+-----------------+----------------------------------------------------+
| MEMORANDUM      | DEPARTMENT OF HEALTH AND HUMAN SERVICES            |
|                 |                                                    |
|                 | PUBLIC HEALTH SERVICE                              |
|                 |                                                    |
|                 | FOOD AND DRUG ADMINISTRATION                       |
|                 |                                                    |
|                 | CENTER FOR DRUG EVALUATION AND RESEARCH            |
+-----------------+----------------------------------------------------+

DATE: July 9, 2001

FROM: Joyce Weaver, Pharm.D., Safety Evaluator

Division of Drug Risk Evaluation I, HFD-430

THROUGH: Julie Beitz, M.D., Director

Division of Drug Risk Evaluation I, HFD-430

TO: Jonathan Wilkin, M.D., Director

> Division of Dermatologic and Dental Drug Products, HFD-540

SUBJECT: Postmarketing Safety Review---PID D010141

Drugs: Topical Corticosteroids

+------------------------------------+---------------------------------+
| Alclometasone dipropionate         | Flurandrenolide                 |
|                                    |                                 |
| Amcinonide                         | Fluticasone propionate          |
|                                    |                                 |
| Betamethasone dipropionate         | Halcinonide                     |
|                                    |                                 |
| Betamethasone valerate             | Halobetasol propionate          |
|                                    |                                 |
| Clobetasol propionate              | Hydrocortisone                  |
|                                    |                                 |
| Clocortolone pivalate              | Hydrocortisone butyrate         |
|                                    |                                 |
| Desonide                           | Hydrocortisone probutate        |
|                                    |                                 |
| Desoximetasone                     | Hydrocortisone valerate         |
|                                    |                                 |
| Dexamethasone                      | Methylprednisolone acetate      |
|                                    |                                 |
| Diflorasone diacetate              | Mometasone furoate monohydrate  |
|                                    |                                 |
| Fluocinolone acetonide             | Prednicarbate                   |
|                                    |                                 |
| Fluocinonide                       | Triamcinolone acetonide         |
+------------------------------------+---------------------------------+

## Reaction: Summary of Adverse Events in Pediatric Patients

INTRODUCTION/ EXECUTIVE SUMMARY

We reviewed 202 AERS adverse event reports for the topical
corticosteroids reported for pediatric patients age 0 to 18 years of
age. Local irritation and application site reactions were the most
frequently reported events in pediatric patients. Numerous systemic
adverse events were reported, including striae, Cushing's syndrome,
growth retardation, hyperglycemia, hirsutism, glaucoma, and adrenal
insufficiency. Some cases resulted in serious outcomes, including
hospitalization and death. Long-term application of topical
corticosteroids in high-risk settings (for example, application to the
genital and groin area in very young patients) resulted in numerous
adverse events. In some cases topical corticosteroids were continued
despite the failure of the dermatoses to improve.

We recommend that the systemic adverse events in the AERS database be
included in the labeling for these products. Additionally, we recommend
information be included on the appropriate duration of use of the
products, including the appropriate duration of use for dermatoses that
prove to be unresponsive to topical corticosteroids.

DRUG INFORMATION/LABELING

The topical corticosteroids are indicated for the relief of inflammatory
and pruritic manifestations of corticosteroid-responsive dermatoses.
Clotrimazole and betamethasone dipropionate cream and lotion are
indicated for the topical treatment of symptomatic inflammatory tinea
pedis, tinea cruris and tinea corporis due to *Epidermophyton floccosum,
Trichophyton metagrophytes,* and *Trichophyton rubrum*. Neomycin and
polymixin B sufates, bacitracin zinc and hydrocortisone cream and
ointment are indicated for the treatment of corticosteroid-responsive
dermatoses with secondary infection.

Many of the topical corticosteroid products are not labeled for use in
pediatric patients. Alclometasone dipropionate cream and ointment and
prednicarbate emollient cream are approved for use in children 1 year of
age and older. Mometasone furoate monohydrate cream and ointment are
approved for use in children 2 years of age and older. Fluocinolone
acetonide topical oil is approved for pediatric patients 6 years of age
and older for up to 4 weeks to treat atopic dermatitis. Fluticasone
propionate cream is approved for pediatric patients 3 months of age and
older for up to 4 weeks. Some products (betamethasone dipropionate
ointment, betamethasone dipropionate cream, betamethasone dipropionate
gel, betamethasone dipropionate lotion, betamethasone dipropionate and
clotrimazole cream and betamethasone dipropionate and clotrimazole
lotion, betamethasone dipropionate and clotrimazole cream, betamethasone
dipropionate and clotrimazole lotion, clobetasol propionate cream,
clobetasol propionate ointment, clobetasol propionate solution,
clobetasol propionate gel, and clobetasol propionate foam) are approved
in pediatric patients 12 years of age and older.

