Title 21—Food and Drugs--Volume 1
PART 201—LABELING
§ 201.1   Drugs; name and place of business of manufacturer, packer, or distributor.
(a) A drug or drug product (as defined in § 320.1 of this chapter) in finished package form is misbranded under section 502 (a) and (b)(1) of the act if its label does not bear conspicuously the name and place of business of the manufacturer, packer, or distributor. This paragraph does not apply to any drug or drug product dispensed in accordance with section 503(b)(1) of the act.
(b) As used in this section, and for purposes of section 502 (a) and (b)(1) of the act, the manufacturer of a drug product is the person who performs all of the following operations that are required to produce the product: (1) Mixing, (2) granulating, (3) milling, (4) molding, (5) lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9) sterilizing, and (10) filling sterile, aerosol, or gaseous drugs into dispensing containers.
(c) If no person performs all of the applicable operations listed in paragraph (b) of this section, no person may be represented as manufacturer except as follows:
(1) If the person performs more than one half of the applicable operations listed in paragraph (b) of this section and acknowledges the contribution of other persons who have performed the remaining applicable operations by stating on the product label that “Certain manufacturing operations have been performed by other firms.”; or
(2) If the person performs at least one applicable operation listed in paragraph (b) of this section and identifies by appropriate designation all other persons who have performed the remaining applicable operations, e.g., “Made by (Person A), Filled by (Person B), Sterilized by (Person C)”; or
(3) If the person performs at least one applicable operation listed in paragraph (b) of this section and the person is listed along with all other persons who have performed the remaining applicable operations as “joint manufacturers.” A list of joint manufacturers shall be qualified by the phrase “Jointly Manufactured By ______,” and the names of all of the manufacturers shall be printed together in the same type size and style; or
(4) If the person performs all applicable operations listed in paragraph (b) of this section except for those operations listed in paragraph (d) of this section. For purposes of this paragraph, person, when it identifies a corporation, includes a parent, subsidiary, or affiliate company where the related companies are under common ownership and control.
(d) The Food and Drug Administration finds that it is the common practice in the drug industry to contract out the performance of certain manufacturing operations listed in paragraph (b) of this section. These operations include: (1) Soft-gelatin encapsulating, (2) aerosol filling, (3) sterilizing by irradiation, (4) lyophilizing, and (5) ethylene oxide sterilization.
(e) A person performs an operation listed in paragraph (b) of this section only if the operation is performed, including the performance of the appropriate in-process quality control operations, except laboratory testing of samples taken during processing, as follows:
(1) By individuals, a majority of whom are employees of the person and, throughout the performance of the operation, are subject to the person's direction and control;
(2) On premises that are continuously owned or leased by the person and subject to the person's direction and control; and
(3) On equipment that is continuously owned or leased by the person. As used in this paragraph, person, when it identifies a corporation, includes a parent, subsidiary, or affiliate company where the related companies are under common ownership and control.
(f) The name of the person represented as manufacturer under paragraph (b) or (c) of this section must be the same as either (1) the name of the establishment (as defined in § 207.1 of this chapter) under which that person is registered at the time the labeled product is produced or (2) the registered establishment name of a parent, subsidiary, or affiliate company where the related companies are under common ownership and control. In addition, the name shall meet the requirements of paragraph (g) of this section.
(g) The requirement for declaration of the name of the manufacturer, packer, or distributor shall be deemed to be satisfied, in the case of a corporate person, only by the actual corporate name, except that the corporate name may be the name of a parent, subsidiary, or affiliate company where the related companies are under common ownership and control. The corporate name may be preceded or followed by the name of the particular division of the corporation. “Company,” “Incorporated,” etc., may be abbreviated or omitted and “The” may be omitted. In the case of an individual, partnership, or association, the name under which the business is conducted shall be used.
(h)(1) Except as provided in this section, no person other than the manufacturer, packer, or distributor may be identified on the label of a drug or drug product.
(2) The appearance on a drug product label of a person's name without qualification is a representation that the named person is the sole manufacturer of the product. That representation is false and misleading, and the drug product is misbranded under section 502(a) of the act, if the person is not the manufacturer of the product in accordance with this section.
(3) If the names of two or more persons appear on the label of a drug or drug product, the label may identify which of the persons is to be contacted for further information about the product.
(4) If a trademark appears on the drug or drug product label or appears as a mark directly on the drug product (e.g., tablet or capsule), the label may identify the holder or licensee of the trademark. The label may also state whether the person identified holds the trademark or is licensee of the trademark.
(5) If the distributor is named on the label, the name shall be qualified by one of the following phrases: “Manufactured for ______”, “Distributed by ______”, “Manufactured by ______ for ______”, “Manufactured for _____by _____”, “Distributor: ______”, “Marketed by ______”. The qualifying phrases may be abbreviated.
(6) If the packer is identified on the label, the name shall be qualified by the phrase “Packed by ______” or “Packaged by ______”. The qualifying phrases may be abbreviated.
(i) The statement of the place of business shall include the street address, city, State, and ZIP Code. For a foreign manufacturer, the statement of the place of business shall include the street address, city, country, and any applicable mailing code. The street address may be omitted if it is shown in a current city directory or telephone directory. The requirement for inclusion of the ZIP Code shall apply to consumer commodity labels developed or revised after July 1, 1969. In the case of nonconsumer packages, the ZIP Code shall appear either on the label or the labeling (including the invoice).
(j) If a person manufactures, packs, or distributes a drug or drug product at a place other than the person's principal place of business, the label may state the principal place of business in lieu of the actual place where such drug or drug product was manufactured or packed or is to be distributed, unless such statement would be misleading.
(k) Paragraphs (b), (c), (d), (e), and (f) of this section, do not apply to the labeling of drug components.
(l) A drug product is misbranded under section 502(a) of the act if its labeling identifies a person as manufacturer, packer, or distributor, and that identification does not meet the requirements of this section.
(m) This section does not apply to biological drug products that are subject to the requirements of section 351 of the Public Health Service Act, 42 U.S.C. 262.
§ 201.2   Drugs and devices; National Drug Code numbers.
The National Drug Code (NDC) number is requested but not required to appear on all drug labels and in all drug labeling, including the label of any prescription drug container furnished to a consumer.
§ 201.5   Drugs; adequate directions for use.
Adequate directions for use means directions under which the layman can use a drug safely and for the purposes for which it is intended. (Section 201.128 defines “intended use.”) Directions for use may be inadequate because, among other reasons, of omission, in whole or in part, or incorrect specification of:
(a) Statements of all conditions, purposes, or uses for which such drug is intended, including conditions, purposes, or uses for which it is prescribed, recommended, or suggested in its oral, written, printed, or graphic advertising, and conditions, purposes, or uses for which the drug is commonly used; except that such statements shall not refer to conditions, uses, or purposes for which the drug can be safely used only under the supervision of a practitioner licensed by law and for which it is advertised solely to such practitioner.
(b) Quantity of dose, including usual quantities for each of the uses for which it is intended and usual quantities for persons of different ages and different physical conditions.
(c) Frequency of administration or application.
(d) Duration of administration or application.
(e) Time of administration or application (in relation to time of meals, time of onset of symptoms, or other time factors).
(f) Route or method of administration or application.
(g) Preparation for use, i.e., shaking, dilution, adjustment of temperature, or, other manipulation or process.
§ 201.6   Drugs; misleading statements.
(a) Among representations in the labeling of a drug which render such drug misbranded is a false or misleading representation with respect to another drug or a device or a food or cosmetic.
(b) The labeling of a drug which contains two or more ingredients may be misleading by reason, among other reasons, of the designation of such drug in such labeling by a name which includes or suggests the name of one or more but not all such ingredients, even though the names of all such ingredients are stated elsewhere in the labeling.
§ 201.10   Drugs; statement of ingredients.
(a) The ingredient information required by section 502(e) of the Federal Food, Drug, and Cosmetic Act shall appear together, without any intervening written, printed, or graphic matter, except the proprietary names of ingredients, which may be included with the listing of established names, and such statements that are specifically required for certain ingredients by the act or regulations in this chapter.
(b) The term ingredient applies to any substance in the drug, whether added to the formulation as a single substance or in admixture with other substances.
(c) The labeling of a drug may be misleading by reason (among other reasons) of:
(1) The order in which the names of the ingredients present in the drug appear in the labeling, or the relative prominence otherwise given such names.
(2) Failure to reveal the proportion of, or other fact with respect to, an ingredient present in such drug, when such proportion or other fact is material in the light of the representation that such ingredient is present in such drug.
(3) The employment of a fanciful proprietary name for a drug or ingredient in such a manner as to imply that the drug or ingredient has some unique effectiveness or composition when, in fact, the drug or ingredient is a common substance, the limitations of which are readily recognized when the drug or ingredient is listed by its established name.
(4) The featuring in the labeling of inert or inactive ingredients in a manner that creates an impression of value greater than their true functional role in the formulation.
(5) Designation of a drug or ingredient by a proprietary name that, because of similarity in spelling or pronunciation, may be confused with the proprietary name or the established name of a different drug or ingredient.
(d)(1) If the drug is in tablet or capsule form or other unit dosage form, any statement of the quantity of an ingredient contained therein shall express the quantity of such ingredient in each such unit. If the drug is not in unit dosage form, any statement of the quantity of an ingredient contained therein shall express the amount of such ingredient in a specified unit of weight or measure of the drug, or the percentage of such ingredient in such drug. Such statements shall be in terms that are informative to licensed practitioners, in the case of a prescription drug, and to the layman, in the case of a nonprescription drug.
(2) A statement of the percentage of an ingredient in a drug shall, if the term percent is used without qualification, mean percent weight-in-weight, if the ingredient and the drug are both solids, or if the ingredient is a liquid and the drug is a solid; percent weight in volume at 68 °F. (20 °C.), if the ingredient is a solid and the drug is a liquid; and percent volume in volume at 68 °F. (20 °C.), if both the ingredient and the drug are liquids, except that alcohol shall be stated in terms of percent volume of absolute alcohol at 60 °F. (15.56 °C.).
(e) A derivative or preparation of a substance named in section 502(e) of the act is an article derived or prepared from such substance by any method, including actual or theoretical chemical action.
(f) If an ingredient is a derivative or preparation of a substance specifically named in section 502(e) of the act and the established name of such ingredient does not indicate that it is a derivative or preparation of the parent substance named in section 502(e) of the act, the labeling shall, in conjunction with the listing of the established name of such ingredient, declare that such article is a derivative or preparation of such parent substance.
(g)(1) If the label or labeling of a prescription drug bears a proprietary name or designation for the drug or any ingredient thereof, the established name, if such there be, corresponding to such proprietary name or designation shall accompany such proprietary name or designation each time it is featured on the label or in the labeling for the drug; but, except as provided in this subparagraph, the established name need not be used with the proprietary name or designation in the running text of the label or labeling. On any label or page of labeling in which the proprietary name or designation is not featured but is used in the running text, the established name shall be used at least once in the running text in association with such proprietary name or designation and in the same type size used in such running text: Provided, however, That if the proprietary name or designation is used in the running text in larger size type, the established name shall be used at least once in association with, and in type at least half as large as the type used for, the most prominent presentation of the proprietary name or designation in such running text. If any labeling includes a column with running text containing detailed information as to composition, prescribing, side effects, or contraindications and the proprietary name or designation is used in such column but is not featured above or below the column, the established name shall be used at least once in such column of running text in association with such proprietary name or designation and in the same type size used in such column of running text: Provided, however, That if the proprietary name or designation is used in such column of running text in larger size type, the established name shall be used at least once in association with, and in type at least half as large as the type used for, the most prominent presentation of the proprietary name or designation in such column of running text. Where the established name is required to accompany or to be used in association with the proprietary name or designation, the established name shall be placed in direct conjunction with the proprietary name or designation, and the relationship between the proprietary name or designation and the established name shall be made clear by use of a phrase such as “brand of” preceding the established name, by brackets surrounding the established name, or by other suitable means.
(2) The established name shall be printed in letters that are at least half as large as the letters comprising the proprietary name or designation with which it is joined, and the established name shall have a prominence commensurate with the prominence with which such proprietary name or designation appears, taking into account all pertinent factors, including typography, layout, contrast, and other printing features.
(h)(1) In the case of a prescription drug containing two or more active ingredients, if the label bears a proprietary name or designation for such mixture and there is no established name corresponding to such proprietary name or designation, the quantitative ingredient information required on the label by section 502(e) of the act shall be placed in direct conjunction with the most prominent display of the proprietary name or designation. The prominence of the quantitative ingredient information shall bear a reasonable relationship to the prominence of the proprietary name.
(2) If the drug is packaged in a container too small to bear the quantitative ingredient information on the main display panel, the quantitative ingredient information required by section 502(e) of the act may appear elsewhere on the label, even though the proprietary name or designation appears on the main display panel of the label; but side- or back-panel placement shall in this case be so arranged and printed as to provide size and prominence of display reasonably related to the size and prominence of the front-panel display.
(i) A drug packaged in a container too small or otherwise unable to accommodate a label with sufficient space to bear the information required for compliance with section 502(e)(1) (A)(ii) and (B) of the act shall be exempt from compliance with those clauses: Provided, That:
(1) The label bears:
(i) The proprietary name of the drug;
(ii) The established name, if such there be, of the drug;
(iii) An identifying lot or control number; and
(iv) The name of the manufacturer, packer, or distributor of the drug; and
(2) All the information required to appear on the label by the act and the regulations in this chapter appears on the carton or other outer container or wrapper if such carton, outer container, or wrapper has sufficient space to bear such information, or such complete label information appears on a leaflet with the package.
§ 201.15   Drugs; prominence of required label statements.
(a) A word, statement, or other information required by or under authority of the act to appear on the label may lack that prominence and conspicuousness required by section 502(c) of the act by reason, among other reasons, of:
(1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;
(2) The failure of such word, statement, or information to appear on two or more parts or panels of the label, each of which has sufficient space therefor, and each of which is so designed as to render it likely to be, under customary conditions of purchase, the part or panel displayed;
(3) The failure of the label to extend over the area of the container or package available for such extension, so as to provide sufficient label space for the prominent placing of such word, statement, or information;
(4) Insufficiency of label space for the prominent placing of such word, statement, or information, resulting from the use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;
(5) Insufficiency of label space for the prominent placing of such word, statement, or information, resulting from the use of label space to give materially greater conspicuousness to any other word, statement, or information, or to any design or device; or
(6) Smallness or style of type in which such word, statement, or information appears, insufficient background contrast, obscuring designs or vignettes, or crowding with other written, printed, or graphic matter.
(b) No exemption depending on insufficiency of label space, as prescribed in regulations promulgated under section 502 (b) or (e) of the act, shall apply if such insufficiency is caused by:
(1) The use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;
(2) The use of label space to give greater conspicuousness to any word, statement, or other information than is required by section 502(c) of the act; or
(3) The use of label space for any representation in a foreign language.
(c)(1) All words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.
(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.
(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear on the labeling in the foreign language.
§ 201.16   Drugs; Spanish-language version of certain required statements.
