fda experience topical corticosteroids and hpa axis suppression 4045
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Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
FDA Experience:Topical Corticosteroids and HPA AxisTopical Corticosteroids and HPA Axis
SuppressionSuppression
Denise Cook, M.D.Medical Officer
Division of Dermatologyand Dental Drug Products
FDA
2Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
OUTLINEOUTLINE
• History of Labels• Regulations and Legislation• Specific Drug Product Data
• History of Labels• Regulations and Legislation• Specific Drug Product Data
3Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Topical Corticosteroid ClassificationTopical Corticosteroid Classification
• Seven Classes – Class I – Superpotent– Class II – High Potency– Classes III, IV, V, VI – Midpotency– Class VII – Low Potency
• Vasoconstrictor Assay
• Seven Classes – Class I – Superpotent– Class II – High Potency– Classes III, IV, V, VI – Midpotency– Class VII – Low Potency
• Vasoconstrictor Assay
4Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
History of LabelsHistory of Labels
5Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
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.
6Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Labels - 1980'sLabels - 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.
• 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.
7Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Two open-label trials withTemovateTM Ointment:
Two open-label trials withTemovateTM 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
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
8Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Two open-label trials with TemovateTM Ointment (cont’d):
Two open-label trials with TemovateTM Ointment (cont’d):
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.
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.
9Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Class Labeling for Topical Corticosteroids 1990
Precautions Section
Pediatric Use Section
10Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Precautions Section
11Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
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.
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.
12Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
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.
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.
13Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
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.
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.
14Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Pediatric Use SectionPediatric Use Section
15Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
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.
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.
16Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
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.
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.
17Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Regulation and LegislationRegulation and Legislation
18Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
1994 - Pediatric Rule
1997 - Section 111 of FDAMA
2002 – Best Pharmaceuticals for Children Act
1994 - Pediatric Rule
1997 - Section 111 of FDAMA
2002 – Best Pharmaceuticals for Children Act
19Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
• allowed for extrapolation of adult efficacy data to pediatric patients when appropriate, plus
• additional safety, pk, and/or dose ranging studies in the targetedpediatric population
• allowed for extrapolation of adult efficacy data to pediatric patients when appropriate, plus
• additional safety, pk, and/or dose ranging studies in the targetedpediatric population
Pediatric Rule
20Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Sponsors are offered 6 months of exclusivity for their chemical moiety if they fairly respond to the Agency’s request for pediatric studies.
Sponsors are offered 6 months of exclusivity for their chemical moiety if they fairly respond to the Agency’s request for pediatric studies.
Section 111 of FDAMA Written Request
21Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Best Pharmaceuticals for Children ActBest Pharmaceuticals for Children Act
• Establishes additional mechanisms for the study of both on-patent and off-patent drugs
• Pediatric Supplements are now Priority Reviews
• Establishes additional mechanisms for the study of both on-patent and off-patent drugs
• Pediatric Supplements are now Priority Reviews
22Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Specific Drug Product DataSpecific 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
• 10 drug products– 8 topical corticosteroid products– 2 combination drug products
• 11 studies• Ages 3 months – adult• Open-label trials• Cosyntropin stimulation test
23Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Dermatop (prednicarbate emollient cream), 0.1%a Class V steroid
Approved May 1996
Pediatric Atopic Dermatitis Trial
Dermatop (prednicarbate emollient cream), 0.1%a Class V steroid
Approved May 1996
Pediatric Atopic Dermatitis Trial
24Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
• 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
• 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
25Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Treatment CriteriaTreatment 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
• >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
26Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Criteria per protocol for a normal adrenal response to ACTH stimulation at 30 and 60 minutes:
Criteria per protocol for a normal adrenal response to ACTH stimulation at 30 and 60 minutes:
• Post stimulation serum cortisol >20 µg/dL
• If pre-stimulation serum cortisol levels > 20 µg/dL, an incremental increase >6 µg/dL in serum cortisol
• Post stimulation serum cortisol >20 µg/dL
• If pre-stimulation serum cortisol levels > 20 µg/dL, an incremental increase >6 µg/dL in serum cortisol
27Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Three patients according to the protocol criteria were suppressed:
2 patients, 1 an 18 month old, had a peak response of 5 µg/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 µg/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."
28Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Cutivate (fluticasone) Cream, 0.05%a Class V steroid
Approved June 17, 1999
Pediatric Atopic Dermatitis andPsoriasis Trial
29Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
• 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
• 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
30Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Treatment CriteriaTreatment Criteria
• At least 35% BSA involvement
• Bid application for 3 - 4 weeks
• Patients up to 2 years limited to120 grams/week
• Patients 3-5 years of age limitedto 180 grams/week
• At least 35% BSA involvement
• Bid application for 3 - 4 weeks
• Patients up to 2 years limited to120 grams/week
• Patients 3-5 years of age limitedto 180 grams/week
31Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
BSA Improvement Over Time(N=46)
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
• 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
32Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Cosyntropin Stimulation TestCosyntropin Stimulation Test
• Test administered at baseline andend of treatment
• Younger age group given 0.125 mg cosyntropin IV
• Older age group given 0.25 mg cosyntropin IV
• Test administered at baseline andend of treatment
• Younger age group given 0.125 mg cosyntropin IV
• Older age group given 0.25 mg cosyntropin IV
33Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Normal responseCosyntropin Stimulation Test
Normal responseCosyntropin Stimulation Test
A serum cortisol level >18 µg/dLat 30 minutes post-stimulation
34Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
2 out of 43 patients experienced adrenal suppression
2 out of 43 patients experienced adrenal suppression
Serum Cortisol (g/dL)
Baseline End-Tx Follow-up
Subject Age/Sex %BSA Severity Duration Amt. Used
Pre-stim
Post-stim
Pre-stim
Post-stim
Pre-stim
Post-stim
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
35Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label Change for Cutivate CreamLabel 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
• 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
36Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Betamethasone Propionate - Approved in 2001Betamethasone 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)
• 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)
37Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Criteria for a Normal HPA Axis ResponseCriteria 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
• 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
38Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Criteria - 30 minute post-stimulationCriteria - 30 minute post-stimulation
• The control plasma cortisol level should exceed 5 µg/100 mL
• The 30-minute level should show an increment of at least 7 µg/100mLabove the basal level
• The 30-minute level should exceed18 µg/100mL
• The control plasma cortisol level should exceed 5 µg/100 mL
• The 30-minute level should show an increment of at least 7 µg/100mLabove the basal level
• The 30-minute level should exceed18 µg/100mL
39Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprolene AF Cream, 0.05%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
• 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
40Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprolene AF Cream, 0.05% (cont’d)Diprolene AF Cream, 0.05% (cont’d)
• 19/60 or 32% of these patients showed evidence of HPA axis suppression
• 11/19 (58%) had a post-stimulation plasma cortisol value < 18 µg/dL
• 6/19 (32%) failed to have an incremental change of at least 7 µg/dL
• 2/19 (11%) had a pre-stimulation cortisol< 5 µg/dL
• 19/60 or 32% of these patients showed evidence of HPA axis suppression
• 11/19 (58%) had a post-stimulation plasma cortisol value < 18 µg/dL
• 6/19 (32%) failed to have an incremental change of at least 7 µg/dL
• 2/19 (11%) had a pre-stimulation cortisol< 5 µg/dL
41Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Suppression by Age GroupSuppression by Age Group
• 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.
• 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.