All of the products include general information regarding the potential
for systemic corticosteroid effects in pediatric patients in the
*Warnings*, *Precautions*, or *Adverse Reactions* sections of the
labeling.

Attachment 1 contains a listing of the topical corticosteroids by
generic name, tradename, NDA number, and approval date.

MEDICAL LITERATURE SUMMARY

There are published reports of systemic adverse events from the topical
use of corticosteroids in pediatric patients.
Hypothalamic-pituitary-adrenal (HPA) axis suppression has been observed
in infants and children with both high potency and low potency topical
corticosteroids.^1,2,3^

Shaffer et al used data from the National Ambulatory Medical Care Survey
to determine the demographic characteristics and diagnoses of patients
who were prescribed betamethasone dipropionate and clotrimazole cream by
family physicians. The study found that family physicians frequently
prescribed betamethasone dipropionate and clotrimazole to children
younger than 5 years of age and for use on genital skin disorders.^4^

SELECTION OF CASE SERIES

We searched AERS on May 16, 2001 for adverse event reports for topical
corticosteroids in patients age 0 to 18 years of age. We retrieved 234
unique reports from AERS. Thirty-two reports were excluded because the
patient had not used topical corticosteroids prior to experiencing the
adverse event, the topical corticosteroid used was ophthalmic or otic,
the report described a congenital anomaly in a neonate born to an adult
woman who had used topical corticosteroids during pregnancy, the report
described obvious misuse of a topical corticosteroid (e.g., a 3-year-old
child using Lotrisone cream as toothpaste), or a legible copy of the
report was not available. We included the 202 remaining reports in this
review.

SUMMARY OF CASES

The characteristics of the 202 cases in the series are presented below.

+-----------------+----------------------------------------------------+
| Age:            | Mean 7.7 yrs, median 7 yrs (range, 8 days to 18    |
|                 | years)                                             |
| (n=199)         |                                                    |
+-----------------+----------------------------------------------------+
| Gender:         | #                                                  |
|                 |                                                    |
|                 | # Male-78, female-111, not specified-13            |
+-----------------+----------------------------------------------------+
| Time to onset:  | Mean 169.3 days, median 30 days (range, 1 day to 7 |
|                 | years)                                             |
| (n=147)         |                                                    |
+-----------------+----------------------------------------------------+
| Location:       | #                                                  |
|                 |                                                    |
|                 | # US-184, non-US-14, unk-4                         |
+-----------------+----------------------------------------------------+

# 

+------------------+------------+-----------+-----------+-------------+
| Report year:     | 1970-2     | 1980-3    | 1990-26   | 2000-3      |
|                  |            |           |           |             |
|                  | 1971-5     | 1982-1    | 1991-4    | 2001-1      |
|                  |            |           |           |             |
|                  | 1973-1     | 1983-6    | 1992-16   |             |
|                  |            |           |           |             |
|                  | 1975-3     | 1984-5    | 1993-15   |             |
|                  |            |           |           |             |
|                  | 1976-1     | 1985-8    | 1994-12   |             |
|                  |            |           |           |             |
|                  | 1977-2     | 1986-6    | 1995-18   |             |
|                  |            |           |           |             |
|                  | 1978-1     | 1987-14   | 1996-10   |             |
|                  |            |           |           |             |
|                  | 1979-1     | 1988-11   | 1997-13   |             |
|                  |            |           |           |             |
|                  |            | 1989-5    | 1998-6    |             |
|                  |            |           |           |             |
|                  |            |           | 1999-3    |             |
+------------------+------------+-----------+-----------+-------------+

Event: Local irritation, application site reaction-66

> Lack of effect-32
>
> Skin depigmentation or discoloration-30
>
> Striae or skin atrophy-30
>
> Cushing's syndrome-6
>
> Growth retardation-5
>
> Hyperglycemia, diabetes-5
>
> Scarring or disfigurement-5

Staphylococcal infection (new or worsened), folliculitis, furunculosis,
staph scalded skin syndrome-5

> Genital hypertrichosis-4
>
> Hirsutism-4
>
> Rosacea-4
>
> Acne-3
>
> Glaucoma-3
>
> Immediate hypersensitivity-3

