Indications and Usage Sectionof Labeling for Human Prescription
Drug and Biological Products —Content and Format

Guidance for Industry
DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit writtencomments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with thedocket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Iris Masucci at 301-796-2500 or(CBER) the Office of Communication, Outreach and Development at 800-835-4709 or 240-4028010.

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)
July 2018
Labeling

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Indications and Usage Sectionof Labeling for Human Prescription
Drug and Biological Products —Content and Format

Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/orOffice of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.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)
July 2018
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TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1

II.

GENERAL PRINCIPLES................................................................................................ 2A.

Scope of the Indication(s) .............................................................................................................. 3

1. Scope of an Indication Relative to the Population Studied .............................................................. 3
2. Age Groups in Indications ............................................................................................................... 4
B. Distribution of Information Among Labeling Sections .............................................................. 6C.

Updating the INDICATIONS AND USAGE Section ................................................................. 6

III.

CONTENT AND FORMAT OF THE INDICATIONS AND USAGE SECTION ..... 6

A.

Indication ........................................................................................................................................ 7

1. The Disease, Condition, or Manifestation Being Treated, Prevented, Mitigated, Cured, orDiagnosed............................................................................................................................................. 8
2. Other Information Necessary To Describe the Approved Indication .............................................. 8
B. Limitations of Use ........................................................................................................................ 10
1. Situations in Which Limitations of Use Would Be Appropriate..................................................... 11
2. Situations in Which Limitations of Use Generally Would Not Be Appropriate ............................. 13
C. Other Considerations for Writing the INDICATIONS AND USAGE Section ...................... 14
1. Identification of Outcomes, Endpoints, and Benefit(s) the Drug Conveys..................................... 14
2. Accelerated Approval..................................................................................................................... 15
3. Required or Recommended Language ........................................................................................... 15
4. Preferred Wording and Wording Generally To Avoid................................................................... 16
D. Formatting the INDICATIONS AND USAGE Section ............................................................ 16
1. Format for Multiple Indications .................................................................................................... 16
2. Format for Limitations of Use ....................................................................................................... 17

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Indications and Usage Section of Labeling for Human Prescription
Drug and Biological Products – Content and Format
Guidance for Industry1

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is notbinding on FDA or the public. You can use an alternative approach if it satisfies the requirements of theapplicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
for this guidance as listed on the title page.

I.

INTRODUCTION

This guidance is intended to assist applicants in drafting the INDICATIONS AND USAGE
section of labeling as described in the regulations for the content and format of labeling forhuman prescription drug and biological products2 (21 CFR 201.57(c)(2)).3
Recommendations include the following:General principles to consider when drafting the INDICATIONS AND USAGE sectionof the labelingWhat information to include in the INDICATIONS AND USAGE sectionWhen to include additional descriptors or qualifiers as part of the indication in the
INDICATIONS AND USAGE sectionWhen to include limitations of use in the INDICATIONS AND USAGE section

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This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug
Administration.
2

This guidance applies to drugs, including biological drug products. For the purposes of this guidance, drug
product or drug will be used to refer to human prescription drug and biological products that are regulated as drugs,
except when there is a difference in the regulation. In such cases, biological products will be used. This guidance
does not apply to those biological products that are also devices.
See the final rule “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological
Products” (71 FR 3922, January 24, 2006) and additional labeling guidances athttps://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm. We
update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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

How to write, organize, and format the information within the INDICATIONS AND
USAGE section

The purpose of this guidance is to help ensure that the INDICATIONS AND USAGE section isclear, concise, useful, and informative and, to the extent possible, consistent within and acrossdrug and therapeutic classes. Applicants should follow the recommendations in this guidance
when developing the INDICATIONS AND USAGE section for a new drug and when revising
this section for a currently approved drug, including when seeking approval of a new indication.
In general, FDA’s guidance documents 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.

GENERAL PRINCIPLES

The primary role of the INDICATIONS AND USAGE section of labeling is to enable healthcare practitioners to readily identify appropriate therapies for patients by clearly communicating
the drug’s approved indication(s). Among other information, the INDICATIONS AND USAGE
section states the disease or condition, or manifestation or symptoms thereof, for which the drug
is approved, as well as whether the drug is indicated for the treatment, prevention, mitigation,
cure, or diagnosis of that disease or condition, including relief of symptoms (21 CFR
201.57(c)(2)). Other sections of labeling (e.g., DOSAGE AND ADMINISTRATION,CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, USE IN SPECIFICPOPULATIONS), as applicable, also provide essential details that enable safe and effective useof a drug, and labeling should be considered in its entirety for individual prescribing decisions.
To comply with the general labeling requirements in 21 CFR 201.56 and 201.57, the
INDICATIONS AND USAGE section must:

Reflect the scientific evidence accurately

Be concisely written to include the information necessary to clearly convey the use(s) for
which the drug has been shown to be safe and effectiveUse terminology that is clinically relevant and scientifically valid and understandable tohealth care practitioners

Additionally, indications that are straightforward, clear, concise, and consistently written will
facilitate the indexing of indications in electronic drug databases. This may, in turn, assist healthcare practitioners in searching indications in electronic medical information systems, thereby
providing easier access to the information in FDA-approved labeling needed for clinical decision
making.

