Guidance for Industry 
 
Topical Acne Drug Products for Over-
the-Counter Human Use  
Revision of Labeling 
and 
Classification of Benzoyl Peroxide as Safe 
and Effective 
 
Small Entity Compliance Guide  
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2011 
OTC 
   
Guidance for Industry 
 
Topical Acne Drug Products for Over-
the-Counter Human Use  
Revision of Labeling 
and 
Classification of Benzoyl Peroxide as Safe 
and Effective 
 
Small Entity Compliance Guide 
 
Additional copies are available from: 
Office of Communications 
Division of Drug Information, WO51, Room 2201 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave. 
Silver Spring, MD  20993  
Phone: 301-796-3400; Fax: 301-847-8714 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2011 
OTC 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION.............................................................................................................2 
II.  BACKGROUND...............................................................................................................3 
III.  SUMMARY OF THE REGULATION...........................................................................3 
IV.  PERMITTED ACTIVE INGREDIENTS, WARNINGS, AND DIRECTIONS.........4 
V.  QUESTIONS AND ANSWERS.......................................................................................7 
i  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
 
Topical Acne Products for Over-the-Counter Human Use  
Revision of Labeling 
and Classification of Benzoyl Peroxide as Safe and Effective 
 
Small Entity Compliance Guide 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to help small businesses understand and comply with FDAs 
regulation regarding over-the-counter (OTC) topical acne drug products published in the Federal 
Register on March 4, 2010 (75 FR 9767).  The final rule makes the following changes to the 
OTC regulations at 21 CFR 333, subpart D: 
  Adds benzoyl peroxide as a generally recognized as safe and effective (GRASE) active 
ingredient in OTC topical acne drug products 
  Sets forth new warnings and a direction that must be included in labeling of OTC topical 
acne drug products that contain benzoyl peroxide 
  Revises labeling requirements for all OTC topical acne drug products, to ensure 
consistency with the standardized Drug Facts formatting and requirements set forth in 21 
CFR 201.66   
 
FDA has prepared this guidance in accordance with section 212 of the Small Business 
Regulatory Fairness Act (Public Law 104-121).   
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited.  The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
                                                 
1 This guidance has been prepared by the Office of Drug Evaluation IV in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  
  2 Contains Nonbinding Recommendations 
 
 
II.  BACKGROUND 
 
In the Federal Register of January 15, 1985 (50 FR 2172), FDA published a proposed rule 
allowing for the use of a number of active ingredients, including benzoyl peroxide (2.5 to 10%), 
in OTC topical acne drug products.   
 
Based on safety concerns raised after publication of the 1985 proposed rule, FDA proposed to 
classify benzoyl peroxide as category III, which meant that more data were needed to properly 
classify benzoyl peroxide as a GRASE active ingredient (56 FR 37622, August 7, 1991).  Shortly 
after proposing to classify benzoyl peroxide as category III, FDA issued a final rule for OTC 
topical acne products that permitted the use of the other active ingredients included in the 1985 
proposed rule  resorcinol, resorcinol monoacetate, salicylic acid, and/or sulfur in certain 
concentrations and combinations (56 FR 41008, August 16, 1991).    
 
Since 1991, new data have been submitted to address the safety concerns regarding benzoyl 
peroxide.  After reviewing the data, FDA concluded that benzoyl peroxide can be adequately 
labeled to minimize risks while delivering effective acne treatment.  The final rule, published on 
March 4, 2010, and effective on March 4, 2011, reflects these conclusions.  Note that although 
the final rule is effective on March 4, 2011, compliance dates for specific requirements under the 
final rule vary depending upon the active ingredient and volume of annual sales, as discussed in 
section V (QUESTIONS AND ANSWERS), Question 4. 
 
 
III.  SUMMARY OF THE REGULATION 
 
FDA issued the March 4, 2010, final rule to classify benzoyl peroxide (in concentrations of 2.5 
to 10%) as a permitted active ingredient in OTC topical acne drug products.  In the final rule, 
FDA concludes that benzoyl peroxide may be used in OTC topical acne products based on our 
review of studies on genotoxicity, tumor promotion with chemical/ultraviolet initiation, animal 
carcinogenicity, and photocarcinogenicity, as well as the related epidemiological data.   
 
In addition to adding benzoyl peroxide to the monograph as a permitted active ingredient, the 
March 4, 2010, final rule adds specific warnings (regarding potential sensitivity and/or irritation) 
and a new direction for use (regarding the use of sunscreen after treatment with benzoyl 
peroxide products) required in the labeling for OTC topical acne products that contain benzoyl 
peroxide.   
 
