Drug Abuse and Dependence 
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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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, 301-796-2500, or 
(CBER) Office of Communication, Outreach and Development, 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 2019 
Labeling 
 
79575dft.docx   
Drug Abuse and Dependence 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  
https://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 
https://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 2019 
Labeling 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  GENERAL PRINCIPLES................................................................................................ 2 
A.  Distribution of Information Among Labeling Sections .............................................................. 2 
B.  Updating the Section ...................................................................................................................... 3 
C.  Terminology ................................................................................................................................... 3 
III.  CONTENT AND FORMAT OF THE DRUG ABUSE AND DEPENDENCE 
SECTION....................................................................................................................................... 4 
A.  9.1 Controlled Substance ............................................................................................................... 4 
1. Prescription Drugs Scheduled Under the Controlled Substances Act ............................................. 4 
2. Prescription Drugs for Which Controlled Substance Scheduling Is Pending ................................. 5 
3. Prescription Drugs Not Controlled Under the Controlled Substances Act That Have Information 
in Subsection 9.2 or 9.3 ........................................................................................................................ 5 
B.  9.2 Abuse ......................................................................................................................................... 6 
1. Information on Abuse ....................................................................................................................... 6 
2. Information on Misuse ..................................................................................................................... 8 
3. Information on Addiction ................................................................................................................. 9 
C.  9.3 Dependence ............................................................................................................................. 10 
1. Information on Physical Dependence and Withdrawal ................................................................. 10 
2. Information on Tolerance .............................................................................................................. 11 
IV.  FORMATTING THE DRUG ABUSE AND DEPENDENCE SECTION ................. 11 
V.  WHAT NOT TO INCLUDE IN THE DRUG ABUSE AND DEPENDENCE 
SECTION..................................................................................................................................... 12 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Drug Abuse and Dependence Section of Labeling for Human 
2  Prescription Drug and Biological Products  
3  Content and Format 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page.  
13   
14   
15   
16   
17  I.  INTRODUCTION  
18   
19  This guidance is intended to assist applicants in writing the DRUG ABUSE AND 
20  DEPENDENCE section of labeling, as described in the regulations for the content and format of 
21  labeling for human prescription drug and biological products (21 CFR 201.57(c)(10)).2, 3  This 
22  guidance applies to: 
23   
24    Prescription drugs controlled under the Controlled Substances Act (CSA)4  
25   
26    Prescription drugs not controlled under the CSA for which there is important information 
27  to convey to health care providers related to abuse and dependence  
28   
29  This guidance discusses and provides recommendations on the following: 
30   
31    The general principles to consider when drafting the DRUG ABUSE AND 
32  DEPENDENCE section of the labeling 
33   
                                                 
1 This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research 
in cooperation with the Center for Biologics Evaluation and Research 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. 
 
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.   
 
