Recommended Warning for Over-
the-Counter Acetaminophen-
Containing Drug Products and 
Labeling Statements Regarding 
Serious Skin Reactions 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2017 
Compliance 
 
  Contains Nonbinding Recommendations 
 
 
Recommended Warning for Over-
the-Counter Acetaminophen-
Containing Drug Products and 
Labeling Statements Regarding 
Serious Skin Reactions
 
 
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) 
 
January 2017 
Compliance 
  Contains Nonbinding Recommendations 
 
 
 
 
 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  DISCUSSION AND POLICY .......................................................................................... 2 
IV.  EXAMPLE OTC DRUG FACTS LABELS WITH RECOMMENDED WARNING 3 
 
 
 
 
  i  Contains Nonbinding Recommendations 
 
 
Recommended Warning for Over-the-Counter Acetaminophen-
Containing Drug Products and Labeling Statements Regarding Serious 
Skin Reactions 
Guidance for Industry1 
 
 
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 
 
FDA is informing manufacturers, members of the medical and scientific community, and other 
interested persons that at this time we do not intend to take action against the marketing of single- 
and combination-ingredient, acetaminophen-containing, nonprescription (commonly referred to 
as over-the-counter (OTC)) drug products bearing an allergy warning as described in this 
guidance (see section III, Discussion and Policy) alerting consumers that the use of 
acetaminophen may cause severe skin reactions.2  This guidance is intended to apply to single- 
and combination-ingredient acetaminophen-containing products marketed under the Tentative 
Final Monograph (TFM) for Internal Analgesic, Antipyretic, and Antirheumatic (IAAA) Drug 
Products for Over-the-Counter Human Use, published in the Federal Register (53 FR 46204, 
November 16, 1988).   
 
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 
 
Acetaminophen, included in many prescription and OTC products, is a common active ingredient 
indicated to treat pain and reduce fever.  On August 1, 2013, FDA issued a Drug Safety 
Communication (DSC) informing the public that use of acetaminophen has been associated with 
                                                 
1 This guidance has been prepared by the Office of Unapproved Labeling Compliance in the Center for Drug 
Evaluation and Research (CDER) at the Food and Drug Administration. 
    
2 Acetaminophen containing combination products include acetaminophen in combination with cough and cold 
products (see 21 CFR 341.40), acetaminophen in combination with antacids (see 21 CFR 331.15), and 
acetaminophen in combination with diuretics (53 FR 46194 at 46201, November 16, 1988) as described in the IAAA 
TFM (53 FR 46204 at 46255, November 16, 1988). 
  Contains Nonbinding Recommendations 
 
 
a risk of rare but serious skin reactions.3  These skin reactions, including Stevens-Johnson 
Syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis, can be 
fatal.   
 
The DSC explained that reddening of the skin, rash, blisters, and detachment of the upper surface 
of the skin can occur with the use of drug products that contain acetaminophen.  These skin 
reactions can occur with the first-time use of acetaminophen or even if acetaminophen has been 
used in the past without any problems.  FDA advised health care professionals to be aware of this 
rare risk and consider acetaminophen, along with other drugs already known to have such an 
association, when assessing patients with potentially drug-induced skin reactions.  FDA also 
advised that anyone who develops a skin rash or reaction while using acetaminophen or any 
other pain reliever/fever reducer should stop taking the drug and seek medical attention right 
away.  Furthermore, the announcement advised that anyone who has experienced a serious skin 
reaction when taking acetaminophen in the past should not take the drug again and should 
contact their health care professional to discuss alternative pain relievers/fever reducers.   
 
In the announcement, FDA stated that it planned to require manufacturers of acetaminophen-
containing prescription drug products to include a warning statement on their product labels to 
address the risk of serious skin reactions and that it would request the same warning be added by 
manufacturers of OTC acetaminophen-containing drug products marketed under an approved 
application.  In the fall of 2013, FDA sent letters to manufacturers holding new drug applications 
(NDA) and abbreviated new drug applications (ANDA) requiring in some cases and requesting 
in others that a warning statement be included on the labeling for all products (both prescription 
and OTC) containing acetaminophen marketed under NDAs and ANDAs.  At this time, all of the  
required labeling changes and most of the requested labeling changes have been made by the 
relevant manufacturers. 
 
