Guidance for Industry Labeling for Human Prescription Drug and Biological Products - Implementing the New Content and Format Requirements [PDF version] Draft Guidance This guidance document is being distributed for comment purposes only.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be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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. 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 Table of Contents INTRODUCTION BACKGROUND CONSIDERATIONS FOR REVISING LABELING General Principles Developing New Sections Data Analyses Updating Claims Distributing Information Among Sections Creating Hierarchy Avoiding Redundancy Using Cross-References Illustrative Example HIGHLIGHTS General Principles Information in Highlights Initial U.S. Approval (§ 201.57(a)(3)) Boxed Warning (§ 201.57(a)(4)) Recent Major Changes (§ 201.57(a)(5)) Indications and Usage (§ 201.57(a)(6)) Dosage and Administration (§ 201.57(a)(7)) Dosage Forms and Strengths (§ 201.57(a)(8)) Contraindications (§ 201.57(a)(9)) Warnings and Precautions (§ 201.57(a)(10)) Adverse Reactions (§ 201.57(a)(11)) Drug Interactions (§ 201.57(a)(12)) Use in Specific Populations (§ 201.57(a)(13)) PROCEDURAL INFORMATION Applications Covered by the Final Rule New NDAs, BLAs, and Efficacy Supplements Approved and Pending Applications Appending FDA-Approved Patient Labeling Submitting Electronic Versions of Labeling Applying for a Waiver from Highlights’ One-Half Page Requirement Class Labeling Mandated Statements Class Labeling Statements That Are Not Mandated by Regulation Abbreviated New Drug Application (ANDA) Products FORMATTING Subheadings Omitted Sections (§ 201.56(d)(4)) Cross-references Type Size APPENDIX A - Frequently Asked Questions APPENDIX B - Prescription Drug Labeling Sections APPENDIX C - Reorganizing Labeling Sections APPENDIX D - Implementation Plan APPENDIX E - Type Size Requirements for Labeling and FDA-Approved Patient Labeling Included with Labeling Guidance for Industry1 Labeling for Human Prescription Drug and Biological Products — Implementing the New Content and Format Requirements2 Contains Nonbinding Recommendations Draft - Not for Implementation This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. INTRODUCTION This guidance is intended to assist applicants in complying with the new content and format requirements of labeling for human prescription drug and biological products (21 CFR 201.56(d) and 201.57).3 FDA recognizes the broad scope and complexity of these new regulations and is issuing this guidance to provide recommendations for applicants revising labeling of already approved products and for applicants drafting labeling for new products to be submitted with a new drug application (NDA) or biologics license application (BLA). FDA also recognizes that, as both applicants and the Agency become more familiar with writing labeling that complies with these new regulations, good examples and practices will emerge. FDA has appended a list of Frequently Asked Questions (FAQs) (Appendix A) and has posted illustrative examples of labeling in the new format at www.fda.gov/cder/regulatory/physLabel/default.htm. The information at this Web site will be updated with new examples, if needed, as they become available. This guidance provides recommendations on the following subjects: Issues to consider when revising labeling for approved products to meet the new content and format requirements, including: how to distribute information among newly created sections when it is important to repeat information in varying levels of detail in different sections how to minimize redundancy when to cross-reference Issues to consider when developing “Highlights of Prescribing Information” (Highlights) Procedural information, including: how to determine which applications are covered how to submit labeling how to apply for a waiver information about class labeling information about abbreviated new drug applications (ANDAs) How to format labeling, including the use of subheadings, cross-references, type size, and how to address omitted sections FDA has also made minor amendments to the regulations for labeling of prescription drug and biological products not subject to the new content and format requirements (see 21 CFR 201.56(e) and 201.80 and sections V.A and V.B of this document). FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. Table of Contents BACKGROUND In January 2006, the Agency published a final rule that amended the requirements for the content and format of labeling for human prescription drug and biological products. The new regulations are designed to make information in prescription drug labeling easier for health care practitioners to access, read, and use, thereby facilitating practitioners’ use of labeling to make prescribing decisions. Changes to the labeling format include the addition of introductory prescribing information, entitled “Highlights of Prescribing Information” (Highlights), and a “Table of Contents” (Contents) for the “Full Prescribing Information” (FPI). Highlights contains selected information from the FPI that health care practitioners most commonly reference and consider most important. The Contents lists the sections and subsections of the FPI. The final rule also reorders and reorganizes the FPI, makes minor changes to the content of the FPI, and sets minimum graphical requirements for the format of the labeling. For the purpose of this guidance, the term new format refers to labeling that meets the content and format requirements at §§ 201.56(d) and 201.57. The term old format refers to labeling formatted to meet the requirements of the 1979 final rule (former §§ 201.56 and 201.57).4 See Appendix B for a listing of prescription drug labeling sections in the old and new formats. This guidance focuses on the major issues applicants may face when developing new labeling or when revising labeling to meet the new requirements and provides procedural information important for implementation. FDA expects that the most challenging aspects of this new regulation will be developing Highlights and distributing information among sections that have been substantially affected by this rule, particularly when the information must be culled from the labeling in the old format. Therefore, the guidance focuses primarily on these issues and not on developing sections that have not been changed by this rule. Additional guidance documents that address content and format for specific FPI sections are available and should be consulted when developing labeling.5 Table of Contents CONSIDERATIONS FOR REVISING LABELING General Principles The FPI in the new format contains substantially the same information as labeling in the old format, typically with reordering and reorganization of the information. For example, new labeling sections (e.g., DRUG INTERACTIONS, USE IN SPECIFIC POPULATIONS, PATIENT COUNSELING INFORMATION) contain information formerly included in the PRECAUTIONS section. Certain sections (e.g., CLINICAL STUDIES, NONCLINICAL TOXICOLOGY) that were previously optional are now required (§ 