CFR > Title 21 - Food and Drugs > CHAPTER I—FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES > SUBCHAPTER C—DRUGS: GENERAL (parts 200 to 299) > PART 201—LABELING > SUBPART B—Labeling Requirements for Prescription Drugs and/or Insulin (§201.50 to §201.58) > 201.57—Specific requirements on content and format of labeling for human prescription drug and biological products described in § 201.56(b)(1).

201.57—Specific requirements on content and format of labeling for human prescription drug and biological products described in § 201.56(b)(1).

The requirements in this section apply only to prescription drug products described in § 201.56(b)(1) and must be implemented according to the schedule specified in § 201.56(c), except for the requirement in paragraph (c)(18) of this section to reprint any FDA-approved patient labeling at the end of prescription drug labeling or accompany the prescription drug labeling, which must be implemented no later than June 30, 2007.
(a) Highlights of prescribing information. The following information must appear in all prescription drug labeling:
(1) Highlights limitation statement. The verbatim statement “These highlights do not include all the information needed to use (insert name of drug product) safely and effectively. See full prescribing information for (insert name of drug product).”
(2) Drug names, dosage form, route of administration, and controlled substance symbol. The proprietary name and the established name of the drug, if any, as defined in section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act (the act) or, for biological products, the proper name (as defined in § 600.3 of this chapter) including any appropriate descriptors. This information must be followed by the drug's dosage form and route of administration. For controlled substances, the controlled substance symbol designating the schedule in which the controlled substance is listed must be included as required by § 1302.04 of this chapter.
(3) Initial U.S. approval. The verbatim statement “Initial U.S. Approval” followed by the four-digit year in which FDA initially approved a new molecular entity, new biological product, or new combination of active ingredients. The statement must be placed on the line immediately beneath the established name or, for biological products, proper name of the product.
(4) Boxed warning. A concise summary of any boxed warning required by paragraph (c)(1) of this section, not to exceed a length of 20 lines. The summary must be preceded by a heading, in upper-case letters, containing the word “WARNING” and other words that are appropriate to identify the subject of the warning. The heading and the summary must be contained within a box and bolded. The following verbatim statement must be placed immediately following the heading of the boxed warning: “See full prescribing information for complete boxed warning.”
(5) Recent major changes. A list of the section(s) of the full prescribing information, limited to the labeling sections described in paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this section, that contain(s) substantive labeling changes that have been approved by FDA or authorized under § 314.70(c)(6) or (d)(2), or § 601.12(f)(1) through (f)(3) of this chapter. The heading(s) and, if appropriate, the subheading(s) of the labeling section(s) affected by the change must be listed together with each section's identifying number and the date (month/year) on which the change was incorporated in labeling. These labeling sections must be listed in the order in which they appear in the full prescribing information. A changed section must be listed under this heading in Highlights for at least 1 year after the date of the labeling change and must be removed at the first printing subsequent to the 1 year period.
(6) Indications and usage. A concise statement of each of the product's indications, as required under paragraph (c)(2) of this section, with any appropriate subheadings. Major limitations of use (e.g., lack of effect in particular subsets of the population, or second line therapy status) must be briefly noted. If the product is a member of an established pharmacologic class, the concise statement under this heading in Highlights must identify the class in the following manner: “(Drug) is a (name of class) indicated for (indication(s)).”
(7) Dosage and administration. A concise summary of the information required under paragraph (c)(3) of this section, with any appropriate subheadings, including the recommended dosage regimen, starting dose, dose range, critical differences among population subsets, monitoring recommendations, and other clinically significant clinical pharmacologic information.
(8) Dosage forms and strengths. A concise summary of the information required under paragraph (c)(4) of this section, with any appropriate subheadings (e.g., tablets, capsules, injectable, suspension), including the strength or potency of the dosage form in metric system (e.g., 10-milligram tablets) and whether the product is scored.
(9) Contraindications. A concise statement of each of the product's contraindications, as required under paragraph (c)(5) of this section, with any appropriate subheadings.
(10) Warnings and precautions. A concise summary of the most clinically significant information required under paragraph (c)(6) of this section, with any appropriate subheadings, including information that would affect decisions about whether to prescribe a drug, recommendations for patient monitoring that are critical to safe use of the drug, and measures that can be taken to prevent or mitigate harm.
