was administered intravenously immediately phatase, lactate dehydrogenase (LDH), aspartate after prestimulation blood samples had been aminotransferase (AST), alanine aminotransferase obtained. The dose of CST was 0.125 mg for subjects (ALT), glucose, total protein, albumin, sodium, in the younger group and 0.25 mg for subjects in the potassium chloride, total carbon dioxide, phospho- older group. A poststimulation blood sample was rus, uric acid, blood urea nitrogen (BUN), creatinine, obtained 30 minutes after the injection of CST.
calcium, and total bilirubin. Hematology assessment Subjects were offered food or drink after the admin- included white blood cell (WBC) count and differen- istration of CST and before collection of the post- tial, red blood cell (RBC) count and morphology, stimulation sample. Serum cortisol was assayed by platelet count, hematocrit, and hemoglobin. Adverse fluorescence-polarization immunoassay (FPIA) in all events were recorded as to nature, severity, and rela- subjects and by high-pressure liquid chromatogra- 390 Friedlander, Hebert, and Allen
Table I. Summary of baseline demographic and
Table II. Summary of baseline dermatologic
groups (total)
groups (total)
*Age and weight were determined at the screening visit ratherthan at baseline.
tion and poststimulation samples) available from 43of the 51 subjects comprising the intent-to-treat pop-ulation. CST results are presented for all subjects (n Plasma fluticasone concentrations were deter- = 46 prestimulation, n = 43 poststimulation) with mined by automated solid-phase extraction using a end-of-treatment CST (at day 22, day 29, or at the Zymark 96-well system (Zymark Corp, Hopkinton, end of treatment for subjects who discontinued, Mass). The extracts were analyzed by HPLC with tan- regardless of treatment duration). Correlations using dem mass spectrometric detection, using a reverse- the Spearman correlation coefficient were also phase column. The calibration range was 50 to 1520 assessed between CST results and age, between the pg/mL from 0.5 mL of plasma, with a limit of detec- ratio of the amount of drug used to the BSA affected, and the ratio of the amount of drug used to the end-of-treatment poststimulation cortisol results.
Statistical analysis
Data, including demographics, adverse events, and occurrence of atrophy and associated signs, Study population
were summarized using the intent-to-treat popula- Fifty-one children, 32 in the younger group (age tion consisting of the 51 enrolled subjects. The CST 3-35 months; median, 20 months) and 19 in the data presented are based on complete blood sample older group (age 36-70 months; median, 50 months) sets (baseline and end of treatment for prestimula- were enrolled, all of whom had atopic dermatitis. In Friedlander, Hebert, and Allen 391
Fig 1. Serum cortisol levels for all subjects at baseline (n = 49 prestimulation, n = 47 post-
stimulation) and end of treatment (n = 46 prestimulation, n = 43 poststimulation) with fluti-
casone propionate (for 22-30 days) before and after 30-minute CST stimulation as assessed by
FPIA. Heavy black bars indicate mean ± 1 standard deviation. Asterisk, Children considered
to have HPA suppression; dagger, apparent laboratory error.
the younger group, 8 children were younger than 12 group and 7.7 g (53.9 g/wk) in the older group. At months (4 were 3-6 months and 4 were 7-11 baseline, cutaneous atrophy was not reported for months). Demographic and baseline dermatologic any child and only one child had telangiectasia characteristics are shown in Tables I and II, respec- (mild). Eight younger children (25%) and 3 older tively. Subjects were evenly distributed between the children (16%) had abnormal pigmentation.
sexes, and the majority were Caucasian (39%). The Five children in the older group discontinued pre- remaining children were African American (29%), maturely, 2 children before treatment because of Asian (16%), American Hispanic (8%), or other (8%).
inability to draw blood, and 3 children during treat- All children had a diagnosis of eczema at baseline, ment because of loss to follow-up (1 patient), inade- considered to be worsening in 76% of patients and quate disease severity at baseline (1), and an abnor- stable in the remainder. The mean duration of the mal baseline CST (1). The 3 children who were dis- current eczematous episodes at this time was 45.7 continued during treatment were treated for less weeks for the younger group and 107.7 weeks for the older group. The mean baseline BSA treated was62.3%, with a range of 35% to 94% in the younger Safety results
group and 67.2%, with a range of 36% to 95%, in the Adrenal responsiveness. The serum cortisol
older group. The mean baseline BSA treated was levels are presented in Fig 1. No meaningful differ- 64% for all subjects. The average amount of drug ences were seen in mean prestimulation and post- used per day was 3.8 g (26.6 g/wk) in the younger stimulation cortisol levels between baseline and the 392 Friedlander, Hebert, and Allen
end of treatment. Mean cortisol levels at baseline pression using 18 µg/dL as the lower limit of normal.