4 The complete list of all scheduled substances can be found at 21 CFR part 1308, which is updated following 
publication in the Federal Register of a drug scheduling action by the Drug Enforcement Administration (DEA).    
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
34    What information to include in the DRUG ABUSE AND DEPENDENCE section, 
35  including common terminology and definitions related to abuse and dependence 
36   
37    How to write, organize, and format the information within the DRUG ABUSE AND 
38  DEPENDENCE section 
39   
40    How information related to topics presented in the DRUG ABUSE AND DEPENDENCE 
41  section should be distributed elsewhere in labeling 
42   
43  The recommendations in this guidance are intended to help ensure that the DRUG ABUSE AND 
44  DEPENDENCE section is useful, informative, and, to the extent possible, consistent in content 
45  and format within and across drug and therapeutic classes.  Applicants should follow the 
46  recommendations in this guidance when developing the DRUG ABUSE AND DEPENDENCE 
47  section for a new drug and when revising this section for a currently approved drug. 
48   
49  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
50  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
51  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
52  the word should in Agency guidances means that something is suggested or recommended, but 
53  not required.  
54   
55   
56  II.  GENERAL PRINCIPLES     
57  Information on a drugs potential for abuse, misuse, addiction, physical dependence, and 
58  tolerance is generally conveyed to health care providers in the DRUG ABUSE AND 
59  DEPENDENCE section of labeling.  Information about a products abuse-deterrent properties 
60  should also be presented in this section.   
61  The primary role of the DRUG ABUSE AND DEPENDENCE section of labeling is to convey 
62  information about a drugs potential for abuse, misuse, addiction, physical dependence, and 
63  tolerance in order to help inform prescribing decisions and facilitate the safe and effective use of 
64  prescription drug products.  This section should be concisely and clearly written to include the 
65  information that accurately summarizes the products abuse potential, signs and symptoms of 
66  withdrawal, and abuse-deterrent properties (if applicable) and to provide information that is 
67  important for the safe and effective use of the product. 
68   
69  A.  Distribution of Information Among Labeling Sections 
70   
71  Generally, detailed information about drug abuse and dependence is included in the DRUG 
72  ABUSE AND DEPENDENCE section of labeling.  Other relevant sections should discuss only 
73  those aspects of the information that are pertinent to those sections scopes and purposes and 
74  should not repeat the identical content or level of detail found in the DRUG ABUSE AND 
75  DEPENDENCE section.  To the extent possible, redundancies in text should be avoided in 
76  labeling, and cross-referencing among sections should be used instead.  
77   
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78  For example, labeling for opioid products typically includes information on abuse, misuse, and 
79  addiction in the BOXED WARNING and WARNINGS AND PRECAUTIONS sections, in 
80  addition to the DRUG ABUSE AND DEPENDENCE section.  For products that have drug 
81  abuse or dependence information in both the WARNINGS AND PRECAUTIONS and DRUG 
82  ABUSE AND DEPENDENCE sections, detailed abuse or dependence information (e.g., 
83  description of study designs and results of abuse liability studies) should generally be included in 
84  the DRUG ABUSE AND DEPENDENCE section, with the succinct description of the adverse 
85  reaction or risk, the clinical implications, and recommendations for managing risks related to 
86  abuse or dependence appearing in the WARNINGS AND PRECAUTIONS section.   
87   
88  The labeling for Schedule II controlled substances typically includes a BOXED WARNING 
89  providing information on abuse and dependence, as well as a related discussion in the 
90  WARNINGS AND PRECAUTIONS subsection for abuse and dependence information.  As 
91  appropriate, labeling for Schedule III, IV, and V products may also include discussions related to 
92  abuse and dependence in a BOXED WARNING or in the WARNINGS AND PRECAUTIONS 
93  section.5  
94   
95  B.  Updating the Section 
96   
97  Holders of marketing applications for drugs have an ongoing obligation to ensure their labeling 
98  is accurate and up to date (21 CFR 201.56(a)(2)).  For example, when new information becomes 
99  available that causes information in labeling to become inaccurate, false, or misleading, the 
100  application holder must take steps to change the content of its labeling, in accordance with 
101   201.56(a) and, as applicable, 21 CFR 314.70, 314.97, and 601.12.  The DRUG ABUSE AND 
102  DEPENDENCE section must be updated as new information about the abuse of and dependence 
103  on the product that warrants inclusion in product labeling becomes available.6  
104   
105  C.  Terminology  
106   
107  The concepts of abuse, misuse, addiction, physical dependence, and tolerance are important for 
108  health care providers to understand to facilitate the safe and effective use of drugs associated 
109  with the development of these behaviors or conditions.  However, these terms are commonly 
110  confused or misinterpreted.  FDA recommends that definitions of these terms be included in the 
111  DRUG ABUSE AND DEPENDENCE section of labeling to ensure common understanding and 
112  to facilitate the diagnosis and management of substance use disorders.  This guidance provides 
                                                 
5 For recommendations on when boxed warnings and warnings/precautions are warranted, 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 (October 2011).  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. 
 