(11) Adverse reactions. (i) A list of the most frequently occurring adverse reactions, as described in paragraph (c)(7) of this section, along with the criteria used to determine inclusion (e.g., incidence rate). Adverse reactions important for other reasons (e.g., because they are serious or frequently lead to discontinuation or dosage adjustment) must not be repeated under this heading in Highlights if they are included elsewhere in Highlights (e.g., Warnings and Precautions, Contraindications).
(ii) For drug products other than vaccines, the verbatim statement “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer's phone number) or FDA at (insert current FDA phone number and Web address for voluntary reporting of adverse reactions ).”
(iii) For vaccines, the verbatim statement “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer's phone number) or VAERS at (insert the current VAERS phone number and Web address for voluntary reporting of adverse reactions ).”
(iv) For manufacturers with a Web site for voluntary reporting of adverse reactions, the Web address of the direct link to the site.
(12) Drug interactions. A concise summary of the information required under paragraph (c)(8) of this section, with any appropriate subheadings.
(13) Use in specific populations. A concise summary of the information required under paragraph (c)(9) of this section, with any appropriate subheadings.
(14) Patient counseling information statement. The verbatim statement “See 17 for Patient Counseling Information” or, if the product has FDA-approved patient labeling, the verbatim statement “See 17 for Patient Counseling Information and (insert either FDA-approved patient labeling or Medication Guide).”
(15) Revision date. The date of the most recent revision of the labeling, identified as such, placed at the end of Highlights.
(b) Full prescribing information: Contents. Contents must contain a list of each heading and subheading required in the full prescribing information under § 201.56(d)(1), if not omitted under § 201.56(d)(4), preceded by the identifying number required under § 201.56(d)(1). Contents must also contain any additional subheading(s) included in the full prescribing information preceded by the identifying number assigned in accordance with § 201.56(d)(2).
(c) Full prescribing information. The full prescribing information must contain the information in the order required under paragraphs (c)(1) through (c)(18) of this section, together with the headings, subheadings, and identifying numbers required under § 201.56(d)(1), unless omitted under § 201.56(d)(4). If additional subheadings are used within a labeling section, they must be preceded by the identifying number assigned in accordance with § 201.56(d)(2).
(1) Boxed warning. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box. The boxed warning ordinarily must be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. The box must contain, in uppercase letters, a heading inside the box that includes the word “WARNING” and conveys the general focus of the information in the box. The box must briefly explain the risk and refer to more detailed information in the “Contraindications” or “Warnings and Precautions” section, accompanied by the identifying number for the section or subsection containing the detailed information.
(2) 1 Indications and usage. This section must state that the drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition.
(i) This section must include the following information when the conditions listed are applicable:
(A) If the drug is used for an indication only in conjunction with a primary mode of therapy (e.g., diet, surgery, behavior changes, or some other drug), a statement that the drug is indicated as an adjunct to that mode of therapy.
(B) If evidence is available to support the safety and effectiveness of the drug or biological product only in selected subgroups of the larger population (e.g., patients with mild disease or patients in a special age group), or if the indication is approved based on a surrogate endpoint under § 314.510 or § 601.41 of this chapter, a succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits, with reference to the “Clinical Studies” section for a discussion of the available evidence.
(C) If specific tests are necessary for selection or monitoring of the patients who need the drug (e.g., microbe susceptibility tests), the identity of such tests.
(D) If information on limitations of use or uncertainty about anticipated clinical benefits is relevant to the recommended intervals between doses, to the appropriate duration of treatment when such treatment should be limited, or to any modification of dosage, a concise description of the information with reference to the more detailed information in the “Dosage and Administration” section.
(E) If safety considerations are such that the drug should be reserved for specific situations (e.g., cases refractory to other drugs), a statement of the information.
(F) If there are specific conditions that should be met before the drug is used on a long term basis (e.g., demonstration of responsiveness to the drug in a short term trial in a given patient), a statement of the conditions; or, if the indications for long term use are different from those for short term use, a statement of the specific indications for each use.
(ii) If there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows that the drug is ineffective or that the therapeutic benefits of the product do not generally outweigh its risks, FDA may require that this section state that there is a lack of evidence that the drug is effective or safe for that use or condition.
