Guidance for Industry 
Warnings and Precautions, 
Contraindications, and Boxed 
Warning Sections of Labeling for 
Human Prescription Drug and 
Biological Products   
Content and Format  
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2011 
Labeling 
   
Guidance for Industry
 
 
Warnings and Precautions, 
Contraindications, and Boxed 
Warning Sections of Labeling for 
Human Prescription Drug and 
Biological Products   
Content and Format  
 
Additional copies are available from: 
 
Office of Communications 
Division of Drug Information 
10001 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 
 
or 
 
Office of Communication, Outreach and  
Development, HFM-40  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
1401 Rockville Pike, Rockville, MD 20852-1448  
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm   
(Tel) 800-835-4709 or 301-827-1800 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
October 2011 
Labeling 
 
O:\OMP Tracking\OMP Guidances\9878 Warning & Precautions\9878cleanFnl.doc 
10/6/2011  Contains Nonbinding Recommendations 
 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................2 
II.  WARNINGS AND PRECAUTIONS SECTION ( 201.57(c)(6)).................................3 
A.  Adverse Reactions That Should Be Included in the WARNINGS AND PRECAUTIONS 
Section......................................................................................................................................................3 
1. Serious Adverse Reactions...............................................................................................................3 
2. Otherwise Clinically Significant Adverse Reactions.......................................................................4 
3. Anticipated Adverse Reactions........................................................................................................4 
4. Adverse Reactions Associated with Unapproved Uses....................................................................5 
B.  Risks or Other Hazards that Should be Included in the WARNINGS AND PRECAUTIONS 
Section......................................................................................................................................................5 
1. Laboratory Test Interference...........................................................................................................5 
2. Drug Interactions.............................................................................................................................5 
3. Need for Monitoring to Assess Safety..............................................................................................6 
C.  Information to Provide in the Description of an Adverse Reaction..........................................6 
D.  Format.............................................................................................................................................7 
1. Individual Subsections.....................................................................................................................7 
2. Order of Adverse Reactions.............................................................................................................7 
3.  Cross-Referencing...........................................................................................................................8 
4. Emphasis in Text..............................................................................................................................8 
III.  CONTRAINDICATIONS SECTION ( 201.57(c)(5))..................................................8 
A.  When to Contraindicate................................................................................................................8 
1. Observed Adverse Reactions............................................................................................................8 
2. Anticipated Adverse Reactions........................................................................................................8 
B.  Information to Provide................................................................................................................10 
C.  Format...........................................................................................................................................11 
1. Bulleted list....................................................................................................................................11 
2. Order of Contraindications............................................................................................................11 
IV.  BOXED WARNING ( 201.57(c)(1))............................................................................11 
A.  When to Use a Boxed Warning...................................................................................................11 
B.  Information to Provide................................................................................................................12 
C.  Format...........................................................................................................................................12 
GLOSSARY.................................................................................................................................13 
 
  i Contains Nonbinding Recommendations 
 
 
 
1
Guidance for Industry  
 
Warnings and Precautions, Contraindications, and Boxed Warning 
Sections of Labeling for Human Prescription Drug and Biological 
2
Products  Content and Format  
 
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) 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.  
An alternative approach may be used if such 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 assist applicants and reviewers in drafting the WARNINGS AND 
PRECAUTIONS, CONTRAINDICATIONS, and BOXED WARNING sections of labeling, as 
described in the final rule amending the requirements for the content and format of labeling for 
human prescription drug and biological products (21 CFR 201.56 and 201.57).3  The 
recommendations in this guidance are intended to help ensure that the labeling is clear, useful, 
informative, and, to the extent possible, consistent in content and format.   
 
This guidance provides recommendations on the following:  
 
  How to decide which adverse reactions or other potential safety hazards are significant 
enough to warrant inclusion in the WARNINGS AND PRECAUTIONS section; what 
information to include when describing those adverse reactions; and how to organize the 
WARNINGS AND PRECAUTIONS section 
                                                 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
(CDER) and Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 
2 This guidance applies to drugs, including biological drug products.  For the purposes of this guidance, drug 
product or drug will be used to refer to human prescription drug and biological products that are regulated as drugs. 
3 See the final rule Requirements on Content and Format of Labeling for Human Prescription Drug and Biological 
Products, 2006, 71 FR 3922, 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm 
 
Note: We update guidances periodically. To make sure you have the most recent version, check the CDER guidance 
page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
  2 Contains Nonbinding Recommendations 
 