Age Group 3mo-1 yrn=4
2yr-5yrn=16
6yr-8yrn=28
9yr-12yrn=12
# suppressed 2 6 9 2
% 50 38 32 17
42Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Statistical Analysis in the Development of HPA Axis Suppression
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
• 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
43Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label Change for Diprolene AF Cream, 0.05%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
• Indication - added an age restriction of 13 years and older
• Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections
44Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprosone Ointment, 0.05%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%)
• 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%)
45Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprosone Ointment, 0.05% (cont’d)Diprosone Ointment, 0.05% (cont’d)
• 15/53 or 28% of patients showed evidence of HPA axis suppression
• 8/15 or 53% had a post-stimulation plasma cortisol value < 18 µg/dL
• 7/15 or 47% failed to have an incremental change of at least 7 µg/dL
• 15/53 or 28% of patients showed evidence of HPA axis suppression
• 8/15 or 53% had a post-stimulation plasma cortisol value < 18 µg/dL
• 7/15 or 47% failed to have an incremental change of at least 7 µg/dL
46Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Suppression by Age GroupSuppression by Age Group
Age Group 3mo-1 yrn=11
2yr-5yrn=21
6yr-8yrn=15
9yr-12yrn=6
# suppressed 4 6 4 1
% 36 29 27 17
47Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Statistical Analysis in the Development of HPA Axis Suppression
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
• No statistically significant effect for
– Drug usage– % BSA– Weight– Age
• Higher proportion of males than females (p=0.006) who developed HPA axis suppression
48Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Recovery of HPA Axis FunctionDiprosone Ointment
Recovery of HPA Axis FunctionDiprosone Ointment
• 2/15 patients were retested
• 100% recovery at 2 weeks
• 2/15 patients were retested
• 100% recovery at 2 weeks
49Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label Change Diprosone Ointment, 0.05%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
• Indication - added an age restriction of 13 years and older
• Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections
50Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprosone Cream, 0.05%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
• 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
51Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprosone Cream, 0.05% (cont’d)Diprosone Cream, 0.05% (cont’d)• 10/43 or 23% of patients showed evidence
of adrenal suppression
• 5/10 or 50% had a post-stimulation plasma cortisol value < 18 µg/dL
• 3/10 or 30% failed to have an incremental change of at least 7 µg/dL
• 2/10 or 20% had a pre-stimulation cortisol< 5 µg/dL
• 10/43 or 23% of patients showed evidence of adrenal suppression
• 5/10 or 50% had a post-stimulation plasma cortisol value < 18 µg/dL
• 3/10 or 30% failed to have an incremental change of at least 7 µg/dL
• 2/10 or 20% had a pre-stimulation cortisol< 5 µg/dL
52Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
HPA Axis Suppression by AgeHPA Axis Suppression by Age
Age Group
3mo-1yrn=3
2yr-5yrn=20
6yr-8yrn=13
9yr-12yrn=7
# suppressed
0 6 3 1
% 0 30 23 14
53Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Statistical Analysis in the Development of HPA Axis Suppression
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 ofdrug used - 81 grams vs. 37 grams (p<0.001)
• There was a numerically higher %BSA involvement
• Numerically, more males developed suppression
• No statistically significant effect for
– Number of days treated– Weight– Age
• Statistical significance found for mean amount ofdrug used - 81 grams vs. 37 grams (p<0.001)
• There was a numerically higher %BSA involvement
• Numerically, more males developed suppression
54Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Recovery of HPA Axis FunctionDiprosone Cream
Recovery of HPA Axis FunctionDiprosone Cream
• 2/10 patients were retested
• 1/2 (50%) recovered HPA axis function at 2 weeks
• 2/10 patients were retested
• 1/2 (50%) recovered HPA axis function at 2 weeks
55Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label Change Diprosone Cream, 0.05%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
• Indication - added an age restriction of 13 years and older
• Clinical Safety Information - Updated in the Clinical Pharmacology, Precautions, General and Pediatric Use Sections
56Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprosone Lotion, 0.05%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
• 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
57Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Diprosone Lotion, 0.05% (cont’d)Diprosone Lotion, 0.05% (cont’d)
• 11/15 or 73% of patients showed evidence of HPA axis suppression
• 10/11 or 91% had a post-stimulation plasma cortisol value < 18 µg/dL
• 1/11 or 9% failed to have an incremental change of at least 7 µg/dL
• 11/15 or 73% of patients showed evidence of HPA axis suppression
• 10/11 or 91% had a post-stimulation plasma cortisol value < 18 µg/dL
• 1/11 or 9% failed to have an incremental change of at least 7 µg/dL
58Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Suppression by Age GroupSuppression by Age Group
