Organ-Specific Warnings:  Internal 
Analgesic, Antipyretic, and 
Antirheumatic Drug Products for 
Over-the-Counter Human Use   
Labeling for Products That Contain 
 
Acetaminophen 
Guidance for Industry 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
November 2015 
OTC
 
   
Organ-Specific Warnings:  Internal 
Analgesic, Antipyretic, and 
Antirheumatic Drug Products for 
Over-the-Counter Human Use   
Labeling for Products That Contain 
  
Acetaminophen
Guidance for Industry 
 
  
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: 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) 
 
November 2015 
OTC 
  Contains Nonbinding Recommendations 
 
 
 
 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DISCUSSION AND POLICY .......................................................................................... 3 
A.  Products labeled for adults only and products labeled for adults and children under 12 
years of age ................................................................................................................................. 3 
B.  Products labeled only for children under 12 years of age .......................................................... 3 
 
 
 
 
  i  Contains Nonbinding Recommendations 
 
 
Organ-Specific Warnings:  Internal Analgesic, Antipyretic, and 
Antirheumatic Drug Products for Over-the-Counter Human Use   
Labeling for Products That Contain Acetaminophen  
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
I.  INTRODUCTION 
 
This guidance is intended to inform manufacturers of certain nonprescription (also referred to as 
over-the-counter or (OTC)) internal analgesic, antipyretic, and antirheumatic (IAAA) drug 
products that contain acetaminophen of the circumstances in which FDA does not intend to 
object to the inclusion of a liver warning that differs from that required under  
201.326(a)(1)(iii)(A) and  201.326(a)(1)(v)(A) (21 CFR 201.326(a)(1)(iii)(A) and 21 CFR 
201.326(a)(1)(v)(A)), provided the warning appears as described below.     
 
In general, FDAs guidance documents 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.  
 
II.  BACKGROUND 
 
In the Federal Register of December 26, 2006 (71 FR 77314), FDA published a proposed rule on 
organ-specific warnings and related labeling for OTC IAAA drug products.  In the Federal 
Register of April 29, 2009 (74 FR 19385), FDA published the final rule (2009 final rule).  On 
November 25, 2009, FDA published a technical amendment (74 FR 61512) to clarify several 
provisions in response to industry feedback.  The 2009 final rule, as amended, changed some of 
the labeling requirements for OTC IAAA drug products to inform consumers about the risk of 
liver injury when using acetaminophen, and the risk of stomach bleeding when using 
nonsteroidal anti-inflammatory drugs.  It went into effect on April 29, 2010, and is codified at 21 
CFR 201.326.   
 
                                                 
1  This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at the Food and Drug 
Administration.  
    
  Contains Nonbinding Recommendations 
 
 
Section 201.326(a)(1)(iii)(A) requires that the labeling for OTC IAAA products that contain 
acetaminophen that are labeled for adults only include the liver warning described below. 
Section 201.326(a)(1)(v)(A) requires that the labeling for OTC IAAA products that contain 
acetaminophen and are labeled for adults and children under 12 years of age must include in their 
labeling a similar but not identical liver warning as described below: 
 
Adults Only ( 201.326(a)(1)(iii)(A)):  
 
Liver warning:  This product contains acetaminophen.  Severe liver damage may occur 
if you take   more than [insert maximum number of daily dosage units] in 24 hours, 
which is the maximum daily amount [optional: for this product]  with other drugs 
containing acetaminophen    3 or more alcoholic drinks every day while using this 
product.  
 
Adults and children under 12 years of age ( 201.326(a)(1)(v)(A)): 
 
Liver warning:  This product contains acetaminophen.  Severe liver damage may occur 
if  adult takes more than [insert maximum number of daily dosage units] in 24 hours, 
which is the maximum daily amount [optional: for this product]  child takes more 
than 5 doses in 24 hours  taken with other drugs containing acetaminophen  adult has 3 
or more alcoholic drinks every day while using this product. 
 
