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					Topical Corticosteroid Adverse
Events in Pediatric Patients
Analysis of Postmarketing Reports

Pediatric Advisory Subcommittee of the Anti
-Infective Drugs Advisory Committee




         Claudia B. Karwoski, Pharm.D.,
      Safety Evaluator, Office of Drug Safety
                October 29, 2003

      Center for Drug Evaluation and Research
                    Outline

• Background
  – Overview of AERS
    • Limitations
    • Strengths
  – Potency of topical corticosteroids
• Methods
• Results of Cases
• Summary



                                         2
 Adverse Event Reporting System

• Spontaneous, voluntary surveillance
  system
  – Voluntary reporting by health care
    professionals and consumers
  – Mandatory reporting by manufacturers
• Approximately 3 million reports in
  database
• Database origin 1969 (SRS)
• AERS implementation Nov 1997
• Contains human drug and “therapeutic”
  biologic reports
• exception = vaccines (VAERS)


                                           3
Adverse Event Reporting System
          Limitations

• Quality of report is variable and often
• Quality of report is variable and often
  incomplete
  incomplete
• Subject to under-reporting (true numerator
• Subject to under-reporting (true numerator
  not known)
  not known)
• Reporting biases exist
• Reporting biases exist
• Exact denominator (# of exposed patients)
• Exact denominator (# of exposed patients)
  is not known
  is not known
  – spontaneous report numbers cannot be used
  – spontaneous report numbers cannot be used
    to determine incidence of adverse event
    to determine incidence of adverse event
• Duplicate reporting occurs
• Duplicate reporting occurs


                                                4
 Adverse Event Reporting System
           Strengths
• Early detection of events not seen in
  clinical trials (“signal generation”)
• One or more reports can trigger further
  evaluation of a safety signal
• Especially useful for detecting serious,
  rare events
• Case series evaluation: identification of
  AE trends, drug indication, population,
  and other clinically significant emerging
  safety concerns
• Relatively inexpensive compared to
  alternative surveillance strategies


                                              5
       Topical Corticosteroid
           Classification
• Seven Classes
  – Class I – Superpotent
  – Class II – High Potency
  – Classes III, IV, V, VI – Midpotency
  – Class VII – Low Potency

• Vasoconstrictor Assay




                                          6
                 Methods

• AERS Search
  – All reports in children 0 to 16 years
  – Reports of adrenal suppression,
    Cushing’s syndrome, and growth
    retardation in children
• Literature Search
  – Published case reports of adrenal
    suppression, Cushing’s syndrome, and
    growth retardation in children


                                            7
Leading Adverse Events in Children
 Following Topical CS Use (n=244)




                                            8
             Based on 2001 review of AERS
    Adrenal Suppression, Cushing’s
   Syndrome, and Growth Retardation

• 24 total cases found in AERS and the
  published literature
• 2 excluded
• 22 cases evaluated
  – Adrenal suppression/hypofunction-8
  – Cushing’s syndrome-13
  – Growth retardation-10
• Six were published in literature


                                         9
   Case Series Characteristics-1
Age (n=21)      Mean 5.3 yrs; median 3 yrs
                Range 44 days to 15 yrs

Gender          Male-14, female-6, not reported-2

Duration        •Mean 21 months, median 6 months
(n=17)          •Range 22 days to 7 years
                •Seven used for more than 1 year (intermittent
                use only mentioned in one case)

Location        US-10, Foreign-12

Year reported   1980-1, 1982-1, 1990-1,1991-1, 1992-2, 1994-2,
                1995-1, 1996-1, 1997-1, 1998-2, 1999-2, 2000-1,
                2001-2, 2002-3, 2003-1

                                                             10
       Case Series Characteristics-2

*Outcome         Death-2               Medically significant-5
                 Disability-1          None reported-6
                 Hospitalization-10

*Indication      Atopic dermatitis-4   Icthyosis-1
                 Eczema-3              Leiner’s disease-1
                 Diaper rash-6         Patches of red skin-1
                 Alopecia/hair loss-   Psoriasis-1
                 2                     Scar from laceration-1
                 Not reported-2        Second-degree burn-1

*More than one possible


                                                           11
      Case Series Characteristics-3

Site of             Diaper area-7       Inner thigh-1
Application         Scalp-4             Neck, pectoral, upper
                    Entire body-2       arm-1
                                        Not reported-9

