Title 21—Food and Drugs--Volume 1
PART 201—LABELING
§ 201.80   Specific requirements on content and format of labeling for human prescription drug and biological products; older drugs not described in § 201.56(b)(1).
Each section heading listed in § 201.56(d), if not omitted under § 201.56(d)(3), shall contain the following information in the following order:
(a) Description. (1) Under this section heading, the labeling shall contain:
(i) The proprietary name and the established name, if any, as defined in section 502(e)(2) of the act, of the drug;
(ii) The type of dosage form and the route of administration to which the labeling applies;
(iii) The same qualitative and/or quantitative ingredient information as required under § 201.100(b) for labels;
(iv) If the product is sterile, a statement of that fact;
(v) The pharmacological or therapeutic class of the drug;
(vi) The chemical name and structural formula of the drug;
(vii) If the product is radioactive, a statement of the important nuclear physical characteristics, such as the principal radiation emission data, external radiation, and physical decay characteristics.
(2) If appropriate, other important chemical or physical information, such as physical constants, or pH, shall be stated.
(b) Clinical Pharmacology. (1) Under this section heading, the labeling shall contain a concise factual summary of the clinical pharmacology and actions of the drug in humans. The summary may include information based on in vitro and/or animal data if the information is essential to a description of the biochemical and/or physiological mode of action of the drug or is otherwise pertinent to human therapeutics. Pharmacokinetic information that is important to safe and effective use of the drug is required, if known, e.g., degree and rate of absorption, pathways of biotransformation, percentage of dose as unchanged drug and metabolites, rate or half-time of elimination, concentration in body fluids associated with therapeutic and/or toxic effects, degree of binding to plasma proteins, degree of uptake by a particular organ or in the fetus, and passage across the blood brain barrier. Inclusion of pharmacokinetic information is restricted to that which relates to clinical use of the drug. If the pharmacological mode of action of the drug is unknown or if important metabolic or pharmacokinetic data in humans are unavailable, the labeling shall contain a statement about the lack of information.
(2) Data that demonstrate activity or effectiveness in in vitro or animal tests and that have not been shown by adequate and well-controlled clinical studies to be pertinent to clinical use may be included under this section of the labeling only under the following circumstances:
(i) In vitro data for anti-infective drugs may be included if the data are immediately preceded by the statement “The following in vitro data are available but their clinical significance is unknown.”
(ii) For other classes of drugs, in vitro and animal data that have not been shown by adequate and well-controlled clinical studies, as defined in § 314.126(b) of this chapter, to be pertinent to clinical use may be used only if a waiver is granted under § 201.58 or § 314.126(c) of this chapter.
(c) Indications and Usage. (1) Under this section heading, the labeling shall state that:
(i) The drug is indicated in the treatment, prevention, or diagnosis of a recognized disease or condition, e.g., penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci; and/or
(ii) The drug is indicated for the treatment, prevention, or diagnosis of an important manifestation of a disease or condition, e.g., chlorothiazide is indicated for the treatment of edema in patients with congestive heart failure; and/or
(iii) The drug is indicated for the relief of symptoms associated with a disease or syndrome, e.g., chlorpheniramine is indicated for the symptomatic relief of nasal congestion in patients with vasomotor rhinitis; and/or
(iv) The drug, if used for a particular indication only in conjuction with a primary mode of therapy, e.g., diet, surgery, or some other drug, is an adjunct to the mode of therapy.
(2)(i) 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 labeling if not included in this section.
(ii) 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 labeling if not included in this section.
(3) This section of the labeling shall also contain the following additional information:
(i) If evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, syndrome, or symptom under consideration, e.g., patients with mild disease or patients in a special age group, the labeling shall describe the available evidence and state the limitations of usefulness of the drug. The labeling shall also identify specific tests needed for selection or monitoring of the patients who need the drug, e.g., microbe susceptibility tests. Information on the approximate kind, degree, and duration of improvement to be anticipated shall be stated if available and shall be based on substantial evidence derived from 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. If the information is relevant to the recommended intervals between doses, the usual duration of treatment, or any modification of dosage, it shall be stated in the “Dosage and Administration” section of the labeling and referenced in this section.
(ii) If safety considerations are such that the drug should be reserved for certain situations, e.g., cases refractory to other drugs, this information shall be stated in this section.
(iii) 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, the labeling shall identify the conditions; or, if the indications for long-term use are different from those for short-term use, the labeling shall identify the specific indications for each use.
(iv) 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, the Food and Drug Administration may require that the labeling state that there is a lack of evidence that the drug is effective for that use or condition.
(v) Any statements comparing the safety or effectiveness, either greater or less, of the drug with other agents for the same indication shall be supported by 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.
(d) Contraindications. Under this section heading, the labeling shall describe those situations in which the drug should not be used because the risk of use clearly outweighs any possible benefit. These situations include administration of the drug to patients known to have a hypersensitivity to it; 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 it; or continued use of the drug in the face of an unacceptably hazardous adverse reaction. Known hazards and not theoretical possibilities shall be listed, e.g., if hypersensitivity to the drug has not been demonstrated, it should not be listed as a contraindication. If no contraindications are known, this section of the labeling shall state “None known.”
(e) Warnings. Under this section heading, the labeling shall describe serious adverse reactions and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur. The labeling shall be revised to include a warning as soon as there is reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved. A specific warning relating to a use not provided for under the “Indications and Usage” section of the labeling may be required by the Food and Drug Administration if the drug is commonly prescribed for a disease or condition, and there is lack of substantial evidence of effectivenes for that disease or condition, and such usage is associated with serious risk or hazard. Special problems, particularly those that may lead to death or serious injury, may be required by the Food and Drug Administration to be placed in a prominently displayed box. The boxed warning ordinarily shall be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. If a boxed warning is required, its location will be specified by the Food and Drug Administration. The frequency of these serious adverse reactions and, if known, the approximate mortality and morbidity rates for patients sustaining the reaction, which are important to safe and effective use of the drug, shall be expressed as provided under the “Adverse Reactions” section of the labeling.
(f) Precautions. Under this section heading, the labeling shall contain the following subsections as appropriate for the drug:
(1) General. This subsection of the labeling shall 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 of the labeling.
(2) Information for patients. This subsection must contain information necessary for patients to use the drug safely and effectively (e.g., precautions concerning driving or the concomitant use of other substances that may have harmful additive effects). Any FDA-approved patient labeling must be referenced in this section and the full text of such patient labeling must be reprinted immediately following the last section of labeling or, alternatively, accompany the prescription drug labeling. The type size requirement for the Medication Guide set forth in § 208.20 of this chapter does not apply to the Medication Guide that is reprinted in or accompanying the prescription drug labeling unless such Medication Guide is to be detached and distributed to patients in compliance with § 208.24 of this chapter.
(3) Laboratory tests. This subsection of the labeling shall identify any laboratory tests that may be helpful in following the patient's response or in identifying possible adverse reactions. If appropriate, information shall 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 done before, during, and after therapy.
(4)(i) Drug interactions. This subsection of the labeling shall contain specific practical guidance for the physician on preventing clinically significant drug/drug and drug/food interactions that may occur in vivo in patients taking the drug. Specific drugs or classes of drugs with which the drug to which the labeling applies may interact in vivo shall be identified, and the mechanism(s) of the interaction shall be briefly described. Information in this subsection of the labeling shall be limited to that pertaining to clinical use of the drug in patients. Drug interactions supported only by animal or in vitro experiments may not ordinarily be included, but animal or in vitro data may be used if shown to be clinically relevant. Drug incompatibilities, i.e., drug interactions that may occur when drugs are mixed in vitro, as in a solution for intravenous administration, shall be discussed under the “Dosage and Administration” section of the labeling rather than under this subsection of the labeling.
(ii) Drug/laboratory test interactions. This subsection of the labeling shall contain practical guidance on known interference of the drug with laboratory tests.
(5) Carcinogenesis, mutagenesis, impairment of fertility. This subsection of the labeling shall state whether long-term studies in animals have been performed to evaluate carcinogenic potential and, if so, the species and results. If reproduction studies or other data in animals reveal a problem or potential problem concerning mutagenesis or impairment of fertility in either males or females, the information shall be described. Any precautionary statement on these topics shall include practical, relevant advice to the physician on the significance of these animal findings. If there is evidence from human data that the drug may be carcinogenic or mutagenic or that it impairs fertility, this information shall be included under the “Warnings” section of the labeling. Also, under “Precautions,” the labeling shall state: “See ‘Warnings’ section for information on carcinogenesis, mutagenesis, and impairment of fertility.”
(6) Pregnancy. This subsection of the labeling 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 of the labeling shall contain the following information:
(i) Teratogenic effects. Under this heading the labeling shall identify one of the following categories that applies to the drug, and the labeling shall bear the statement required under the 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 shall state: “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 shall also contain a description of the human studies. If animal reproduction studies are available and they fail to demonstrate a risk to the fetus, the labeling shall 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 shall also contain a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child.
( 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 shall state: “ 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 shall state: “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 shall 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.
( 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 shall state: “ ( 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 shall 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 shall state: “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 shall contain a description of any available data on the effect of the drug on the later growth, development, and functional maturation of the child.
( 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 shall state: “ See ‘Warnings’ section.” Under the “Warnings” section, the labeling states: “( 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 the fetus.”
( e )  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 shall state: “ See ‘Contraindications’ section.” Under “Contraindications,” the labeling shall state: “(Name of drug) may ( can ) cause fetal harm when administered to a pregnant woman. ( Describe the human data and any pertinant 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 the fetus.”
(ii) Nonteratogenic effects. Under this heading the labeling shall 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 shall 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.
(7) 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 section of the labeling, this subsection of the labeling shall 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, this subsection of the labeling shall state that the information is unknown.
(8) Nursing mothers. (i) If a drug is absorbed systemically, this subsection of the labeling shall 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 shall be described.
(ii) If a drug is absorbed systemically and is known to be excreted in human milk, this subsection of the labeling shall 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 shall 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 shall state: “Caution should be exercised when ( name of drug ) is administered to a nursing woman.”
(iii) If a drug is absorbed systemically and information on excretion in human milk is unknown, this subsection of the labeling shall 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 shall 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 shall 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.”
(9) Pediatric use. (i) Pediatric population(s)/pediatric patient(s): For the purposes of paragraphs (f)(9)(ii) through (f)(9)(viii) 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.
(ii) If there is a specific pediatric indication (i.e., an indication different from those approved for adults) that is supported by adequate and well-controlled studies in the pediatric population, it shall be described under the “Indications and Usage” section of the labeling, and appropriate pediatric dosage information shall be given under the “Dosage and Administration” section of the labeling. The “Pediatric use” subsection shall 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 of the labeling should be discussed in more detail, if appropriate, under the “Clinical Pharmacology” or “Clinical Studies” section. As appropriate, this information shall also be contained in the “Contraindications,” “Warnings,” and elsewhere in the “Precautions” sections.
(iii) 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 shall be summarized in the “Pediatric use” subsection of the labeling and discussed in more detail, if appropriate, under the “Clinical Pharmacology” and “Clinical Studies” sections. Appropriate pediatric dosage shall be given under the “Dosage and Administration” section of the labeling. The “Pediatric use” subsection of the labeling shall 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 shall also be contained in the “Contraindications,” “Warnings,” and elsewhere in the “Precautions” sections.
(iv) FDA may approve a drug for pediatric use based on adequate and well-controlled studies in adults, with other information supporting pediatric use. In such cases, the agency will have concluded that the course of the disease and the effects of the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult populations to permit extrapolation from the adult efficacy data to pediatric patients. The additional information supporting pediatric use must ordinarily include data on the pharmacokinetics of the drug in the pediatric population for determination of appropriate dosage. Other information, such as data from pharmacodynamic studies of the drug in the pediatric population, data from other studies supporting the safety or effectiveness of the drug in pediatric patients, pertinent premarketing or postmarketing studies or experience, may be necessary to show that the drug can be used safely and effectively in pediatric patients. 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 shall 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).” Data summarized in the preceding prescribed statement in this subsection of the labeling shall 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 shall be included in the “Dosage and Administration” section of the labeling. 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 shall be cited briefly in the “Pediatric use” subsection and, as appropriate, in the “Contraindications,” “Warnings,” “Precautions,” and “Dosage and Administration” sections.
(v) 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 of the labeling shall 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 shall be described in this subsection of the labeling, or, if appropriate, the hazard shall be stated in the “Contraindications” or “Warnings” section of the labeling and this subsection shall refer to it.
(vi) 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 of the labeling shall 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 shall be described in this subsection of the labeling, or, if appropriate, the hazard shall be stated in the “Contraindications” or “Warnings” section of the labeling and this subsection shall refer to it.
(vii) If the sponsor believes that none of the statements described in paragraphs (f)(9)(ii) through (f)(9)(vi) of this section is appropriate or relevant to the labeling of a particular drug, the sponsor shall 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.
(viii) 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 shall be made, generally in the “Contraindications,” “Warnings,” or “Precautions” section.
(10) Geriatric use. (i) A specific geriatric indication, if any, that is supported by adequate and well-controlled studies in the geriatric population shall be described under the “Indications and Usage” section of the labeling, and appropriate geriatric dosage shall be stated under the “Dosage and Administration” section of the labeling. The “Geriatric use” subsection shall 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 of the labeling shall pertain to use of the drug in persons 65 years of age and older. Data summarized in this subsection of the labeling shall be discussed in more detail, if appropriate, under “Clinical Pharmacology” or the “Clinical Studies” section. As appropriate, this information shall also be contained in “Contraindications,” “Warnings,” and elsewhere in “Precautions.”
(ii) Specific statements on geriatric use of the drug for an indication approved for adults generally, as distinguished from a specific geriatric indication, shall be contained in the “Geriatric use” subsection and shall 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, biological 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 shall contain the following statement(s) or reasonable alternative, as applicable, taking into account available information:
(A) 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 shall 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.”
(B) 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 shall 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.
(C) 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 of the labeling shall contain a brief description of observed differences or specific monitoring or dosage requirements and, as appropriate, shall refer to more detailed discussions in the “Contraindications,” “Warnings,” “Dosage and Administration,” or other sections of the labeling.
(iii)(A) If specific pharmacokinetic or pharmacodynamic studies have been carried out in the elderly, they shall be described briefly in the “Geriatric use” subsection of the labeling and in detail under the “Clinical Pharmacology” section. The “Clinical Pharmacology” section and “Drug interactions” subsection of the “Precautions” section 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 utilize concomitant drugs.
(B) If a drug is known to be substantially excreted by the kidney, the “Geriatric use” subsection shall include the statement:
“This drug is known to be substantially excreted by the kidney, and the risk of toxic 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.”
(iv) If use of the drug in the elderly appears to cause a specific hazard, the hazard shall be described in the “Geriatric use” subsection of the labeling, or, if appropriate, the hazard shall be stated in the “Contraindications,” “Warnings,” or “Precautions” section of the labeling, and the “Geriatric use” subsection shall refer to those sections.
(v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of this section may include statements, if they would be useful in enhancing safe use of the drug, that reflect good clinical practice or past experience in a particular situation, e.g., for a sedating drug, it could be stated that:
“Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of (name of drug) and observed closely.”
(vi) If the sponsor believes that none of the requirements described in paragraphs (f)(10)(i) through (f)(10)(v) of this section is appropriate or relevant to the labeling of a particular drug, the sponsor shall provide reasons for omission of the statements and may propose an alternative statement. FDA may permit omission of the statements if FDA determines that no statement described in those paragraphs is appropriate or relevant to the drug's labeling. FDA may permit use of an alternative statement if the agency determines that such statement is accurate and appropriate.