6 See 21 CFR 201.56(a)(2).  
 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
113  recommendations for definitions for abuse- and dependence-related terminology that should be 
114  included in this section of labeling (see sections III.B and C of this guidance).7   
115   
116   
117  III.  CONTENT AND FORMAT OF THE DRUG ABUSE AND DEPENDENCE 
118  SECTION 
119   
120  The DRUG ABUSE AND DEPENDENCE section is composed of three subsections 
121  ( 201.57(c)(10)).  The following information provides recommendations for the content of each 
122  subsection.   
123   
124  A.  9.1 Controlled Substance 
125  Under the CSA, controlled substances are placed in one of five schedules based on their potential 
126  for abuse, whether they have a currently accepted medical use in the United States, and the 
127  degree of dependence that abuse of the drug or other substance may cause.8  Drugs in each 
128  schedule are subject to a set of requirements governing their manufacture, distribution, and 
129  dispensing, among other things.  In general, the requirements that are most restrictive apply to 
130  drugs scheduled in Schedule I and II; and those that are relatively less restrictive cover drugs 
131  scheduled in Schedule III, IV, and V. 
132  1.  Prescription Drugs Scheduled Under the Controlled Substances Act 
133  If a drug is scheduled under the CSA, the Controlled Substance subsection must state that the 
134  drug is a controlled substance and identify the schedule under which the drug is controlled 
135  ( 201.57(c)(10)(i)).  This subsection should identify the proprietary name (if a proprietary name 
136  exists) and the active ingredient(s) or drug substance(s) that is (are) controlled.  This information 
137  should be conveyed in a single sentence.  For example:  
138    DRUG-X contains active ingredient-Y, a Schedule II controlled substance. 
139   
140  If the drug product does not have a proprietary name, this subsection should identify the active 
141  ingredient(s) or drug substance(s) that is (are) controlled.  For example:  
142   
143    Active ingredient-Y is a Schedule II controlled substance. 
144   
145  For some drug products that are controlled substances, there may be additional legal 
146  requirements that should be noted in labeling because they are relevant to prescribers.  For 
                                                 
7 Not all definitions recommended in this guidance for use in labeling are the same as the definitions used for the 
purposes of making a clinical diagnosis, such as those in the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5).  
 
8 See Section 202 of the Controlled Substances Act (21 U.S.C. 812(b)), which describes the five schedules for 
controlled substances.  All controlled substances with approved U.S. marketing applications have a currently 
accepted medical use in treatment in the United States and fall within Schedules II through V.  
 
 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
147  example, these would include the requirements under the CSA (as amended by the Drug 
148  Addiction Treatment Act of 2000)9 for the use of buprenorphine products for the treatment of 
149  opioid dependence.  In such instances, information about the legal requirements should be briefly 
150  stated in the Controlled Substance subsection following the sentence about the controlled 
151  substance scheduling.    
152   
153  2.  Prescription Drugs for Which Controlled Substance Scheduling Is Pending  
154   
155  If scheduling of the controlled substance is pending when the application is approved under 
156  section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the initial labeling 
157  should reflect that the schedule will be determined after the Drug Enforcement Administration 
158  (DEA) has issued a final scheduling decision.10  For example:  
159   
160    DRUG-X contains active ingredient-Y.  (Controlled substance schedule to be 
161  determined after review by the Drug Enforcement Administration.) 
162   
163  Once DEA has issued a scheduling decision assigning a controlled substance schedule, the 
164  labeling must be updated with the controlled substance scheduling information.11 
165   
166  3.  Prescription Drugs Not Controlled Under the Controlled Substances Act That 
167  Have Information in Subsection 9.2 or 9.3  
168   
169  In some situations, even though a drug is not scheduled as a controlled substance, its labeling 
170  may include information to convey to health care providers in subsection 9.2 Abuse or 9.3 
171  Dependence.  For example, a demonstrated lack of abuse potential for a new drug in a 
172  therapeutic category in which most other products are controlled substances may be relevant 
173  information to include in subsection 9.2.  Additionally, labeling for a non-controlled drug may 
174  include information on physical dependence in subsection 9.3 when discontinuation of the drug 
175  has been shown to cause a withdrawal syndrome.  
176   
177  When information is included in subsection 9.2 or 9.3 of labeling for non-controlled drugs, 
178  subsection 9.1 should include a single sentence stating that the active ingredient(s) or drug 
179  substance(s) is (are) not controlled.  For example: 
180   
181    DRUG-X contains active ingredient-Y, which is not a controlled substance. 
                                                 
9 See 21 U.S.C. 823(g). 
 
10 With the enactment of the Improving Regulatory Transparency for New Medical Therapies Act in 2015, FDA 
approval of a new drug may not take effect until DEA issuance of an interim final rule under 21 U.S.C. 811(j) 
establishing schedule placement for the drug, in accordance with 21 U.S.C. 355(x).  See Public Law 114-89, 129 
Stat. 698 (Nov. 25, 2015). 
 