(iii) Any statements comparing the safety or effectiveness of the drug with other agents for the same indication must, except for biological products, be supported by substantial evidence derived from adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless this requirement is waived under § 201.58 or § 314.126(c) of this chapter. For biological products, such statements must be supported by substantial evidence.
(iv) For drug products other than biological products, all indications listed in this section must be supported by substantial evidence of effectiveness based on adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless the requirement is waived under § 201.58 or § 314.126(c) of this chapter. Indications or uses must not be implied or suggested in other sections of the labeling if not included in this section.
(v) For biological products, all indications listed in this section must be supported by substantial evidence of effectiveness. Indications or uses must not be implied or suggested in other sections of the labeling if not included in this section.
(3) 2 Dosage and administration. (i) This section must state the recommended dose and, as appropriate:
(A) The dosage range,
(B) An upper limit beyond which safety and effectiveness have not been established, or beyond which increasing the dose does not result in increasing effectiveness,
(C) Dosages for each indication and subpopulation,
(D) The intervals recommended between doses,
(E) The optimal method of titrating dosage,
(F) The usual duration of treatment when treatment duration should be limited,
(G) Dosing recommendations based on clinical pharmacologic data (e.g., clinically significant food effects),
(H) Modification of dosage needed because of drug interactions or in special patient populations (e.g., in children, in geriatric age groups, in groups defined by genetic characteristics, or in patients with renal or hepatic disease),
(I) Important considerations concerning compliance with the dosage regimen,
(J) Efficacious or toxic concentration ranges and therapeutic concentration windows of the drug or its metabolites, if established and clinically significant. Information on therapeutic drug concentration monitoring (TDM) must also be included in this section when TDM is necessary.
(ii) Dosing regimens must not be implied or suggested in other sections of the labeling if not included in this section.
(iii) Radiation dosimetry information must be stated for both the patient receiving a radioactive drug and the person administering it.
(iv) This section must also contain specific direction on dilution, preparation (including the strength of the final dosage solution, when prepared according to instructions, in terms of milligrams of active ingredient per milliliter of reconstituted solution, unless another measure of the strength is more appropriate), and administration of the dosage form, if needed (e.g., the rate of administration of parenteral drug in milligrams per minute; storage conditions for stability of the reconstituted drug, when important; essential information on drug incompatibilities if the drug is mixed in vitro with other drugs or diluents; and the following verbatim statement for parenterals: “Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.”)
(4) 3 Dosage forms and strengths. This section must contain information on the available dosage forms to which the labeling applies and for which the manufacturer or distributor is responsible, including:
(i) The strength or potency of the dosage form in metric system (e.g., 10 milligram tablets), and, if the apothecary system is used, a statement of the strength in parentheses after the metric designation; and
(ii) A description of the identifying characteristics of the dosage forms, including shape, color, coating, scoring, and imprinting, when applicable. The National Drug Code number(s) for the drug product must not be included in this section.
(5) 4 Contraindications. This section must describe any situations in which the drug should not be used because the risk of use (e.g., certain potentially fatal adverse reactions) clearly outweighs any possible therapeutic benefit. Those situations include use of the drug in patients who, because of their particular age, sex, concomitant therapy, disease state, or other condition, have a substantial risk of being harmed by the drug and for whom no potential benefit makes the risk acceptable. Known hazards and not theoretical possibilities must be listed (e.g., if severe hypersensitivity to the drug has not been demonstrated, it should not be listed as a contraindication). If no contraindications are known, this section must state “None.”
(6) 5 Warnings and precautions. (i) General. This section must describe clinically significant adverse reactions (including any that are potentially fatal, are serious even if infrequent, or can be prevented or mitigated through appropriate use of the drug), other potential safety hazards (including those that are expected for the pharmacological class or those resulting from drug/drug interactions), limitations in use imposed by them (e.g., avoiding certain concomitant therapy), and steps that should be taken if they occur (e.g., dosage modification). The frequency of all clinically significant adverse reactions and the approximate mortality and morbidity rates for patients experiencing the reaction, if known and necessary for the safe and effective use of the drug, must be expressed as provided under paragraph (c)(7) of this section. In accordance with §§ 314.70 and 601.12 of this chapter, the labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established. A specific warning relating to a use not provided for under the “Indications and Usage” section may be required by FDA in accordance with sections 201(n) and 502(a) of the act if the drug is commonly prescribed for a disease or condition and such usage is associated with a clinically significant risk or hazard.