(g) Adverse Reactions. An adverse reaction is an undesirable effect, reasonably associated with the use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence.
(1) This section of the labeling shall list the adverse reactions that occur with the drug and with drugs in the same pharmacologically active and chemically related class, if applicable.
(2) In this listing, adverse reactions may be categorized by organ system, by severity of the reaction, by frequency, or by toxicological mechanism, or by a combination of these, as appropriate. If frequency information from adequate clinical studies is available, the categories and the adverse reactions within each category shall be listed in decreasing order of frequency. An adverse reaction that is significantly more severe than the other reactions listed in a category, however, shall be listed before those reactions, regardless of its frequency. If frequency information from adequate clinical studies is not available, the categories and adverse reactions within each category shall be listed in decreasing order of severity. The approximate frequency of each adverse reaction shall be expressed in rough estimates or orders of magnitude essentially as follows: “The most frequent adverse reaction(s) to ( name of drug ) is (are) ( list reactions ). This (these) occur(s) in about (e.g., one-third of patients; one in 30 patients; less than one-tenth of patients). Less frequent adverse reactions are ( list reactions ), which occur in approximately (e.g., one in 100 patients). Other adverse reactions, which occur rarely, in approximately (e.g., one in 1,000 patients), are ( list reactions ).” Percent figures may not ordinarily be used unless they are documented by adequate and well-controlled studies as defined in § 314.126(b) of this chapter, they are shown to reflect general experience, and they do not falsely imply a greater degree of accuracy than actually exists.
(3) The “Warnings” section of the labeling or, if appropriate, the “Contraindications” section of the labeling shall identify any potentially fatal adverse reaction.
(4) Any claim comparing the drug to which the labeling applies with other drugs in terms of frequency, severity, or character of adverse reactions shall 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.
(h) Drug Abuse and Dependence. Under this section heading, the labeling shall contain the following subsections, as appropriate for the drug:
(1) Controlled Substance. If the drug is controlled by the Drug Enforcement Administration, the schedule in which it is controlled shall be stated.
(2) Abuse. This subsection of the labeling shall be based primarily on human data and human experience, but pertinent animal data may also be used. This subsection shall state the types of abuse that can occur with the drug and the adverse reactions pertinent to them. Particularly susceptible patient populations shall be identified.
(3) Dependence. This subsection of the labeling shall describe characteristic effects resulting from both psychological and physical dependence that occur with the drug and shall identify the quantity of the drug over a period of time that may lead to tolerance or dependence, or both. Details shall be provided on the adverse effects of chronic abuse and the effects of abrupt withdrawal. Procedures necessary to diagnose the dependent state shall be provided, and the principles of treating the effects of abrupt withdrawal shall be described.
(i) Overdosage. Under this section heading, the labeling shall describe the signs, symptoms, and laboratory findings of acute overdosage and the general principles of treatment. This section shall be based on human data, when available. If human data are unavailable, appropriate animal and in vitro data may be used. Specific information shall be provided about the following:
(1) Signs, symptoms, and laboratory findings associated with an overdosage of the drug.
(2) Complications that can occur with the drug (for example, organ toxicity or delayed acidosis).
(3) Oral LD 50 of the drug in animals; concentrations of the drug in biologic fluids associated with toxicity and/or death; physiologic variables influencing excretion of the drug, such as urine pH; and factors that influence the dose response relationship of the drug, such as tolerance. The pharmacokinetic data given in the “Clinical Pharmacology” section also may be referenced here, if applicable to overdoses.
(4) The amount of the drug in a single dose that is ordinarily associated with symptoms of overdosage and the amount of the drug in a single dose that is likely to be life-threatening.
(5) Whether the drug is dialyzable.
(6) Recommended general treatment procedures and specific measures for support of vital functions, such as proven antidotes, gastric lavage, and forced diuresis. Unqualified recommendations for which data are lacking with the specific drug or class of drugs, especially treatment using another drug (for example, central nervous system stimulants, respiratory stimulants) may not be stated unless specific data or scientific rationale exists to support safe and effective use.
(j) Dosage and Administration. This section of the labeling shall state the recommended usual dose, the usual dosage range, and, if appropriate, an upper limit beyond which safety and effectiveness have not been established; dosages shall be stated for each indication when appropriate. Dosing regimens must not be implied or suggested in other sections of labeling if not included in this section. This section shall also state the intervals recommended between doses, the optimal method of titrating dosage, the usual duration of treatment, and any modification of dosage needed in special patient populations, e.g., in children, in geriatric age groups, or in patients with renal or hepatic disease. Specific tables or monographs may be included to clarify dosage schedules. Radiation dosimetry information shall be stated for both the patient receiving a radioactive drug and the person administering it. This section shall also contain specific direction on dilution, preparation (including the strength of the final dosage solution, when prepared according to instructions, in terms of milligrams 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 drug or reconstituted drug, when important; essential information on drug incompatibilities if the drug is mixed in vitro with other drugs; and the following statement for parenterals: “Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.”
(k) How Supplied. This section of the labeling shall contain information on the available dosage forms to which the labeling applies and for which the manufacturer or distributor is responsible. The information shall ordinarily include:
(1) The strength of the dosage form, e.g., 10-milligram tablets, in metric system and, if the apothecary system is used, a statement of the strength is placed in parentheses after the metric designation;
(2) The units in which the dosage form is ordinarily available for prescribing by practitioners, e.g., bottles of 100;
(3) Appropriate information to facilitate identification of the dosage forms, such as shape, color, coating, scoring, and National Drug Code; and
(4) Special handling and storage conditions.
(l) Animal Pharmacology and/or Animal Toxicology. In most cases, the labeling need not include this section. Significant animal data necessary for safe and effective use of the drug in humans shall ordinarily be included in one or more of the other sections of the labeling, as appropriate. Commonly for a drug that has been marketed for a long time, and in rare cases for a new drug, chronic animal toxicity studies have not been performed or completed for a drug that is administered over prolonged periods or is implanted in the body. The unavailability of such data shall be stated in the appropriate section of the labeling for the drug. If the pertinent animal data cannot be appropriately incorporated into other sections of the labeling, this section may be used.
(m) “Clinical Studies” and “References”. These sections may appear in labeling in the place of a detailed discussion of a subject that is of limited interest but nonetheless important. A reference to a specific important clinical study may be made in any section of the format required under §§ 201.56 and 201.57 if the study is essential to an understandable presentation of the available information. References may appear in sections of the labeling format, other than the “Clinical Studies” or “References” section, in rare circumstances only. A clinical study or reference may be cited in prescription drug labeling only under the following conditions:
(1)(i) If the clinical study is cited in the labeling in place of a detailed discussion of data and information concerning an indication for use of the drug, the clinical study must constitute an adequate and well-controlled study as described in § 314.126(b) of this chapter, except for biological products, and must not imply or suggest indications or uses or dosing regimens not stated in the “Indications and Usage” or “Dosage and Administration” section.
(ii) When prescription drug labeling must summarize or otherwise rely on a recommendation by an authoritative scientific body, or on a standardized methodology, scale, or technique, because the information is important to prescribing decisions, the labeling may include a reference to the source of the information.
(2) If the clinical study or reference is cited in the labeling in the place of a detailed discussion of data and information concerning a risk or risks from the use of the drug, the risk or risks shall also be identified or discussed in the appropriate section of the labeling for the drug.
§ 201.100   Prescription drugs for human use.
A drug subject to the requirements of section 503(b)(1) of the act shall be exempt from section 502(f)(1) if all the following conditions are met:
(a) The drug is:
(1)(i) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of prescription drugs; or
(ii) In the possession of a retail, hospital, or clinic pharmacy, or a public health agency, regularly and lawfully engaged in dispensing prescription drugs; or
(iii) In the possession of a practitioner licensed by law to administer or prescribe such drugs; and
(2) It is to be dispensed in accordance with section 503(b)
(b) The label of the drug bears:
(1) The statement “Rx only” and
(2) The recommended or usual dosage and
(3) The route of administration, if it is not for oral use; and
(4) The quantity or proportion of each active ingredient, as well as the information required by section 502 (d) and (e); and
(5) If it is for other than oral use, the names of all inactive ingredients, except that:
(i) Flavorings and perfumes may be designated as such without naming their components.
(ii) Color additives may be designated as coloring without naming specific color components unless the naming of such components is required by a color additive regulation prescribed in subchapter A of this chapter.
(iii) Trace amounts of harmless substances added solely for individual product identification need not be named. If it is intended for administration by parenteral injection, the quantity or proportion of all inactive ingredients, except that ingredients added to adjust the pH or to make the drug isotonic may be declared by name and a statement of their effect; and if the vehicle is water for injection it need not be named.
(6) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug.
(7) A statement directed to the pharmacist specifying the type of container to be used in dispensing the drug product to maintain its identity, strength, quality, and purity. Where there are standards and test procedures for determining that the container meets the requirements for specified types of containers as defined in an official compendium, such terms may be used. For example, “Dispense in tight, light-resistant container as defined in the National Formulary”. Where standards and test procedures for determining the types of containers to be used in dispensing the drug product are not included in an official compendium, the specific container or types of containers known to be adequate to maintain the identity, strength, quality, and purity of the drug products shall be described. For example, “Dispense in containers which (statement of specifications which clearly enable the dispensing pharmacist to select an adequate container)”: Provided, however, That in the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, but which are packaged within an outer container from which they are removed for dispensing or use, the information required by paragraph (b) (2), (3), (5), and (7) of this section may be contained in other labeling on or within the package from which it is to be dispensed; the information referred to in paragraph (b)(1) of this section may be placed on such outer container only; and the information required by paragraph (b)(6) of this section may be on the crimp of the dispensing tube. The information required by this paragraph (b)(7) is not required for prescription drug products packaged in unit-dose, unit-of-use, on other packaging format in which the manufacturer's original package is designed and intended to be dispensed to patients without repackaging.
(c)(1) Labeling on or within the package from which the drug is to be dispensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented; and
(2) If the article is subject to section 505 of the act, the labeling bearing such information is the labeling authorized by the approved new drug application or required as a condition for the certification or the exemption from certification requirements applicable to preparations of insulin or antibiotic drugs.
(d) Any labeling, as defined in section 201(m) of the act, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the drug, that furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for the use of the drug (other than dose information required by paragraph (b)(2) of this section and § 201.105(b)(2) contains:
(1) Adequate information for such use, including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant warnings, hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented; and if the article is subject to section 505 of the act, the parts of the labeling providing such information are the same in language and emphasis as labeling approved or permitted, under the provisions of section 505, and any other parts of the labeling are consistent with and not contrary to such approved or permitted labeling; and
(2) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed.
(3) The information required, and in the format specified, by §§ 201.56, 201.57, and 201.80.
(e) All labeling described in paragraph (d) of this section bears conspicuously the name and place of business of the manufacturer, packer, or distributor, as required for the label of the drug under § 201.1.
(f) Reminder labeling which calls attention to the name of the drug product but does not include indications or dosage recommendations for use of the drug product is exempted from the provisions of paragraph (d) of this section. This reminder labeling shall contain only the proprietary name of the drug product, if any; the established name of the drug product, if any; the established name of each active ingredient in the drug product; and, optionally, information relating to quantitative ingredient statements, dosage form, quantity of package contents, price, the name and address of the manufacturer, packer, or distributor or other written, printed, or graphic matter containing no representation or suggestion relating to the drug product. If the Commissioner finds that there is evidence of significant incidence of fatalities or serious injury associated with the use of a particular prescription drug, he may withdraw this exemption by so notifying the manufacturer, packer, or distributor of the drug by letter. Reminder labeling, other than price lists and catalogs solely intended to convey price information including, but not limited to, those subject to the requirements of § 200.200 of this chapter, is not permitted for a prescription drug product whose labeling contains a boxed warning relating to a serious hazard associated with the use of the drug product. Reminder labeling which is intended to provide consumers with information concerning the price charged for a prescription for a particular drug product shall meet all of the conditions contained in § 200.200 of this chapter. Reminder labeling, other than that subject to the requirements of § 200.200 of this chapter, is not permitted for a drug for which an announcement has been published pursuant to a review of the labeling claims for the drug by the National Academy of Sciences/National Research Council (NAS/NRC), Drug Efficacy Study Group, and for which no claim has been evaluated as higher than “possibly effective.” If the Commissioner finds the circumstances are such that reminder labeling may be misleading to prescribers of drugs subject to NAS/NRC evaluation, such reminder labeling will not be allowed and the manufacturer, packer, or distributor will be notified either in the publication of the conclusions on the effectiveness of the drug or by letter.
§ 201.105   Veterinary drugs.
A drug subject to the requirements of section 503(f)(1) of the act shall be exempt from section 502(f)(1) of the act if all the following conditions are met:
(a) The drug is:
(1)(i) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of drugs that are to be used only by or on the prescription or other order of a licensed veterinarian; or
(ii) In the possession of a retail, hospital, or clinic pharmacy, or other person authorized under State law to dispense veterinary prescription drugs, who is regularly and lawfully engaged in dispensing drugs that are to be used only by or on the prescription or other order of a licensed veterinarian; or
(iii) In the possession of a licensed veterinarian for use in the course of his professional practice; and
(2) To be dispensed in accordance with section 503(f) of the act.
(b) The label of the drug bears:
(1) The statement “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian”; and
(2) The recommended or usual dosage; and
(3) The route of administration, if it is not for oral use; and
(4) The quantity or proportion of each active ingredient as well as the information required by section 502(e) of the act; and
(5) If it is for other than oral use, the names of all inactive ingredients, except that:
(i) Flavorings and perfumes may be designated as such without naming their components.
(ii) Color additives may be designated as coloring without naming specific color components unless the naming of such components is required by a color additive regulation prescribed in subchapter A of this chapter.
(iii) Trace amounts of harmless substances added solely for individual product identification need not be named.
(6) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug;
(c)(1) Labeling on or within the package from which the drug is to be dispensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which veterinarians licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented; and
(2) If the article is subject to section 512 or 572 of the act, the labeling bearing such information is the labeling authorized by the approved new animal drug application or contained in the index listing: Provided, however , That the information required by paragraph (c)(1) of this section may be omitted from the dispensing package if, but only if, the article is a drug for which directions, hazards, warnings, and use information are commonly known to veterinarians licensed by law to administer the drug. Upon written request, stating reasonable grounds therefore, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso.
(d) Any labeling, as defined in section 201(m) of the act, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the drug, that furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for the use of the drug (other than dose information required by paragraph (b)(2) of this section and § 201.100(b)(2)) contains:
(1) Adequate information for such use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant warnings, hazards, contraindications, side effects, and precautions, and including information relevant to compliance with the new animal drug provisions of the act, under which veterinarians licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented; and if the article is subject to section 512 or 572 of the act, the parts of the labeling providing such information are the same in language and emphasis as labeling approved, permitted, or indexed under the provisions of section 512 or 572, and any other parts of the labeling are consistent with and not contrary to such approved, permitted, or indexed labeling; and
(2) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed;
(e) All labeling, except labels and cartons, bearing information for use of the drug also bears the date of the issuance or the date of the latest revision of such labeling.
(f) A prescription drug intended for both human and veterinary use shall comply with paragraphs (e) and (f) of this section and § 201.100.
§ 201.115   New drugs or new animal drugs.
A new drug shall be exempt from section 502(f)(1) of the act:
(a) To the extent to which such exemption is claimed in an approved application with respect to such drug under section 505 or 512 of the act or an index listing with respect to such drug under section 572 of the act; or
(b) If no application under section 505 or 512 of the act is approved and no request for addition to the index is granted under section 572 with respect to such drug but it complies with section 505(i), 512(j), or 572(g) of the act and regulations thereunder.
