Guidance for Industry 

 
 
Organ-Specific Warnings:  Internal 

Analgesic, Antipyretic, and 

Antirheumatic Drug Products for 

Over-the-Counter Human Use  

Small Entity Compliance Guide  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

 
July 2010 

OTC 

 
 
   
Guidance for Industry 

 
 
Organ-Specific Warnings:  Internal 

Analgesic, Antipyretic, and 

Antirheumatic Drug Products for 

Over-the-Counter Human Use Small 

Entity Compliance Guide  

 
 
 
 
 
 
 
Additional copies are available from: 

Office of Communications 
 
Division of  Drug Information, WO51, Room  2201 
 
10903 New Hampshire Ave. 

Silver Spring, MD 20993-0002 
 
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) 

 
 
July 2010 

OTC 

 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   SUMMARY OF THE REGULATION AND THIS GUIDANCE................................ 1 
 
III.   QUESTIONS AND ANSWERS....................................................................................... 4 
 
  Contains Nonbinding Recommendations 
 
Guidance for Industry1 
 
 
Organ-Specific Warnings; Internal Analgesic, Antipyretic,  
and Antirheumatic Drug Products for Over-the-Counter  
Human Use  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 organ-
specific labeling regulation for over-the-counter (OTC) internal analgesic, antipyretic, and 
antirheumatic (IAAA) drug products.  The regulation requires IAAA manufacturers to label their 
products with specific warnings and related information to alert consumers about potential liver 
injury and stomach bleeding associated with IAAA drug products.  Manufacturers must be in 
compliance with the final rule beginning on April 29, 2010.  The Food and Drug Administration 
(FDA) has prepared this guidance in accordance with section 212 of the Small Business 
Regulatory Fairness Act (Public Law 104-121).   
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's 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.   SUMMARY OF THE REGULATION AND THIS GUIDANCE 
 
In the Federal Register of December 26, 2006 (71 FR 77314), the FDA published a proposed 
rule on the requirements for compliance with FDAs organ-specific labeling regulation for OTC 
IAAA drug products. In the Federal Register of April 29, 2009 (74 FR 19385), the FDA 
                                                 
1  This small business compliance guide was developed by the Office of Nonprescription Products in the Center for 
Drug Evaluation and Research, FDA.  
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  Contains Nonbinding Recommendations 
 
published the final rule (2009 final rule), codified at 21 CFR 201.326.2  On November 25, 2009, 
FDA published technical amendments to clarify several points in response to industry feedback.   
 
The 2009 final rule changed the labeling requirements for OTC IAAA drug products by adding 
new warnings about liver injury for those using acetaminophen, and stomach bleeding for those 
using nonsteroidal anti-inflammatory drugs (NSAIDs).  The rule also makes related changes to 
the principal display panel (PDP), ingredient listings, and other labeling information to highlight 
the presence of acetaminophen or NSAIDs and draw attention to the organ-specific warnings.  
Table 1 summarizes the requirements in the final rule.  The specific language to be used in 
required warnings is shown in Table 2.   You also will need to refer directly to the final rule for 
additional formatting instructions, such as type sizes, that are not described in this guidance.    
 
                                                 
2  The regulation  published in  the Code  of Federal Regulations  (CFR) will reflect both the final rule and the technical 
amendments.  This regulation replaces the alcohol warning that was previously in 21 CFR 201.322; the alcohol 
warning is now in 21 CFR 203.326(a)(1)(iii)(A).  
 
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  Contains Nonbinding Recommendations 
 