201.56(d)). Therefore, although labeling in the old format for approved products does not contain the new section headings, most of the content already is included in the labeling under different headings or subheadings. For example, information from the old WARNINGS section and old PRECAUTIONS section is consolidated into a single new section (WARNINGS AND PRECAUTIONS) and information in certain old PRECAUTIONS subsections (e.g., Information for Patients, Drug Interactions, Pregnancy, Labor and Delivery, Nursing Mothers, Pediatric Use, Geriatric Use) is relocated to new labeling sections (e.g., PATIENT COUNSELING INFORMATION, DRUG INTERACTIONS, USE IN SPECIFIC POPULATIONS). FDA recommends following these general principles when revising labeling in the old format. Developing New Sections FDA expects that most sections or subsections from labeling in the old format can be moved, with little or no modification, to corresponding sections in the new format. See Appendix C for information on how to reorganize labeling sections and subsections within the new format. In some cases, however, the labeling in the old format may not include the information specified by the new regulations or the content of a section may be inadequate. If the information or section in the old format is inadequate, it must be revised (§ 201.56(a)). If the labeling in the old format lacks an entire section that is required in the new format, then the section must be developed unless it is clearly inapplicable (§ 201.56(d)). For example, if the labeling in the old format does not contain an Information for Patients subsection in the PRECAUTIONS section, the applicant must develop a PATIENT COUNSELING INFORMATION section unless the section is clearly inapplicable to use of the drug. Data Analyses FDA recognizes that revising labeling to comply with the new regulations is an excellent opportunity to update labeling content to ensure that it accurately reflects current knowledge. FDA expects that, in most cases, the revisions will involve limited rewriting aimed at clarifying text, eliminating redundancies, and updating outdated terminology. FDA emphasizes that no new data analyses of the information in the old format are required as long as the labeling that is developed is truthful and accurate. However, if new information is available that causes the labeling to be inaccurate, the labeling must be updated to incorporate the new information (§ 201.56(a)(2)). In some cases, new data analyses may be necessary. Updating Claims Although the content of information in labeling in the old format will not significantly change when converted to the new format, the process of updating labeling provides a unique opportunity for the applicant to systematically evaluate information in labeling to identify unsubstantiated claims or outdated information and revise it accordingly. By regulation, all express or implied claims in labeling must be supported by substantial evidence.6 If unsubstantiated claims currently exist in labeling, the applicant must revise the labeling to remove such claims (§ 201.56(a)(3)). Distributing Information Among Sections When revising labeling in the old format to comply with the new regulations, applicants will face many decisions about where to put information and whether to repeat information in more than one section. Often sections or subsections can be moved with little or no modification (see Appendix C). In some cases, it will be more appropriate to move certain information from a labeling section in the old format to a different labeling section in the new format or to consolidate similar issues under a new subheading. In other cases, it will be appropriate to divide portions of information in a single labeling section among two or more sections. The following general principles and examples are offered to help applicants make decisions about where to locate information in the new format. Creating Hierarchy It is often important to repeat information in varying levels of detail in different labeling sections, based on the type and clinical relevance of the information. Important clinical information relevant to prescribing decisions should be identified, prioritized, and located in the labeling section that most appropriately communicates the type of information being considered. Avoiding Redundancy Detailed information about a particular topic should be consolidated in a single labeling section. Often, other sections of labeling should more briefly describe or refer to the topic, but not repeat the same level of detail. For example, clinically relevant information about a drug interaction that rises to the level of a warning will typically be described in the WARNINGS AND PRECAUTIONS section, with supporting detail in the DRUG INTERACTIONS section and other sections as appropriate (e.g., DOSAGE AND ADMINISTRATION section if a dosage modification is necessary). In some instances, information repeated in different sections of labeling in the old format can be combined in the new format. For example, the old WARNINGS and old PRECAUTIONS sections sometimes each contained information about a similar issue; this information can now be consolidated under one subheading in the new WARNINGS AND PRECAUTIONS section. When moving and consolidating information in labeling, optional subheadings can be ordered to reflect the importance and relative public health significance of the information. Using Cross-References When information about the same topic is contained in more than one section, the section with greatest clinical relevance (i.e., containing the most important information relevant to prescribing) will typically include a succinct description and will cross-reference the related sections that contain additional detail. If the detailed information is appropriately divided into more than one section, those sections should cross-reference each other. In some cases, cross-references are required (e.g., § 201.57(c)(1), (c)(6)(iv), and (c)(15)(ii)). Illustrative Example The Agency expects that distributing information among certain sections may present special challenges. Based on our experience in developing mock labeling, we have identified several basic principles. The following discussion of distributing information among labeling sections illustrates these principles. Although drug interaction information has been selected for this example, these principles also apply to other labeling sections. Drug interaction information typically appears in the CLINICAL PHARMACOLOGY and DRUG INTERACTIONS sections. Frequently, there is a subset of information that is clinically relevant and essential for prescribing decisions. That subset of information may be distributed among several sections, including the BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION (§ 201.57(c)(3)(i)(H) and (c)(8)). FDA recommends using a descriptive header of summary concepts preceding a discussion of specific information (e.g., “CYP3A inhibitor”). When drug interaction information rises to the level of a warning, precaution, or contraindication or necessitates a dosage adjustment, this information