  What situations warrant a contraindication; what information to provide in those 
situations when the use of the product is contraindicated; and how to organize the 
CONTRAINDICATIONS section 
  When to include a boxed warning; and what information to include in the BOXED 
WARNING section 
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.  WARNINGS AND PRECAUTIONS SECTION ( 201.57(c)(6)) 
 
A.  Adverse Reactions That Should Be Included in the WARNINGS AND 
PRECAUTIONS Section 
 
The WARNINGS AND PRECAUTIONS section is intended to identify and describe a discrete 
set of adverse reactions and other potential safety hazards that are serious or are otherwise 
clinically significant because they have implications for prescribing decisions or for patient 
management.  To include an adverse event in the section, there should be reasonable evidence of 
a causal association between the drug and the adverse event, but a causal relationship need not 
have been definitively established.4    
 
Some factors to consider in assessing whether there is reasonable evidence of a causal 
relationship include: (1) the frequency of reporting; 2) whether the adverse event rate in the drug 
treatment group exceeds the rate in the placebo and active-control group in controlled trials; (3) 
evidence of a dose-response relationship; (4) the extent to which the adverse event is consistent 
with the pharmacology of the drug; (5) the temporal association between drug administration and 
the event; (6) existence of dechallenge and rechallenge experience; and (7) whether the adverse 
event is known to be caused by related drugs. 
 
1.  Serious Adverse Reactions  
 
An adverse reaction that results in any of the following outcomes should be considered 
serious and included in the WARNINGS AND PRECAUTIONS section: 
   
  Death  
  A life-threatening adverse event 
  Inpatient hospitalization or prolongation of existing hospitalization 
  A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
  A congenital anomaly or birth defect 
                                                 
4 See the Glossary for definitions of "adverse event" and "adverse reaction." 
  3 Contains Nonbinding Recommendations 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition ( 312.32(a) and 314.80(a)). 
 
 
2.  Otherwise Clinically Significant Adverse Reactions 
 
Adverse reactions that do not meet the definition of a serious adverse reaction, but are 
otherwise clinically significant because they have implications for prescribing decisions 
or patient management, should also be included in the WARNINGS AND 
PRECAUTIONS section.  The following can be factors in determining whether an 
adverse reaction is otherwise clinically significant: 
 
  Indication   
 
The relative seriousness of the disease or condition treated should be considered.  For 
example, non-serious adverse reactions (e.g., nausea, pruritis, alopecia) caused by 
drugs intended to treat minor, self-limiting conditions (e.g., allergic rhinitis, cosmetic 
conditions, transient insomnia) may be considered clinically significant.  However, 
those same adverse reactions caused by drugs intended to treat serious or life-
threatening conditions (e.g., cancer) may be considered much less clinically 
significant and not appropriate for inclusion in this section. 
 
  Incidence 
 
A high absolute risk or rate of occurrence of an adverse reaction can be a factor in 
deciding whether to include the reaction in this section.    
 
The following types of adverse reactions could be considered otherwise clinically 
significant:  
 
  An adverse reaction that may lead to a potentially serious outcome unless the 
dosage or regimen is adjusted, the drug is discontinued, or another drug is 
administered to prevent the serious outcome  
  An adverse reaction that could be prevented or managed with appropriate patient 
selection, monitoring, or avoidance of concomitant therapy, and prevention or 
management of the adverse reaction is needed to avoid a potentially serious 
outcome 
  An adverse reaction that can significantly affect patient compliance, particularly 
when noncompliance has potentially serious consequences 
 
3.  Anticipated Adverse Reactions 
 
  4 Contains Nonbinding Recommendations 
 
There are circumstances in which an adverse reaction that has not been observed with a 
drug can nonetheless be anticipated to occur.  The WARNINGS AND PRECAUTIONS 
section should include serious or otherwise clinically significant adverse reactions (as 
described in section II.A) that are anticipated to occur with a drug if: 
 
  It appears likely that the adverse reaction will occur with the drug based on what is 
known about the pharmacology, chemistry, or class of the drug (e.g., a drug with a 
large QT prolongation effect would be likely to cause Torsades des Pointes 
arrhythmia even if no cases have yet been seen). 
OR 
  Animal data raise substantial concern about the potential for occurrence of the 
adverse reaction in humans (e.g., animal data demonstrating that a drug has 
teratogenic effects) 
Generally, when deemed important for the prescriber, the labeling should acknowledge 
that the adverse reaction has not been observed with the subject drug, but may be 
anticipated to occur. 
 