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A.

Scope of the Indication(s)Governing regulations articulate parameters for the evidentiary standard necessary for anindication to be listed in the INDICATIONS AND USAGE section of labeling. For drug
products other than biological products, absent an applicable waiver, “all indications listed in the
INDICATIONS AND USAGE section must be supported by substantial evidence ofeffectiveness based on adequate and well-controlled studies” as defined in 21 CFR 314.126(b)(§ 201.57(c)(2)(iv)).4 For biological products, indications “must be supported by substantial
evidence of effectiveness” (§ 201.57(c)(2)(v)). Any statements in this section of the labelingcomparing the safety or effectiveness of drug or biological products with other agents for thesame indications must be similarly supported – that is, for drugs, they must be supported bysubstantial evidence of effectiveness based on adequate and well-controlled studies and, forbiological products, they must be supported by substantial evidence of effectiveness(§ 201.57(c)(2)(iii)).
Pursuant to the governing regulations, “[i]ndications or uses must not be implied or suggested inother sections of the labeling if not included” in the INDICATIONS AND USAGE section(§ 201.57(c)(2)(iv) and (v)). However, FDA may require a specific warning relating to anunapproved use in the WARNINGS AND PRECAUTIONS section of the labeling if the drug iscommonly prescribed for a disease or condition and if such usage is associated with a clinicallysignificant risk or hazard (§ 201.57(c)(6)(i)).5
1.

Scope of an Indication Relative to the Population Studied

The INDICATIONS AND USAGE section should clearly communicate the scope of theapproved indication, including the population to which the determination of safety andeffectiveness is applicable. The indicated population may mirror the studied population, forexample, in terms of patient demographics or severity of disease or condition, but can sometimes
differ. In some cases, FDA’s expert reviewers may fairly and responsibly conclude, based on
their scientific training and experience, that the available evidence supports approval of an
indication that is broader or narrower in scope than the precise population studied.6 Applicantsshould discuss the scope of a proposed indication with the applicable review division.7
Indications may be written to include certain patient populations that may have been absent or
specifically excluded from the clinical studies that supported approval (e.g., geriatric patients,
4

The Director of CDER may, on the Director's own initiative or on the petition of an interested person, waive inwhole or in part any of the criteria in 21 CFR 314.126(b) with respect to a specific clinical investigation, either prior
to the investigation or in the evaluation of a completed study. A waiver petition must explain why the study, as
conducted, will still yield substantial evidence of effectiveness (see 21 CFR 314.126(c)). Additionally, an applicant
may submit a request to the Director of CDER or the Director of CBER asking for a waiver of any requirement
under 21 CFR 201.56, 201.57 or 201.80 (see 21 CFR 201.58).
5

See the guidance for industry Warnings and Precautions, Contraindications, and Boxed Warning Sections ofLabeling for Human Prescription Drug and Biological Products — Content and Format.
6

See generally 21 U.S.C 355(d).

7

See 21 CFR 312.41.

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pregnant women, patients taking certain concomitant drugs, patients with a different severity or
stage of a disease). An indication for a broader population than the patient population studied incontrolled trials may be appropriate after careful consideration of the generalizability of theevidence, consistencies in the disease process across different groups, and the drug’s overall
benefits and risks.
For example, if a study evaluating a drug in adults enrolled patients of a certain age range andexcluded patients taking certain concomitant drugs, and available evidence does not suggest the
drug would be unsafe or ineffective in adult patients outside that age range or in those taking theother drugs, the indication should be worded to reflect the broader age group (i.e., “in adults”)
rather than the exact ages studied. In addition, unless available evidence suggests otherwise, theindication should not exclude use in patients taking the concomitant drugs. Recommendations
regarding age groups outside of an adult population are discussed in section II.A.2.
Similarly, if a drug were studied only in patients with a moderate form or stage of a disease andthere is reason to believe, based on the generalizability of the data, consistencies in the disease
process, and the drug’s benefits and risks, that the drug would be both safe and effective in a
broader group with the condition, an indication covering the broader population may beappropriate. In some cases, an indication covering the overall disease population can beconsidered. Specifics regarding the patient population studied should be described in the
CLINICAL STUDIES section of the labeling.
Conversely, an indication may be approved for a population narrower than that which wasstudied. For example, a study may enroll and randomize patients, but then stratify participantsby the presence or absence of a specific genomic marker. If the study demonstrated benefit onlyin patients who had tested positive for the marker, FDA’s expert reviewers may fairly andresponsibly conclude, based on their scientific training and experience, that the available
evidence supports approval of an indication in a population that is narrower in scope than the
population that was studied.8
There may also be circumstances in which the indication should reflect the precise population
studied. For example, some study designs such as prognostic enrichment strategies (e.g.,enrolling only people with a prior myocardial infarction in a study examining the effects of an
antiplatelet drug) and most predictive enrichment strategies (e.g., enrolling only people with a
specific genomic marker) may identify the population in which the benefits outweigh the risks or
the only population in which effectiveness is reasonably likely.9 In such cases, the indication
should reflect only the population studied, unless and until evidence becomes available tosupport a determination that broader safety and effectiveness can be expected.
2.