Table 1: Summary of Labeling Requirements 
 
Acetaminophen     Requirements apply to any OTC IAAA product 
Products  containing acetaminophen, either alone or in 
(21 CFR 201.326(a)(1))  combination with other active ingredients. 
 	  Acetaminophen must be included in the statement 
of identity on the principal display panel (PDP). 
 	  A see new warning information flag must appear 
on the PDP of all products that were first marketed 
on or before April 29, 2010, and must continue to be 
used for 1 year after the flag is first added to the 
PDP. 
 	  The Warnings section of Drug Facts labeling must 
include a liver warning, and related warnings 
against using more than one acetaminophen product 
at the same time, and ask a doctor warnings for 
persons who have liver disease or are taking 
warfarin. 
 	  If a retail product has both an outer and inner 
package/container, the liver warning must appear 
on both. 
 	  Different warning language is used for products 
labeled only for adults, only for children under 12 
years old, or for adults and children under 12 years 
old. 
 	  Specific language to be used in required warnings is 
shown in Table 2 of this guidance. 
 	  Required labeling also must follow the instructions 
on format and placement detailed in the regulations 
(e.g., bolding/highlighting, type size, order of 
warnings). 
NSAID products     Applies to any OTC IAAA product containing any 
(21 CFR 201.326(a)(2))  NSAID active ingredient, either alone or in combination 
  with other active ingredients. 
(NSAIDs include, but     The word NSAID must be included in the statement of 
are not limited to, the  identity on the PDP, either as part of the ingredient name  
following active  (e.g., ibuprofen (NSAID), or after the intended action 
ingredients:  of the NSAID ingredient (e.g., Pain Reliever 
aspirin, carbaspirin  (NSAID)).
calcium, choline     A see new warning information flag must appear on 
salicylate, ibuprofen,  the PDP of all products that were first marketed on or 
ketoprofen, magnesium   before April 29, 2010, and must continue to be used for 
salicylate, naproxen  1 year after the flag is first added to the PDP.
sodium, and sodium  
   The Ingredients section of the label must contain the 
salicylate.) 
term NSAID* after the NSAID ingredient, with an 
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  Contains Nonbinding Recommendations 
 
asterisk statement at the end of the ingredient list that 
states *nonsteroidal anti-inflammatory drug. 
   The Warnings section of Drug Facts labeling must 
include a stomach bleeding warning and related ask a 
doctor warnings. 
   If a retail product has both an outer and inner 
package/container, the stomach bleeding warning must 
appear on both. 
   Different warning language is used for products labeled 
only for adults, only for children under 12 years old, or 
for adults and children under 12 years old. 
   For products labeled only for children under 12 years 
old, the Directions section of the label must state this 
product does not contain directions or complete 
warnings for adult use.  
   Specific language to be used in required warnings is 
shown in Table 2 of this guidance. 
   Required labeling also must follow the instructions on 
format and placement detailed in the regulations (e.g., 
bolding/highlighting, type size, order of warnings). 
 
 
 
III.   QUESTIONS AND ANSWERS 

 
Question:   Is the product I manufacture subject to this rule?  
 
Answer:   This rule applies to all OTC IAAA drug products that contain acetaminophen or 
any NSAID, either as a single active ingredient or in combination with any other 
active ingredients. This rule applies to OTC IAAA drug products marketed under 
an OTC monograph or an approved new drug application (NDA) or abbreviated 
new drug application (ANDA). This rule does not apply to topical drug products 
that contain acetaminophen or NSAIDs.  
 
Question:   How do I know if an active ingredient in my product is an NSAID?  
 
Answer:   NSAIDs are analgesic/antipyretic ingredients used to relieve pain, fever, and/or 
inflammation. They include, but are not limited to, aspirin, carbaspirin calcium,  
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, 
and sodium salicylate.  If you are uncertain whether an ingredient is an NSAID, 
ask the FDA Contact shown below. 
 
Question:   I manufacture an OTC IAAA product with annual sales of less than $25,000.  Is 
my drug product subject to this rule?  
 
Answer:   Yes. Small businesses are not exempt from this rule. 
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  Contains Nonbinding Recommendations 
 
 
Question:  When must I be in compliance with this rule?  Can I still distribute inventory 
that was labeled, but not shipped, before the new requirements became 
effective? 
 
Answer:   This rule (including the November 25, 2009, technical amendments) became  
effective on April 29, 2010.  After that time, all products that you introduce or deliver 
for introduction into interstate commerce must be labeled in compliance with this 
rule.  
 
Question:   What will happen if I fail to comply with this rule by April 29, 2010?  
 
Answer:   Beginning April 29, 2010, your drug product will be misbranded under section 
502(f)(2) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352(f)(2)), and 
subject to regulatory action.  
 
Question:    Does the regulation specify the exact language I must use for warnings and other 
required label statements?  
   
Answer:   Table 2 shows the exact language that must be used for the required warning 
statements.  The rule also specifies exact language for some other required 
statements (e.g., statement of identity, ingredient lists, directions); these are 
indicated by quotation marks in Table 1.   
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  Contains Nonbinding Recommendations 
 