should be discussed briefly in the applicable section(s), with details in the DRUG INTERACTIONS section (§ 201.57(c)(8)). The DRUG INTERACTIONS section contains clinically relevant information, such as the need to modify a dose or regimen. It can include information about the observed absence of a drug interaction if that interaction would otherwise be anticipated or is of special concern (e.g., other drugs in the class need a dosage adjustment or if the drugs are commonly coadministered). More detail about drug interaction studies, including negative results of drug interaction studies, and any clinically relevant, nonclinical data should be included in the CLINICAL PHARMACOLOGY section. Table of Contents HIGHLIGHTS General Principles The purpose of Highlights is to provide immediate access to the information that practitioners most commonly refer to and view as most important. Highlights is intended to serve as an information tool, drawing attention to this information and guiding the practitioner to the section in the FPI where detailed information can be obtained. Highlights is not a verbatim repetition of selected information from the FPI, or simply a repetition of the Contents, but a concise, informative summary of crucial prescribing information. Rarely, it may be appropriate to repeat information verbatim from the FPI (e.g., a succinct boxed warning statement or short indication statement), but in most cases, the information should be summarized and presented in an easily accessible format (e.g., bulleted, tabular). It is critical that the summarized content of Highlights be consistent with the more detailed information in the FPI, but not all of that information will be included in Highlights. Selecting the information to include in Highlights requires judgment about the data in relation to the clinical setting in which the drug is used. The information considered of greatest importance will vary, depending on factors such as differences in safety profiles or dosing considerations for different indications or populations. Information about a topic, or similar topics, extracted from the FPI should be grouped together and summarized with a brief, clear statement. For example, several warnings from the FPI about a similar issue could be condensed into one bulleted item under the Warnings and Precautions heading in Highlights. Summarized information should be presented in direct language that is succinct and imparts a complete piece of information (e.g., for a warning: a description of the risk, its consequences, and the actions to take to prevent or mitigate it). In some cases, the information can be summarized in a few words, while in others, a few short phrases or sentences are more appropriate. Each summarized statement should be located under the appropriate Highlights heading and must cross-reference the section(s) or subsection(s) of the FPI that contains more detailed information (§ 201.56(d)(3)). Information in Highlights Initial U.S. Approval (§ 201.57(a)(3)) On the line immediately beneath the established name (or for biologics, the proper name of the product), the verbatim statement “Initial U.S. Approval” must be presented, followed by the four-digit year in which FDA initially approved the new molecular entity, the new biological product, or the new combination of active ingredients (e.g., Initial U.S. Approval: 2004). Multiple dates should not be listed for products with multiple formulations approved or licensed in different years. For these products, list the initial approval date of the new molecular entity, new biologic product, or new combination of active ingredients. Boxed Warning (§ 201.57(a)(4)) The Boxed Warning in Highlights must contain a concise summary of the information from the BOXED WARNING in the FPI, and is limited in length to 20 lines. Because the BOXED WARNING in the FPI is an abbreviated description of the drug’s most important warnings and contraindications, the Boxed Warning in Highlights serves to emphasize such information, as well as to direct attention to the complete box and to the sections in the FPI that contain more detailed information. FDA recommends that the information under the Boxed Warning heading in Highlights be summarized in a bulleted format, with each bullet communicating a discrete warning or contraindication. In rare instances, the BOXED WARNING in the FPI may be sufficiently concise to warrant repeating the statement verbatim in the Boxed Warning in Highlights. Recent Major Changes (§ 201.57(a)(5)) When substantive labeling changes are made to any of the following sections of the FPI, the heading(s) of the changed section(s) must be listed in Highlights under the heading Recent Major Changes: Boxed Warning Indications and Usage Dosage and Administration Contraindications Warnings and Precautions Minor corrections, such as typographical errors or grammatical changes, are not considered substantive labeling changes. What must be included At a minimum, the section heading, identifying number, and the date on which the change was incorporated in the labeling in month/year format (e.g., 6/2005 or June 2005) If appropriate, the section subheading (e.g., when there are multiple subheading listings for a section) Multiple labeling changes If there are changes in more than one section of the labeling, the sections in Recent Major Changes should be listed in the same order as they appear in the FPI. If there is more than one change in the same labeling section during the 1-year period listed and the change is to the content under the same subheading, the date that supersedes the previous one should be listed. For example, if a new indication (hypertension) was added to the labeling in March 2005, and a limitation to the hypertension indication was added in June 2005, the change under the Recent Major Changes heading should be listed as: Indications and Usage, Hypertension (1.2)     6/2005 If there is more than one change in the same labeling section during the 1-year period listed, but the change is to the content under different subheadings, each section heading, subheading, identifying number, and date should be listed separately. For example: Indications and Usage, Hypertension (1.2)     6/2005 Indications and Usage, Heart Failure (1.3)     9/2005 Listing related information from different FPI sections When a drug product is approved for a new indication, new information is often added to other sections of labeling (e.g., DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL STUDIES). If there are changes in any of the five applicable sections, each changed section should be listed under the Recent Major Changes heading. For example: Indications and Usage, Hypertension (1.2)            June 2005 Dosage and Administration, Hypertension (2.2)     June 2005 Warnings and Precautions, Hyperkalemia (5.6)     June 2005 Marking text in the FPI with a vertical line The corresponding new or modified text in the FPI sections listed under Recent Major Changes must be marked with a vertical line on the left edge (§ 201.57(d)(9)). It is unusual for information to be completely deleted from