§ 201.116   Drugs having commonly known directions.
A drug shall be exempt from section 502(f)(1) of the act insofar as adequate directions for common uses thereof are known to the ordinary individual.
§ 201.117   Inactive ingredients.
A harmless drug that is ordinarily used as an inactive ingredient, such as a coloring, emulsifier, excipient, flavoring, lubricant, preservative, or solvent, in the preparation of other drugs shall be exempt from section 502(f)(1) of the act. This exemption shall not apply to any substance intended for a use which results in the preparation of a new drug, unless an approved new-drug application provides for such use.
§ 201.119   In vitro diagnostic products.
(a) “In vitro diagnostic products” are those reagents, instruments and systems intended for use in the diagnosis of disease or in the determination of the state of health in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation and examination of specimens taken from the human body. These products are drugs or devices as defined in section 201(g) and 201(h), respectively, of the Federal Food, Drug, and Cosmetic Act (the act) or are a combination of drugs and devices, and may also be a biological product subject to section 351 of the Public Health Service Act.
(b) A product intended for use in the diagnosis of disease and which is an in vitro diagnostic product as defined in paragraph (a) of this section shall be deemed to be in compliance with the requirements of this section and section 502(f)(1) of the act if it meets the requirements of § 809.10 of this chapter.
§ 201.120   Prescription chemicals and other prescription components.
A drug prepared, packaged, and primarily sold as a prescription chemical or other component for use by registered pharmacists in compounding prescriptions or for dispensing in dosage unit form upon prescriptions shall be exempt from section 502(f)(1) of the act if all the following conditions are met:
(a) The drug is an official liquid acid or official liquid alkali, or is not a liquid solution, emulsion, suspension, tablet, capsule, or other dosage unit form; and
(b) The label of the drug bears:
(1) The statement “For prescription compounding”; and
(2) If in substantially all dosage forms in which it may be dispensed it is subject to section 503(b)(1) of the act, the statement “Rx only”; or
(3) If it is not subject to section 503(b)(1) of the act and is by custom among retail pharmacists sold in or from the interstate package for use by consumers, “adequate directions for use” in the conditions for which it is so sold.
(c) This exemption shall not apply to any substance intended for use in compounding which results in a new drug, unless an approved new-drug application covers such use of the drug in compounding prescriptions.
§ 201.122   Drugs for processing, repacking, or manufacturing.
A drug in a bulk package, except tablets, capsules, or other dosage unit forms, intended for processing, repacking, or use in the manufacture of another drug shall be exempt from section 502(f)(1) of the act if its label bears the statement “Caution: For manufacturing, processing, or repacking”; and if in substantially all dosage forms in which it may be dispensed it is subject to section 503(b)(1) of the act, the statement “Rx only”, or if in substantially all dosage forms in which it may be dispensed it is subject to section 503(f)(1) of the act, the statement “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian”. This exemption and the exemption under § 201.120 may be claimed for the same article. However, the exemption shall not apply to a substance intended for a use in manufacture, processing, or repacking which causes the finished article to be a new drug or new animal drug, unless:
(a) An approved new drug application or new animal drug application or a new animal drug index listing covers the production and delivery of the drug substance to the application or index listing holder by persons named in the application or in the request for determination of eligibility for indexing, and, for a new drug substance, the export of it by such persons under § 314.410 of this chapter; or
(b) If no application is approved with respect to such new drug or new animal drug, and it is not listed in the index, the label statement “Caution: For manufacturing, processing, or repacking” is immediately supplemented by the words “in the preparation of a new drug or new animal drug limited by Federal law to investigational use”, and the delivery is made for use only in the manufacture of such new drug or new animal drug limited to investigational use as provided in part 312 or § 511.1 or § 516.125 of this chapter; or
(c) A new drug application or new animal drug application or a request for addition to the index covering the use of the drug substance in the production and marketing of a finished drug product has been submitted but not yet approved, disapproved, granted, or denied, the bulk drug is not exported, and the finished drug product is not further distributed after it is manufactured until after the new drug application or new animal drug application is approved or the request for addition to the index is granted.
§ 201.125   Drugs for use in teaching, law enforcement, research, and analysis.
A drug subject to § 201.100 or § 201.105, shall be exempt from section 502(f)(1) of the act if shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry, or medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical use, or in chemical analysis, or physical testing, and is to be used only for such instruction, law enforcement, research, analysis, or testing.
§ 201.127   Drugs; expiration of exemptions.
(a) If a shipment or delivery, or any part thereof, of a drug which is exempt under the regulations in this section is made to a person in whose possession the article is not exempt, or is made for any purpose other than those specified, such exemption shall expire, with respect to such shipment or delivery or part thereof, at the beginning of that shipment or delivery. The causing of an exemption to expire shall be considered an act which results in such drug being misbranded unless it is disposed of under circumstances in which it ceases to be a drug or device.
(b) The exemptions conferred by §§ 201.117, 201.119, 201.120, 201.122, and 201.125 shall continue until the drugs are used for the purposes for which they are exempted, or until they are relabeled to comply with section 502(f)(1) of the act. If, however, the drug is converted, compounded, or manufactured into a dosage form limited to prescription dispensing, no exemption shall thereafter apply to the article unless the dosage form is labeled as required by section 503(b) and §§ 201.100 or 201.105.
§ 201.128   Meaning of “intended uses”.
The words intended uses or words of similar import in §§  201.5, 201.115, 201.117, 201.119, 201.120, 201.122, and 1100.5 of this chapter refer to the objective intent of the persons legally responsible for the labeling of an article (or their representatives). The intent may be shown by such persons' expressions, the design or composition of the article, or by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. Objective intent may be shown, for example, by circumstances in which the article is, with the knowledge of such persons or their representatives, offered or used for a purpose for which it is neither labeled nor advertised; provided, however, that a firm would not be regarded as intending an unapproved new use for an approved drug based solely on that firm's knowledge that such drug was being prescribed or used by health care providers for such use. The intended uses of an article may change after it has been introduced into interstate commerce by its manufacturer. If, for example, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he or she received the article, such packer, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses.
§ 201.129   Drugs; exemption for radioactive drugs for research use.
A radioactive drug intended for administration to human research subjects during the course of a research project intended to obtain basic research information regarding metabolism (including kinetics, distribution, and localization) of a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry (but not intended for immediate therapeutic, diagnostic, or similar purposes), under the conditions set forth in § 361.1 of this chapter, shall be exempt from section 502(f)(1) of the act if the packaging, label, and labeling are in compliance with § 361.1(f) of this chapter.
§ 201.130   Exemption from adequate directions for use for a nonprescription drug product with an additional condition for nonprescription use (ACNU).
A nonprescription drug product approved under section 505(c) or 505(j) of the Federal Food, Drug, and Cosmetic Act with an ACNU as defined in § 201.67(b)(1) is exempt from section 502(f)(1) only if all the following conditions are met:
(a) The label of the drug must include instructions for the ACNU as follows:
(1) Content of instructions for the ACNU must either be:
(i) ACNU Instructions, which read as follows: “To check if this drug is safe for you, go to [insert where or how consumers can find information about the ACNU; for example, applicant's website, applicant's phone number, or specific retail location] and [insert action to be taken by consumer]. Do not take this drug without completing this step”; or
(ii) Alternative ACNU Instructions: FDA may approve an NDA applicant's revisions to the ACNU Instructions when the revisions are appropriate for a specific drug product and the applicant supports the revisions with adequate data or other information that demonstrate sufficient consumer understanding of the revised statement.
(2) The locations of instructions for the ACNU are as follows:
(i) If the purpose of the ACNU is for self-selection, the instructions for the ACNU must appear under the “Use” or “Uses” heading required in § 201.66(c)(4) as the first statement, followed by the other information required in § 201.66(c)(4);
(ii) If the purpose of the ACNU is for actual use, the instructions for the ACNU must appear under the “Directions” heading required in § 201.66(c)(6) as the first direction, followed by the other information required in § 201.66(c)(6); or
(iii) If the purpose of the ACNU is for both self-selection and actual use, the instructions for the ACNU must appear under the “Use” or “Uses” heading as the first statement, followed by the other information required in § 201.66(c)(4) and may also appear under the “Directions” heading as the first direction, followed by the other information required in § 201.66(c)(6).
(b) The label of the drug must include a statement about the ACNU as follows:
(1) The content of the statement about the ACNU must either be:
(i) The ACNU Statement, which reads as follows: “You must complete an extra step to see if this drug is safe for you before you use it. Do not take this drug without completing this step. See the Drug Facts Labeling for more information”; or
(ii) An Alternative ACNU Statement: FDA may approve an NDA applicant's revisions to the ACNU Statement when the revisions are appropriate for a specific drug product and the applicant supports the revisions with adequate data or other information that demonstrate sufficient consumer understanding of the revised statement.
(2) The statement about the ACNU must be in the form and manner required by § 201.67(c).
(c) The labeling of the drug must comply with other applicable labeling requirements for nonprescription drug products under this part, including the format and content requirements for nonprescription drug product labeling under § 201.66.
(d) The ACNU must be implemented by the applicant in accordance with the following, as approved by FDA in the application:
(1) The key elements of the ACNU under § 314.56(c)(1)(iv) of this chapter for NDAs or § 314.56(c)(2)(ii) of this chapter for ANDAs; and
(2) The operationalization of the ACNU under § 314.56(c)(1)(vii) of this chapter for NDAs or § 314.56(c)(2)(iii) of this chapter for ANDAs.
§ 201.150   Drugs; processing, labeling, or repacking.
(a) Except as provided by paragraphs (b) and (c) of this section, a shipment or other delivery of a drug which is, in accordance with the practice of the trade, to be processed, labeled, or repacked in substantial quantity at an establishment other than that where originally processed or packed, shall be exempt, during the time of introduction into and movement in interstate commerce and the time of holding in such establishment, from compliance with the labeling and packaging requirements of sections 501(b) and 502 (b), (d), (e), (f), and (g) of the act if:
(1) The person who introduced such shipment or delivery into interstate commerce is the operator of the establishment where such drug is to be processed, labeled, or repacked; or
(2) In case such person is not such operator, such shipment or delivery is made to such establishment under a written agreement, signed by and containing the post-office addresses of such person and such operator, and containing such specifications for the processing, labeling, or repacking, as the case may be, of such drug in such establishment as will insure, if such specifications are followed, that such drug will not be adulterated or misbranded within the meaning of the act upon completion of such processing, labeling, or repacking. Such person and such operator shall each keep a copy of such agreement until 2 years after the final shipment or delivery of such drug from such establishment, and shall make such copies available for inspection at any reasonable hour to any officer or employee of the Department who requests them.
(b) An exemption of a shipment or other delivery of a drug under paragraph (a)(1) of this section shall, at the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment, become void ab initio if the drug comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed.
(c) An exemption of a shipment or other delivery of a drug under paragraph (a)(2) of this section shall become void ab initio with respect to the person who introduced such shipment or delivery into interstate commerce upon refusal by such person to make available for inspection a copy of the agreement, as required by such paragraph (a)(2) of this section.
(d) An exemption of a shipment or other delivery of a drug under paragraph (a)(2) of this section shall expire:
(1) At the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment if the drug comprising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed; or
(2) Upon refusal by the operator of the establishment where such drug is to be processed, labeled, or repacked, to make available for inspection a copy of the agreement, as required by such clause.
§ 201.161   Medical gases.
(a) Oxygen, nitrogen, carbon dioxide, helium, and nitrous oxide gases intended for drug use, and medically appropriate combinations of any of these gases intended for drug use, are exempted from the requirements of § 201.100(b)(2) and (3), and (c)(1), provided that, where applicable, the requirements of §§ 201.328 and 211.94(e)(2) of this chapter are met and the labeling bears, in addition to any other information required by the Federal Food, Drug, and Cosmetic Act, the following:
(1)(i) In the case of oxygen, a warning statement providing that uninterrupted use of high concentrations of oxygen over a long duration, without monitoring its effect on oxygen content of arterial blood, may be harmful; that oxygen should not be used on patients who have stopped breathing unless used in conjunction with resuscitative equipment; and, in the case of oxygen that may be provided without a prescription for use in the event of depressurization or other environmental oxygen deficiency, or for oxygen deficiency or for use in emergency resuscitation when administered by properly trained personnel, a warning statement providing that oxygen may be used for emergency use only when administered by properly trained personnel for oxygen deficiency and resuscitation, and that for all other medical applications a prescription is required.
(ii) In the case of nitrogen, carbon dioxide, helium, nitrous oxide, and medically appropriate combinations of any of the gases listed in paragraph (a) of this section, a warning statement providing that the administration of the gas or gas combination (as applicable) may be hazardous or contraindicated; and that the gas or gas combination (as applicable) should be used only by or under the supervision of a licensed practitioner who is experienced in the use and administration of the gas or gas combination (as applicable) and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and the precautions to be taken.
(2) Any needed directions concerning the conditions for storage and warnings against the inherent dangers in the handling of the specific compressed gas.
(b) [Reserved]
§ 201.200   Disclosure of drug efficacy study evaluations in labeling and advertising.
(a)(1) The National Academy of Sciences—National Research Council, Drug Efficacy Study Group, has completed an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug procedures between 1938 and 1962. The results are compiled in “Drug Efficacy Study, A Report to the Commissioner of Food and Drugs from the National Academy of Sciences (1969).” As the report notes, this review has made “an audit of the state of the art of drug usage that has been uniquely extensive in scope and uniquely intensive in time” and is applicable to more than 80 percent of the currently marketed drugs. The report further notes that the quality of the evidence of efficacy, as well as the quality of the labeling claims, is poor. Labeling and other promotional claims have been evaluated as “effective,” “probably effective,” “possibly effective,” “ineffective,” “ineffective as a fixed combination,” and “effective but,” and a report for each drug in the study has been submitted to the Commissioner.
(2) The Food and Drug Administration is processing the reports, seeking voluntary action on the part of the drug manufacturers and distributors in the elimination or modification of unsupported promotional claims, and initiating administrative actions as necessary to require product and labeling changes.
(3) Delays have been encountered in bringing to the attention of the prescribers of prescription items the conclusions of the expert panels that reviewed the promotional claims.
(b) The Commissioner of Food and Drugs concludes that:
(1) The failure to disclose in the labeling of a drug and in other promotional material the conclusions of the Academy experts that a claim is “ineffective,” “possibly effective,” “probably effective,” or “ineffective as a fixed combination,” while labeling and promotional material bearing any such claim are being used, is a failure to disclose facts that are material in light of the representations made and causes the drug to be misbranded.
(2) The Academy classification of a drug as other than “effective” for a claim for which such drug is recommended establishes that there is a material weight of opinion among qualified experts contrary to the representation made or suggested in the labeling, and failure to reveal this fact causes such labeling to be misleading.
(c) Therefore, after publication in the Federal Register of a Drug Efficacy Study Implementation notice on a prescription drug, unless exempted or otherwise provided for in the notice, all package labeling (other than the immediate container or carton label, unless such labeling contains information required by § 201.100(c)(1) in lieu of a package insert), promotional labeling, and advertisements shall include, as part of the information for practitioners under which the drug can be safely and effectively used, an appropriate qualification of all claims evaluated as other than “effective” by a panel of the National Academy of Sciences—National Research Council, Drug Efficacy Study Group, if such claims continue to be included in either the labeling or advertisements. However, this qualifying information will be required in advertisements only if promotional material is included therein for claims evaluated as less than “effective” or if such claims are included in the indications section of the portion of the advertisement containing the information required in brief summary by § 202.1(e)(1) of this chapter. When, however, the Food and Drug Administration classification of such claim is “effective” (for example, on the basis of revision of the language of the claim or submission or existence of adequate data), such qualification is not necessary. When the Food and Drug Administration classification of the claim, as stated in the implementation notice, differs from that of the Academy but is other than “effective,” the qualifying statement shall refer to this classification in lieu of the Academy's classification.