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Age Groups in Indications

See generally 21 USC 355(d).

9See the draft guidance for industry Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs
and Biological Products. When final, this guidance will represent FDA’s current thinking on this topic.

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Approval of a drug in pediatric patients10 is generally based on sufficient data from studies in thefollowing populations:

A pediatric population onlyBoth adult and pediatric populations



Adults, with supporting data in a pediatric population (e.g., safety,
pharmacokinetic data) that allow extrapolation of effectiveness to a pediatricpopulation11One pediatric population that allows extrapolation of effectiveness to anotherpediatric population12

In certain circumstances (see section II.A.1), it may be appropriate to consider an indication for
an adult population in an age group broader than the population that was studied. However, thisapproach is generally not appropriate across pediatric populations or between adult and pediatricpopulations because of the statutory requirements related to pediatric assessments13 and theunique clinical considerations for pediatric patients. For example, pediatric patients may
metabolize drugs differently from adults (in an age-related manner), are susceptible to different
safety risks, and often require different dosing regimens even after correction for weight.
For these reasons, age groups should be included in indications. As such, an indication should
state that a drug is approved, for example, “in adults,” “in pediatric patients X years of age andolder,” or “in adults and pediatric patients X years of age and older.”Applicants should discuss the scope of and age groups for a proposed indication with theapplicable review division.14
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The labeling regulations define pediatric patients as those ranging in age from birth through 16 years (21CFR 201.57(c)(9)(iv)).
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Although it may be appropriate to extrapolate effectiveness, it is generally not appropriate to extrapolate safetywith respect to pediatric populations.
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See section 505B(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR
201.57(c)(9)(iv). See also the draft guidance for industry and review staff Pediatric Information Incorporated Into
Human Prescription Drug and Biological Products Labeling. When final, this guidance will represent FDA’s
current thinking on this topic.
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The Pediatric Research Equity Act (Public Law 108-155) generally requires certain applications for, among otherthings, a new indication to contain a pediatric assessment unless the applicant has obtained a waiver or deferral.
Pediatric assessments “shall contain data, gathered using appropriate formulations for each age group for which theassessment is required that are adequate (i) to assess the safety and effectiveness of the drug or the biologicalproduct for the claimed indications in all relevant pediatric subpopulations; and (ii) to support dosing andadministration for each pediatric subpopulation for which the drug or the biological product is safe and effective”(section 505(B)(a) of the FD&C Act).
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See 21 CFR 312.41.

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B.

Distribution of Information Among Labeling Sections

Generally, the section of the full prescribing information to which particular drug information ismost relevant will contain the most detailed discussion of such information. Other sections
should discuss only those aspects of the information that are pertinent to those other sections’scopes and purposes. There may be instances when it is necessary to include information in the
INDICATIONS AND USAGE section that is discussed in greater detail elsewhere in thelabeling. For example, the INDICATIONS AND USAGE section may include a limitation ofuse that has a cross-reference to a more detailed discussion of the information supporting thelimitation in the WARNINGS AND PRECAUTIONS section (see section III.B). Because
detailed information about topics such as clinical studies and risks related to limitations of use
will generally be found elsewhere in the labeling, the information in the INDICATIONS AND
USAGE section should be concise.
C.

Updating the INDICATIONS AND USAGE Section

The INDICATIONS AND USAGE section “must be updated when new information becomes
available that causes the labeling to be inaccurate, false, or misleading” (§ 201.56(a)(2)).15 In
addition, it is appropriate in certain circumstances for application holders to update this section
to reflect current practices for writing indications for a particular group of drugs (for example,
when more information becomes available about the drug, drug class, or specific disease or whenthe endpoints become better established). Application holders should review the INDICATIONSAND USAGE section regularly to ensure that it reflects current science and, to the extent
possible, maintains consistency within a pharmacologic or therapeutic class.16

III.

