Guidance for Industry
 
 
 
Adverse Reactions Section 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) 
January 2006 
Labeling 
 
   
Guidance for Industry
 
 
 
Adverse Reactions Section of Labeling for 
Human Prescription Drug and Biological 
Products   Content and Format 
 
 
 
 Additional copies are available from: 
 
 Office of Training and Communications 
 Division of Drug Information, HFD-240  
Center for Drug Evaluation and Research 
Food and Drug Administration 
 5600 Fishers Lane,  
Rockville, MD  20857  
(Tel) 301-827-4573 
(Internet) http://www.fda.gov/cder/guidance/index.htm 
  
or 
 
 Office of Communication, Training and  
Manufacturers Assistance, HFM-40  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
1401 Rockville Pike, Rockville, MD 20852-1448  
(Tel) 800-835-4709 or 301-827-1800 
   (Internet) http://www.fda.gov/cber/guidelines.htm   
 
 
 
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) 
January 2006 
Labeling 
  Contains Nonbinding Recommendations 
Table of Contents 
 
 
 
I.  INTRODUCTION.................................................................................................................1 
II.  BACKGROUND...................................................................................................................1 
III.  ADVERSE REACTIONS SECTION  CONTENT AND FORMAT............................2 
A.  Making the Most Clinically Important Information Accessible................................................2 
B.  Adverse Reactions From Clinical Trials......................................................................................3 
C.  Presentation of Adverse Reaction Information From Spontaneous Reports...........................7 
IV.  GENERAL PRINCIPLES FOR SELECTING AND CHARACTERIZING DATA IN 
THE ADVERSE REACTIONS SECTION........................................................................8 
A.  Selecting Adverse Events for Inclusion........................................................................................8 
B.  Rare, Serious Reactions.................................................................................................................8 
C.  Determining Adverse Reaction Rates..........................................................................................8 
D.  Avoiding Nonspecific Terms.........................................................................................................9 
E.  Comparative Safety Claims..........................................................................................................9 
F.  Negative Findings...........................................................................................................................9 
V.  GENERAL PRINCIPLES FOR PRESENTING ADVERSE REACTIONS DATA IN A 
TABLE OR LIST..................................................................................................................9 
A.  Pooling Data...................................................................................................................................9 
B.  Classifying Adverse Reactions....................................................................................................10 
C.  Categorizing Adverse Reactions.................................................................................................10 
D.  Frequency Cutoff.........................................................................................................................10 
E.  Quantitative Data.........................................................................................................................10 
F.  Denominator.................................................................................................................................10 
G.  Subgroup Rates............................................................................................................................10 
H.  Percentages...................................................................................................................................11 
I.  Adverse Reaction Rates for Drug Less Than for Placebo........................................................11 
J.  Significance Testing.....................................................................................................................11 
VI.  UPDATING THE ADVERSE REACTIONS SECTION................................................11 
A.  Sources of Information................................................................................................................11 
B.  New or Outdated Information....................................................................................................11 
GLOSSARY.................................................................................................................................13 
  Contains Nonbinding Recommendations 
 
1
Guidance for Industry  
Adverse Reactions Section of Labeling for Human Prescription 
2
Drug and Biological 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.  
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 applicants and reviewers in drafting the ADVERSE 
REACTIONS section of prescription drug labeling as required by 21 CFR 201.57(c)(7).  Its 
primary purpose is to aid in (1) selecting information for inclusion in the section, (2) 
characterizing adverse reactions selected for inclusion, (3) organizing and presenting the 
information within the section, and (4) updating adverse reaction information.  The goal of this 
guidance is to assist applicants in designing ADVERSE REACTIONS sections that contain the 
drug safety information important to patient management decisions and that convey the 
information in a clear and accessible format.  
 