(d) For new drugs and antibiotics, supplements to provide for revised labeling in accord with paragraph (c) of this section shall be submitted under the provisions of § 314.70 and § 514.8 of this chapter within 90 days after publication of the implementation notice in the Federal Register or by May 15, 1972, for those drugs for which notices have been published and such labeling shall be put into use as soon as possible but not later than the end of the time period allowed for submitting supplements to provide for revised labeling.
(e) Qualifying information required in drug labeling by paragraph (c) of this section in order to advise prescribers of a drug of the findings made by a panel of the Academy in evaluating a claim as other than “effective” shall be at least of the same size and color and degree of prominence as other printing in the labeling and shall be presented in a prominent box using one of the following formats and procedures:
(1) In drug labeling the box statement may entirely replace the indications section and be in the following format:
Based on a review of this drug by the National Academy of Sciences—National Research Council and/or other information, FDA has classified the indication(s) as follows:
Effective: ( list or state in paragraph form ).
“Probably” effective: ( list or state in paragraph form ).
“Possibly” effective: ( list or state in paragraph form ).
Final classification of the less-than-effective indications requires further investigation.
(2) Or the indication(s) for which the drug has been found effective may appear outside the boxed statement and be followed immediately by the following boxed statement:
Based on a review of this drug by the National Academy of Sciences—National Research Council and/or other information, FDA has classified the other indication(s) as follows:
“Probably” effective: ( list or state in paragraph form ).
“Possibly” effective: ( list or state in paragraph form ).
Final classification of the less-than-effective indications requires further investigation.
(3) In drug labeling (other than that which is required by § 201.100(c)(1)) which may contain a promotional message, the promotional message shall be keyed to the boxed statement by the same means as those provided for advertisements in paragraph (f)(2) of this section.
(f) Qualifying information required in prescription drug advertising by paragraph (c) of this section shall contain a prominent boxed statement of the advertised indication(s) and of the limitations of effectiveness using the same format, language, and emphasis as that required in labeling by paragraph (e) of this section.
(1) The boxed statement shall appear in (or next to) the information required in brief summary by § 202.1(e)(1) of this chapter and shall have prominence at least equal to that provided for other information presented in the brief summary and shall have type size, captions, color, and other physical characteristics comparable to the information required in the brief summary.
(2) Less-than-effective indication(s) in the promotional message of an advertisement which is a single page or less shall be keyed to the boxed statement by asterisk, by an appropriate statement, or by other suitable means providing adequate emphasis on the boxed statement. On each page where less-than-effective indication(s) appear in a mutiple page advertisement, an asterisk shall be placed after the most prominent mention of the indi- cation(s); if the degree of prominence does not vary, an asterisk shall be placed after the first mention of the indication. The asterisk shall refer to a notation at the bottom of the page which shall state “This drug has been evaluated as probably effective (or possibly effective whichever is appropriate) for this indication” and “See Brief Summary” or “See Prescribing Information,” the latter legend to be used only if the advertisement carries the required information for professional use as set forth in § 201.100(c)(1).
(3) For less-than-effective indications which are included in the advertisement only as a part of the information required in brief summary, the disclosure information shall appear in this portion of the advertisement in the same manner as is specified for labeling in paragraph (e) of this section.
(g) The Commissioner may find circumstances are such that, while the elimination of claims evaluated as other than effective will generally eliminate the need for disclosure about such claims, there will be instances in which the change in the prescribing or promotional profile of the drug is so substantial as to require a disclosure of the reason for the change so that the purchaser or prescriber is not misled by being left unaware through the sponsor's silence that a basic change has taken place. The Food and Drug Administration will identify these situations in direct correspondence with the drug promoters, after which the failure to make the disclosure will be regarded as misleading and appropriate action will be taken.
§ 201.300   Notice to manufacturers, packers, and distributors of glandular preparations.
(a) Under date of December 4, 1941, in a notice to manufacturers of glandular preparations, the Food and Drug Administration expressed the opinion that preparations of inert glandular materials intended for medicinal use should, in view of the requirement of section 201(n) of the Federal Food, Drug, and Cosmetic Act (52 Stat. 1041; 21 U.S.C. 321(n)), be labeled with a statement of the material fact that there is no scientific evidence that the articles contain any therapeutic or physiologically active constituents. Numerous preparations of such inert glandular materials were subsequently marketed with disclaimers of the type suggested. The term inert glandular materials means preparations incapable of exerting an action or effect of some significant or measurable benefit in one way or another, i.e., in the diagnosis, cure, mitigation, treatment, or prevention of disease, or in affecting the structure or any function of the body.
(b) Manufacturers have heretofore taken advantage of § 201.100 permitting omission of directions for use when the label bears the prescription legend. Section 201.100(c) requires that the labeling of the drug, which may include brochures readily available to licensed practitioners, bear information as to the use of the drug by practitioners licensed by law to administer it. Obviously, information adequate for the use of an inert glandular preparation is not available to practitioners licensed by law.
(c) The Department of Health and Human Services is of the opinion that inert glandular materials may not be exempted from the requirements of section 502(f)(1) of the act that they bear adequate directions for use; and, accordingly, that their labeling must include among other things, representations as to the conditions for which such articles are intended to be used or as to the structure or function of the human body that they are intended to affect. Since any such representations offering these articles for use as drugs would be false or misleading, such articles will be considered to be misbranded if they are distributed for use as drugs.
(d) The amended regulations provide also that in the case of drugs intended for parenteral administration there shall be no exemption from the requirement that their labelings bear adequate directions for use. Such inert glandular materials for parenteral use are therefore subject to the same comment as applies to those intended for oral administration.
§ 201.301   Notice to manufacturers, packers, and distributors of estrogenic hormone preparations.
Some drug preparations fabricated wholly or in part from estradiol and labeled as to potency in terms of international units or in terms of international units of estrone activity have been marketed. The international unit of the estrus-producing hormone was established by the International Conference on the Standardization of Sex Hormones at London, England, on August 1, 1932. This unit was defined as “the specific estrus-producing activity contained in 0.1 gamma ( = 0.0001 mg.) of the standard” hydroxyketonic hormone found in urine (estrone). The International Conference declared that it did not recommend the determination of the activity of nonhydroxyketonic forms of estrogenic hormones in units of estrone because of the varying ratios between the activity of such nonhydroxyketonic estrogenic hormones and estrone, when measured by different methods on test animals. There is no international unit for measuring the activity of estradiol and no accepted relationship between its activity and that of estrone, either in test animals or in humans. The declaration of potency of estradiol in terms of international units or in terms of international units of estrone activity is therefore considered misleading, within the meaning of 21 U.S.C. 352(a). The declaration of the estradiol content of an estrogenic hormone preparation in terms of weight is considered appropriate.
§ 201.302   Notice to manufacturers, packers, and distributors of drugs for internal use which contain mineral oil.
(a) In the past few years research studies have altered medical opinion as to the usefulness and harmfulness of mineral oil in the human body. These studies have indicated that when mineral oil is used orally near mealtime it interferes with absorption from the digestive tract of provitamin A and the fat-soluble vitamins A, D, and K, and consequently interferes with the utilization of calcium and phosphorus, with the result that the user is left liable to deficiency diseases. When so used in pregnancy it predisposes to hemorrhagic disease of the newborn.
(b) There is accumulated evidence that the indiscriminate administration of mineral oil to infants may be followed by aspiration of the mineral oil and subsequent “lipoid pneumonia.”
(c) In view of these facts, the Department of Health and Human Services will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act a drug for oral administration consisting in whole or in part of mineral oil, the labeling of which encourages its use in pregnancy or indicates or implies that such drug is for administration to infants.
(d) It is also this Department's view that the act requires the labelings of such drugs to bear a warning against consumption other than at bedtime and against administration to infants. The following form of warning is suggested: “Caution: To be taken only at bedtime. Do not use at any other time or administer to infants, except upon the advice of a physician.”
(e) This statement of interpretation does not in any way exempt mineral oil or preparations containing mineral oil from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act.
§ 201.303   Labeling of drug preparations containing significant proportions of wintergreen oil.
(a) Because methyl salicylate (wintergreen oil) manifests no toxicity in the minute amounts in which it is used as a flavoring, it is mistakenly regarded by the public as harmless even when taken in substantially larger amounts. Actually, it is quite toxic when taken in quantities of a teaspoonful or more. Wintergreen oil and preparations containing it have caused a number of deaths through accidental misuse by both adults and children. Children are particularly attracted by the odor and are likely to swallow these products when left within reach.
(b) To safeguard against fatalities from this cause, the Department of Health and Human Services will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act any drug containing more than 5 percent methyl salicylate (wintergreen oil), the labeling of which fails to warn that use otherwise than as directed therein may be dangerous and that the article should be kept out of reach of children to prevent accidental poisoning.
(c) This statement of interpretation in no way exempts methyl salicylate (wintergreen oil) or its preparations from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act.
§ 201.304   Tannic acid and barium enema preparations.
(a) It has become a widespread practice for tannic acid to be added to barium enemas to improve X-ray pictures. Tannic acid is capable of causing diminished liver function and severe liver necrosis when absorbed in sufficient amounts. The medical literature reports a number of deaths associated with the addition of tannic acid to barium enemas. There is a lack of scientific evidence to establish the conditions, if any, under which tannic acid is safe and effective for use in enemas. Tannic acid for rectal use to enhance X-ray visualization is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act.
(b) In view of the hazards involved when tannic acid is used in barium enemas, any shipments of tannic acid labeled to come within the exemptions under 502(f) of the Act containing such phrases as: “Caution: For manufacturing, processing, or repackaging,” “For prescription compounding,” or “Diagnostic reagent—For professional use only” will be regarded by the Commissioner of Food and Drugs as misbranded within the meaning of section 502(f) of the Federal Food, Drug, and Cosmetic Act unless the label and the labeling bear conspicuously a warning to the effect: “ Warning— Not for use in enemas.”
(c) Any tannic acid intended for use by man and found within the jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled contrary to this section after 60 days from the date of its publication in the Federal Register may be made the subject of regulatory proceedings.
§ 201.305   Isoproterenol inhalation preparations (pressurized aerosols, nebulizers, powders) for human use; warnings.
(a) Accumulating reports have been received by the Food and Drug Administration and have appeared in the medical literature of severe paradoxical bronchoconstriction associated with repeated, excessive use of isoproterenol inhalation preparations in the treatment of bronchial asthma and other chronic bronchopulmonary disorders. The cause of this paradoxical reaction is unknown; it has been observed, however, that patients have not responded completely to other forms of therapy until use of the isoproterenol inhalation preparation was discontinued. In addition, sudden unexpected deaths have been associated with the excessive use of isoproterenol inhalation preparations. The mechanism of these deaths and their relationship, if any, to the cases of severe paradoxical bronchospasm are not clear. Cardiac arrest was noted in several of these cases of sudden death.
(b) On the basis of the above information and after discussion with and concurrence of the Respiratory and Anesthetic Drugs Advisory Committee for Food and Drug Administration, the Commissioner of Food and Drugs concludes that in order for the labeling of such drugs to bear adequate information for their safe use, as required by § 201.100, such labeling must include the following:
Warning: Occasional patients have been reported to develop severe paradoxical airway resistance with repeated, excessive use of isoproterenol inhalation preparations. The cause of this refractory state is unknown. It is advisable that in such instances the use of this preparation be discontinued immediately and alternative therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn.
Deaths have been reported following excessive use of isoproterenol inhalation preparations and the exact cause is unknown. Cardiac arrest was noted in several instances.
(c)(1) The Commissioner also concludes that in view of the manner in which these preparations are self-administered for relief of attacks of bronchial asthma and other chronic bronchopulmonary disorders, it is necessary for the protection of users that warning information to patients be included as a part of the label and as part of any instructions to patients included in the package dispensed to the patient as follows:
Warning: Do not exceed the dose prescribed by your physician. If difficulty in breathing persists, contact your physician immediately.
(2) The warning on the label may be accomplished (i) by including it on the immediate container label with a statement directed to pharmacists not to remove the label or (ii) by including in the package a printed warning with instructions to pharmacists to place the warning on the container prior to dispensing.
(d) The marketing of isoproterenol inhalation preparations may be continued if all the following conditions are met:
(1) Within 30 days following the date of publication of this section in the Federal Register:
(i) The label and labeling of such preparations shipped within the jurisdiction of the act are in accordance with paragraphs (b) and (c) of this section.
(ii) The holder of an approved new-drug application for such preparation submits a supplement to his new-drug application to provide for appropriate labeling changes as described in paragraphs (b) and (c) of this section.
(2) Within 90 days following the date of publication of this section in the Federal Register, the manufacturer, packer, or distributor of any drug containing isoproterenol intended for inhalation for which a new-drug approval is not in effect submits a new-drug application containing satisfactory information of the kinds required by § 314.50 of this chapter, including appropriate labeling as described in paragraphs (b) and (c) of this section.
(3) The applicant submits additional information required for the approval of the application as may be specified in a written communication from the Food and Drug Administration.
(e) After 270 days following expiration of said 90 days, regulatory proceedings based on section 505(a) of the Federal Food, Drug, and Cosmetic Act may be initiated with regard to any such drug shipped within the jurisdiction of the act for which an approved new-drug application is not in effect.
§ 201.306   Potassium salt preparations intended for oral ingestion by man.
(a) The Food and Drug Administration will initiate no regulatory action with respect to the continued marketing of coated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet provided all the following conditions are met:
(1) Within 30 days from the date of publication of this statement of policy in the Federal Register:
(i) The labeling of the drug bears the prescription caution statement quoted in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act;
(ii) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the “full disclosure” labeling requirements of § 201.100 of this chapter, including the following warning statement:
Warning —There have been several reports, published and unpublished, concerning nonspecific small-bowel lesions consisting of stenosis, with or without ulceration, associated with the administration of enteric-coated thiazides with potassium salts. These lesions may occur with enteric-coated potassium tablets alone or when they are used with nonenteric-coated thiazides, or certain other oral diuretics. These small-bowel lesions have caused obstruction, hemorrhage, and perforation. Surgery was frequently required and deaths have occurred. Based on a large survey of physicians and hospitals, both United States and foreign, the incidence of these lesions is low, and a causal relationship in man has not been definitely established. Available information tends to implicate enteric-coated potassium salts, although lesions of this type also occur spontaneously. Therefore, coated potassium-containing formulations should be administered only when indicated, and should be discontinued immediately if abdominal pain, distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated potassium tablets should be used only when adequate dietary supplementation is not practicable.
(iii) Any other labeling or additional advertising for the drug conforms to the labeling described in paragraph (a)(1)(ii) of this section, in accordance with §§ 202.1 and 201.100 of this chapter.
(2) Within 90 days from the date of publication of this statement of policy in the Federal Register, the manufacturer, packer, or distributor of the drug shall submit a new-drug application containing satisfactory information of the kind required by § 314.50 of this chapter, with appropriate labeling as described in this paragraph.