(ii) Other special care precautions. This section must contain information regarding any special care to be exercised by the practitioner for safe and effective use of the drug (e.g., precautions not required under any other specific section or subsection).
(iii) Monitoring: Laboratory tests. This section must identify any laboratory tests helpful in following the patient's response or in identifying possible adverse reactions. If appropriate, information must be provided on such factors as the range of normal and abnormal values expected in the particular situation and the recommended frequency with which tests should be performed before, during, and after therapy.
(iv) Interference with laboratory tests. This section must briefly note information on any known interference by the product with laboratory tests and reference the section where the detailed information is presented (e.g., “Drug Interactions” section).
(7) 6 Adverse reactions. This section must describe the overall adverse reaction profile of the drug based on the entire safety database. For purposes of prescription drug labeling, an adverse reaction is an undesirable effect, reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse events observed during use of a drug, only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.
(i) Listing of adverse reactions. This section must list the adverse reactions that occur with the drug and with drugs in the same pharmacologically active and chemically related class, if applicable. The list or lists must be preceded by the information necessary to interpret the adverse reactions (e.g., for clinical trials, total number exposed, extent and nature of exposure).
(ii) Categorization of adverse reactions. Within a listing, adverse reactions must be categorized by body system, by severity of the reaction, or in order of decreasing frequency, or by a combination of these, as appropriate. Within a category, adverse reactions must be listed in decreasing order of frequency. If frequency information cannot be reliably determined, adverse reactions must be listed in decreasing order of severity.
(A) Clinical trials experience. This section must list the adverse reactions identified in clinical trials that occurred at or above a specified rate appropriate to the safety database. The rate of occurrence of an adverse reaction for the drug and comparators (e.g., placebo) must be presented, unless such data cannot be determined or presentation of comparator rates would be misleading. If adverse reactions that occurred below the specified rate are included, they must be included in a separate listing. If comparative rates of occurrence cannot be reliably determined (e.g., adverse reactions were observed only in the uncontrolled trial portion of the overall safety database), adverse reactions must be grouped within specified frequency ranges as appropriate to the safety database for the drug (e.g., adverse reactions occurring at a rate of less than 1/100, adverse reactions occurring at a rate of less than 1/500) or descriptively identified, if frequency ranges cannot be determined. For adverse reactions with significant clinical implications, the listings must be supplemented with additional detail about the nature, frequency, and severity of the adverse reaction and the relationship of the adverse reaction to drug dose and demographic characteristics, if data are available and important.
(B) Postmarketing experience. This section of the labeling must list the adverse reactions, as defined in paragraph (c)(7) of this section, that are identified from domestic and foreign spontaneous reports. This listing must be separate from the listing of adverse reactions identified in clinical trials.
(iii) Comparisons of adverse reactions between drugs. For drug products other than biological products, any claim comparing the drug to which the labeling applies with other drugs in terms of frequency, severity, or character of adverse reactions must be based on adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless this requirement is waived under § 201.58 or § 314.126(c) of this chapter. For biological products, any such claim must be based on substantial evidence.
(8) 7 Drug interactions. (i) This section must contain a description of clinically significant interactions, either observed or predicted, with other prescription or over-the-counter drugs, classes of drugs, or foods (e.g., dietary supplements, grapefruit juice), and specific practical instructions for preventing or managing them. The mechanism(s) of the interaction, if known, must be briefly described. Interactions that are described in the “Contraindications” or “Warnings and Precautions” sections must be discussed in more detail under this section. Details of drug interaction pharmacokinetic studies that are included in the “Clinical Pharmacology” section that are pertinent to clinical use of the drug must not be repeated in this section.
(ii) This section must also contain practical guidance on known interference of the drug with laboratory tests.
(9) 8 Use in specific populations. This section must contain the following subsections:
(i) 8.1 Pregnancy. This subsection may be omitted only if the drug is not absorbed systemically and the drug is not known to have a potential for indirect harm to the fetus. For all other drugs, this subsection must contain the following information:
(A) Teratogenic effects. Under this subheading, the labeling must identify one of the following categories that applies to the drug, and the labeling must bear the statement required under the category:
(1) Pregnancy category A. If adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling must state: “Pregnancy Category A. Studies in pregnant women have not shown that (name of drug) increases the risk of fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, (name of drug) should be used during pregnancy only if clearly needed.” The labeling must also contain a description of the human studies. If animal reproduction studies are also available and they fail to demonstrate a risk to the fetus, the labeling must also state: “Reproduction studies have been performed in (kinds of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug).” The labeling must also contain a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child.