An increasing number of medications restricted to prescription use only are being labeled solely in Spanish for distribution in the Commonwealth of Puerto Rico where Spanish is the predominant language. Such labeling is authorized under § 201.15(c). One required warning, the wording of which is fixed by law in the English language, could be translated in various ways, from literal translation to loose interpretation. The statutory nature of this warning requires that the translation convey the meaning properly to avoid confusion and dilution of the purpose of the warning. Section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act requires, at a minimum, that the label bear the statement “Rx only.” The Spanish-language version of this must be “Solamente Rx”.
§ 201.17   Drugs; location of expiration date.
When an expiration date of a drug is required, e.g., expiration dating of drug products required by § 211.137 of this chapter, it shall appear on the immediate container and also the outer package, if any, unless it is easily legible through such outer package. However, when single-dose containers are packed in individual cartons, the expiration date may properly appear on the individual carton instead of the immediate product container.
§ 201.18   Drugs; significance of control numbers.
The lot number on the label of a drug should be capable of yielding the complete manufacturing history of the package. An incorrect lot number may be regarded as causing the article to be misbranded.
§ 201.19   Drugs; use of term “infant”.
The regulations affecting special dietary foods (§ 105.3(e) of this chapter) define an infant as a child not more than 12 months old. Apart from this, the Food and Drug Administration has not established any definition of the term infant. Some question has arisen whether, for the purposes of drug labeling, an infant means a child up to 1 year of age or a child up to 2 years of age. Until the term is more precisely defined by legislation or formal regulation, where the exact meaning of the term is significant, manufacturers should qualify any reference to “infant” to indicate whether it refers to a child who is not more than 1 year of age, or a child not more than 2 years of age.
§ 201.20   Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human use.
(a) The label for over-the-counter and prescription drug products intended for human use administered orally, nasally, rectally, or vaginally, or for use in the area of the eye, containing FD&C Yellow No. 5 as a color additive using the names FD&C Yellow No. 5 and tartrazine. The labeling for over-the-counter and prescription drug products shall bear a statement such as “Contains FD&C Yellow No. 5 (tartrazine) as a color additive” or “Contains color additives including FD&C Yellow No. 5 (tartrazine)”. The labels of certain drug products subject to this labeling requirement that are also cosmetics, such as antibacterial mouthwashes and fluoride toothpastes, need not comply with this requirement provided they comply with the requirements of § 701.3 of this chapter.
(b) For prescription drugs for human use containing FD&C Yellow No. 5 that are administered orally, nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by § 201.100(d) shall bear the warning statement “This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.” This warning statement shall appear in the “Precautions” section of the labeling.
(c) The label for over-the-counter drug products intended for human use administered orally, nasally, rectally, or vaginally containing FD&C Yellow No. 6 shall specifically declare the presence of FD&C Yellow No. 6 by listing the color additive using the name FD&C Yellow No. 6. The labeling for over-the-counter and prescription drug products containing FD&C Yellow No. 6 shall declare the presence of FD&C Yellow No. 6. The labels of certain drug products subject to this labeling requirement that are also cosmetics, such as antibacterial mouthwashes and fluoride toothpastes, need not comply with this requirement provided they comply with the requirements of § 701.3 of this chapter.
§ 201.21   Declaration of presence of phenylalanine as a component of aspartame in over-the-counter and prescription drugs for human use.
(a) Aspartame is the methylester of a dipeptide composed of two amino acids, phenylalanine and aspartic acid. When these two amino acids are so combined to form aspartame (1-methyl N -L-α-aspartyl-L-phenylalanine), they produce an intensely sweet-tasting substance, approximately 180 times as sweet as sucrose. The Food and Drug Administration has determined that aspartame when used at a level no higher than reasonably required to perform its intended technical function is safe for use as an inactive ingredient in human drug products, provided persons with phenylketonuria, who must restrict carefully their phenylalanine intake, are alerted to the presence of phenylalanine in the drug product and the amount of the ingredient in each dosage unit.
(b) The label and labeling of all over-the-counter human drug products containing aspartame as an inactive ingredient shall bear a statement to the following effect: Phenylketonurics: Contains Phenylalanine (_)mg Per (Dosage Unit).
(c) The package labeling and other labeling providing professional use information concerning prescription drugs for human use containing aspartame as an inactive ingredient shall bear a statement to the following effect under the “Precautions” section of the labeling, as required in § 201.57(f)(2): Phenylketonurics: Contains Phenylalanine (_)mg Per (Dosage Unit).
(d) Holders of approved new drug applications who reformulate their drug products under the provisions of this section shall submit supplements under § 314.70 of this chapter to provide for the new composition and the labeling changes.
§ 201.22   Prescription drugs containing sulfites; required warning statements.
(a) Sulfites are chemical substances that are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation of the active drug ingredient may result in instability and a loss of potency of the drug product. Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, and potassium metabisulfite. Recent studies have demonstrated that sulfites may cause allergic-type reactions in certain susceptible persons, especially asthmatics. The labeling for any prescription drug product to which sulfites have been added as an inactive ingredient, regardless of the amount added, must bear the warning specified in paragraph (b) or (c) of this section.
(b) The labeling required by §§ 201.57 and 201.100(d) for prescription drugs for human use containing a sulfite, except epinephrine for injection when intended for use in allergic or other emergency situations, shall bear the warning statement “Contains ( insert the name of the sulfite, e.g., sodium metabisulfite ), a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.” This statement shall appear in the “Warnings” section of the labeling.
(c) The labeling required by §§ 201.57 and 201.100(d) for sulfite-containing epinephrine for injection for use in allergic emergency situations shall bear the warning statement “Epinephrine is the preferred treatment for serious allergic or other emergency situations even though this product contains ( insert the name of the sulfite, e.g., sodium metabisulfite ), a sulfite that may in other products cause allergic-type reactions including anaphylactic symptoms or life-threatening or less severe asthmatic episodes in certain susceptible persons. The alternatives to using epinephrine in a life-threatening situation may not be satisfactory. The presence of a sulfite(s) in this product should not deter administration of the drug for treatment of serious allergic or other emergency situations.” This statement shall appear in the “Warnings” section of the labeling.
§ 201.23   Required pediatric studies.
(a) A manufacturer of a marketed drug product, including a biological drug product, that is used in a substantial number of pediatric patients, or that provides a meaningful therapeutic benefit over existing treatments for pediatric patients, as defined in §§ 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose label does not provide adequate information to support its safe and effective use in pediatric populations for the approved indications may be required to submit an application containing data adequate to assess whether the drug product is safe and effective in pediatric populations. The application may be required to contain adequate evidence to support dosage and administration in some or all pediatric subpopulations, including neonates, infants, children, and adolescents, depending upon the known or appropriate use of the drug product in such subpopulations. The applicant may also be required to develop a pediatric formulation for a drug product that represents a meaningful therapeutic benefit over existing therapies for pediatric populations for whom a pediatric formulation is necessary, unless the manufacturer demonstrates that reasonable attempts to produce a pediatric formulation have failed.
(b) The Food and Drug Administration (FDA) may by order, in the form of a letter, after notifying the manufacturer of its intent to require an assessment of pediatric safety and effectiveness of a pediatric formulation, and after offering an opportunity for a written response and a meeting, which may include an advisory committee meeting, require a manufacturer to submit an application containing the information or request for approval of a pediatric formulation described in paragraph (a) of this section within a time specified in the order, if FDA finds that:
(1) The drug product is used in a substantial number of pediatric patients for the labeled indications and the absence of adequate labeling could pose significant risks to pediatric patients; or
(2) There is reason to believe that the drug product would represent a meaningful therapeutic benefit over existing treatments for pediatric patients for one or more of the claimed indications, and the absence of adequate labeling could pose significant risks to pediatric patients.
(c)(1) An applicant may request a full waiver of the requirements of paragraph (a) of this section if the applicant certifies that:
(i) Necessary studies are impossible or highly impractical because, e.g., the number of such patients is so small or geographically dispersed, or
(ii) There is evidence strongly suggesting that the product would be ineffective or unsafe in all pediatric age groups.
(2) An applicant may request a partial waiver of the requirements of paragraph (a) of this section with respect to a specified pediatric age group, if the applicant certifies that:
(i) The product:
(A) Does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group, and
(B) Is not likely to be used in a substantial number of patients in that age group, and
(C) The absence of adequate labeling could not pose significant risks to pediatric patients; or
(ii) Necessary studies are impossible or highly impractical because, e.g., the number of patients in that age group is so small or geographically dispersed, or
(iii) There is evidence strongly suggesting that the product would be ineffective or unsafe in that age group, or
(iv) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.
(3) FDA shall grant a full or partial waiver, as appropriate, if the agency finds that there is a reasonable basis on which to conclude that one or more of the grounds for waiver specified in paragraphs (c)(2) or (c)(3) of this section have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formulation, the waiver will cover only those pediatric age groups requiring that formulation. If a waiver is granted because there is evidence that the product would be ineffective or unsafe in pediatric populations, this information will be included in the product's labeling.
(d) If a manufacturer fails to submit a supplemental application containing the information or request for approval of a pediatric formulation described in paragraph (a) of this section within the time specified by FDA, the drug product may be considered misbranded or an unapproved new drug or unlicensed biologic.
§ 201.24   Labeling for systemic antibacterial drug products.
The labeling of all systemic drug products intended for human use indicated to treat a bacterial infection, except a mycobacterial infection, must bear the following statements:
(a) At the beginning of the label, under the product name, the labeling must state:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ( insert name of antibacterial drug product ) and other antibacterial drugs, ( insert name of antibacterial drug product ) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
(b) In the “Indications and Usage” section, the labeling must state:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ( insert name of antibacterial drug product ) and other antibacterial drugs, ( insert name of antibacterial drug product ) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
(c) In the “Precautions” section, under the “General” subsection, the labeling must state:
Prescribing ( insert name of antibacterial drug product ) in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
(d) In the “Precautions” section, under the “Information for Patients” subsection, the labeling must state:
Patients should be counseled that antibacterial drugs including ( insert name of antibacterial drug product ) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ( insert name of antibacterial drug product ) is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ( insert name of antibacterial drug product ) or other antibacterial drugs in the future.
§ 201.25   Bar code label requirements.
(a) Who is subject to these bar code requirements? Manufacturers, repackers, relabelers, and private label distributors of a human prescription drug product or an over-the-counter (OTC) drug product that is regulated under the Federal Food, Drug, and Cosmetic Act or the Public Health Service Act are subject to these bar code requirements unless they are exempt from the registration and drug listing requirements in section 510 of the Federal Food, Drug, and Cosmetic Act.
(b) What drugs are subject to these bar code requirements? The following drug products are subject to the bar code label requirements:
(1) Prescription drug products, however:
(i) The bar code requirement does not apply to the following entities:
(A) Prescription drug samples;
(B) Allergenic extracts;
(C) Intrauterine contraceptive devices regulated as drugs;
(D) Medical gases;
(E) Radiopharmaceuticals; and
(F) Low-density polyethylene form fill and seal containers that are not packaged with an overwrap.
(ii) The bar code requirement does not apply to prescription drugs sold by a manufacturer, repacker, relabeler, or private label distributor directly to patients, but versions of the same drug product that are sold to or used in hospitals are subject to the bar code requirements.
(2) Biological products; and
(3) OTC drug products that are dispensed pursuant to an order and are commonly used in hospitals. For purposes of this section, an OTC drug product is “commonly used in hospitals” if it is packaged for hospital use, labeled for hospital use (or uses similar terms), or marketed, promoted, or sold to hospitals.
(c) What does the bar code look like? Where does the bar code go? (1) Each drug product described in paragraph (b) of this section must have a bar code that contains, at a minimum, the appropriate National Drug Code (NDC) number in a linear bar code that meets European Article Number/Uniform Code Council (EAN/UCC) or Health Industry Business Communications Council (HIBCC) standards or another standard or format that has been approved by the relevant Food and Drug Administration Center Director.  Additionally, the bar code must:
(i) Be surrounded by sufficient blank space so that the bar code can be scanned correctly; and
(ii) Remain intact under normal conditions of use.
(2) The bar code must appear on the drug's label as defined by section 201(k) of the Federal Food, Drug, and Cosmetic Act.
(d) Can a drug be exempted from the bar code requirement? (1) On our own initiative, or in response to a written request from a manufacturer, repacker, relabeler or private label distributor, we may exempt a drug product from the bar code label requirements set forth in this section. The exemption request must document why:
(i) compliance with the bar code requirement would adversely affect the safety, effectiveness, purity or potency of the drug or not be technologically feasible, and the concerns underlying the request could not reasonably be addressed by measures such as package redesign or use of overwraps; or
(ii) an alternative regulatory program or method of product use renders the bar code unnecessary for patient safety.
(2) Requests for an exemption should be sent to the Office of Compliance, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Silver Spring, MD 20993-0002 (requests involving a drug product or biological product regulated by the Center for Drug Evaluation and Research) or to the Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002 (requests involving a biological product regulated by the Center for Biologics Evaluation and Research).
§ 201.26   Exceptions or alternatives to labeling requirements for human drug products held by the Strategic National Stockpile.
(a) The appropriate FDA Center Director may grant an exception or alternative to any provision listed in paragraph (f) of this section and not explicitly required by statute, for specified lots, batches, or other units of a human drug product, if the Center Director determines that compliance with such labeling requirement could adversely affect the safety, effectiveness, or availability of such product that is or will be included in the Strategic National Stockpile.
(b)(1)(i) A Strategic National Stockpile official or any entity that manufactures (including labeling, packing, relabeling, or repackaging), distributes, or stores a human drug product that is or will be included in the Strategic National Stockpile may submit, with written concurrence from a Strategic National Stockpile official, a written request for an exception or alternative described in paragraph (a) of this section to the Center Director.
(ii) The Center Director may grant an exception or alternative described in paragraph (a) of this section on his or her own initiative.
(2) A written request for an exception or alternative described in paragraph (a) of this section must:
(i) Identify the specified lots, batches, or other units of the human drug product that would be subject to the exception or alternative;
(ii) Identify the labeling provision(s) listed in paragraph (f) of this section that are the subject of the exception or alternative request;
(iii) Explain why compliance with such labeling provision(s) could adversely affect the safety, effectiveness, or availability of the specified lots, batches, or other units of a human drug product that are or will be held in the Strategic National Stockpile;
(iv) Describe any proposed safeguards or conditions that will be implemented so that the labeling of the product includes appropriate information necessary for the safe and effective use of the product, given the anticipated circumstances of use of the product;
(v) Provide a draft of the proposed labeling of the specified lots, batches, or other units of the human drug product subject to the exception or alternative; and
(vi) Provide any other information requested by the Center Director in support of the request.
(c) The Center Director must respond in writing to all requests under this section.
(d) A grant of an exception or alternative under this section will include any safeguards or conditions deemed appropriate by the Center Director so that the labeling of product subject to the exception or alternative includes the information necessary for the safe and effective use of the product, given the anticipated circumstances of use.
(e) If you are a sponsor receiving a grant of a request for an exception or alternative to the labeling requirements under this section:
(1) You need not submit a supplement under § 314.70(a) through (c) or § 601.12(f)(1) through (f)(2) of this chapter; however,
(2) You must report any grant of a request for an exception or alternative under this section as part of your annual report under §§ 314.70(d) or 601.12(f)(3) of this chapter.