FDAs guidance documents, including this guidance, 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 
 
As this guidance seeks to bring greater consistency to the content and format of the ADVERSE 
REACTIONS section, the Agency emphasizes that reviewer and applicant judgment remain 
critical in assessing how or whether to present information on an adverse reaction.  FDA 
reviewers and applicants should assess such factors as seriousness, severity, frequency, and 
                                                 
1 This guidance has been prepared by the Medical Policy Coordinating Committee in the Center for Drug Evaluation and 
Research (CDER) in conjunction with the Center for Biologics Evaluation and Research (CBER).   
 
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. 
 
  Contains Nonbinding Recommendations 
strength of causal association in determining which adverse reactions to include in the 
ADVERSE REACTIONS section and in characterizing those reactions.  In general, the 
ADVERSE REACTIONS section includes only information that would be useful to health care 
practitioners making treatment decisions and monitoring and advising patients.  Exhaustive lists 
of every reported adverse event, including those that are infrequent and minor, commonly 
observed in the absence of drug therapy or not plausibly related to drug therapy should be 
avoided (see  201.57(c)(7) and the Glossary at the end of this guidance for a definition of 
Adverse Reaction).  Such lists are not informative and tend to obscure the more clinically 
meaningful information.   
 
III.  ADVERSE REACTIONS SECTION  CONTENT AND FORMAT 
 
The ADVERSE REACTIONS section is required to list the adverse reactions that occur with the 
drug and with drugs in the same pharmacologically active and chemically related class, if 
applicable ( 201.57(c)(7)(i)).  Separate lists are required for adverse reactions identified from 
clinical trials ( 201.57(c)(7)(ii)(A)) and those identified from spontaneous reports after a drug 
has been marketed ( 201.57(c)(7)(ii)(B)).   This section of the guidance provides 
recommendations for ensuring that information about the most clinically important adverse 
reactions is readily accessible (see III.A), and for organizing the information on adverse 
reactions from clinical trials (see III.B) and from postmarketing safety reports (see III.C).   
 
A.  Making the Most Clinically Important Information Accessible 
 
Typically, adverse reactions for a given drug will have varying clinical significance 
(ranging from serious to minor) and certain adverse reactions that have relatively serious 
clinical implications will be discussed, often in greater detail, in other sections of labeling 
(e.g., WARNINGS AND PRECAUTIONS, CONTRAINDICATIONS, and BOXED 
WARNING).  The ADVERSE REACTIONS section should make it easier for health 
care practitioners to recognize and retain the adverse reactions information that is most 
important to prescribing decisions.  The beginning of the ADVERSE REACTIONS 
section should identify the most clinically significant adverse reactions and direct 
practitioners to more detailed information about those reactions, if any.  For example, the 
section should first: 
 
  Identify and cross-reference all serious and otherwise important adverse reactions 
described in greater detail in other labeling sections, especially BOXED WARNING 
or WARNINGS AND PRECAUTIONS (e.g., see WARNINGS AND 
PRECAUTIONS (5.1)). 
 
  Identify the most commonly occurring adverse reactions (e.g., all adverse reactions 
occurring at a rate of 10 percent or greater in the treatment group and at a rate at least 
twice the placebo rate). 
 
  Identify adverse reactions, if any, that resulted in a significant rate of discontinuation 
or other clinical intervention (e.g., dosage adjustment, need for other therapy to treat 
an adverse reaction) in clinical trials. 
  2 Contains Nonbinding Recommendations 
 
 
B.  Adverse Reactions From Clinical Trials 
 
The presentation of adverse reactions identified from clinical trials is the major 
component of the ADVERSE REACTIONS section.  The ADVERSE REACTIONS 
section must include a listing of all such reactions that occurred at or above a specified 
rate that is appropriate to the drugs safety database (see III.B.3), a separate listing of 
those adverse reactions that occurred below the specified rate, but for which there is 
some basis to believe there is a causal relationship between the drug and the event (see 
III.B.4), and, to the extent information is available and relevant, additional detail about 
the nature, frequency, severity, duration, dose-response, and demographic characteristics 
of those adverse reactions with significant clinical implications ( 201.57(c)(7)(ii)(A)).  
The following is the recommended organization of adverse reactions identified from 
clinical trials. 
 