(2) Pregnancy category B. If animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women, the labeling must state: “Pregnancy Category B. Reproduction studies have been performed in (kind(s) of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug ). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.” If animal reproduction studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling must state: “Pregnancy Category B. Reproduction studies in (kind(s) of animal(s)) have shown (describe findings) at (x) times the human dose. Studies in pregnant women, however, have not shown that (name of drug) increases the risk of abnormalities when administered during the first (second, third, or all) trimester(s) of pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is remote, if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, (name of drug) should be used during pregnancy only if clearly needed.” The labeling must also contain a description of the human studies and a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child.
(3) Pregnancy category C. If animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks, the labeling must state: “Pregnancy Category C. (Name of drug) has been shown to be teratogenic (or to have an embryocidal effect or other adverse effect) in (name(s) of species) when given in doses (x) times the human dose. There are no adequate and well-controlled studies in pregnant women. (Name of drug) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.” The labeling must contain a description of the animal studies. If there are no animal reproduction studies and no adequate and well-controlled studies in humans, the labeling must state: “Pregnancy Category C. Animal reproduction studies have not been conducted with (name of drug ). It is also not known whether (name of drug) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. (Name of drug) should be given to a pregnant woman only if clearly needed.” The labeling must contain a description of any available data on the effect of the drug on the later growth, development, and functional maturation of the child.
(4) Pregnancy category D. If there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective), the labeling must state: “Pregnancy Category D. See ‘Warnings and Precautions’ section.” Under the “Warnings and Precautions” section, the labeling must state: “(Name of drug) can cause fetal harm when administered to a pregnant woman. (Describe the human data and any pertinent animal data.) If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.”
(5) Pregnancy category X. If studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit (for example, safer drugs or other forms of therapy are available), the labeling must state: “Pregnancy Category X. See ‘Contraindications’ section.” Under “Contraindications,” the labeling must state: “(Name of drug) may (can) cause fetal harm when administered to a pregnant woman. (Describe the human data and any pertinent animal data.) (Name of drug) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.”
(B) Nonteratogenic effects. Under this subheading the labeling must contain other information on the drug's effects on reproduction and the drug's use during pregnancy that is not required specifically by one of the pregnancy categories, if the information is relevant to the safe and effective use of the drug. Information required under this heading must include nonteratogenic effects in the fetus or newborn infant (for example, withdrawal symptoms or hypoglycemia) that may occur because of a pregnant woman's chronic use of the drug for a preexisting condition or disease.
(ii) 8.2 Labor and delivery. If the drug has a recognized use during labor or delivery (vaginal or abdominal delivery), whether or not the use is stated in the Indications and Usage section, this subsection must describe the available information about the effect of the drug on the mother and the fetus, on the duration of labor or delivery, on the possibility that forceps delivery or other intervention or resuscitation of the newborn will be necessary, and the effect of the drug on the later growth, development, and functional maturation of the child. If any information required under this subsection is unknown, it must state that the information is unknown.
(iii) 8.3 Nursing mothers. (A) If a drug is absorbed systemically, this subsection must contain, if known, information about excretion of the drug in human milk and effects on the nursing infant. Pertinent adverse effects observed in animal offspring must be described.
(B) If a drug is absorbed systemically and is known to be excreted in human milk, this subsection must contain one of the following statements, as appropriate. If the drug is associated with serious adverse reactions or if the drug has a known tumorigenic potential, the labeling must state: “Because of the potential for serious adverse reactions in nursing infants from (name of drug) (or, “Because of the potential for tumorigenicity shown for (name of drug) in (animal or human) studies), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.” If the drug is not associated with serious adverse reactions and does not have a known tumorigenic potential, the labeling must state: “Caution should be exercised when (name of drug) is administered to a nursing woman.”