Age Group 3mo-1 yrn=0
2yr-5yrn=0
6yr-8yrn=10
9yr-12yrn=5
# suppressed None enrolled
None enrolled
7 4
% - - 70 80
59Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Statistical Analysis in the Development of HPA Axis Suppression
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
• 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
60Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Recovery of HPA Axis FunctionDiprosone Lotion
Recovery of HPA Axis FunctionDiprosone Lotion
• 6/11 patients were retested• 4/6 (67%) recovered HPA axis function
at 2 weeks
• 6/11 patients were retested• 4/6 (67%) recovered HPA axis function
at 2 weeks
61Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label Change Diprosone Lotion, 0.05%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
• Indication – added an age restriction of 13 years and older
• Clinical Safety Information – Updated in the Clinical Pharmacology, Precautions: General and Pediatric Use Sections
62Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Comparison of HPA Axis CriteriaBetamethasone Dipropionate
Comparison of HPA Axis CriteriaBetamethasone Dipropionate
HPA Axis Suppression Criteria - serum cortisol levels Drug Product 5 µg/dL ; >18 µg/dL; ≥7 µg/dL > 18 µg/dL
Diprolene AF Cream 19/60 (32%) 11/60 (18%)
Diprosone Ointment 15/53 (28%) 8/53 (15%)
Diprosone Cream 10/43 (23%) 5/43 (12%)
Diprosone Lotion 11/15 (73%) 10/15 (67%)
63Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Lotrisone CreamLotrisone 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
• 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
64Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Lotrisone Cream (cont’d)Lotrisone Cream (cont’d)
• 17/43 (39.5%) demonstrated adrenal suppression in the tinea pedis study
• 8/17 (47.1%) demonstrated adrenal suppression in the tinea cruris study
• 17/43 (39.5%) demonstrated adrenal suppression in the tinea pedis study
• 8/17 (47.1%) demonstrated adrenal suppression in the tinea cruris study
65Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label ChangeLotrisone Cream and Lotion
Label ChangeLotrisone 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
• 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
66Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Clobetasol Propionate- Clobex Lotion and Temovate E Cream
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
• 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
67Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Construct of HPA Axis EvaluationConstruct 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.
• 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.
68Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Adolescent studyAdolescent 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
• 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
69Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
HPA axis suppressionHPA axis suppression
• 9/14 (64%) of subjects treated with Clobex Lotion suppressed
• 2/10 (20%) of subjects treated with Temovate E Cream suppressed
• 9/14 (64%) of subjects treated with Clobex Lotion suppressed
• 2/10 (20%) of subjects treated with Temovate E Cream suppressed
70Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Statistical AnalysisStatistical 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
• 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
71Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Recovery of HPA Axis FunctionRecovery 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
• 1/4 of patients treated with Clobex Lotion remained suppressed after 2 weeks
• 1/1 patient retested after treatment with Temovate E Cream recovered
72Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Adult StudyAdult 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
• 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
73Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
HPA Axis SuppressionHPA Axis Suppression
• 5 / 9 (56%) of subjects treated with Clobex Lotion suppressed
• 4 / 9 (44%) of subjects treated with Temovate E Cream suppressed
• 5 / 9 (56%) of subjects treated with Clobex Lotion suppressed
• 4 / 9 (44%) of subjects treated with Temovate E Cream suppressed
74Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Recovery of HPA Axis FunctionRecovery 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
• 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
75Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Adult StudyAdult 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
• 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
76Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
HPA Axis FunctionHPA 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
• 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
77Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
Label for Clobex LotionLabel 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
• 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
78Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
SummarySummary
• 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
• 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
79Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003
FDA Experience:Topical Corticosteroids and HPA AxisTopical Corticosteroids and HPA Axis
SuppressionSuppression
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