 
Table 2: Required Wording for Warnings 
 
Acetaminophen  NSAIDs 
Products  Liver warning: This product  Stomach bleeding warning:   
Labeled for  contains acetaminophen.   This product contains an NSAID, 
Adults Only   Severe liver damage may occur  which may cause severe stomach 
if you take   more than [insert  bleeding. The chance is higher if 
maximum number of daily  you    are age 60 or older    have 
dosage units] in 24 hours,  had stomach ulcers or bleeding 
which is the maximum daily  problems    take a blood thinning 
amount [optional: for this  (anticoagulant) or steroid drug   
product]   with other drugs    take other drugs containing 
containing acetaminophen    3  prescription or nonprescription 
or more alcoholic drinks every  NSAIDs (aspirin, ibuprofen, 
day while using this product.  naproxen, or others)   have 3 or 
  more alcoholic drinks every day 
Do not use with any other  while using this product    take 
drug containing acetaminophen  more or for a longer time than 
(prescription or non- directed. 
prescription). If you are not   
sure whether a drug contains  Ask a doctor before use if   
acetaminophen, ask a doctor or    stomach bleeding warning 
pharmacist.  applies to you    you have a 
  history of stomach problems, such 
Ask a doctor before use if you  as heartburn   you have high 
have liver disease.  blood pressure, heart disease, liver 
  cirrhosis, or kidney disease    you 
Ask a doctor or pharmacist  are taking a diuretic. 
before use if you are taking the   
blood thinning drug warfarin.  Stop use and ask a doctor if you 
[Note: this statement does not  experience any of the following 
apply to combination products  signs of stomach bleeding:     feel  
that contain acetaminophen and  faint     vomit blood      have 
NSAIDs, which are already  bloody or black stools     have 
required to include a warning  stomach pain that does not get 
about blood thinning  better. 
drugs under the stomach   
bleeding warning 
for NSAIDs. ] 
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  Contains Nonbinding Recommendations 
 
Acetaminophen  NSAIDs 
Products labeled  Liver warning: This product  Stomach bleeding warning:  
only for children  contains acetaminophen.   This product contains an NSAID, 
under 12 years of  Severe liver damage may occur  which may cause severe stomach 
age  if your child takes    more than  bleeding. The chance is higher if 
5 doses in 24 hours, which is  your child     has had stomach 
the maximum daily amount    ulcers or bleeding problems    
  with other drugs containing    takes a blood thinning 
acetaminophen.   (anticoagulant) or steroid drug 
      takes other drugs containing 
Do not use with any other  prescription or nonprescription 
drug containing acetaminophen  NSAIDs (aspirin, ibuprofen, 
(prescription or non- naproxen, or others)     takes 
prescription). If you are not  more or for a longer time 
sure whether a drug contains  than directed. 
acetaminophen, ask a doctor or   
pharmacist.  Ask a doctor before use if   
    stomach bleeding warning 
Ask a doctor before use if  applies to your child     child has 
your child has liver disease.  a history of stomach problems, 
  such as heartburn     child has not 
Ask a doctor or pharmacist  been drinking fluids     child has 
before use if your child is  lost a lot of fluid due to vomiting 
taking the blood thinning drug  or diarrhea    child has high 
warfarin. [Note: this  blood pressure, heart disease, liver 
statement does not apply to  cirrhosis, or kidney disease   
combination products that    child is taking a diuretic. 
contain acetaminophen and   
NSAIDs, which  Stop use and ask a doctor if 
are already required to include  child experiences any of the 
a warning about blood thinning  following signs of stomach 
drugs under the stomach  bleeding:     feels faint     vomits 
bleeding warning for NSAIDs.]  blood     has bloody or black 
  stools     has stomach pain that 
  does not get better. 
  
Products Labeled  Liver warning: This  Stomach bleeding warning: 
for Adults and  product contains  This product contains an 
Children Under  acetaminophen.  Severe liver  NSAID, which may cause  
12 Years of Age  damage may occur if    adult  severe stomach bleeding. The 
takes more than [insert  chance is higher if the user   
maximum number of daily     has had stomach ulcers or 
dosage units] in 24 hours,  bleeding problems      takes a 
which is the maximum daily  blood thinning (anticoagulant) 
amount    child takes more  or steroid drug     takes other 
than 5 doses in 24 hours    drugs containing prescription 
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  Contains Nonbinding Recommendations 
 