4.  Adverse Reactions Associated with Unapproved Uses 
 
FDA may require in the WARNINGS AND PRECAUTIONS section a discussion of an 
adverse reaction associated with an unapproved use if the drug is commonly prescribed 
for a disease or condition and such usage is associated with a clinically significant risk or 
hazard ( 201.57(c)(6)(i)).  The description should include a statement indicating that 
safety and effectiveness have not been established in that setting and that the use is not 
approved by FDA.  
 
B.  Risks or Other Hazards that Should be Included in the WARNINGS AND 
PRECAUTIONS Section 
 
1.  Laboratory Test Interference 
 
The WARNINGS AND PRECAUTIONS section must briefly note information on any 
known drug interference with laboratory tests ( 201.57(c)(6)(iv)).  Interference with a 
laboratory test means that the laboratory test result is inaccurate because the drug 
interferes with the assay (e.g., a false positive or negative test result is obtained that does 
not accurately reflect the quantity, presence, or absence of the analyte).  It does not refer 
to a situation in which the test result is accurate, but outside the normal range because of 
the physiological effects caused by the drug or its metabolites.  
 
Only clinically significant interferences should be included.  Interference with a 
laboratory test would be considered clinically significant if reliance on the erroneous test 
result would influence clinical decision-making (e.g., false positive hemoccult test).     
 
2.  Drug Interactions 
 
  5 Contains Nonbinding Recommendations 
 
The WARNINGS AND PRECAUTIONS section should briefly describe any known or 
predicted drug interactions with serious or otherwise clinically significant outcomes and 
cross-reference to any more detailed information elsewhere in the labeling (e.g., 
DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, or CLINICAL 
PHARMACOLOGY sections).  
 
3.  Need for Monitoring to Assess Safety 
 
The WARNINGS AND PRECAUTIONS section must identify any laboratory tests that 
would be helpful or necessary to identify possible adverse reactions ( 201.57(c)(6)(iii)), 
or to prevent a serious adverse reaction.  Information about the frequency of testing and 
expected ranges of normal and abnormal values should also be provided if available. 
 
In general, information on monitoring to assess safety appears in WARNINGS AND 
PRECAUTIONS, and information on monitoring to assess effectiveness appears in 
DOSAGE AND ADMINISTRATION.  In some cases, however, there may not be a clear 
distinction between monitoring for safety and effectiveness (e.g., cardiac monitoring to 
assess both safety and effectiveness in patients receiving antiarrhythmic drugs or INR 
testing to assess both safety and effectiveness in patients receiving warfarin), resulting in 
some overlap of information in WARNINGS AND PRECAUTIONS and DOSAGE 
AND ADMINISTRATION.  Sections IIB, IIC, and IID in FDAs Dosage and 
Administration Final Guidance (Dosage and Administration Section of Labeling for 
Human Prescription Drug and Biological Products  Content and Format) state that the 
DOSAGE AND ADMINISTRATION section of the labeling should contain monitoring 
information to assess both effectiveness and safety, specifically how such monitoring 
affects dosing of the drug (e.g., titrating the dose, modifying the dose, or discontinuing 
treatment).   
  
 
C.  Information to Provide in the Description of an Adverse Reaction 
 
There should be a succinct description of each topic selected for inclusion in the WARNINGS 
AND PRECAUTIONS section.  The description should cross-reference any more detailed 
discussion of the risk elsewhere in labeling (e.g. ADVERSE REACTIONS, DRUG 
INTERACTIONS, USE IN SPECIFIC POPULATIONS, CLINICAL STUDIES).  The 
description should be limited to the following information, and information should be included 
only if known and important to clinical decision making: 
 
  A succinct description of the adverse reaction and outcome (e.g., when the reaction 
occurs, whether the reaction abates over time despite continued treatment, time to 
resolution, significant sequelae).  
  A numerical estimate of risk or adverse reaction rate5 
                                                 
5 In characterizing overall adverse reaction experience, nonspecific terms that lack a commonly understood or 
precise meaning should be avoided because use of such terms can be misleading. For example, the terms rare, 
infrequent, and frequent do not provide meaningful information about the adverse events frequency of occurrence. 
  6 Contains Nonbinding Recommendations 
 
  Known risk factors for the adverse reaction (e.g., age, gender, race, genetic 
polymorphism, comorbid conditions, dose, duration of use, coadministered drugs) 
  Steps to take to decrease the likelihood, shorten the duration, or minimize the severity of 
an adverse reaction.  These steps could include, for example, necessary evaluation prior 
to use, titration and other kinds of dose adjustment, monitoring during dose adjustment or 
prolonged use, avoidance of other drugs or substances, or special care during comorbid 
events (e.g., dehydration, infection)  
  How to treat or otherwise manage an adverse reaction that has occurred 
The information and advice provided should be reasonably qualified, where appropriate, to 
convey whatever uncertainties may exist about judgments and conclusions made (e.g., 
concerning causality assessments, estimated adverse reaction rates, and value of proposed 
monitoring). 
 