(f) The Center Director may grant an exception or alternative under this section to the following provisions of this chapter, to the extent that the requirements in these provisions are not explicitly required by statute:
(1) § 201.1(h)(1) through (h)(2), (h)(5) through (h)(6), and (i);
(2) § 201.10(a), (d)(2), (f), (g)(1), and (h)(1);
(3) § 201.17;
(4) § 201.18;
(5) § 201.19;
(6) § 201.20;
(7) § 201.21;
(8) § 201.22;
(9) § 201.24; and
(10) § 312.6.
§ 201.50   Statement of identity.
(a) The label of prescription and insulin-containing drugs in package form shall bear as one of its principal features a statement of the identity of the drug.
(b) Such statement of identity shall be in terms of the established name of the drug. In the case of a prescription drug that is a mixture and that has no established name, the requirement for statement of identity shall be deemed to be satisfied by a listing of the quantitative ingredient information as prescribed by § 201.10.
(c) The statement of identity of a prescription drug shall also comply with the placement, size and prominence requirements of § 201.10.
§ 201.51   Declaration of net quantity of contents.
(a) The label of a prescription or insulin-containing drug in package form shall bear a declaration of the net quantity of contents. This shall be expressed in the terms of weight, measure, numerical count, or a combination of numerical count and weight or measure. The statement of quantity of drugs in tablet, capsule, ampule, or other unit dosage form shall be expressed in terms of numerical count; the statement of quantity for drugs in other dosage forms shall be in terms of weight if the drug is solid, semi-solid, or viscous, or in terms of fluid measure if the drug is liquid. When the drug quantity statement is in terms of the numerical count of the drug units, it shall be augmented to give the weight or measure of the drug units or the quantity of each active ingredient in each drug unit or, when quantity does not accurately reflect drug potency, a statement of the drug potency.
(b) Statements of weight of the contents shall in the case of prescription drugs be expressed in terms of avoirdupois pound, ounce, and grain or of kilogram, gram, and subdivisions thereof. A statement of liquid measure of the contents shall in the case of prescription drugs be expressed in terms of the U.S. gallon of 231 cubic inches and quart, pint, fluid-ounce, and fluid-dram subdivisions thereof, or of the liter and milliliter, or cubic centimeter, and shall express the volume at 68 °F. (20 °C.). A statement of the liquid measure of the contents in the case of insulin-containing drugs shall be expressed in terms of the liter and milliliter, or cubic centimeter, and shall express the volume at 68 °F. (20 °C.).
(c) The declaration shall contain only such fractions as are generally used in expressing the quantity of the drug. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than three places, except in the case of a statement of the quantity of an active ingredient in a unit of a drug.
(d) The declaration shall appear as a distinct item on the label and, in the case of large volume parenterals, may be embossed on the glass.
(e) The declaration shall accurately reveal the quantity of drug in the package exclusive of wrappers and other material packed therewith.
(f) A statement of the quantity of a prescription or insulin-containing drug in terms of weight or measure applicable to such drug, under the provisions of paragraph (a) of this section, shall express with prominence and conspicuousness the number of the largest whole unit, as specified in paragraph (b) of this section, that are contained in the package. Any remainder shall be expressed in terms of common or decimal fractions of such unit or in terms of the next smaller whole unit and common or decimal fractions thereof.
(g) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large. In the case of a liquid drug in ampules or vials, intended for injection, the declaration shall be considered to express the minimum quantity and the variation above the stated measure shall comply with the excess volume prescribed by the National Formulary or the U.S. Pharmacopeia for filling of ampules. In the case of a solid drug in ampules or vials, the declaration shall be considered to express the accurate net weight. Variations shall comply with the limitations provided in the U.S. Pharmacopeia or the National Formulary.
(h) A drug shall be exempt from compliance with the net quantity declaration required by this section if it is an ointment labeled “sample”, “physician's sample”, or a substantially similar statement and the contents of the package do not exceed 8 grams.
§ 201.55   Statement of dosage.
Section 201.100(b)(2) requires that labels for prescription drugs bear a statement of the recommended or usual dosage. Since the dosage for some prescription drugs varies within extremely wide limits, depending upon the conditions being treated, it may not be possible in all cases to present an informative or useful statement of the recommended or usual dosage in the space available on the label or carton of the package. It is the view of the Food and Drug Administration that when such a situation prevails, compliance with this requirement would be met by a statement such as “See package insert for dosage information”, where the detailed information is contained in such insert. However, if an informative, realistic, recommended or usual dosage can readily be set forth on the label, it should appear thereon.
§ 201.56   Requirements on content and format of labeling for human prescription drug and biological products.
(a) General requirements. Prescription drug labeling described in § 201.100(d) must meet the following general requirements:
(1) The labeling must contain a summary of the essential scientific information needed for the safe and effective use of the drug.
(2) The labeling must be informative and accurate and neither promotional in tone nor false or misleading in any particular. In accordance with §§ 314.70 and 601.12 of this chapter, the labeling must be updated when new information becomes available that causes the labeling to become inaccurate, false, or misleading.
(3) The labeling must be based whenever possible on data derived from human experience. No implied claims or suggestions of drug use may be made if there is inadequate evidence of safety or a lack of substantial evidence of effectiveness. Conclusions based on animal data but necessary for safe and effective use of the drug in humans must be identified as such and included with human data in the appropriate section of the labeling.
(b) Categories of prescription drugs subject to the labeling content and format requirements in §§ 201.56(d) and 201.57. (1) The following categories of prescription drug products are subject to the labeling requirements in paragraph (d) of this section and § 201.57 in accordance with the implementation schedule in paragraph (c) of this section:
(i) Prescription drug products for which a new drug application (NDA), biologics license application (BLA), or efficacy supplement was approved by the Food and Drug Administration (FDA) between June 30, 2001 and June 30, 2006;
(ii) Prescription drug products for which an NDA, BLA, or efficacy supplement is pending on June 30, 2006; or
(iii) Prescription drug products for which an NDA, BLA, or efficacy supplement is submitted anytime on or after June 30, 2006.
(2) Prescription drug products not described in paragraph (b)(1) of this section are subject to the labeling requirements in paragraph (e) of this section and § 201.80.
(c) Schedule for implementing the labeling content and format requirements in §§ 201.56(d) and 201.57. For products described in paragraph (b)(1) of this section, labeling conforming to the requirements in paragraph (d) of this section and § 201.57 must be submitted according to the following schedule:
(1) For products for which an NDA, BLA, or efficacy supplement is submitted for approval on or after June 30, 2006, proposed conforming labeling must be submitted as part of the application.
(2) For products for which an NDA, BLA, or efficacy supplement is pending on June 30, 2006, or that has been approved any time from June 30, 2005, up to and including June 30, 2006, a supplement with proposed conforming labeling must be submitted no later than June 30, 2009.
(3) For products for which an NDA, BLA, or efficacy supplement has been approved anytime from June 30, 2004, up to and including June 29, 2005, a supplement with proposed conforming labeling must be submitted no later than June 30, 2010.
(4) For products for which an NDA, BLA, or efficacy supplement has been approved anytime from June 30, 2003, up to and including June 29, 2004, a supplement with proposed conforming labeling must be submitted no later than June 30, 2011.
(5) For products for which an NDA, BLA, or efficacy supplement has been approved anytime from June 30, 2002, up to and including June 29, 2003, a supplement with proposed conforming labeling must be submitted no later than June 30, 2012.
(6) For products for which an NDA, BLA, or efficacy supplement has been approved anytime from June 30, 2001, up to and including June 29, 2002, a supplement with proposed conforming labeling must be submitted no later than June 30, 2013.
(d) Labeling requirements for new and more recently approved prescription drug products. This paragraph applies only to prescription drug products described in paragraph (b)(1) of this section and must be implemented according to the schedule specified in paragraph (c) of this section.
(1) Prescription drug labeling described in § 201.100(d) must contain the specific information required under § 201.57(a), (b), and (c) under the following headings and subheadings and in the following order:
Product Names, Other Required Information
Boxed Warning
Recent Major Changes
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Boxed Warning
1 Indications and Usage
2 Dosage and Administration
3 Dosage Forms and Strengths
4 Contraindications
5 Warnings and Precautions
6 Adverse Reactions
7 Drug Interactions
8 Use in Specific Populations
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric use
8.5 Geriatric use
9 Drug Abuse and Dependence
9.1 Controlled substance
9.2 Abuse
9.3 Dependence
10 Overdosage
11 Description
12 Clinical Pharmacology
12.1 Mechanism of action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 Nonclinical Toxicology
13.1 Carcinogenesis, mutagenesis, impairment of fertility
13.2 Animal toxicology and/or pharmacology
14 Clinical Studies
15 References
16 How Supplied/Storage and Handling
17 Patient Counseling Information
(2) Additional nonstandard subheadings that are used to enhance labeling organization, presentation, or ease of use (e.g., for individual warnings or precautions, or for each drug interaction) must be assigned a decimal number that corresponds to their placement in labeling. The decimal numbers must be consistent with the standardized identifying numbers listed in paragraph (d)(1) of this section (e.g., subheadings added to the “Warnings and Precautions” section must be numbered 5.1, 5.2, and so on).
(3) Any reference in Highlights to information appearing in the full prescribing information must be accompanied by the identifying number (in parentheses) corresponding to the location of the information in the full prescribing information.
(4) Omit clearly inapplicable sections, subsections, or specific information. If sections or subsections required under paragraph (d)(1) of this section are omitted from the full prescribing information, the heading “Full Prescribing Information: Contents” must be followed by an asterisk and the following statement must appear at the end of Contents: “* Sections or subsections omitted from the full prescribing information are not listed.”
(5) Any risk information that is required under § 201.57(c)(9)(iv) is considered “appropriate pediatric contraindications, warnings, or precautions” within the meaning of section 505A(l)(2) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355A(l)(2)), whether such information appears in the “Contraindications,” “Warnings and Precautions,” or “Use in Specific Populations” section of labeling.
(e) Labeling requirements for older prescription drug products. This paragraph applies only to approved prescription drug products not described in paragraph (b)(1) of this section.
(1) Prescription drug labeling described in § 201.100(d) must contain the specific information required under § 201.80 under the following section headings and in the following order:
Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Drug Abuse and Dependence
Overdosage
Dosage and Administration
How Supplied
(2) The labeling may contain the following additional section headings if appropriate and if in compliance with § 201.80(l) and (m):
Animal Pharmacology and/or Animal Toxicology
Clinical Studies
References
(3) Omit clearly inapplicable sections, subsections, or specific information.
(4) The labeling may contain a “Product Title” section preceding the “Description” section and containing only the information required by § 201.80(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and (a)(1)(iv) and § 201.100(e). The information required by § 201.80(a)(1)(i) through (a)(1)(iv) must appear in the “Description” section of the labeling, whether or not it also appears in a “Product Title.”
(5) The labeling must contain the date of the most recent revision of the labeling, identified as such, placed prominently immediately after the last section of the labeling.
(6) The requirement in § 201.80(f)(2) to reprint any FDA-approved patient labeling at the end of prescription drug labeling or accompany the prescription drug labeling must be implemented no later than June 30, 2007.
§ 201.57   Specific requirements on content and format of labeling for human prescription drug and biological products described in § 201.56(b)(1).
The requirements in this section apply only to prescription drug products described in § 201.56(b)(1) and must be implemented according to the schedule specified in § 201.56(c), except for the requirement in paragraph (c)(18) of this section to reprint any FDA-approved patient labeling at the end of prescription drug labeling or accompany the prescription drug labeling, which must be implemented no later than June 30, 2007.
(a) Highlights of prescribing information. The following information must appear in all prescription drug labeling:
(1) Highlights limitation statement. The verbatim statement “These highlights do not include all the information needed to use ( insert name of drug product ) safely and effectively. See full prescribing information for (insert name of drug product).”
(2) Drug names, dosage form, route of administration, and controlled substance symbol. The proprietary name and the established name of the drug, if any, as defined in section 502(e)(3) of the Federal Food, Drug, and Cosmetic Act (the act) or, for biological products, the proper name (as defined in § 600.3 of this chapter) including any appropriate descriptors. This information must be followed by the drug's dosage form and route of administration. For controlled substances, the controlled substance symbol designating the schedule in which the controlled substance is listed must be included as required by § 1302.04 of this chapter.
(3) Initial U.S. approval. The verbatim statement “Initial U.S. Approval” followed by the four-digit year in which FDA initially approved a new molecular entity, new biological product, or new combination of active ingredients. The statement must be placed on the line immediately beneath the established name or, for biological products, proper name of the product.
(4) Boxed warning. A concise summary of any boxed warning required by paragraph (c)(1) of this section, not to exceed a length of 20 lines. The summary must be preceded by a heading, in upper-case letters, containing the word “WARNING” and other words that are appropriate to identify the subject of the warning. The heading and the summary must be contained within a box and bolded. The following verbatim statement must be placed immediately following the heading of the boxed warning: “See full prescribing information for complete boxed warning.”
(5) Recent major changes. A list of the section(s) of the full prescribing information, limited to the labeling sections described in paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this section, that contain(s) substantive labeling changes that have been approved by FDA or authorized under § 314.70(c)(6) or (d)(2), or § 601.12(f)(1) through (f)(3) of this chapter. The heading(s) and, if appropriate, the subheading(s) of the labeling section(s) affected by the change must be listed together with each section's identifying number and the date (month/year) on which the change was incorporated in labeling. These labeling sections must be listed in the order in which they appear in the full prescribing information. A changed section must be listed under this heading in Highlights for at least 1 year after the date of the labeling change and must be removed at the first printing subsequent to the 1 year period.
(6) Indications and usage. A concise statement of each of the product's indications, as required under paragraph (c)(2) of this section, with any appropriate subheadings. Major limitations of use (e.g., lack of effect in particular subsets of the population, or second line therapy status) must be briefly noted. If the product is a member of an established pharmacologic class, the concise statement under this heading in Highlights must identify the class in the following manner: “(Drug) is a (name of class) indicated for (indication(s)).”
(7) Dosage and administration. A concise summary of the information required under paragraph (c)(3) of this section, with any appropriate subheadings, including the recommended dosage regimen, starting dose, dose range, critical differences among population subsets, monitoring recommendations, and other clinically significant clinical pharmacologic information.
(8) Dosage forms and strengths. A concise summary of the information required under paragraph (c)(4) of this section, with any appropriate subheadings (e.g., tablets, capsules, injectable, suspension), including the strength or potency of the dosage form in metric system (e.g., 10-milligram tablets) and whether the product is scored.
(9) Contraindications. A concise statement of each of the product's contraindications, as required under paragraph (c)(5) of this section, with any appropriate subheadings.
(10) Warnings and precautions. A concise summary of the most clinically significant information required under paragraph (c)(6) of this section, with any appropriate subheadings, including information that would affect decisions about whether to prescribe a drug, recommendations for patient monitoring that are critical to safe use of the drug, and measures that can be taken to prevent or mitigate harm.
(11) Adverse reactions. (i) A list of the most frequently occurring adverse reactions, as described in paragraph (c)(7) of this section, along with the criteria used to determine inclusion (e.g., incidence rate). Adverse reactions important for other reasons (e.g., because they are serious or frequently lead to discontinuation or dosage adjustment) must not be repeated under this heading in Highlights if they are included elsewhere in Highlights (e.g., Warnings and Precautions, Contraindications).