Acetaminophen  NSAIDs 
  taken with other drugs  or nonprescription NSAIDs 
containing acetaminophen      (aspirin, ibuprofen, naproxen, or 
adult has 3 or more alcoholic  others)     takes more or for a 
drinks everyday while using  longer time than directed      is 
this product.  age 60 or older    has 3 or more 
  alcoholic drinks everyday while 
Do not use with any other drug  using this product. 
containing acetaminophen   
(prescription or non- Ask a doctor before use if   
prescription). If you are not     stomach bleeding warning 
sure whether a drug contains  applies to user    user has 
acetaminophen, ask a doctor or  history of stomach problems, 
pharmacist.  such as heartburn     user has 
  high blood pressure, heart 
Ask a doctor before use if the  disease, liver cirrhosis, or kidney 
user has liver disease.  disease   
    user takes a diuretic     user 
Ask a doctor or pharmacist  has not been drinking fluids   
before use if the user is taking    user has lost a lot of fluid due 
the blood thinning drug  to vomiting or  diarrhea. 
warfarin. [Note:  this   
statement does not apply to  Stop use and ask a doctor if user 
combination products that  experiences any of the following 
contain acetaminophen and  signs of stomach bleeding:   
NSAIDs, which are already     feels faint      vomits blood    
required to include a warning    has bloody or black stools   
about blood thinning    has stomach pain that does not 
drugs under the stomach  get better. 
bleeding warning for NSAIDs.]   
 
 
 
Question:  Are the required warnings different for children and adults?  
 
Answer:  Yes. Different language is used for products labeled for adults only, products 
labeled only for children under 12 years of age, and products labeled for both 
adults and children under 12 years old. Please refer to Table 2 above for details.   
 
Question:  Does the regulation also contain instructions about the format and/or 
appearance of warnings and other required labeling? 
 
Answer:   Yes. You must refer to the regulation for specific instructions about the 
appearance, format, and placement of the required labeling (e.g., 
bolding/highlighting, type size and prominence, order of acetaminophen and/or 
NSAID warnings, and other applicable warnings).  Your labeling also must 
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  Contains Nonbinding Recommendations 
 
comply with other applicable labeling requirements under the OTC monograph 
for IAAA drugs as well as the general labeling regulations for all OTC drugs in 
21 CFR part 201, subpart C, including the Drug Facts labeling requirements in 
21 CFR 201.66. 
 
Question:  The retail package of my product has both an outer carton and an immediate 
container. Are the liver injury and stomach bleeding warnings required on 
the outer carton and the immediate container? 
 
Answer:   Yes, these warnings must appear on both the outer container (e.g., carton) and the 
immediate (inner) container of a retail package.  If the immediate container is a 
blister card, the warnings must appear on the blister card and remain intact and 
readable when the drug product is removed from the blister card.  The warnings 
do not need to be included on each blister unit. 
 
Question:  The retail package of my product consists of multi-dose blister cards inside a 
carton. What must I do to comply with the requirements to put the liver or 
stomach bleeding warning on the immediate container?  
 
Answer:   Each blister card is considered a separate immediate container.  In this case, the 
appropriate warning must appear on each blister card and remain intact and 
readable when individual doses of the product are removed from the blister card.  
This point was clarified in the technical amendments published on November 25, 
2009. 
 
Question:     Apart from blister cards, are there any exceptions or special provisions for 
other kinds of immediate containers that have limited space for labeling, 
such as stick packs and sachets? 
 
Answer:   No. FDA believes that these types of immediate containers can accommodate the 
required warnings. We also are concerned that consumers may routinely remove 
these packages from the outer carton and fail to see the liver injury and stomach 
bleeding warnings if they are only printed on the carton.  
 
Question:  What products are required to have the see new warning information flag 
on the PDP? How long must the flag remain on the PDP? 
 
Answer:  The see new warning information must appear on the PDP of all OTC 
acetaminophen- or NSAID-containing IAAA products first marketed on or before 
April 29, 2010, and remain on the product for at least 1 year after the product is 
initially introduced into interstate commerce.  Products newly introduced after 
that date do not require the flag, but must have all other organ-specific labeling 
required by this rule. 
  
Question:   Do I need preapproval from FDA for labeling changes required by this rule?   
 
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  Contains Nonbinding Recommendations 
 
Answer:  	 For products marketed under the IAAA monograph, you do not need preapproval of 
labeling changes. For products marketed under NDAs and ANDAs, you will need to 
submit a CBE 0 (change to be effective immediately) labeling supplement.  
 
Question: 	  Do I need to list my revised labeling with FDA?  
 
Answer: 	  Yes. This change in labeling 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  Federal Food, Drug, and Cosmetic 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/DrugRegi 
strationandListing/ucm078801.htm. 
 
Question: 	 Does this rule apply to topical IAAA products?   
 
Answer: 	  No, only internal (oral) OTC IAAA products are affected by this rule.  
 
Question:   	 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 Arlene Solbeck, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, MS 5411, Silver 
Spring, MD 20993, 3017962090.    
 
 
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