FDA also indicated that it planned to encourage manufacturers of acetaminophen-containing 
drug products marketed under the TFM to similarly add a warning about serious skin reactions to 
their product labels. 
 
III.  DISCUSSION AND POLICY 
 
FDA recommends that manufacturers of all acetaminophen-containing OTC drug products (both 
single- and combination-ingredient acetaminophen products) marketed pursuant to the TFM for 
IAAA Drug Products include language in labeling warning consumers that acetaminophen may 
cause severe skin reactions.  
 
At this time, FDA does not intend to take action against the marketing of products containing the 
following allergy warning language, as long as those products are otherwise marketed in 
compliance with the TFM and applicable regulations: 
 
                                                 
3 FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever 
reducer acetaminophen. http://www.fda.gov/Drugs/DrugSafety/ucm363041.htm. 
  2  Contains Nonbinding Recommendations 
 
 
Allergy alert: Acetaminophen may cause severe skin reactions.  Symptoms may 
include: [bullet] skin reddening [bullet] blisters [bullet] rash 
If a skin reaction occurs, stop use and seek medical help right away. 
 
This guidance does not address alternative allergy warning language that may otherwise 
misbrand the product. 
 
The recommended allergy warning should appear under the Warnings heading section of the 
Drug Facts label under the subheading Allergy Alert, and, when included, must directly follow 
the liver warning (21 CFR 201.326) on acetaminophen-containing drug products.  FDA 
recommends that this warning be included on all packaging configurations. 
 
For products that contain both acetaminophen and aspirin, the Allergy alert warning, when 
included, must appear after the Reyes syndrome warning and before the Liver and Stomach 
bleeding warnings (21 CFR 201.326). 
 
IV.  EXAMPLE OTC DRUG FACTS LABELS WITH RECOMMENDED WARNING 
 
Products Containing Acetaminophen Only 
 
Drug Facts 
Active Ingredient (in each [insert dosage form])                                                                             Purpose 
Acetaminophen XXX mg................................................................Pain reliever/fever reducer 
Uses 
(Insert as described in an applicable OTC drug monograph or approved drug application.) 
Warnings 
Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take:  
  more than [insert quantity and dosage form] in 24 hours, which is the maximum daily amount  
  with other drugs containing acetaminophen  
  3 or more alcoholic drinks every day while using this product   
 
Allergy alert: Acetaminophen may cause severe skin reactions. Symptoms may include: 
  skin reddening 
  blisters 
  rash 
If a skin reaction occurs, stop use and seek medical help right away. 
Do not use  
  with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure 
whether a drug contains acetaminophen, ask a doctor or pharmacist.  
  for more than 10 days for pain unless directed by a doctor  
  for more than 3 days for fever unless directed by a doctor  
Ask a doctor before use if you have  
  liver disease  
Ask a doctor or pharmacist before use if  
  you are taking the blood thinning drug warfarin  
Stop using and ask a doctor if  
  symptoms do not improve  
  new symptoms occur  
  pain or fever persists or gets worse  
  3  Contains Nonbinding Recommendations 
 
 
If pregnant or breast-feeding, ask a health professional before use. 
 
Keep out of reach of children. In case of accidental overdose, get medical help or contact a Poison Control 
Center right away. Prompt medical attention is critical for adults as well as for children even if you do not 
notice any signs or symptoms. 
Directions 
(Insert as described in an applicable OTC drug monograph or approved drug application.) 
Other Information 
(Insert any additional information that is not included under the other subheadings but which is required or 
is made optional under an OTC drug monograph(s), other OTC drug regulation(s), approved drug 
application, statute, or OTC drug guidance.) 
Inactive Ingredients 
(Insert a list of each inactive ingredient, using its established name.)  
Questions or Comments 
 (Insert optional heading used to provide a telephone number of a source to answer questions about the 
drug product or to receive reports of adverse events associated with the use of the drug product.) 
 