Adrenal insufficiency-2

Bruising-2

Fungal infection-2

Gynecomastia-2

Lesions, unspecified-2

Immunodeficiency and PCP-2

Mental status or mood change-2

Perioral dermatitis-2

Seizure-2

> Others (1 case each):

alopecia, amenorrhea, asthenia, asthma exacerbation, deafness, delayed
puberty, dizziness, dyspepsia, granulomatous lesion, hypertonia,
idiopathic thrombocytopenic purpura, myasthenia, obesity, perforated
duodenal ulcer, pseudotumor cerebri, shortness of breath, skin cancer,
underdeveloped breasts, underdeveloped penis, urinary tract infection,
vaginal bleeding

(more than 1 event per case possible)

Indication: Eczema-36

Tinea-24

Diaper rash-21

Unspecified rash-19

Atopic dermatitis-12

Psoriasis-12

Dermatitis-9

Unspecified fungal infection-6

Poison ivy-5

Alopecia-4

Seborrhea-4

Others (reported in fewer than 4 cases)-

> Abrasions, acne, allergic contact dermatitis, anal fissure, chemical
> burn, dry red scale, eosinophilia pustular folliculitis, erythema,
> granuloma annulare, heat rash, hypertrophic scars, icthyosis,
> inflammation of finger, insect bite, keloids, keratosis pilaris,
> Leiner's disease, mastocytosis, mosquito bite, necrobiasis lipoidica
> dibeticorum, patches of red skin, red scaly plaque, saliva rash,
> scabies pruritus, staph infection, scar from laceration, vitiligo

(indication for use of topical steroid not stated in 21 cases)

+----------------------------------+-----------------------------------+
| Drugs and dosage forms           |                                   |
| implicated                       |                                   |
|                                  |                                   |
| More than one product was        |                                   |
| implicated in some cases; the    |                                   |
| strength of the product used was |                                   |
| not reported in most cases.      |                                   |
+----------------------------------+-----------------------------------+
| Alclometasone dipropionate       | Diflorasone diacetate             |
|                                  | ointment---2                      |
| > cream---5                      |                                   |
| >                                | Fluocinolone acetonide            |
| > ointment---1                   |                                   |
| >                                | > cream---8                       |
| > dosage form not stated---1     | >                                 |
|                                  | > solution---1                    |
| ## Amcinonide                    | >                                 |
|                                  | > dosage form not stated---2      |
| > cream---3                      |                                   |
| >                                | Fluocinonide                      |
| > dosage form not stated---2     |                                   |
|                                  | > cream---3                       |
| Betamethasone dipropionate       | >                                 |
|                                  | > ointment---1                    |
| > cream---6                      |                                   |
| >                                | Flurandrenolide                   |
| > cream, augmented---7           |                                   |
| >                                | > cream---1                       |
| > gel---1                        | >                                 |
| >                                | > tape---2                        |
| > lotion---1                     |                                   |
| >                                | Fluticasone propionate            |
| > ointment---5                   |                                   |
|                                  | > cream---4                       |
| Betamethasone and neomycin       | >                                 |
| cream---1                        | > ointment---1                    |
|                                  |                                   |
| Betamethasone valerate           | ###### Halcinonide cream---2      |
|                                  |                                   |
| > cream---2                      | Halobetasol propionate cream---1  |
| >                                |                                   |
| > ointment---1                   | Hydrocortisone                    |
|                                  |                                   |
| Betamethasone valerate and       | > cream---5                       |
| gentamicin                       | >                                 |
|                                  | > lotion---1                      |
| > ointment---3                   | >                                 |
|                                  | > ointment---2                    |
| Betamethasone dipropionate and   |                                   |
| clotrimazole cream---52          | Hydrocortisone valerate           |
|                                  |                                   |
| Clobetasol propionate            | > cream---11                      |
|                                  | >                                 |
| > cream---7                      | > ointment---1                    |
| >                                |                                   |
| > ointment---4                   | Hydrocortisone and clioquinol---2 |
| >                                |                                   |
| > lotion---1                     | Mometasone furoate monohydrate    |
|                                  |                                   |
| #######                          | > cream---15                      |
|  Clocortolone pivalate cream---1 | >                                 |
|                                  | > lotion---6                      |
| Desonide cream---1               | >                                 |
|                                  | > ointment---5                    |
| ####### Desoximetasone           |                                   |
|                                  | ## Triamcinolone acetonide        |
| > cream---6                      |                                   |
| >                                | > cream---3                       |
| > gel---1                        | >                                 |
| >                                | > ointment---1                    |
| > dosage form not stated---3     |                                   |
|                                  | Triamcinolone acetonide and       |
| Dexamethasone and neomycin       | nystatin cream---18               |
| cream---1                        |                                   |
+----------------------------------+-----------------------------------+

