Drug Abuse and Dependence Section of Labeling for Human Prescription Drug and Biological Products — Content and Format Guidance for Industry

Administrative draft guidance, not enacted legislation.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

79575dft.docx
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

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., 4 th 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

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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

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Drug Abuse and Dependence Section of Labeling for Human	1
Prescription Drug and Biological Products —	2
Content and Format	3
Guidance for Industry1
4
5
6
7
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	8
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	9
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	10
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	11
for this guidance as listed on the title page.	12
13
14
15
16
I. 	INTRODUCTION	17
18
This guidance is intended to assist applicants in writing the DRUG ABUSE AND	19
DEPENDENCE section of labeling, as described in the regulations for the content and format of	20
labeling for human prescription drug and biological products (21 CFR 201.57(c)(10)).2, 3 This	21
guidance applies to:	22
23
• 	Prescription drugs controlled under the Controlled Substances Act (CSA)4	
24
25
• 	Prescription drugs not controlled under the CSA for which there is important information	26
to convey to health care providers related to abuse and dependence	27
28
This guidance discusses and provides recommendations on the following:	29
30
• 	The general principles to consider when drafting the DRUG ABUSE AND	31
DEPENDENCE section of the labeling	32
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).

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• 	What information to include in the DRUG ABUSE AND DEPENDENCE section,	34
including common terminology and definitions related to abuse and dependence	35
36
• 	How to write, organize, and format the information within the DRUG ABUSE AND	37
DEPENDENCE section	38
39
• 	How information related to topics presented in the DRUG ABUSE AND DEPENDENCE	40
section should be distributed elsewhere in labeling	41
42
The recommendations in this guidance are intended to help ensure that the DRUG ABUSE AND	43
DEPENDENCE section is useful, informative, and, to the extent possible, consistent in content	44
and format within and across drug and therapeutic classes. Applicants should follow the	45
recommendations in this guidance when developing the DRUG ABUSE AND DEPENDENCE	46
section for a new drug and when revising this section for a currently approved drug.	47
48
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	49
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	50
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	51
the word should in Agency guidances means that something is suggested or recommended, but	52
not required.	53
54
55
II. 	GENERAL PRINCIPLES	56
Information on a drug’s potential for abuse, misuse, addiction, physical dependence, and	57
tolerance is generally conveyed to health care providers in the DRUG ABUSE AND	58
DEPENDENCE section of labeling. Information about a product’s abuse-deterrent properties	59
should also be presented in this section.	60
The primary role of the DRUG ABUSE AND DEPENDENCE section of labeling is to convey	61
information about a drug’s potential for abuse, misuse, addiction, physical dependence, and	62
tolerance in order to help inform prescribing decisions and facilitate the safe and effective use of	63
prescription drug products. This section should be concisely and clearly written to include the	64
information that accurately summarizes the product’s abuse potential, signs and symptoms of	65
withdrawal, and abuse-deterrent properties (if applicable) and to provide information that is	66
important for the safe and effective use of the product.	67
68
A. 	Distribution of Information Among Labeling Sections	69
70
Generally, detailed information about drug abuse and dependence is included in the DRUG	71
ABUSE AND DEPENDENCE section of labeling. Other relevant sections should discuss only	72
those aspects of the information that are pertinent to those sections’ scopes and purposes and	73
should not repeat the identical content or level of detail found in the DRUG ABUSE AND	74
DEPENDENCE section. To the extent possible, redundancies in text should be avoided in	75
labeling, and cross-referencing among sections should be used instead.	76
77

