Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
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
Adverse Reactions Section of Labeling for
Human Prescription Drug and Biological
Products — Content and Format

Guidance for Industry
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
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

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
Guidance for Industry1
Adverse Reactions Section of Labeling for Human Prescription
Drug and Biological Products — Content and Format2
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.
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. 	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.
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.

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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.

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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 drug’s 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], [sex 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 n’s refer to those exposed to drug and not control.

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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.

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(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 drug’s
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 drug’s 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

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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

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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, sex) (§
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:

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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.

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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 drug’s 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 drug’s 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 Products—Content and Format.

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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

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The rates for reactions that are specific to a subgroup (e.g., sex-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

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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)).

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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.