## Site of application: Face/neck-40

Buttocks/groin/genitals (including "diaper area")-32

Legs/feet-22

Arms/hands-19

Head/scalp-12

Trunk-8

"Entire body"-4

Axilla-2

Periocular-2

Not stated-79

##  (more than one site of application per case possible)

## 

## Outcome: Death-1

> Disability-5

Hospitalization-14

Life threatening-1

(outcome not stated in most cases)

Seventy-eight male children, 111 female children, and 13 children of
unspecified gender experienced adverse events after receiving topical
corticosteroids. The patients ranged in age from 8 days to 18 years with
a mean age of 7.7 years. Sixty-five (32.2%) of the adverse events
occurred in pediatric patients younger than 3 years of age, and 32
(15.8%) events occurred in infants. One hundred forty (69.3%) of the
adverse events occurred in patients younger than 12 years of age. The
patients in the case series had received topical corticosteroids for 1
day to 7 years before experiencing the adverse event. The median time to
onset was 30 days. In 40 cases, application of topical corticosteroids
continued for 90 days or longer, and in 17 cases application of topical
corticosteroids continued for over a year.

Betamethasone-containing products were the most frequently implicated in
reports of adverse reactions (79, 39%). Betamethasone dipropionate and
clotrimazole cream was implicated in 52 (25.7%) reports, more than any
other product. The most commonly reported events were local irritation
and application site reactions (66), lack of effect (32), skin
depigmentation or discoloration (30), and skin striae or atrophy (30).
Outcome was not reported in most cases; however, serious outcomes
(death-1, disability-5, hospitalization-14, life threatening-1) were
reported. The most common indications for use were eczema (36), tinea
infections (24), diaper rash (21), unspecified rash (19), atopic
dermatitis (12), and psoriasis (12). The products were applied most
often to the face and/or neck (40) or to the buttocks, groin, and/or
genital area (32). Positive dechallenge was reported in 21 cases and
positive rechallenge was reported in three cases. The area of
application was occluded in five cases, and covering (but not occlusion)
with "Kling wrap" was reported in one case. In many cases in which
occlusion was not reported, partial occlusion might have occurred with
clothing or a diaper.

In some cases topical corticosteroids were continued for extended
periods of time in high-risk settings. Twenty-two patients younger than
4 years of age received topical corticosteroids for longer than 4 weeks.
Seven of these patients received the drugs for longer than 6 months.
Fifteen patients had topical corticosteroids applied to their
groin/genitals (including "diaper area") longer than 4 weeks. Four of
these patients received the drugs for longer than 6 months.

Sometimes topical corticosteroids were continued despite the failure of
the treatment. The reports do not explain why the topical
corticosteroids were continued when they were not effective. In twelve
of the cases in the series, topical corticosteroids were continued for
longer than 4 weeks even though the dermatoses did not improve. In one
case the topical corticosteroid was continued for one year despite "lack
of effect."

Two cases from the series are presented below.

AERS 5209109, MFR A0006921, US (NY) 1995

A registered nurse reported that her 9-year-old daughter received
fluticasone cream for several weeks to treat an unspecified rash. After
several weeks, the child developed fatigue, polydipsia, polyuria,
glycosuria, and hypergylcemia. She was diagnosed with insulin-dependent
diabetes. Fluticasone was discontinued and the child was treated with
insulin.

AERS 1000000771, MFR 97100307, US (CO) 1997

A dermatologist reported that a 21-month-old girl received betamethasone
dipropionate and clotrimazole cream twice daily almost since birth to
treat diaper rash. Examination by the dermatologist noted folliculitis
around the neck, and epidermal atrophy, hypopigmentation and
telangiectasis in the perineal area, mons pubis, and inguinal creases.
Betamethasone dipropionate and clotrimazole cream was discontinued, and
the diaper rash was treated with a cream not containing corticosteroid
(Desitin®). The folliculitis was treated with ketoconazole. The child's
condition was improving at the time of the report.

# Cases of Adrenal Insufficiency, Cushing's Syndrome, and Growth Retardation

A subset of eleven pediatric patients experienced adrenal insufficiency
(2), Cushing's syndrome (7), and/or growth retardation (5) after
receiving topical corticosteroids. A listing of these cases is presented
in Attachment 2. These patients ranged from 5 months to 15 years of age.
Two patients each used betamethasone valerate cream, clobetasol
propionate cream, and mometasone ointment. The following other topical
corticosteroids were cited in one report each:

betamethasone ointment;

betamethasone dipropionate and clotrimazole cream;

betamethasone and neomycin cream;

clobetasol propionate scalp lotion;

flumetasone pivalate;

fluocinonide cream;

flurandrenolide tape;

mometasone cream; and

triamcinolone cream.