The final rule also requires the use of new warnings and directions in the labeling of all OTC 
acne drug products (including those products that contain benzoyl peroxide).  These changes 
ensure that the labeling for OTC topical acne products meets the standardized OTC drug labeling 
content and format requirements in 21 CFR 201.66, which had not yet been established when the 
monograph for OTC topical acne products (allowing for the use of resorcinol, resorcinol 
monoacetate, salicylic acid, and/ or sulfur as active ingredients) was published in 1991.  
 
  3 Contains Nonbinding Recommendations 
 
 
IV.  PERMITTED ACTIVE INGREDIENTS, WARNINGS, AND DIRECTIONS 
 
The final rule lists all permitted active ingredients for OTC topical acne products, and their 
respective permissible concentrations and ingredient combinations, as set forth in 21 CFR 
333.310 and 21 CFR 333.320.  The monograph, as amended by the final rule, permits use of 
three single active ingredients and two combinations of active ingredients, which are listed 
below.  
 
Permitted single active ingredient products: 
  Benzoyl peroxide in concentrations of 2.5 to 10 percent. 
  Salicylic acid in concentrations of 0.5 to 2 percent. 
  Sulfur in concentrations of 3 to 10 percent. 
 
Permitted combination active ingredient products.  
  Resorcinol in 2 percent concentration in combination with sulfur in concentrations of 
between 3 and 8 percent. 
  Resorcinol monoacetate in 3 percent concentration in combination with sulfur in 
concentrations of between 3 and 8 percent. 
 
The final rule also revises the labeling requirements for OTC topical acne products, as set forth 
in 21 CFR 333.350.  Table 1 provides warnings and directions required in labeling of all OTC 
topical acne products marketed under the monograph as amended by the final rule.  Table 2 
provides additional warnings and directions required in labeling of OTC topical acne products 
that contain benzoyl peroxide, sulfur, or a combination of active ingredients.   
 
  4 Contains Nonbinding Recommendations 
 
Table 1.  Summary of Warnings and Directions Required for 
All OTC Topical Acne Ingredients 
 
Active  Warnings  Directions 
Ingredient(s) 
All   For external use only   clean the skin thoroughly before applying 
  this product 
When using this product    cover the entire affected area with a thin 
 skin irritation and dryness is  layer one to three times daily 
more likely to occur if you use   because excessive drying of the skin may 
another topical acne medication  occur, start with one application daily, 
at the same time. If irritation  then gradually increase to two or three 
occurs, only use one topical acne  times daily if needed or as directed by a 
medication at a time.  doctor 
   if bothersome dryness or peeling occurs, 
reduce application to once a day or every 
other day. 
 
Products, such as soaps and masks, 
which are applied and removed should 
include appropriate directions in addition 
to the directions set forth above.  For 
example, the second bullet of the 
standard directions listed above may be 
revised to read cover the entire affected 
area with a thin layer and rinse 
thoroughly one to three times daily.   
 
In addition to the required directions, all 
OTC topical acne products marketed 
under the monograph may contain the 
following optional direction:  
Sensitivity Test for a New User. Apply 
product sparingly to one or two small 
affected areas during 
the first 3 days. If no discomfort occurs, 
follow the directions stated (select one of 
the following: elsewhere on this label, 
above, or below).  
 
  5 Contains Nonbinding Recommendations 
 
Table 2.  Additional Required Warnings and Directions for OTC Topical Acne 
Products Containing Benzoyl Peroxide, Sulfur, or a Combination of Active 
Ingredients 
Active  Additional Required Warnings  Additional Required Directions 
Ingredient(s) 
Benzoyl  Do not use if you    if going outside, apply sunscreen 
peroxide   have very sensitive skin   after using this product. If 
 are sensitive to benzoyl peroxide  irritation or sensitivity develops, 
  stop use of both products and ask 
When using this product   a doctor. 
 avoid unnecessary sun exposure and 
use a sunscreen  
 avoid contact with the eyes, lips, and 
mouth 
 avoid contact with hair and dyed 
fabrics, which may be bleached by this 
product  
 skin irritation may occur, characterized 
by redness, burning, itching, peeling, 
or possibly swelling. Irritation may be 
reduced by using the product less 
frequently or in a lower concentration. 
 
Stop use and ask a doctor if  
 irritation becomes severe 
Sulfur  Do not use on    
 broken skin  
 large areas of the skin 
 
When using this product  
 apply only to areas with acne 
 
Combinations  Do not use on    
of active   broken skin  
ingredients   large areas of the skin 
 
When using this product  
 apply only to areas with acne 
 rinse right away with water if it gets in 
eyes 
 
Stop use and ask a doctor  
 if skin irritation occurs or gets worse 
 
 
  6 Contains Nonbinding Recommendations 
 
V.  QUESTIONS AND ANSWERS 
 
Question 1:  Is the product I manufacture subject to this rule?  
 
