Topical Corticosteroid Adverse Events in Pediatric Patients Analysis of Postmarketing Reports

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Topical Corticosteroid Adverse Events in
Pediatric PatientsAnalysis 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
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Outline

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

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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)

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Adverse Event Reporting SystemLimitations

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

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Adverse Event Reporting SystemStrengths

• 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

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Topical Corticosteroid Classification

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

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Methods

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

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Leading Adverse Events in Children Following
Topical CS Use (n244)
Based on 2001 review of AERS
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Adrenal Suppression, Cushings Syndrome, and
Growth Retardation

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

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Case Series Characteristics-1
Age (n21) Mean 5.3 yrs median 3 yrs Range 44 days to 15 yrs Mean 5.3 yrs median 3 yrs Range 44 days to 15 yrs
Gender Male-14, female-6, not reported-2 Male-14, female-6, not reported-2
Duration (n17) Mean 21 months, median 6 months Range 22 days to 7 years Seven used for more than 1 year (intermittent use only mentioned in one case) Mean 21 months, median 6 months 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 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
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Case Series Characteristics-2
Outcome Death-2 Disability-1 Hospitalization-10 Medically significant-5 None reported-6
Indication Atopic dermatitis-4 Eczema-3 Diaper rash-6 Alopecia/hair loss-2 Not reported-2 Icthyosis-1 Leiners disease-1 Patches of red skin-1 Psoriasis-1 Scar from laceration-1 Second-degree burn-1
More than one possible
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Case Series Characteristics-3
Site of Application Diaper area-7 Scalp-4 Entire body-2 Inner thigh-1 Neck, pectoral, upper 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 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
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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

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Laboratory Evidence of Adrenal SuppressionSelecte
d Cases-1
Age/ Sex Product Duration Test
4 mo M Hydrocortisone Clobetasol 2 mo Decreased levels of ACTH (5pg/ml nl 10-42), cortisol (1 mcg/dl nl 9-25), and 24-h urinary free cortisol 15mcg/day nl lt90) ACTH test showed no increase in cortisol level
4.5 mo M Clobetasol 2.5 mo Morning evening cortisol low 0.5 mcg/dl (nl 5-18) and 0.8mcg/dl (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
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Laboratory Evidence of Adrenal SuppressionSelecte
d Cases-2
Age Product Duration Test
1 yr M Clobetasol 2 mo Serum cortisol low 0.5 mcg/dl (nl lt13.8) 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 M Betamethasone valerate/ gentamicin ointment 7 yrs Serum cortisol 0.9 mcg/dl (nl 5-15) ACTH 9.6 pg/ml (nl 9-52) Rapid ACTH test cortisol levels were 1.1, 4.3, and 2.8 mcg/dl before and 30 and 60 minutes after ACTH injection
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Laboratory Evidence of Adrenal SuppressionSelecte
d Cases-3
Age Product Duration Test
15 mo M Clobetasol 10 mo Morning evening cortisol was 0.5 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.
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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

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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

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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)

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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

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Acknowledgements

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