In four cases the patients used more than one topical corticosteroid
product. The topical corticosteroid was used for a median of 300 (range,
22 to 1825) days. In two cases each the children received topical
corticosteroids to treat diaper rash and eczema. Other diagnoses for the
use of topical corticosteroids included alopecia, icthyosis, Leiner\'s
disease, psoriasis, treatment of a scar, and unspecified patches of red
skin. Five patients were hospitalized, and one patient with Cushing's
syndrome died of a respiratory infection.

Two cases are presented below.

AERS 4918014, MFR 9207239, Maylasia 1992 (literature report)

A 6-week-old infant with icthyosis was treated intermittently with
betamethasone cream for 4 weeks. The product used was not specified. The
baby was hospitalized with severe dyspnea, generalized edema, Cushingoid
features, and heart failure. The infant initially responded to
unspecified treatment, but eventually died of a respiratory system
infection.

AERS 5231157, MFR 9409043, US (FL) 1994

A 2-year-old girl with atopic dermatitis was prescribed mometasone
furoate ointment. Treatment with the ointment continued for the next 4
years. A physician reported the 6-year-old child experienced growth
retardation.

CONCLUSION/RECOMMENDATION

We reviewed 202 AERS adverse events for the topical corticosteroids
reported for pediatric patients age 0 to 18 years of age. Local
irritation and application site reactions were the most frequently
reported events in pediatric patients. Numerous systemic adverse events
were reported, including striae, Cushing's syndrome, growth retardation,
hyperglycemia, hirsutism, glaucoma, and adrenal insufficiency. Some
cases resulted in serious outcomes, including hospitalization and death.
Long-term application of topical corticosteroids in high-risk settings
(for example, application to the genital and groin area in very young
patients) resulted in numerous adverse events. In some cases topical
corticosteroids were continued despite treatment failure.

We recommend that the systemic adverse events in the AERS database be
included in the labeling for these products. Additionally, the labeling
of each product should advise practitioners of the appropriate duration
of use of the product. The labeling should give information regarding
how quickly improvement in dermatoses should occur after therapy with a
topical corticosteroid is started, and practitioners should be advised
to discontinue the product if improvement does not occur within this
timeframe.

**[References]{.underline}**

1\. Ellison, JA, Patel L, Ray D, et al. Hypothalamic-pituitary-adrenal
function and glucocorticoid sensitivity in atopic dermatitis. Pediatrics
2000; 105(4): 794-799.

2\. Turpeinen M. Adrenocortical response to adrenocorticotropic hormone
in relation to duration of topical therapy and percutaneous absorption
of hydrocortisone in children with dermatitis. Eur J Pediatr 1989;
148(8): 729-31.\
\
3. Turpeinen M, Salo OP, Leisti S. Effect of percutaneous absorption of
hydrocortisone on adrenocortical responsiveness in infants with severe
skin disease. Br J Dermatol 1986; 115(4): 475-84.

4\. Shaffer MP, Feldman SR, Fleischer AB Jr. Use of
clotrimazole/betamethasone diproprionate by family physicians. Fam Med
2000; 32(8): 561-5.

.

+-----------------------------------------------------------------------+
| Joyce Weaver, Pharm.D., Safety Evaluator                              |
|                                                                       |
| Concur:                                                               |
+-----------------------------------------------------------------------+
| Claudia B. Karwoski, Pharm.D., Team Leader                            |
+-----------------------------------------------------------------------+