CONTENT AND FORMAT OF THE INDICATIONS AND USAGE SECTION

The INDICATIONS AND USAGE section includes the indication and, as appropriate, any
identified limitations of use.17 The INDICATIONS AND USAGE section “must state that the
drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognizeddisease or condition, or of a manifestation of a recognized disease or condition, or for the reliefof symptoms associated with a recognized disease or condition” (§ 201.57(c)(2)). When drafting
the INDICATIONS AND USAGE section, applicants should consider what information isneeded to clearly convey the approved indication and whether other information in addition to
the identification of the disease or condition is warranted.
For many drugs, the indication will be sufficiently conveyed by stating the disease or condition
being treated, prevented, mitigated, cured, or diagnosed, and the approved age group(s) (seesection II.A.). For example, indications may be straightforward for many conditions (e.g.,
15

Application holders update their labeling using the procedures in 21 CFR 314.70 or 601.12, as applicable.

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See generally 21 CFR 201.56(a).

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See 21 CFR 201.57(c)(2).

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symptomatic conditions such as pain, allergic rhinitis). In such circumstances, endpoints anddescriptions of benefit should be summarized in the CLINICAL STUDIES section of labelingand should not be included in the indication.
On the other hand, other scenarios may warrant the inclusion of more information in theindication. Such scenarios could include cases in which a drug may target different aspects of adisease (e.g., in multiple sclerosis) or cases where endpoints are not well-standardized (e.g., inheart failure); in these scenarios, the specific benefits of the drug should be stated. For example,
for a drug indicated for the treatment of insomnia, the indication should state whether the drug
affects sleep onset, sleep maintenance, or both, in order to facilitate appropriate prescribing for
an individual patient. Similarly, for many outcome studies, when there is an overall effect on acomposite endpoint, the indication should identify the components of the composite (e.g.,
cardiovascular death, myocardial infarction, and stroke). In such cases, it would be critical toclearly state in the indication what benefit the drug has been shown to convey (seesection III.C.1).
Details of studies that describe the basis for approval (e.g., “Effectiveness was demonstrated in
two 12-week trials in patients with FEV1 less than 60% of predicted.”) should not be included in
the INDICATIONS AND USAGE section. This section is not intended to be a description of thedata supporting the determination of effectiveness, and the inclusion of such statements here
could have the unintended consequence of inappropriately limiting use of the drug in practice(e.g., inadvertently suggesting short-term use of a drug indicated for a chronic condition).
Likewise, discussions of disease definitions (e.g., diagnostic criteria for major depressive
disorder) should not be included. These types of details should be discussed in the CLINICALSTUDIES section of labeling (see section III.C.1).
Specific components of and other considerations for the INDICATIONS AND USAGE section
are discussed in detail in sections A through D below.
A.

Indication

The indication should begin “DRUG-X is indicated” and must include the following elements
required under 21 CFR 201.57(c)(2)(i):

The disease, condition, or manifestation of the disease or condition (e.g., symptom(s))
being treated, prevented, mitigated, cured, or diagnosedWhen applicable, other information necessary to describe the approved indication (e.g.,
descriptors of the population to be treated, adjunctive or concomitant therapy, or
specific tests needed for patient selection)

The following subsections provide details on each element of an indication listed above, alongwith illustrative examples demonstrating how to draft these elements so they are clear, concise,and easily identifiable and searchable.

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1.

The Disease, Condition, or Manifestation Being Treated, Prevented, Mitigated,
Cured, or Diagnosed

The INDICATIONS AND USAGE section must state that the drug “is indicated for thetreatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of amanifestation of a recognized disease or condition, or for relief of symptoms associated with arecognized disease or condition” (§ 201.57(c)(2)). The disease, condition, or manifestation
should be included in the indication using high-level terms that are clinically relevant andscientifically valid (e.g., asthma, diabetes mellitus, pain). Although FDA does not endorse any
particular resource for terms used to describe diseases, conditions, or symptoms, all terminology
should be well understood and easily recognizable by health care practitioners.
2.

Other Information Necessary To Describe the Approved Indication

In addition to identifying the disease, condition, or symptom for which the drug is approved,
there may be additional critical aspects of an indication that are important to include. Examples
of such situations are described in items a through c below.
a. Selected patient subgroups or disease subpopulations for whom the drug isapproved
In some cases, additional descriptors or qualifiers are critical to include as part of the indication
to clearly identify the patient population for whom the drug is approved. In addition to including
the approved age group(s) (see section II.A.2), other circumstances in which such additional
information would be important include, but are not limited to, indicating a drug for patientspreviously treated with other therapies (e.g., hormone-refractory prostate cancer), patients with acertain classification of a disease (e.g., World Health Organization Group I pulmonary arterial
hypertension), or patients with other important identifying variables (e.g., immunocompetentpatients). For example, if a drug is for use only in patients with a history of coronary disease
events (i.e., as secondary prevention), the indication should clearly convey the patient population
for which the drug is approved.
If evidence is available to support the safety and effectiveness of the drug only in selected
subgroups of the larger population with the target disease or condition, “this section must
include…a succinct description of the limitations of usefulness” (§ 201.57(c)(2)(i)(B)). Thus,
the indication should include information on the subgroup(s) for whom the drug is approved.
For example:

DRUG-X is indicated for the treatment of adult and pediatric patients 12
years of age and older with moderate to severe plaque psoriasis who are
candidates for phototherapy or systemic therapy.