11 See 21 CFR 201.57(a)(2), 201.57(c)(10)(i), and 1302.03.  To update the labeling following the scheduling action, 
a supplement to the application must be submitted by the applicant to update product labeling to reflect the DEA 
scheduling action described in the interim final rule or final rule.  See 21 CFR 314.70.  
 
  
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182   
183  If the non-controlled drug does not have a proprietary name, subsection 9.1 should identify the 
184  active ingredient(s) or drug substance(s) that is (are) not controlled.  For example: 
185   
186    Active ingredient-Y is not a controlled substance. 
187   
188  A statement that a drug is not a controlled substance should not be included in labeling when 
189  there is no information in subsections 9.2 or 9.3.   
190   
191  B.  9.2 Abuse 
192   
193  This subsection of labeling should contain, as appropriate, information about the drug related to 
194  abuse, misuse, and addiction that is important for prescribers to consider.  Sources of information 
195  for these topics can include evidence from the clinical development program, human abuse 
196  liability or human abuse potential studies, and, in some cases, relevant nonclinical data.  
197   
198  1.  Information on Abuse 
199   
200  Subsection 9.2 must state the types of abuse that can occur with the drug and the adverse 
201  reactions pertinent to them and must identify particularly susceptible patient populations, if 
202  known ( 201.57(c)(10)(ii)).  This subsection should also summarize the information that 
203  supports recommendations on how to prevent or mitigate risks associated with abuse and will 
204  typically be cross-referenced in other sections of labeling (e.g., BOXED WARNING or 
205  WARNINGS AND PRECAUTIONS).   
206   
207  The subsection must be based primarily on human data and human experience, but pertinent 
208  animal data may also be used ( 201.57(c)(10)(ii)).  If there are pertinent animal data, the clinical 
209  implications of those data should be summarized in this subsection, and the relevant details of 
210  the animal studies should be presented in the Animal Toxicology and/or Pharmacology 
211  subsection of the NONCLNICAL TOXICOLOGY section of labeling.   
212   
213  For drugs with a risk of abuse, the following single sentence should be included in the Abuse 
214  subsection:12 
215   
216    Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable 
217  psychological or physiological effects.  
218  Examples of abuse include, but are not limited to, the use of a prescription drug to get high or 
219  feel euphoric effects. 
220  The term abuse should not be used to describe accidental or inadvertent exposure to a 
221  prescription drug because abuse requires intentional administration on the part of the abuser.   
222   
                                                 