Although the currently proposed maximum daily dose of acetaminophen for adults is 4,000 
milligrams (mg),2 some OTC IAAA products that contain acetaminophen have directions for use 
that provide a maximum daily dose of acetaminophen for that product that is less than 4,000 mg.  
Directions for use can result in a maximum daily dose of acetaminophen that is less than 4,000 
mg for a variety of reasons, including additional active ingredient(s) in the drug product, and 
administration and dosage limitations based upon specific product indications and intended uses.  
In other instances, the limit on the daily dose of acetaminophen can be the result of a voluntary 
limitation by the manufacturer.  For example, the maximum number of daily dosage units for an 
OTC acetaminophen-diphenhydramine combination drug intended as a nighttime sleep aid and 
internal analgesic product is limited by the products indication, and the total daily dose of 
acetaminophen for the product is significantly less than 4,000 mg.  The optional statement, for 
this product, in the first bullet of  201.326(a)(1)(iii)(A) and  201.326(a)(1)(v)(A) is intended 
to provide language to help consumers understand that the maximum number of daily dosage 
units for a product might not reflect the maximum daily dose of acetaminophen.  However, the 
Agency understands that in certain circumstances, despite this optional statement, the wording of 
the first bulleted warning required under  201.326(a)(1)(iii)(A) and  201.326(a)(1)(v)(A) might 
be interpreted as indicating that severe liver damage is associated with a total daily dose of 
acetaminophen that is less than 4,000 mg.  This suggestion is not the intent of the regulation. 
 
                                                 
2 The Tentative Final Monograph for Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for OTC 
Human Use currently proposes that an OTC IAAA product with a daily dose of acetaminophen that does not exceed 
4,000 milligrams (mg) in 24 hours, among other things, be considered generally recognized as safe and effective and 
not misbranded (see 53 FR 46204 at 46257 (November 16, 1988)).   
  2  Contains Nonbinding Recommendations 
 
 
To address this potential confusion for OTC acetaminophen-containing products with directions 
for use that result in a maximum daily dose of less than 4,000 mg of acetaminophen, the Agency 
does not intend to object to the inclusion of liver warnings as described in section III.A below in 
the labeling of such products.   
 
III.  DISCUSSION AND POLICY 
 
A.  Products labeled for adults only and products labeled for adults and children 
under 12 years of age 
 
When an OTC IAAA product containing acetaminophen is labeled for adults only or labeled for 
adults and children under 12 years of age and its directions for use result in a maximum daily 
dose of acetaminophen for the product that is less than 4,000 mg for adults, FDA does not intend 
to object if a manufacturer chooses to use the following language on the drugs labeling, in place 
of the first bullet of the liver warnings required by  201.326(a)(1)(iii)(A) and  
201.326(a)(1)(v)(A), respectively:  
 
Adults Only:  
 
Liver warning:  This product contains acetaminophen. Severe liver damage may occur if 
you take  more than 4,000 mg of acetaminophen in 24 hours  with other drugs 
containing acetaminophen  3 or more alcoholic drinks every day while using this 
product. 
 
Adults and children under 12 years of age: 
 
Liver warning:  This product contains acetaminophen. Severe liver damage may occur if 
 adult takes more than 4,000 mg of acetaminophen in 24 hours  child takes more than 
5 doses in 24 hours  taken with other drugs containing acetaminophen  adult has 3 or 
more alcoholic drinks every day while using this product. 
 
FDA believes that this alternative language in the first bullet should eliminate the potential 
confusion described above and help ensure appropriate dosing of OTC acetaminophen-
containing products, while also informing consumers that using more than the currently proposed 
maximum daily dose of 4,000 mg of acetaminophen for adults may result in severe liver damage.   
 
B.  Products labeled only for children under 12 years of age 
  
OTC IAAA products containing acetaminophen that are labeled only for children under 12 years 
of age must continue to include in their labeling the liver warning required under  
201.326(a)(1)(iv) and described below : 
 
Children under 12 years of age:  
 
  3  Contains Nonbinding Recommendations 
 
 
Liver warning:  This product contains acetaminophen. Severe liver damage may occur if your 
child takes:  more than 5 doses in 24 hours, which is the maximum daily amount [optional: for 
this product]  with other drugs containing acetaminophen. 
 
   
   
  4