(ii) For drug products other than vaccines, the verbatim statement “To report SUSPECTED ADVERSE REACTIONS, contact ( insert name of manufacturer ) at ( insert manufacturer's phone number ) or FDA at ( insert current FDA phone number and Web address for voluntary reporting of adverse reactions ).”
(iii) For vaccines, the verbatim statement “To report SUSPECTED ADVERSE REACTIONS, contact ( insert name of manufacturer ) at ( insert manufacturer's phone number ) or VAERS at ( insert the current VAERS phone number and Web address for voluntary reporting of adverse reactions ).”
(iv) For manufacturers with a Web site for voluntary reporting of adverse reactions, the Web address of the direct link to the site.
(12) Drug interactions. A concise summary of the information required under paragraph (c)(8) of this section, with any appropriate subheadings.
(13) Use in specific populations. A concise summary of the information required under paragraph (c)(9) of this section, with any appropriate subheadings.
(14) Patient counseling information statement. The verbatim statement “See 17 for Patient Counseling Information” or, if the product has FDA-approved patient labeling, the verbatim statement “See 17 for Patient Counseling Information and (insert either FDA-approved patient labeling or Medication Guide).”
(15) Revision date. The date of the most recent revision of the labeling, identified as such, placed at the end of Highlights.
(b) Full prescribing information: Contents. Contents must contain a list of each heading and subheading required in the full prescribing information under § 201.56(d)(1), if not omitted under § 201.56(d)(4), preceded by the identifying number required under § 201.56(d)(1). Contents must also contain any additional subheading(s) included in the full prescribing information preceded by the identifying number assigned in accordance with § 201.56(d)(2).
(c) Full prescribing information. The full prescribing information must contain the information in the order required under paragraphs (c)(1) through (c)(18) of this section, together with the headings, subheadings, and identifying numbers required under § 201.56(d)(1), unless omitted under § 201.56(d)(4). If additional subheadings are used within a labeling section, they must be preceded by the identifying number assigned in accordance with § 201.56(d)(2).
(1) Boxed warning. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box. The boxed warning ordinarily must be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. The box must contain, in uppercase letters, a heading inside the box that includes the word “WARNING” and conveys the general focus of the information in the box. The box must briefly explain the risk and refer to more detailed information in the “Contraindications” or “Warnings and Precautions” section, accompanied by the identifying number for the section or subsection containing the detailed information.
(2) 1 Indications and usage. This section must state that the drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a recognized disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symptoms associated with a recognized disease or condition.
(i) This section must include the following information when the conditions listed are applicable:
(A) If the drug is used for an indication only in conjunction with a primary mode of therapy (e.g., diet, surgery, behavior changes, or some other drug), a statement that the drug is indicated as an adjunct to that mode of therapy.
(B) If evidence is available to support the safety and effectiveness of the drug or biological product only in selected subgroups of the larger population (e.g., patients with mild disease or patients in a special age group), or if the indication is approved based on a surrogate endpoint under § 314.510 or § 601.41 of this chapter, a succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits, with reference to the “Clinical Studies” section for a discussion of the available evidence.
(C) If specific tests are necessary for selection or monitoring of the patients who need the drug (e.g., microbe susceptibility tests), the identity of such tests.
(D) If information on limitations of use or uncertainty about anticipated clinical benefits is relevant to the recommended intervals between doses, to the appropriate duration of treatment when such treatment should be limited, or to any modification of dosage, a concise description of the information with reference to the more detailed information in the “Dosage and Administration” section.
(E) If safety considerations are such that the drug should be reserved for specific situations (e.g., cases refractory to other drugs), a statement of the information.
(F) If there are specific conditions that should be met before the drug is used on a long term basis (e.g., demonstration of responsiveness to the drug in a short term trial in a given patient), a statement of the conditions; or, if the indications for long term use are different from those for short term use, a statement of the specific indications for each use.
(ii) If there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows that the drug is ineffective or that the therapeutic benefits of the product do not generally outweigh its risks, FDA may require that this section state that there is a lack of evidence that the drug is effective or safe for that use or condition.
(iii) Any statements comparing the safety or effectiveness of the drug with other agents for the same indication must, except for biological products, be supported by substantial evidence derived from adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless this requirement is waived under § 201.58 or § 314.126(c) of this chapter. For biological products, such statements must be supported by substantial evidence.
(iv) For drug products other than biological products, all indications listed in this section must be supported by substantial evidence of effectiveness based on adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless the requirement is waived under § 201.58 or § 314.126(c) of this chapter. Indications or uses must not be implied or suggested in other sections of the labeling if not included in this section.
(v) For biological products, all indications listed in this section must be supported by substantial evidence of effectiveness. Indications or uses must not be implied or suggested in other sections of the labeling if not included in this section.
(3) 2 Dosage and administration. (i) This section must state the recommended dose and, as appropriate:
(A) The dosage range,
(B) An upper limit beyond which safety and effectiveness have not been established, or beyond which increasing the dose does not result in increasing effectiveness,
(C) Dosages for each indication and subpopulation,
(D) The intervals recommended between doses,
(E) The optimal method of titrating dosage,
(F) The usual duration of treatment when treatment duration should be limited,
(G) Dosing recommendations based on clinical pharmacologic data (e.g., clinically significant food effects),
(H) Modification of dosage needed because of drug interactions or in special patient populations (e.g., in children, in geriatric age groups, in groups defined by genetic characteristics, or in patients with renal or hepatic disease),
(I) Important considerations concerning compliance with the dosage regimen,
(J) Efficacious or toxic concentration ranges and therapeutic concentration windows of the drug or its metabolites, if established and clinically significant. Information on therapeutic drug concentration monitoring (TDM) must also be included in this section when TDM is necessary.
(ii) Dosing regimens must not be implied or suggested in other sections of the labeling if not included in this section.
(iii) Radiation dosimetry information must be stated for both the patient receiving a radioactive drug and the person administering it.
(iv) This section must also contain specific direction on dilution, preparation (including the strength of the final dosage solution, when prepared according to instructions, in terms of milligrams of active ingredient per milliliter of reconstituted solution, unless another measure of the strength is more appropriate), and administration of the dosage form, if needed (e.g., the rate of administration of parenteral drug in milligrams per minute; storage conditions for stability of the reconstituted drug, when important; essential information on drug incompatibilities if the drug is mixed in vitro with other drugs or diluents; and the following verbatim statement for parenterals: “Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.”)
(4) 3 Dosage forms and strengths. This section must contain information on the available dosage forms to which the labeling applies and for which the manufacturer or distributor is responsible, including:
(i) The strength or potency of the dosage form in metric system (e.g., 10 milligram tablets), and, if the apothecary system is used, a statement of the strength in parentheses after the metric designation; and
(ii) A description of the identifying characteristics of the dosage forms, including shape, color, coating, scoring, and imprinting, when applicable. The National Drug Code number(s) for the drug product must not be included in this section.
(5) 4 Contraindications. This section must describe any situations in which the drug should not be used because the risk of use (e.g., certain potentially fatal adverse reactions) clearly outweighs any possible therapeutic benefit. Those situations include use of the drug in patients who, because of their particular age, sex, concomitant therapy, disease state, or other condition, have a substantial risk of being harmed by the drug and for whom no potential benefit makes the risk acceptable. Known hazards and not theoretical possibilities must be listed (e.g., if severe hypersensitivity to the drug has not been demonstrated, it should not be listed as a contraindication). If no contraindications are known, this section must state “None.”
(6) 5 Warnings and precautions. (i) General. This section must describe clinically significant adverse reactions (including any that are potentially fatal, are serious even if infrequent, or can be prevented or mitigated through appropriate use of the drug), other potential safety hazards (including those that are expected for the pharmacological class or those resulting from drug/drug interactions), limitations in use imposed by them (e.g., avoiding certain concomitant therapy), and steps that should be taken if they occur (e.g., dosage modification). The frequency of all clinically significant adverse reactions and the approximate mortality and morbidity rates for patients experiencing the reaction, if known and necessary for the safe and effective use of the drug, must be expressed as provided under paragraph (c)(7) of this section. In accordance with §§ 314.70 and 601.12 of this chapter, the labeling must be revised to include a warning about a clinically significant hazard as soon as there is reasonable evidence of a causal association with a drug; a causal relationship need not have been definitely established. A specific warning relating to a use not provided for under the “Indications and Usage” section may be required by FDA in accordance with sections 201(n) and 502(a) of the act if the drug is commonly prescribed for a disease or condition and such usage is associated with a clinically significant risk or hazard.
(ii) Other special care precautions. This section must contain information regarding any special care to be exercised by the practitioner for safe and effective use of the drug (e.g., precautions not required under any other specific section or subsection).
(iii) Monitoring: Laboratory tests. This section must identify any laboratory tests helpful in following the patient's response or in identifying possible adverse reactions. If appropriate, information must be provided on such factors as the range of normal and abnormal values expected in the particular situation and the recommended frequency with which tests should be performed before, during, and after therapy.
(iv) Interference with laboratory tests. This section must briefly note information on any known interference by the product with laboratory tests and reference the section where the detailed information is presented (e.g., “Drug Interactions” section).
(7) 6 Adverse reactions. This section must describe the overall adverse reaction profile of the drug based on the entire safety database. For purposes of prescription drug labeling, an adverse reaction is an undesirable effect, reasonably associated with use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse events observed during use of a drug, only those adverse events for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event.
(i) Listing of adverse reactions. This section must list the adverse reactions that occur with the drug and with drugs in the same pharmacologically active and chemically related class, if applicable. The list or lists must be preceded by the information necessary to interpret the adverse reactions (e.g., for clinical trials, total number exposed, extent and nature of exposure).
(ii) Categorization of adverse reactions. Within a listing, adverse reactions must be categorized by body system, by severity of the reaction, or in order of decreasing frequency, or by a combination of these, as appropriate. Within a category, adverse reactions must be listed in decreasing order of frequency. If frequency information cannot be reliably determined, adverse reactions must be listed in decreasing order of severity.
(A) Clinical trials experience. This section must list the adverse reactions identified in clinical trials that occurred at or above a specified rate appropriate to the safety database. The rate of occurrence of an adverse reaction for the drug and comparators (e.g., placebo) must be presented, unless such data cannot be determined or presentation of comparator rates would be misleading. If adverse reactions that occurred below the specified rate are included, they must be included in a separate listing. If comparative rates of occurrence cannot be reliably determined (e.g., adverse reactions were observed only in the uncontrolled trial portion of the overall safety database), adverse reactions must be grouped within specified frequency ranges as appropriate to the safety database for the drug (e.g., adverse reactions occurring at a rate of less than 1/100, adverse reactions occurring at a rate of less than 1/500) or descriptively identified, if frequency ranges cannot be determined. For adverse reactions with significant clinical implications, the listings must be supplemented with additional detail about the nature, frequency, and severity of the adverse reaction and the relationship of the adverse reaction to drug dose and demographic characteristics, if data are available and important.
(B) Postmarketing experience. This section of the labeling must list the adverse reactions, as defined in paragraph (c)(7) of this section, that are identified from domestic and foreign spontaneous reports. This listing must be separate from the listing of adverse reactions identified in clinical trials.
(iii) Comparisons of adverse reactions between drugs. For drug products other than biological products, any claim comparing the drug to which the labeling applies with other drugs in terms of frequency, severity, or character of adverse reactions must be based on adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless this requirement is waived under § 201.58 or § 314.126(c) of this chapter. For biological products, any such claim must be based on substantial evidence.
(8) 7 Drug interactions. (i) This section must contain a description of clinically significant interactions, either observed or predicted, with other prescription or over-the-counter drugs, classes of drugs, or foods (e.g., dietary supplements, grapefruit juice), and specific practical instructions for preventing or managing them. The mechanism(s) of the interaction, if known, must be briefly described. Interactions that are described in the “Contraindications” or “Warnings and Precautions” sections must be discussed in more detail under this section. Details of drug interaction pharmacokinetic studies that are included in the “Clinical Pharmacology” section that are pertinent to clinical use of the drug must not be repeated in this section.
(ii) This section must also contain practical guidance on known interference of the drug with laboratory tests.
(9) 8 Use in specific populations. This section must contain the following subsections:
(i) 8.1 Pregnancy. This subsection of the labeling must contain the following information in the following order under the subheadings “Pregnancy Exposure Registry,” “Risk Summary,” “Clinical Considerations,” and “Data”:
(A) Pregnancy exposure registry. If there is a scientifically acceptable pregnancy exposure registry for the drug, contact information needed to enroll in the registry or to obtain information about the registry must be provided following the statement: “There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ( name of drug ) during pregnancy.”
(B) Risk summary. The Risk Summary must contain risk statement(s) based on data from all relevant sources (human, animal, and/or pharmacologic) that describe, for the drug, the risk of adverse developmental outcomes ( i.e., structural abnormalities, embryo-fetal and/or infant mortality, functional impairment, alterations to growth). When multiple data sources are available, the statements must be presented in the following order: Human, animal, pharmacologic. The source(s) of the data must be stated. The labeling must state the percentage range of live births in the United States with a major birth defect and the percentage range of pregnancies in the United States that end in miscarriage, regardless of drug exposure. If such information is available for the population(s) for which the drug is labeled, it must also be included. When use of a drug is contraindicated during pregnancy, this information must be stated first in the Risk Summary. When applicable, risk statements as described in paragraphs (c)(9)(i)(B)( 1 ) and ( 2 ) of this section must include a cross-reference to additional details in the relevant portion of the “Data” subheading in the “Pregnancy” subsection of the labeling. If data demonstrate that a drug is not systemically absorbed following a particular route of administration, the Risk Summary must contain only the following statement: “( Name of drug ) is not absorbed systemically following (route of administration), and maternal use is not expected to result in fetal exposure to the drug.”
( 1 ) Risk statement based on human data. When human data are available that establish the presence or absence of any adverse developmental outcome(s) associated with maternal use of the drug, the Risk Summary must summarize the specific developmental outcome(s); their incidence; and the effects of dose, duration of exposure, and gestational timing of exposure. If human data indicate that there is an increased risk for a specific adverse developmental outcome in infants born to women exposed to the drug during pregnancy, this risk must be quantitatively compared to the risk for the same outcome in infants born to women who were not exposed to the drug but who have the disease or condition for which the drug is indicated to be used. When risk information is not available for women with the disease or condition for which the drug is indicated, the risk for the specific outcome must be compared to the rate at which the outcome occurs in the general population. The Risk Summary must state when there are no human data or when available human data do not establish the presence or absence of drug-associated risk.
( 2 ) Risk statement based on animal data. When animal data are available, the Risk Summary must summarize the findings in animals and based on these findings, describe, for the drug, the potential risk of any adverse developmental outcome(s) in humans. This statement must include: The number and type(s) of species affected, timing of exposure, animal doses expressed in terms of human dose or exposure equivalents, and outcomes for pregnant animals and offspring. When animal studies do not meet current standards for nonclinical developmental toxicity studies, the Risk Summary must so state. When there are no animal data, the Risk Summary must so state.
( 3 ) Risk statement based on pharmacology. When the drug has a well-understood mechanism of action that may result in adverse developmental outcome(s), the Risk Summary must explain the mechanism of action and the potential associated risks.