(b) The Food and Drug Administration may initiate regulatory proceedings after 30 days from the date of publication of this section, with respect to the marketing of uncoated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet or with respect to liquid preparations containing potassium chloride or other potassium salts which supply 20 milligrams or more of potassium per milliliter, labeled or intended for human use, unless all the following conditions are met:
(1) The labeling of the drug bears the prescription statement quoted in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; and
(2) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the “full disclosure” labeling requirements of § 201.100 of this chapter, including a recommendation that patients be directed to dissolve any such tablets in an appropriate amount of liquid and to dilute any such liquid preparations adequately to assure against gastrointestinal injury associated with the oral ingestion of concentrated potassium salt preparations.
§ 201.307   Sodium phosphates; package size limitation, warnings, and directions for over-the-counter sale.
(a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that multiple container sizes of sodium phosphates oral solution available in the marketplace have caused consumer confusion and appear to have been involved in several consumer deaths. Sodium phosphates oral solution has been marketed in 45-milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and 90-mL container sizes of sodium phosphates oral solution are often recommended and prescribed by physicians for bowel cleansing prior to surgery and diagnostic procedures of the colon. Sodium phosphates oral solution (adult dose 20 mL to 45 mL) is also used as an over-the-counter (OTC) laxative for the relief of occasional constipation. Accidental overdosing and deaths have occurred because the 240-mL container was mistakenly used instead of the 45-mL or 90-mL container. The Food and Drug Administration is limiting the amount of sodium phosphates oral solution to not more than 90 mL (3 ounces (oz)) per OTC container because of the serious health risks associated with the ingestion of larger than intended doses of this product. Further, because an overdose of either oral or rectal enema sodium phosphates can cause an electrolyte imbalance, additional warning and direction statements are required for the safe use of any OTC laxative drug product containing sodium phosphates.
(b) Any OTC drug product for laxative or bowel cleansing use containing sodium phosphates as an active ingredient when marketed as described in paragraph (a) of this section is misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless packaged and labeled as follows:
(1) Package size limitation for sodium phosphates oral solution: Container shall not contain more than 90 mL (3 oz).
(2) Warnings. The following sentences shall appear in boldface type as the first statement under the heading “Warnings.”
(i) Oral dosage forms. “Taking more than the recommended dose in 24 hours can be harmful.”
(ii) Rectal enema dosage forms. “Using more than one enema in 24 hours can be harmful.”
(3) Directions—(i) The labeling of all orally or rectally administered OTC drug products containing sodium phosphates shall contain the following directions in boldface type immediately preceding the dosage information: “Do not” (“take” or “use”) “more unless directed by a doctor. See Warnings.”
(ii) For products containing dibasic sodium phosphate/monobasic sodium phosphate identified in § 334.16(d) marketed as a solution. Adults and children 12 years of age and over: Oral dosage is dibasic sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate 9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a single daily dose. “Do not take more than 45 mL (9 teaspoonfuls or 3 tablespoonfuls) in a 24-hour period.” Children 10 and 11 years of age: Oral dosage is dibasic sodium phosphate 1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g (10 to 20 mL dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a single daily dose. “Do not take more than 20 mL (4 teaspoonfuls) in a 24-hour period.” Children 5 to 9 years of age: Oral dosage is dibasic sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to 5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a single daily dose. “Do not take more than 10 mL (2 teaspoonfuls) in a 24-hour period.” Children under 5 years of age: ask a doctor.
(c) After June 22, 1998, for package size limitation and September 18, 1998, for labeling in accord with paragraph (b) of this section, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce, or any such drug product that is repackaged or relabeled after these dates regardless of the date the product was manufactured, initially introduced, or initially delivered for introduction into interstate commerce, that is not in compliance with this section is subject to regulatory action.
§ 201.308   Ipecac syrup; warnings and directions for use for over-the-counter sale.
(a) It is estimated that each year about 500,000 accidental poisonings occur in the United States and result in approximately 1,500 deaths, of which over 400 are children. In the emergency treatment of these poisonings, ipecac syrup is considered the emetic of choice. The immediate availability of this drug for use in such situations is critical, since rapid treatment may be the difference between life and death. The restriction of this drug to prescription sale limits its availability in emergencies. On the other hand, it is the consensus of informed medical opinion that ipecac syrup should be used only under medical supervision in the emergency treatment of poisonings. In view of these facts, the question of whether ipecac syrup labeled as an emergency treatment for use in poisonings should be available over the counter has been controversial.
(b) In connection with its study of this problem, the Food and Drug Administration has obtained the views of medical authorities. It is the unanimous recommendation of the American Academy of Pediatrics, the American Association of Poison Control Centers, the American Medical Association, and the Medical Advisory Board of the Food and Drug Administration that ipecac syrup in 1 fluid ounce containers be permitted to be sold without prescription so that it will be readily available in the household for emergency treatment of poisonings, under medical supervision, and that the drug be appropriately packaged and labeled for this purpose.
(c) In view of the above recommendations, the Commissioner of Food and Drugs has determined that it is in the interest of the public health for ipecac syrup to be available for sale without prescription, provided that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and its label bears, in addition to other required label information, the following, in a prominent and conspicuous manner:
(1) A statement conspicuously boxed and in red letters, to the effect: “For emergency use to cause vomiting in poisoning. Before using, call physician, the Poison Control Center, or hospital emergency room immediately for advice.”
(2) A warning to the effect: “Warning—Keep out of reach of children. Do not use in unconscious persons. Ordinarily, this drug should not be used if strychnine, corrosives such as alkalies (lye) and strong acids, or petroleum distillates such as kerosine, gasoline, coal oil, fuel oil, paint thinner, or cleaning fluid have been ingested.”
(3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1 year of age.
§ 201.309   Acetophenetidin (phenacetin)-containing preparations; necessary warning statement.
(a) In 1961, the Food and Drug Administration, pursuant to its statutory responsibility for the safety and effectiveness of drugs shipped in interstate commerce, began an active investigation of reports of possible toxic effects and renal damage due to misuse of the drug acetophenetidin. This study led to the decision that there was probable cause to conclude that misuse and prolonged use of the drug were in fact responsible for kidney lesions and disease. The Commissioner of Food and Drugs, in December 1963, appointed an ad hoc Advisory Committee of Inquiry on Possible Nephrotoxicity Associated With the Abuse of Acetophenetidin (Phenacetin)-Containing Preparations. This committee, composed of scientists in the fields of pharmacology and medicine, on April 23, 1964, submitted its findings and conclusions in the matter and recommended that all acetophenetidin (phenacetin)-containing preparations bear a warning as provided in section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act.
(b) On the basis of the studies made by the Food and Drug Administration and the report of the Advisory Committee, the Commissioner of Food and Drugs has concluded that it is necessary for the protection of users that the label and labeling of all acetophenetidin (phenacetin)-containing preparations bear a warning statement to the following effect: “Warning—This medication may damage the kidneys when used in large amounts or for a long period of time. Do not take more than the recommended dosage, nor take regularly for longer than 10 days without consulting your physician.”
§ 201.310   Phenindione; labeling of drug preparations intended for use by man.
(a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that phenindione, a synthetic anticoagulant drug, has caused a number of cases of agranulocytosis (with two fatalities). There are also reports implicating the drug in cases of hepatitis and hypersensitivity reactions. In view of the potentially serious effects found to be associated with preparations of this drug intended for use by man, the Commissioner of Food and Drugs will regard such preparations as misbranded within the meaning of section 502(f) (1) and (2) of the Federal Food, Drug, and Cosmetic Act, unless the label and labeling on or within the package from which the drug is to be dispensed, and any other labeling furnishing or purporting to furnish information for use of the drug, bear a conspicuous warning statement to the following effect: “Warning: Agranulocytosis and hepatitis have been associated with the use of phenindione. Patients should be instructed to report promptly prodromal symptoms such as marked fatigue, chill, fever, and sore throat. Periodic blood studies and liver function tests should be performed. Use of the drug should be discontinued if leukopenia occurs or if evidence of hypersensitivity, such as dermatitis or fever, appears.”
(b) Regulatory action may be initiated with respect to preparations of phenindione intended for use by man found within the jurisdiction of the act on or after November 25, 1961, unless such preparations are labeled in accordance with paragraph (a) of this section.
§ 201.311   [Reserved]
§ 201.312   Magnesium sulfate heptahydrate; label declaration on drug products.
Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or usual name.
§ 201.313   Estradiol labeling.
The article presently recognized in The National Formulary under the heading “Estradiol” and which is said to be “17-cis-beta estradiol” is the same substance formerly recognized in the United States Pharmacopeia under the designation “Alpha Estradiol.” The substance should no longer be referred to in drug labeling as “Alpha Estradiol.” The Food and Drug Administration would not object to label references to the article as simply “Estradiol”; nor would it object if the label of a preparation containing this substance referred to the presence of “Estradiol (formerly known as Alpha Estradiol).”
§ 201.314   Labeling of drug preparations containing salicylates.
(a) The label of any oral drug preparation intended for sale without prescription and which contains any salicylate ingredient (including aspirin, salicylamide, other salicylates, and combinations) must conspicuously bear, on a clearly contrasting background, the warning statement: “Keep out of reach of children [highlighted in bold type]. In case of overdose, get medical help or contact a Poison Control Center right away,” or “Keep out of reach of children [highlighted in bold type],” except that if the article is an aspirin preparation, it shall bear the first of these warning statements. Such a warning statement is required for compliance with section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act and is intended to guard against accidental poisonings. Safety closures that prevent access to the drug by young children are also recommended to guard against accidental poisonings.
(b) Effervescent preparations and preparations containing para-aminosalicylate as the only salicylate ingredient are exempted from this labeling requirement.
(c) Aspirin tablets sold as such and containing no other active ingredients, except tablets which cannot be readily subdivided into a child's dose because of their coating or size, should always bear dosage directions for each age group down to 3 years of age, with a statement such as “For children under 3 years of age, consult your physician.” It is recommended that:
(1) Aspirin tablets especially made for pediatric use be produced only in 1 1/4 -grain size to reduce the hazard of errors in dosage;
(2) By June 1, 1967, manufacturers and distributors of 1 1/4 -grain size aspirin tablets discontinue the distribution of such tablets in retail containers containing more than 36 tablets, to reduce the hazard of accidental poisoning;
(3) The flavoring of 5-grain aspirin tablets or other “adult aspirin tablets” be discontinued; and
(4) Labeling giving undue emphasis to the pleasant flavor of flavored aspirin tablets be discontinued.
(d) Salicylate preparations other than aspirin tablets sold as such may, at the option of the distributor, be labeled for use by adults only. If their labeling and advertising clearly offer them for administration to adults only.
(e)(1) It is the obligation of the distributor who labels a salicylate preparation for administration to children to make certain that the article is suitable for such use and labeled with adequate directions for use in the age group for which it is offered, but in no case should such an article bear directions for use in children under 3 years of age. If the directions provide for administration to children as young as 3 years of age, the label should bear the statement, “For children under 3 years of age consult your physician.” However, if the directions provide for administration to children only of an age greater than 3 years (for example, the dosage instructions provide for administration of the article to children only down to age 6), the label should bear a statement such as, “For younger children consult your physician.”
(2) A statement such as, “For children under 3 years of age consult your physician” or “For younger children consult your physician” is not required on the label of an article clearly offered for administration to adults only.
(f) If the labeling or advertising of a salicylate preparation offers it for use in arthritis or rheumatism, the label and labeling should clearly state that the beneficial effects claimed are limited to: “For the temporary relief of minor aches and pains of arthritis and rheumatism.” The qualifying phrase “for the temporary relief of minor aches and pains” should appear with the same degree of prominence and conspicuousness as the phrase “arthritis and rheumatism”. The label and labeling should bear in juxtaposition with such directions for use conspicuous warning statements to the effect: “Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician immediately.” The salicylate dosage should not exceed 60 grains in a 24-hour period or 10 grains in a 4-hour period. If the article contains other analgesics, the salicylate dosage should be appropriately reduced.
(g)(1) The label of any drug containing more than 5 percent methyl salicylate (wintergreen oil) should bear a conspicuous warning such as: “Do not use otherwise than as directed.” These drug products must also include the “Keep out of reach of children” warning and the accidental ingestion warning as required in § 330.1(g) of this chapter.
(2) If the preparation is a counterirritant or rubefacient, it should also bear a caution such as, “Caution: Discontinue use if excessive irritation of the skin develops. Avoid getting into the eyes or on mucous membranes.” (See also § 201.303.)
(h)(1) The labeling of orally or rectally administered over-the-counter drug products containing aspirin or nonaspirin salicylates as active ingredients subject to this paragraph is required to prominently bear the following warning: “Reye's syndrome [subheading in bold type]: Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye's syndrome, a rare but serious illness.”
(2) This warning statement shall appear on the immediate container labeling. In cases where the immediate container is not the retail package, the retail package also must bear the warning statement. In addition, the warning statement shall appear on any labeling that contains warnings and, in such cases, the warning statement shall be the first warning statement under the heading “Warnings.”
(3) Over-the-counter drug products subject to this paragraph and labeled solely for use by children (pediatric products) shall not recommend the product for use in treating flu or chicken pox.
(4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of this section that is not labeled as required by these paragraphs and that is initially introduced or initially delivered for introduction into interstate commerce after the following dates is misbranded under sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and Cosmetic Act.
(i) Compliance by October 18, 2004, for OTC drug products containing aspirin and nonaspirin salicylates as an active ingredient and marketed under a new drug application or abbreviated new drug application.
(ii) Compliance by April 19, 2004, for OTC antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as an active ingredient and have annual sales greater than $25,000.
(iii) Compliance by April 18, 2005, for OTC antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as an active ingredient and have annual sales less than $25,000.
(iv) Compliance dates for all other OTC drug products containing aspirin and nonaspirin salicylates as an active ingredient and marketed under an OTC drug monograph (for internal analgesic, antipyretic, and antirheumatic drug products, or for menstrual drug products) will be established when the final monographs for those products are published in a future issue of the Federal Register. In the interim, these products should continue to be labeled with the previous Reye's syndrome warning that appears in paragraph (h)(1) of this section.
§ 201.315   Over-the-counter drugs for minor sore throats; suggested warning.
The Food and Drug Administration has studied the problem of the labeling of lozenges or troches containing a local anesthetic, chewing gum containing aspirin, various mouth washes and gargles and other articles sold over the counter for the relief of minor irritations of the mouth or throat. It will not object to the labeling of suitable articles of this type “For the temporary relief of minor sore throats”, provided this is immediately followed in the labeling with a warning statement in prominent type essentially as follows: “Warning—Severe or persistent sore throat or sore throat accompanied by high fever, headache, nausea, and vomiting may be serious. Consult physician promptly. Do not use more than 2 days or administer to children under 3 years of age unless directed by physician.”
§ 201.316   Drugs with thyroid hormone activity for human use; required warning.
(a) Drugs with thyroid hormone activity have been promoted for, and continue to be dispensed and prescribed for, use in the treatment of obesity, although their safety and effectiveness for that use have never been established.
(b) Drugs for human use with thyroid hormone activity are misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the following boxed warning at the beginning of the “Warnings” section:
Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects.
§ 201.317   Digitalis and related cardiotonic drugs for human use in oral dosage forms; required warning.
(a) Digitalis and related cardiotonic drugs for human use in oral dosage forms have been promoted for, and continue to be dispensed and prescribed for, use in the treatment of obesity, although their safety and effectiveness for that use have never been established.
(b) Digitalis and related cardiotonic drugs for human use in oral dosage forms are misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the following boxed warning at the beginning of the “Warnings” section:
Digitalis alone or with other drugs has been used in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs in the treatment of obesity is dangerous.