# Attachment 1--- 

# Products by Generic name, tradename, NDA number, and approval date

+-----------------------------------------------------------------------+
| Alclometasone dipropionate products:                                  |
|                                                                       |
| (Aclovate ointment; NDA 018702---12/14/1982)                          |
|                                                                       |
| (Aclovate cream; NDA 018707---12/14/1982)                             |
|                                                                       |
| Amcinonide products:                                                  |
|                                                                       |
| (Cyclocort cream; NDA 018116---10/18/1979)                            |
|                                                                       |
| (Cyclocort ointment; NDA 018498---11/13/1981)                         |
|                                                                       |
| (Cyclocort lotion; NDA 019729---6/13/1988)                            |
|                                                                       |
| Betamethasone dipropionate products:                                  |
|                                                                       |
| (Diprosone cream; NDA 017536---1/29/1975)                             |
|                                                                       |
| (Diprosone ointment; NDA 017691---4/15/1976)                          |
|                                                                       |
| (Diprosone lotion; NDA 017781---2/1/1977)                             |
|                                                                       |
| (Diprosone aerosol; NDA 017829---5/24/1977)                           |
|                                                                       |
| (Diprolene ointment; NDA 018741---7/27/1983)                          |
|                                                                       |
| (Diprolene cream; NDA 019408---1/31/1986)                             |
|                                                                       |
| (Diprolene AF cream; NDA 019555---4/27/1987)                          |
|                                                                       |
| (Diprolene gel; NDA 019408---11/22/91)                                |
|                                                                       |
| (Diprolene lotion; NDA 019716---8/1/1988)                             |
|                                                                       |
| Betamethasone dipropionate and clotrimazole products:                 |
|                                                                       |
| (Lotrisone cream; NDA 018827---7/10/1984)                             |
|                                                                       |
| (Lotrisone lotion; NDA 020010---12/8/2000)                            |
|                                                                       |
| Betamethasone valerate products:                                      |
|                                                                       |
| (Luxiq aerosol; NDA 020934---2/28/1999)                               |
|                                                                       |
| Clobetasol propionate products:                                       |
|                                                                       |
| (Temovate cream; NDA 019322---12/27/1985)                             |
|                                                                       |
| (Temovate ointment; NDA 019323---12/27/1985)                          |
|                                                                       |
| (Temovate solution; NDA 019966---2/22/1990)                           |
|                                                                       |
| (Temovate gel; NDA 020337---4/29/1994)                                |
|                                                                       |
| (Temovate E cream; NDA 020340---6/17/1994)                            |
|                                                                       |
| (Olux foam; NDA 021142---5/26/2000)                                   |
|                                                                       |
| Clocortolone pivalate products:                                       |
|                                                                       |
| (Cloderm cream; NDA 017765---8/22/1977)                               |
|                                                                       |
| Desonide products:                                                    |
|                                                                       |
| (Tridesilon cream; NDA 017010---1/04/1972)                            |
|                                                                       |
| (Tridesilon ointment; NDA 017426---11/1/1974)                         |
|                                                                       |
| (Desowen cream; NDA 019048---12/14/1984)                              |
|                                                                       |
| > (Desowen lotion; NDA 072354---1/24/1992)                            |
| >                                                                     |
| > (Desowen ointment; NDA 071425---6/15/1988)                          |
|                                                                       |
| Desoximetasone products:                                              |
|                                                                       |
| (Topicort cream; NDA 017856---2/28/1977)                              |
|                                                                       |
| (Topicort LP cream; NDA 018309---3/28/1980)                           |
|                                                                       |
| (Topicort gel; NDA 018586---3/29/1982)                                |
|                                                                       |
| (Topicort ointment; NDA 018594---10/3/1983)                           |
|                                                                       |
| (Topicort ointment; NDA 018763---9/30/1983)                           |
|                                                                       |
| Dexamethasone products:                                               |
|                                                                       |
| (Decaspray aerosol; NDA 012731---3/29/1961)                           |
|                                                                       |
| Diflorasone diacetate products:                                       |
|                                                                       |
| (Florone cream; NDA 017741---9/14/1977)                               |
|                                                                       |
| (Florone ointment; NDA 017994---3/1/1978)                             |
|                                                                       |
| (Florone E cream; NDA 019259---8/28/1985)                             |
|                                                                       |
| (Psorcon E ointment; NDA 019260---8/28/1985)                          |
|                                                                       |
| (Psorcon E cream; NDA 020205---11/20/1992)                            |
|                                                                       |
| Fluocinolone acetonide products:                                      |
|                                                                       |
| (FS Shampoo; NDA 020001---8/27/1990)                                  |
