FDA Experience:

Topical Corticosteroids and HPA Axis Suppression

Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products FDA
Pediatric Subcommittee of the AIDAC October 29-30, 2003 ,

OUTLINE
History of Labels Regulations and Legislation Specific Drug Product Data

Pediatric Subcommittee of the AIDAC October 29-30, 2003 ,

Topical Corticosteroid Classification

Seven Classes
Class I Superpotent Class II High Potency Classes III, IV, V, VI Midpotency Class VII Low Potency

Vasoconstrictor Assay

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History of Labels

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Labels - 1970's
Lidex (fluocinonide) Gel, 0.05% - Class II steroid Precaution Section: If extensive areas are treated, the possibility exists of increased systemic absorption and suitable precautions should be taken.
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Labels - 1980's
TEMOVATETM (clobetasol cream and ointment), 0.05%, a Class I steroid - Approved in 1985 PRECAUTIONS: General: TEMOVATETM is a highly potent topical corticosteroid that has been shown to suppress the HPA axis at doses as low as 2 g per day. Pediatric Use: Use of TEMOVATETM Cream and Ointment in children under 12 years of age is not recommended.
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Two open-label trials with TemovateTM Ointment:

Trial 1: 6 adult patients with psoriasis applied 7 grams/day to 30% BSA for 7 days ACTH stimulation was performed at baseline and 2 post-treatment A.M. cortisols 3/6 or 50% of patients exhibited decreases in cortisol production
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Two open-label trials with TM Ointment (contd): Temovate

Trial 2: Objective - determine the largest dose over a 7 day period that would not cause significant suppression of the adrenal gland 3 doses were used - 7 grams/day, 3.5 grams/day, 2.0 grams/day Suppression was determined by A.M. plasma cortisol levels and urinary corticoid concentrations None of the psoriatic patients suppressed at 7.0 grams/day or 3.5 grams/day but doses as low as 2.0 grams/day caused marked suppression of cortisol secretion in patients with atopic dermatitis.
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Class Labeling for Topical Corticosteroids 1990

Precautions Section

Pediatric Use Section

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Precautions Section

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General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.
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Patients applying a potent topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.
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If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent steroid. Recovery of HPA axis function is generally prompt upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur requiring supplemental systemic corticosteroids.
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Pediatric Use Section

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Safety and effectiveness in children and infants have not been established. Because of a higher ratio of skin surface area to body mass, children are at a greater risk than adults of HPA-axis-suppression when they are treated with topical corticosteroids. They are therefore also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of Cushing's syndrome while on treatment.
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HPA axis suppression, Cushing's syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

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Regulation and Legislation

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1994 - Pediatric Rule 1997 - Section 111 of FDAMA 2002 Best Pharmaceuticals for Children Act
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Pediatric Rule
allowed for extrapolation of adult efficacy data to pediatric patients when appropriate, plus additional safety, pk, and/or dose ranging studies in the targeted pediatric population
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Section 111 of FDAMA Written Request

Sponsors are offered 6 months of exclusivity for their chemical moiety if they fairly respond to the Agencys request for pediatric studies.

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Best Pharmaceuticals for Children Act

Establishes additional mechanisms for the study of both on-patent and off-patent drugs Pediatric Supplements are now Priority Reviews

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Specific Drug Product Data

10 drug products
8 topical corticosteroid products 2 combination drug products

11 studies Ages 3 months adult Open-label trials Cosyntropin stimulation test

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Dermatop (prednicarbate emollient cream), 0.1% a Class V steroid Approved May 1996 Pediatric Atopic Dermatitis Trial

