# Presentation: 661181

## FDA Experience:

- Topical Corticosteroids and HPA Axis
- Suppression

- Denise Cook, M.D.
- Medical OfficerDivision of Dermatology
- and Dental Drug Products
- FDA

## OUTLINE

**History of Labels**
**Regulations and Legislation**
**Specific Drug Product Data**

## Topical Corticosteroid Classification

**Seven Classes **
- Class I – Superpotent
- Class II  – High Potency
- Classes III, IV, V, VI – Midpotency
- Class VII – Low Potency
**Vasoconstrictor Assay**

## History of Labels

## 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.

## 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.

## 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

## 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.

## Class Labeling for Topical Corticosteroids 1990

- Precautions Section
- Pediatric Use Section

## Precautions Section

## 	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.

## 	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.

## 	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.

## Pediatric Use Section

## 	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.	

## 	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. 

## Regulation and Legislation

## 1994 -  Pediatric Rule

1997 - Section 111 of FDAMA

2002 – Best Pharmaceuticals for 
			Children Act

- 1997 - Section 111 of FDAMA
- 2002 – Best Pharmaceuticals for
- 			Children Act

## 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

- additional safety, pk, and/or dose ranging studies in the targeted
- 	pediatric population

- Pediatric Rule

## 
	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

## 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**

## 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**

## Dermatop (prednicarbate emollient cream), 0.1%
				a Class V steroid

Approved May 1996

Pediatric Atopic Dermatitis Trial

- 				a Class V steroid
- Approved May 1996
- Pediatric Atopic Dermatitis Trial

## 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

- 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

## 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

## 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

## 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."

##  Cutivate (fluticasone) Cream, 0.05%

- a Class V steroid
- Approved June 17, 1999
- Pediatric Atopic Dermatitis and
- Psoriasis Trial

## 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

- 29 patients – 3 months to 2 years old
- 14 patients – 3 years to 5 years old

## 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

## 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**

## 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

## Normal responseCosyntropin Stimulation Test 

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

## 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 |

## 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**

## 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)

## 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

## Criteria - 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/100mL
- 	above the basal level
- The 30-minute level should exceed
- 	18 μg/100mL

## 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**

## 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

## Suppression 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.

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

## 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

## 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

## 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%)

## 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

## Suppression by Age Group

| Age Group | 3mo-1 yr
n=11 | 2yr-5yr
n=21 | 6yr-8yr
n=15 | 9yr-12yr
n=6 |
| --- | --- | --- | --- | --- |
| # suppressed | 4 | 6 | 4 | 1 |
| % | 36 | 29 | 27 | 17 |

## 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

## Recovery of HPA Axis FunctionDiprosone Ointment

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

## 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

## 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

## 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

## HPA Axis Suppression by Age

| Age Group | 3mo-1yr
n=3 | 2yr-5yr
n=20 | 6yr-8yr
n=13 | 9yr-12yr
n=7 |
| --- | --- | --- | --- | --- |
| # suppressed | 0 | 6  | 3  | 1  |
| % | 0 | 30 | 23 | 14 |

## Statistical Analysis in the Development of HPA Axis Suppression

- No statistically significant effect for
-  Number of days treated
-  Weight
-  Age
- Statistical significance found for mean amount of
- 	drug used - 81 grams vs. 37 grams (p<0.001)
- There was a numerically higher %BSA involvement
- Numerically, more males developed suppression

## Recovery of HPA Axis FunctionDiprosone Cream

- 2/10 patients were retested
- 1/2 (50%) recovered HPA axis function at 2 weeks

## 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

## 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

## 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

## Suppression by Age Group

| Age Group | 3mo-1 yr
n=0 | 2yr-5yr
n=0 | 6yr-8yr
n=10 | 9yr-12yr
n=5 |
| --- | --- | --- | --- | --- |
| # suppressed | None enrolled | None enrolled | 7 | 4 |
| % | - | - | 70 | 80 |

## 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**

## Recovery of HPA Axis FunctionDiprosone Lotion

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

## 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**

## Comparison of HPA Axis CriteriaBetamethasone Dipropionate

## 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

## 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**

## 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**

## 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

## 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.

## 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**

## HPA axis suppression

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

## 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**

## Recovery of HPA Axis Function

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

## Adult Study

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

## HPA Axis Suppression

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

## Recovery of HPA Axis Function

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

## Adult Study

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

## 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**

## 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**

## 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**

## FDA Experience:

- Topical Corticosteroids and HPA Axis
- Suppression