Indications and Usage Section 
of Labeling for Human Prescription 
Drug and Biological Products   
Content and Format 
 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 written 
comments 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 the 
docket 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 240-402-
8010.  
 
 
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 
 
10844dft.doc 
07/03/18   
Indications and Usage Section 
of 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/or 
 
Office 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 
Labeling 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  GENERAL PRINCIPLES................................................................................................ 2 
A.  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 .............................................................. 6 
C.  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, or 
Diagnosed ............................................................................................................................................. 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 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Indications and Usage Section of Labeling for Human Prescription 
1 
Drug and Biological Products  Content and Format  
2 
Guidance for Industry1 
3 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  This guidance is intended to assist applicants in drafting the INDICATIONS AND USAGE 
17  section of labeling as described in the regulations for the content and format of labeling for 
18  human prescription drug and biological products2 (21 CFR 201.57(c)(2)).3 
19   
20  Recommendations include the following: 
21   
22    General principles to consider when drafting the INDICATIONS AND USAGE section 
23  of the labeling 
24   
25    What information to include in the INDICATIONS AND USAGE section 
26   
27    When to include additional descriptors or qualifiers as part of the indication in the 
28  INDICATIONS AND USAGE section 
29   
30    When to include limitations of use in the INDICATIONS AND USAGE section  
31   
                                                 
1 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. 
 