(C) Clinical considerations. Under the subheading “Clinical Considerations,” the labeling must provide relevant information, to the extent it is available, under the headings “Disease-associated maternal and/or embryo/fetal risk,” “Dose adjustments during pregnancy and the postpartum period,” “Maternal adverse reactions,” “Fetal/Neonatal adverse reactions,” and “Labor or delivery”:
( 1 ) Disease-associated maternal and/or embryo/fetal risk. If there is a serious known or potential risk to the pregnant woman and/or the embryo/fetus associated with the disease or condition for which the drug is indicated to be used, the labeling must describe the risk.
( 2 ) Dose adjustments during pregnancy and the postpartum period. If there are pharmacokinetic data that support dose adjustment(s) during pregnancy and the postpartum period, a summary of this information must be provided.
( 3 ) Maternal adverse reactions. If use of the drug is associated with a maternal adverse reaction that is unique to pregnancy or if a known adverse reaction occurs with increased frequency or severity in pregnant women, the labeling must describe the adverse reaction and available intervention(s) for monitoring or mitigating the reaction. The labeling must describe, if known, the effect of dose, timing, and duration of exposure on the risk to the pregnant woman of experiencing the adverse reaction.
( 4 ) Fetal/Neonatal adverse reactions. If it is known or anticipated that treatment of the pregnant woman increases or may increase the risk of an adverse reaction in the fetus or neonate, the labeling must describe the adverse reaction, the potential severity and reversibility of the adverse reaction, and available intervention(s) for monitoring or mitigating the reaction. The labeling must describe, if known, the effect of dose, timing, and duration of exposure on the risk.
( 5 ) Labor or delivery. If the drug is expected to affect labor or delivery, the labeling must provide information about the effect of the drug on the pregnant woman and the fetus or neonate; the effect of the drug on the duration of labor and delivery; any increased risk of adverse reactions, including their potential severity and reversibility; and must provide information about available intervention(s) that can mitigate these effects and/or adverse reactions. The information described under this heading is not required for drugs approved for use only during labor and delivery.
(D) Data —( 1 ) “Data” subheading. Under the subheading “Data,” the labeling must describe the data that are the basis for the Risk Summary and Clinical Considerations.
( 2 ) Human and animal data headings. Human and animal data must be presented separately, beneath the headings “Human Data” and “Animal Data,” and human data must be presented first.
( 3 ) Description of human data. For human data, the labeling must describe adverse developmental outcomes, adverse reactions, and other adverse effects. To the extent applicable, the labeling must describe the types of studies or reports, number of subjects and the duration of each study, exposure information, and limitations of the data. Both positive and negative study findings must be included.
( 4 ) Description of animal data. For animal data, the labeling must describe the following: Types of studies, animal species, dose, duration and timing of exposure, study findings, presence or absence of maternal toxicity, and limitations of the data. Description of maternal and offspring findings must include dose-response and severity of adverse developmental outcomes. Animal doses or exposures must be described in terms of human dose or exposure equivalents and the basis for those calculations must be included.
(ii) 8.2 Lactation. This subsection of the labeling must contain the following information in the following order under the subheadings “Risk Summary,” “Clinical Considerations,” and “Data”:
(A) Risk summary. When relevant human and/or animal lactation data are available, the Risk Summary must include a cross-reference to the “Data” subheading in the “Lactation” subsection of the labeling. When human data are available, animal data must not be included unless the animal model is specifically known to be predictive for humans. When use of a drug is contraindicated during breastfeeding, this information must be stated first in the Risk Summary.
( 1 ) Drug not absorbed systemically. If data demonstrate that the drug is not systemically absorbed by the mother, the Risk Summary must contain only the following statement: “( Name of drug ) is not absorbed systemically by the mother following (route of administration), and breastfeeding is not expected to result in exposure of the child to ( name of drug ).”
( 2 ) Drug absorbed systemically. If the drug is absorbed systemically, the Risk Summary must describe the following to the extent relevant information is available:
( i ) Presence of drug in human milk. The Risk Summary must state whether the drug and/or its active metabolite(s) are present in human milk. If there are no data to assess this, the Risk Summary must so state. If studies demonstrate that the drug and/or its active metabolite(s) are not detectable in human milk, the Risk Summary must state the limits of the assay used. If studies demonstrate the presence of the drug and/or its active metabolite(s) in human milk, the Risk Summary must state the concentration of the drug and/or its active metabolite(s) in human milk and the actual or estimated daily dose for an infant fed exclusively with human milk. The actual or estimated amount of the drug and/or its active metabolite(s) ingested by the infant must be compared to the labeled infant or pediatric dose, if available, or to the maternal dose. If studies demonstrate the presence of the drug and/or its active metabolite(s) in human milk but the drug and/or its active metabolite(s) are not expected to be systemically bioavailable to the breast-fed child, the Risk Summary must describe the disposition of the drug and/or its active metabolite(s). If only animal lactation data are available, the Risk Summary must state only whether or not the drug and/or its active metabolite(s) were detected in animal milk and specify the animal species.
( ii ) Effects of drug on the breast-fed child. The Risk Summary must include information, on the known or predicted effects on the child from exposure to the drug and/or its active metabolite(s) through human milk or from contact with breast or nipple skin (for topical products). The Risk Summary also must include information on systemic and/or local adverse reactions. If there are no data to assess the effects of the drug and/or its active metabolite(s) on the breast-fed child, the Risk Summary must so state.
( iii ) Effects of drug on milk production. The Risk Summary must describe the effects of the drug and/or its active metabolite(s) on milk production. If there are no data to assess the effects of the drug and/or its active metabolite(s) on milk production, the Risk Summary must so state.
( 3 ) Risk and benefit statement. For drugs absorbed systemically, unless breastfeeding is contraindicated during drug therapy, the following risk and benefit statement must appear at the end of the Risk Summary: “The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ( name of drug ) and any potential adverse effects on the breast-fed child from ( name of drug ) or from the underlying maternal condition.”
(B) Clinical considerations. Under “Clinical Considerations,” the following information must be provided to the extent it is available and relevant:
( 1 ) Minimizing exposure. The labeling must describe ways to minimize exposure in the breast-fed child if: The drug and/or its active metabolite(s) are present in human milk in clinically relevant concentrations; the drug does not have an established safety profile in infants; and the drug is used either intermittently, in single doses, or for short courses of therapy. When applicable, the labeling must also describe ways to minimize a breast-fed child's oral intake of topical drugs applied to the breast or nipple skin.
( 2 ) Monitoring for adverse reactions. The labeling must describe available intervention(s) for monitoring or mitigating the adverse reaction(s) presented in the Risk Summary.
(C) Data. Under the subheading “Data,” the labeling must describe the data that are the basis for the Risk Summary and Clinical Considerations.
(iii) 8.3 Females and males of reproductive potential. When pregnancy testing and/or contraception are required or recommended before, during, or after drug therapy and/or when there are human and/or animal data that suggest drug-associated fertility effects, this subsection of labeling must contain this information under the subheadings “Pregnancy Testing,” “Contraception,” and “Infertility,” in that order.
(iv) 8.4 Pediatric use. (A) Pediatric population(s)/pediatric patient(s): For the purposes of paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(H) of this section, the terms pediatric population(s) and pediatric patient(s) are defined as the pediatric age group, from birth to 16 years, including age groups often called neonates, infants, children, and adolescents.
(B) If there is a specific pediatric indication different from those approved for adults that is supported by adequate and well-controlled studies in the pediatric population, it must be described under the “Indications and Usage” section, and appropriate pediatric dosage information must be given under the “Dosage and Administration” section. The “Pediatric use” subsection must cite any limitations on the pediatric indication, need for specific monitoring, specific hazards associated with use of the drug in any subsets of the pediatric population (e.g., neonates), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. Data summarized in this subsection should be discussed in more detail, if appropriate, under the “Clinical Pharmacology” or “Clinical Studies” section. As appropriate, this information must also be contained in the “Contraindications” and/or “Warnings and Precautions” section(s).
(C) If there are specific statements on pediatric use of the drug for an indication also approved for adults that are based on adequate and well-controlled studies in the pediatric population, they must be summarized in the “Pediatric use” subsection and discussed in more detail, if appropriate, under the “Clinical Pharmacology” and “Clinical Studies” sections. Appropriate pediatric dosage must be given under the “Dosage and Administration” section. The “Pediatric use” subsection of the labeling must also cite any limitations on the pediatric use statement, need for specific monitoring, specific hazards associated with use of the drug in any subsets of the pediatric population (e.g., neonates), differences between pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. As appropriate, this information must also be contained in the “Contraindications” and/or “Warnings and Precautions” section(s).
(D)( 1 ) When a drug is approved for pediatric use based on adequate and well-controlled studies in adults with other information supporting pediatric use, the “Pediatric use” subsection of the labeling must contain either the following statement or a reasonable alternative:
The safety and effectiveness of ( drug name ) have been established in the age groups ___ to ___ (note any limitations, e.g., no data for pediatric patients under 2, or only applicable to certain indications approved in adults). Use of ( drug name ) in these age groups is supported by evidence from adequate and well-controlled studies of ( drug name ) in adults with additional data ( insert wording that accurately describes the data submitted to support a finding of substantial evidence of effectiveness in the pediatric population ).
( 2 ) Data summarized in the preceding prescribed statement in this subsection must be discussed in more detail, if appropriate, under the “Clinical Pharmacology” or the “Clinical Studies” section. For example, pediatric pharmacokinetic or pharmacodynamic studies and dose response information should be described in the “Clinical Pharmacology” section. Pediatric dosing instructions must be included in the “Dosage and Administration” section. Any differences between pediatric and adult responses, need for specific monitoring, dosing adjustments, and any other information related to safe and effective use of the drug in pediatric patients must be cited briefly in the “Pediatric use” subsection and, as appropriate, in the “Contraindications,” “Warnings and Precautions,” and “Dosage and Administration” sections.
(E) If the requirements for a finding of substantial evidence to support a pediatric indication or a pediatric use statement have not been met for a particular pediatric population, the “Pediatric use” subsection must contain an appropriate statement such as “Safety and effectiveness in pediatric patients below the age of (__) have not been established.” If use of the drug in this pediatric population is associated with a specific hazard, the hazard must be described in this subsection, or, if appropriate, the hazard must be stated in the “Contraindications” or “Warnings and Precautions” section and this subsection must refer to it.
(F) If the requirements for a finding of substantial evidence to support a pediatric indication or a pediatric use statement have not been met for any pediatric population, this subsection must contain the following statement: “Safety and effectiveness in pediatric patients have not been established.” If use of the drug in premature or neonatal infants, or other pediatric subgroups, is associated with a specific hazard, the hazard must be described in this subsection, or, if appropriate, the hazard must be stated in the “Contraindications” or “Warnings and Precautions” section and this subsection must refer to it.
(G) If the sponsor believes that none of the statements described in paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are appropriate or relevant to the labeling of a particular drug, the sponsor must provide reasons for omission of the statements and may propose alternative statement(s). FDA may permit use of an alternative statement if FDA determines that no statement described in those paragraphs is appropriate or relevant to the drug's labeling and that the alternative statement is accurate and appropriate.
(H) If the drug product contains one or more inactive ingredients that present an increased risk of toxic effects to neonates or other pediatric subgroups, a special note of this risk must be made, generally in the “Contraindications” or “Warnings and Precautions” section.
(v) 8.5 Geriatric use. (A) A specific geriatric indication, if any, that is supported by adequate and well-controlled studies in the geriatric population must be described under the “Indications and Usage” section, and appropriate geriatric dosage must be stated under the “Dosage and Administration” section. The “Geriatric use” subsection must cite any limitations on the geriatric indication, need for specific monitoring, specific hazards associated with the geriatric indication, and other information related to the safe and effective use of the drug in the geriatric population. Unless otherwise noted, information contained in the “Geriatric use” subsection must pertain to use of the drug in persons 65 years of age and older. Data summarized in this subsection must be discussed in more detail, if appropriate, under “Clinical Pharmacology” or the “Clinical Studies” section. As appropriate, this information must also be contained in the “Warnings and Precautions” and/or “Contraindications” section(s).
(B) Specific statements on geriatric use of the drug for an indication approved for adults generally, as distinguished from a specific geriatric indication, must be contained in the “Geriatric use” subsection and must reflect all information available to the sponsor that is relevant to the appropriate use of the drug in elderly patients. This information includes detailed results from controlled studies that are available to the sponsor and pertinent information from well-documented studies obtained from a literature search. Controlled studies include those that are part of the marketing application and other relevant studies available to the sponsor that have not been previously submitted in the investigational new drug application, new drug application, biologics license application, or a supplement or amendment to one of these applications (e.g., postmarketing studies or adverse drug reaction reports). The “Geriatric use” subsection must contain the following statement(s) or reasonable alternative, as applicable, taking into account available information:
( 1 ) If clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified such differences, the “Geriatric use” subsection must include the following statement:
Clinical studies of ( name of drug ) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
( 2 ) If clinical studies (including studies that are part of marketing applications and other relevant studies available to the sponsor that have not been submitted in the sponsor's applications) included enough elderly subjects to make it likely that differences in safety or effectiveness between elderly and younger subjects would have been detected, but no such differences (in safety or effectiveness) were observed, and other reported clinical experience has not identified such differences, the “Geriatric use” subsection must contain the following statement:
Of the total number of subjects in clinical studies of ( name of drug ), __ percent were 65 and over, while __ percent were 75 and over. (Alternatively, the labeling may state the total number of subjects included in the studies who were 65 and over and 75 and over.) No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
( 3 ) If evidence from clinical studies and other reported clinical experience available to the sponsor indicates that use of the drug in elderly patients is associated with differences in safety or effectiveness, or requires specific monitoring or dosage adjustment, the “Geriatric use” subsection must contain a brief description of observed differences or specific monitoring or dosage requirements and, as appropriate, must refer to more detailed discussions in the “Contraindications,” “Warnings and Precautions,” “Dosage and Administration,” or other sections.
(C)( 1 ) If specific pharmacokinetic or pharmacodynamic studies have been carried out in the elderly, they must be described briefly in the “Geriatric use” subsection and in detail under the “Clinical Pharmacology” section. The “Clinical Pharmacology” and “Drug Interactions” sections ordinarily contain information on drug/disease and drug/drug interactions that is particularly relevant to the elderly, who are more likely to have concomitant illness and to use concomitant drugs.
( 2 ) If a drug is known to be substantially excreted by the kidney, the “Geriatric use” subsection must include the statement:
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
(D) If use of the drug in the elderly appears to cause a specific hazard, the hazard must be described in the “Geriatric use” subsection, or, if appropriate, the hazard must be stated in the “Contraindications” or “Warnings and Precautions” section, and the “Geriatric use” subsection must refer to those sections.
(E) Labeling under paragraphs (c)(9)(v)(A) through (c)(9)(v)(C) of this section may include statements, if they are necessary for safe and effective use of the drug, and reflect good clinical practice or past experience in a particular situation, e.g., for a sedating drug, it could be stated that:
Sedating 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.
(F) If the sponsor believes that none of the requirements described in paragraphs (c)(9)(v)(A) through (c)(9)(v)(E) of this section are appropriate or relevant to the labeling of a particular drug, the sponsor must provide reasons for omission of the statements and may propose 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.
(vi) Additional subsections. Additional subsections may be included, as appropriate, if sufficient data are available concerning the use of the drug in other specified subpopulations (e.g., renal or hepatic impairment).