12 For this purpose, this guidance uses, with some modifications, the American Psychiatric Associations definition 
of abuse found in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-
IV-TR). 
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223  The Abuse subsection should summarize the types of abuse that can occur with the drug based on 
224  clinical experience with the drug or drugs within the same class.  This discussion should specify 
225  the risks of abuse and the types of adverse reactions that may occur, as well as any information 
226  about the typical clinical presentation that may occur with non-therapeutic use of the drug.  For 
227  example: 
228   
229    Abuse of DRUG-X poses a risk of overdosage, which may lead to death, central nervous 
230  system and respiratory depression, hypotension, and seizures. 
231   
232  OR 
233   
234    Signs and symptoms of central nervous system stimulant abuse include the following:  
235  tachycardia, tachypnea, hypertension, sweating, dilated pupils, hyperactivity, restlessness, 
236  insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and 
237  abdominal pain. 
238   
239  This subsection must identify, if known, particularly susceptible patient populations at risk for 
240  abuse ( 201.57(c)(10)(ii)).  For example: 
241   
242    Patients at high risk of DRUG-X abuse include those with a history of prolonged use of 
243  products containing active ingredient-Y, those with a history of drug or alcohol abuse, or 
244  those who use DRUG-X in combination with other abused drugs. 
245   
246  a.  Product-specific risks related to abuse  
247   
248  The Abuse subsection should include risks specific to abuse of the product, such as those related 
249  to a products particular formulation.  These discussions may include information on risks 
250  resulting from inappropriate routes or methods of administration.  For example: 
251   
252    Inappropriate manipulation (e.g., chewing, crushing, dissolving) or self-administration by 
253  an inappropriate route (e.g., snorting or injecting) enhances release of active ingredient-Y 
254  and increases the risk of overdose or death. 
255   
256    Inappropriate intravenous, intramuscular, or subcutaneous use of DRUG-X can result in 
257  death, local tissue necrosis, infection, pulmonary granulomas, and an increased risk of 
258  endocarditis and valvular heart injury. 
259   
260  If there is evidence of abuse of the product when used in combination with another drug product, 
261  this information should be included in this subsection. 
262   
263  b.  Abuse potential studies 
264   
265  Results from human abuse potential studies that adequately characterize the abuse potential of 
266  the drug product should be summarized in the Abuse subsection.  When an assessment of abuse 
267  potential is appropriate and the findings do not suggest a potential for abuse, it may be important, 
268  in some instances, to include a summary of such data in this subsection of labeling (e.g., when a 
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269  drug product is in a therapeutic category of drugs typically known to have abuse potential, but 
270  thorough abuse potential studies show no risk of abuse).  Under certain circumstances (e.g., 
271  when a human abuse potential study was not conducted because of safety concerns), animal data 
272  indicative of the potential for abuse may be summarized.   
273   
274  c.  Products with abuse-deterrent properties 
275   
276  If studies conducted to evaluate the abuse-deterrent properties of a drug product are included in 
277  labeling, summaries of such studies should appear in the Abuse subsection.  For example, for 
278  opioid drug products, when premarket data show that a products abuse-deterrent properties can 
279  be expected to result in a meaningful reduction in that products abuse, these data, together with 
280  an accurate characterization of what the data mean, should generally be included in the Abuse 
281  subsection of labeling.13  FDA presently has limited data correlating the abuse-deterrent 
282  properties of certain opioid drug products, as demonstrated by premarket studies, with the impact 
283  of those properties on abuse or adverse reactions associated with abuse in the postapproval 
284  setting.  When postmarketing data become available that provide further information on the 
285  impact, if any, of abuse-deterrent properties on abuse liability, these data should be summarized 
286  in product labeling.  
287   
288  2.  Information on Misuse 
289   
290  For a drug with a risk of misuse that would negatively impact health or functioning, the 
291  following single sentence should be included in the Abuse subsection: 
292    Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a 
293  way other than prescribed by a health care provider or for whom it was not prescribed.  
294  Examples of misuse include: 
295    Patients intentionally using a prescription drug for a condition different from the 
296  condition for which the drug is prescribed 
297   
298    Patients intentionally taking a drug for therapeutic purposes at a higher dose or taking the 
299  drug at a different dosing interval than prescribed 
300   
301    Individuals intentionally using a drug for therapeutic purposes when the drug is not 
302  prescribed for them  
303   
304  Misuse is defined in the context of therapeutic use, while abuse is defined in the context of non-
305  therapeutic use.  The terms misuse and abuse are similar in that they both represent the 
306  intentional intake of a drug in a way other than prescribed or by an individual for whom the drug 
307  is not prescribed.  If the drug is used for therapeutic purposes, other than as prescribed, either for 
308  an approved or unapproved use, the use will represent misuse.  If the drug is taken for what could 
                                                 