(C) If a drug is absorbed systemically and information on excretion in human milk is unknown, this subsection must contain one of the following statements, as appropriate. If the drug is associated with serious adverse reactions or has a known tumorigenic potential, the labeling must state: “It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from (name of drug) (or, “Because of the potential for tumorigenicity shown for (name of drug) in (animal or human) studies), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.” If the drug is not associated with serious adverse reactions and does not have a known tumorigenic potential, the labeling must state: “It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when (name of drug) is administered to a nursing woman.”
(iv) 8.4 Pediatric use. (A) Pediatric population(s)/pediatric patient(s): For the purposes of paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(H) of this section, the terms pediatric population(s) and pediatric patient(s) are defined as the pediatric age group, from birth to 16 years, including age groups often called neonates, infants, children, and adolescents.
(B) If there is a specific pediatric indication different from those approved for adults that is supported by adequate and well-controlled studies in the pediatric population, it must be described under the “Indications and Usage” section, and appropriate pediatric dosage information must be given under the “Dosage and Administration” section. The “Pediatric use” subsection must cite any limitations on the pediatric indication, need for specific monitoring, specific hazards associated with use of the drug in any subsets of the pediatric population (e.g., neonates), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. Data summarized in this subsection should be discussed in more detail, if appropriate, under the “Clinical Pharmacology” or “Clinical Studies” section. As appropriate, this information must also be contained in the “Contraindications” and/or “Warnings and Precautions” section(s).
(C) If there are specific statements on pediatric use of the drug for an indication also approved for adults that are based on adequate and well-controlled studies in the pediatric population, they must be summarized in the “Pediatric use” subsection and discussed in more detail, if appropriate, under the “Clinical Pharmacology” and “Clinical Studies” sections. Appropriate pediatric dosage must be given under the “Dosage and Administration” section. The “Pediatric use” subsection of the labeling must also cite any limitations on the pediatric use statement, need for specific monitoring, specific hazards associated with use of the drug in any subsets of the pediatric population (e.g., neonates), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. As appropriate, this information must also be contained in the “Contraindications” and/or “Warnings and Precautions” section(s).
(D) (1) When a drug is approved for pediatric use based on adequate and well-controlled studies in adults with other information supporting pediatric use, the “Pediatric use” subsection of the labeling must contain either the following statement or a reasonable alternative:
The safety and effectiveness of (drug name) have been established in the age groups ___ to ___ (note any limitations, e.g., no data for pediatric patients under 2, or only applicable to certain indications approved in adults). Use of (drug name) in these age groups is supported by evidence from adequate and well-controlled studies of (drug name) in adults with additional data (insert wording that accurately describes the data submitted to support a finding of substantial evidence of effectiveness in the pediatric population).
(2) Data summarized in the preceding prescribed statement in this subsection must be discussed in more detail, if appropriate, under the “Clinical Pharmacology” or the “Clinical Studies” section. For example, pediatric pharmacokinetic or pharmacodynamic studies and dose response information should be described in the “Clinical Pharmacology” section. Pediatric dosing instructions must be included in the “Dosage and Administration” section. Any differences between pediatric and adult responses, need for specific monitoring, dosing adjustments, and any other information related to safe and effective use of the drug in pediatric patients must be cited briefly in the “Pediatric use” subsection and, as appropriate, in the “Contraindications,” “Warnings and Precautions,” and “Dosage and Administration” sections.
(E) If the requirements for a finding of substantial evidence to support a pediatric indication or a pediatric use statement have not been met for a particular pediatric population, the “Pediatric use” subsection must contain an appropriate statement such as “Safety and effectiveness in pediatric patients below the age of (__) have not been established.” If use of the drug in this pediatric population is associated with a specific hazard, the hazard must be described in this subsection, or, if appropriate, the hazard must be stated in the “Contraindications” or “Warnings and Precautions” section and this subsection must refer to it.
(F) If the requirements for a finding of substantial evidence to support a pediatric indication or a pediatric use statement have not been met for any pediatric population, this subsection must contain the following statement: “Safety and effectiveness in pediatric patients have not been established.” If use of the drug in premature or neonatal infants, or other pediatric subgroups, is associated with a specific hazard, the hazard must be described in this subsection, or, if appropriate, the hazard must be stated in the “Contraindications” or “Warnings and Precautions” section and this subsection must refer to it.