3 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 at 
https://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.   
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
32    How to write, organize, and format the information within the INDICATIONS AND 
33  USAGE section  
34   
35  The purpose of this guidance is to help ensure that the INDICATIONS AND USAGE section is 
36  clear, concise, useful, and informative and, to the extent possible, consistent within and across 
37  drug and therapeutic classes.  Applicants should follow the recommendations in this guidance 
38  when developing the INDICATIONS AND USAGE section for a new drug and when revising 
39  this section for a currently approved drug, including when seeking approval of a new indication.    
40   
41  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
42  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
43  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
44  the word should in Agency guidances means that something is suggested or recommended, but 
45  not required.  
46   
47   
48  II.  GENERAL PRINCIPLES 
49   
50  The primary role of the INDICATIONS AND USAGE section of labeling is to enable health 
51  care practitioners to readily identify appropriate therapies for patients by clearly communicating 
52  the drugs approved indication(s).  Among other information, the INDICATIONS AND USAGE 
53  section states the disease or condition, or manifestation or symptoms thereof, for which the drug 
54  is approved, as well as whether the drug is indicated for the treatment, prevention, mitigation, 
55  cure, or diagnosis of that disease or condition, including relief of symptoms (21 CFR 
56  201.57(c)(2)).  Other sections of labeling (e.g., DOSAGE AND ADMINISTRATION, 
57  CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, USE IN SPECIFIC 
58  POPULATIONS), as applicable, also provide essential details that enable safe and effective use 
59  of a drug, and labeling should be considered in its entirety for individual prescribing decisions.  
60   
61  To comply with the general labeling requirements in 21 CFR 201.56 and 201.57, the 
62  INDICATIONS AND USAGE section must:  
63   
64    Reflect the scientific evidence accurately 
65   
66    Be concisely written to include the information necessary to clearly convey the use(s) for 
67  which the drug has been shown to be safe and effective 
68   
69    Use terminology that is clinically relevant and scientifically valid and understandable to 
70  health care practitioners 
71   
72  Additionally, indications that are straightforward, clear, concise, and consistently written will 
73  facilitate the indexing of indications in electronic drug databases.  This may, in turn, assist health 
74  care practitioners in searching indications in electronic medical information systems, thereby 
75  providing easier access to the information in FDA-approved labeling needed for clinical decision 
76  making. 
77   
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
78  A.  Scope of the Indication(s)  
79   
80  Governing regulations articulate parameters for the evidentiary standard necessary for an 
81  indication to be listed in the INDICATIONS AND USAGE section of labeling.  For drug 
82  products other than biological products, absent an applicable waiver, all indications listed in the 
83  INDICATIONS AND USAGE section must be supported by substantial evidence of 
84  effectiveness based on adequate and well-controlled studies as defined in 21 CFR 314.126(b) 
85  ( 201.57(c)(2)(iv)).4  For biological products, indications must be supported by substantial 
86  evidence of effectiveness ( 201.57(c)(2)(v)).  Any statements in this section of the labeling 
87  comparing the safety or effectiveness of drug or biological products with other agents for the 
88  same indications must be similarly supported  that is, for drugs, they must be supported by 
89  substantial evidence of effectiveness based on adequate and well-controlled studies and, for 
90  biological products, they must be supported by substantial evidence of effectiveness 
91  ( 201.57(c)(2)(iii)). 
92   
93  Pursuant to the governing regulations, [i]ndications or uses must not be implied or suggested in 
94  other sections of the labeling if not included in the INDICATIONS AND USAGE section 
95  ( 201.57(c)(2)(iv) and (v)).  However, FDA may require a specific warning relating to an 
96  unapproved use in the WARNINGS AND PRECAUTIONS section of the labeling if the drug is 
97  commonly prescribed for a disease or condition and if such usage is associated with a clinically 
98  significant risk or hazard ( 201.57(c)(6)(i)).5  
99   
100  1.  Scope of an Indication Relative to the Population Studied 
101   
102  The INDICATIONS AND USAGE section should clearly communicate the scope of the 
103  approved indication, including the population to which the determination of safety and 
104  effectiveness is applicable.  The indicated population may mirror the studied population, for 
105  example, in terms of patient demographics or severity of disease or condition, but can sometimes 
106  differ.  In some cases, FDAs expert reviewers may fairly and responsibly conclude, based on 
107  their scientific training and experience, that the available evidence supports approval of an 
108  indication that is broader or narrower in scope than the precise population studied.6  Applicants 
109  should discuss the scope of a proposed indication with the applicable review division.7 
110   
111  Indications may be written to include certain patient populations that may have been absent or 
112  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 in 
whole 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 of 
Labeling 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. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
113  pregnant women, patients taking certain concomitant drugs, patients with a different severity or 
114  stage of a disease).  An indication for a broader population than the patient population studied in 
115  controlled trials may be appropriate after careful consideration of the generalizability of the 
116  evidence, consistencies in the disease process across different groups, and the drugs overall 
117  benefits and risks.  
118   
119  For example, if a study evaluating a drug in adults enrolled patients of a certain age range and 
120  excluded patients taking certain concomitant drugs, and available evidence does not suggest the 
121  drug would be unsafe or ineffective in adult patients outside that age range or in those taking the 
122  other drugs, the indication should be worded to reflect the broader age group (i.e., in adults) 
123  rather than the exact ages studied.  In addition, unless available evidence suggests otherwise, the 
124  indication should not exclude use in patients taking the concomitant drugs.  Recommendations 
125  regarding age groups outside of an adult population are discussed in section II.A.2.    
126   
127  Similarly, if a drug were studied only in patients with a moderate form or stage of a disease and 
128  there is reason to believe, based on the generalizability of the data, consistencies in the disease 
129  process, and the drugs benefits and risks, that the drug would be both safe and effective in a 
130  broader group with the condition, an indication covering the broader population may be 
131  appropriate.  In some cases, an indication covering the overall disease population can be 
132  considered.  Specifics regarding the patient population studied should be described in the 
133  CLINICAL STUDIES section of the labeling.   
134   
135  Conversely, an indication may be approved for a population narrower than that which was 
136  studied.  For example, a study may enroll and randomize patients, but then stratify participants 
137  by the presence or absence of a specific genomic marker.  If the study demonstrated benefit only 
138  in patients who had tested positive for the marker, FDAs expert reviewers may fairly and 
139  responsibly conclude, based on their scientific training and experience, that the available 
140  evidence supports approval of an indication in a population that is narrower in scope than the 
141  population that was studied.8 
142   
143  There may also be circumstances in which the indication should reflect the precise population 
144  studied.  For example, some study designs such as prognostic enrichment strategies (e.g., 
145  enrolling only people with a prior myocardial infarction in a study examining the effects of an 
146  antiplatelet drug) and most predictive enrichment strategies (e.g., enrolling only people with a 
147  specific genomic marker) may identify the population in which the benefits outweigh the risks or 
148  the only population in which effectiveness is reasonably likely.9  In such cases, the indication 
149  should reflect only the population studied, unless and until evidence becomes available to 
150  support a determination that broader safety and effectiveness can be expected.   
151   
152  2.  Age Groups in Indications 
153   
                                                 
8 See generally 21 USC 355(d). 
 
9 See 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 FDAs current thinking on this topic. 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
154  Approval of a drug in pediatric patients10 is generally based on sufficient data from studies in the 
155  following populations:  
156   
157    A pediatric population only 
158   
159    Both adult and pediatric populations 
160   
161    Adults, with supporting data in a pediatric population (e.g., safety, 
162  pharmacokinetic data) that allow extrapolation of effectiveness to a pediatric 
163  population11 
164   
165    One pediatric population that allows extrapolation of effectiveness to another 
166  pediatric population12 
167   
168  In certain circumstances (see section II.A.1), it may be appropriate to consider an indication for 
169  an adult population in an age group broader than the population that was studied.  However, this 
170  approach is generally not appropriate across pediatric populations or between adult and pediatric 
171  populations because of the statutory requirements related to pediatric assessments13 and the 
172  unique clinical considerations for pediatric patients.  For example, pediatric patients may 
173  metabolize drugs differently from adults (in an age-related manner), are susceptible to different 
174  safety risks, and often require different dosing regimens even after correction for weight.   
175   
176  For these reasons, age groups should be included in indications.  As such, an indication should 
177  state that a drug is approved, for example, in adults, in pediatric patients X years of age and 
178  older, or in adults and pediatric patients X years of age and older.   
179   
180  Applicants should discuss the scope of and age groups for a proposed indication with the 
181  applicable review division.14 
                                                 
10 The labeling regulations define pediatric patients as those ranging in age from birth through 16 years (21 
CFR 201.57(c)(9)(iv)). 
 