Ambiguous and uninformative statements (e.g., use with caution) should be avoided.  Instead, 
specific treatment or management strategies should be noted (e.g., consider lower doses or more 
frequent monitoring). Terminology that generally infers a contraindication (e.g., Do not use or 
Drug X should not be used) should not appear in the WARNINGS AND PRECAUTIONS 
section. 
 
D.  Format  
 
1.  Individual Subsections 
 
Each adverse reaction, syndrome, or group of reactions with a common pathogenesis 
(e.g., allergic contact dermatitis, maculopapular drug rash) included in the WARNINGS 
AND PRECAUTIONS section should have its own numbered subsection.  The 
subsection title should accurately characterize the risk (e.g., 5.1 Thromboembolic 
Disorders, 5.2 Peripheral Neuropathy). When necessary, information in a subsection can 
be organized under non-numbered subheadings using formatting techniques such as 
underlining or italicizing for the subheading titles.  For example, the text of a subsection 
entitled 5.1 Thromboembolic Disorders can include the subheadings Deep Vein 
Thrombosis and Thrombotic Stroke (not 5.1.1 Deep Vein Thrombosis and 5.1.2 
Thrombotic Stroke). Subsection headings that are not useful for signaling the content of 
the subsection (e.g., General) should be avoided. 
 
  2.  Order of Adverse Reactions 
 
The order in which adverse reactions are presented in the WARNINGS AND 
PRECAUTIONS section should reflect the relative clinical significance of the adverse 
reactions.  Factors to consider include the relative seriousness of the adverse reaction, the 
ability to prevent or mitigate the adverse reaction, and the likelihood of its occurrence.  
                                                                                                                                                             
Footnote 5 continued: If categorizing adverse reactions by frequency, ranges would be helpful in understanding the 
drugs safety profile and the ranges should be clearly defined (e.g., occurring at a rate less than 1/100, occurring at a 
rate of less than 1/500). 
  7 Contains Nonbinding Recommendations 
 
 
3.   Cross-Referencing  
 
When more detailed information about an adverse reaction is included in another labeling 
section, the WARNINGS AND PRECAUTIONS section should cross-reference that 
section (e.g., ADVERSE REACTIONS, DRUG INTERACTIONS, CLINICAL 
PHARMACOLOGY), rather than repeat the same information. To the extent possible, 
redundancies should be avoided in labeling, and cross-referencing should be used instead. 
 
4.  Emphasis in Text 
 
Bolded text or other emphasis can be used to highlight particular adverse reactions or 
parts of the discussion of particular adverse reactions (e.g., steps to be taken to avoid a 
problem, subpopulations at particular risk).  Emphasis should be used sparingly so that its 
effect is not diminished.  Thus, the entire text of a subsection in WARNINGS AND 
PRECAUTIONS should not be bolded; rather, bolding should be limited to only one or 
two sentences. Consider whether information to be emphasized should rise to the level of 
a Boxed Warning (see Section IV on BOXED WARNING).  
. 
III.  CONTRAINDICATIONS SECTION ( 201.57(c)(5))   
 
A.  When to Contraindicate  
 
A drug should be contraindicated only in those clinical situations for which the risk from use 
clearly outweighs any possible therapeutic benefit.  Only known hazards, and not theoretical 
possibilities, can be the basis for a contraindication.  If there are no known contraindications for 
a drug, this section must state None. 
   
1.  Observed Adverse Reactions 
 
For observed adverse reactions, the following would ordinarily be reason to 
contraindicate a drug: 
 
  The risk of the adverse reaction in the clinical situation to which the contraindication 
applies, based on both likelihood and severity of the adverse reaction, outweighs any 
potential benefit to any patient. 
AND 
  The causal relationship between exposure to the drug and the adverse reaction is well 
established. 
 
2.  Anticipated Adverse Reactions 
 
Adverse reactions that are anticipated to occur when a drug is used in a specific clinical 
situation can be the basis for a contraindication. 
 