labeling (e.g., removing a warning as opposed to moving the warning to a different section), but if this occurs, the review division will determine how best to identify this change. Initial submission of revised labeling in the new format The Agency acknowledges that whether to include the Recent Major Changes heading when converting labeling to the new format may be unclear because it is difficult to anticipate if the 1-year time period for listing the changed labeling section will elapse before the labeling in the new format is approved. Therefore, applicants should include any substantive labeling changes under the Recent Major Changes heading in the draft labeling submitted for review. At the time of approval, the review division will determine whether the section is still applicable. Removing a listing from Recent Major Changes A changed section must be listed under Recent Major Changes for at least 1 year after the date the labeling change was approved and can continue to be listed until the labeling is reprinted for the first time after the 1-year period. When the 1-year time period expires, the applicant can choose (1) to reprint labeling immediately to remove the listing or (2) to wait until the next reprinting to remove the listing. FDA recommends that applicants notify the Agency in their Annual Report about removal of a listing from Recent Major Changes and the corresponding vertical line in the FPI (see 21 CFR 314.70(b)(2)(v)(C)(1) and 601.12(f)(3)(i)(D)(1)). Indications and Usage (§ 201.57(a)(6)) Information under the Indications and Usage heading must include a concise statement of each of the drug’s indications, briefly noting any major limitations. FDA recommends that the information be presented in a bulleted format. In unusual circumstances, it may be appropriate to present the indications verbatim from the FPI (e.g., when a product has one indication and the statement in the FPI is sufficiently concise). For a product with limitations of use that are applicable to all of the product’s indications or with a major safety concern associated with all its uses, it is appropriate to list those limitations or concerns together, under an appropriately titled subheading (e.g., Important Limitations). If the drug is a member of an established pharmacologic class, the information under Indications and Usage must include the statement “(Drug) is a (name of class) indicated for (indication(s)).” If the drug is not a member of an established pharmacologic class, the statement should be omitted. Dosage and Administration (§ 201.57(a)(7)) Information under the Dosage and Administration heading must contain a concise summary of the recommended dosage regimen, starting dose, dose range, critical differences among population subsets, monitoring recommendations, if any, and other clinically significant clinical pharmacology information that affects dosing recommendations (e.g., dosing adjustments recommended for concomitant therapy, specific populations with coexisting conditions, clinically relevant food effects). FDA recommends a tabular format to enhance accessibility of information (e.g., when there are different dosing regimens for different indications). When applicable and important, special storage or handling information can be mentioned under this heading (e.g., special handling of chemotherapeutic agents, need for refrigeration, reconstitution prior to administration of the drug). Dosage Forms and Strengths (§ 201.57(a)(8)) Information under the Dosage Forms and Strengths heading must include a concise summary of the dosage form and strength and whether the drug product is scored. If a drug product has numerous dosage forms, bulleted subheadings (e.g., capsules, tablets, injectable, suspension) or tabular presentations are recommended. Contraindications (§ 201.57(a)(9)) Information under the Contraindications heading must include either a concise summary of the situations in which the drug should not be used because the risk clearly outweighs any possible therapeutic benefit or the statement “none” if no contraindicated situations have been identified. “Relative contraindications” (i.e., circumstances under which the drug may be used with caution) are not true contraindications and are not appropriate for inclusion under this heading. Warnings and Precautions (§ 201.57(a)(10)) Information under the Warnings and Precautions heading must include a concise summary of the most clinically significant safety concerns that affect decisions about whether to prescribe the drug, recommendations for patient monitoring to ensure safe use of the drug, and measures that can be taken to prevent or mitigate harm. Thus, although it is unlikely that all of the safety information listed in the FPI will be included in Highlights, the most clinically significant safety concerns should be addressed. Adverse Reactions (§ 201.57(a)(11)) Most frequently occurring adverse reactions Information under the Adverse Reactions heading must include a listing of the most frequently occurring adverse reactions, even if they are included elsewhere in Highlights, and the criteria used to determine inclusion (e.g., incidence rate). The listing should be concise, not lengthy or comprehensive. This listing may include adverse reactions that are important for reasons other than frequency (e.g., leading to discontinuation or dosage adjustments) unless they are included elsewhere in Highlights (e.g., under Warnings and Precautions or Contraindications). The adverse reactions listed as most frequently occurring or most common should be selected from the table of adverse reactions from clinical trials in the FPI. Rates of most common adverse reactions vary, but should be appropriate to the nature of a drug’s adverse reactions profile and the size and composition of the safety database. The criteria for determining inclusion must be identified along with the listing (e.g., >2%). If adverse reaction profiles vary significantly for different indications, list the most common adverse reactions by indication. Also note if different criteria for determining inclusion are used for different indications. Adverse reaction reporting contact information Highlights must also contain adverse reaction reporting contact information that includes: The verbatim statement “To report SUSPECTED ADVERSE REACTIONS, contact” followed by the manufacturer’s name and phone number for adverse reaction reporting, the manufacturer’s Web address of the direct link to its Web site for voluntary reporting of adverse reactions (if available),7 and FDA’s phone number and Web address for voluntary reporting of adverse reactions (see below). FDA’s phone numbers and Web addresses for voluntary reporting of adverse reactions: MedWatch (for drug products other than vaccines) Phone number – 1-800-FDA-1088 Web address – www.fda.gov/medwatch VAERS (for vaccines) Phone number – 1-800-822-7967 Web address – www.fda.gov/vaers8 Drug Interactions (§ 201.57(a)(12)) Information under the Drug Interactions heading includes a concise summary of: a list of other drugs (or classes of drugs) or foods that interact or are predicted