FDA Experience:: Topical Corticosteroids and HPA Axis Suppression

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

October 29-30,, 2003 2
Topical Corticosteroid Classification
Seven Classes
Class I Superpotent
Class II High Potency
Classes III, IV, V, VI Midpotency
Class VII Low Potency
Vasoconstrictor Assay

October 29-30,, 2003 3
History of Labels

October 29-30,, 2003 4
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.

October 29-30,, 2003 5
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.

October 29-30,, 2003 6
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

October 29-30,, 2003 7
Two open-label trials with
TemovateTM Ointment (contd):
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.
October 29-30,, 2003 8
Class Labeling for Topical Corticosteroids 1990
Precautions Section
Pediatric Use Section

October 29-30,, 2003 9
Precautions Section

October 29-30,, 2003 10
General: Systemic absorption of topical
corticosteroids can produce reversible
hypothalamic-pituitary-adrenal (HPA) axis
suppression with the potential for gluco-
corticosteroid 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.

October 29-30,, 2003 11
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.

October 29-30,, 2003 12
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.
October 29-30,, 2003 13
Pediatric Use Section

October 29-30,, 2003 14
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.

October 29-30,, 2003 15
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.

October 29-30,, 2003 16
Regulation and Legislation

October 29-30,, 2003 17
1994 - Pediatric Rule
1997 - Section 111 of FDAMA
2002 Best Pharmaceuticals for

Children Act

October 29-30,, 2003 18
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

October 29-30,, 2003 19
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.

October 29-30,, 2003 20
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

October 29-30,, 2003 21
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

October 29-30,, 2003 22
Dermatop (prednicarbate emollient cream), 0.1%
a Class V steroid
Approved May 1996
Pediatric Atopic Dermatitis Trial

October 29-30,, 2003 23
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

October 29-30,, 2003 24
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

October 29-30,, 2003 25
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

October 29-30,, 2003 26
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 post-
stimulation cortisol value that decreased from baseline.
At that time, the Agency agreed with an outside
endocrinologist that since these 3 patients had a post-
stimulation 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."
October 29-30,, 2003 27
Cutivate (fluticasone) Cream, 0.05%
a Class V steroid
Approved June 17, 1999
Pediatric Atopic Dermatitis and

Psoriasis Trial

October 29-30,, 2003 28
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

October 29-30,, 2003 29
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
October 29-30,, 2003 30
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

October 29-30,, 2003 31
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
October 29-30,, 2003 32
Normal response
Cosyntropin Stimulation Test
A serum cortisol level >18 g/dL

at 30 minutes post-stimulation

October 29-30,, 2003 33
2 out of 43 patients experienced
adrenal suppression
Serum Cortisol (g/dL)
Baseline End-Tx Follow-up
Subject Age/Sex %BSA Severity Duration Amt. Pre- Post- Pre- Post- Pre- Post-
Used stim stim stim stim stim stim
B201 5 yrs/M 95 (95) 22 (9) 4 weeks 561.0 22.1 33.9 7.1 11.8 2.1 19.8
grams
B202 2 yrs/M 35 (35) 17 (7) 5 weeks 176.5 10.8 28.6 2.1 9.4 LTF LTF
grams

October 29-30,, 2003 34
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

October 29-30,, 2003 35
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)
October 29-30,, 2003 36
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

October 29-30,, 2003 37
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

October 29-30,, 2003 38
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

October 29-30,, 2003 39
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
October 29-30,, 2003 40
Suppression by Age Group
Age Group 3mo-1 yr 2yr-5yr 6yr-8yr 9yr-12yr
n=4 n=16 n=28 n=12
# suppressed 2 6 9 2
% 50 38 32 17
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.
October 29-30,, 2003 41
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
October 29-30,, 2003 42
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

October 29-30,, 2003 43
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%)
October 29-30,, 2003 44
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

7/15 or 47% failed to have an incremental

October 29-30,, 2003 45
n=11 n=21 n=15 n=6
# suppressed 4 6 4 1
% 36 29 27 17

October 29-30,, 2003 46
No statistically significant effect for
Drug usage
% BSA
Weight
Age
Higher proportion of males than
females (p=0.006) who developed
HPA axis suppression
October 29-30,, 2003 47
Recovery of HPA Axis Function
Diprosone Ointment
2/15 patients were retested
100% recovery at 2 weeks