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For example, labeling for opioid products typically includes information on abuse, misuse, and	78
addiction in the BOXED WARNING and WARNINGS AND PRECAUTIONS sections, in	79
addition to the DRUG ABUSE AND DEPENDENCE section. For products that have drug	80
abuse or dependence information in both the WARNINGS AND PRECAUTIONS and DRUG	81
ABUSE AND DEPENDENCE sections, detailed abuse or dependence information (e.g.,	82
description of study designs and results of abuse liability studies) should generally be included in	83
the DRUG ABUSE AND DEPENDENCE section, with the succinct description of the adverse	84
reaction or risk, the clinical implications, and recommendations for managing risks related to	85
abuse or dependence appearing in the WARNINGS AND PRECAUTIONS section.	86
87
The labeling for Schedule II controlled substances typically includes a BOXED WARNING	88
providing information on abuse and dependence, as well as a related discussion in the	89
WARNINGS AND PRECAUTIONS subsection for abuse and dependence information. As	90
appropriate, labeling for Schedule III, IV, and V products may also include discussions related to	91
abuse and dependence in a BOXED WARNING or in the WARNINGS AND PRECAUTIONS	92
section.5	
93
94
B. 	Updating the Section	95
96
Holders of marketing applications for drugs have an ongoing obligation to ensure their labeling	97
is accurate and up to date (21 CFR 201.56(a)(2)). For example, when new information becomes	98
available that causes information in labeling to become inaccurate, false, or misleading, the	99
application holder must take steps to change the content of its labeling, in accordance with	100
§ 201.56(a) and, as applicable, 21 CFR 314.70, 314.97, and 601.12. The DRUG ABUSE AND	101
DEPENDENCE section must be updated as new information about the abuse of and dependence	102
on the product that warrants inclusion in product labeling becomes available.6	
103
104
C. 	Terminology	105
106
The concepts of abuse, misuse, addiction, physical dependence, and tolerance are important for	107
health care providers to understand to facilitate the safe and effective use of drugs associated	108
with the development of these behaviors or conditions. However, these terms are commonly	109
confused or misinterpreted. FDA recommends that definitions of these terms be included in the	110
DRUG ABUSE AND DEPENDENCE section of labeling to ensure common understanding and	111
to facilitate the diagnosis and management of substance use disorders. This guidance provides	112
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).

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recommendations for definitions for abuse- and dependence-related terminology that should be	113
included in this section of labeling (see sections III.B and C of this guidance).7	
114
115
116
III. 	CONTENT AND FORMAT OF THE DRUG ABUSE AND DEPENDENCE	117
SECTION	118
119
The DRUG ABUSE AND DEPENDENCE section is composed of three subsections	120
(§ 201.57(c)(10)). The following information provides recommendations for the content of each	121
subsection.	122
123
A. 	9.1 Controlled Substance	124
Under the CSA, controlled substances are placed in one of five schedules based on their potential	125
for abuse, whether they have a currently accepted medical use in the United States, and the	126
degree of dependence that abuse of the drug or other substance may cause.8 Drugs in each	127
schedule are subject to a set of requirements governing their manufacture, distribution, and	128
dispensing, among other things. In general, the requirements that are most restrictive apply to	129
drugs scheduled in Schedule I and II; and those that are relatively less restrictive cover drugs	130
scheduled in Schedule III, IV, and V.	131
1. 	Prescription Drugs Scheduled Under the Controlled Substances Act	132
If a drug is scheduled under the CSA, the Controlled Substance subsection must state that the	133
drug is a controlled substance and identify the schedule under which the drug is controlled	134
(§ 201.57(c)(10)(i)). This subsection should identify the proprietary name (if a proprietary name	135
exists) and the active ingredient(s) or drug substance(s) that is (are) controlled. This information	136
should be conveyed in a single sentence. For example:	137
• 	DRUG-X contains active ingredient-Y, a Schedule II controlled substance.	138
139
If the drug product does not have a proprietary name, this subsection should identify the active	140
ingredient(s) or drug substance(s) that is (are) controlled. For example:	141
142
• 	Active ingredient-Y is a Schedule II controlled substance.	143
144
For some drug products that are controlled substances, there may be additional legal	145
requirements that should be noted in labeling because they are relevant to prescribers. For	146
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.