(c) This section does not apply to digoxin products for oral use.
§ 201.319   Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil tragacanth, and xanthan gum) as active ingredients; required warnings and directions.
(a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that esophageal obstruction and asphyxiation have been associated with the ingestion of water-soluble gums, hydrophilic gums, and hydrophilic mucilloids including, but not limited to, agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil, tragacanth, and xanthan gum. Esophageal obstruction and asphyxiation due to orally-administered drug products containing water-soluble gums, hydrophilic gums, and hydrophilic mucilloids as active ingredients are significant health risks when these products are taken without adequate fluid or when they are used by individuals with esophageal narrowing or dysfunction, or with difficulty in swallowing. Additional labeling is needed for the safe and effective use of any OTC drug product for human use containing a water-soluble gum, hydrophilic gum, or hydrophilic mucilloid as an active ingredient when marketed in a dry or incompletely hydrated form to include, but not limited to, the following dosage forms: Capsules, granules, powders, tablets, and wafers. Granular dosage forms containing psyllium are not generally recognized as safe and effective as OTC laxatives (see § 310.545(a)(12)(i)(B) of this chapter) and may not be marketed without an approved new drug application because the warnings and directions in paragraph (b) of this section have been found inadequate for these products.
(b) Any drug products for human use containing a water-soluble gum, hydrophilic gum, or hydrophilic mucilloid as an active ingredient in an oral dosage form when marketed in a dry or incompletely hydrated form as described in paragraph (a) of this section are misbranded within the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the following warnings (under the subheading “Choking”) and directions:
“ ‘Choking’ [highlighted in bold type]: Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention;” and
“ ‘Directions’ [highlighted in bold type]:” (Select one of the following, as appropriate: “Take” or “Mix”) “this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning.”
(c) After February 28, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce, or any such drug product that is repackaged or relabeled after this date regardless of the date the product was manufactured, initially introduced, or initially delivered for introduction into interstate commerce, that is not in compliance with this section is subject to regulatory action.
§ 201.320   Warning statements for drug products containing or manufactured with chlorofluorocarbons or other ozone-depleting substances.
(a)(1) All drug products containing or manufactured with chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or any other class I substance designated by the Environmental Protection Agency (EPA) shall, except as provided in paragraph (b) or (c) of this section, bear the following warning statement:
Warning: Contains [or Manufactured with, if applicable] [ insert name of substance ], a substance which harms public health and the environment by destroying ozone in the upper atmosphere.
(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.
(b)(1) For prescription drug products for human use, the following alternative warning statement may be used:
The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or name of other class I substance, if applicable]:
This product contains [or is manufactured with, if applicable] [ insert name of substance ], a substance which harms the environment by destroying ozone in the upper atmosphere.
Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.
(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.
(3) If the warning statement in paragraph (b)(1) of this section is used, the following warning statement must be placed on the package labeling intended to be read by the physician (physician package insert) after the “How supplied” section, which describes special handling and storage conditions on the physician labeling:
The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or name of other class I substance, if applicable]:
Warning: Contains [or Manufactured with, if applicable] [ insert name of substance ], a substance which harms public health and the environment by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the information for the patient [or patient information leaflet, if applicable] of this product under the Environmental Protection Agency's (EPA's) regulations. The patient's warning states that the patient should consult his or her physician if there are questions about alternatives.
(c)(1) For over-the-counter drug products for human use, the following alternative warning statement may be used:
The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFC's) [or other class I substance, if applicable]:
Warning: Contains [or Manufactured with, if applicable] [ insert name of substance ], a substance which harms public health and environment by destroying ozone in the upper atmosphere.
CONSULT WITH YOUR PHYSICIAN OR HEALTH PROFESSIONAL IF YOU HAVE ANY QUESTION ABOUT THE USE OF THIS PRODUCT.
(2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and understood by consumers under normal conditions of purchase.
(d) This section does not replace or relieve a person from any requirements imposed under 40 CFR part 82.
§ 201.323   Aluminum in large and small volume parenterals used in total parenteral nutrition.
(a) The aluminum content of large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy must not exceed 25 micrograms per liter (µg/L).
(b) The package insert of LVP's used in TPN therapy must state that the drug product contains no more than 25 µg/L of aluminum. This information must be contained in the “Precautions” section of the labeling of all large volume parenterals used in TPN therapy.
(c) Except as provided in paragraph (d) of this section, the maximum level of aluminum present at expiry must be stated on the immediate container label of all small volume parenteral (SVP) drug products and pharmacy bulk packages (PBPs) used in the preparation of TPN solutions. The aluminum content must be stated as follows: “Contains no more than __ µg/L of aluminum.” The immediate container label of all SVP's and PBP's that are lyophilized powders used in the preparation of TPN solutions must contain the following statement: “When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than __ µg/L.” This maximum level of aluminum must be stated as the highest of:
(1) The highest level for the batches produced during the last 3 years;
(2) The highest level for the latest five batches, or
(3) The maximum historical level, but only until completion of production of the first five batches after July 26, 2004.
(d) If the maximum level of aluminum is 25 µg/L or less, instead of stating the exact amount of aluminum as required in paragraph (c) of this section, the immediate container label may state: “Contains no more than 25 µg/L of aluminum.” If the SVP or PBP is a lyophilized powder, the immediate container label may state: “When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than 25 µg/L”.
(e) The package insert for all LVP's, all SVP's, and PBP's used in TPN must contain a warning statement. This warning must be contained in the “Warnings” section of the labeling. The warning must state:
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
(f) Applicants and manufacturers must use validated assay methods to determine the aluminum content in parenteral drug products. The assay methods must comply with current good manufacturing practice requirements. Applicants must submit to the Food and Drug Administration validation of the method used and release data for several batches. Manufacturers of parenteral drug products not subject to an approved application must make assay methodology available to FDA during inspections. Holders of pending applications must submit an amendment under § 314.60 or § 314.96 of this chapter.
§ 201.325   Over-the-counter drugs for vaginal contraceptive and spermicide use containing nonoxynol 9 as the active ingredient; required warnings and labeling information.
(a) Studies indicate that use of vaginal contraceptive drug products containing nonoxynol 9 does not protect against infection from the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), or against the transmission of other sexually transmitted diseases (STDs). Studies also indicate that use of vaginal contraceptive drug products containing nonoxynol 9 can increase vaginal irritation, such as the disruption of the vaginal epithelium, and also can cause epithelial disruption when used in the rectum. These effects may increase the risk of transmission of the AIDS virus (HIV) from an infected partner. Therefore, consumers should be warned that these products do not protect against the transmission of the AIDS virus (HIV) or other STDs, that use of these products can increase vaginal and rectal irritation, which may increase the risk of getting the AIDS virus (HIV) from an HIV infected partner, and that the products are not for rectal use. Consumers should also be warned that these products should not be used by persons who have HIV/AIDS or are at high risk for HIV/AIDS.
(b) The labeling of OTC vaginal contraceptive and spermicide drug products containing nonoxynol 9 as the active ingredient, whether subject to the ongoing OTC drug review or an approved drug application, must contain the following warnings under the heading “Warnings,” in accordance with 21 CFR 201.66.
(1) “[bullet] For vaginal use only [bullet] Not for rectal (anal) use” [both warnings in bold type].
(2) “Sexually transmitted diseases (STDs) alert [in bold type]: This product does not [word “not” in bold type] protect against HIV/AIDS or other STDs and may increase the risk of getting HIV from an infected partner”.
(3) “Do not use” [in bold type] if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control”.
(4) “When using this product [in bold type] [optional, bullet] you may get vaginal irritation (burning, itching, or a rash)”.
(5) “Stop use and ask a doctor if [in bold type] [optional, bullet] you or your partner get burning, itching, a rash, or other irritation of the vagina or penis”.
(c) The labeling of this product states under the “Other information” section of the Drug Facts labeling in accordance with § 201.66(c)(7), “[bullet] when used correctly every time you have sex, latex condoms greatly reduce, but do not eliminate, the risk of catching or spreading HIV, the virus that causes AIDS.
(d) The labeling of this product includes the following statements either on the outside container or wrapper of the retail package, under the “Other information” section of the Drug Facts labeling in accordance with § 201.66(c)(7), or in a package insert:
(1) “[bullet] studies have raised safety concerns that products containing the spermicide nonoxynol 9 can irritate the vagina and rectum. Sometimes this irritation has no symptoms. This irritation may increase the risk of getting HIV/AIDS from an infected partner”.
(2) “[bullet] you can use nonoxynol 9 for birth control with or without a diaphragm or condom if you have sex with only one partner who is not infected with HIV and who has no other sexual partners or HIV risk factors”.
(3) “[bullet] use a latex condom without nonoxynol 9 if you or your sex partner has HIV/AIDS, multiple sex partners, or other HIV risk factors”.
(4) “[bullet] ask a health professional if you have questions about your best birth control and STD prevention methods”.
(e) Any drug product subject to this section that is not labeled as required and that is initially introduced or initially delivered for introduction into interstate commerce after June 19, 2008, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352), is a new drug under section 505 of the act (21 U.S.C. 355), and is subject to regulatory action.
§ 201.326   Over-the-counter drug products containing internal analgesic/antipyretic active ingredients; required warnings and other labeling.
(a) Labeling. The labeling for all over-the-counter (OTC) drug products containing any internal analgesic/antipyretic active ingredients (including, but not limited to, acetaminophen, aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate) alone or in combination must bear the following labeling in accordance with §§ 201.60, 201.61, and 201.66.
(1) Acetaminophen —(i) Statement of identity. The statement of identity appears in accord with §§ 201.61 and 299.4 of this chapter. The ingredient name “acetaminophen” must appear highlighted (e.g., fluorescent or color contrast) or in bold type, be in lines generally parallel to the base on which the package rests as it is designed to be displayed, and be in one of the following sizes, whichever is greater:
(A) At least one-quarter as large as the size of the most prominent printed matter on the principal display panel (PDP), or
(B) At least as large as the size of the “Drug Facts” title, as required in § 201.66(d)(2). The presence of acetaminophen must appear as part of the established name of the drug, as defined in § 299.4 of this chapter. Combination products containing acetaminophen and a nonanalgesic ingredient(s) (e.g., cough-cold) must include the name “acetaminophen” and the name(s) of the other active ingredient(s) in the product on the PDP in accord with this paragraph. Only the name “acetaminophen” must appear highlighted or in bold type, and in a prominent print size, as described in this paragraph.
(ii) Active Ingredient and Purpose Headings. The information required under § 201.66(c)(2) and (c)(3) of this chapter must be included under these headings. The information under these headings, but not the headings, may appear highlighted.
(iii) For products labeled for adults only. The labeling of the product states the following warnings under the heading “Warnings”:
(A) The liver warning states “Liver warning [heading in bold type]: This product contains acetaminophen. Severe liver damage may occur if you take [bullet] more than [insert maximum number of daily dosage units] in 24 hours, which is the maximum daily amount [optional: ‘for this product’] [bullet] with other drugs containing acetaminophen [bullet] 3 or more alcoholic drinks every day while using this product”. This “Liver” warning must be the first warning under the “Warnings” heading. For products that contain both acetaminophen and aspirin, this “Liver” warning must appear after the “Reye's syndrome” and “Allergy alert” warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B) and before the “Stomach bleeding” warning in paragraph (a)(2)(iii)(A) of this section. If there is an outer and immediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning does not need to be included on each blister unit.
(B) “Do not use with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.”
(C) “Ask a doctor before use if you have liver disease”.
(D) “Ask a doctor or pharmacist before use if you are taking the blood thinning drug warfarin” except on the labeling of combination products that contain acetaminophen and NSAID(s).
(iv) For products labeled only for children under 12 years of age.
(A) Warnings. The labeling of the product states the following warnings under the heading “Warnings”:
( 1 ) The liver warning states “Liver warning [heading in bold type]: This product contains acetaminophen. Severe liver damage may occur if your child takes [bullet] more than 5 doses in 24 hours, which is the maximum daily amount [optional: ‘for this product’] [bullet] with other drugs containing acetaminophen”. This “Liver” warning must be the first warning under the “Warnings” heading. If there is an outer and immediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit.
( 2 ) “Do not use with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.”
( 3 ) “Ask a doctor before use if your child has liver disease”.
( 4 ) “Ask a doctor or pharmacist before use if your child is taking the blood thinning drug warfarin” except on the labeling of combination products that contain acetaminophen and NSAID(s).
(B) Directions. The labeling of the product contains the following information under the heading “Directions”: “this product does not contain directions or complete warnings for adult use” [in bold type].
(v) For products labeled for adults and children under 12 years of age. The labeling of the product states all of the warnings in paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of this section with the following modifications:
(A) The liver warning states “Liver warning [heading in bold type]: This product contains acetaminophen. Severe liver damage may occur if [bullet] adult takes more than [insert maximum number of daily dosage units] in 24 hours, which is the maximum daily amount [optional: ‘for this product’] [bullet] child takes more than 5 doses in 24 hours [bullet] taken with other drugs containing acetaminophen [bullet] adult has 3 or more alcoholic drinks everyday while using this product.” If there is an outer and immediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit.
(B) “Ask a doctor before use if the user has liver disease.”
(C) “Do not use with any other drug containing acetaminophen (prescription or nonprescription). If you are not sure whether a drug contains acetaminophen, ask a doctor or pharmacist.”
(D) “Ask a doctor or pharmacist before use if the user is taking the blood thinning drug warfarin” except on the labeling of combination products that contain acetaminophen and NSAID(s).
(2) Nonsteroidal anti-inflammatory analgesic/antipyretic active ingredients—including, but not limited to, aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium, and sodium salicylate.
(i) Statement of identity. The statement of identity appears in accord with §§ 201.61 and 299.4 of this chapter. The word “(NSAID)” must appear highlighted (e.g., fluorescent or color contrast) or in bold type, be in lines generally parallel to the base on which the package rests as it is designed to be displayed, and be in one of the following sizes, whichever is greater:
(A) At least one-quarter as large as the size of the most prominent printed matter on the PDP, or
(B) At least as large as the size of the “Drug Facts” title, as required in § 201.66(d)(2). The word “(NSAID)” must appear as part of the established name of the drug, as defined in § 299.4 of this chapter, or after the general pharmacological (principal intended) action of the NSAID ingredient. Combination products containing an NSAID and a nonanalgesic ingredient(s) (e.g., cough-cold) must include the name of the NSAID ingredient and the word “(NSAID)” in accordance with this paragraph, and the name(s) of the other active ingredient(s) in the product on the PDP. Only the word “(NSAID)” needs to appear highlighted or in bold type, and in a prominent print size, as described in this paragraph.
(ii) Active Ingredient and Purpose Headings. The information required under § 201.66(c)(2) and (c)(3) of this chapter must be included under these headings. The active ingredient(s) section of the product's labeling, as defined in § 201.66(c)(2), contains the term “(NSAID*)” after the NSAID active ingredient with an asterisk statement at the end of the active ingredient(s) section that defines the term “NSAID” and states “* nonsteroidal anti-inflammatory drug.” The information under these headings may appear highlighted. However, the headings “Active Ingredient” and “Purpose” may not appear highlighted.
(iii) For products labeled for adults only. The labeling of the product states the following warnings under the heading “Warnings”:
(A) The stomach bleeding warning states “Stomach bleeding warning [heading in bold type]: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you [bullet] are age 60 or older [bullet] have had stomach ulcers or bleeding problems [bullet] take a blood thinning (anticoagulant) or steroid drug [bullet] take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) [bullet] have 3 or more alcoholic drinks every day while using this product [bullet] take more or for a longer time than directed”. This “Stomach bleeding” warning must appear after the “Reye's syndrome” and “Allergy alert” warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For products that contain both acetaminophen and aspirin, the acetaminophen “Liver” warning in paragraph (a)(1)(iii) of this section must appear before the “Stomach bleeding” warning in this paragraph. If there is an outer and immediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit.