If a drug should be reserved for use in specific situations (e.g., cases refractory to other drugs)
because of safety concerns, “this section must include…a statement of the information”
pertaining to such situations (§ 201.57(c)(2)(i)(E)). For example:

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

DRUG-X is indicated for the treatment of moderate to severe active
rheumatoid arthritis in adult patients who have had an inadequate response
to TNF antagonist therapy.

For drugs approved for use only after other drug therapies have failed (e.g., an indication forsecond-line use), consideration should be given as to whether it is necessary to specify the nameof the drug(s) or drug class(es) the patients are to have initially received or instead to word theindication more broadly (e.g., for use in previously treated patients).
b. Adjunctive or concomitant therapy or therapeutic modalities to use before
initiating drug therapy, such as diet or exercise or another drug
If the drug is approved for use only in conjunction with a primary mode of therapy (e.g., diet,surgery, behavior changes, or another drug), “[t]his section must include…a statement that the
drug is indicated as an adjunct to that mode of therapy” (§ 201.57(c)(2)(i)(A)). For example:

DRUG-X is indicated in adults for the treatment of high-grade malignant
glioma as an adjunct to surgery and radiation.

For drugs approved for use as adjunctive therapy, consideration should be given as to whether it
is necessary to specify the name of the drug(s) or drug class(es) the patients are to receive
concomitantly or instead to word the indication more broadly (e.g., as adjunctive therapy or as
part of a combination regimen).
c. Specific tests needed to select patients in whom to use the drug
If specific tests are necessary for selection or monitoring of patients who need the drug, “[t]his
section must include…the identity of such tests” (§ 201.57(c)(2)(i)(C)).18 For example:

DRUG-X is indicated for the treatment of adult patients with metastatic
non-small cell lung cancer whose tumors are anaplastic lymphoma kinase(ALK)-positive as detected by an FDA-approved test.

In general, information on tests used for monitoring appears in other labeling sections (e.g.,
DOSAGE AND ADMINISTRATION or WARNINGS AND PRECAUTIONS).19

18

When appropriate, the labeling should identify the type of FDA-approved or cleared in vitro companion diagnostic
device with which the product is approved, rather than a particular manufacturer’s device. See the guidance forindustry and FDA staff In Vitro Companion Diagnostic Devices.
19

See the following two guidances for industry: (1) Dosage and Administration Section of Labeling for Human
Prescription Drug and Biological Products — Content and Format and (2) Warnings and Precautions,Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products— Content and Format.

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B.

Limitations of Use

Limitations of use are presented separately from the indication within the INDICATIONS AND
USAGE section (see section III.D.2). A limitation of use is included when there is reasonable
concern or uncertainty among FDA’s expert reviewers, who are qualified by scientific training
and experience, about a drug’s risk-benefit profile. Limitations of use should be distinguishedfrom contraindications. A contraindication “must describe any situations in which the drug
should not be used because the risk of use (e.g., certain potentially fatal adverse reactions)clearly outweighs any possible therapeutic benefit” (§ 201.57(c)(5)). However, there are cases inwhich the evidence falls short of requiring a contraindication, but suggests that use of the drug
may be inadvisable. There are also cases in which there is sufficient uncertainty about the drug’s
benefits in certain clinical situations to suggest that the drug should generally not be used inthose settings. In these cases, a limitation of use may be appropriate. To avoid redundancy
within the labeling, contraindications should not be restated as limitations of use in the
INDICATIONS AND USAGE section.
Limitations of use should be included in the INDICATIONS AND USAGE section only when
the awareness of such information is important for practitioners to ensure the safe and effective
use of the drug. In most cases, limitations of use will identify a particular patient population inwhich a drug should generally not be used. If evidence is available to support the safety andeffectiveness of the drug only in selected subgroups of the larger population, the INDICATIONSAND USAGE section “must include…a succinct description of the limitations of usefulness ofthe drug and any uncertainty about anticipated clinical benefits, with reference to the ‘ClinicalStudies’ section for a discussion of the available evidence” (§ 201.57(c)(2)(i)(B)). Suchinformation would be appropriate to include as a separate limitation of use — rather thannarrowing the language of the indication itself — when needed to inform practitioners that there
is a reasonable concern or uncertainty about the drug’s safety or effectiveness outside thespecific population for which the drug is approved.
In contrast, information that essentially narrows or further defines a drug’s approved indicationand is used to direct appropriate therapy (e.g., identifying particular subsets of the population forwhom the drug is approved, drugs to be used only after other drug therapies have failed, or
specific tests needed to identify patients to be treated) should be incorporated directly into theindication whenever possible (see section III.A.2). This information should not be presented as aseparate limitation of use. Whereas a limitation of use most often will be included to identify apatient population in which the drug should generally not be used (i.e., discouraging its use),
information that specifies the patient population in which the drug should be used (i.e.,
encouraging its use) should, wherever possible, be incorporated in the indication itself. For
example, if a drug should be used only after failure of or as an adjunct to another drug ortreatment modality, the indication should include this information rather than having it presented
separately as a limitation of use.
Although there are invariably areas of uncertainty about a drug’s effectiveness, not all drugs will
include limitations of use in the INDICATIONS AND USAGE section. Information considered
for a limitation of use should be evaluated to decide if it may be better suited to another sectionof the labeling (e.g., WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS,