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 59 pediatric patients enrolled 2 targeted populations - patients between 1 month and 2 years - patients between 2 and 12 years 10 patients were <2 years old 49 patients were 2 years old
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Treatment Criteria
>20% body surface area (BSA) involvement Twice daily for 21 consecutive days ACTH Stimulation Test Cosyntropin administered at baseline and day 22 Patients 15 kg received 0.25 mg IV Patients < 15 kg received 0.125 mg IV
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Criteria per protocol for a normal adrenal response to ACTH stimulation at 30 and 60 minutes:
Post stimulation serum cortisol >20 g/dL If pre-stimulation serum cortisol levels > 20 g/dL, an incremental increase >6 g/dL in serum cortisol
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Three patients according to the protocol criteria were suppressed: 2 patients, 1 an 18 month old, had a peak response of 5 g/dL change from baseline. 1 patient had a poststimulation cortisol value that decreased from baseline. At that time, the Agency agreed with an outside endocrinologist that since these 3 patients had a poststimulation response that was greater than 20 g/dL, although they didn't have the required incremental rise, they would not be considered suppressed. This led to the current label that reads that "none of the 59 patients showed evidence of HPA axis suppression."
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Cutivate (fluticasone) Cream, 0.05% a Class V steroid Approved June 17, 1999 Pediatric Atopic Dermatitis and Psoriasis Trial
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 43 patients were evaluable ( all with moderate to severe atopic dermatitis) 29 patients 3 months to 2 years old 14 patients 3 years to 5 years old

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Treatment Criteria
At least 35% BSA involvement Bid application for 3 - 4 weeks Patients up to 2 years limited to 120 grams/week Patients 3-5 years of age limited to 180 grams/week
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BSA Improvement Over Time (N=46)

23 (50%) had a decrease of 50% by 2 weeks 9 (20%) had a decrease of 50% by 3 weeks 4 (9%) had a 50% decrease by 4 weeks

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Cosyntropin Stimulation Test

Test administered at baseline and end of treatment Younger age group given 0.125 mg cosyntropin IV Older age group given 0.25 mg cosyntropin IV
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Normal response Cosyntropin Stimulation Test

A serum cortisol level >18 g/dL at 30 minutes post-stimulation

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2 out of 43 patients experienced adrenal suppression

Serum Cortisol (Qg/dL) Baseline End-Tx Follow-up

Subject

Age/Sex

%BSA

Severity

Duration

Amt. Used

Prestim

Poststim

Prestim

Poststim

Prestim

Poststim

B201

5 yrs/M

95 (95)

22 (9)

4 weeks

561.0 grams

22.1

33.9

7.1

11.8

2.1

19.8

B202

2 yrs/M

35 (35)

17 (7)

5 weeks

176.5 grams

10.8

28.6

2.1

9.4

LTF

LTF

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Label Change for Cutivate Cream

Indication Children as young as 3 months of age for up to 4 weeks of use Safety Update Information Precautions: General and Pediatric Use Sections

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Betamethasone Propionate - Approved in 2001

Diprolene AF Cream, 0.05% - a Class II steroid Diprosone Ointment, 0.05% - a Class II steroid Diprosone Cream, 0.05% - a Class III steroid Diprosone Lotion, 0.05% - a Class V steroid Lotrisone Cream and Lotion (clotrimazole and betamethasone propionate)
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Criteria for a Normal HPA Axis Response

Follow the Cortrosyn label Failure of any one of 3 criteria would indicate suppression of the HPA axis Stimulation should occur at baseline and end of treatment
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Criteria - 30 minute post-stimulation

The control plasma cortisol level should exceed 5 g/100 mL The 30-minute level should show an increment of at least 7 g/100mL above the basal level The 30-minute level should exceed 18 g/100mL
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Diprolene AF Cream, 0.05%

60 evaluable patients, ages 1-12 years with atopic dermatitis Mean BSA involvement - 58% (range: 35% - 95%) Used study drug bid for 2 - 3 weeks
Limited to 45 grams/week
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Diprolene AF Cream, 0.05% (contd)

19/60 or 32% of these patients showed evidence of HPA axis suppression 11/19 (58%) had a post-stimulation plasma cortisol value < 18 g/dL 6/19 (32%) failed to have an incremental change of at least 7 g/dL 2/19 (11%) had a pre-stimulation cortisol < 5 g/dL
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Suppression by Age Group

Age Group 3mo-1 yr n=4 2 50 2yr-5yr n=16 6 38 6yr-8yr n=28 9 32 9yr-12yr n=12 2 17

# suppressed %

Recovery of normal HPA axis function 4 patients were retested 2 weeks post- treatment and 3 of the 4 recovered normal function of the HPA axis.
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Statistical Analysis in the Development of HPA Axis Suppression

No correlation between amount of drug used, body weight, age or sex and the incidence of adrenal gland suppression Statistical relationship did exist between BSA and risk of HPA axis suppression for an increase of 1% BSA involved, risk of HPA axis suppression increased 4.4% p 0.01
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Label Change for Diprolene AF Cream, 0.05% Indication - added an age restriction of 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections

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Diprosone Ointment, 0.05%

53 evaluable subjects with atopic dermatitis Age Range - 6 months to 12 years old Medication applied bid for 2 to 3 weeks Mean BSA Involvement - 58% (range: 35% - 99%)
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Diprosone Ointment, 0.05% (contd)

15/53 or 28% of patients showed evidence of HPA axis suppression 8/15 or 53% had a post-stimulation plasma cortisol value < 18 g/dL 7/15 or 47% failed to have an incremental change of at least 7 g/dL
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Suppression by Age Group

Age Group 3mo-1 yr n=11 2yr-5yr n=21 6yr-8yr n=15 9yr-12yr n=6

# suppressed

36

29

27

17

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Statistical Analysis in the Development of HPA Axis Suppression No statistically significant effect for Drug usage % BSA Weight Age Higher proportion of males than females (p=0.006) who developed HPA axis suppression
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Recovery of HPA Axis Function Diprosone Ointment

2/15 patients were retested 100% recovery at 2 weeks

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Label Change Diprosone Ointment, 0.05%

Indication - added an age restriction of 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections
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Diprosone Cream, 0.05%

43 evaluable patients with atopic dermatitis Age Range - 1 year to 12 years old Mean BSA Involvement - 40% (range: 35% - 90%) Medication applied bid for 2-3 weeks
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Diprosone Cream, 0.05% (contd)

10/43 or 23% of patients showed evidence of adrenal suppression 5/10 or 50% had a post-stimulation plasma cortisol value < 18 g/dL 3/10 or 30% failed to have an incremental change of at least 7 g/dL 2/10 or 20% had a pre-stimulation cortisol < 5 g/dL
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HPA Axis Suppression by Age

Age Group 3mo-1yr n=3 2yr-5yr n=20 6yr-8yr n=13 9yr-12yr n=7

# suppressed %

30

23

14

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Statistical Analysis in the Development of HPA Axis Suppression

No statistically significant effect for Number of days treated Weight Age Statistical significance found for mean amount of drug used - 81 grams vs. 37 grams (p<0.001) There was a numerically higher %BSA involvement Numerically, more males developed suppression
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Recovery of HPA Axis Function Diprosone Cream 2/10 patients were retested 1/2 (50%) recovered HPA axis function at 2 weeks
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Label Change Diprosone Cream, 0.05%

Indication - added an age restriction of 13 years and older Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections

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Diprosone Lotion, 0.05%

15 evaluable patients with atopic dermatitis Age Range - 6 to 12 years old Mean BSA Involvement - 45% (range: 35% - 72%) Medication applied bid for 2-3 weeks
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Diprosone Lotion, 0.05% (contd)

11/15 or 73% of patients showed evidence of HPA axis suppression 10/11 or 91% had a post-stimulation plasma cortisol value < 18 g/dL 1/11 or 9% failed to have an incremental change of at least 7 g/dL

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Suppression by Age Group

Age Group 3mo-1 yr n=0 2yr-5yr n=0 6yr-8yr n=10 9yr-12yr n=5

# suppressed

None enrolled -

None enrolled -

70

80

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Statistical Analysis in the Development of HPA Axis Suppression

Numerical analysis Subjects exhibiting HPA axis suppression
Larger mean amount of drug used (92.8 g vs. 69.4 g) Slightly higher %BSA involved (45.8% vs. 41.8%) Lower mean weights at visit 1 (65 lbs. vs. 81 lbs.) Lower mean weights at visit 4 (65 lbs. vs. 80 lbs.) Differences with respect to age and days of treatment were miniscule

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Recovery of HPA Axis Function Diprosone Lotion

6/11 patients were retested 4/6 (67%) recovered HPA axis function at 2 weeks

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Label Change Diprosone Lotion, 0.05%

Indication added an age restriction of 13 years and older Clinical Safety Information Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections

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Comparison of HPA Axis Criteria Betamethasone Dipropionate

Drug Product Diprolene AF Cream Diprosone Ointment Diprosone Cream Diprosone Lotion
HPA Axis Suppression Criteria - serum cortisol levels 5 g/dL ; >18 g/dL; 7 g/dL > 18 g/dL

19/60 (32%) 15/53 (28%) 10/43 (23%) 11/15 (73%)