Products Containing Acetaminophen and Aspirin 
 
Drug Facts 
Active Ingredient (in each [insert dosage form])                                                                             Purpose 
Acetaminophen XXX mg................................................................Pain reliever/fever reducer 
Aspirin XXX mg (NSAID)*.............................................................Pain reliever/fever reducer 
*nonsteroidal anti-inflammatory drug 
Uses 
(Insert as described in an applicable OTC drug monograph or approved drug application.) 
Warnings 
Reyes syndrome: Children and teenagers who have or are recovering from chicken pox or flu-like 
symptoms should not use this product. When using this product, if changes in behavior with nausea and 
vomiting occur, consult a doctor because these symptoms could be an early sign of Reyes syndrome, a rare 
but serious illness. 
 
Allergy alert: Aspirin may cause a severe allergic reaction which may include: 
  hives. 
  facial swelling. 
  asthma (wheezing). 
  shock. 
 
Allergy alert: Acetaminophen may cause severe skin reactions. Symptoms may include: 
  skin reddening 
  blisters 
  rash 
If a skin reaction occurs, stop use and seek medical help right away. 
 
Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take:  
  more than [insert quantity and dosage form] in 24 hours, which is the maximum daily amount  
  with other drugs containing acetaminophen  
  3 or more alcoholic drinks every day while using this product   
 
Stomach Bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. 
The chance is higher if you 
  are age 60 or older 
  have had stomach ulcers or bleeding problems 
  take a blood thinning (anticoagulant) or steroid drug 
  4  Contains Nonbinding Recommendations 
 
 
  take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, 
or others) 
  have 3 or more alcoholic drinks every day while using this product 
  take more or for a longer time than directed 
Do not use  
  with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure 
whether a drug contains acetaminophen, ask a doctor or pharmacist.  
  for more than 10 days for pain unless directed by a doctor  
  for more than 3 days for fever unless directed by a doctor  
Ask a doctor before use if  
  stomach bleeding warning applies to you 
  you have a history of stomach problems, such as heartburn 
  you have high blood pressure, heart disease, liver cirrhosis, or kidney disease  
  you are taking a diuretic 
 
Stop using and ask a doctor if  
  symptoms do not improve  
  new symptoms occur  
  pain or fever persists or gets worse  
  you experience any of the following signs of stomach bleeding:  
  feel faint 
  vomit blood 
  have bloody or black stools 
  have stomach pain that does not get better 
  if ringing in the ears or a loss of hearing occurs, consult a doctor before taking any more of this 
product. 
If pregnant or breast-feeding, ask a health professional before use. 
 
It is especially important not to use aspirin during the last 3 months of pregnancy unless definitely directed 
to do so by a doctor because it may cause problems in the unborn child or complications during delivery. 
 
Keep out of reach of children. In case of accidental overdose, get medical help or contact a Poison Control 
Center right away. Prompt medical attention is critical for adults as well as for children even if you do not 
notice any signs or symptoms. 
Directions 
(Insert as described in an applicable OTC drug monograph or approved drug application.) 
Other Information 
(Insert any additional information that is not included under the other subheadings but which is required or 
is made optional under an OTC drug monograph(s), other OTC drug regulation(s), approved drug 
application, statute, or OTC drug guidance.) 
Inactive Ingredients 
(Insert a list of each inactive ingredient, using its established name.)  
Questions or Comments 
 (Insert optional heading used to provide a telephone number of a source to answer questions about the 
drug product or to receive reports of adverse events associated with the use of the drug product.) 
  
For additional questions regarding this guidance, contact Emily Baker, Office of Unapproved 
Drugs and Labeling Compliance, Center for Drug Evaluation and Research, Food and Drug 
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, 301-796-7524, 
Emily.Baker@fda.hhs.gov.  
  5