11 Although it may be appropriate to extrapolate effectiveness, it is generally not appropriate to extrapolate safety 
with respect to pediatric populations. 
 
12 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 FDAs 
current thinking on this topic. 
 
13 The Pediatric Research Equity Act (Public Law 108-155) generally requires certain applications for, among other 
things, 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 the 
assessment is required that are adequate (i) to assess the safety and effectiveness of the drug or the biological 
product for the claimed indications in all relevant pediatric subpopulations; and (ii) to support dosing and 
administration 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). 
 
14 See 21 CFR 312.41. 
 
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
182   
183  B.  Distribution of Information Among Labeling Sections 
184   
185  Generally, the section of the full prescribing information to which particular drug information is 
186  most relevant will contain the most detailed discussion of such information.  Other sections 
187  should discuss only those aspects of the information that are pertinent to those other sections 
188  scopes and purposes.  There may be instances when it is necessary to include information in the 
189  INDICATIONS AND USAGE section that is discussed in greater detail elsewhere in the 
190  labeling.  For example, the INDICATIONS AND USAGE section may include a limitation of 
191  use that has a cross-reference to a more detailed discussion of the information supporting the 
192  limitation in the WARNINGS AND PRECAUTIONS section (see section III.B).  Because 
193  detailed information about topics such as clinical studies and risks related to limitations of use 
194  will generally be found elsewhere in the labeling, the information in the INDICATIONS AND 
195  USAGE section should be concise.  
196   
197  C.  Updating the INDICATIONS AND USAGE Section 
198   
199  The INDICATIONS AND USAGE section must be updated when new information becomes 
200  available that causes the labeling to be inaccurate, false, or misleading ( 201.56(a)(2)).15  In 
201  addition, it is appropriate in certain circumstances for application holders to update this section 
202  to reflect current practices for writing indications for a particular group of drugs (for example, 
203  when more information becomes available about the drug, drug class, or specific disease or when 
204  the endpoints become better established).  Application holders should review the INDICATIONS 
205  AND USAGE section regularly to ensure that it reflects current science and, to the extent 
206  possible, maintains consistency within a pharmacologic or therapeutic class.16 
207   
208   
209  III.  CONTENT AND FORMAT OF THE INDICATIONS AND USAGE SECTION 
210   
211  The INDICATIONS AND USAGE section includes the indication and, as appropriate, any 
212  identified limitations of use.17  The INDICATIONS AND USAGE section must state that the 
213  drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized 
214  disease or condition, or of a manifestation of a recognized disease or condition, or for the relief 
215  of symptoms associated with a recognized disease or condition ( 201.57(c)(2)).  When drafting 
216  the INDICATIONS AND USAGE section, applicants should consider what information is 
217  needed to clearly convey the approved indication and whether other information in addition to 
218  the identification of the disease or condition is warranted.   
219   
220  For many drugs, the indication will be sufficiently conveyed by stating the disease or condition 
221  being treated, prevented, mitigated, cured, or diagnosed, and the approved age group(s) (see 
222  section 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.  
 
