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 Topical Corticosteroids and HPA Axis and HPA Axis Suppression Suppression Denise Cook, M.D. Medical Officer Division of Dermatology and Dental Drug Products FDA

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Page 1: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 2: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 3: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 4: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

4Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003

History of LabelsHistory of Labels

Page 5: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 6: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 7: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 8: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 9: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 10: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

10Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003

Precautions Section

Page 11: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 12: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 13: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 14: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

14Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003

Pediatric Use SectionPediatric Use Section

Page 15: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 16: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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.

Page 17: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

17Pediatric Subcommittee of the AIDAC of the AIDAC October October 29-30, 2003, 2003

Regulation and LegislationRegulation and Legislation

Page 18: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 19: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 20: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 21: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 22: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 23: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 24: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 25: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 26: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 27: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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."

Page 28: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 29: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 30: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 31: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 32: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 33: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 34: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 35: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 36: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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)

Page 37: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 38: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 39: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 40: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 41: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 42: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 43: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 44: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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%)

Page 45: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 46: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 47: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 48: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 49: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 50: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 51: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

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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

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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

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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

Page 55: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

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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

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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

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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

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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

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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

Page 61: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

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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%)

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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

Page 64: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 65: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

Page 66: FDA Experience Topical Corticosteroids and Hpa Axis Suppression 4045

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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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