|                                                                       |
| (Synalar cream; NDA 012787---2/15/1963)                               |
|                                                                       |
| (Synalar ointment; NDA 013960---6/19/1963)                            |
|                                                                       |
| (Synalar solution; NDA 015296---5/27/1964)                            |
|                                                                       |
| (Synalar-HP cream; NDA 016161---7/25/1967)                            |
|                                                                       |
| (Derma-smoothe FS oil; NDA 019452---2/3/1988)                         |
|                                                                       |
| Fluocinonide products:                                                |
|                                                                       |
| (Lidex cream; NDA 016908---6/30/1971)                                 |
|                                                                       |
| (Lidex ointment; NDA 016909---9/22/1971)                              |
|                                                                       |
| (Lidex gel; NDA 017373---5/15/1973)                                   |
|                                                                       |
| (Lidex solution; NDA 018849---4/8/1984)                               |
|                                                                       |
| Flurandrenolide products:                                             |
|                                                                       |
| (Cordran ointment; NDA 012806---10/18/1965)                           |
|                                                                       |
| (Cordran lotion; NDA 013790---3/19/1963)                              |
|                                                                       |
| (Cordran tape; NDA 016455---7/29/1969)                                |
|                                                                       |
| Fluticasone propionate products:                                      |
|                                                                       |
| (Cutivate ointment; NDA 019957---12/14/1990)                          |
|                                                                       |
| (Cutivate cream; NDA 019958---12/18/1990)                             |
|                                                                       |
| Halcinonide products:                                                 |
|                                                                       |
| (Halog cream; NDA 017556---11/27/1974)                                |
|                                                                       |
| (Halog solution; NDA 017823---5/4/1977)                               |
|                                                                       |
| (Halog ointment; NDA 017824---6/15/1977)                              |
|                                                                       |
| (Halog-E cream; NDA 018234---1/24/1980)                               |
|                                                                       |
| Halobetasol propionate products:                                      |
|                                                                       |
| (Ultravate cream; NDA 019967---12/27/1990)                            |
|                                                                       |
| (Ultravate ointment; NDA 019968---12/17/1990)                         |
|                                                                       |
| Hydrocortisone products:                                              |
|                                                                       |
| (Cortef cream; NDA 009460---8/20/1954)                                |
|                                                                       |
| (Cortef ointment; NDA 008917---7/28/1953)                             |
|                                                                       |
| (Cortril ointment; NDA 009176---5/24/1972)                            |
|                                                                       |
| Hydrocortisone butyrate products:                                     |
|                                                                       |
| (Locoid cream; NDA 018514---3/31/1982)                                |
|                                                                       |
| (Locoid ointment; NDA 018652---10/29/1982)                            |
|                                                                       |
| (Locoid solution; NDA 019116---2/25/1987)                             |
|                                                                       |
| (Locoid lipocream; NDA 020769---9/8/1997)                             |
|                                                                       |
| Hydrocortisone buteprate product:                                     |
|                                                                       |
| (Pandel cream; NDA 020453---2/28/1997)                                |
|                                                                       |
| Hydrocortisone valerate products:                                     |
|                                                                       |
| (Westcort cream; NDA 017950---before 1/1/1982)                        |
|                                                                       |
| (Westcort ointment; NDA 018726---8/8/1983)                            |
|                                                                       |
| Methylprednisolone acetate products:                                  |
|                                                                       |
| (Medrol acetate ointment; NDA 012421---6/21/1960)                     |
|                                                                       |
| Mometasone furoate monohydrate                                        |
|                                                                       |
| (Elocon cream; NDA 019625---5/6/1987)                                 |
|                                                                       |
| (Elocon lotion; NDA 019796---3/30/1989)                               |
|                                                                       |
| (Elocon ointment; NDA 019543---4/30/1987)                             |
|                                                                       |
| Prednicarbate products:                                               |
|                                                                       |
| (Dermatop cream; NDA 019568---9/23/1991)                              |
|                                                                       |
| (Dermatop emollient cream; NDA 020279---10/29/1993)                   |
|                                                                       |
| Triamcinolone acetonide products:                                     |
|                                                                       |
| (Kenalog ointment; NDA 011600---6/17/1977)                            |
|                                                                       |
| (Kenalog cream; NDA 011601---11/13/1978)                              |
|                                                                       |
| (Kenalog spray; NDA 012104---10/11/1974)                              |
|                                                                       |
| (Kenalog orabase ointment; NDA 012097---3/4/1960)                     |
+-----------------------------------------------------------------------+