October 29-30,, 2003 48
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

October 29-30,, 2003 49
Diprosone Cream, 0.05%
43 evaluable patients with atopic dermatitis

Age Range - 1 year to 12 years old
35% - 90%)
Medication applied bid for 2-3 weeks

October 29-30,, 2003 50
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
2/10 or 20% had a pre-stimulation cortisol
< 5 g/dL
October 29-30,, 2003 51
HPA Axis Suppression by Age
Age 3mo-1yr 2yr-5yr 6yr-8yr 9yr-12yr
Group n=3 n=20 n=13 n=7
# 0 6 3 1
suppressed
% 0 30 23 14

October 29-30,, 2003 52
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

October 29-30,, 2003 53
Diprosone Cream
1/2 (50%) recovered HPA axis

function at 2 weeks

October 29-30,, 2003 54
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,

October 29-30,, 2003 55
Diprosone Lotion, 0.05%
15 evaluable patients with atopic dermatitis

Age Range - 6 to 12 years old
35% - 72%)
Medication applied bid for 2-3 weeks

October 29-30,, 2003 56
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

October 29-30,, 2003 57
n=0 n=0 n=10 n=5
# suppressed None None 7 4

enrolled enrolled
% - - 70 80

October 29-30,, 2003 58
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

October 29-30,, 2003 59
Diprosone Lotion

4/6 (67%) recovered HPA axis function at
2 weeks

October 29-30,, 2003 60
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:

October 29-30,, 2003 61
Comparison of HPA Axis Criteria
Betamethasone Dipropionate

October 29-30,, 2003 62
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

October 29-30,, 2003 63
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

October 29-30,, 2003 64
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
October 29-30,, 2003 65
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

October 29-30,, 2003 66
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.

October 29-30,, 2003 67
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

October 29-30,, 2003 68
HPA axis suppression
9/14 (64%) of subjects treated with
Clobex Lotion suppressed
2/10 (20%) of subjects treated with
Temovate E Cream suppressed

October 29-30,, 2003 69
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

October 29-30,, 2003 70
1/4 of patients treated with Clobex
Lotion remained suppressed after 2
weeks
1/1 patient retested after treatment with
Temovate E Cream recovered

October 29-30,, 2003 71
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
50 gram/week limit

October 29-30,, 2003 72
HPA Axis Suppression
5 / 9 (56%) of subjects treated with
Clobex Lotion suppressed
4 / 9 (44%) of subjects treated with
Temovate E Cream suppressed

October 29-30,, 2003 73
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

October 29-30,, 2003 74
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
50 gram/week limit

October 29-30,, 2003 75
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

October 29-30,, 2003 76
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

October 29-30,, 2003 77
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

October 29-30,, 2003 78
FDA Experience:
Topical Corticosteroids and HPA Axis
Suppression

October 29-30,, 2003 79

FDA Experience:: Topical Corticosteroids and HPA Axis Suppression

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FDA Experience:

Topical Corticosteroids and HPA Axis

Denise Cook, M.D.

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Lidex (fluocinonide) Gel, 0.05% - Class II

Precaution Section: If extensive areas are

Pediatric Subcommittee of the AIDAC

PRECAUTIONS: General: TEMOVATETM is a

Pediatric Use: Use of TEMOVATETM Cream and

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Use Section

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

1997 - Section 111 of FDAMA

2002 Best Pharmaceuticals for

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Sponsors are offered 6 months of

Pediatric Subcommittee of the AIDAC

Establishes additional mechanisms for

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Approved May 1996

Pediatric Atopic Dermatitis Trial

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Post stimulation serum cortisol >20 g/dL

If pre-stimulation serum cortisol levels > 20

Pediatric Subcommittee of the AIDAC

Approved June 17, 1999

Pediatric Atopic Dermatitis and

Pediatric Subcommittee of the AIDAC

29 patients 3 months to 2 years old

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

Test administered at baseline and

A serum cortisol level >18 g/dL

Pediatric Subcommittee of the AIDAC

Baseline End-Tx Follow-up

Pediatric Subcommittee of the AIDAC

Pediatric Subcommittee of the AIDAC

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

Follow the Cortrosyn label

Failure of any one of 3 criteria would

Stimulation should occur at baseline

Pediatric Subcommittee of the AIDAC

The control plasma cortisol level should

Pediatric Subcommittee of the AIDAC

Mean BSA involvement - 58%

Used study drug bid for 2 - 3 weeks