(B) “Ask a doctor before use if [bullet] stomach bleeding warning applies to you [bullet] you have a history of stomach problems, such as heartburn [bullet] you have high blood pressure, heart disease, liver cirrhosis, or kidney disease [bullet] you are taking a diuretic”.
(C) “Stop use and ask a doctor if [bullet] you experience any of the following signs of stomach bleeding:” [add the following as second level of statements: “[bullet] feel faint [bullet] vomit blood [bullet] have bloody or black stools [bullet] have stomach pain that does not get better”].
(iv) For products labeled only for children under 12 years of age.
(A) Warnings. The labeling of the product states the following warnings under the heading “Warnings”:
( 1 ) The stomach bleeding warning states “Stomach bleeding warning [heading in bold type]: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if your child [bullet] has had stomach ulcers or bleeding problems [bullet] takes a blood thinning (anticoagulant) or steroid drug [bullet] takes other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) [bullet] takes more or for a longer time than directed”. The “Stomach bleeding” warning must appear after the “Reye's syndrome” and “Allergy alert” warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and immediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit.
( 2 ) “Ask a doctor before use if [bullet] stomach bleeding warning applies to your child [bullet] child has a history of stomach problems, such as heartburn [bullet] child has not been drinking fluids [bullet] child has lost a lot of fluid due to vomiting or diarrhea [bullet] child has high blood pressure, heart disease, liver cirrhosis, or kidney disease [bullet] child is taking a diuretic”.
( 3 ) “Stop use and ask a doctor if [bullet] child experiences any of the following signs of stomach bleeding:” [add the following as second level of statements: [bullet] feels faint [bullet] vomits blood [bullet] has bloody or black stools [bullet] has stomach pain that does not get better”].
(B) Directions. The labeling of the product contains the following information under the heading “Directions”: “this product does not contain directions or complete warnings for adult use” [in bold type].
(v) For products labeled for adults and children under 12 years of age. The labeling of the product states all of the warnings in paragraphs (a)(2)(iii)(A) through (a)(2)(iii)(C) of this section with the following modifications:
(A) The Stomach bleeding warning states “Stomach bleeding warning [heading in bold type]: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if the user [bullet] has had stomach ulcers or bleeding problems [bullet] takes a blood thinning (anticoagulant) or steroid drug [bullet] takes other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) [bullet] takes more or for a longer time than directed [bullet] is age 60 or older [bullet] has 3 or more alcoholic drinks everyday while using this product”. The “Stomach bleeding” warning must appear after the “Reye's syndrome“ and “Allergy alert” warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and immediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit.
(B) The labeling states “Ask a doctor before use if [bullet] stomach bleeding warning applies to user [bullet] user has history of stomach problems, such as heartburn [bullet] user has high blood pressure, heart disease, liver cirrhosis, or kidney disease [bullet] user takes a diuretic [bullet] user has not been drinking fluids [bullet] user has lost a lot of fluid due to vomiting or diarrhea”.
(C) The labeling states “Stop use and ask a doctor if [bullet] user experiences any of the following signs of stomach bleeding:” [add the following as second level of statements: [bullet] feels faint [bullet] vomits blood [bullet] has bloody or black stools [bullet] has stomach pain that does not get better”].
(b) New warnings information statement. The labeling of any drug product subject to this section that is initially introduced or initially delivered for introduction into interstate commerce before or on April 29, 2010, must bear on its PDP, as defined in § 201.60, the statement “See new warnings information”. This statement must appear highlighted (e.g., fluorescent or color contrast) or in bold type, be in lines generally parallel to the base on which the package rests as it is designed to be displayed, and be in one of the following sizes, whichever is greater:
(1) At least one-quarter as large as the size of the most prominent printed matter on the PDP, or
(2) At least as large as the size of the “Drug Facts” title, as required in § 201.66(d)(2). The new warnings information statement must remain on the PDP of the drug product for at least 1 year from the date the product is initially introduced into interstate commerce.
(c) Requirements to supplement approved application. Holders of approved applications for OTC drug products that contain internal analgesic/antipyretic active ingredients that are subject to the requirements of paragraph (a) of this section must submit supplements under § 314.70(c) of this chapter to include the required information in the product's labeling. Such labeling may be put into use without advance approval of FDA provided it includes at least the exact information included in paragraph (a) of this section.
§ 201.327   Over-the-counter sunscreen drug products; required labeling based on effectiveness testing.
The following provisions apply to sunscreen products containing aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, oxybenzone, padimate O, sulisobenzone, titanium dioxide, trolamine salicylate, or zinc oxide, alone or in combination. The provisions do not apply to sunscreen products marketed under approved new drug applications or abbreviated new drug applications.
(a) Principal display panel. In addition to the statement of identity in paragraph (b) of this section, the following labeling shall be prominently placed on the principal display panel:
(1) Effectiveness claim —(i) For products that pass the broad spectrum test in paragraph (j) of this section. (A) The labeling states “Broad Spectrum SPF [insert numerical SPF value resulting from testing under paragraph (i) of this section]”.
(B) Prominence. The Broad Spectrum SPF statement shall appear as continuous text with no intervening text or graphic. The entire text shall appear in the same font style, size, and color with the same background color.
(ii) For sunscreen products that do not pass the broad spectrum test in paragraph (j) of this section. The labeling states “SPF [insert numerical SPF value resulting from testing under paragraph (i) of this section]”. The entire text shall appear in the same font style, size, and color with the same background color.
(2) Water resistance statements —(i) For products that provide 40 minutes of water resistance according to the test in paragraph (i)(7)(i) of this section. The labeling states “Water Resistant (40 minutes)”.
(ii) For products that provide 80 minutes of water resistance according to the test in paragraph (i)(7)(ii) of this section. The labeling states “Water Resistant (80 minutes)”.
(b) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the drug as a “sunscreen.”
(c) Indications. The labeling of the product states, under the heading “Uses,” the phrases listed in this paragraph (c), as appropriate. Other truthful and nonmisleading statements, describing only the uses that have been established and listed in this paragraph (c), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) relating to misbranding and the prohibition in section 301(d) of the FD&C Act against the introduction or delivery for introduction into interstate commerce of unapproved new drugs in violation of section 505(a) of the FD&C Act.
(1) For all sunscreen products, the following indication statement must be included under the heading “Uses”: “[Bullet] helps prevent sunburn”. See § 201.66(b)(4) of this chapter for definition of bullet.
(2) For sunscreen products with a Broad Spectrum SPF value of 15 or higher according to the tests in paragraphs (i) and (j) of this section, the labeling may include the following statement in addition to the indication in § 201.327(c)(1): “[Bullet] if used as directed with other sun protection measures (see Directions [in bold italic font]), decreases the risk of skin cancer and early skin aging caused by the sun”.
(3) Any labeling or promotional materials that suggest or imply that the use, alone, of any sunscreen reduces the risk of or prevents skin cancer or early skin aging will cause the product to be misbranded under section 502 of the FD&C Act (21 U.S.C. 352).
(d) Warnings. The labeling of the product contains the following warnings under the heading “Warnings”.
(1) For all sunscreen products. (i) The labeling states “Do not use [bullet] on damaged or broken skin”.
(ii) The labeling states “When using this product [bullet] keep out of eyes. Rinse with water to remove.”
(iii) The labeling states “Stop use and ask a doctor if [bullet] rash occurs”.
(2) For sunscreen products that are broad spectrum with SPF values of at least 2 but less than 15 according to the SPF test in paragraph (i) of this section or that do not pass the broad spectrum test in paragraph (j) of this section. The first statement under the heading “Warnings” states “Skin Cancer/Skin Aging Alert [in bold font]; Spending time in the sun increases your risk of skin cancer and early skin aging. This product has been shown only to help prevent sunburn, not [in bold font] skin cancer or early skin aging.”
(e) Directions. The labeling of the product contains the following statements, as appropriate, under the heading “Directions.” More detailed directions applicable to a particular product formulation may also be included.
(1) For all sunscreen products. (i) As an option, the labeling may state “For sunscreen use:”.
(ii) The labeling states “[bullet] apply [select one of the following: ‘Liberally’ or ‘generously’] [and, as an option: ‘And evenly’] 15 minutes before sun exposure”.
(iii) As an option, the labeling may state “[bullet] apply to all skin exposed to the sun”.
(iv) The labeling states “[bullet] children under 6 months of age: Ask a doctor”.
(2) For sunscreen products with a Broad Spectrum SPF value of 15 or higher according to the tests in paragraphs (i) and (j) of this section. The labeling states “[bullet] Sun Protection Measures. [in bold font] Spending time in the sun increases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with a Broad Spectrum SPF value of 15 or higher and other sun protection measures including: [Bullet] limit time in the sun, especially from 10 a.m.-2 p.m. [bullet] wear long-sleeved shirts, pants, hats, and sunglasses”.
(3) For products that satisfy the water resistance test in paragraph (i)(7) of this section. The labeling states “[bullet] reapply: [Bullet] after [select one of the following determined by water resistance test: ‘40 minutes of’ or ‘80 minutes of’] swimming or sweating [bullet] immediately after towel drying [bullet] at least every 2 hours”.
(4) For products that do not satisfy the water resistance test in paragraph (i)(7) of this section. The labeling states “[bullet] reapply at least every 2 hours [bullet] use a water resistant sunscreen if swimming or sweating”.
(f) Other information. The labeling of the product contains the following statement under the heading “Other information:” “[bullet] protect the product in this container from excessive heat and direct sun”.
(g) False and misleading claims. There are claims that would be false and/or misleading on sunscreen products. These claims include but are not limited to the following: “Sunblock,” “sweatproof,” and “waterproof.” These or similar claims will cause the product to be misbranded under section 502 of the FD&C Act (21 U.S.C. 352).
(h) Labeling of products containing a combination of sunscreen and skin protectant active ingredients. Statements of identity, indications, warnings, and directions for use, respectively, applicable to each ingredient in the product may be combined to eliminate duplicative words or phrases so that the resulting information is clear and understandable. Labeling provisions in § 347.50(e) of this chapter shall not apply to these products.
(i) SPF test procedure —(1) UV source (solar simulator). (i) Emission spectrum. A single port or multiport solar simulator should be filtered so that it provides a continuous emission spectrum from 290 to 400 nanometers (nm) with a limit of 1,500 Watts per square meter (W/m 2 ) on total irradiance for all wavelengths between 250 and 1,400 nm.
(A) The solar simulator should have the following percentage of erythema-effective radiation in each specified range of wavelengths:
Solar Simulator Emission Spectrum
1 Calculation of erythema action spectrum described in § 201.327(i)(1)(ii) of this section.
(B) In addition, UVA II (320-340 nm) irradiance should equal or exceed 20 percent of the total UV (290-400 nm) irradiance. UVA I (340-400 nm) irradiance should equal or exceed 60 percent of the total UV irradiance.
(ii) Erythema action spectrum. (A) Calculate the erythema action spectrum weighting factor (V i ) at each wavelength λ:
( 1 ) V i (λ) = 1.0 (250 <λ ≤298 nm)
( 2 ) V i (λ) = 10 0.094 * ( 298 −λ) (298 <λ ≤328 nm)
( 3 ) V i (λ) = 10 0.015 * ( 140 −λ) (328 <λ ≤400 nm)
(B) Calculate the erythema-effective UV dose (E) delivered by a solar simulator as follows:
(C) The emission spectrum must be determined using a handheld radiometer with a response weighted to match the spectrum in ISO 17166 CIE S 007/E entitled “Erythemal reference action spectrum and standard erythema dose,” dated 1999 (First edition, 1999-12-15; corrected and reprinted 2000-11-15), which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy from the ISO Copyright Office, Case Postale 56, CH-1211, Geneva 20, Switzerland, telephone +41-22-749-01-11 or fax +41-22-74-09-47. http://www.iso.org. You may inspect a copy at the Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993, call 301-796-2090, or at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, call 202-741-6030, or go to: http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html. The solar simulator output should be measured before and after each phototest or, at a minimum, at the beginning and end of each test day. This radiometer should be calibrated using side-by-side comparison with the spectroradiometer (using the weighting factors determined according to paragraph (i)(1)(ii)(A) of this section) at the time of the annual spectroradiometric measurement of the solar simulator as described in paragraph (i)(1)(iv) of this section.
(iii) Operation. A solar simulator should have no significant time-related fluctuations (within 20 percent) in radiation emissions after an appropriate warm-up time and demonstrate good beam uniformity (within 20 percent) in the exposure plane. The delivered dose to the UV exposure site must be within 10 percent of the expected dose.
(iv) Periodic measurement. To ensure that the solar simulator delivers the appropriate spectrum of UV radiation, the emission spectrum of the solar simulator should be measured at least annually with an appropriate and accurately calibrated spectroradiometer system (results should be traceable to the National Institute for Standards and Technology). In addition, the solar simulator must be recalibrated if there is any change in the lamp bulb or the optical filtering components ( i.e., filters, mirrors, lenses, collimating devices, or focusing devices). Daily solar simulator radiation intensity should be monitored with a broadband radiometer with a response weighted to match the erythema action spectrum in ISO 17166 CIE S 007/E entitled “Erythemal reference action spectrum and standard erythema dose,” which is incorporated by reference in paragraph (i)(1)(ii)(C) of this section. If a lamp must be replaced due to failure or aging during a phototest, broadband device readings consistent with those obtained for the original calibrated lamp will suffice until measurements can be performed with the spectroradiometer at the earliest possible opportunity.
(2) SPF standard —(i) Preparation. The SPF standard should be a formulation containing 7-percent padimate O and 3-percent oxybenzone.
Composition of the Padimate O/oxybenzone SPF Standard
1 Quantity sufficient to make 100 grams.
Step 1. Add the ingredients of Part A into a suitable stainless steel kettle equipped with a propeller agitator. Mix at 77 to 82 °C until uniform.
Step 2. Add the water of Part B into a suitable stainless steel kettle equipped with a propeller agitator and begin mixing at 77 to 82 °C. Add the remaining ingredients of Part B and mix until uniform.
Step 3. Add the batch of Step 1 to the batch of Step 2 and mix at 77 to 82 °C until smooth and uniform. Slowly cool the batch to 49 to 54 °C.
Step 4. Add the benzyl alcohol of Part C to the batch of Step 3 at 49 to 54 °C. Mix until uniform. Continue to cool batch to 35 to 41 °C.
Step 5. Add sufficient water of Part D to the batch of Step 4 at 35 to 41 °C to obtain 100 grams of SPF standard. Mix until uniform. Cool batch to 27 to 32 °C.
(ii) HPLC assay. Use the following high performance liquid chromatography (HPLC) procedure to verify the concentrations of padimate O and oxybenzone in the SPF standard:
(A) Instrumentation. ( 1 ) Equilibrate a suitable liquid chromatograph to the following or equivalent conditions:
( 2 ) Use HPLC grade reagents for mobile phase.
(B) Preparation of the HPLC reference standard. ( 1 ) Weigh 0.50 gram (g) of oxybenzone USP reference standard into a 250-mL volumetric flask. Dissolve and dilute to volume with isopropanol. Mix well.
( 2 ) Weigh 0.50 g of padimate O USP reference standard into a 250-mL volumetric flask. Dissolve and dilute to volume with isopropanol. Mix well.