  8 Contains Nonbinding Recommendations 
 
Anticipated adverse reactions are distinguishable from theoretical possibilities. 
Anticipated adverse reactions are supported by data (e.g., from known pharmacologic 
effects, class effect, chemical relationships to other drugs known to cause reactions, 
animal studies) and may be considered for the CONTRAINDICATIONS section. 
Adverse reactions based wholly on theory (theoretical possibilities) are not supported by 
data and would not be appropriate to include in the CONTRAINDICATIONS section.  
 
Ordinarily, a drug should be contraindicated on the basis of an anticipated adverse 
reaction if the risk of the adverse reaction in the clinical situation to which the 
contraindication will apply, based on both likelihood and severity of the adverse reaction, 
outweighs any potential benefit to any patient: 
AND EITHER 
  Based on what is known about the pharmacology, chemistry, or class of the drug, 
it appears highly likely that the adverse reaction is caused by the drug. 
OR 
  Animal data raise substantial concern about the potential for occurrence of the 
adverse reaction in humans (e.g., animal data demonstrating that a drug has 
teratogenic effects). 
 
The labeling should acknowledge that the adverse reaction has not yet been observed, but 
is anticipated to occur.  
 
The following illustrate clinical situations for which a contraindication might be appropriate: 
 
  Use in the presence of a comorbid condition or coexistent physiological state (e.g., existing 
hepatic disease, renal disease, congenital long QT syndrome, hypokalemia, pregnancy or 
childbearing potential, CYP 2D6 poor metabolizer6) 
 
  Use in the presence of a demographic risk factor, such as age, gender or other factors (e.g., 
contraindication in females of reproductive potential, in children below a certain age) 
 
  Use in a defined subset of patients (e.g., people with mild disease) where the risks of the drug 
are such that the drug should never be used in that subset of the larger population7 
 
 
                                                 
6 Use of a particular drug in a patient with a slow metabolizer status would be contraindicated only in situations 
where the dose of the drug could not be adequately adjusted. 
7 The INDICATIONS AND USAGE section must contain information about use of the drug when safety 
considerations are such that the drug should be reserved for certain patients (e.g., patients with severe disease) or 
situations (e.g., patients refractory to other drugs) ( 201.57(c)(2)(i)(B) and (E)).  In rare cases, when the risks of the 
drug clearly outweigh any possible therapeutic benefit and the drug should never be used in a selected patient subset, 
a contraindication for use of the drug in that subset should also be described in the CONTRAINDICATIONS 
section. 
  9 Contains Nonbinding Recommendations 
 
  Use with coadministered drugs where the combination is dangerous (e.g., MAO inhibitor 
with a tricyclic antidepressant; a drug known to prolong the QT interval with a drug known 
to interfere with the metabolism of that drug) 
 
  Use of a drug in patients with known hypersensitivity when severe hypersensitivity reactions 
have been observed to occur with the drug. 
 
A contraindication in patients with hypersensitivity reactions should be included in 
labeling only when there are demonstrated cases of hypersensitivity with the product or 
such reactions may be anticipated based on data from similar drugs (e.g., those in the 
same pharmacological class or with similar chemical structures, or when cross-sensitivity 
within a class is a recognized phenomenon). When the risk of using the drug in a patient 
at risk for such a reaction outweighs the potential benefits (i.e., it would be clinically 
inappropriate to rechallenge a patient with a history of a hypersensitivity reaction to the 
drug or a similar drug), a contraindication to use in such patients should be included.  
Along with the contraindication statement, the labeling should briefly describe the type 
and nature of the observed (or anticipated) reaction(s), and cross-reference to a more 
detailed discussion elsewhere in the labeling, as appropriate.   
 
For example: 
 
DRUG-X is contraindicated in patients with a history of a hypersensitivity reaction to 
[active ingredient]. Reactions have included anaphylaxis and anaphylactoid reactions [see 
Adverse Reactions (6.2)]. 
 
If no such hypersensitivity reactions as noted above have been observed or are unlikely to 
occur based on the drug's characteristics, no contraindication for hypersensitivity 
reactions will be included.  
 
Contraindications based on drug interactions with serious outcomes should be described briefly 
in the CONTRAINDICATIONS section and cross-referenced to more detailed information in the 
DRUG INTERACTIONS or CLINICAL PHARMACOLOGY sections.  
 
B.  Information to Provide 
 
Contraindications should be worded using precise language, e.g., Drug X is contraindicated in 
patients with condition Y (instead of Drug X should not be used in patients with condition Y).  
If a drug has more than one contraindication, use an introductory statement (e.g., "Drug X is 
contraindicated in:") followed by a bulleted list identifying each contraindication. 
 