to interact in clinically significant ways with the drug practical instructions for preventing or decreasing the likelihood of the interaction Descriptive subheadings of summary concepts (e.g., CYP3A inhibitor) may precede specific information. In general, drugs that were found not to interact or to interact in a nonclinically relevant way should not be included under this heading, nor should details of drug interaction studies. However, it may be appropriate to include pertinent negative findings of drug interaction studies under this heading if the interaction would otherwise be anticipated or is of special concern (e.g., other drugs in the class need a dosage adjustment or if the drugs are commonly coadministered). A tabular format is recommended for presentation of drug interaction information for drugs with numerous clinically significant interactions. Interactions with particularly serious clinical consequences that are summarized under the Contraindications or Warnings and Precautions heading in Highlights would be described in greater detail in the DRUG INTERACTIONS section in the FPI. Because some drugs are associated with a large number of clinically significant drug interactions, it may not be possible to concisely summarize all the critical information in Highlights. In these instances, include a statement under the Drug Interactions heading in Highlights that alerts the prescriber to the presence and significance of the drug interaction information in the FPI. Use in Specific Populations (§ 201.57(a)(13)) Information under the Use in Specific Populations heading includes a concise summary of any clinically important differences in response or recommendations for use of the drug in specific populations (e.g., differences between adult and pediatric responses, need for specific monitoring in patients with hepatic impairment, need for dosing adjustments in patients with renal impairment). Typically, information under this heading includes limitations or precautions for specific populations or established differences in response. Ordinarily, the absence of information about the safety and effectiveness of a drug in a specific population (e.g., pregnant women, children) should not be included under this heading. It may be appropriate to include some information about use in specific populations under other headings in Highlights (e.g., Contraindications, Warnings and Precautions, Dosage and Administration) based on the type and clinical relevance of the information. Table of Contents PROCEDURAL INFORMATION Applications Covered by the Final Rule Section 201.56(b)(1) provides that the final rule applies to prescription drug products with an NDA, BLA, or efficacy supplement that: is submitted on or after the effective date of the final rule, is pending on the effective date of the final rule, or has been approved in the 5 years prior to the effective date of the final rule. Although FDA recognizes the effort involved in revising labeling, the Agency strongly believes that the new format is a significant advance in communicating drug information. Therefore, we encourage applicants with products to which the final rule does not apply to voluntarily revise the labeling of their products to comply with the new content and format requirements. New NDAs, BLAs, and Efficacy Supplements After the effective date of the final rule, draft labeling submitted with new NDAs, BLAs, and efficacy supplements must be in the new format. Consistent with current practice, the labeling will be reviewed with the application or supplement. The following efficacy supplements trigger the requirement to revise labeling to the new format: A new indication or a significant modification of an existing indication, including removal of a major limitation of use A new dosage regimen, including an increase or decrease in daily dosage or a change in frequency of administration A comparative efficacy or comparative pharmacokinetics claim naming another drug A change expected to significantly affect the size of the patient population to be given the drug, either broadening or narrowing the population (e.g., pediatrics, geriatrics) Clinical data to verify and describe the clinical benefit for a drug approved based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity (see 21 CFR 314.510 and 601.41) A labeling supplement with clinical data9 Approved and Pending Applications The timing for submitting labeling in the new format is based on the implementation plan (see § 201.56(c) and Appendix D), but an applicant can voluntarily convert product labeling to the new format prior to the date specified in the implementation plan. For an approved application, the labeling would be submitted as a prior approval labeling supplement.10 Applicants voluntarily revising older labeling would also submit draft labeling as a prior approval labeling supplement. Under § 201.56(c)(2), for applications pending when the rule becomes effective, FDA would approve labeling in the old format and the applicant then would have the implementation period to submit a prior approval labeling supplement. When more than one approval for the same product occurred in the 5 years prior to the effective date of the final rule (e.g., NDA and efficacy supplement), the date of the most recent approval determines the timing of submission of labeling in the new format according to the implementation plan. After labeling is approved in the new format, any subsequent changes to Highlights, other than identified minor exceptions, require submission of a prior approval supplement (§§ 314.70(b) and (c) and 601.12(f)). Appending FDA-Approved Patient Labeling The final rule requires that, 1 year after the effective date, any FDA-approved patient labeling either accompany the labeling or be reprinted immediately following the last section of the labeling (§§ 201.57(c)(18) and 201.80(f)(2)).11 Prior to the final rule, the regulations required that any printed patient information or Medication Guide required to be distributed to patients be reprinted at the end of labeling. The final rule changes these requirements as follows: Any FDA-approved patient labeling, and not just labeling required by regulation to be distributed to patients, must be reprinted in or accompany the labeling. Because distribution of Medication Guides to patients has always been required (see 21 CFR part 208), the final rule does not change this requirement. This requirement applies to the labeling of all drugs, not just those subject to the new format requirements. The final rule provides the option of either reprinting the FDA-approved patient labeling (including Medication Guides) immediately following the last section of labeling or having the FDA-approved patient labeling accompany the labeling as a separate document. When the only change to the labeling is the addition of FDA-approved patient labeling (either reprinted in or accompanying the labeling as a separate document), a labeling supplement is unnecessary. The Agency recommends notifying FDA of this change in the annual report (see §§ 314.81 and 601.12). If there are changes to the