(G) If the sponsor believes that none of the statements described in paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are appropriate or relevant to the labeling of a particular drug, the sponsor must provide reasons for omission of the statements and may propose alternative statement(s). FDA may permit use of an alternative statement if FDA determines that no statement described in those paragraphs is appropriate or relevant to the drug's labeling and that the alternative statement is accurate and appropriate.
(H) If the drug product contains one or more inactive ingredients that present an increased risk of toxic effects to neonates or other pediatric subgroups, a special note of this risk must be made, generally in the “Contraindications” or “Warnings and Precautions” section.
(v) 8.5 Geriatric use. (A) A specific geriatric indication, if any, that is supported by adequate and well-controlled studies in the geriatric population must be described under the “Indications and Usage” section, and appropriate geriatric dosage must be stated under the “Dosage and Administration” section. The “Geriatric use” subsection must cite any limitations on the geriatric indication, need for specific monitoring, specific hazards associated with the geriatric indication, and other information related to the safe and effective use of the drug in the geriatric population. Unless otherwise noted, information contained in the “Geriatric use” subsection must pertain to use of the drug in persons 65 years of age and older. Data summarized in this subsection must be discussed in more detail, if appropriate, under “Clinical Pharmacology” or the “Clinical Studies” section. As appropriate, this information must also be contained in the “Warnings and Precautions” and/or “Contraindications” section(s).
(B) Specific statements on geriatric use of the drug for an indication approved for adults generally, as distinguished from a specific geriatric indication, must be contained in the “Geriatric use” subsection and must reflect all information available to the sponsor that is relevant to the appropriate use of the drug in elderly patients. This information includes detailed results from controlled studies that are available to the sponsor and pertinent information from well-documented studies obtained from a literature search. Controlled studies include those that are part of the marketing application and other relevant studies available to the sponsor that have not been previously submitted in the investigational new drug application, new drug application, biologics license application, or a supplement or amendment to one of these applications (e.g., postmarketing studies or adverse drug reaction reports). The “Geriatric use” subsection must contain the following statement(s) or reasonable alternative, as applicable, taking into account available information:
(1) If clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified such differences, the “Geriatric use” subsection must include the following statement:
Clinical studies of (name of drug) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
(2) If clinical studies (including studies that are part of marketing applications and other relevant studies available to the sponsor that have not been submitted in the sponsor's applications) included enough elderly subjects to make it likely that differences in safety or effectiveness between elderly and younger subjects would have been detected, but no such differences (in safety or effectiveness) were observed, and other reported clinical experience has not identified such differences, the “Geriatric use” subsection must contain the following statement:
Of the total number of subjects in clinical studies of (name of drug), __ percent were 65 and over, while __ percent were 75 and over. (Alternatively, the labeling may state the total number of subjects included in the studies who were 65 and over and 75 and over.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
(3) If evidence from clinical studies and other reported clinical experience available to the sponsor indicates that use of the drug in elderly patients is associated with differences in safety or effectiveness, or requires specific monitoring or dosage adjustment, the “Geriatric use” subsection must contain a brief description of observed differences or specific monitoring or dosage requirements and, as appropriate, must refer to more detailed discussions in the “Contraindications,” “Warnings and Precautions,” “Dosage and Administration,” or other sections.
(C) (1) If specific pharmacokinetic or pharmacodynamic studies have been carried out in the elderly, they must be described briefly in the “Geriatric use” subsection and in detail under the “Clinical Pharmacology” section. The “Clinical Pharmacology” and “Drug Interactions” sections ordinarily contain information on drug/disease and drug/drug interactions that is particularly relevant to the elderly, who are more likely to have concomitant illness and to use concomitant drugs.
(2) If a drug is known to be substantially excreted by the kidney, the “Geriatric use” subsection must include the statement:
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
(D) If use of the drug in the elderly appears to cause a specific hazard, the hazard must be described in the “Geriatric use” subsection, or, if appropriate, the hazard must be stated in the “Contraindications” or “Warnings and Precautions” section, and the “Geriatric use” subsection must refer to those sections.
(E) Labeling under paragraphs (c)(9)(v)(A) through (c)(9)(v)(C) of this section may include statements, if they are necessary for safe and effective use of the drug, and reflect good clinical practice or past experience in a particular situation, e.g., for a sedating drug, it could be stated that:
Sedating dru