13 For more information, see the guidance for industry Abuse-Deterrent Opioids  Evaluation and Labeling (April 
2015). 
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309  be considered its desirable non-therapeutic effects (e.g., sedative, stimulant, euphoric, mind-
310  altering effects), the use will represent abuse.   
311   
312  For example, if a person takes a friend's prescription opioid analgesic for a toothache, that usage 
313  is considered misuse of the drug.  However, if a person takes a friend's prescription opioid 
314  analgesic for its desirable non-therapeutic effects (e.g., euphoria), that usage is considered abuse 
315  of the drug.   Drug misuse is also differentiated from a medication error, in which a patient 
316  mistakenly (versus intentionally) uses a drug in a manner other than prescribed.14 
317  As appropriate, information on misuse should be summarized in the Abuse subsection and may 
318  include a discussion of the adverse reactions associated with intentional therapeutic use of a drug 
319  product in an inappropriate way.  A discussion of populations that may be vulnerable to misuse 
320  should also be provided, if known.  
321  3.  Information on Addiction 
322   
323  Relevant information about addiction to the drug should be summarized in the Abuse subsection.  
324  This discussion should provide, as available, information regarding the clinical presentation of 
325  addiction to the drug, risk factors that may render a patient particularly vulnerable to addiction to 
326  the drug, and the adverse effects associated with addiction to the drug.  
327   
328  For drugs with a risk of addiction, the following single sentence should be included in the Abuse 
329  subsection:15 
330   
331    Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that 
332  may include a strong desire to take the drug, difficulties in controlling drug use (e.g., 
333  continuing drug use despite harmful consequences, giving a higher priority to drug use 
334  than other activities and obligations), and possible tolerance or physical dependence. 
335   
336  Physical dependence is not synonymous with addiction; a patient may be physically dependent 
337  on a drug without having an addiction to the drug.  Similarly, abuse is not synonymous with 
338  addiction.  Tolerance, physical dependence, and withdrawal are all expected biological 
339  phenomena that are the consequences of chronic treatment with certain drugs.  These phenomena 
340  by themselves do not indicate a state of addiction.   
341   
                                                 
14 The National Coordinating Council on Medication Error Reporting and Prevention (NCCMERP) defines a 
medication error as follows:  A medication error is any preventable event that may cause or lead to inappropriate 
medication use or patient harm while the medication is in the control of the health care professional, patient, or 
consumer.  Such events may be related to professional practice, health care products, procedures, and systems, 
including prescribing; order communication; product labeling, packaging, and nomenclature; compounding; 
dispensing; distribution; administration; education; monitoring; and use.  This definition can be found at 
https://www.nccmerp.org/about-medication-errors.  
 
15 For this purpose, this guidance uses, with some modifications, the International Classification of Diseases (ICD-
10) definition of dependence syndrome as the definition of addiction. 
 
 
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342  C.  9.3 Dependence  
343  This subsection of labeling must contain, as appropriate, information about the drug related to 
344  physical dependence, withdrawal, and tolerance.  Under  201.57(c)(10)(iii), the subsection must 
345  describe characteristic effects resulting from the psychological and physical dependence that 
346  occurs with the drug and must identify, if known, the quantity of the drug over a period of time 
347  that may lead to tolerance or dependence, or both.16  The Dependence subsection should 
348  summarize signs and symptoms of withdrawal after chronic use or abuse of the drug, whereas the 
349  Abuse subsection should discuss abuse-related adverse reactions.  Procedures necessary to 
350  diagnose the dependent state and the principles of treating or mitigating the effects of abrupt 
351  withdrawal must be described in this subsection ( 201.57(c)(10)(iii)).  
352  This subsection should summarize the information that supports recommendations to health care 
353  providers on how to prevent or mitigate risks associated with physical dependence, withdrawal, 
354  and tolerance.  Other sections of labeling that discuss clinical implications related to dependence 
355  (e.g., DOSAGE AND ADMINISTRATION or WARNINGS AND PRECAUTIONS) should 
356  cross-reference to the Dependence subsection as appropriate.  
357  1.  Information on Physical Dependence and Withdrawal 
358  For drugs to which patients may develop physical dependence, the following single sentence 
359  should be included in the Dependence subsection: 
360    Physical dependence is a state that develops as a result of physiological adaptation in 
361  response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt 
362  discontinuation or a significant dose reduction of a drug. 
363   
364  The appearance of a withdrawal syndrome when administration of the drug is terminated or 
365  when an antagonist is administered is the only actual evidence of physical dependence.  Physical 
366  dependence is associated not only with the repeated use of known drugs of abuse, but with drugs 
367  with no abuse potential as well.  For example, physical dependence to propranolol (a beta-
368  blocker used for the management of hypertension) is known to occur, and abrupt discontinuation 
369  may be followed by a propranolol withdrawal syndrome resulting in increased blood pressure 
370  (temporarily higher than before starting propranolol), headache, chest pain, palpitations, and 
371  sweating. 
372  In a person who is physically dependent on a drug, a withdrawal syndrome is normally 
373  anticipated when the drug is abruptly withdrawn, when the dose is reduced, or when the patient 
                                                 
