1. 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 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

2. 2 OutlineOutline Background –Overview of AERS Limitations Strengths –Potency of topical corticosteroids Methods Results of Cases Summary Background –Overview of AERS Limitations Strengths –Potency of topical corticosteroids Methods Results of Cases Summary

3. 3 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) 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)

4. 4 Adverse Event Reporting System Limitations 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 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

5. 5 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 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

6. 6 Topical Corticosteroid Classification Seven Classes –Class I – Superpotent –Class II – High Potency –Classes III, IV, V, VI – Midpotency –Class VII – Low Potency Vasoconstrictor Assay

7. 7 MethodsMethods 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 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

8. 8 Leading Adverse Events in Children Following Topical CS Use (n=244) Based on 2001 review of AERS

9. 9 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 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

10. 10 Case Series Characteristics-1 Age (n=21)Mean 5.3 yrs; median 3 yrs Range 44 days to 15 yrs GenderMale-14, female-6, not reported-2 Duration (n=17) 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) LocationUS-10, Foreign-12 Year reported1980-1, 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

11. 11 Case Series Characteristics-2 *OutcomeDeath-2 Disability-1 Hospitalization-10 Medically significant-5 None reported-6 *IndicationAtopic dermatitis-4 Eczema-3 Diaper rash-6 Alopecia/hair loss- 2 Not reported-2 Icthyosis-1 Leiner’s disease-1 Patches of red skin-1 Psoriasis-1 Scar from laceration-1 Second-degree burn-1 *More than one possible

12. 12 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 *ProductsClobetasol 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

13. 13 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 Presented with: –Weight gain or other Cushingoid features-12 –Growth retardation-10 –Acute adrenal insufficiency-1 –Skin striae and depigmentation-1 –Unknown-1

14. 14 Laboratory Evidence of Adrenal Suppression Selected Cases-1 Age/ Sex ProductDurationTest 4 mo M Hydrocortisone Clobetasol 2 moDecreased levels of ACTH (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 mo M Clobetasol2.5 moMorning & 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

15. 15 Laboratory Evidence of Adrenal Suppression Selected Cases-2 AgeProductDurationTest 1 yr MClobetasol2 moSerum 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 M Betamethasone valerate/ gentamicin ointment 7 yrsSerum 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

16. 16 Laboratory Evidence of Adrenal Suppression Selected Cases-3 AgeProductDurationTest 15 mo M Clobetasol10 moMorning & 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.

17. 17 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 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

18. 18 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 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

19. 19 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) 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)

20. 20 SummarySummary 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 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

21. 21 Acknowledgements Joyce Weaver, Pharm. D., Safety Evaluator, DDRE, Office of Drug Safety Marilyn R. Pitts, Pharm.D., Safety Evaluator, DDRE, Office of Drug Safety Joyce Weaver, Pharm. D., Safety Evaluator, DDRE, Office of Drug Safety Marilyn R. Pitts, Pharm.D., Safety Evaluator, DDRE, Office of Drug Safety