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example, these would include the requirements under the CSA (as amended by the Drug	147
Addiction Treatment Act of 2000)9 for the use of buprenorphine products for the treatment of	148
opioid dependence. In such instances, information about the legal requirements should be briefly	149
stated in the Controlled Substance subsection following the sentence about the controlled	150
substance scheduling.	151
152
2. 	Prescription Drugs for Which Controlled Substance Scheduling Is Pending	153
154
If scheduling of the controlled substance is pending when the application is approved under	155
section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the initial labeling	156
should reflect that the schedule will be determined after the Drug Enforcement Administration	157
(DEA) has issued a final scheduling decision.10 For example:	158
159
• 	DRUG-X contains active ingredient-Y. (Controlled substance schedule to be	160
determined after review by the Drug Enforcement Administration.)	161
162
Once DEA has issued a scheduling decision assigning a controlled substance schedule, the	163
labeling must be updated with the controlled substance scheduling information.11	
164
165
3. 	Prescription Drugs Not Controlled Under the Controlled Substances Act That	166
Have Information in Subsection 9.2 or 9.3	167
168
In some situations, even though a drug is not scheduled as a controlled substance, its labeling	169
may include information to convey to health care providers in subsection 9.2 Abuse or 9.3	170
Dependence. For example, a demonstrated lack of abuse potential for a new drug in a	171
therapeutic category in which most other products are controlled substances may be relevant	172
information to include in subsection 9.2. Additionally, labeling for a non-controlled drug may	173
include information on physical dependence in subsection 9.3 when discontinuation of the drug	174
has been shown to cause a withdrawal syndrome.	175
176
When information is included in subsection 9.2 or 9.3 of labeling for non-controlled drugs,	177
subsection 9.1 should include a single sentence stating that the active ingredient(s) or drug	178
substance(s) is (are) not controlled. For example:	179
180
• 	DRUG-X contains active ingredient-Y, which is not a controlled substance.	181
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
If the non-controlled drug does not have a proprietary name, subsection 9.1 should identify the	183
active ingredient(s) or drug substance(s) that is (are) not controlled. For example:	184
185
• 	Active ingredient-Y is not a controlled substance.	186
187
A statement that a drug is not a controlled substance should not be included in labeling when	188
there is no information in subsections 9.2 or 9.3.	189
190
B. 	9.2 Abuse	191
192
This subsection of labeling should contain, as appropriate, information about the drug related to	193
abuse, misuse, and addiction that is important for prescribers to consider. Sources of information	194
for these topics can include evidence from the clinical development program, human abuse	195
liability or human abuse potential studies, and, in some cases, relevant nonclinical data.	196
197
1. 	Information on Abuse	198
199
Subsection 9.2 must state the types of abuse that can occur with the drug and the adverse	200
reactions pertinent to them and must identify particularly susceptible patient populations, if	201
known (§ 201.57(c)(10)(ii)). This subsection should also summarize the information that	202
supports recommendations on how to prevent or mitigate risks associated with abuse and will	203
typically be cross-referenced in other sections of labeling (e.g., BOXED WARNING or	204
WARNINGS AND PRECAUTIONS).	205
206
The subsection must be based primarily on human data and human experience, but pertinent	207
animal data may also be used (§ 201.57(c)(10)(ii)). If there are pertinent animal data, the clinical	208
implications of those data should be summarized in this subsection, and the relevant details of	209
the animal studies should be presented in the Animal Toxicology and/or Pharmacology	210
subsection of the NONCLNICAL TOXICOLOGY section of labeling.	211
212
For drugs with a risk of abuse, the following single sentence should be included in the Abuse	213
subsection:12	
214
215
• 	Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable	216
psychological or physiological effects.	217
Examples of abuse include, but are not limited to, the use of a prescription drug to get “high” or	218
feel euphoric effects.	219
The term abuse should not be used to describe accidental or inadvertent exposure to a	220
prescription drug because abuse requires intentional administration on the part of the abuser.	221
222
12 For this purpose, this guidance uses, with some modifications, the American Psychiatric Association’s definition
of abuse found in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-
IV-TR).

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The Abuse subsection should summarize the types of abuse that can occur with the drug based on	223
clinical experience with the drug or drugs within the same class. This discussion should specify	224
the risks of abuse and the types of adverse reactions that may occur, as well as any information	225
about the typical clinical presentation that may occur with non-therapeutic use of the drug. For	226
example:	227
228
• 	Abuse of DRUG-X poses a risk of overdosage, which may lead to death, central nervous	229
system and respiratory depression, hypotension, and seizures.	230
231
OR	232
233
• 	Signs and symptoms of central nervous system stimulant abuse include the following:	234
tachycardia, tachypnea, hypertension, sweating, dilated pupils, hyperactivity, restlessness,	235
insomnia, decreased appetite, loss of coordination, tremors, flushed skin, vomiting, and	236
abdominal pain.	237
238
This subsection must identify, if known, particularly susceptible patient populations at risk for	239
abuse (§ 201.57(c)(10)(ii)). For example:	240
241
• 	Patients at high risk of DRUG-X abuse include those with a history of prolonged use of	242
products containing active ingredient-Y, those with a history of drug or alcohol abuse, or	243
those who use DRUG-X in combination with other abused drugs.	244
245
a. 	Product-specific risks related to abuse	246
247
The Abuse subsection should include risks specific to abuse of the product, such as those related	248
to a product’s particular formulation. These discussions may include information on risks	249
resulting from inappropriate routes or methods of administration. For example:	250
251
• 	Inappropriate manipulation (e.g., chewing, crushing, dissolving) or self-administration by	252
an inappropriate route (e.g., snorting or injecting) enhances release of active ingredient-Y	253
and increases the risk of overdose or death.	254
255
• 	Inappropriate intravenous, intramuscular, or subcutaneous use of DRUG-X can result in	256
death, local tissue necrosis, infection, pulmonary granulomas, and an increased risk of	257
endocarditis and valvular heart injury.	258
259
If there is evidence of abuse of the product when used in combination with another drug product,	260
this information should be included in this subsection.	261
262
b. 	Abuse potential studies	263
264
Results from human abuse potential studies that adequately characterize the abuse potential of	265
the drug product should be summarized in the Abuse subsection. When an assessment of abuse	266
potential is appropriate and the findings do not suggest a potential for abuse, it may be important,	267
in some instances, to include a summary of such data in this subsection of labeling (e.g., when a	268

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drug product is in a therapeutic category of drugs typically known to have abuse potential, but	269
thorough abuse potential studies show no risk of abuse). Under certain circumstances (e.g.,	270
when a human abuse potential study was not conducted because of safety concerns), animal data	271
indicative of the potential for abuse may be summarized.	272
273
c. 	Products with abuse-deterrent properties	274
275
If studies conducted to evaluate the abuse-deterrent properties of a drug product are included in	276
labeling, summaries of such studies should appear in the Abuse subsection. For example, for	277
opioid drug products, when premarket data show that a product’s abuse-deterrent properties can	278
be expected to result in a meaningful reduction in that product’s abuse, these data, together with	279
an accurate characterization of what the data mean, should generally be included in the Abuse	280
subsection of labeling.13 FDA presently has limited data correlating the abuse-deterrent	281
properties of certain opioid drug products, as demonstrated by premarket studies, with the impact	282
of those properties on abuse or adverse reactions associated with abuse in the postapproval	283
setting. When postmarketing data become available that provide further information on the	284
impact, if any, of abuse-deterrent properties on abuse liability, these data should be summarized	285
in product labeling.	286
287
2. 	Information on Misuse	288
289
For a drug with a risk of misuse that would negatively impact health or functioning, the	290
following single sentence should be included in the Abuse subsection:	291
• 	Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a	292
way other than prescribed by a health care provider or for whom it was not prescribed.	293
Examples of misuse include:	294
• 	Patients intentionally using a prescription drug for a condition different from the	295
condition for which the drug is prescribed	296
297
• 	Patients intentionally taking a drug for therapeutic purposes at a higher dose or taking the	298
drug at a different dosing interval than prescribed	299
300
• 	Individuals intentionally using a drug for therapeutic purposes when the drug is not	301
prescribed for them	302
303
Misuse is defined in the context of therapeutic use, while abuse is defined in the context of non-	304
therapeutic use. The terms misuse and abuse are similar in that they both represent the	305
intentional intake of a drug in a way other than prescribed or by an individual for whom the drug	306
is not prescribed. If the drug is used for therapeutic purposes, other than as prescribed, either for	307
an approved or unapproved use, the use will represent misuse. If the drug is taken for what could	308
13 For more information, see the guidance for industry Abuse-Deterrent Opioids — Evaluation and Labeling (April
2015).

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be considered its desirable non-therapeutic effects (e.g., sedative, stimulant, euphoric, mind-	309
altering effects), the use will represent abuse.	310
311
For example, if a person takes a friend's prescription opioid analgesic for a toothache, that usage	312
is considered misuse of the drug. However, if a person takes a friend's prescription opioid	313
analgesic for its desirable non-therapeutic effects (e.g., euphoria), that usage is considered abuse	314
of the drug. 	Drug misuse is also differentiated from a medication error, in which a patient	315
mistakenly (versus intentionally) uses a drug in a manner other than prescribed.14	
316
As appropriate, information on misuse should be summarized in the Abuse subsection and may	317
include a discussion of the adverse reactions associated with intentional therapeutic use of a drug	318
product in an inappropriate way. A discussion of populations that may be vulnerable to misuse	319
should also be provided, if known.	320
3. 	Information on Addiction	321
322
Relevant information about addiction to the drug should be summarized in the Abuse subsection.	323
This discussion should provide, as available, information regarding the clinical presentation of	324
addiction to the drug, risk factors that may render a patient particularly vulnerable to addiction to	325
the drug, and the adverse effects associated with addiction to the drug.	326
327
For drugs with a risk of addiction, the following single sentence should be included in the Abuse	328
subsection:15	
329
330
• 	Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that	331
may include a strong desire to take the drug, difficulties in controlling drug use (e.g.,	332
continuing drug use despite harmful consequences, giving a higher priority to drug use	333
than other activities and obligations), and possible tolerance or physical dependence.	334
335
Physical dependence is not synonymous with addiction; a patient may be physically dependent	336
on a drug without having an addiction to the drug. Similarly, abuse is not synonymous with	337
addiction. Tolerance, physical dependence, and withdrawal are all expected biological	338
phenomena that are the consequences of chronic treatment with certain drugs. These phenomena	339
by themselves do not indicate a state of addiction.	340
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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C. 	9.3 Dependence	342
This subsection of labeling must contain, as appropriate, information about the drug related to	343
physical dependence, withdrawal, and tolerance. Under § 201.57(c)(10)(iii), the subsection must	344
describe characteristic effects resulting from the psychological and physical dependence that	345
occurs with the drug and must identify, if known, the quantity of the drug over a period of time	346
that may lead to tolerance or dependence, or both.16 The Dependence subsection should	347
summarize signs and symptoms of withdrawal after chronic use or abuse of the drug, whereas the	348
Abuse subsection should discuss abuse-related adverse reactions. Procedures necessary to	349
diagnose the dependent state and the principles of treating or mitigating the effects of abrupt	350
withdrawal must be described in this subsection (§ 201.57(c)(10)(iii)).	351
This subsection should summarize the information that supports recommendations to health care	352
providers on how to prevent or mitigate risks associated with physical dependence, withdrawal,	353
and tolerance. Other sections of labeling that discuss clinical implications related to dependence	354
(e.g., DOSAGE AND ADMINISTRATION or WARNINGS AND PRECAUTIONS) should	355
cross-reference to the Dependence subsection as appropriate.	356
1. 	Information on Physical Dependence and Withdrawal	357
For drugs to which patients may develop physical dependence, the following single sentence	358
should be included in the Dependence subsection:	359
• 	Physical dependence is a state that develops as a result of physiological adaptation in	360
response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt	361
discontinuation or a significant dose reduction of a drug.	362
363
The appearance of a withdrawal syndrome when administration of the drug is terminated or	364
when an antagonist is administered is the only actual evidence of physical dependence. Physical	365
dependence is associated not only with the repeated use of known drugs of abuse, but with drugs	366
with no abuse potential as well. For example, physical dependence to propranolol (a beta-	367
blocker used for the management of hypertension) is known to occur, and abrupt discontinuation	368
may be followed by a “propranolol withdrawal syndrome” resulting in increased blood pressure	369
(temporarily higher than before starting propranolol), headache, chest pain, palpitations, and	370
sweating.	371
In a person who is physically dependent on a drug, a withdrawal syndrome is normally	372
anticipated when the drug is abruptly withdrawn, when the dose is reduced, or when the patient	373
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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is administered an antagonist. The withdrawal syndrome for the drug should be described in the	374
Dependence subsection. For example:	375
• 	Physical dependence can occur in patients treated with DRUG-X. Abrupt cessation or	376
dose reduction following chronic use can result in withdrawal symptoms, including	377
extreme fatigue and depression.	378
379
• 	If DRUG-X is abruptly discontinued in a physically dependent patient, a withdrawal	380
syndrome may occur, typically characterized by restlessness, lacrimation, rhinorrhea,	381
perspiration, chills, myalgia, and mydriasis.	382
383
Measures that should be taken to manage symptoms of withdrawal should also be included in	384
this subsection. For example:	385
386
• 	Discontinue DRUG-X by gradual taper over a 2-week period to reduce the risk of	387
symptoms of withdrawal [see Dosage and Administration (2.x)].	388
389
2. 	Information on Tolerance	390
For drugs to which patients may develop tolerance, the following single sentence should be	391
included in the Dependence subsection:	392
• 	Tolerance is a physiological state characterized by a reduced response to a drug after	393
repeated administration (i.e., a higher dose of a drug is required to produce the same	394
effect that was once obtained at a lower dose).	395
396
Tolerance may develop to some drug effects much more rapidly than to other effects of the same	397
drug. For example, an individual might develop tolerance to the euphoria that opioids may	398
induce; however, the subject might not develop tolerance to the respiratory depressant effects of	399
the same opioid. This discrepancy in the development of tolerance to different opioid-related	400
effects may lead to overdose and death.	401
402
Relevant information about developing tolerance to the drug, if available, should be provided in	403
this subsection, including a discussion of the dosage or exposure at which tolerance is likely to	404
develop. For example:	405
• 	Tolerance may develop during chronic therapy with DRUG-X.	406
407
IV. 	FORMATTING THE DRUG ABUSE AND DEPENDENCE SECTION	408
409
Formatting for the DRUG ABUSE AND DEPENDENCE section must meet the requirements of	410
§ 201.57(d) and should follow the general formatting recommendations available in guidance.17	
411
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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When information within a subsection warrants further delineation, a consistent format for	412
headings and subheadings should be used (e.g., italics or underlining).	413
414
415
V. 	WHAT NOT TO INCLUDE IN THE DRUG ABUSE AND DEPENDENCE	416
SECTION	417
418
Labeling may not include speculative or promotional language (§ 201.56(a)).	419
420
FDA recommends that the following information generally not be included in the DRUG	421
ABUSE AND DEPENDENCE section of labeling:	422
423
• 	Detailed information on the proper disposal of controlled substances, which typically	424
appears elsewhere in labeling (e.g., in the PATIENT COUNSELING INFORMATION	425
section).	426
427
• 	Lengthy definitions — other than those recommended for inclusion in labeling in this	428
guidance — or discussions related to abuse and dependence.	429