   1.  Description of Data Sources 
 
The presentation of adverse reactions information identified from clinical trials 
must be preceded by information necessary to interpret the adverse reactions  
( 201.57(c)(7)(i)).  This information would ordinarily include a description of 
the overall clinical trial database from which adverse reaction data have been 
drawn, including a discussion of overall exposure (number of patients, dose, 
schedule, duration), demographics of the exposed population, designs of the trials 
in which exposure occurred (e.g., placebo-controlled, active-controlled), and any 
critical exclusions from the safety database. 
 
Sample Database Description  
 
The data described below reflect exposure to drug X in [n]3 
patients, including [n] exposed for 6 months and [n] exposed for 
greater than one year.  Drug X was studied primarily in placebo- 
and active-controlled trials (n = __, and n = ___, respectively), 
and in long-term follow up studies.  The population was [age 
range], [gender distribution], [race distribution] and had 
[diseases/conditions].   Most patients received doses [describe 
range, route of administration, frequency, duration, as 
appropriate]. 
   
2.  Statement on the Significance of Adverse Reaction Data Obtained From 
Clinical Trials 
 
To help place in perspective the significance of adverse reaction data obtained   
from clinical trials, the following statement, or an appropriate modification, 
should precede the presentation of adverse reactions from clinical trials: 
                                                 
3 All ns refer to those exposed to drug and not control. 
  3 Contains Nonbinding Recommendations 
 
Because clinical trials are conducted under widely varying 
conditions, adverse reaction rates observed in the clinical 
trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates 
observed in practice. 
 
3.   Presentation of Common Adverse Reactions (the Adverse Reactions 
Table) 
 
The ADVERSE REACTIONS section next should list the adverse reactions 
identified from clinical trials that occurred at or above a specified rate appropriate 
to the database (for purposes of this guidance, common adverse reactions).  The 
listing must include the rate of occurrence of an adverse reaction for the drug and 
any comparators (active- or placebo-controls), unless such data cannot be 
determined or presenting the rates for a comparator would be misleading ( 
201.57(c)(7)(ii)(A)).  To permit side-by-side comparison of adverse reaction 
rates, common adverse reactions are typically presented in a table. 4 
  
a.  Use Best Available Data 
 
The data in the listing of common adverse reactions should be derived 
from placebo-controlled and/or dose-response studies if these data are 
available and the databases are sufficiently large to be informative.  If 
these data are unavailable or not sufficiently informative, the primary 
table should be based on active-controlled data.  If concurrently controlled 
data are unavailable, overall rates from well-monitored, single-arm 
databases can be used to provide some indication of what was observed in 
treated patients.  In general, only the most informative data should be 
presented in the table.  For example, if placebo-controlled data were 
available and sufficiently informative, there would usually be no need to 
present in a table active-controlled data, single-arm trial data, or the 
overall safety data, even if they are from larger databases.  If a data source 
is not used in the development of a table, but provides important 
information about adverse reactions listed in the table that is not found in 
the trials used in the development of the table (e.g., information about 
prolonged duration of therapy), that information can be discussed in the 
commentary following the table (see III.B.5). 
 
b.  Description of Data Sources for the Table 
 
The table should be accompanied by a description of the data sources 
reflected in the table, the basis for including adverse reactions in the table 
                                                 
4 A table can include less common, even rare, important events when the database is large enough to provide a 
meaningful comparison to a control group.  
  4 Contains Nonbinding Recommendations 
(e.g., all reactions occurring at > n% in the treated group and for which the 
rate for drug exceeds the rate for placebo), and the way in which adverse 
reaction rates were derived (e.g., for a given adverse reaction, was the rate 
derived from all reported adverse events of that type not present at 
baseline or from a subset of reported events deemed by investigators to be 
drug-related).  The description of data sources should indicate the types of 
studies from which the information in the table was derived and whether 
the study data were pooled.  This information can be provided in text 
preceding the table, in a footnote to the table, in the title to the table, or 
some combination of these.  
 
  c.  How Many Tables? 
 