(10) 9 Drug abuse and dependence. This section must contain the following information, as appropriate:
(i) 9.1 Controlled substance. If the drug is controlled by the Drug Enforcement Administration, the schedule in which it is controlled must be stated.
(ii) 9.2 Abuse. This subsection must state the types of abuse that can occur with the drug and the adverse reactions pertinent to them, and must identify particularly susceptible patient populations. This subsection must be based primarily on human data and human experience, but pertinent animal data may also be used.
(iii) 9.3 Dependence. This subsection must describe characteristic effects resulting from both psychological and physical dependence that occur with the drug and must identify the quantity of the drug over a period of time that may lead to tolerance or dependence, or both. Details must be provided on the adverse effects of chronic abuse and the effects of abrupt withdrawal. Procedures necessary to diagnose the dependent state and the principles of treating the effects of abrupt withdrawal must be described.
(11) 10 Overdosage. This section must be based on human data. If human data are unavailable, appropriate animal and in vitro data may be used. The following specific information must be provided:
(i) Signs, symptoms, and laboratory findings associated with an overdosage of the drug;
(ii) Complications that can occur with the drug (for example, organ toxicity or delayed acidosis);
(iii) Concentrations of the drug in biologic fluids associated with toxicity 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;
(iv) 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;
(v) Whether the drug is dialyzable; and
(vi) Recommended general treatment procedures and specific measures for support of vital functions (e.g., proven antidotes, gastric lavage, forced diuresis, or as per Poison Control Center). Such recommendations must be based on data available for the specific drug or experience with pharmacologically related drugs. Unqualified recommendations for which data are lacking for the specific drug or class of drugs must not be stated.
(12) 11 Description. (i) This section must contain:
(A) The proprietary name and the established name, if any, as defined in section 502(e)(2) of the act, of the drug or, for biological products, the proper name (as defined in § 600.3 of this chapter) and any appropriate descriptors;
(B) The type of dosage form(s) and the route(s) of administration to which the labeling applies;
(C) The same qualitative and/or quantitative ingredient information as required under § 201.100(b) for drug labels or §§ 610.60 and 610.61 of this chapter for biological product labels;
(D) If the product is sterile, a statement of that fact;
(E) The pharmacological or therapeutic class of the drug;
(F) For drug products other than biological products, the chemical name and structural formula of the drug; and
(G) 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.
(ii) If appropriate, other important chemical or physical information, such as physical constants or pH, must be stated.
(13) 12 Clinical pharmacology. (i) This section must contain information relating to the human clinical pharmacology and actions of the drug in humans. Pharmacologic information based on in vitro data using human biomaterials or pharmacologic animal models, or relevant details about in vivo study designs or results (e.g., drug interaction studies), may be included in this section if essential to understand dosing or drug interaction information presented in other sections of the labeling. This section must include the following subsections:
(A) 12.1 Mechanism of action. This subsection must summarize what is known about the established mechanism(s) of the drug's action in humans at various levels (e.g., receptor, membrane, tissue, organ, whole body). If the mechanism of action is not known, this subsection must contain a statement about the lack of information.
(B) 12.2 Pharmacodynamics. This subsection must include a description of any biochemical or physiologic pharmacologic effects of the drug or active metabolites related to the drug's clinical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity. Exposure-response relationships (e.g., concentration-response, dose-response) and time course of pharmacodynamic response (including short-term clinical response) must be included if known. If this information is unknown, this subsection must contain a statement about the lack of information. Detailed dosing or monitoring recommendations based on pharmacodynamic information that appear in other sections (e.g., “Warnings and Precautions” or “Dosage and Administration”) must not be repeated in this subsection, but the location of such recommendations must be referenced.
(C) 12.3 Pharmacokinetics. This subsection must describe the clinically significant pharmacokinetics of a drug or active metabolites, (i.e., pertinent absorption, distribution, metabolism, and excretion parameters). Information regarding bioavailability, the effect of food, minimum concentration (C min ), maximum concentration (C max ), time to maximum concentration (T max ), area under the curve (AUC), pertinent half-lives (t 1/2 ), time to reach steady state, extent of accumulation, route(s) of elimination, clearance (renal, hepatic, total), mechanisms of clearance (e.g., specific enzyme systems), drug/drug and drug/food (e.g., dietary supplements, grapefruit juice) pharmacokinetic interactions (including inhibition, induction, and genetic characteristics), and volume of distribution (V d ) must be presented if clinically significant. Information regarding nonlinearity in pharmacokinetic parameters, changes in pharmacokinetics over time, and binding (plasma protein, erythrocyte) parameters must also be presented if clinically significant. This section must also include the results of pharmacokinetic studies (e.g., of metabolism or interaction) that establish the absence of an effect, including pertinent human studies and in vitro data. Dosing recommendations based on clinically significant factors that change the product's pharmacokinetics (e.g., age, gender, race, hepatic or renal dysfunction, concomitant therapy) that appear in other sections (e.g., “Warnings and Precautions,” “Dosage and Administration” or “Use in Specific Populations”) must not be repeated in this subsection, but the location of such recommendations must be referenced.
(ii) 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 only under the following circumstances:
(A) 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.”
(B) For other classes of drugs, in vitro and animal data that have not been shown by adequate and well-controlled studies, as defined in § 314.126(b) of this chapter, to be necessary for the safe and effective use may be included in this section only if a waiver is granted under § 201.58 or § 314.126(c) of this chapter.
(14) 13 Nonclinical toxicology. This section must contain the following subsections as appropriate:
(i) 13.1 Carcinogenesis, mutagenesis, impairment of fertility. This subsection must state whether long term studies in animals have been performed to evaluate carcinogenic potential and, if so, the species and results. If results from reproduction studies or other data in animals raise concern about mutagenesis or impairment of fertility in either males or females, this must be described. Any precautionary statement on these topics must include practical, relevant advice to the prescriber on the significance of these animal findings. Human data suggesting that the drug may be carcinogenic or mutagenic, or suggesting that it impairs fertility, as described in the “Warnings and Precautions” section, must not be included in this subsection of the labeling.
(ii) 13.2 Animal toxicology and/or pharmacology. Significant animal data necessary for safe and effective use of the drug in humans that is not incorporated in other sections of labeling must be included in this section (e.g., specifics about studies used to support approval under § 314.600 or § 601.90 of this chapter, the absence of chronic animal toxicity data for a drug that is administered over prolonged periods or is implanted in the body).
(15) 14 Clinical studies. This section must discuss those clinical studies that facilitate an understanding of how to use the drug safely and effectively. Ordinarily, this section will describe the studies that support effectiveness for the labeled indication(s), including discussion of study design, population, endpoints, and results, but must not include an encyclopedic listing of all, or even most, studies performed as part of the product's clinical development program. If a specific important clinical study is mentioned in any section of the labeling required under §§ 201.56 and 201.57 because the study is essential to an understandable presentation of the information in that section of the labeling, any detailed discussion of the study must appear in this section.
(i) For drug products other than biological products, any clinical study that is discussed in prescription drug labeling that relates to an indication for or use of the drug must be adequate and well-controlled as described in § 314.126(b) of this chapter and must not imply or suggest indications or uses or dosing regimens not stated in the “Indications and Usage” or “Dosage and Administration” section. For biological products, any clinical study that is discussed that relates to an indication for or use of the biological product must constitute or contribute to substantial evidence 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) Any discussion of a clinical study that relates to a risk from the use of the drug must also refer to the other sections of the labeling where the risk is identified or discussed.
(16) 15 References. 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.
(17) 16 How supplied/storage and handling. This section must contain information on the available dosage forms to which the labeling applies and for which the manufacturer or distributor is responsible. The information must include, as appropriate:
(i) The strength or potency of the dosage form in metric system (e.g., 10 milligram tablets) and, if the apothecary system is used, a statement of the strength in parentheses after the metric designation;
(ii) The units in which the dosage form is ordinarily available for prescribing by practitioners (e.g., bottles of 100);
(iii) Appropriate information to facilitate identification of the dosage forms, such as shape, color, coating, scoring, imprinting, and National Drug Code number; and
(iv) Special handling and storage conditions.
(18) 17 Patient counseling information. This section 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 this section or, alternatively, accompany the prescription drug labeling. Any FDA-approved patient labeling printed immediately following this section or accompanying the labeling is subject to the type size requirements in paragraph (d)(6) of this section, except for a Medication Guide to be detached and distributed to patients in compliance with § 208.24 of this chapter. Medication Guides for distribution to patients are subject to the type size requirements set forth in § 208.20 of this chapter.
(d) Format requirements. All labeling information required under paragraphs (a), (b), and (c) of this section must be printed in accordance with the following specifications:
(1) All headings and subheadings required by paragraphs (a) and (c) of this section must be highlighted by bold type that prominently distinguishes the headings and subheadings from other labeling information. Reverse type is not permitted as a form of highlighting.
(2) A horizontal line must separate the information required by paragraphs (a), (b), and (c) of this section.
(3) The headings listed in paragraphs (a)(5) through (a)(13) of this section must be presented in the center of a horizontal line.
(4) If there are multiple subheadings listed under paragraphs (a)(4) through (a)(13) of this section, each subheading must be preceded by a bullet point.
(5) The labeling information required by paragraphs (a)(1) through (a)(4), (a)(11)(ii) through (a)(11)(iv), and (a)(14) of this section must be in bold print.
(6) The letter height or type size for all labeling information, headings, and subheadings set forth in paragraphs (a), (b), and (c) of this section must be a minimum of 8 points, except for labeling information that is on or within the package from which the drug is to be dispensed, which must be a minimum of 6 points.
(7) The identifying numbers required by § 201.56(d) and paragraphs (c)(1) through (c)(18) of this section must be presented in bold print and must precede the heading or subheading by at least two square em's (i.e., two squares of the size of the letter “m” in 8 point type).
(8) The information required by paragraph (a) of this section, not including the information required under paragraph (a)(4) of this section, must be limited in length to an amount that, if printed in 2 columns on a standard sized piece of typing paper (8 1/2 by 11 inches), single spaced, in 8 point type with 1/2 -inch margins on all sides and between columns, would fit on one-half of the page.
(9) Sections or subsections of labeling that are identified as containing recent major changes under paragraph (a)(5) of this section must be highlighted in the full prescribing information by the inclusion of a vertical line on the left edge of the new or modified text.
(10) For the information required by paragraph (b) of this section, each section heading must be in bold print. Each subheading within a section must be indented and not bolded.
§ 201.58   Waiver of labeling requirements.
An applicant may ask the Food and Drug Administration to waive any requirement under §§ 201.56, 201.57, and 201.80. A waiver request must be submitted in writing to the Director (or the Director's designee), Center for Drug Evaluation and Research, Food and Drug Administration, Central Document Room, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or, if applicable, the Director (or the Director's designee), Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002. The waiver must be granted or denied in writing by the Director or the Director's designee.
§ 201.60   Principal display panel.
The term principal display panel, as it applies to over-the-counter drugs in package form and as used in this part, means the part of a label that is most likely to be displayed, presented, shown, or examined under customary conditions of display for retail sale. The principal display panel shall be large enough to accommodate all the mandatory label information required to be placed thereon by this part with clarity and conspicuousness and without obscuring designs, vignettes, or crowding. Where packages bear alternate principal display panels, information required to be placed on the principal display panel shall be duplicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of contents for all packages of substantially the same size, the term area of the principal display panel means the area of the side or surface that bears the principal display panel, which area shall be:
(a) In the case of a rectangular package where one entire side properly can be considered to be the principal display panel side, the product of the height times the width of that side;
(b) In the case of a cylindrical or nearly cylindrical container, 40 percent of the product of the height of the container times the circumference; and
(c) In the case of any other shape of container, 40 percent of the total surface of the container: Provided, however, That where such container presents an obvious “principal display panel” such as the top of a triangular or circular package, the area shall consist of the entire top surface.
§ 201.61   Statement of identity.
(a) The principal display panel of an over-the-counter drug in package form shall bear as one of its principal features a statement of the identity of the commodity.
(b) Such statement of identity shall be in terms of the established name of the drug, if any there be, followed by an accurate statement of the general pharmacological category(ies) of the drug or the principal intended action(s) of the drug. In the case of an over-the-counter drug that is a mixture and that has no established name, this requirement shall be deemed to be satisfied by a prominent and conspicuous statement of the general pharmacological action(s) of the mixture or of its principal intended action(s) in terms that are meaningful to the layman. Such statements shall be placed in direct conjunction with the most prominent display of the proprietary name or designation and shall employ terms descriptive of general pharmacological category(ies) or principal intended action(s); for example, “antacid,” “analgesic,” “decongestant,” “antihistaminic,” etc. The indications for use shall be included in the directions for use of the drug, as required by section 502(f)(1) of the act and by the regulations in this part.
(c) The statement of identity shall be presented in bold face type on the principal display panel, shall be in a size reasonably related to the most prominent printed matter on such panel, and shall be in lines generally parallel to the base on which the package rests as it is designed to be displayed.
§ 201.62   Declaration of net quantity of contents.
(a) The label of an over-the-counter drug in package form shall bear a declaration of the net quantity of contents. This shall be expressed in the terms of weight, measure, numerical count, or a combination or numerical count and weight, measure, or size. The statement of quantity of drugs in tablet, capsule, ampule, or other unit form and the quantity of devices shall be expressed in terms of numerical count; the statement of quantity for drugs in other dosage forms shall be in terms of weight if the drug is solid, semisolid, or viscous, or in terms of fluid measure if the drug is liquid. The drug quantity statement shall be augmented when necessary to give accurate information as to the strength of such drug in the package; for example, to differentiate between several strengths of the same drug “100 tablets, 5 grains each” or “100 capsules, 125 milligrams each” or “100 capsules, 250 milligrams each”: Provided, That:
(1) In the case of a firmly established, general consumer usage and trade custom of declaring the quantity of a drug in terms of linear measure or measure of area, such respective term may be used. Such term shall be augmented when necessary for accuracy of information by a statement of the weight, measure, or size of the individual units or of the entire drug; for example, the net quantity of adhesive tape in package form shall be expressed in terms of linear measure augmented by a statement of its width.
(2) Whenever the Commissioner determines for a specific packaged drug that an existing practice of declaring net quantity of contents by weight, measure, numerical count, or a combination of these does not facilitate value comparisons by consumers, he shall by regulation designate the appropriate term or terms to be used for such article.
(b) Statements of weight of the contents shall be expressed in terms of avoirdupois pound and ounce. A statement of liquid measure of the contents shall be expressed in terms of the U.S. gallon of 231 cubic inches and quart, pint, and fluid-ounce subdivisions thereof, and shall express the volume at 68 °F (20 °C). See also paragraph (p) of this section.
(c) The declaration may contain common or decimal fractions. A common fraction shall be in terms of halves, quarters, eights, sixteenths, or thirty-seconds; except that if there exists a firmly established, general consumer usage and trade custom of employing different common fractions in the net quantity declaration of a particular commodity, they may be employed. A common fraction shall be reduced to its lowest terms; a decimal fraction shall not be carried out to more than two places. A statement that includes small fractions of an ounce shall be deemed to permit smaller variations than one which does not include such fractions.
(d) The declaration shall be located on the principal display panel of the label, and with respect to packages bearing alternate principal panels it shall be duplicated on each principal display panel.