labeling other than those listed in the annual report, submit the appropriate labeling supplement (e.g., changes being effected (CBE) or prior approval). Submitting Electronic Versions of Labeling For information about submitting labeling electronically, applicants should consult the guidances for industry on Providing Regulatory Submissions in Electronic Format — Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications and Providing Regulatory Submissions in Electronic Format — Content of Labeling.12 Applying for a Waiver from Highlights’ One-Half Page Requirement The new regulations require that Highlights, excluding the boxed warning, be limited in length to one-half page (§ 201.57(d)(8)). FDA recognizes that under certain circumstances, particularly when a product has many indications or many serious warnings that merit inclusion in Highlights, it may not be possible to accommodate all the required information within one-half page. In this case, the applicant can submit a waiver request with the submission (e.g., NDA, BLA, efficacy supplement, or labeling supplement). (See 21 CFR 201.58.) The applicant should prominently identify the submission as one that includes a waiver request. In the waiver request, the applicant should explain why the one-half page requirement could not be met. The Agency will discuss the waiver request with the applicant during labeling negotiations and will formally document its decision in an action letter. Class Labeling Mandated Statements In some instances, a statement(s) for a drug or class of drugs is required by regulation to be included in a particular section of the labeling. For example, 21 CFR 310.517 requires that labeling for oral hypoglycemics of the sulfonylurea class include a statement in the WARNINGS section. When converting labeling to the new format, the statement must be included in the corresponding section in the new format (e.g., a statement required to be included in the BOXED WARNING in the old format must be included in the BOXED WARNING in the new format). For sections that have been altered or eliminated, see Table 1 for the location of the statement in the new format. Table 1 — Location of Statements Required To Be Included in Labeling Location in Old Format Location in FPI of New Format WARNINGS WARNINGS AND PRECAUTIONS PRECAUTIONS (General) WARNINGS AND PRECAUTIONS PRECAUTIONS (Drug Interactions) DRUG INTERACTIONS PRECAUTIONS (Special Populations) USE IN SPECIFIC POPULATIONS PRECAUTIONS (Information for Patients) PATIENT COUNSELING INFORMATION HOW SUPPLIED (or after HOW SUPPLIED) HOW SUPPLIED/STORAGE AND HANDLING The Agency will consider, on a case-by-case basis, those instances where statements are required to be included in labeling in the new format, but not in a specific labeling section. Whether a specific statement required by regulation must appear in Highlights will be determined by the Agency. Class Labeling Statements That Are Not Mandated by Regulation In some cases, the labeling of all members of a class of drugs includes identical statements, even though they are not mandated by regulation. These class labeling statements describe a risk or effect that is typically associated with members of the class, based on what is known about the pharmacology or chemistry of the drugs. For example, the boxed warning about the risk of using an ACE inhibitor during the second and third trimesters of pregnancy is uniformly presented in all labeling for this class of drugs. To ensure consistent presentation of class labeling statements within drug classes, the Agency will determine during the labeling review and approval process: (1) the appropriate location of a class labeling statement in the FPI, (2) whether the information merits inclusion in Highlights, and (3) the content and location of the summarized statement in Highlights. Applicants should propose content and location of class labeling statements in the new format in the draft labeling submitted with their applications or supplements. Abbreviated New Drug Application (ANDA) Products Under 21 CFR 314.94(a)(8), the labeling of a drug product submitted for approval under an ANDA must be the same as the labeling of the listed drug referenced in the ANDA, except for changes required because: differences have been approved under a suitability petition filed under 21 CFR 314.93 the ANDA product and the reference listed drug are produced or distributed by different manufacturers aspects of the listed drug’s labeling are protected by patent or exclusivity Thus, if the labeling of the reference listed drug is revised to comply with the final rule, the labeling of the ANDA product must also be revised in accordance with 21 CFR 314.127(a)(7). ANDA applicants are encouraged to consult the guidance for industry on revising ANDA labeling following revision of the reference listed drug labeling for information about when and how to submit labeling supplements.13 Table of Contents FORMATTING The final rule includes certain formatting requirements (e.g., ordering, numbering, type size) that were designed to enhance readability and accessibility of labeling information (§ 201.57(d)). Beyond these requirements, the Agency expects that some flexibility in formatting will be necessary because of variability in the type and quantity of labeling information for different drugs. The Agency recommends the use of a two-column format for Highlights and Contents because this format enhances effective communication of the labeling information. Other general recommendations for specific formatting issues are described below. Subheadings The use of subheadings, in addition to those required by the final rule to help organize information in the FPI, is encouraged (e.g., to identify individual warnings). Each subheading that is used must be assigned a decimal number that corresponds to its placement and order in the FPI (§§ 201.56(d)(2) and 201.57(c)). Omitted Sections (§ 201.56(d)(4)) Any required section, subsection, or specific information that is clearly inapplicable must be omitted from Highlights and the FPI. For example, if a drug is indicated for use only in males, and there are no preclinical or clinical data relevant to women of childbearing potential, the Pregnancy, Labor and Delivery, and Nursing Mothers subsections would be omitted because they are not applicable. When a section or subsection is omitted from the FPI, the section must also be omitted from the Contents (§ 201.56(d)(4)). The heading “Full Prescribing Information: Contents” must be followed by an asterisk and the following statement must appear at the end of the Contents: “*Sections or subsections omitted from the Full Prescribing Information are not listed” (§ 201.56(d)(4)). In the example of a drug indicated for use only in males, the Contents heading appears as follows: FULL PRESCRIBING INFORMATION: CONTENTS* The numbering in the Contents and FPI appears as follows: 8 USE IN SPECIFIC POPULATIONS 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE At the end of the Contents, the following statement appears: *Sections or subsections omitted from the Full Prescribing Information