A single adverse reaction table will usually be adequate.  However, it may 
be more informative to present data in more than one table when a drugs 
adverse reaction profile differs substantially from one setting or 
population to another, the adverse reactions that differ are clearly drug 
related, and the data have important implications for use (or nonuse) and 
monitoring.  Situations in which there may be important differences 
between rates include different indications, formulations, demographic 
subgroups, study durations, dosing regimens, and types of studies (e.g., 
intensely monitored small studies vs. a large outcome study).  In these 
situations, the content of the additional table or tables should be limited to 
only those adverse reactions for which there were meaningful differences 
in rates.   
 
4.  Presentation of Less Common Adverse Reactions 
 
The ADVERSE REACTIONS section next should present those adverse reactions 
that occurred below the specified rate for inclusion in the common adverse 
reactions table or listing, but for which there is some basis to believe there is a 
causal relationship between the drug and the event (for purposes of this guidance, 
less common adverse reactions).  It is difficult to establish that very low 
frequency adverse events are caused by a drug, and there will often be large 
numbers of these events reported, most of them not caused by the drug.  Lengthy 
lists of adverse events unlikely to have been caused by the drug are of little or no 
value to prescribers, and are therefore inappropriate for inclusion in labeling.   
 
Serious, low-frequency adverse events generally will be listed when there is 
reason to suspect that the drug may have caused the event.  Typical reasons to 
suspect causality for an event include (1) timing of onset or termination with 
respect to drug use, (2) plausibility in light of the drugs known pharmacology, 
(3) occurrence at a frequency above that expected in the treated population, and 
(4) occurrence of an event typical of drug-induced adverse reactions (e.g., liver 
necrosis, agranulocytosis, Stevens-Johnson syndrome).  For serious events that 
are typical of drug-induced adverse reactions, the occurrence of even a single 
  5 Contains Nonbinding Recommendations 
event could be a basis for inclusion in the list.  When none of these reasons exist, 
however, an event should be excluded from the list.  For example, in a large study 
of a non-cardiovascular drug in elderly patients, a certain number of acute 
myocardial infarctions might be expected unrelated to the study drug.  If the rate 
in the study does not exceed the expected rate, those adverse events should be 
excluded from the ADVERSE REACTIONS section. 
 
Non-serious, low-frequency adverse events should be listed only when there is 
strong evidence that the drug caused the event.  Such evidence may include, for 
example, positive challenge/dechallenge tests or rate of occurrence in a large 
controlled trial that, although low, is markedly imbalanced between drug and 
control arms.  
 
5.  Commentary on Listings of Common and Less Common Adverse 
Reactions 
 
  For adverse reactions with significant clinical implications (e.g., those that are 
most commonly occurring, that result in discontinuation or dose modification, or 
that require monitoring), the listings of common and less common adverse 
reactions must be supplemented with additional details about the nature, 
frequency, severity, dose-response, and demographic characteristics of the 
adverse reaction, to the extent data are available and important ( 
201.57(c)(7)(ii)(A)).  It is more likely that supplemental information will be 
needed for the more commonly occurring adverse reactions.   
 
  a.  Information on Nature, Frequency, and Severity  
 
To the extent information is available and important and bears on the 
nature, frequency, and severity of clinically important adverse reactions, 
the commentary must discuss applicable factors ( 201.57(c)(7)(ii)(A)).  
Examples include:  
 
  Concomitant therapy   
  Time course of the reaction 
  Steps that can diminish the likelihood or severity of, or prevent, 
adverse reactions 
  Changes in adverse reaction rates as a function of duration of therapy 
(e.g., increasing or decreasing (tolerance) rates with increasing 
duration of therapy, adverse reactions that emerge only with long-term 
use) 
 
b.  Dose-Response Information 
 
The commentary must identify clinically significant adverse reactions that 
exhibit a dose response ( 201.57(c)(7)(ii)(A)).  It may be helpful to 
  6 Contains Nonbinding Recommendations 
include a small table showing the dose response for adverse reactions for 
which dose response would be expected to influence dose selection. 
 
