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 

Guidance for Industry1

Adverse Reactions Section of Labeling for Human Prescription 

Drug and Biological Products — Content and Format2

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. 

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. 
Contains Nonbinding Recommendations 

2

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. 
Contains Nonbinding Recommendations 

3

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 placeboand 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 n’s refer to those exposed to drug and not control. 
Contains Nonbinding Recommendations 

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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. 
Contains Nonbinding Recommendations 

5

(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 
Contains Nonbinding Recommendations 

6

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 
Contains Nonbinding Recommendations 

7

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: 
Contains Nonbinding Recommendations 

8

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. 
Contains Nonbinding Recommendations 

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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 wellcontrolled 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. 
Contains Nonbinding Recommendations 

10

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 
Contains Nonbinding Recommendations 

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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 
Contains Nonbinding Recommendations 

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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)). 
Contains Nonbinding Recommendations 

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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.