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CLINICAL STUDIES). For example, although there may be circumstances in which alimitation of use will be further described in (and cross-referenced to) a subsection in the
WARNINGS AND PRECAUTIONS section, most warnings and precautions will typically not
be repeated as limitations of use. Only information that provides a clearer understanding of thescope of the approved indication to facilitate safe and effective prescribing decisions should be
included as a limitation of use. Moreover, an absence of data in a particular population subset
should generally not appear as a limitation of use unless there is reasonable concern about the
drug’s safety or effectiveness in that group.
1.

Situations in Which Limitations of Use Would Be Appropriate

The following are examples of situations in which it may be appropriate to include a separate
limitation of use within the INDICATIONS AND USAGE section:a. Drugs for which there is reasonable concern or uncertainty about effectivenessor safety in a certain clinical situation
As recommended in section II.A.2, the approved age group(s) should be included in an
indication. If there is a concern or uncertainty about safety or effectiveness in a population
outside the approved age group (e.g., younger patients), a limitation of use should be included
about that population. The inclusion of a limitation of use will differentiate between (1) acircumstance in which use of the drug in a certain population outside of the approved population
raises a reasonable concern or uncertainty about safety or effectiveness and (2) a circumstance inwhich an indication is simply directed to a certain group (e.g., patients within a particular age
range). The concern that warranted the limitation of use should typically be described elsewherein labeling (e.g., WARNINGS AND PRECAUTIONS and USE IN SPECIFIC POPULATIONS
sections), with a cross-reference in the limitation of use to the section of labeling where thisdetailed information can be found. For example:

DRUG-X is indicated for the treatment of hypertension in adults andpediatric patients 1 year of age and older.
Limitations of Use
In patients younger than one year of age, DRUG-X can adversely affectkidney development [see Warnings and Precautions (5.X) and Use inSpecific Populations (8.4)]

The governing regulation states that “[i]f there is a common belief that a drug may be effective
for a certain use or if there is a common use of the drug for a condition, but the preponderance ofevidence related to the use or condition shows that the drug is ineffective or that the therapeutic
benefits do not generally outweigh its risks, FDA may require that [the INDICATIONS AND
USAGE] section state that there is a lack of evidence that the drug is effective or safe for that use
or condition” (§ 201.57(c)(2)(ii)). A limitation of use may be of particular importance in thesecircumstances if proven alternative therapies exist for the condition in question. For example:

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

DRUG-X is indicated in adults for the acute treatment of migraine
headache with or without aura.
Limitations of Use
Multiple clinical trials failed to establish the effectiveness of DRUG-X forthe prophylaxis of migraine headaches [see Clinical Studies (14.X)].

b. Drugs approved without evidence of benefits known to occur with other drugs
in the same class
If a drug is approved without having demonstrated a particular benefit that has been
demonstrated with other drugs in the same pharmacologic or therapeutic class, it may be
important to convey the differences among products under a “Limitations of Use” heading in the
INDICATIONS AND USAGE section. For example, the INDICATIONS AND USAGE section
for a new HMG-CoA reductase inhibitor that is approved based on its serum lipid-lowering
effects (without evidence of a beneficial effect on cardiovascular morbidity and mortality) would
typically be presented as follows:

DRUG-X is indicated as an adjunctive therapy to diet to reduce elevatedtotal cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides andto increase HDL cholesterol in adult patients with primary hyperlipidemia
or mixed lipidemia.
Limitations of Use
The effect of DRUG-X on cardiovascular morbidity and mortality has notbeen determined.

c. Drugs with dose, duration, or long-term use considerations
If information on limitations of use or uncertainty about anticipated benefits is relevant to therecommended dosing intervals, to appropriate treatment duration when treatment should be
limited, or to any dosage modification, the INDICATIONS AND USAGE section “mustinclude…a concise description of the information, with a reference to the more detailed
information in the ‘Dosage and Administration’ section” (§ 201.57(c)(2)(i)(D)). Under thesecircumstances, information about important dose or duration considerations, such as how long a
drug can safely be used or uncertainty about the risks and benefits of treatment beyond a certain
period (e.g., long-term cumulative toxicity), should be included as a limitation of use. For
example:

DRUG-X is indicated for the management of elevated plasma uric acidlevels in adult patients with tumor lysis syndrome.