c.  Demographic and Other Subgroups 
 
  The commentary must include clinically important information about 
observed differences, or lack of observed differences, in adverse reactions 
in various demographic groups (e.g., age, racial, gender) ( 
201.57(c)(7)(ii)(A)).  If information is available and important, the 
commentary should also discuss observed differences, or lack of observed 
differences, for other subgroups (e.g., renal failure, liver failure, different 
severity levels of same disease).  Where there is no reliable information on 
differences or similarities in adverse reaction profiles among demographic 
subgroups, that fact should be disclosed, along with an explanation of why 
such information is unavailable (e.g., clinical trials were not designed or 
powered to detect differences in these populations). 
 
    d.  Multiple Indications  
 
The commentary should summarize any important differences or 
similarities in the adverse reactions profiles for different indications.  If 
there are substantial and clinically important differences in adverse 
reaction profiles between indications, and the differences cannot be 
adequately summarized in the commentary, there should be separate 
listings of adverse reactions for each indication.  When warranted, 
clinically important differences or similarities in adverse reaction profiles 
for multiple indications can also be identified in a more prominent 
location in the ADVERSE REACTIONS section (e.g., at the beginning of 
the section).  
 
    e.  Multiple Formulations 
 
If a drug has multiple formulations and a certain formulation or 
formulations present unique adverse reaction concerns, the commentary 
should identify clinically important concerns. 
 
C.  Presentation of Adverse Reaction Information From Spontaneous Reports 
 
The ADVERSE REACTIONS section must list adverse reactions identified from 
domestic and foreign spontaneous reports ( 201.57(c)(7)(ii)(B)).  This listing must be 
separate from the listing of adverse reactions identified in clinical trials ( 
201.57(c)(7)(ii)(B)) and must also be preceded by information necessary to interpret the 
adverse reactions (201.57(c)(7)(i)). To help practitioners interpret the significance of 
data obtained from postmarketing spontaneous reports, the following statement, or an 
appropriate modification, should precede these data: 
 
  7 Contains Nonbinding Recommendations 
The following adverse reactions have been identified during 
postapproval use of drug X.  Because these reactions are reported 
voluntarily from a population of uncertain size, it is not always 
possible to reliably estimate their frequency or establish a causal 
relationship to drug exposure. 
 
Decisions about whether to include an adverse event from spontaneous reports in 
labeling are typically based on one or more of the following factors:  (1) 
seriousness of the event, (2) number of reports, or (3) strength of causal 
relationship to the drug.  When an adverse reaction identified from spontaneous 
reporting is included in the labeling, the number of spontaneous reports ordinarily 
is not cited, because the number can quickly become outdated.  If the number of 
reports is cited, the period of observation should be stated.   
 
IV.  GENERAL PRINCIPLES FOR SELECTING AND CHARACTERIZING DATA 
IN THE ADVERSE REACTIONS SECTION  
 
A.  Selecting Adverse Events for Inclusion 
 
The definition of adverse reactions does not include all adverse events observed during 
use of a drug.  It is limited to those events for which there is some basis to believe there 
is a causal relationship between occurrence of an adverse event and the use of a drug  
( 201.57(c)(7)).  Decisions on whether there is some basis to believe there is a causal 
relationship are a matter of judgment and are based on factors such as:  (1) the frequency 
of reporting, (2) whether the adverse event rate for the drug exceeds the placebo rate, (3) 
the extent of dose-response, (4) the extent to which the adverse event is consistent with 
the pharmacology of the drug, (5) the timing of the event relative to the time of drug 
exposure, (6) existence of challenge and dechallenge experience, and (7) whether the 
adverse event is known to be caused by related drugs.     
 
B.  Rare, Serious Reactions 
 
For serious adverse events that are unusual in the absence of drug therapy (e.g., liver 
failure, agranulocytosis, rhabdomyolysis, idiopathic thrombocytopenic purpura, 
intussusception), there is a basis to believe there is a causal relationship between the 
event and the drug at a very low rate of occurrence.  Therefore, these events are generally 
listed in the adverse reactions section even if there are only one or two reported events, 
unless it is clear that a causal relationship can be excluded. 
 
