Over-the-Counter (OTC) Topical Acne Drug Products and Hypersensitivity-Related Drug Events:

Post-market Data from the FDA Adverse Event Reporting System A. Ferguson, J. Swann , J. Tonning, T. Pham, P. Diak, A. Brinker, H. Mehta, S. Proestel†

U.S. Food and Drug Administration, CDER, Silver Spring, Maryland

† The authors of this poster have no financial interest to disclose.

¥ Acknowledgements: M. Chen, L. Governale, J. Mathew, G. Chai

TABLE 1. Demographic and Clinical Characteristics of the Serious Cases associated with Hypersensitivity Events for the

OTC topical Acne Products (N=131) FAERS search period: 1969 through 01-28-2013

FIGURE 1.

Hypersensitivity-Specific Case Selection

BACKGROUND

We searched the FAERS database for reports of OTC topical acne products associated

with hypersensitivity reactions submitted from the database inception (1969) to January

28, 2013. To provide context for the adverse event reports submitted to the FAERS

database, the retail sales of these products were assessed using the OTC International

Market Tracking database.

Because of the clinical significance of anaphylaxis, each hypersensitivity case-report was

further evaluated to identify cases of anaphylaxis. Each case of anaphylaxis met the

following criteria: 1) Reporting of one of the following adverse events: anaphylaxis,

anaphylactoid reaction, anaphylactic shock, anaphylactoid shock, angioedema, or shock

OR 2) Involvement of skin or mucosal tissue, AND compromise of at least one of the

following organ systems: respiratory or cardiovascular. The remaining cases were

considered non-anaphylaxis in nature and classified as a non-anaphylaxis hypersensitivity

reaction.

METHODS

Benzoyl peroxide, salicylic acid, sulfur and resorcinol/sulfur are marketed, active

ingredients for over-the-counter (OTC) topical acne monograph products for the treatment

of acne vulgaris. Both single-ingredient and combination OTC topical acne products are

regulated under the OTC monograph in 21 CFR 333 and are considered GRAS/E

(Generally Recognized as Safe and Effective). In 2006, the Federal Food, Drug and

Cosmetic Act was amended, by Public Law 109-462, to require that all serious adverse

events be reported for dietary supplements and nonprescription OTC drugs marketed

without an approved application when used in the US. This analysis was initiated due to

the identification of an increasing number of hypersensitivity-related reports associated

with the use of OTC topical acne monograph products.

We assessed data from the FDA Adverse Event Reporting System (FAERS) to evaluate

the postmarket adverse event experience for topical OTC acne monograph products in

association with serious hypersensitivity reactions, with benzoyl peroxide, salicylic acid,

sulfur or resorcinol/sulfur as active ingredients.

PURPOSE

LIMITATIONS OF FAERS

Limitations of FAERS data include: underreporting, stimulated reporting, biased

reporting, variable quality and content, and no certainty that the reported event is due to

the product.

TABLE 1. Demographic and Clinical Characteristics of the Serious Cases associated

with Hypersensitivity

Events for the OTC topical Acne Products (N=131)

FAERS search period: 1969 through 01-28-2013

FAERS SEARCH RESULTS n = 141

EXCLUDED REPORTS (n= 19)

Reasons for exclusion:

Not a product of interest

Not used for acne

A result of accidental exposure

CASE SERIES

N = 131

Benzoyl Peroxide (n= 110)

Salicylic Acid (n= 21)

Resorcinol-Sulfur (n= 0)

Sulfur (n= 0)

DISCUSSION AND CONCLUSION

FDA postmarket data demonstrate that there may be an association of serious

hypersensitivity reactions, including anaphylaxis, with use of OTC topical acne

monograph products containing benzoyl peroxide and salicylic acid. While multiple

active ingredients are allowable for marketing, we only observed hypersensitivity adverse

events with benzoyl peroxide and salicylic acid. The reason for this observation is not

known; however high use associated with products containing these two active

ingredients may contribute to this observation (see Figure 2). In addition, based on the

information reported to FDA, we cannot determine if the hypersensitivity reactions were

triggered by the acne products’ active ingredients, benzoyl peroxide and salicylic acid, the

inactive ingredients, or by a combination of both.

Based on these findings, the FDA issued a drug safety communication in June 2014 to

alert the public regarding rare but serious hypersensitivity reactions with certain OTC

topical acne products. This warning alerts consumers to the following:

● To test the product upon first use, by applying a small amount topically to affected

area for three days; if no discomfort is experienced, then continued product use is

recommended per directions.

● To stop use with topical acne products and immediately seek medical attention if

they experience hypersensitivity reactions such as throat tightness, difficulty

breathing, feeling faint, swelling of the eyes, face, lips or tongue; develop hives or

itching.

● To avoid using an OTC topical acne product again if they have previously

experienced a hypersensitivity reaction with its use.

RESULTS

We identified 131 cases associated with OTC topical acne products (benzoyl peroxide,

n=110; salicylic acid, n=21). Reported adverse events ranged from application site reactions

to anaphylaxis. Of the 131 cases, 50 met our case definition for anaphylaxis. No fatalities

were identified; however, hospitalization was required in 44% of these cases. Four patients

reported a reappearance of their hypersensitivity reaction once the suspected product was

reintroduced (positive rechallenge). The OTC topical acne products cited in these cases

were marketed under various brand names such as Proactiv, Neutrogena, MaxClarity, Oxy,

Ambi, Aveeno, Clean & Clear, and store brands. These products are available as gels,

lotions, face washes, solutions, cleansing pads, toners, and face scrubs.

In 2012, approximately 15.7 million bottles/packages of OTC topical acne products were

sold from retail store outlets. Of these, the majority of OTC topical acne products contained

salicylic acid at approximately 61% (9.6 million bottles/packages). OTC topical acne

products containing benzoyl peroxide followed at 35% (5.4 million bottles/packages).

0.0

2.0

4.0

6.0

8.0

10.0

12.0

2007 2008 2009 2010 2011 2012

Num

ber o

f bot

tles/

pack

ages

(mill

ions

)

Year

Nationally estimated number of bottles/packages of over-the-counter topical acne products sold from U.S. retail store outlets, years 2007-2012

SALICYLIC ACID BENZOYL PEROXIDE SALICYLIC ACID/BENZOYL PEROXIDE (Acne Pack)

SULFUR RESORCINOL/SULFUR (Combo) RESORCINOL

SALICYLIC ACID/SULFUR (Combo)

Source: OTC International Market Tracking (OTCIMS). Years 2007-2012. Data extracted April 2013.

FIGURE 2. Nationally estimated number of bottles/packages of OTC topical acne products sold from U.S. retail store outlets, years

2007-2012

Selected Characteristics

Benzoyl

Peroxide

n=110

Salicylic Acid

n=21

Age (years)

Range

Mean

Median

n=80

11-78

32

27

n=16

14-55

30

28

Sex

Female

Male

93

17

20

1

Time to Onset (Days)

Immediate

15 minutes to < 24 hours

1 Day – 3 Days

4 Days - 30 Days

> 30 Days

n=76

15

31

8

18

4

n=14

0

9

4

1

0

Hypersensitivity

Classification1

Anaphylaxis

Non-Anaphylactic

Hypersensitivity

43

67

7

14