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Limitations of Use
The activity of DRUG-X may be neutralized by the development of antidrug antibodies if more than a single course of treatment is administered[see Dosage and Administration (2.X) and Warnings and Precautions(5.X)].
It is generally not necessary to limit duration of use in the INDICATIONS AND USAGE section
unless such a limited duration is essential to ensure the safe and effective use of the drug. If
clinical trials evaluated the effectiveness of a drug for a chronic condition only in short-term
trials of sufficient duration to support such an approval (e.g., drugs for major depressive disorderor hypertension), but the drug is indicated for long-term use due to the chronic nature of thecondition and because there is no known or anticipated safety or efficacy concern from continued
use, a description of the duration of use from the clinical trials or information about the lack oflonger term data generally should not be included in the INDICATIONS AND USAGE section.
Information on the length of the clinical trials should instead be discussed in detail in the
CLINICAL STUDIES section of the labeling.
If there are specific conditions that should be met before the drug is used on a long-term basis(e.g., demonstration of responsiveness to the drug after short-term use in an individual patient),
the INDICATIONS AND USAGE section “must include…a statement of the conditions; or if
the indications for long term use are different from those for short term use, a statement of thespecific indications for each use” (§ 201.57(c)(2)(i)(F)). For drugs with these characteristics, alimitation of use may be used to address such issues. For example:

DRUG-X is indicated for the treatment of severe spasticity in adultpatients with spinal cord injury, brain injury, or multiple sclerosis.
Limitations of Use
Prior to implantation of a device for chronic intrathecal infusion of
DRUG-X, confirm a positive clinical response to DRUG-X in a screening
phase [see Dosage and Administration (2.X)].

2.

Situations in Which Limitations of Use Generally Would Not Be Appropriate

Limitations of use generally would not be appropriate in the following situations:a. To restate information already included in the indication
For example, if an indication is clearly worded as being approved for use in combination withanother drug, there is no need for a limitation of use stating that the subject drug should be used
only in combination and not as monotherapy.

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b. To address the absence of data in populations in which the drug was notstudiedFor example, if an oncology drug was studied in and is indicated for use in patients with a cancerof a specific mutation, there should not be a limitation of use about the absence of data inpatients with typical (wild-type) forms, unless there is reasonable concern about the drug’s safety
or effectiveness in such patients. Likewise, if a drug is approved to reduce the risk of rejection inpatients receiving a heart transplant, there should not be a limitation of use about the lack of dataon use in lung transplants. Similarly, if a vaccine is approved for use in children 12 months
through 12 years of age, there should not be a limitation of use about the absence of data in otherage groups.
C.

Other Considerations for Writing the INDICATIONS AND USAGE Section

1.

Identification of Outcomes, Endpoints, and Benefit(s) the Drug Conveys

The approved indication will generally convey the benefit of the treatment (i.e., the disease,condition, manifestation, or symptoms of the disease or condition being treated, prevented,
mitigated, cured, or diagnosed), and it is usually not necessary to fully describe the specific way
benefit was measured in clinical trials (i.e., identifying outcomes or endpoints) when thetreatment affects a broad range of manifestations of the disease (e.g., an indication for thesymptoms of allergic rhinitis). In some cases, however, a broad disease indication may not beappropriate because, for example, the drug may affect only certain signs, symptoms, ormanifestations of the disease (see section III). An indication identifying an outcome or endpoint
may be considered, for example, when the drug’s effect on the overall disease is not wellunderstood, when different drugs have different effects on various manifestations of the diseases,
when clinical trials evaluated only one or some of the manifestations of the disease, or when theendpoints are different from typical effectiveness measures. For example:

DRUG-X is indicated to improve walking in adult patients with multiple sclerosis.

For certain other conditions, the drug’s indication may be to reduce the risk of significant
morbidity and mortality, which describes the demonstrated benefit more accurately than would amore broadly written indication indicating the product simply as a treatment for the condition
itself. In such cases, the specific endpoint(s) for which the drug has demonstrated benefits
should be incorporated into the indication. For example:

DRUG-X is indicated to reduce the risk of nonfatal myocardial infarction, fatal
and nonfatal stroke, and revascularization procedures in adult patients withclinically evident coronary heart disease.