are not listed. In most cases when clinically relevant information about a drug is not available, the section or subsection should be omitted. Infrequently, describing the absence of data will provide important information for the prescriber and, therefore, the section or subsection should be included. For example, if a drug has not been adequately studied in a specific patient population (e.g., hepatically impaired), the labeling should include a Hepatic Impairment subsection that describes the lack of information. Cross-references Cross-referencing is encouraged, and in some cases required (e.g., § 201.57(c)(1), (c)(6)(iv), and (c)(15)(ii)), because it reduces the need to repeat detailed information about a similar issue in several different sections (see III.B.3 of this guidance for more information). The preferred presentation of cross-references in Highlights is the numerical identifier in parentheses following the summarized labeling information (e.g., (1.1)). The preferred presentation of cross-references in the FPI is the section heading followed by the numerical identifier (e.g., see Indications and Usage (1.1)). Because cross-references are embedded in the text in the FPI, the use of italics to achieve emphasis is encouraged. Type Size The final rule requires different minimum type sizes for trade labeling (i.e., labeling on or within the package from which the drug is to be dispensed) and for labeling disseminated in other settings (e.g., labeling that accompanies prescription drug promotional materials). (See § 201.57(d)(6).) Appendix E shows minimum type size requirements for labeling in the new format (§ 201.57) and in the old format (§ 201.80), including requirements for FDA-approved patient labeling. The Agency encourages a minimum type size of 10 points for FDA-approved patient labeling. Table of Contents APPENDIX A - Frequently Asked Questions Where to Locate Information Q1. Where should microbiology data be presented in the CLINICAL PHARMACOLOGY section? A1. A subsection in the CLINICAL PHARMACOLOGY section can be created (e.g., 12.4 Microbiology) and all of the microbiology information for antimicrobial products consolidated into that subsection. Q2. Labeling for some products includes disease-specific pathophysiology or epidemiology information. In the new format, where should this information be presented? A2. In rare cases when a brief description of disease pathophysiology may facilitate understanding of a drug’s pharmacology, the information may be included in the Mechanism of Action subsection of the CLINICAL PHARMACOLOGY section (§ 201.57(c)(13)(i)(A)). Epidemiologic information is discouraged because it is quickly outdated and will therefore require the applicant to frequently update the product’s labeling. Q3. What section of the labeling should contain animal efficacy data when a drug is approved based on effectiveness data from studies in animals (§§ 314.610 and 601.91)? A3. In general, the specifics about animal efficacy study results should be presented in the Animal Toxicology and/or Pharmacology subsection of the NONCLINICAL TOXICOLOGY section of labeling. However, other sections should disclose that effectiveness was derived solely from animal studies and explain why (e.g., INDICATIONS AND USAGE, CLINICAL STUDIES). For example, the CLINICAL STUDIES section should make it clear that no human efficacy studies were conducted due to ethical considerations and that approval was based solely on evidence of effectiveness in animals. This section should also include a cross-reference to the Animal Toxicology and/or Pharmacology subsection. In addition, the labeling provided to patients must explain that the drug’s approval was based on efficacy studies conducted in animals alone (§§ 314.610(b)(3) and 601.91(b)(3)). Q4. Can the proprietary (or proper) and established names be repeated at the beginning of the FPI? A4. The proprietary and established names, as well as other product identification information must be presented in Highlights (§ 201.57(a)(2)). The proprietary and established names can be repeated at the beginning of the FPI, or at the beginning of each page of the FPI (e.g., as a header), if this enhances product identification on subsequent pages of labeling. Scope Q5. Are combination products subject to this new labeling rule? A5. Combination products that are comprised of a prescription drug and biologic, a prescription drug and device, or a biologic and device that were reviewed under a BLA or NDA are subject to the new labeling rule, if the prescription drug component is subject to the new labeling rule (see § 201.56(b)). Applicants with these products must submit revised labeling to conform with the new requirements to the original NDA or BLA. In addition, applicants with combination products reviewed under device authorities should contact the Office of Combination Products regarding whether the drug or biological product component is subject to the prescription drug labeling rule. (See 21 CFR part 3.) Procedural Q6. How should a labeling supplement be submitted for a product reviewed in more than one division? A6. For a product with marketing applications in more than one review division, the applicant should continue to follow the procedures established with the divisions for submitting labeling supplements. If the applicant is uncertain about where to submit a supplement that converts labeling to the new format, the division where the original NDA or BLA was approved should be contacted for assistance. Q7. Does the adverse reaction reporting contact information have to be presented as part of the “fair balance” information in promotional materials? A7. There is no requirement to include the adverse reaction reporting contact information in promotional materials. Formatting Q8. Can the proprietary and established (or proper) names be presented on the same line in Highlights? A8. To conserve space in Highlights, the proprietary and established names should be presented on the same line, unless they are too long. In that case, the established name should be presented on the line underneath the proprietary name. Q9. Is there a preferred format for the revision date? A9. The date of the most recent revision must be presented at the end of Highlights (§ 201.57(a)(15)). The preferred format is “Revised: Month Year” or “Revised: Month/Year” (i.e., Revised: June 2003 or Revised: 6/2003). Q10. Should Latin abbreviations be used in the DOSAGE AND ADMINISTRATION section (e.g., qd versus once daily)? A10. The Agency recommends that Latin abbreviations be avoided because of the greater potential for medication errors should an abbreviation be misread. Table of Contents APPENDIX B - Prescription Drug Labeling Sections Old Format* New Format** Description Clinical Pharmacology Indications and Usage Contraindications Warnings Precautions Adverse Reactions Drug Abuse and Dependence Overdosage Dosage and Administration How Supplied Optional sections:   Animal Pharmacology   and/or Animal Toxicology   Clinical Studies   References HIGHLIGHTS OF PRESCRIBING INFORMATION   Product Names, Other Required Information   