Same

1
FDA Experience
Topical Corticosteroids and HPA Axis Suppression
Denise Cook, M.D. Medical OfficerDivision of
Dermatology and Dental Drug Products FDA
2
OUTLINE

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

3
Topical Corticosteroid Classification

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

4
History of Labels
5
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.

6
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.

7
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

8
Two open-label trials with TemovateTM Ointment
(contd)

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

9
Class Labeling for Topical Corticosteroids 1990
Precautions Section Pediatric Use Section
10
Precautions Section
11

• 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.

12

• 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.

13

• 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.

14

• Pediatric Use Section

15

• 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.

16

• 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.

17
Regulation and Legislation
18

• 1994 - Pediatric Rule
• 1997 - Section 111 of FDAMA
• 2002 Best Pharmaceuticals for
• Children Act

19
Pediatric Rule

• allowed for extrapolation of adult efficacy data
  to pediatric patients when appropriate, plus
• additional safety, pk, and/or dose ranging
  studies in the targeted
• pediatric population

20
Section 111 of FDAMA Written Request

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

21
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

22
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

23

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

24

• 59 pediatric patients enrolled
• 2 targeted populations
• - patients between 1 month and 2 years
• - patients between 2 and 12 years
• 10 patients were lt2 years old
• 49 patients were 2 years old

25
Treatment Criteria

• gt20 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 lt 15 kg received 0.125 mg IV

26
Criteria per protocol for a normal adrenal
response to ACTH stimulation at 30 and 60 minutes

• Post stimulation serum cortisol gt20 µg/dL
• If pre-stimulation serum cortisol levels gt 20
  µg/dL, an incremental increase gt6 µg/dL in serum
  cortisol

27
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."
28
Cutivate (fluticasone) Cream, 0.05 a Class V
steroid Approved June 17, 1999 Pediatric Atopic
Dermatitis and Psoriasis Trial
29

• 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

30
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

31
BSA Improvement Over Time(N46)

• 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

32
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

33
Normal responseCosyntropin Stimulation Test
A serum cortisol level gt18 µg/dL at 30 minutes
post-stimulation
34
2 out of 43 patients experienced adrenal
suppression
Serum Cortisol (?g/dL) Serum Cortisol (?g/dL) Serum Cortisol (?g/dL) Serum Cortisol (?g/dL) Serum Cortisol (?g/dL) Serum Cortisol (?g/dL)
Baseline Baseline End-Tx End-Tx Follow-up 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
35
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

36
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)

37
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

38
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

39
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

40
Diprolene AF Cream, 0.05 (contd)

• 19/60 or 32 of these patients showed evidence of
  HPA axis suppression
• 11/19 (58) had a post-stimulation plasma
  cortisol value lt 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
• lt 5 µg/dL

41
Suppression by Age Group
Age Group 3mo-1 yr n4 2yr-5yr n16 6yr-8yr n28 9yr-12yr n12
suppressed 2 6 9 2
50 38 32 17

• Recovery of normal HPA axis function
• 4 patients were retested 2 weeks post- treatment
  and 3 of the 4 recovered normal function of the
  HPA axis.

42
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

43
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

44
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)

45
Diprosone Ointment, 0.05 (contd)

• 15/53 or 28 of patients showed evidence of HPA
  axis suppression
• 8/15 or 53 had a post-stimulation plasma
  cortisol value lt 18 µg/dL
• 7/15 or 47 failed to have an incremental change
  of at least 7 µg/dL

46
Suppression by Age Group
Age Group 3mo-1 yr n11 2yr-5yr n21 6yr-8yr n15 9yr-12yr n6
suppressed 4 6 4 1
36 29 27 17
47
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 (p0.006)
  who developed HPA axis suppression

48
Recovery of HPA Axis FunctionDiprosone Ointment

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

49
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

50
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

51
Diprosone Cream, 0.05 (contd)

• 10/43 or 23 of patients showed evidence of
  adrenal suppression
• 5/10 or 50 had a post-stimulation plasma
  cortisol value lt 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
• lt 5 µg/dL

52
HPA Axis Suppression by Age
Age Group 3mo-1yr n3 2yr-5yr n20 6yr-8yr n13 9yr-12yr n7
suppressed 0 6 3 1
0 30 23 14
53
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 (plt0.001)
• There was a numerically higher BSA involvement
• Numerically, more males developed suppression

54
Recovery of HPA Axis FunctionDiprosone Cream

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

55
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

56
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

57
Diprosone Lotion, 0.05 (contd)

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

58
Suppression by Age Group
Age Group 3mo-1 yr n0 2yr-5yr n0 6yr-8yr n10 9yr-12yr n5
suppressed None enrolled None enrolled 7 4
- - 70 80
59
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

60
Recovery of HPA Axis FunctionDiprosone Lotion

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

61
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

62
Comparison of HPA Axis CriteriaBetamethasone
Dipropionate
63
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

64
Lotrisone Cream (contd)

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

65
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

66
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

67
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.

68
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

69
HPA axis suppression

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

70
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

71
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

72
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

73
HPA Axis Suppression

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

74
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

75
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

76
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

77
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 lt 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

78
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

79
FDA Experience
Topical Corticosteroids and HPA Axis Suppression