16 See generally 21 CFR 201.56(a). 
 
17 See 21 CFR 201.57(c)(2). 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
223  symptomatic conditions such as pain, allergic rhinitis).  In such circumstances, endpoints and 
224  descriptions of benefit should be summarized in the CLINICAL STUDIES section of labeling 
225  and should not be included in the indication.   
226   
227  On the other hand, other scenarios may warrant the inclusion of more information in the 
228  indication.  Such scenarios could include cases in which a drug may target different aspects of a 
229  disease (e.g., in multiple sclerosis) or cases where endpoints are not well-standardized (e.g., in 
230  heart failure); in these scenarios, the specific benefits of the drug should be stated.  For example, 
231  for a drug indicated for the treatment of insomnia, the indication should state whether the drug 
232  affects sleep onset, sleep maintenance, or both, in order to facilitate appropriate prescribing for 
233  an individual patient.  Similarly, for many outcome studies, when there is an overall effect on a 
234  composite endpoint, the indication should identify the components of the composite (e.g., 
235  cardiovascular death, myocardial infarction, and stroke).  In such cases, it would be critical to 
236  clearly state in the indication what benefit the drug has been shown to convey (see 
237  section III.C.1). 
238   
239  Details of studies that describe the basis for approval (e.g., Effectiveness was demonstrated in 
240  two 12-week trials in patients with FEV  less than 60% of predicted.) should not be included in 
1
241  the INDICATIONS AND USAGE section.  This section is not intended to be a description of the 
242  data supporting the determination of effectiveness, and the inclusion of such statements here 
243  could have the unintended consequence of inappropriately limiting use of the drug in practice 
244  (e.g., inadvertently suggesting short-term use of a drug indicated for a chronic condition).  
245  Likewise, discussions of disease definitions (e.g., diagnostic criteria for major depressive 
246  disorder) should not be included.  These types of details should be discussed in the CLINICAL 
247  STUDIES section of labeling (see section III.C.1). 
248   
249  Specific components of and other considerations for the INDICATIONS AND USAGE section 
250  are discussed in detail in sections A through D below. 
251   
252  A.  Indication 
253   
254  The indication should begin DRUG-X is indicated and must include the following elements 
255  required under 21 CFR 201.57(c)(2)(i): 
256   
257    The disease, condition, or manifestation of the disease or condition (e.g., symptom(s)) 
258  being treated, prevented, mitigated, cured, or diagnosed 
259   
260    When applicable, other information necessary to describe the approved indication (e.g., 
261  descriptors of the population to be treated, adjunctive or concomitant therapy, or 
262  specific tests needed for patient selection)  
263    
264  The following subsections provide details on each element of an indication listed above, along 
265  with illustrative examples demonstrating how to draft these elements so they are clear, concise, 
266  and easily identifiable and searchable.  
267   
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
268  1.  The Disease, Condition, or Manifestation Being Treated, Prevented, Mitigated, 
269  Cured, or Diagnosed  
270   
271  The INDICATIONS AND USAGE section must state that the drug is indicated for the 
272  treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of a 
273  manifestation of a recognized disease or condition, or for relief of symptoms associated with a 
274  recognized disease or condition ( 201.57(c)(2)).  The disease, condition, or manifestation 
275  should be included in the indication using high-level terms that are clinically relevant and 
276  scientifically valid (e.g., asthma, diabetes mellitus, pain).  Although FDA does not endorse any 
277  particular resource for terms used to describe diseases, conditions, or symptoms, all terminology 
278  should be well understood and easily recognizable by health care practitioners.   
279   
280  2.  Other Information Necessary To Describe the Approved Indication  
281   
282  In addition to identifying the disease, condition, or symptom for which the drug is approved, 
283  there may be additional critical aspects of an indication that are important to include.  Examples 
284  of such situations are described in items a through c below.   
285   
286  a.  Selected patient subgroups or disease subpopulations for whom the drug is 
287  approved  
288   
289  In some cases, additional descriptors or qualifiers are critical to include as part of the indication 
290  to clearly identify the patient population for whom the drug is approved.  In addition to including 
291  the approved age group(s) (see section II.A.2), other circumstances in which such additional 
292  information would be important include, but are not limited to, indicating a drug for patients 
293  previously treated with other therapies (e.g., hormone-refractory prostate cancer), patients with a 
294  certain classification of a disease (e.g., World Health Organization Group I pulmonary arterial 
295  hypertension), or patients with other important identifying variables (e.g., immunocompetent 
296  patients).  For example, if a drug is for use only in patients with a history of coronary disease 
297  events (i.e., as secondary prevention), the indication should clearly convey the patient population 
298  for which the drug is approved.   
299   
300  If evidence is available to support the safety and effectiveness of the drug only in selected 
301  subgroups of the larger population with the target disease or condition, this section must 
302  include...a succinct description of the limitations of usefulness ( 201.57(c)(2)(i)(B)).  Thus, 
303  the indication should include information on the subgroup(s) for whom the drug is approved.  
304  For example: 
305   
306    DRUG-X is indicated for the treatment of adult and pediatric patients 12 
307  years of age and older with moderate to severe plaque psoriasis who are 
308  candidates for phototherapy or systemic therapy. 
309   
310  If a drug should be reserved for use in specific situations (e.g., cases refractory to other drugs) 
311  because of safety concerns, this section must include...a statement of the information 
312  pertaining to such situations ( 201.57(c)(2)(i)(E)).  For example: 
313   
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
314    DRUG-X is indicated for the treatment of moderate to severe active 
315  rheumatoid arthritis in adult patients who have had an inadequate response 
316  to TNF antagonist therapy. 
317   
318  For drugs approved for use only after other drug therapies have failed (e.g., an indication for 
319  second-line use), consideration should be given as to whether it is necessary to specify the name 
320  of the drug(s) or drug class(es) the patients are to have initially received or instead to word the 
321  indication more broadly (e.g., for use in previously treated patients). 
322   
323  b.  Adjunctive or concomitant therapy or therapeutic modalities to use before 
324  initiating drug therapy, such as diet or exercise or another drug 
325   
326  If the drug is approved for use only in conjunction with a primary mode of therapy (e.g., diet, 
327  surgery, behavior changes, or another drug), [t]his section must include...a statement that the 
328  drug is indicated as an adjunct to that mode of therapy ( 201.57(c)(2)(i)(A)).  For example: 
329   
330    DRUG-X is indicated in adults for the treatment of high-grade malignant 
331  glioma as an adjunct to surgery and radiation. 
332   
333  For drugs approved for use as adjunctive therapy, consideration should be given as to whether it 
334  is necessary to specify the name of the drug(s) or drug class(es) the patients are to receive 
335  concomitantly or instead to word the indication more broadly (e.g., as adjunctive therapy or as 
336  part of a combination regimen). 
337   
338  c.  Specific tests needed to select patients in whom to use the drug 
339   
340  If specific tests are necessary for selection or monitoring of patients who need the drug, [t]his 
341  section must include...the identity of such tests ( 201.57(c)(2)(i)(C)).18  For example: 
342   
343    DRUG-X is indicated for the treatment of adult patients with metastatic 
344  non-small cell lung cancer whose tumors are anaplastic lymphoma kinase 
345  (ALK)-positive as detected by an FDA-approved test. 
346   
347  In general, information on tests used for monitoring appears in other labeling sections (e.g., 
348  DOSAGE AND ADMINISTRATION or WARNINGS AND PRECAUTIONS).19  
349   
                                                 