11/60 (18%) 8/53 (15%) 5/43 (12%) 10/15 (67%)

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Lotrisone Cream
Tinea Pedis Study Tinea Cruris Study Both studies were in the adolescent population ages 12 16 years Medication was applied twice daily Study duration
4 weeks for tinea pedis 2 weeks for tinea cruris

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Lotrisone Cream (contd)

17/43 (39.5%) demonstrated adrenal suppression in the tinea pedis study 8/17 (47.1%) demonstrated adrenal suppression in the tinea cruris study

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Label Change Lotrisone Cream and Lotion

An Expanded Indications Section
Added an age restriction patients 17 years and older Recommended that effective treatment may be obtained without the use of a corticosteroid for noninflammatory tinea infections

Updated Safety Information Precautions: General, Pediatric Use, Geriatric Use and Dosage and Administration Sections
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Clobetasol Propionate - Clobex Lotion and Temovate E Cream

Class I steroids 3 studies
2 adult studies one in psoriasis and one in atopic dermatitis 1 pediatric study (ages 12 17 years) in atopic dermatitis

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Construct of HPA Axis Evaluation

The control plasma cortisol level should exceed 5 micrograms/100 mL The 30 minute level should show an increment of at least 7 micrograms/100 mL above basal level The 30 minute level should exceed 18 micrograms/100 mL
Exceptions:
plasma cortisol levels were drawn at 60 minutes post-stimulation. In adult studies, subjects were stimulated with cosyntropin weekly.
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Adolescent study
24 evaluable patients 14 treated with Clobex Lotion and 10 treated with Temovate E Cream Moderate to severe atopic dermatitis BSA treated at least 20% Medication applied BID for 2 weeks 50 grams/week limit
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HPA axis suppression

9/14 (64%) of subjects treated with Clobex Lotion suppressed 2/10 (20%) of subjects treated with Temovate E Cream suppressed

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Statistical Analysis
Mean %BSA treated was higher for patients with adrenal suppression 32.8% vs. 27.7% for Clobex Lotion 35% vs. 25.3% for Temovate E Cream

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Recovery of HPA Axis Function

1/4 of patients treated with Clobex Lotion remained suppressed after 2 weeks 1/1 patient retested after treatment with Temovate E Cream recovered

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Adult Study
18 evaluable patients 9 treated with Clobex Lotion and 9 treated with Temovate E Cream Moderate to Severe Atopic Dermatitis Mean BSA treated 19.3 % for Clobex Lotion and 19.4% for Temovate E Cream Medication applied BID for 2 weeks 50 gram/week limit

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HPA Axis Suppression

5 / 9 (56%) of subjects treated with Clobex Lotion suppressed 4 / 9 (44%) of subjects treated with Temovate E Cream suppressed

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Recovery of HPA Axis Function

1 / 3 patients on Clobex Lotion failed to recover function 7 days post treatment 2 /2 patients on Temovate E Cream recovered function 7 days post treatment

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Adult Study
20 evaluable patients 10 treated with Clobex lotion and 10 treated with Temovate E Cream Moderate to Severe Plaque Psoriasis Mean BSA treated 16.2 % for Clobex Lotion and 17.9 % for Temovate E Cream Medication applied BID for 4 weeks 50 gram/week limit

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HPA Axis Function

8 / 10 (80%) of subjects treated with Clobex Lotion suppressed 3 / 10 (30%) of subjects with Temovate E Cream suppressed 1 / 2 subjects with Clobex Lotion retested remained suppressed after 8 days 0 / 3 subjects on Temovate E Cream were retested
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Label for Clobex Lotion

Indication restricted to patients 18 years or older 2 consecutive weeks not to exceed 50 grams (50 mL or 1.75 fl. Oz) per week Moderate or severe psoriasis, for localized lesions < 10% BSA can be treated an additional 2 weeks Updated Safety Information Indications and Usage, Precautions: General and Pediatric Use, and Dosage and Administration Sections
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Summary
HPA axis suppression does occur with the use of topical corticosteroids The adrenal suppression is not limited to the super potent class of topical corticosteroids The type of vehicle may contribute to the extent of absorption of the active chemical moiety The suppression appears, in most cases, to be reversible upon cessation of drug usage
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FDA Experience:
Topical Corticosteroids and HPA Axis Suppression

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