( 3 ) Pipet 3.0 mL of the oxybenzone solution and 7.0 mL of the padimate O solution into a 100-mL volumetric flask. Dilute to volume with isopropanol and mix well.
(C) HPLC system suitability. ( 1 ) Make three replicate 10-microliter injections of the HPLC reference standard (described in paragraph (i)(2)(ii)(B) of this section). The relative standard deviation in peak areas should not be more than 2.0 percent for either oxybenzone or padimate O.
( 2 ) Calculate the resolution (R) between the oxybenzone and padimate O peaks from one chromatogram as follows:
(D) SPF standard assay —( 1 ) The SPF standard is diluted to the same concentration as the HPLC reference standard according to the following steps:
( i ) Step 1. Weigh 1.0 g of the SPF standard (described in paragraph (i)(2)(i) of this section) into a 50-mL volumetric flask.
( ii ) Step 2. Add approximately 30 mL of isopropanol and heat with swirling until contents are evenly dispersed.
( iii ) Step 3. Cool to room temperature (15 to 30 °C) and dilute to volume with isopropanol. Mix well.
( iv ) Step 4. Pipet 5.0 mL of the preparation into a 50-mL volumetric flask and dilute to volume with isopropanol. Mix well.
( 2 )( i ) Inject 10-microliter of diluted SPF standard from paragraph (i)(2)(D)( 1 ) of this section and calculate the amount of oxybenzone and padimate O as follows:
( ii ) The percent of oxybenzone and padimate O in the SPF standard should be between 95 and 105.
(3) Test subjects —(i) Number of subjects. A test panel should include enough subjects to produce a minimum of 10 valid test results. A maximum of three subjects may be rejected from this panel based on paragraph (i)(5)(v)) of this section.
(ii) Medical history. (A) Obtain a medical history from each subject with emphasis on the effects of sunlight on the subject's skin. Determine that each subject is in good general health with skin type I, II, or III as follows:
( 1 ) Always burns easily; never tans (sensitive).
( 2 ) Always burns easily; tans minimally (sensitive).
( 3 ) Burns moderately; tans gradually (light brown) (normal).
( 4 ) Burns minimally; always tans well (moderate brown) (normal).
( 5 ) Rarely burns; tans profusely (dark brown) (insensitive).
( 6 ) Never burns; deeply pigmented (insensitive).
(B) Skin type is based on first 30 to 45 minutes of sun exposure after a winter season of no sun exposure. Determine that each subject is not taking topical or systemic medication that is known to alter responses to UV radiation. Determine that each subject has no history of sensitivities to topical products and/or abnormal responses to sunlight, such as a phototoxic or photoallergic response.
(iii) Physical examination. Conduct a physical examination to determine the presence of sunburn, suntan, scars, active dermal lesions, and uneven skin tones on the areas of the back to be tested. A suitable source of low power UVA, such as a Woods lamp, is helpful in this process. If any of these conditions are present, the subject is not qualified to participate in the study. The presence of nevi, blemishes, or moles will be acceptable if, in the physician's judgment, they will neither compromise the study nor jeopardize a subject's safety. Subjects with dysplastic nevi should not be enrolled. Excess hair on the back is acceptable if the hair is clipped. Shaving is unacceptable because it may remove a significant portion of the stratum corneum and temporarily alter the skin's response to UV radiation.
(iv) Informed consent. Obtain legally effective written informed consent from all test subjects.
(4) Sunscreen application. (i) Test site. Test sites are locations on each subject's back, between the beltline and the shoulder blades (scapulae) and lateral to the midline, where skin responses to UV radiation are determined. Responses on unprotected skin (no test material applied) and protected skin (sunscreen test product(s) or SPF standard applied) are determined at separate unprotected and protected test sites, respectively. Test sites should be randomly located in a blinded manner. Each test site should be a minimum of 30 square centimeters and outlined with indelible ink.
(ii) Test subsite. Test subsites are the locations to which UV radiation is administered within a test site. At least five test subsites should receive UV doses within each test site. Test subsites should be at least 0.5 square centimeters (cm 2 ) in area and should be separated from each other by at least 0.8 cm. Each test subsite should be outlined with indelible ink.
(iii) Applying test materials. Apply the sunscreen test product and the SPF standard at 2 milligrams per square centimeter (mg/cm 2 ) to their respective test sites. Use a finger cot compatible with the sunscreen to spread the product as evenly as possible.
(iv) Waiting period. Wait at least 15 minutes after applying a sunscreen product before exposing the test sites to UV radiation as described in paragraph (i)(5)) of this section. For water resistant sunscreen products, proceed with the water resistance testing procedure described in paragraph (i)(7) of this section after waiting at least 15 minutes.
(5) UV exposure —(i) Definition of minimal erythema dose (MED). The minimal erythema dose (MED) is the smallest UV dose that produces perceptible redness of the skin (erythema) with clearly defined borders at 16 to 24 hours after UV exposure. The MED for unprotected skin (MED u ) is determined on a test site that does not have sunscreen applied. The MED for protected skin (MED p ) is determined on a test site that has sunscreen applied. An MED p is determined for the SPF standard (ssMED p ). An MED p is determined for the sunscreen test product (tpMED p ).
(ii) UV exposure for initial MED u . For each test subject, administer a series of UV radiation doses expressed as J/m 2 -eff (as determined according to paragraph (a)(2) of this section) to the test subsites within an unprotected test site using an accurately calibrated solar simulator. Select doses that are a geometric series represented by 1.25 n ( i.e., each dose is 25 percent greater than the previous dose).
(iii) UV exposure for final MED u , ssMED p , and tpMED p . For each subject, determine the final MED u , ssMED p , and tpMED p by administering a series of five UV doses to the appropriate test sites. The middle dose (X) in each of these dose series ( i.e., the third dose) should equal the initial MED u times the expected SPF. Note that the expected SPF equals 1 and 16.3 for the final MED u and ssMED p , respectively. The remaining UV doses in the series depend upon the expected SPF value of the sunscreen test product(s).
For products with an expected SPF less than 8, administer UV doses that increase by 25 percent with each successive dose ( i.e., 0.64X, 0.80X, 1.00X, 1.25X, and 1.56X). For products with an expected SPF from 8 to 15, administer UV doses that increase by 20 percent with each successive dose ( i.e., 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X). For products with an expected SPF higher than 15, administer UV doses that increase by 15 percent with each successive dose ( i.e., 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X).
(iv) Evaluation of test subsites. In order that the person who evaluates the test subsites is not biased, he/she should not be the same person who applied the sunscreen drug product to the test site or administered the UV doses. After UV doses are administered, all immediate responses should be recorded. These may include an immediate darkening or tanning, typically grayish or purplish in color, which fades in 30 to 60 minutes; an immediate reddening at the subsite, due to heating of the skin, which fades rapidly; and an immediate generalized heat response, spreading beyond the subsite, which fades in 30 to 60 minutes. After the immediate responses are noted, each subject should shield the exposed area from further UV radiation until the MED is determined. Determine the MED 16 to 24 hours after UV exposure. Because erythema is evaluated 16 to 24 hours after UV exposure, the final MED u , ssMED p , and tpMED p are typically determined the day following determination of the initial MED u . Evaluate the erythema responses of each test subsite using either tungsten or warm white fluorescent lighting that provides at least 450 lux of illumination at the test site. For the evaluation, the test subject should be in the same position as when the test site was irradiated.
(v) Invalid test data. Reject test data for a test subject if erythema is not present on either the unprotected or protected test sites; or erythema is present at all subsites; or the responses are inconsistent with the series of UV doses administered; or the subject was noncompliant (e.g., the subject withdraws from the test due to illness or work conflicts or does not shield the exposed testing sites from further UV radiation until the MED is determined).
(6) Determination of SPF. (i) Calculate an SPF value for each test subject (SPF i ) as follows:
(ii) Calculate the mean
(7) Determination of water resistance. The following procedure should be performed in an indoor fresh water pool, whirlpool, and/or hot tub maintained at 23 to 32 °C. Fresh water is clean drinking water that meets the standards in 40 CFR part 141. The pool and air temperature and the relative humidity should be recorded.
(i) Water resistance (40 minutes). The labeled SPF should be determined after 40 minutes of water immersion using the following procedure:
(A) Step 1: Apply the sunscreen as described in paragraph (d) of this section.
(B) Step 2: Perform moderate activity in water for 20 minutes.
(C) Step 3: Rest out of water for 15 minutes. Do not towel test site(s).
(D) Step 4: Perform moderate activity in water for 20 minutes.
(E) Step 5: Allow test sites to dry completely without toweling.
(F) Step 6: Apply the SPF standard as described in paragraph (d) of this section.
Step 1. Expose test sites to UV doses as described in paragraph (e) of this section.
(ii) Water resistance (80 minutes). The labeled SPF should be determined after 80 minutes of water immersion using the following procedure:
(A) Step 1: Apply the sunscreen as described in paragraph (d) of this section.
(B) Step 2: Perform moderate activity in water for 20 minutes.
(C) Step 3: Rest out of water for 15 minutes. Do not towel test site(s).
(D) Step 4: Perform moderate activity in water for 20 minutes.
(E) Step 5: Rest out of water for 15 minutes. Do not towel test site(s).
(F) Step 6: Perform moderate activity in water for 20 minutes.
(G) Step 7: Rest out of water for 15 minutes. Do not towel test site(s).
(H) Step 8: Perform moderate activity in water for 20 minutes.
(I) Step 9: Allow test sites to dry completely without toweling.
(J) Step 10: Apply the SPF standard as described in paragraph (d) of this section.
(K) Step 11: Expose test sites to UV doses as described in paragraph (e) of this section.
(j) Broad spectrum test procedure —(1) UV Spectrometry. (i) Plate. Use optical-grade polymethylmethacrylate (PMMA) plates suitable for UV transmittance measurements. The plate should be roughened on one side to a three dimensional surface topography measure (Sa) between 2 and 7 micrometers and must have a rectangular application area of at least 16 square centimeters (with no side shorter than 4 cm).
(ii) Sample holder. The sample holder should hold the PMMA plate in a horizontal position to avoid flowing of the sunscreen drug product from one edge of the PMMA plate to the other. It should be mounted as close as possible to the input optics of the spectrometer to maximize capture of forward scattered radiation. The sample holder should be a thin, flat plate with a suitable aperture through which UV radiation can pass. The PMMA plate should be placed on the upper surface of the sample holder with the roughened side facing up.
(iii) Light source. The light source should produce a continuous spectral distribution of UV radiation from 290 to 400 nanometers.
(iv) Input optics. Unless the spectrometer is equipped with an integrating sphere, an ultraviolet radiation diffuser should be placed between the sample and the input optics of the spectrometer. The diffuser will be constructed from any UV radiation transparent material (e.g., Teflon ® or quartz). The diffuser ensures that the radiation received by the spectrometer is not collimated. The spectrometer input slits should be set to provide a bandwidth that is less than or equal to 1 nanometer.
(v) Dynamic range of the spectrometer. The dynamic range of the spectrometer should be sufficient to measure transmittance accurately through a highly absorbing sunscreen product at all terrestrial solar UV wavelengths (290 to 400 nm).
(2) Sunscreen product application to PMMA plate. The accuracy of the test depends upon the application of a precisely controlled amount of sunscreen product with a uniform distribution over the PMMA plate. The product is applied at 0.75 mg per square centimeter to the roughened side of the PMMA plate. The sunscreen product should be applied in a series of small dots over the entire PMMA plate and then spread evenly using a gloved finger. Spreading should be done with a very light spreading action for approximately 30 seconds followed by spreading with greater pressure for approximately 30 seconds. The plate should then be allowed to equilibrate for 15 minutes in the dark before the pre-irradiation described in paragraph (c) of this section.
(3) Sunscreen product pre-irradiation. To account for lack of photostability, apply the sunscreen product to the PMMA plate as described in paragraph (b) of this section and then irradiate with a solar simulator described in section 352.70(b) of this chapter. The irradiation dose should be 4 MEDs which is equivalent to an erythemal effective dose of 800 J/m 2 ( i.e., 800 J/m 2 -eff).
(4) Calculation of mean transmittance values. After pre-irradiation described in paragraph (c) of this section, mean transmittance values should be determined for each wavelength λ over the full UV spectrum (290 to 400 nanometers). The transmittance values should be measured at 1 nanometer intervals. Measurements of spectral irradiance transmitted for each wavelength λ through control PMMA plates coated with 15 microliters of glycerin (no sunscreen product) should be obtained from at least 5 different locations on the PMMA plate [C1(λ), C2(λ), C3(λ), C4(λ), and C5(λ)]. In addition, a minimum of 5 measurements of spectral irradiance transmitted for each wavelength λ through the PMMA plate covered with the sunscreen product will be similarly obtained after pre-irradiation of the sunscreen product [P1(λ), P2(λ), P3(λ), P4(λ), and P5(λ)].
The mean transmittance for each wavelength,
(5) Calculation of mean absorbance values. (i) Mean transmittance values,
(ii) The calculation yields 111 monochromatic absorbance values in 1 nanometer increments from 290 to 400 nanometers.
(6) Number of plates. For each sunscreen product, mean absorbance values should be determined from at least three individual PMMA plates. Because paragraph (d) of this section requires at least 5 measurements per plate, there should be a total of at least 15 measurements.
(7) Calculation of the critical wavelength. The critical wavelength is identified as the wavelength at which the integral of the spectral absorbance curve reaches 90 percent of the integral over the UV spectrum from 290 to 400 nm. The following equation defines the critical wavelength:
§ 201.328   Labeling of medical gas containers.
(a) Portable cryogenic medical gas containers. For the purposes of this section a “portable cryogenic medical gas container” is one that is capable of being transported and is intended to be attached to a medical gas supply system within a hospital, health care entity, nursing home, other facility, or home health care setting, or is a base unit used to fill small cryogenic gas containers for use by individual patients. The term does not include cryogenic containers that are not designed to be connected to a medical gas supply system, e.g., tank trucks, trailers, rail cars, or small cryogenic gas containers for use by individual patients (including portable liquid oxygen units as defined at § 868.5655 of this chapter).
(1) Each portable cryogenic medical gas container must be conspicuously marked with a 360° wraparound label identifying its contents. Such label must meet the requirements of § 211.94(e)(2) of this chapter and the following additional requirements.
(i) If the container holds a single gas, the name of the gas held in the container must be printed on the label in one of the following ways:
(A) Using lettering that appears in the color designated for the gas in paragraph (c) of this section and that is printed against a white background, or
(B) Using lettering that appears in white against a background that is painted in the color for the gas designated in paragraph (c) of this section.
(ii) The lettering for the name of the gas on the label must be at least 2 inches high.
(iii) The name of the gas must be printed continuously around the label and be capable of being read around the entire container.
(iv) The label must be on the sidewall of the container, as close to the top of the container as possible but below the top weld seam.
(v) A portable cryogenic medical gas container may only be colored in the color or colors designated in paragraph (c) of this section if the gas or gases held within the container correspond to that color or those colors.
(2) A label on the container (either the 360° wraparound label required in paragraph (a)(1) of this section or a separate label) must include, in conspicuous lettering, the phrase “For Medical Use”, “Medical Gas,” or some similar phrase that indicates the gas is for medical use.
(b) High-pressure medical gas cylinders. Each high-pressure medical gas cylinder must be colored on the shoulder portion of the cylinder in the color or colors designated in paragraph (c) of this section. The color or colors must be visible when viewed from the top of cylinder.
(c) Medical gas colors. The colors required to identify medical gases under paragraph (a) and (b) of this section are: