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Guidance for Industry 

Warnings and Precautions, 

Contraindications, and Boxed 

Warning Sections of Labeling for 

Human Prescription Drug and 

Biological Products — 

Content and Format 

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 90 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (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) Janet Norden at 301-796-2270, or 

(CBER) Toni Stifano at 301-827-6190. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

January 2006 

Labeling 
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Guidance for Industry

Warnings and Precautions, 

Contraindications, and Boxed 

Warning Sections of Labeling for 

Human Prescription Drug and 

Biological Products — 

Content and Format 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information, HFD-210 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

(Internet) http://www.fda.gov/cder/guidance/index.htm 

or 

 Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

 Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

(Tel) 800-835-4709 or 301-827-1800 

(Internet) http://www.fda.gov/cber/guidelines.htm. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

Center for Biologics Evaluation and Research (CBER) 

January 2006 

Labeling 
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TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. WARNINGS AND PRECAUTIONS SECTION (§ 201.57(c)(6))................................. 2

A. Adverse Reactions and Information to Include ..........................................................................2

1. Observed Adverse Reactions............................................................................................................2

2. Expected Adverse Reactions ............................................................................................................2

3. Additional Considerations ...............................................................................................................3

4. Adverse Reactions Associated with Unapproved Uses ....................................................................4

5. Drug Interactions.............................................................................................................................4

6. Monitoring .......................................................................................................................................4

B. Information to Provide..................................................................................................................4

C. Format.............................................................................................................................................5

1. Subheadings.....................................................................................................................................5

2. Order of Adverse Reactions.............................................................................................................6

3. Emphasis in Text..............................................................................................................................6

4. Cross-Referencing............................................................................................................................6

III. CONTRAINDICATIONS SECTION (§ 201.57(c)(5)) .................................................. 6

A. When to Contraindicate ................................................................................................................6

1. Observed Adverse Reactions............................................................................................................6

2. Expected Adverse Reactions ............................................................................................................7

3. Likely Clinical Situations.................................................................................................................7

B. Information to Provide..................................................................................................................8

C. Format.............................................................................................................................................8

1. Subheadings.....................................................................................................................................8

2. Order of Contraindications..............................................................................................................8

3. Text Emphasis ..................................................................................................................................9

IV. BOXED WARNING (§ 201.57(c)(1)) .............................................................................. 9

A. When to Use a Boxed Warning.....................................................................................................9

B. Information to Provide................................................................................................................10

C. Format...........................................................................................................................................10

GLOSSARY................................................................................................................................. 11
Contains Nonbinding Recommendations

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1 

Guidance for Industry1 2 

3 

4 Warnings and Precautions, Contraindications, and Boxed Warning 

5 Sections of Labeling for Human Prescription Drug and Biological 

Products — Content and Format2 6 

7 

8 

9 

10 

11 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 

12 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

13 bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements 

14 of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

15 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

16 the appropriate number listed on the title page of this guidance. 

17 

18 

19 

20 

21 I. INTRODUCTION 

22 

23 This guidance is intended to assist applicants and reviewers in drafting the WARNINGS AND 

24 PRECAUTIONS, CONTRAINDICATIONS, and BOXED WARNING sections of labeling, as 

25 described in the final rule amending the requirements for the content and format of labeling for 

human prescription drug and biological products (21 CFR 201.56 and 201.57).3 26 The 

27 recommendations in this guidance are intended to help ensure that the labeling is clear, useful, 

28 informative, and to the extent possible, consistent in content and format. 

29 

30 This guidance provides recommendations on the following: 

31 

32 • How to decide which adverse reactions are significant enough to warrant inclusion in the 

33 WARNINGS AND PRECAUTIONS section; what information to include when 

34 describing those adverse reactions; and how to organize the section 

 

1

 This guidance has been prepared by the Medical Policy Coordinating Committees in the Center for Drug 

Evaluation and Research (CDER) and 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. 

3

 See the final rule “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological 

Products” published in the Federal Register in January 2006. 
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35 • What situations warrant a contraindication; what information to provide in those 

36 situations when the use of the product is contraindicated; and how to organize the 

37 CONTRAINDICATIONS section 

38 • When to include a boxed warning; and what information to include in the BOXED 

39 WARNING section 

40 

41 FDA's guidance documents, including this guidance, do not establish legally enforceable 

42 responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 

43 be viewed only as recommendations, unless specific regulatory or statutory requirements are 

44 cited. The use of the word should in Agency guidances means that something is suggested or 

45 recommended, but not required.

46 

47 II. WARNINGS AND PRECAUTIONS SECTION (§ 201.57(c)(6)) 

48 

49 A. Adverse Reactions and Information to Include 

50 

51 1. Observed Adverse Reactions 

52 

53 This section includes clinically significant adverse reactions observed in association with 

54 the use of a drug for which there is reasonable evidence of a causal association between 

55 the drug and the adverse reaction (a causal relationship need not have been established): 

56 

57 IF 

58 • The adverse reaction is serious (see glossary for definition of serious adverse 

59 reaction). 

60 OR 

61 • The adverse reaction does not meet the definition of a serious adverse reaction, but is 

62 still considered clinically significant (otherwise clinically significant). Adverse 

63 reactions that are considered otherwise clinically significant could include: 

64 — Adverse reactions that require discontinuation, dosage or regimen adjustment, 

65 or addition of another drug 

66 — Adverse reactions that could be prevented or managed with appropriate patient 

67 selection or avoidance of concomitant therapy 

68 — Adverse reactions that significantly affect patient compliance 

69 OR 

70 • The product interferes with a laboratory test. 

71 2. Expected Adverse Reactions 

72 

73 There are circumstances in which an adverse reaction can be expected to occur with a 

74 drug, despite its not having been observed with that drug, based on observations from 
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75 other members of the drug class or animal studies. An expected adverse reaction may not 

76 be observed, for example, in clinical trials for newer drugs in a class where the trials are 

77 designed to exclude populations that were determined to be vulnerable to the adverse 

78 reaction with earlier members of the drug class. 

79 

80 The WARNINGS AND PRECAUTIONS section includes adverse reactions that are 

81 expected to occur with a drug, but have yet to be observed if: 

82 

83 • The reaction is serious or otherwise clinically significant as discussed above 

84 

85 AND EITHER 

86 • Based on what is known about the pharmacology, chemistry, or class of the drug, it 

87 appears likely that the adverse reaction will occur with the drug. 

88 OR 

89 • Animal data raise substantial concern about the potential for occurrence of the 

90 adverse reaction in humans (e.g., animal data demonstrating that a drug has 

91 teratogenic effects). 

92 In these cases, the labeling should acknowledge that the adverse reaction has not been 

93 observed, but may be expected to occur. 

94 

95 3. Additional Considerations 

96 

97 The following factors should also be considered in determining whether to include an 

98 adverse reaction in the WARNINGS AND PRECAUTIONS section of labeling: 

99 

100 • Indication 

101 

102 The relative seriousness of the disease or condition for which a drug is indicated will 

103 influence whether an adverse reaction would be considered clinically significant and thus 

104 appropriate for inclusion in the WARNINGS AND PRECAUTIONS section. For 

105 example, for a drug intended to treat a minor, self-limiting condition (e.g., allergic 

106 rhinitis, cosmetic conditions, transient insomnia), a nonserious adverse reaction (e.g., 

107 nausea, pruritis, alopecia) may be considered clinically significant and, therefore, 

108 appropriate for inclusion in the section. For a drug intended to treat a serious or life109 threatening condition (e.g., cancer), the same adverse reaction may be considered much 

110 less clinically significant and not appropriate for inclusion in the section. 
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111 

112 • Incidence 

113 

114 Typically, the nature of an adverse reaction and a drug’s indication are the most 

115 influential factors in determining whether an adverse reaction should be included in the 

116 WARNINGS AND PRECAUTIONS section. In some cases, however, the absolute risk 

117 or rate of an adverse reaction can be an important factor when deciding whether to 

118 include the reaction in this section (e.g., when the risk or rate is high). 

119 

120 • Ability to Manage or Prevent an Adverse Reaction 

121 

122 The ability to manage or prevent an adverse reaction through patient monitoring, proper 

123 dose selection or titration, or avoidance of concomitant therapy can also be an important 

124 factor in deciding whether to discuss an adverse reaction in the WARNINGS AND 

125 PRECAUTIONS section. 

126 

127 4. Adverse Reactions Associated with Unapproved Uses 

128 

129 FDA may require a specific warning relating to an unapproved use if the drug is 

130 commonly prescribed for a disease or condition and such usage is associated with a 

131 clinically significant risk or hazard (§ 201.57(c)(6)(i)). Clinically significant adverse 

132 reactions that appear to be linked primarily to an unapproved use of a drug (e.g., use for a 

133 disease, condition, or population not included in the INDICATIONS AND USE section, 

134 use of an unapproved dose or regimen) should be identified and discussed in the 

135 WARNINGS AND PRECAUTIONS section. The discussion should include a statement 

136 indicating that safety and effectiveness have not been established in that setting and that 

137 the use is not approved by FDA. 

138 

139 5. Drug Interactions 

140 

141 The WARNINGS AND PRECAUTIONS section should include a discussion of any 

142 known or predicted drug interactions with serious or otherwise clinically significant 

143 outcomes, with a cross-reference to any additional information in the DRUG 

144 INTERACTIONS or CLINICAL PHARMACOLOGY sections. 

145 

146 6. Monitoring

147 

148 The WARNINGS AND PRECAUTIONS section must identify any laboratory tests 

149 helpful in following the patient’s response or in identifying possible adverse reactions 

150 (§ 201.57(c)(6)(iii)), and, if appropriate, information about the frequency of testing and 

151 expected ranges of normal and abnormal values. 

152 

153 B. Information to Provide 

154 

155 The WARNINGS AND PRECAUTIONS section should contain the following 

156 information for each adverse reaction, if such information is known: 
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157 

158 • A description of the adverse reaction and outcome (e.g., time to resolution, significant 

159 sequelae) 

• An estimate of risk or adverse reaction rate4 160 

161 • A discussion of known risk factors for the adverse reaction (e.g., age, gender, race, 

162 comorbid conditions, dose, duration of use, coadministered drugs) 

163 • A discussion of steps to take to reduce the risk of, decrease the likelihood of, shorten 

164 the duration of, or minimize the severity of an adverse reaction. These steps could 

165 include, for example, necessary evaluation prior to use, titration and other kinds of 

166 dose adjustment, monitoring during dose adjustment or prolonged use, avoidance of 

167 other drugs or substances, or special care during comorbid events (e.g., dehydration, 

168 infection) 

169 • A discussion of how to treat, or otherwise manage, an adverse reaction that has 

170 occurred 

171 Although the following issues would typically be discussed elsewhere in labeling, they 

172 can also be mentioned in the WARNINGS AND PRECAUTIONS section when such 

173 information would help prescribers understand the clinical significance of an adverse 

174 reaction: 

175 

176 • A discussion of the mechanism of the adverse reaction 

177 • The source of information about the adverse reaction (e.g., it may be informative to 

178 know whether the information is from clinical trials or postmarketing reports, or 

179 whether an adverse reaction was seen only in foreign experience with the drug) 

180 

181 The information and advice provided in this section should be reasonably qualified, 

182 where appropriate, to convey whatever uncertainties may exist about judgments and 

183 conclusions made (e.g., concerning causality assessments, estimated adverse reaction 

184 rates, and value of proposed monitoring). 

185 

186 C. Format 

187 

188 1. Subheadings 

189 

190 FDA recommends that each adverse reaction, syndrome, or constellation of reactions 

191 (e.g., thrombotic events, hemorrhagic events) included in the WARNINGS AND 

192 PRECAUTIONS section have its own subheading. There would ordinarily be no reason 

 

4

 When the risk for an adverse reaction is highest during early exposure, crude risk (# of adverse reactions/# patients 

exposed) may be the best estimate. For adverse reactions that occur after prolonged exposure, there should be an 

adjustment for duration of exposure by use of either overall exposed person time if the risk is constant over time, or 

by calculation of cumulative incidence for a specified exposure time in a survival analysis. 
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193 to further subcategorize adverse reactions (e.g., separating observed and expected adverse 

194 reactions by placing them under different subheadings). 

195 

196 2. Order of Adverse Reactions 

197 

198 The order in which adverse reactions are presented should reflect the relative public 

199 health significance of the adverse reactions. Factors to consider include the relative 

200 seriousness of the adverse reaction, the ability to prevent or mitigate the adverse reaction, 

201 the likelihood of occurrence, and the size of the population that is potentially affected. In 

202 general, the relative seriousness of the adverse reaction and the ability to prevent or 

203 mitigate it weigh more heavily than the likelihood of occurrence or the size of the 

204 affected population. 

205 

206 3. Emphasis in Text 

207 

208 Bolded text, or other emphasis, can be used to highlight particular adverse reactions or 

209 parts of the discussion of particular adverse reactions (e.g., steps to be taken to avoid a 

210 problem, subpopulations at particular risk). Emphasis should be used sparingly so that its 

211 impact is not diminished. When information is to be emphasized, also consider whether 

212 that information should be in a boxed warning (see section IV on BOXED WARNING 

213 section). 

214 

215 4. Cross-Referencing 

216 

217 Information discussed in the WARNINGS AND PRECAUTIONS section often is 

218 discussed or mentioned in other sections of the labeling (e.g., ADVERSE REACTIONS, 

219 DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS). Information 

220 appearing in other locations should be appropriately cross-referenced. 

221 

222 

223 III. CONTRAINDICATIONS SECTION (§ 201.57(c)(5)) 

224 

225 A. When to Contraindicate 

226 

227 A drug should be contraindicated only in those clinical situations for which the risk from 

228 use clearly outweighs any possible therapeutic benefit. Only known hazards, and not 

229 theoretical possibilities, must be listed. If there are no known contraindications for a 

230 drug, this section must state “None.” 

231 

232 1. Observed Adverse Reactions 

233 

234 For observed adverse reactions, the following would ordinarily be reason to 

235 contraindicate a drug: 

236 
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237 • The risk of the adverse reaction in the clinical situation to which the contraindication 

238 will apply, based on both likelihood and severity of the adverse reaction, outweighs 

239 any potential benefit to the patient. 

240 AND 

241 • The causal relationship between exposure to the drug and the adverse reaction is well 

242 established. 

243 

244 2. Expected Adverse Reactions 

245 

246 Adverse reactions that are expected to occur when a drug is used in a specific clinical 

situation can be the basis for a contraindication.5 247 The following would ordinarily be 

248 reason to contraindicate a drug on the basis of an expected adverse reaction. 

249 

250 The risk of the adverse reaction in the clinical situation to which the contraindication will 

251 apply, based on both likelihood and severity of the adverse reaction, outweighs any 

252 potential benefit to the patient 

253 AND EITHER 

254 • Based on what is known about the pharmacology, chemistry, or class of the drug, it 

255 appears highly likely that the adverse reaction will occur with the drug. 

256 OR 

257 • Animal data raise substantial concern about the potential for occurrence of the 

258 adverse reaction in humans (e.g., animal data demonstrating that a drug has 

259 teratogenic effects). 

260 

261 The labeling should acknowledge that the adverse reaction has not yet been observed, but 

262 is expected to occur. 

263 

264 3. Likely Clinical Situations 

265 

266 A contraindication usually involves one or more of the following clinical situations: 

267 

268 • Comorbid condition or coexistent physiological state (e.g., existing hepatic disease, 

269 renal disease, congenital long QT syndrome, hypokalemia, pregnancy or childbearing 

potential, CYP 2D6 poor metabolizer6 270 ) 

271 

272 • Demographic risk factor (e.g., age, sex, race, genetic vulnerability) 

 

5

 Expected adverse reactions are distinguishable from “theoretical possibilities” because there are data (e.g., from 

class, chemistry, animal studies) to support the expected adverse reaction. 

6

 Use of a particular drug in a patient with a slow metabolizer status would be contraindicated only if there were no 

way to lower the dose to adjust for the compromised metabolic state. 
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273 

274 • The risks of the drug are such that the drug should never be used in a selected subset 

of the larger population with a disease7 275 

276 

277 • Coadministered drug where the combination is dangerous (e.g., MAO inhibitor and 

278 sympathomimetic drug, a drug known to prolong the QT interval and a drug known to 

interfere with the metabolism of that drug)8 279 

280 

281 Contraindications based on drug interactions with serious outcomes should be described 

282 in the CONTRAINDICATIONS section and cross-referenced to more detailed 

283 information in the DRUG INTERACTIONS or CLINICAL PHARMACOLOGY 

284 sections. 

285 

286 B. Information to Provide 

287 

288 For each listed contraindication, provide the following information: 

289 

290 • Brief description of the contraindicated situation or scenario, including any pertinent 

291 demographic or identifiable predisposing characteristics 

292 

293 • Description of anticipated consequences of the contraindicated use 

294 

295 C. Format 

296 

297 1. Subheadings 

298 

299 FDA recommends that each contraindication be identified by its own subheading. 

300 

301 2. Order of Contraindications 

302 

303 The order in which contraindications are presented should reflect the relative public 

304 health significance of the listed contraindications. Factors to consider include the 

305 likelihood of occurrence and the size of the population that is potentially affected. 

306 

 

7

 The INDICATIONS AND USAGE section must contain information about use of the drug when safety 

considerations are such that the drug should be reserved for certain patients (e.g., patients with severe disease) or 

situations (e.g., patients refractory to other drugs) (§ 201.57(c)(2)(i)(B) and (E)). In rare cases, when the risks of the 

drug clearly outweigh any possible therapeutic benefit and the drug should never be used in a selected patient subset, 

a contraindication for use of the drug in that subset should also be described in the CONTRAINDICATIONS 

section. 