(e) The declaration shall appear as a distinct item on the principal display panel, shall be separated, by at least a space equal to the height of the lettering used in the declaration, from other printed label information appearing above or below the declaration and, by at least a space equal to twice the width of the letter “N” of the style of type used in the quantity of contents statement, from other printed label information appearing to the left or right of the declaration. It shall not include any term qualifying a unit of weight, measure, or count, such as “giant pint” and “full quart”, that tends to exaggerate the amount of the drug in the container. It shall be placed on the principal display panel within the bottom 30 percent of the area of the label panel in lines generally parallel to the base on which the package rests as it is designed to be displayed: Provided, That:
(1) On packages having a principal display panel of 5 square inches or less the requirement for placement within the bottom 30 percent of the area of the label panel shall not apply when the declaration of net quantity of contents meets the other requirements of this part; and
(2) In the case of a drug that is marketed with both outer and inner retail containers bearing the mandatory label information required by this part and the inner container is not intended to be sold separately, the net quantity of contents placement requirement of this section applicable to such inner container is waived.
(3) The principal display panel of a drug marketed on a display card to which the immediate container is affixed may be considered to be the display panel of the card, and the type size of the net quantity of contents statement is governed by the dimensions of the display card.
(f) The declaration shall accurately reveal the quantity of drug or device in the package exclusive of wrappers and other material packed therewith: Provided, That in the case of drugs packed in containers designed to deliver the drug under pressure, the declaration shall state the net quantity of the contents that will be expelled when the instructions for use as shown on the container are followed. The propellant is included in the net quantity declaration.
(g) The declaration shall appear in conspicuous and easily legible boldface print or type in distinct contrast (by typography, layout, color, embossing, or molding) to other matter on the package; except that a declaration of net quantity blown, embossed, or molded on a glass or plastic surface is permissible when all label information is so formed on the surface. Requirements of conspicuousness and legibility shall include the specifications that:
(1) The ratio of height to width of the letter shall not exceed a differential of 3 units to 1 unit, i.e., no more than 3 times as high as it is wide.
(2) Letter heights pertain to upper case or capital letters. When upper and lower case or all lower case letters are used, it is the lower case letter “o” or its equivalent that shall meet the minimum standards.
(3) When fractions are used, each component numeral shall meet one-half the minimum height standards.
(h) The declaration shall be in letters and numerals in a type size established in relationship to the area of the principal display panel of the package and shall be uniform for all packages of substantially the same size by complying with the following type specifications:
(1) Not less than one-sixteenth inch in height on packages the principal display panel of which has an area of 5 square inches or less.
(2) Not less than one-eighth inch in height on packages the principal display panel of which has an area of more than five but not more than 25 square inches.
(3) Not less than three-sixteenths inch in height on packages the principal display panel of which has an area of more than 25 but not more than 100 square inches.
(4) Not less than one-fourth inch in height on packages the principal display panel of which has an area of more than 100 square inches, except not less than one-half inch in height if the area is more than 400 square inches.
(i) On packages containing less than 4 pounds or 1 gallon and labeled in terms of weight or fluid measure:
(1) The declaration shall be expressed both in ounces, with identification by weight or by liquid measure and, if applicable (1 pound or 1 pint or more) followed in parentheses by a declaration in pounds for weight units, with any remainder in terms of ounces or common or decimal fractions of the pound (see examples set forth in paragraphs (k) (1) and (2) of this section), or in the case of liquid measure, in the largest whole units (quarts, quarts and pints, or pints, as appropriate) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart (see examples set forth in paragraphs (k) (3) and (4) of this section). If the net weight of the package is less than 1 ounce avoirdupois or the net fluid measure is less than 1 fluid ounce, the declaration shall be in terms of common or decimal fractions of the respective ounce and not in terms of drams.
(2) The declaration may appear in more than one line. The term net weight shall be used when stating the net quantity of contents in terms of weight. Use of the terms net or net contents in terms of fluid measure or numerical count is optional. It is sufficient to distinguish avoirdupois ounce from fluid ounce through association of terms; for example, “Net wt. 6 oz” or “6 oz net wt.,” and “6 fl oz” or “net contents 6 fl oz”.
(j) On packages containing 4 pounds or 1 gallon or more and labeled in terms of weight or fluid measure, the declaration shall be expressed in pounds for weight units with any remainder in terms of ounces or common or decimal fractions of the pound; in the case of fluid measure, it shall be expressed in the largest whole unit (gallons, followed by common or decimal fractions of a gallon or by the next smaller whole unit or units (quarts or quarts and pints)) with any remainder in terms of fluid ounces or common or decimal fractions of the pint or quart; see paragraph (k)(5) of this section.
(k) Examples:
(1) A declaration of 1 1/2 pounds weight shall be expressed as “Net wt. 24 oz (1 lb 8 oz),” or “Net wt. 24 oz (1 1/2 lb)” or “Net wt. 24 oz (1.5 lb)”.
(2) A declaration of three-fourths pound avoirdupois weight shall be expressed as “Net wt. 12 oz”.
(3) A declaration of 1 quart liquid measure shall be expressed as “Net contents 32 fl oz (1 qt)” or “32 fl oz (1 qt)”.
(4) A declaration of 1 3/4 quarts liquid measure shall be expressed as “Net contents 56 fl oz (1 qt 1 pt 8 oz)” or “Net contents 56 fl oz (1 qt 1.5 pt),” but not in terms of quart and ounce such as “Net 56 fl oz (1 qt 24 oz).”
(5) A declaration of 2 1/2 gallons liquid measure shall be expressed as “Net contents 2 gal 2 qt,” “Net contents 2.5 gallons,” or “Net contents 2 1/2 gal” but not as “2 gal 4 pt”.
(l) For quantities, the following abbreviations and none other may be employed. Periods and plural forms are optional:
(m) On packages labeled in terms of linear measure, the declaration shall be expressed both in terms of inches and, if applicable (1 foot or more), the largest whole units (yards, yards and feet, feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of inches and any remainder shall be in terms of inches or common or decimal fractions of the foot or yard; if applicable, as in the case of adhesive tape, the initial declaration in linear inches shall be preceded by a statement of the width. Examples of linear measure are “86 inches (2 yd 1 ft 2 in),” “90 inches (2 1/2 yd),” “30 inches (2.5 ft),” “ 3/4 inch by 36 in (1 yd),” etc.
(n) On packages labeled in terms of area measure, the declaration shall be expressed both in terms of square inches and, if applicable (1 square foot or more), the largest whole square unit (square yards, square yards and square feet, square feet). The declaration in terms of the largest whole units shall be in parentheses following the declaration in terms of square inches and any remainder shall be in terms of square inches or common or decimal fractions of the square foot or square yard; for example, “158 sq inches (1 sq ft 14 sq in).”
(o) Nothing in this section shall prohibit supplemental statements at locations other than the principal display panel(s) describing in nondeceptive terms the net quantity of contents, provided that such supplemental statements of net quantity of contents shall not include any term qualifying a unit of weight, measure, or count that tends to exaggerate the amount of the drug contained in the package; for example, “giant pint” and “full quart.” Dual or combination declarations of net quantity of contents as provided for in paragraphs (a) and (i) of this section are not regarded as supplemental net quantity statements and shall be located on the principal display panel.
(p) A separate statement of net quantity of contents in terms of the metric system of weight or measure is not regarded as a supplemental statement and an accurate statement of the net quantity of contents in terms of the metric system of weight or measure may also appear on the principal display panel or on other panels.
(q) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large.
(r) A drug shall be exempt from compliance with the net quantity declaration required by this section if it is an ointment labeled “sample,” “physician's sample,” or a substantially similar statement and the contents of the package do not exceed 8 grams.
§ 201.63   Pregnancy/breast-feeding warning.
(a) The labeling for all over-the-counter (OTC) drug products that are intended for systemic absorption, unless specifically exempted, shall contain a general warning under the heading “Warning” (or “Warnings” if it appears with additional warning statements) as follows: “If pregnant or breast-feeding, ask a health professional before use.” [first four words of this statement in bold type] In addition to the written warning, a symbol that conveys the intent of the warning may be used in labeling.
(b) Where a specific warning relating to use during pregnancy or while nursing has been established for a particular drug product in a new drug application (NDA) or for a product covered by an OTC drug final monograph in part 330 of this chapter, the specific warning shall be used in place of the warning in paragraph (a) of this section, unless otherwise stated in the NDA or in the final OTC drug monograph.
(c) The following OTC drugs are exempt from the provisions of paragraph (a) of this section:
(1) Drugs that are intended to benefit the fetus or nursing infant during the period of pregnancy or nursing.
(2) Drugs that are labeled exclusively for pediatric use.
(d) The Food and Drug Administration will grant an exemption from paragraph (a) of this section where appropriate upon petition under the provisions of § 10.30 of this chapter. Decisions with respect to requests for exemptions shall be maintained in a permanent file for public review by the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
(e) The labeling of orally or rectally administered OTC aspirin and aspirin-containing drug products must bear a warning that immediately follows the general warning identified in paragraph (a) of this section. The warning shall be as follows:
“It is especially important not to use” (select “aspirin” or “carbaspirin calcium,” as appropriate) “during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.”
§ 201.64   Sodium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended for oral ingestion shall contain the sodium content per dosage unit (e.g., tablet, teaspoonful) if the sodium content of a single maximum recommended dose of the product (which may be one or more dosage units) is 5 milligrams or more. OTC drug products intended for oral ingestion include gum and lozenge dosage forms, but do not include dentifrices, mouthwashes, or mouth rinses.
(b) The sodium content shall be expressed in milligrams per dosage unit and shall include the total amount of sodium regardless of the source, i.e., from both active and inactive ingredients. The sodium content shall be rounded-off to the nearest whole number. The sodium content per dosage unit shall follow the heading “Other information” as stated in § 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion shall contain the following statement under the heading “Warning” (or “Warnings” if it appears with additional warning statements) if the amount of sodium present in the labeled maximum daily dose of the product is more than 140 milligrams: “Ask a doctor before use if you have [in bold type] [bullet] 1 a sodium-restricted diet”. The warnings in §§ 201.64(c), 201.70(c), 201.71(c), and 201.72(c) may be combined, if applicable, provided the ingredients are listed in alphabetical order, e g., a calcium or sodium restricted diet.
1 See § 201 .66(b)(4) of this chapter for definition of bullet symbol.
(d) The term sodium free may be used in the labeling of OTC drug products intended for oral ingestion if the amount of sodium in the labeled maximum daily dose is 5 milligrams or less and the amount of sodium per dosage unit is 0 milligram (when rounded-off in accord with paragraph (b) of this section).
(e) The term very low sodium may be used in the labeling of OTC drug products intended for oral ingestion if the amount of sodium in the labeled maximum daily dose is 35 milligrams or less.
(f) The term low sodium may be used in the labeling of OTC drug products intended for oral ingestion if the amount of sodium in the labeled maximum daily dose is 140 milligrams or less.
(g) The term salt is not synonymous with the term sodium and shall not be used interchangeably or substituted for the term sodium.
(h) The terms sodium free, very low sodium, and low sodium shall be in print size and style no larger than the product's statement of identity and shall not be unduly prominent in print size or style compared to the statement of identity.
(i) Any product subject to this paragraph that contains sodium bicarbonate, sodium phosphate, or sodium biphosphate as an active ingredient for oral ingestion and that is not labeled as required by this paragraph and that is initially introduced or initially delivered for introduction into interstate commerce after April 22, 1997, is misbranded under sections 201(n) and 502 (a) and (f) of the Federal Food, Drug, and Cosmetic Act (the act).
(j) Any product subject to paragraphs (a) through (h) of this section that is not labeled as required 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.
(1) As of the date of approval of the application for any single entity and combination products subject to drug marketing applications approved on or after April 23, 2004.
(2) Septemeber 24, 2005, for all OTC drug products subject to any OTC drug monograph, not yet the subject of any OTC drug monograph, or subject to drug marketing applications approved before April 23, 2004.
(k) The labeling of OTC drug products intended for rectal administration containing dibasic sodium phosphate and/or monobasic sodium phosphate shall contain the sodium content per delivered dose if the sodium content is 5 milligrams or more. The sodium content shall be expressed in milligrams or grams. If less than 1 gram, milligrams should be used. The sodium content shall be rounded-off to the nearest whole number if expressed in milligrams (or nearest tenth of a gram if expressed in grams). The sodium content per delivered dose shall follow the heading “Other information” as stated in § 201.66(c)(7). Any product subject to this paragraph that contains dibasic sodium phosphate and/or monobasic sodium phosphate as an active ingredient intended for rectal administration and that is not labeled as required by this paragraph and that is initially introduced or initially delivered for introduction into interstate commerce after November 29, 2005, is misbranded under sections 201(n) and 502(a) and (f) of the act.
§ 201.66   Format and content requirements for over-the-counter (OTC) drug product labeling.
(a) Scope. This section sets forth the content and format requirements for the labeling of all OTC drug products. Where an OTC drug product is the subject of an applicable monograph or regulation that contains content and format requirements that conflict with this section, the content and format requirements in this section must be followed unless otherwise specifically provided in the applicable monograph or regulation.
(b) Definitions. The following definitions apply to this section:
(1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201 et seq. (21 U.S.C. 321 et seq. )).
(2) Active ingredient means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.
(3) Approved drug application means a new drug (NDA) or abbreviated new drug (ANDA) application approved under section 505 of the act (21 U.S.C. 355).
(4) Bullet means a geometric symbol that precedes each statement in a list of statements. For purposes of this section, the bullet style is limited to solid squares or solid circles, in the format set forth in paragraph (d)(4) of this section.
(5) Established name of a drug or ingredient thereof means the applicable official name designated under section 508 of the act (21 U.S.C. 358), or, if there is no designated official name and the drug or ingredient is recognized in an official compendium, the official title of the drug or ingredient in such compendium, or, if there is no designated official name and the drug or ingredient is not recognized in an official compendium, the common or usual name of the drug or ingredient.
(6) FDA means the Food and Drug Administration.
(7) Heading means the required statements in quotation marks listed in paragraphs (c)(2) through (c)(9) of this section, excluding subheadings (as defined in paragraph (a)(9) of this section).
(8) Inactive ingredient means any component other than an active ingredient.
(9) Subheading means the required statements in quotation marks listed in paragraphs (c)(5)(ii) through (c)(5)(vii) of this section.
(10) Drug facts labeling means the title, headings, subheadings, and information required under or otherwise described in paragraph (c) of this section.
(11) Title means the heading listed at the top of the required OTC drug product labeling, as set forth in paragraph (c)(1) of this section.
(12) Total surface area available to bear labeling means all surfaces of the outside container of the retail package or, if there is no such outside container, all surfaces of the immediate container or container wrapper except for the flanges at the tops and bottoms of cans and the shoulders and necks of bottles and jars.
(c) Content requirements. The outside container or wrapper of the retail package, or the immediate container label if there is no outside container or wrapper, shall contain the title, headings, subheadings, and information set forth in paragraphs (c)(1) through (c)(8) of this section, and may contain the information under the heading in paragraph (c)(9) of this section, in the order listed.
(1) (Title) “Drug Facts”. If the drug facts labeling appears on more than one panel, the title “Drug Facts (continued)” shall appear at the top of each subsequent panel containing such information.