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 manufacturers device.  See the guidance for 
industry 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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Draft  Not for Implementation 
350  B.  Limitations of Use  
351   
352  Limitations of use are presented separately from the indication within the INDICATIONS AND 
353  USAGE section (see section III.D.2).  A limitation of use is included when there is reasonable 
354  concern or uncertainty among FDAs expert reviewers, who are qualified by scientific training 
355  and experience, about a drugs risk-benefit profile.  Limitations of use should be distinguished 
356  from contraindications.  A contraindication must describe any situations in which the drug 
357  should not be used because the risk of use (e.g., certain potentially fatal adverse reactions) 
358  clearly outweighs any possible therapeutic benefit ( 201.57(c)(5)).  However, there are cases in 
359  which the evidence falls short of requiring a contraindication, but suggests that use of the drug 
360  may be inadvisable.  There are also cases in which there is sufficient uncertainty about the drugs 
361  benefits in certain clinical situations to suggest that the drug should generally not be used in 
362  those settings.  In these cases, a limitation of use may be appropriate.  To avoid redundancy 
363  within the labeling, contraindications should not be restated as limitations of use in the 
364  INDICATIONS AND USAGE section.   
365   
366  Limitations of use should be included in the INDICATIONS AND USAGE section only when 
367  the awareness of such information is important for practitioners to ensure the safe and effective 
368  use of the drug.  In most cases, limitations of use will identify a particular patient population in 
369  which a drug should generally not be used.  If evidence is available to support the safety and 
370  effectiveness of the drug only in selected subgroups of the larger population, the INDICATIONS 
371  AND USAGE section must include...a succinct description of the limitations of usefulness of 
372  the drug and any uncertainty about anticipated clinical benefits, with reference to the Clinical 
373  Studies section for a discussion of the available evidence ( 201.57(c)(2)(i)(B)).  Such 
374  information would be appropriate to include as a separate limitation of use  rather than 
375  narrowing the language of the indication itself  when needed to inform practitioners that there 
376  is a reasonable concern or uncertainty about the drugs safety or effectiveness outside the 
377  specific population for which the drug is approved.   
378   
379  In contrast, information that essentially narrows or further defines a drugs approved indication 
380  and is used to direct appropriate therapy (e.g., identifying particular subsets of the population for 
381  whom the drug is approved, drugs to be used only after other drug therapies have failed, or 
382  specific tests needed to identify patients to be treated) should be incorporated directly into the 
383  indication whenever possible (see section III.A.2).  This information should not be presented as a 
384  separate limitation of use.  Whereas a limitation of use most often will be included to identify a 
385  patient population in which the drug should generally not be used (i.e., discouraging its use), 
386  information that specifies the patient population in which the drug should be used (i.e., 
387  encouraging its use) should, wherever possible, be incorporated in the indication itself.  For 
388  example, if a drug should be used only after failure of or as an adjunct to another drug or 
389  treatment modality, the indication should include this information rather than having it presented 
390  separately as a limitation of use. 
391   
392  Although there are invariably areas of uncertainty about a drugs effectiveness, not all drugs will 
393  include limitations of use in the INDICATIONS AND USAGE section.  Information considered 
394  for a limitation of use should be evaluated to decide if it may be better suited to another section 
395  of the labeling (e.g., WARNINGS AND PRECAUTIONS, USE IN SPECIFIC POPULATIONS, 
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396  CLINICAL STUDIES).  For example, although there may be circumstances in which a 
397  limitation of use will be further described in (and cross-referenced to) a subsection in the 
398  WARNINGS AND PRECAUTIONS section, most warnings and precautions will typically not 
399  be repeated as limitations of use.  Only information that provides a clearer understanding of the 
400  scope of the approved indication to facilitate safe and effective prescribing decisions should be 
401  included as a limitation of use.  Moreover, an absence of data in a particular population subset 
402  should generally not appear as a limitation of use unless there is reasonable concern about the 
403  drugs safety or effectiveness in that group. 
404     
405  1.  Situations in Which Limitations of Use Would Be Appropriate  
406   
407  The following are examples of situations in which it may be appropriate to include a separate 
408  limitation of use within the INDICATIONS AND USAGE section:   
409   
410  a.  Drugs for which there is reasonable concern or uncertainty about effectiveness 
411  or safety in a certain clinical situation 
412   
413  As recommended in section II.A.2, the approved age group(s) should be included in an 
414  indication.  If there is a concern or uncertainty about safety or effectiveness in a population 
415  outside the approved age group (e.g., younger patients), a limitation of use should be included 
416  about that population.  The inclusion of a limitation of use will differentiate between (1) a 
417  circumstance in which use of the drug in a certain population outside of the approved population 
418  raises a reasonable concern or uncertainty about safety or effectiveness and (2) a circumstance in 
419  which an indication is simply directed to a certain group (e.g., patients within a particular age 
420  range).  The concern that warranted the limitation of use should typically be described elsewhere 
421  in labeling (e.g., WARNINGS AND PRECAUTIONS and USE IN SPECIFIC POPULATIONS 