8

 There should be consistency across labeling for contraindicated products (i.e., if use of drug A with drug B is 

contraindicated in the labeling for drug A, the use of drug B with drug A should be contraindicated in the labeling 

for drug B). For drugs that are regulated in different reviewing divisions, there should be cross-divisional 

coordination and agreement on contraindicated coadministration of drugs. 
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307 3. Text Emphasis 

308 

309 Bolded text, or other emphasis, can be used to highlight particular contraindicated 

310 situations or parts of the discussions of these situations. Emphasis should be used 

311 sparingly so that its impact is not diminished. When information is to be emphasized, 

312 also consider whether that information should be in a boxed warning (see BOXED 

313 WARNING below). 

314 

315 

316 IV. BOXED WARNING (§ 201.57(c)(1)) 

317 

318 A. When to Use a Boxed Warning 

319 

320 A boxed warning is ordinarily used to highlight for prescribers one of the following 

321 situations: 

322 

323 • There is an adverse reaction so serious in proportion to the potential benefit from the 

324 drug (e.g., a fatal, life-threatening or permanently disabling adverse reaction) that it is 

325 essential that it be considered in assessing the risks and benefits of using a drug 

326 OR 

327 • There is a serious adverse reaction that can be prevented or reduced in frequency or 

328 severity by appropriate use of the drug (e.g., patient selection, careful monitoring, 

329 avoiding certain concomitant therapy, addition of another drug or managing patients 

330 in a specific manner, avoiding use in a specific clinical situation) 

331 OR 

332 • FDA approved the drug with restrictions to assure safe use because FDA concluded 

333 that the drug can be safely used only if distribution or use is restricted (e.g., under 21 

334 CFR part 314, subpart H, § 314.520 “Approval with restrictions to assure safe use”). 

335 

336 A boxed warning can also be used in other situations to highlight warning information 

337 that is especially important to the prescriber. Information included in the WARNINGS 

338 AND PRECAUTIONS and CONTRAINDICATIONS sections should therefore be 

339 evaluated to determine whether it should also be placed in a boxed warning. 

340 

341 Boxed warnings are more likely to be based on observed adverse reactions, but there are 

342 instances when a boxed warning based on an expected adverse reaction would be 

343 appropriate. For example, a contraindication during pregnancy based on evidence in 

344 humans that drugs in a pharmacologic class pose a serious risk of developmental toxicity 

345 during that time would usually be in a boxed warning for all drugs in that class, even 

346 those in which the adverse reaction has not been seen. 

347 

348 A boxed warning can also be considered for a drug that has important risk/benefit 

349 information that is unique among drugs in a drug class (e.g., to note that a drug is the 
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350 only one in its class to have a particular risk that makes it inappropriate for use as a first 

351 line therapy).

352 

353 B. Information to Provide 

354 

355 A boxed warning provides a brief, concise summary of the information that is critical for 

356 a prescriber to be aware of, including any restriction on distribution or use. If there is a 

357 more detailed discussion of the concern in either the CONTRAINDICATIONS or 

358 WARNINGS AND PRECAUTIONS section, or any other labeling section that contains 

359 pertinent information (e.g., DOSAGE AND ADMINISTRATION), a cross-reference to 

360 that section must be provided (§ 201.57(c)(1)). 

361 

362 C. Format 

363 

364 FDA recommends the information in the boxed warning be presented in a bulleted format 

365 (or some alternative format, such as subheadings) that helps to make the information 

366 visually accessible. 

367 
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368 

369 GLOSSARY 

370 

371 

372 Adverse Reaction (21 CFR 201.57(c)(7)): For purposes of prescription drug labeling and this 

373 guidance, an adverse reaction is an undesirable effect, reasonably associated with the use of a 

374 drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in 

375 its occurrence. This definition does not include all adverse events observed during use of a drug, 

376 only those for which there is some basis to believe there is a causal relationship between the drug 

377 and the occurrence of the adverse event. 

378 

379 Adverse reactions may include signs and symptoms, changes in laboratory parameters, and 

380 changes in other measures of critical body function, such as vital signs and electrocardiogram 

381 (ECG). 

382 

383 Adverse Event (or adverse experience): For the purposes of this guidance, an adverse event 

384 refers to any untoward medical event associated with the use of a drug in humans, whether or not 

385 considered drug-related. 

386 

387 Serious Adverse Reaction: For purposes of this guidance, the term serious adverse reaction

388 refers to any reaction occurring at any dose that results in any of the following outcomes: Death, 

389 a life-threatening adverse experience, inpatient hospitalization or prolongation of existing 

390 hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or 

391 birth defect. Important medical events that may not result in death, be life-threatening, or require 

392 hospitalization may be considered serious adverse drug reactions when, based upon appropriate 

393 medical judgment, they may jeopardize the patient or subject and may require medical or 

394 surgical intervention to prevent one of the outcomes listed in this definition. 

395