*Products           Clobetasol propionate-7
                    Mometasone furoate-7
                    Betamethasone valerate-5
                    Betamethasone dipropionate-3
                    Flurandrenolide tape-2
                    Fluocinonide-1
                    Triamicinolone-1
                    Hydrocortisone-1

*More than one product use in 4 cases

                                                                12
          Clinical Findings

• Presented with:
  – Weight gain or other Cushingoid
    features-12
  – Growth retardation-10
  – Acute adrenal insufficiency-1
  – Skin striae and depigmentation-1
  – Unknown-1




                                       13
Laboratory Evidence of Adrenal Suppression
                        Selected Cases-1
Age/   Product           Duration   Test
Sex
4 mo   Hydrocortisone    2 mo       •Decreased levels of ACTH
M      Clobetasol                   (5pg/ml; nl 10-42), cortisol (1
                                    mcg/dl; nl 9-25), and 24-h urinary
                                    free cortisol 15mcg/day; nl <90)
                                    •ACTH test showed no increase in
                                    cortisol level
4.5    Clobetasol        2.5 mo     •Morning & evening cortisol low:
mo                                  0.5 mcg/dl (nl 5-18) and 0.8mcg/dl
M                                   (nl 2-13), respectively
                                    •ACTH stimulation test at 2 months
                                    showed continued suppression:
                                    cortisol levels were 5.4, 4.3, and
                                    2.8 mcg/dl before and 30 and 60
                                    minutes after IV ACTH 150mcg
                                                                14
Laboratory Evidence of Adrenal Suppression
                        Selected Cases-2

Age     Product         Duration   Test

1 yr M Clobetasol       2 mo       •Serum cortisol low: 0.5 mcg/dl (nl
                                   <13.8)
                                   •Recovery after 2 months by ACTH
                                   stimulation test: cortisol levels
                                   were 2.8, 20, and 23 mcg/dl before
                                   and 30 and 60 minutes after ACTH
                                   injection
11 yr   Betamethasone   7 yrs      •Serum cortisol 0.9 mcg/dl (nl 5-15)
M       valerate/                  •ACTH 9.6 pg/ml (nl 9-52)
        gentamicin                 •Rapid ACTH test: cortisol levels
        ointment                   were 1.1, 4.3, and 2.8 mcg/dl before
                                   and 30 and 60 minutes after ACTH
                                   injection

                                                                15
Laboratory Evidence of Adrenal Suppression
                   Selected Cases-3

Age   Product      Duration   Test

15 mo Clobetasol   10 mo      •Morning & evening cortisol was 0.5
M                             and 0.47mcg/dl, respectively.
                              •Following dc of topical steroid,
                              morning cortisol rose to 2.9 mcg/dl
                              after 12 days and 14.2 mcg/dl after
                              17 days.
                              •A synacthen test was performed 3
                              weeks later and morning cortisol
                              was 6.4, rising to 28 and 18.1
                              mcg/dl at 30 and 60 minutes after
                              250mcg synacthen IM.




                                                          16
    Factors Affecting Absorption-1

• Size of area
  – Two reported use on entire body
  – Three reported use in more than one location
• Duration of treatment
  – 3 months or longer in 11
  – More than one year in 7
• Use of occlusive dressing
  – Probable occlusion by diaper in 7




                                                   17
   Factors Affecting Absorption-2
• Small children higher ratio of skin surface
  to weight
  – 5 cases involved infants
• Thickness of stratum corneum and vascular
  supply of area
  – diaper area in 7 cases
  – 1 case of application to second degree burns




                                                   18
             Other Factors

• 15 reported use of “superpotent” or
  “potent” topical corticosteroid products
• Use of more than one topical
  corticosteroid product (4 cases)
• Use without medical supervision (4 cases)
• Concomitant or prior use of systemic
  corticosteroid products (2 cases)




                                          19
                Summary

• Small number of postmarketing cases
  – Due to underreporting associated with
    spontaneous reporting systems
  – Lack of clinical suspicion
    • Failure to recognize that topical
      corticosteroids may be systemically absorbed
    • Assumption that adrenal suppression is an
      unusual complication of topical corticosteroid
      therapy; therefore routine testing not done
    • Signs and symptoms may be subtle and non-
      specific; therefore, attribution made to other
      causes

                                                 20
        Acknowledgements
Joyce Weaver, Pharm. D., Safety Evaluator,
  DDRE, Office of Drug Safety

Marilyn R. Pitts, Pharm.D., Safety Evaluator,
 DDRE, Office of Drug Safety




                                                21

				
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