422  sections), with a cross-reference in the limitation of use to the section of labeling where this 
423  detailed information can be found.  For example: 
424   
425    DRUG-X is indicated for the treatment of hypertension in adults and 
426  pediatric patients 1 year of age and older.  
427   
428  Limitations of Use 
429  In patients younger than one year of age, DRUG-X can adversely affect 
430  kidney development [see Warnings and Precautions (5.X) and Use in 
431  Specific Populations (8.4)] 
432   
433  The governing regulation states that [i]f there is a common belief that a drug may be effective 
434  for a certain use or if there is a common use of the drug for a condition, but the preponderance of 
435  evidence related to the use or condition shows that the drug is ineffective or that the therapeutic 
436  benefits do not generally outweigh its risks, FDA may require that [the INDICATIONS AND 
437  USAGE] section state that there is a lack of evidence that the drug is effective or safe for that use 
438  or condition ( 201.57(c)(2)(ii)).  A limitation of use may be of particular importance in these 
439  circumstances if proven alternative therapies exist for the condition in question.  For example: 
440   
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441    DRUG-X is indicated in adults for the acute treatment of migraine 
442  headache with or without aura. 
443   
444  Limitations of Use  
445  Multiple clinical trials failed to establish the effectiveness of DRUG-X for 
446  the prophylaxis of migraine headaches [see Clinical Studies (14.X)]. 
447   
448  b.  Drugs approved without evidence of benefits known to occur with other drugs 
449  in the same class 
450   
451  If a drug is approved without having demonstrated a particular benefit that has been 
452  demonstrated with other drugs in the same pharmacologic or therapeutic class, it may be 
453  important to convey the differences among products under a Limitations of Use heading in the 
454  INDICATIONS AND USAGE section.  For example, the INDICATIONS AND USAGE section 
455  for a new HMG-CoA reductase inhibitor that is approved based on its serum lipid-lowering 
456  effects (without evidence of a beneficial effect on cardiovascular morbidity and mortality) would 
457  typically be presented as follows:    
458   
459    DRUG-X is indicated as an adjunctive therapy to diet to reduce elevated 
460  total cholesterol, LDL cholesterol, apolipoprotein B, and triglycerides and 
461  to increase HDL cholesterol in adult patients with primary hyperlipidemia 
462  or mixed lipidemia.   
463   
464  Limitations of Use 
465  The effect of DRUG-X on cardiovascular morbidity and mortality has not 
466  been determined. 
467   
468  c.  Drugs with dose, duration, or long-term use considerations 
469   
470  If information on limitations of use or uncertainty about anticipated benefits is relevant to the 
471  recommended dosing intervals, to appropriate treatment duration when treatment should be 
472  limited, or to any dosage modification, the INDICATIONS AND USAGE section must 
473  include...a concise description of the information, with a reference to the more detailed 
474  information in the Dosage and Administration section ( 201.57(c)(2)(i)(D)).  Under these 
475  circumstances, information about important dose or duration considerations, such as how long a 
476  drug can safely be used or uncertainty about the risks and benefits of treatment beyond a certain 
477  period (e.g., long-term cumulative toxicity), should be included as a limitation of use.  For 
478  example: 
479   
480    DRUG-X is indicated for the management of elevated plasma uric acid 
481  levels in adult patients with tumor lysis syndrome. 
482 
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483   
484  Limitations of Use 
485  The activity of DRUG-X may be neutralized by the development of anti-
486  drug antibodies if more than a single course of treatment is administered 
487  [see Dosage and Administration (2.X) and Warnings and Precautions 
488  (5.X)]. 
489   
490  It is generally not necessary to limit duration of use in the INDICATIONS AND USAGE section 
491  unless such a limited duration is essential to ensure the safe and effective use of the drug.  If 
492  clinical trials evaluated the effectiveness of a drug for a chronic condition only in short-term 
493  trials of sufficient duration to support such an approval (e.g., drugs for major depressive disorder 
494  or hypertension), but the drug is indicated for long-term use due to the chronic nature of the 
495  condition and because there is no known or anticipated safety or efficacy concern from continued 
496  use, a description of the duration of use from the clinical trials or information about the lack of 
497  longer term data generally should not be included in the INDICATIONS AND USAGE section.  
498  Information on the length of the clinical trials should instead be discussed in detail in the 
499  CLINICAL STUDIES section of the labeling. 
500   
501  If there are specific conditions that should be met before the drug is used on a long-term basis 
502  (e.g., demonstration of responsiveness to the drug after short-term use in an individual patient), 
503  the INDICATIONS AND USAGE section must include...a statement of the conditions; or if 
504  the indications for long term use are different from those for short term use, a statement of the 
505  specific indications for each use ( 201.57(c)(2)(i)(F)).  For drugs with these characteristics, a 
506  limitation of use may be used to address such issues.  For example: 
507   
508    DRUG-X is indicated for the treatment of severe spasticity in adult 
509  patients with spinal cord injury, brain injury, or multiple sclerosis.  
510   
511  Limitations of Use 
512  Prior to implantation of a device for chronic intrathecal infusion of 
513  DRUG-X, confirm a positive clinical response to DRUG-X in a screening 
514  phase [see Dosage and Administration (2.X)]. 
515   
516  2.  Situations in Which Limitations of Use Generally Would Not Be Appropriate  
517   
518  Limitations of use generally would not be appropriate in the following situations: 
519   
520  a.  To restate information already included in the indication  