16 Terminology used to describe substance-related disorders continues to evolve, and a lexicon is being adopted in 
which past categories of substance abuse and substance dependence (as described in the Diagnostic and Statistical 
Manual of Mental Disorders, Fourth Edition (DSM-IV)) are combined into an overarching diagnosis of substance 
use disorder (as described in DSM-5), which is measured on a continuum from mild to severe.  Accordingly, 
information about substance use disorders is generally parsed out between subsections 9.2 Abuse and 9.3 
Dependence.  Although addiction has historically been associated with the concept of psychological dependence, for 
the purposes of labeling, discussions related to addiction should appear in subsection 9.2 Abuse because addiction as 
it is currently understood relates more closely to abuse than to the subject matter discussed in 9.3 Dependence. 
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Draft  Not for Implementation 
374  is administered an antagonist.  The withdrawal syndrome for the drug should be described in the 
375  Dependence subsection.  For example:  
376    Physical dependence can occur in patients treated with DRUG-X.  Abrupt cessation or 
377  dose reduction following chronic use can result in withdrawal symptoms, including 
378  extreme fatigue and depression.  
379   
380    If DRUG-X is abruptly discontinued in a physically dependent patient, a withdrawal 
381  syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea, 
382  perspiration, chills, myalgia, and mydriasis.   
383   
384  Measures that should be taken to manage symptoms of withdrawal should also be included in 
385  this subsection.  For example: 
386   
387    Discontinue DRUG-X by gradual taper over a 2-week period to reduce the risk of 
388  symptoms of withdrawal [see Dosage and Administration (2.x)]. 
389   
390  2.  Information on Tolerance 
391  For drugs to which patients may develop tolerance, the following single sentence should be 
392  included in the Dependence subsection: 
393    Tolerance is a physiological state characterized by a reduced response to a drug after 
394  repeated administration (i.e., a higher dose of a drug is required to produce the same 
395  effect that was once obtained at a lower dose).   
396   
397  Tolerance may develop to some drug effects much more rapidly than to other effects of the same 
398  drug.  For example, an individual might develop tolerance to the euphoria that opioids may 
399  induce; however, the subject might not develop tolerance to the respiratory depressant effects of 
400  the same opioid.  This discrepancy in the development of tolerance to different opioid-related 
401  effects may lead to overdose and death. 
402   
403  Relevant information about developing tolerance to the drug, if available, should be provided in 
404  this subsection, including a discussion of the dosage or exposure at which tolerance is likely to 
405  develop.  For example: 
406    Tolerance may develop during chronic therapy with DRUG-X. 
407   
408  IV.  FORMATTING THE DRUG ABUSE AND DEPENDENCE SECTION 
409   
410  Formatting for the DRUG ABUSE AND DEPENDENCE section must meet the requirements of 
411   201.57(d) and should follow the general formatting recommendations available in guidance.17  
                                                 
17 See the guidance for industry Labeling for Human Prescription Drug and Biological Products  Implementing 
the PLR Content and Format Requirements (February 2013). 
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Draft  Not for Implementation 
412  When information within a subsection warrants further delineation, a consistent format for 
413  headings and subheadings should be used (e.g., italics or underlining).  
414   
415   
416  V.  WHAT NOT TO INCLUDE IN THE DRUG ABUSE AND DEPENDENCE 
417  SECTION 
418   
419  Labeling may not include speculative or promotional language ( 201.56(a)).  
420   
421  FDA recommends that the following information generally not be included in the DRUG 
422  ABUSE AND DEPENDENCE section of labeling: 
423   
424    Detailed information on the proper disposal of controlled substances, which typically 
425  appears elsewhere in labeling (e.g., in the PATIENT COUNSELING INFORMATION 
426  section).   
427   
428    Lengthy definitions  other than those recommended for inclusion in labeling in this 
429  guidance  or discussions related to abuse and dependence.  
  12