Answer:  If you manufacture an OTC topical drug product to treat acne, your drug product is 
subject to this rule if your product: 
  Contains any of the active ingredients listed above under  333.310 (i.e., benzoyl 
peroxide, resorcinol, resorcinol monoacetate, salicylic acid, sulfur) or a combination of 
these ingredients permitted under  333.320 
  Is marketed under the OTC acne monograph (21 CFR part 333, subpart D)  
 
Question 2:  Does this rule apply to OTC products marketed under a new drug application 
(NDA)?  
 
Answer:  No, this rule does not apply to NDA products.  The labeling of products marketed 
under an NDA is subject to prior review and approval by FDA.  
 
Question 3:  I manufacture a product containing one or more of the specified ingredients, 
but with annual sales of less than $25,000.  Is my drug product subject to this rule?  
 
Answer:  Yes, the final rule applies to products with annual sales of less than $25,000, but 
the compliance dates are dependent upon the active ingredient used in the product (see 
below). 
 
Question 4:  When must I be in compliance with this rule? 
 
Answer:  The exact compliance date for your product will depend on the active ingredient 
and volume of annual sales, as shown below: 
  March 4, 2011:  Products containing benzoyl peroxide with annual sales of $25,000 or 
more  
  March 2, 2012:  Products containing benzoyl peroxide with annual sales of less than 
$25,000 
  March 4, 2015:  Products containing resorcinol, resorcinol monoacetate, salicylic acid, 
and/or sulfur, regardless of annual sales 
 
Question 5:  This final rule also updated the labeling requirements for all OTC topical acne 
products for consistency with 21 CFR 201.66.  What is 21 CFR 201.66 about? 
   
Answer:  In addition to finalizing the OTC topical acne monograph by resolving the status of 
the active ingredient, benzoyl peroxide, the final rule also updates the monograph labeling 
for products containing any of the active ingredients in the monograph.  These changes were 
made to improve the compatibility of the acne monograph labeling language with the Drug 
Facts formatting requirements in 21 CFR 201.66.   
 
  7 Contains Nonbinding Recommendations 
 
Question 6:  Where should the new labeling appear in the package? 
 
Answer:  The relevant, required language shown in tables 1 and 2 should be included in the 
Warnings and Directions section of Drug Facts, respectively, on the carton labeling.  We do 
not require a consumer package insert in this rule. 
 
Question 7:  Do I need preapproval from FDA of the new labeling/principal display panel 
(PDP) before I begin to use it?  
 
Answer:  No.  Provided that the product and its labeling comply with the monograph for 
topical OTC acne drugs, you do not need preapproval of the labeling.   
 
Question 8:  Do the new labeling requirements apply to all topical formulations containing 
the active ingredients included in this final rule?  
 
Answer:  Yes, this final rule applies to all OTC topical acne products, whether a gel, lotion, 
cream, mask, face wash, rinse, or other forms to be applied to the skin.  In addition, this final 
rule applies whether the topical OTC acne product is intended to be left on the skin or 
applied and then rinsed off. 
  
Question 9:  What will happen if I fail to comply with this rule by the compliance date?  
 
Answer:  If you fail to comply with this rule by the appropriate compliance date (see 
question 4, above), your drug product will be deemed an unapproved new drug under section 
505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(a)) and 
misbranded under section 502(f)(1) and (f)(2) of the FD&C Act (21 U.S.C. 352(f)(1) and 
352(f)(2)).  As a result, your drug may be subject to regulatory enforcement action. 
 
Question 10:  Do I need to update my listing information, reflecting this revised labeling, 
with FDA? 
 
Answer:  Yes.  Labeling that is revised to meet the requirements of this rule should be 
submitted to FDA through the drug listing process.  Any updates must be submitted every 
June and December (section 510(j)(2) of the FD&C Act; 21 CFR 207.21(b)).  However, 
registrants (and, if applicable, private label distributors) are encouraged to submit updates 
through the registration and listing system more frequently, as changes occur.  Information 
on this process can be found at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistrationand
Listing/ucm078801.htm. 
 
  8 Contains Nonbinding Recommendations 
 
Question 11:  If I have questions about whether the drug product I manufacture is subject 
to this rule, how to comply with the rule, or any related issues, whom should I contact at 
FDA?  
 
Answer:  You should contact the Division of Nonprescription Regulation Development, 
Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 5426, Silver Spring, MD  20993, 301-796-2090.   
 
Question 12:  Where can I find a copy of the Federal Register notice that contains the final 
rule?   
 
Answer:  You can access the final rule at: 
http://www.regulations.gov/#!documentDetail;D=FDA-1981-N-0114-0001.  You also can 
access additional information about the rulemaking history for the OTC acne drug product 
monograph on FDAs Web site, at:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-
CounterOTCDrugs/StatusofOTCRulemakings/ucm069967.htm.   
  9