521   
522  For example, if an indication is clearly worded as being approved for use in combination with 
523  another drug, there is no need for a limitation of use stating that the subject drug should be used 
524  only in combination and not as monotherapy.  
525   
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526  b.  To address the absence of data in populations in which the drug was not 
527  studied 
528   
529  For example, if an oncology drug was studied in and is indicated for use in patients with a cancer 
530  of a specific mutation, there should not be a limitation of use about the absence of data in 
531  patients with typical (wild-type) forms, unless there is reasonable concern about the drugs safety 
532  or effectiveness in such patients.  Likewise, if a drug is approved to reduce the risk of rejection in 
533  patients receiving a heart transplant, there should not be a limitation of use about the lack of data 
534  on use in lung transplants.  Similarly, if a vaccine is approved for use in children 12 months 
535  through 12 years of age, there should not be a limitation of use about the absence of data in other 
536  age groups. 
537   
538  C.  Other Considerations for Writing the INDICATIONS AND USAGE Section 
539   
540  1.  Identification of Outcomes, Endpoints, and Benefit(s) the Drug Conveys 
541   
542  The approved indication will generally convey the benefit of the treatment (i.e., the disease, 
543  condition, manifestation, or symptoms of the disease or condition being treated, prevented, 
544  mitigated, cured, or diagnosed), and it is usually not necessary to fully describe the specific way 
545  benefit was measured in clinical trials (i.e., identifying outcomes or endpoints) when the 
546  treatment affects a broad range of manifestations of the disease (e.g., an indication for the 
547  symptoms of allergic rhinitis).  In some cases, however, a broad disease indication may not be 
548  appropriate because, for example, the drug may affect only certain signs, symptoms, or 
549  manifestations of the disease (see section III).  An indication identifying an outcome or endpoint 
550  may be considered, for example, when the drugs effect on the overall disease is not well 
551  understood, when different drugs have different effects on various manifestations of the diseases, 
552  when clinical trials evaluated only one or some of the manifestations of the disease, or when the 
553  endpoints are different from typical effectiveness measures.  For example:  
554   
555    DRUG-X is indicated to improve walking in adult patients with multiple sclerosis. 
556   
557  For certain other conditions, the drugs indication may be to reduce the risk of significant 
558  morbidity and mortality, which describes the demonstrated benefit more accurately than would a 
559  more broadly written indication indicating the product simply as a treatment for the condition 
560  itself.  In such cases, the specific endpoint(s) for which the drug has demonstrated benefits 
561  should be incorporated into the indication.  For example: 
562   
563    DRUG-X is indicated to reduce the risk of nonfatal myocardial infarction, fatal 
564  and nonfatal stroke, and revascularization procedures in adult patients with 
565  clinically evident coronary heart disease. 
566   
567  The CLINICAL STUDIES section of labeling must discuss those studies that facilitate an 
568  understanding of how to use the drug safely and effectively ( 201.57(c)(15)).  The information 
569  presented in that section ordinarily includes, among other things, a description of the study 
570  population, endpoints, and results.  For example, if an indication were written for an overall 
571  effect on a composite endpoint, the details on the endpoints studied and results (e.g., which 
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572  component of a composite endpoint drove the overall combined finding) would be discussed in 
573  detail in the CLINICAL STUDIES section.  Additionally, if only one component of a composite 
574  primary endpoint was affected and indicating the drug for the composite would misrepresent the 
575  true result, an indication for the single component can be considered, with the explanation of the 
576  study results summarized in the CLINICAL STUDIES section. 
577     
578  2.  Accelerated Approval 
579   
580  If a drug is approved for an indication based on an effect on a surrogate endpoint or an 
581  intermediate clinical endpoint under section 506(c) of the Federal Food, Drug, and Cosmetic Act 
582  (FD&C Act) (21 U.S.C. 356(c)) and 21 CFR 314.510 or 601.41 (i.e., accelerated approval), the 
583  INDICATIONS AND USAGE section must include...a succinct description of the limitations 
584  of usefulness of the drug and any uncertainty about anticipated clinical benefits, with a reference 
585  to the Clinical Studies section for a discussion of the available evidence 
586  ( 201.57(c)(2)(i)(B)).20   
587   
588  3.  Required or Recommended Language  
589   
590  Under governing statutory and regulatory provisions, certain products have required or 
591  recommended language for the INDICATIONS AND USAGE section.  For example: 
592   
593    Labeling for systemic antibacterial drug products must include a specific 
594  statement in the INDICATIONS AND USAGE section about strategies for 
595  reducing the development of drug-resistant bacteria and maintaining the 
596  effectiveness of the subject drug and other antibacterial drugs (21 
597  CFR 201.24(b)). 
598   
599    Section 505(u)(2)(B) of the FD&C Act (21 U.S.C. 355(u)(2)(B)) requires that 
600  labeling for certain products containing a single enantiomer of a previously 
601  approved racemic drug include a statement that the non-racemic product is not 
602  approved, and has not been shown to be safe and effective, for any condition of 
603  use of the previously approved racemic drug.  For such products approved under 
604  505(u), this information should be presented as a limitation of use. 
605   
606    Other FDA guidances (e.g., clinical/medical guidances) recommend specific 
607  wording for the INDICATIONS AND USAGE section for certain indications.21   
608   
                                                 