Boxed Warning   Recent Major Changes   Indications and Usage   Dosage and Administration   Dosage Forms and Strengths   Contraindications   Warnings and Precautions   Adverse Reactions   Drug Interactions   Use in Specific Populations FULL PRESCRIBING INFORMATION: CONTENTS FULL PRESCRIBING INFORMATION    Boxed Warning   1 Indications and Usage   2 Dosage and Administration   3 Dosage Forms and Strengths   4 Contraindications   5 Warnings and Precautions   6 Adverse Reactions   7 Drug Interactions   8 Use in Specific Populations   9 Drug Abuse and Dependence   10 Overdosage   11 Description   12 Clinical Pharmacology   13 Nonclinical Toxicology   14 Clinical Studies   15 References   16 How Supplied/Storage and Handling   17 Patient Counseling Information * As required by 21 CFR 201.56(e) and 201.80. **As required by 21 CFR 201.56(d) and 201.57 Table of Contents APPENDIX C - Reorganizing Labeling Sections Location in Old Format --> Location in FPI in New Format       Boxed Warning --> Boxed Warning Description --> Description Clinical Pharmacology --> Clinical Pharmacology Indications and Usage --> Indications and Usage Contraindications --> Contraindications Warnings --> Warnings and Precautions Precautions         General --> Warnings and Precautions     Information for Patients --> Patient Counseling Information     Laboratory Tests --> Warnings and Precautions     Drug Interactions --> Drug Interactions     Drug/Laboratory Test Interactions --> Warnings and Precautions     Carcinogenesis, Mutagenesis,         Impairment of Fertility --> Nonclinical Toxicology (Carcinogenesis,     Mutagenesis, Impairment of Fertility)     Pregnancy --> Use in Specific Populations (Pregnancy)     Labor and Delivery --> Use in Specific Populations (Labor and Delivery)     Nursing Mothers --> Use in Specific Populations (Nursing Mothers)     Pediatric Use --> Use in Specific Populations (Pediatric Use)     Geriatric Use --> Use in Specific Populations (Geriatric Use) Adverse Reactions --> Adverse Reactions Drug Abuse and Dependence --> Drug Abuse and Dependence Overdosage --> Overdosage Dosage and Administration --> Dosage and Administration How Supplied --> Dosage Forms and Strengths   --> How Supplied/Storage and Handling Animal Pharmacology     and/or Animal Toxicology --> Nonclinical Toxicology (Animal Toxicology and/or Pharmacology) Animal Pharmacology     and/or Animal Toxicology --> Nonclinical Toxicology (Animal Toxicology and/or Pharmacology) Clinical Studies --> Clinical Studies References --> References Table of Contents APPENDIX D - Implementation Plan Applications (NDAs, BLAs, and Efficacy Supplements) Required to Conform to New Labeling Requirements Time by Which Conforming Labeling Must Be Submitted to the Agency for Approval Applications submitted on or after June 30, 2006 Time of submission Applications pending on June 30, 2006 and applications approved any time from June 30, 2005, up to and including June 30, 2006 June 30, 2009 Applications approved any time from June 30, 2004, up to and including June 29, 2005 June 30, 2010 Applications approved any time from June 30, 2003, up to and including June 29, 2004 June 30, 2011 Applications approved any time from June 30, 2002, up to and including June 29, 2003 June 30, 2012 Applications approved any time from June 30, 2001, up to and including June 29, 2002 June 30, 2013 Applications approved prior to June 30, 2001 Voluntarily at any time Table of Contents APPENDIX E - Type Size Requirements for Labeling and FDA-Approved Patient Labeling Included with Labeling   Type Size Requirements for Labeling FDA-Approved Patient Labeling Included with Labeling Type Size Requirements for FDA-Approved Patient Labeling New Format (21 CFR 201.57) Trade Labeling (i.e., labeling on or within the package from which the drug is to be dispensed) Minimum 6-point type FDA-approved patient labeling that is not for distribution to patients Minimum 6-point type Any FDA-approved patient labeling (except a Medication Guide) that is for distribution to patients Minimum 6-point type* Medication Guide that is for distribution to patients Minimum 10-point type Other Labeling (e.g., labeling accompanying promotional materials) Minimum 8-point type FDA-approved patient labeling that is not for distribution to patients Minimum 8-point type Any FDA-approved patient labeling (except a Medication Guide) that is for distribution to patients Minimum 8-point type* Medication Guide that is for distribution to patients Minimum 10-point type Old Format (21 CFR 201.80) Trade Labeling and Other Labeling No minimum requirement FDA-approved patient labeling that is not for distribution to patients No minimum requirement Any FDA-approved patient labeling (except a Medication Guide) that is for distribution to patients No minimum requirement* Medication Guide that is for distribution to patients Minimum 10-point type * FDA does not require, but encourages a minimum type size of 10 points for this information. Table of Contents 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 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. 3 This guidance applies to drugs, including biological drug products. For the purposes of this guidance, drug or drug product will be used to refer to human prescription drug and biological products that are regulated as drugs. 4 See 44 FR 37434, “Labeling and Prescription Drug Advertising; Content and Format for Human Prescription Drugs,” Final Rule, June 26, 1979. 5 See the following FDA guidances for industry: Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format and Clinical Studies Section of Labeling for Human Prescription Drugs and Biological Products — Content and Format. FDA has issued a draft guidance, Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format. Once finalized, it will represent the Agency’s thinking on this topic. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm 6 See § 201.56(a)(3). See also §§ 201.57(c)(2)(iii), (c)(2)(iv), (c)(2)(v), (c)(7)(iii), and (c)(15)(i), and 201.80(c)(2)(i), (c)(2)(ii), (g)(4), and (m)(1)(i). 7 If a manufacturer does not have a Web site for voluntary reporting of adverse reactions, the manufacturer is not required to create one. 8 For vaccines, this Web address is also used for required reporting by health care providers. 9 See FDA’s draft guidance for industry Submitting Separate Marketing Applications and Clinical Data for the Purposes of Assessing User Fees for the definition of clinical data. Once finalized, this guidance will represent the Agency’s thinking on this topic. 10 See §§ 314.70(b) and 601.12(f) about supplements requiring FDA approval before the change is made. 11 The term FDA-approved patient labeling refers to any labeling that has been reviewed and approved by the Agency that provides information for patients and is intended for distribution to patients who are prescribed a drug. 12 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm. 13 See FDA’s guidance for industry Revising ANDA Labeling Following Revision of the RLD Labeling. Table of Contents

Updated February 2, 2006

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