Over-the-Counter 
Pediatric Oral Liquid 
Drug Products 
Containing 
Acetaminophen 
 
Guidance for Industry 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2015 
Drug Safety     
   
Over-the-Counter 
Pediatric Oral Liquid 
Drug Products 
Containing 
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 
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 
 
August 2015 
Drug Safety Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
I.  INTRODUCTION .............................................................................................................................................. 1 
II.  BACKGROUND ................................................................................................................................................ 2 
III.  RECOMMENDATIONS ................................................................................................................................... 3 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
Over-the-Counter Pediatric Oral Liquid  
Drug Products Containing 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 staff responsible for this guidance as listed on the 
title page.  
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to help drug manufacturers, packagers, and labelers minimize the risk 
to consumers of acetaminophen-related liver damage associated with the use of nonprescription 
also known as over-the-counter or OTCpediatric oral liquid acetaminophen drug products.  Many 
of these products are marketed under the OTC conditions stated in FDAs Tentative Final 
Monograph for Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for OTC 
Human Use (the IAAA TFM).2  FDA plans to address portions of the tentative final monograph 
through the notice and comment rulemaking process.  In the meantime, however, to encourage 
safer use of these products, we are providing recommendations regarding acetaminophen 
concentration, container labels, carton labeling, and packaging of such products as well as for  
any associated delivery devices.  FDAs recommendations are designed to encourage safer use of 
these products by minimizing the potential for acetaminophen overdosing due to medication 
errors or accidental ingestion.  Unless otherwise specified, these recommendations apply to both 
single-ingredient and combination-ingredient OTC oral liquid drug products (such as 
suspensions, solutions, elixirs, and syrups) that are labeled for use in children under 12 years of 
age and contain acetaminophen.  This guidance does not address OTC acetaminophen oral liquid 
drug products for use in both children and adults or for adults only.    
 
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.  
 
 
                                                 
1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) at FDA.  
2 Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Tentative 
Final Monograph, 53 FR 46204 (November 16, 1988), available at 
www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-
CounterOTCDrugs/StatusofOTCRulemakings/UCM078460.pdf.  
  1  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
Acetaminophen is marketed in many OTC drug products as a pain reliever and fever reducer.  
Most OTC acetaminophen products are marketed under FDAs ongoing rulemaking to establish 
a final monograph for OTC IAAA drug products.3  These products must conform to the 
conditions described in the IAAA TFM and FDAs general regulations for OTC drug marketing 
(21 CFR 330.1) and labeling (21 CFR 330.10 and part 201).  They also must be labeled with 
acetaminophen-related warnings and other information as specified in 21 CFR 201.326.   
 
OTC pediatric oral liquid drug products containing acetaminophen have been associated with 
overdoses due to medication errors that resulted in serious adverse events, including severe liver 
damage and death.  In particular, there have been reports of overdose attributed to confusion 
between concentrated acetaminophen drops (80 milligrams (mg)/0.8 milliliters (mL) and 80 
mg/mL) and acetaminophen oral liquid (160 mg/5 mL).  In addition to overdoses due to dosing 
errors, there have been reports of overdose from accidental ingestion by children. 
 
This guidance is part of FDAs ongoing initiative to reduce the risk of acetaminophen-related 
liver injury associated with all OTC and prescription acetaminophen-containing products.  As 
part of that initiative, in June of 2009, three FDA committees, the Drug Safety and Risk 
Management Advisory Committee, the Nonprescription Drugs Advisory Committee, and the 
Anesthetic and Life Support Drugs Advisory Committee, met jointly to consider a range of risk 
reduction measures.  Among other measures, these Advisory Committees recommended moving 
to a single, standardized acetaminophen concentration for OTC pediatric oral liquid drug 
products because the availability of multiple concentrations causes confusion and errors among 
both consumers and health care professionals.4  
 
In May of 2011, FDA convened a joint meeting of the Nonprescription Drugs Advisory 
Committee and the Pediatric Advisory Committee to discuss the use of acetaminophen in 
children. 5  Shortly before the meeting, the Consumer Healthcare Products Association (CHPA) 
proposed to voluntarily phase out all of the existing single-ingredient concentrated drop 
formulations of OTC pediatric oral liquid drug products and market only the 160 mg/5 mL 
                                                 
3 For more information about the IAAA monograph, see FDAs Web site at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-
CounterOTCDrugs/StatusofOTCRulemakings/ucm070484.htm#Original, and Internal Analgesic, Antipyretic, and 
Antirheumatic Drug Products for Over-the-Counter Human Use; Tentative Final Monograph, 53 FR 46204 
(November 16, 1988) (IAAA TFM), available at 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-
CounterOTCDrugs/StatusofOTCRulemakings/UCM078460.pdf. 
4 Summary Minutes of the Joint Meeting of the Drug Safety and Risk Management Advisory Committee, 
Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee, held 
June 29-30, 2009, are available at 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskMana
gementAdvisoryCommittee/UCM179888.pdf. 
5 Summary Minutes of the Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric 
Advisory Committee, held May 17-18, 2011, are available at 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/NonprescriptionDrugsAd
visoryCommittee/UCM264147.pdf. 
  2  Contains Nonbinding Recommendations 
formulation.6  At the Advisory Committee meeting, FDA took note of CHPAs voluntary 
transition to a single concentration of pediatric oral liquid acetaminophen.   
In response to CHPAs voluntary transition to a single concentration of OTC oral liquid 
acetaminophen products, FDA published a Drug Safety Communication on December 22, 2011, 
to inform the public of the 160 mg/5 mL concentration now marketed for children ages 2 to 3 
years and to recommend that end users of the product read the Drug Facts label to identify the 
concentration of the oral liquid acetaminophen, dosage, and directions for use.7   
 