C.  Determining Adverse Reaction Rates  
 
The rate of an identified adverse reaction is ordinarily derived from all reported adverse 
events of that type in the database used.  Determining a rate based on a subset of reported 
events that individual investigators believe to be causally related to drug exposure is 
discouraged.  Excluding events from the rate calculation based on the judgment of 
individual investigators introduces bias and inconsistency in rate determinations. 
 
  8 Contains Nonbinding Recommendations 
D.  Avoiding Nonspecific Terms 
 
In characterizing overall adverse reaction experience, nonspecific terms that lack a 
commonly understood or precise meaning are discouraged, as use of such terms can be 
misleading.  For example, the phrase well-tolerated is a vague and subjective judgment 
about a drugs adverse reaction profile for which there are no commonly understood 
parameters.  In addition, the terms rare, infrequent, and frequent do not provide 
meaningful information about the frequency of occurrence of adverse reactions.  Specific 
frequency ranges (e.g., adverse reactions occurring in < 1/500) provide more precise 
information about incidence. 
 
E.  Comparative Safety Claims 
 
Comparative safety claims for drugs in terms of frequency, severity, or character of 
adverse reaction must be based on data from adequate and well-controlled studies (as 
defined in 21 CFR 314.126), unless this requirement is waived ( 201.57(c)(7)(iii)).5  
Details of studies that are the basis for comparative safety claims would ordinarily be 
discussed in the CLINICAL STUDIES section of the labeling.  Care should be taken to 
avoid inclusion of comparator rates that would imply a comparative safety claim that is 
unsubstantiated or otherwise misleading (e.g., if an excessive dose of an active 
comparator was used).  If the requirement that claims be based on adequate and well-
controlled studies is waived to permit inclusion of comparative rates (e.g., because the 
identity and rates of adverse reactions for the active comparator are important to 
understanding the significance of the information), the comparator rates should be 
qualified by a disclaimer indicating that the data are not an adequate basis for comparison 
of rates between the study drug and the active control.6 
 
F.  Negative Findings 
 
A negative finding can be reported if the absence of the reaction is convincingly 
demonstrated in a trial of adequate design and power. 
 
V.  GENERAL PRINCIPLES FOR PRESENTING ADVERSE REACTIONS DATA IN 
A TABLE OR LIST 
 
A.  Pooling Data 
 
If there are no major study-to-study differences in study design, study population, and 
adverse reaction rates, an overall pooling of safety data from multiple studies may 
increase the precision of adverse reaction rates and provide a more clinically useful 
representation of a drugs adverse reaction profile.  
 
                                                 
5 The requirement can be waived under 21 CFR 201.58, or 21 CFR 314.126(c), if applicable. 
6 Also see the discussion of comparative data in the guidance for industry on Clinical Studies Section of Labeling for 
Human Prescription Drug and Biological ProductsContent and Format. 
  9 Contains Nonbinding Recommendations 
B.  Classifying Adverse Reactions 
 
Adverse reactions should be classified using meaningful and specific terms that best 
communicate the nature and significance of the reaction.  There should ordinarily be a 
common classification scheme across all studies in the safety database.  Events that are 
reported under different terms in the database, but that represent the same phenomenon 
(e.g., sedation, somnolence, drowsiness) should ordinarily be grouped together as a single 
adverse reaction to avoid diluting or obscuring the true effect.  Similarly, adverse events 
reported in more than one body system that appear to represent a common 
pathophysiologic event should be grouped together to better characterize the reaction.  
For example, an allergic-type adverse event that has respiratory (wheezing) and 
dermatologic (rash, urticaria) manifestations should be classified as a single adverse 
reaction (e.g., hypersensitivity).   
 
C.  Categorizing Adverse Reactions 
 
Within a listing, adverse reactions must be categorized by body system, by severity of 
reaction, in order of decreasing frequency, or by a combination of these, as appropriate.  
Within a category, adverse reactions must be listed in decreasing order of frequency.  If 
frequency cannot be reliably determined, adverse reactions must be listed in decreasing 
order of severity ( 201.57(c)(7)(ii)). 
   
D.  Frequency Cutoff 
 
The frequency cutoff for the listing of common adverse reactions identified from clinical 
trials (usually the adverse reactions table) must be appropriate to the safety database  
( 201.57(c)(7)(ii)(A)).  Factors that could influence selection of a frequency cut-off 
include the size of the safety database, the designs of the trials in the database, and the 
nature of the indication.  The frequency cutoff should be noted in the listing or table 
header, in the text accompanying the listing or table, or in a footnote.   
 
E.  Quantitative Data 
 
For quantitative data (e.g., abnormal laboratory values, vital signs, ECGs), it is usually 
preferable to present rates of abnormal values and to specify the cutoff value for 
inclusion (e.g., five times the upper limit of normal) than to refer to a grading system. 
 
F.  Denominator 
 
The denominator (N = number of patients) should be provided for each column in a table 
or listing, except for the listing of adverse reactions identified from postmarketing 
spontaneous reports (see III.C).  
 
G.  Subgroup Rates 
 
  10 Contains Nonbinding Recommendations 
The rates for reactions that are specific to a subgroup (e.g., gender-specific reactions such 
as menstrual irregularity) should be determined using the appropriate denominator, and 
that denominator should be identified in a footnote.  If rates of specific adverse reactions 
were gathered for only a subgroup of patients or studies (e.g., an adverse effect on a 
laboratory test), that fact should be disclosed in a footnote. 
 
H.  Percentages 
 
Adverse reaction rates expressed in percentages should ordinarily be rounded to the 
nearest integer.  An exception would be for particularly serious adverse reactions (e.g., 
stroke, intracranial hemorrhage, agranulocytosis) occurring at low rates in a large study 
where fractions of a percent may be meaningful.  
 
I.  Adverse Reaction Rates for Drug Less Than for Placebo 
 
Adverse reactions for which the placebo rate equals or exceeds the rate for the drug (after 
rounding) should not be included in the ADVERSE REACTIONS section unless there is 
some compelling factor (e.g., timing) that suggests that the event is caused by the drug.  
In that case, the adverse reaction should be discussed in the commentary following the 
table.  
 
J.  Significance Testing 
 
Results of significance testing should be omitted unless they provide useful information 
and are based on a prespecified hypothesis in an adequately designed and powered study. 
 
VI.  UPDATING THE ADVERSE REACTIONS SECTION  
 
A.  Sources of Information 
 
Sources of information to be considered when updating the ADVERSE REACTIONS 
section of labeling include controlled trials or epidemiologic studies conducted after 
marketing approval, manufacturer's safety-related labeling supplements, and other 
analyses of postmarketing adverse events, including single cases or case series from the 
literature or from spontaneous reporting.  
 
B.  New or Outdated Information 
 
Applicants are urged to review at least annually the content of the ADVERSE 
REACTIONS section to ensure that the information remains current.  We expect the 
labeling to be consistent with newly acquired information from controlled trials or 
spontaneous reports and with the evolution of labeling in the pertinent drug class.  
Conversely, when there is reliable new adverse reaction information (either overall 
information or information relevant to a particular adverse reaction) that is inconsistent 
with the information in the ADVERSE REACTIONS section, we expect the outdated 
information to be deleted from all affected sections of the labeling or appropriately 
  11 Contains Nonbinding Recommendations 
modified, and the new information incorporated in all relevant parts of the labeling.  The 
applicant must update the labeling when new information becomes available that causes 
the labeling to become inaccurate, false, or misleading (21 CFR 201.56(a)(2)).   
  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 body function, such as vital signs and ECG. 
 
Adverse Event (or adverse experience):  For the purposes of this guidance, the term adverse 
event refers to any untoward medical event 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 reaction occurring at any dose that results in any of the following outcomes:  death, 
a life-threatening adverse experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability or incapacity, 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 adverse reactions 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