The CLINICAL STUDIES section of labeling “must discuss those studies that facilitate anunderstanding of how to use the drug safely and effectively” (§ 201.57(c)(15)). The information
presented in that section ordinarily includes, among other things, a description of the study
population, endpoints, and results. For example, if an indication were written for an overall
effect on a composite endpoint, the details on the endpoints studied and results (e.g., which

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component of a composite endpoint drove the overall combined finding) would be discussed indetail in the CLINICAL STUDIES section. Additionally, if only one component of a composite
primary endpoint was affected and indicating the drug for the composite would misrepresent thetrue result, an indication for the single component can be considered, with the explanation of thestudy results summarized in the CLINICAL STUDIES section.
2.

Accelerated Approval

If a drug is approved for an indication based on an effect on a surrogate endpoint or anintermediate clinical endpoint under section 506(c) of the Federal Food, Drug, and Cosmetic Act(FD&C Act) (21 U.S.C. 356(c)) and 21 CFR 314.510 or 601.41 (i.e., accelerated approval), the
INDICATIONS AND USAGE section “must include…a succinct description of the limitationsof usefulness of the drug and any uncertainty about anticipated clinical benefits, with a reference
to the Clinical Studies section for a discussion of the available evidence”(§ 201.57(c)(2)(i)(B)).20
3.

Required or Recommended Language

Under governing statutory and regulatory provisions, certain products have required orrecommended language for the INDICATIONS AND USAGE section. For example:
Labeling for systemic antibacterial drug products must include a specificstatement in the INDICATIONS AND USAGE section about strategies for
reducing the development of drug-resistant bacteria and maintaining theeffectiveness of the subject drug and other antibacterial drugs (21CFR 201.24(b)).

Section 505(u)(2)(B) of the FD&C Act (21 U.S.C. 355(u)(2)(B)) requires thatlabeling for certain products containing a single enantiomer of a previously
approved racemic drug include a statement that the non-racemic product is not
approved, and has not been shown to be safe and effective, for any condition ofuse of the previously approved racemic drug. For such products approved under505(u), this information should be presented as a limitation of use.



Other FDA guidances (e.g., clinical/medical guidances) recommend specificwording for the INDICATIONS AND USAGE section for certain indications.21

20

See the draft guidance for industry Labeling for Human Prescription Drug and Biological Products Approved
Under the Accelerated Approval Regulatory Pathway. When final, this guidance will represent FDA’s current
thinking on this topic.
21

Additional labeling guidances are available on the FDA Drugs guidance web page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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4.

Preferred Wording and Wording Generally To Avoid22

Consistent with this guidance and the regulatory framework, as a general matter, care should betaken when considering use of the following terms and phrases:
a. “Reduce the risk” versus “prevent”
If the indication for a drug is to reduce the risk of the occurrence of a particular clinical outcome,phrases such as “reduce the risk of” or “reduce the incidence of” should be considered rather
than using “prevent” in the indication. The use of a term such as prevent may imply a guaranteeof success that is not supported by the data. However, for certain indications, the use of terms
such as prevent (e.g., for preventive vaccines) or prophylaxis (e.g., drugs for post-exposure
prophylaxis) in the indication may be appropriate because, in a given context, these terms arewell established and understood by the clinical community.
b. “Only”
The INDICATIONS AND USAGE section should be worded clearly to convey the approved useof the drug, making inclusion of the word “only” unnecessary (i.e., the indication generally
should not state “DRUG-X is indicated only for…”).
c. “Also indicated”
When a new indication is added to the INDICATIONS AND USAGE section, the phrase “is also
indicated” generally should not be used because it may imply that the new indication is lessimportant than the existing indication(s).
d. Product identification in the indication
The indication should include the proprietary name (or trade name). If the product does not havea proprietary or trade name, the indication should include the nonproprietary name (i.e.,established name for a drug product or proper name for a biological product).
To avoid unnecessary clutter and to enhance clarity, other information (such as the nonproprietary name, dosage form, route of administration) generally should not be included in theindication. The established pharmacologic class appears with the indication only in Highlights(§ 201.57(a)(6)).
D.

Formatting the INDICATIONS AND USAGE Section

1.

Format for Multiple Indications

When a drug is approved for more than one indication, the format of the INDICATIONS AND
USAGE section should be carefully considered. For some drugs, it may be preferable to assign asubsection to each indication (e.g., 1.1 Disease-A, 1.2 Disease-B), but for others, it may be
22

See generally 21 CFR 201.56.

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preferable to present distinct indications using only bullets (e.g., “DRUG-X is indicated for:”followed by a bulleted list) immediately under the main section heading or within a subsection.
2.

Format for Limitations of Use

Limitations of use are presented separately from the indication within the INDICATIONS AND
USAGE section, under the heading Limitations of Use and not usually under a separate
numbered subsection. If, however, a drug has multiple indications and the limitations of use
apply to all of them, it may be preferable to use a separate numbered subsection for Limitationsof Use within the section. The INDICATIONS AND USAGE section should be formatted toclearly show if the limitations apply to all or to only some of the indications.

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