were 13.76 µg/dL (standard deviation [SD], 6.94 However, the HPLC value was actually higher than µg/dL) before stimulation and 30.53 µg/dL (SD, 7.23 14.5 µg/dL, the lower limit of normal for the HPLC µg/dL) after stimulation, and at the end of treatment assay. In addition, the FPIA prestimulation and post- these values were 12.32 µg/dL (SD, 6.92 µg/dL) stimulation cortisol levels were normal, 13.1 µg/dL before stimulation and 28.84 µg/dL (SD, 7.16 µg/dL) and 22.4 µg/dL, respectively, and the follow-up FPIA after stimulation (Fig 1). Furthermore, the mean dif- and HPLC prestimulation and poststimulation corti- ferences between baseline and end of treatment in sol levels were also normal, so this child ultimately prestimulation and poststimulation cortisol values were small (–1.78 µg/dL, P = .1734; –2.49 µg/dL, P = Very little correlation existed between age and either FPIA- or HPLC-generated cortisol data (P > .1 Of the 43 children with end-of-treatment post- at all time points; correlation coefficient [r] of age stimulation cortisol values, only 2 (4.7%) had values with baseline and end of treatment for FPIA data, that did not exceed 18.0 µg/dL. The baseline values –0.20 and –0.17, respectively; correlation coefficient of these 2 subjects were 22.1µg/dL (prestimulation), [r] with baseline and end of treatment for HPLC 33.9 µg/dL (poststimulation) and 10.8 µg/dL (pres- data, –0.16 and –0.19, respectively). There was some timulation), 28.6 µg/dL (poststimulation). The end- correlation between the ratio of the amount of drug of-treatment values were 7.1 µg/dL (prestimulation), used to BSA affected and end-of-treatment poststim- 11.8 µg/dL (poststimulation) and 2.1 µg/dL (prestim- ulation cortisol results (r = –0.40; P = .02).
ulation), 9.4 µg/dL (poststimulation), respectively.
Relationship of plasma fluticasone concen-
These 2 children, 1 from each age group, were con- trations to cortisol levels. No child had measur-
sidered to exhibit HPA axis suppression. One of able fluticasone values at baseline. Six of 25 children these children (age 5 years, 101 cm, 18.1 kg) had (24%) who had plasma samples taken at end of treat- normal CST at follow-up, 12 days after the last dose ment for measurement of fluticasone had measur- of study medication (2.1 µg/dL, prestimulation and able concentrations of the drug, 3 in each age group.
19.8 µg/dL, poststimulation). This child had 95% BSA The mean fluticasone plasma concentrations were affected and was treated for a duration of 4 weeks 112.1 pg/mL (range, 59-155 pg/mL) in the younger (561.0 g of medication used). The other child (age 2 group, 163.1 pg/mL (range, 109-264 pg/mL) in the years, 91 cm, 13.1 kg), who had 35% BSA affected older group, and 137.6 pg/mL (range, 59-264 pg/mL) and was treated for a duration of 5 weeks (176.5 g of medication used), was lost to follow-up. The 5-year- There were insufficient data to analyze relation- old used more medication than the others in this age ships between plasma fluticasone concentrations group (mean, 209.1 g), and the 2-year-old used more and cortisol levels. However, detectable plasma fluti- than the mean amount used in his age group (96.7 casone concentrations were present in only 1 of the g) but less than the maximum amount of 355.7 g.
2 children considered to have adrenal suppression These 2 subjects are shown in Fig 1 as the 2 points (plasma fluticasone concentration, 116.5 pg/mL (indicated with an asterisk) with the lowest end-of- (0.01165 µg/dL), end-of-treatment poststimulation cortisol value, 11.8 µg/dL) and in only 1 of the 2 chil- Two other children in the younger group had end- dren in whom there was the suggestion of evolving of-treatment poststimulation cortisol levels indicat- adrenal suppression (plasma fluticasone concentra- ing adrenal suppression by HPLC but not by FPIA.
tion, 122.0 pg/mL, end-of-treatment poststimulation However, since the FPIA level trended low in one cortisol value, 19.8 µg/dL). The child with the high- subject and did not show an increase of 7 µg/dL or est plasma fluticasone concentration (264 pg/mL) more in the other subject, it was noted that this pos- did not have adrenal suppression (end-of-treatment sibly suggested evolving adrenal suppression in poststimulation cortisol value, 23.3 µg/dL).
these 2 children. Of note is that the protocol exclu- Adverse events involving the skin. Twenty-five
sion criteria were violated by the use of long-term children (50%) had 39 adverse events, most fre- corticosteroid treatment in one child within 4 weeks quently fever and cold symptoms. Only 7 drug- of the study. Both of these children had a normal related adverse events were reported in 5 children.
One event occurred in 1 subject in the younger Finally, one investigator reported mild adrenal group and 6 events occurred in 4 subjects in the suppression in a child in the younger group. Owing older group (1 event in 3 subjects and 3 events in 1 to a laboratory error, this younger child’s cortisol subject). These 7 events were local events and level was assessed by both FPIA and HPLC. The included 1 event each of burning and urticaria (both HPLC value, 17.2 µg/dL, was thought to suggest sup- resolved without action the day they were reported), Friedlander, Hebert, and Allen 393
1 event of erythematous rash (resolved with discon- Specifically, it has a low potential for HPA axis sup- tinuation of the practice of applying drug to moist pression and for induction of atrophogenic effects, skin after bathing), and 3 events of telangiectasia (2 even after extensive application (mean baseline BSA facial and 1 nonfacial). The facial telangiectasia in both subjects may have been a preexisting conditionunmasked with resolution of the eczema. Both cases The Fluticasone in Pediatrics Safety Study Group con- of facial telangiectasia were resolved within 1 month sists of the following investigators: P. J. Honig, A. Paller, D.
after cessation of study drug. In addition, 1 subject J. Hogan, A. W. Lucky, J. Hanifin, A. Hebert, E. Siegfried, S.
with facial and nonfacial telangiectasia also had mild A. Raimer, S. Fallon Friedlander, D. B. Allen DB, and Y. H.
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