FDA is issuing this guidance to address ongoing concerns about the potential for acetaminophen 
overdose associated with these products and to promote their safe use.  Besides overdose due to 
confusion associated with the multiple pediatric formulations with varying concentrations, there 
have also been reports of overdose attributed to: 
 
1. Concomitant administration of two products containing acetaminophen;8 
2. Inadequate prominence of acetaminophen concentration information on container labels 
and carton labeling; 
3. Inconsistent and/or confusing units of measurement (e.g., cc, mL, tsp, and tbsp) under 
Directions in the Drug Facts Panel and elsewhere in labeling; 
4. Dosage delivery device not being packaged with the medication; and 
5. Poorly designed delivery devices (e.g., devices with difficult-to-read markings or device 
designs that make it difficult to dispense a precise dose.   
 
 FDA issued a guidance for industry on dosage delivery devices in 2011 to help address points 4 
and 5.9 
 
 
III.  RECOMMENDATIONS 
 
To avoid confusion and the potential for dosing errors, FDA recommends that OTC oral liquids 
containing acetaminophen for pediatric use be formulated, packaged, labeled, and provided with 
an appropriate dosing device as described below.  Unless noted otherwise, the following 
recommendations apply to both single-ingredient and combination-ingredient OTC oral liquid 
                                                 
6  See May 4, 2011, CHPA press release entitled OTC Industry Announces Voluntary Transition to One 
Concentration of Single-Ingredient Pediatric Liquid Acetaminophen Medicines, available at 
http://www.chpa.org/05_04_11_PedAcet.aspx. 
7 FDA Drug Safety Communication: Addition of another concentration of liquid acetaminophen marketed for 
infants, available at http://www.fda.gov/Drugs/DrugSafety/ucm284741.htm.  
8 Mitigating the risk of concomitant administration is addressed in the Organ-Specific Warnings: Internal Analgesic, 
Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use  Small Entity Compliance Guide, 
July 2010.  See Table 2 of that guidance. We update guidances periodically.  To make sure you have the most recent 
version of a guidance, check the FDA Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
9 FDA guidance for industry Dosage Delivery Devices for Orally Ingested OTC Liquid Drug Products, available at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
  3  Contains Nonbinding Recommendations 
drug products that contain acetaminophen and are labeled only for use in children under 12 years 
of age.10 
 
Product Concentration 
 
  All single-ingredient acetaminophen oral liquids for pediatric use marketed under the 
conditions specified in the IAAA TFM should have a concentration of 160 mg 
acetaminophen per 5 mL. 
 
Label and Labeling 
 
  For single-ingredient acetaminophen oral liquids, the statements 160 mg/5 mL or  
160 mg per 5 mL should be prominently presented on the principal display panel (PDP) 
of the container label and carton labeling immediately below or to the right of the active 
ingredient name (i.e., acetaminophen) and in the same font size as the active ingredient 
name. 
 
  If age is presented on the PDP, the age should correspond to the age range and units of 
age (e.g., months or years) as stated in the Drug Facts Panel under the heading 
Directions.    
    
  If there is an image of a child on the PDP, the image should be representative of the age 
group identified under Directions in the Drug Facts label.  For example, a product 
labeled for use in children 2 years of age or older should not show an infant on the PDP.  
 
  Use of the word new should always include a statement that specifies what is new 
about the product (such as new directions or a new delivery device).  This statement 
should be in conjunction with and have  the same prominence as the word new.  Unless 
required by the Agency, any statement describing the product as new should not appear 
for a period longer than 6 months. 
 
  The dosing directions in the Drugs Facts label should be provided only in milliliters 
(mL). 
 
  If an included dosage delivery device is not clearly visible at point-of-sale, an image or 
picture of the dosage delivery device should appear on the PDP.  It should be located on 
the lower half of the PDP and the dosage delivery device may appear empty or depict the 
lowest labeled dose. 
 
                                                 
10 The Agency may consider issuing future guidance to industry that addresses additional topics such as patient 
populations;, age- or weight-based dosing;, formulation properties (e.g., solubility, viscosity);, and instructions for 
cleaning, reuse, and storage of delivery devices.  
  4  Contains Nonbinding Recommendations 
Drug Delivery11 
 
  The product package should include an appropriate dosage delivery device, such as a 
calibrated and labeled oral syringe or dosing cup.9 
 
  As the dosing directions should be in milliliters (mL), accordingly the dosage delivery 
devices should have calibrated units of liquid measurement expressed in milliliters (mL) 
only.  
 
  If a firm wants to provide a dosage delivery device other than a  graduated, clearly 
marked oral cup or syringe, it should conduct usability studies before the device is 
introduced into the market to ensure the device can be easily understood and accurately 
used by consumers.  In such cases, we encourage the firm to discuss the proposed 
innovative dosage delivery device with FDA before introducing the device into the 
market. 
 
  We recommend the adoption of container features designed to improve safety by 
potentially contributing to more accurate dosing and helping to reduce the incidence and 
magnitude of accidental acetaminophen ingestion by children, such as an appropriate 
flow restrictor contained in the opening of the immediate container.  If a flow restrictor is 
included, it should be attached to the container in a way that prevents it from being 
pushed into the bottle or easily removed.  Firms are encouraged to discuss innovative 
containers/packaging features with FDA before introduction into the market.12   
                                                 
11 This guidance is not intended to address the adequacy of dosage delivery devices to deliver the labeled dosage. 
12 If applicable, these products must be compliant with the poison prevention packaging standards found in Title 16 
of the Code of Federal Regulations (16 CFR 1700.15). 
 
  5