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 FDAs 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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609  4.  Preferred Wording and Wording Generally To Avoid22  
610   
611  Consistent with this guidance and the regulatory framework, as a general matter, care should be 
612  taken when considering use of the following terms and phrases: 
613   
614  a.  Reduce the risk versus prevent 
615   
616  If the indication for a drug is to reduce the risk of the occurrence of a particular clinical outcome, 
617  phrases such as reduce the risk of or reduce the incidence of should be considered rather 
618  than using prevent in the indication.  The use of a term such as prevent may imply a guarantee 
619  of success that is not supported by the data.  However, for certain indications, the use of terms 
620  such as prevent (e.g., for preventive vaccines) or prophylaxis (e.g., drugs for post-exposure 
621  prophylaxis) in the indication may be appropriate because, in a given context, these terms are 
622  well established and understood by the clinical community.    
623   
624  b.  Only 
625   
626  The INDICATIONS AND USAGE section should be worded clearly to convey the approved use 
627  of the drug, making inclusion of the word only unnecessary (i.e., the indication generally 
628  should not state DRUG-X is indicated only for...). 
629   
630  c.  Also indicated 
631    
632  When a new indication is added to the INDICATIONS AND USAGE section, the phrase is also 
633  indicated generally should not be used because it may imply that the new indication is less 
634  important than the existing indication(s).     
635   
636  d.  Product identification in the indication  
637   
638  The indication should include the proprietary name (or trade name).  If the product does not have 
639  a proprietary or trade name, the indication should include the nonproprietary name (i.e., 
640  established name for a drug product or proper name for a biological product). 
641   
642  To avoid unnecessary clutter and to enhance clarity, other information (such as the non-
643  proprietary name, dosage form, route of administration) generally should not be included in the 
644  indication.  The established pharmacologic class appears with the indication only in Highlights 
645  ( 201.57(a)(6)). 
646   
647  D.  Formatting the INDICATIONS AND USAGE Section  
648   
649    1.  Format for Multiple Indications 
650   
651  When a drug is approved for more than one indication, the format of the INDICATIONS AND 
652  USAGE section should be carefully considered.  For some drugs, it may be preferable to assign a 
653  subsection 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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654  preferable to present distinct indications using only bullets (e.g., DRUG-X is indicated for: 
655  followed by a bulleted list) immediately under the main section heading or within a subsection. 
656   
657  2.  Format for Limitations of Use 
658   
659  Limitations of use are presented separately from the indication within the INDICATIONS AND 
660  USAGE section, under the heading Limitations of Use and not usually under a separate 
661  numbered subsection.  If, however, a drug has multiple indications and the limitations of use 
662  apply to all of them, it may be preferable to use a separate numbered subsection for Limitations 
663  of Use within the section.  The INDICATIONS AND USAGE section should be formatted to 
664  clearly show if the limitations apply to all or to only some of the indications.  
665   
666   
667   
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