For each listed contraindication, provide the following information: 
 
  Brief description of the contraindicated situation or scenario, including any pertinent 
demographic or identifiable predisposing characteristics  
 
  Description of observed or anticipated consequences of the contraindicated use  
  10 Contains Nonbinding Recommendations 
 
 
C.  Format  
 
1.  Bulleted list 
 
If a drug has more than one contraindication, FDA recommends that each 
contraindication be identified in a bulleted list. 
  
2.  Order of Contraindications  
 
The order in which contraindications are presented should reflect the relative clinical 
significance of the listed contraindications.  Factors to consider include the severity of the 
risk and the likelihood of occurrence.  
 
 
IV.  BOXED WARNING ( 201.57(c)(1)) 
 
A.  When to Use a Boxed Warning  
 
A boxed warning is ordinarily used to highlight for prescribers one of the following situations: 
 
  There is an adverse reaction so serious in proportion to the potential benefit from the drug 
(e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential 
that it be considered in assessing the risks and benefits of using the drug 
OR 
  There is a serious adverse reaction that can be prevented or reduced in frequency or 
severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding 
certain concomitant therapy, addition of another drug or managing patients in a specific 
manner, avoiding use in a specific clinical situation) 
      OR 
  FDA approved the drug with restrictions to ensure safe use because FDA concluded that 
the drug can be safely used only if distribution or use is restricted (e.g., under 21 CFR 
314.520 and 601.42 Approval with restrictions to assure safe use or under 505-1(f)(3) of 
the Federal Food, Drug, and Cosmetic Act (FDCA) "Risk Evaluation and Mitigation 
Strategies Elements to assure safe use). 
 
Infrequently, a boxed warning can also be used in other situations to highlight warning 
information that is especially important to the prescriber (e.g., reduced effectiveness in certain 
patient populations).  Information included in the WARNINGS AND PRECAUTIONS and 
CONTRAINDICATIONS sections should therefore be evaluated to determine whether it 
warrants inclusion in a boxed warning.   
 
Boxed warnings are most likely to be based on observed serious adverse reactions, but there are 
instances when a boxed warning based on an anticipated adverse reaction would be appropriate.  
  11 Contains Nonbinding Recommendations 
 
For example, a contraindication to use during pregnancy based on evidence in humans or 
animals that drugs in a pharmacologic class pose a serious risk of developmental toxicity during 
pregnancy would usually be in a boxed warning for all drugs in that class, even those in which 
the adverse reaction has not been observed.  
 
A boxed warning can also be considered for a drug that poses riskbenefit considerations that are 
unique among drugs in a drug class (e.g., to note when a drug is the only one in its class to have 
a particular risk and is indicated as second line therapy because of that risk).  
 
B.  Information to Provide  
 
A boxed warning provides a brief, concise summary of the information that is critical for a 
prescriber to consider, including any restriction on distribution or use.  There is typically a more 
detailed discussion of the risk elsewhere in the labeling (e.g., in CONTRAINDICATIONS or 
WARNINGS AND PRECAUTIONS sections), that must be identified by a cross-reference ( 
201.57(c)(1)).   
 
C.  Format  
 
The BOXED WARNING section in the full prescribing information must be formatted in 
accordance with  201.57(d).  The information in the boxed warning should be in bold print and 
presented in a bulleted format or some alternative format, such as the use of subheadings, that 
helps to make the information visually accessible.   
  
  12 Contains Nonbinding Recommendations 
 
 
GLOSSARY 
 
 
Adverse Reaction (21 CFR 201.57(c)(7)):  For purposes of prescription drug labeling and this 
guidance, an adverse reaction is an undesirable effect, reasonably associated with the use of a 
drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in 
its occurrence.  This definition does not include all adverse events observed during use of a drug, 
only those for which there is some basis to believe there is a causal relationship between the drug 
and the occurrence of the adverse event.   
 
Adverse reactions may include signs and symptoms, changes in laboratory parameters, and 
changes in other measures of critical bodily function, such as vital signs and electrocardiogram 
(ECG). 
 
Adverse Event:  For the purposes of this guidance, an adverse event refers to any untoward 
medical occurrence associated with the use of a drug in humans, whether or not considered drug 
related. 
 
Serious Adverse Reaction:  For purposes of this guidance, the term serious adverse reaction 
refers to any event or reaction that results in any of the following outcomes:  Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly or birth defect.  Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.   
  
  13