### Attachment 2---AERS cases of growth retardation, adrenal insufficiency, or Cushing's Syndrome a/w use of topical corticosteroids in pediatric patients

<table>
<colgroup>
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 12%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 7%" />
<col style="width: 14%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Mfr report #</td>
<td>Loca-tion</td>
<td>yr</td>
<td>Age (yrs)</td>
<td>Gender</td>
<td>Drug and dose</td>
<td>application site</td>
<td>duration (days)</td>
<td>indication</td>
<td>AE</td>
<td>Outcome</td>
<td>comment</td>
</tr>
<tr class="even">
<td>B0104663A</td>
<td>France</td>
<td>2001</td>
<td>15</td>
<td>M</td>
<td><p>clobetasol propionate cream</p>
<p>(Dermaval)</p>
<p>10 - 20 mg/d</p></td>
<td></td>
<td>45</td>
<td>psoriasis</td>
<td>Depigmentation, striae, possible adrenal insufficiency</td>
<td>HO</td>
<td>Positive dechallenge</td>
</tr>
<tr class="odd">
<td>97-10-8020</td>
<td>AUS</td>
<td>1997</td>
<td>14</td>
<td>M</td>
<td><p>mometasone ointment (Elocon)</p>
<p>15 g Q2-3 days &amp;</p>
<p>betamethasone ointment 30 g Q 7-10 days</p></td>
<td>entire body</td>
<td></td>
<td>eczema</td>
<td>adrenal insufficiency, delayed puberty, growth suppression</td>
<td></td>
<td>bone scan showed 2-3 yr growth delay; prednisolone cc med</td>
</tr>
<tr class="even">
<td>B0042474</td>
<td>Japan</td>
<td>1996</td>
<td>10</td>
<td>F</td>
<td>flumetasone pivalate clobetasol, propionate (Dermovate)</td>
<td>Scalp</td>
<td>180</td>
<td></td>
<td>Cushing’s syndrome, obesity, inc hair growth, acne</td>
<td>HO</td>
<td></td>
</tr>
<tr class="odd">
<td>95-08-0174</td>
<td>US (NJ)</td>
<td>1995</td>
<td>3</td>
<td>M</td>
<td><p>fluocinonide, triamcinolone, mometasone cream</p>
<p>(Elocon)</p></td>
<td></td>
<td>455</td>
<td>patches of red skin</td>
<td>growth retardation, leukoderma</td>
<td></td>
<td>Digoxon and furosemide cc meds</td>
</tr>
<tr class="even">
<td>94-10-0184</td>
<td>US (CO)</td>
<td>1994</td>
<td>1.25</td>
<td>M</td>
<td>betamethasone and clotrimazole cream (Lotrisone)</td>
<td>diaper area</td>
<td>120</td>
<td>diaper rash</td>
<td>growth retardation</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>94-09-043</td>
<td>US (FL)</td>
<td>1994</td>
<td>6</td>
<td>F</td>
<td>mometasone furoate ointment (Elocon)</td>
<td></td>
<td>1460</td>
<td>atopic dermatitis</td>
<td>growth retardation</td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>92-09-024</td>
<td>US (MD)</td>
<td>1992</td>
<td>9</td>
<td>F</td>
<td>betamethasone valerate cream (Valisone)</td>
<td></td>
<td>1825</td>
<td>eczema</td>
<td>growth retardation</td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>92-07-239</td>
<td>May-lasia</td>
<td>1992</td>
<td>0.12</td>
<td>M</td>
<td><p>betamethasone valerate</p>
<p>cream</p></td>
<td></td>
<td>28</td>
<td>icthyosis</td>
<td>Cushing’s syndrome</td>
<td>DE</td>
<td>1 m/o infant; DE due to respiratory infection</td>
</tr>
<tr class="even">
<td>92-05-178</td>
<td>France</td>
<td>1992</td>
<td>0.67</td>
<td>M</td>
<td><p>neomycin &amp; betamethasone cream</p>
<p>(Diprosone)</p>
<p>1.5 mg betamethasone/day</p></td>
<td>scalp, diaper area</td>
<td>180</td>
<td>Leiner's disease</td>
<td>Cushing’s syndrome</td>
<td>DS, HO</td>
<td>8 m/o baby; residual retardation</td>
</tr>
<tr class="odd">
<td>US91070727A</td>
<td>US (TX)</td>
<td>1991</td>
<td>14</td>
<td>F</td>
<td>flurandrenolide tape (Cordran tape)</td>
<td>inner thigh</td>
<td>22</td>
<td>Tx scar from repair of laceration</td>
<td>Disfigurement, Cushing’s syndrome</td>
<td>HO</td>
<td></td>
</tr>
<tr class="even">
<td>G0003711</td>
<td>Hong Kong</td>
<td>1990</td>
<td>0.42</td>
<td>M</td>
<td>clobetasol propionate cream (Temovate) 1.78 g/ day</td>
<td>diaper area</td>
<td>300</td>
<td>diaper rash</td>
<td>Cushing’s syndrome</td>
<td>HO</td>
<td>5 m/o baby given 1 tube (25 g) every 2 weeks for 10 months; positive
dechallenge</td>
</tr>
</tbody>
</table>