(2) “Active ingredient” or “Active ingredients” “(in each [insert the dosage unit stated in the directions for use (e.g., tablet, 5 mL teaspoonful) or in each gram as stated in §§ 333.110 and 333.120 of this chapter])”, followed by the established name of each active ingredient and the quantity of each active ingredient per dosage unit. Unless otherwise provided in an applicable OTC drug monograph or approved drug application, products marketed without discrete dosage units (e.g., topicals) shall state the proportion (rather than the quantity) of each active ingredient.
(3) “Purpose” or “Purposes”, followed by the general pharmacological category(ies) or the principal intended action(s) of the drug or, where the drug consists of more than one ingredient, the general pharmacological categories or the principal intended actions of each active ingredient. When an OTC drug monograph contains a statement of identity, the pharmacological action described in the statement of identity shall also be stated as the purpose of the active ingredient.
(4) “Use” or “Uses”, followed by the indication(s) for the specific drug product.
(5) “Warning” or “Warnings”, followed by one or more of the following, if applicable:
(i) “For external use only” [in bold type] for topical drug products not intended for ingestion, or “For” (select one of the following, as appropriate: “rectal” or “vaginal”) “use only” [in bold type].
(ii) All applicable warnings listed in paragraphs (c)(5)(ii)(A) through (c)(5)(ii)(G) of this section with the appropriate subheadings highlighted in bold type:
(A) Reye's syndrome warning for drug products containing salicylates set forth in § 201.314(h)(1). This warning shall follow the subheading “Reye's syndrome:”
(B) Allergic reaction and asthma alert warnings. Allergic reaction warnings set forth in any applicable OTC drug monograph or approved drug application for any product that requires a separate allergy warning. This warning shall follow the subheading “Allergy alert:” The asthma alert warning set forth in §§ 341.76(c)(5) and 341.76(c)(6) of this chapter. This warning shall follow the subheading “Asthma alert:”
(C) Flammability warning, with appropriate flammability signal word(s) (e.g., §§ 341.74(c)(5)(iii), 344.52(c), 358.150(c), and 358.550(c) of this chapter). This warning shall follow a subheading containing the appropriate flammability signal word(s) described in an applicable OTC drug monograph or approved drug application.
(D) Water soluble gums warning set forth in § 201.319. This warning shall follow the subheading “Choking:”
(E) Liver warning set forth in § 201.326(a)(1)(iii) and/or stomach bleeding warning set forth in § 201.326(a)(2)(iii). The liver warning shall follow the subheading “Liver warning:” and the stomach bleeding warning shall follow the subheading “Stomach bleeding warning:”
(F) Sore throat warning set forth in § 201.315. This warning shall follow the subheading “Sore throat warning:”
(G) Warning for drug products containing sodium phosphates set forth in § 201.307(b)(2)(i) or (b)(2)(ii). This warning shall follow the subheading “Dosage warning:”
(H) Sexually transmitted diseases (STDs) warning for vaginal contraceptive and spermicide drug products containing nonoxynol 9 set forth in § 201.325(b)(2). This warning shall follow the subheading “Sexually transmitted diseases (STDs) alert:”
(iii) “Do not use” [in bold type], followed by all contraindications for use with the product. These contraindications are absolute and are intended for situations in which consumers should not use the product unless a prior diagnosis has been established by a doctor or for situations in which certain consumers should not use the product under any circumstances regardless of whether a doctor or health professional is consulted.
(iv) “Ask a doctor before use if you have” [in bold type] or, for products labeled only for use in children under 12 years of age, “Ask a doctor before use if the child has” [in bold type], followed by all warnings for persons with certain preexisting conditions (excluding pregnancy) and all warnings for persons experiencing certain symptoms. The warnings under this heading are those intended only for situations in which consumers should not use the product until a doctor is consulted.
(v) “Ask a doctor or pharmacist before use if you are” [in bold type] or, for products labeled only for use in children under 12 years of age, “Ask a doctor or pharmacist before use if the child is” [in bold type], followed by all drug-drug and drug-food interaction warnings.
(vi) “When using this product” [in bold type], followed by the side effects that the consumer may experience, and the substances (e.g., alcohol) or activities (e.g., operating machinery, driving a car, warnings set forth in § 369.21 of this chapter for drugs in dispensers pressurized by gaseous propellants) to avoid while using the product.
(vii) “Stop use and ask a doctor if” [in bold type], followed by any signs of toxicity or other reactions that would necessitate immediately discontinuing use of the product. For all OTC drug products under an approved drug application whose packaging does not include a toll-free number through which consumers can report complaints to the manufacturer or distributor of the drug product, the following text shall immediately follow the subheading: “[Bullet] side effects occur. You may report side effects to FDA at 1-800-FDA-1088.” The telephone number must appear in a minimum 6-point bold letter height or type size.
(viii) Any required warnings in an applicable OTC drug monograph, other OTC drug regulations, or approved drug application that do not fit within one of the categories listed in paragraphs (c)(5)(i) through (c)(5)(vii), (c)(5)(ix), and (c)(5)(x) of this section.
(ix) The pregnancy/breast-feeding warning set forth in § 201.63(a); the third trimester warning set forth in § 201.63(e) for products containing aspirin or carbaspirin calcium; the third trimester warning set forth in approved drug applications for products containing ketoprofen, naproxen sodium, and ibuprofen (not intended exclusively for use in children).
(x) The “Keep out of reach of children” warning and the accidental overdose/ingestion warning set forth in § 330.1(g) of this chapter.
(6) “Directions”, followed by the directions for use described in an applicable OTC drug monograph or approved drug application.
(7) “Other information”, followed by additional information that is not included under paragraphs (c)(2) through (c)(6), (c)(8), and (c)(9) of this section, but which is required by or is made optional under an applicable OTC drug monograph, other OTC drug regulation, or is included in the labeling of an approved drug application.
(i) Required information about certain ingredients in OTC drug products (e.g., sodium in § 201.64(b), calcium in § 201.70(b), magnesium in § 201.71(b), and potassium in § 201.72(b)) shall appear as follows: “each (insert appropriate dosage unit) contains:” [in bold type (insert name(s) of ingredient(s) (in alphabetical order) and the quantity of each ingredient). This information shall be the first statement under this heading.
(ii) The phenylalanine/aspartame content required by § 201.21(b), if applicable, shall appear as the next item of information.
(iii) Additional information that is authorized to appear under this heading shall appear as the next item(s) of information. There is no required order for this subsequent information.
(8) “Inactive ingredients”, followed by a listing of the established name of each inactive ingredient. If the product is an OTC drug product that is not also a cosmetic product, then the inactive ingredients shall be listed in alphabetical order. If the product is an OTC drug product that is also a cosmetic product, then the inactive ingredients shall be listed as set forth in § 701.3(a) or (f) of this chapter, the names of cosmetic ingredients shall be determined in accordance with § 701.3(c) of this chapter, and the provisions in § 701.3(e), (g), (h), (l), (m), (n), and (o) of this chapter and § 720.8 of this chapter may also apply, as appropriate. If there is a difference in the labeling provisions in this § 201.66 and §§ 701.3 and 720.8 of this chapter, the labeling provisions in this § 201.66 shall be used.
(9) “Questions?” or “Questions or comments?”, followed by the telephone number of a source to answer questions about the product. It is recommended that the days of the week and times of the day when a person is available to respond to questions also be included. A graphic of a telephone or telephone receiver may appear before the heading. The telephone number must appear in a minimum 6-point bold type.
(d) Format requirements. The title, headings, subheadings, and information set forth in paragraphs (c)(1) through (c)(9) of this section shall be presented on OTC drug products in accordance with the following specifications. In the interest of uniformity of presentation, FDA strongly reccommends that the Drug Facts labeling be presented using the graphic specifications set forth in appendix A to part 201.
(1) The title “Drug Facts” or “Drug Facts (continued)” shall use uppercase letters for the first letter of the words “Drug” and “Facts.” All headings and subheadings in paragraphs (c)(2) through (c)(9) of this section shall use an uppercase letter for the first letter in the first word and lowercase letters for all other words. The title, headings, and subheadings in paragraphs (c)(1), (c)(2), and (c)(4) through (c)(9) of this section shall be left justified.
(2) The letter height or type size for the title “Drug Facts” shall appear in a type size larger than the largest type size used in the Drug Facts labeling. The letter height or type size for the title “Drug Facts (continued)” shall be no smaller than 8-point type. The letter height or type size for the headings in paragraphs (c)(2) through (c)(9) of this section shall be the larger of either 8-point or greater type, or 2-point sizes greater than the point size of the text. The letter height or type size for the subheadings and all other information described in paragraphs (c)(2) through (c)(9) of this section shall be no smaller than 6-point type.
(3) The title, heading, subheadings, and information in paragraphs (c)(1) through (c)(9) of this section shall be legible and clearly presented, shall have at least 0.5-point leading (i.e., space between two lines of text), and shall not have letters that touch. The type style for the title, headings, subheadings, and all other required information described in paragraphs (c)(2) through (c)(9) of this section shall be any single, clear, easy-to-read type style, with no more than 39 characters per inch. The title and headings shall be in bold italic, and the subheadings shall be in bold type, except that the word “(continued)” in the title “Drug Facts (continued)” shall be regular type. The type shall be all black or one color printed on a white or other contrasting background, except that the title and the headings may be presented in a single, alternative, contrasting color unless otherwise provided in an approved drug application, OTC drug monograph (e.g., current requirements for bold print in §§ 341.76 and 341.80 of this chapter), or other OTC drug regulation (e.g., the requirement for a box and red letters in § 201.308(c)(1)).
(4) When there is more than one statement, each individual statement listed under the headings and subheadings in paragraphs (c)(4) through (c)(7) of this section shall be preceded by a solid square or solid circle bullet of 5-point type size. Bullets shall be presented in the same shape and color throughout the labeling. The first bulleted statement on each horizontal line of text shall be either left justified or separated from an appropriate heading or subheading by at least two square “ems” (i.e., two squares of the size of the letter “M”). If more than one bulleted statement is placed on the same horizontal line, the end of one bulleted statement shall be separated from the beginning of the next bulleted statement by at least two square “ems” and the complete additional bulleted statement(s) shall not continue to the next line of text. Additional bulleted statements appearing on each subsequent horizontal line of text under a heading or subheading shall be vertically aligned with the bulleted statements appearing on the previous line.
(5) The title, headings, subheadings, and information set forth in paragraphs (c)(1) through (c)(9) of this section may appear on more than one panel on the outside container of the retail package, or the immediate container label if there is no outside container or wrapper. The continuation of the required content and format onto multiple panels must retain the required order and flow of headings, subheadings, and information. A visual graphic (e.g., an arrow) shall be used to signal the continuation of the Drug Facts labeling to the next adjacent panel.
(6) The heading and information required under paragraph (c)(2) of this section shall appear immediately adjacent and to the left of the heading and information required under paragraph (c)(3) of this section. The active ingredients and purposes shall be aligned under the appropriate headings such that the heading and information required under paragraph (c)(2) of this section shall be left justified and the heading and information required under paragraph (c)(3) of this section shall be right justified. If the OTC drug product contains more than one active ingredient, the active ingredients shall be listed in alphabetical order. If more than one active ingredient has the same purpose, the purpose need not be repeated for each active ingredient, provided the information is presented in a manner that readily associates each active ingredient with its purpose (i.e., through the use of brackets, dot leaders, or other graphical features). The information described in paragraphs (c)(4) and (c)(6) through (c)(9) of this section may start on the same line as the required headings. None of the information described in paragraph (c)(5) of this section shall appear on the same line as the “Warning” or “Warnings” heading.
(7) Graphical images (e.g., the UPC symbol) and information not described in paragraphs (c)(1) through (c)(9) of this section shall not appear in or in any way interrupt the required title, headings, subheadings, and information in paragraphs (c)(1) through (c)(9) of this section. Hyphens shall not be used except to punctuate compound words.
(8) The information described in paragraphs (c)(1) through (c)(9) of this section shall be set off in a box or similar enclosure by the use of a barline. A distinctive horizontal barline extending to each end of the “Drug Facts” box or similar enclosure shall provide separation between each of the headings listed in paragraphs (c)(2) through (c)(9) of this section. When a heading listed in paragraphs (c)(2) through (c)(9) of this section appears on a subsequent panel immediately after the “Drug Facts (continued)” title, a horizontal hairline shall follow the title and immediately precede the heading. A horizontal hairline extending within two spaces on either side of the “Drug Facts” box or similar enclosure shall immediately follow the title and shall immediately precede each of the subheadings set forth in paragraph (c)(5) of this section, except the subheadings in paragraphs (c)(5)(ii)(A) through (c)(5)(ii)(G) of this section.
(9) The information set forth in paragraph (c)(6) of this section under the heading “Directions” shall appear in a table format when dosage directions are provided for three or more age groups or populations. The last line of the table may be the horizontal barline immediately preceding the heading of the next section of the labeling.
(10) If the title, headings, subheadings, and information in paragraphs (c)(1) through (c)(9) of this section, printed in accordance with the specifications in paragraphs (d)(1) through (d)(9) of this section, and any other FDA required information for drug products, and, as appropriate, cosmetic products, other than information required to appear on a principle display panel, requires more than 60 percent of the total surface area available to bear labeling, then the Drug Facts labeling shall be printed in accordance with the specifications set forth in paragraphs (d)(10)(i) through (d)(10)(v) of this section. In determining whether more than 60 percent of the total surface area available to bear labeling is required, the indications for use listed under the “Use(s)” heading, as set forth in paragraph (c)(4) of this section, shall be limited to the minimum required uses reflected in the applicable monograph, as provided in § 330.1(c)(2) of this chapter.
(i) Paragraphs (d)(1), (d)(5), (d)(6), and (d)(7) of this section shall apply.
(ii) Paragraph (d)(2) of this section shall apply except that the letter height or type size for the title “Drug Facts (continued)” shall be no smaller than 7-point type and the headings in paragraphs (c)(2) through (c)(9) of this section shall be the larger of either 7-point or greater type, or 1-point size greater than the point size of the text.
(iii) Paragraph (d)(3) of this section shall apply except that less than 0.5-point leading may be used, provided the ascenders and descenders do not touch.
(iv) Paragraph (d)(4) of this section shall apply except that if more than one bulleted statement is placed on the same horizontal line, the additional bulleted statements may continue to the next line of text, and except that the bullets under each heading or subheading need not be vertically aligned.
(v) Paragraph (d)(8) of this section shall apply except that the box or similar enclosure required in paragraph (d)(8) of this section may be omitted if the Drug Facts labeling is set off from the rest of the labeling by use of color contrast.
(11)(i) The following labeling outlines the various provisions in paragraphs (c) and (d) of this section:
(ii) The following sample label illustrates the provisions in paragraphs (c) and (d) of this section:
(iii) The following sample label illustrates the provisions in paragraphs (c) and (d) of this section, including paragraph (d)(10) of this section, which permits modifications for small packages:
(iv) The following sample label illustrates the provisions in paragraphs (c) and (d) of this section for a drug product marketed with cosmetic claims:
(e) Exemptions and deferrals. FDA on its own initiative or in response to a written request from any manufacturer, packer, or distributor, may exempt or defer, based on the circumstances presented, one or more specific requirements set forth in this section on the basis that the requirement is inapplicable, impracticable, or contrary to public health or safety. Requests for exemptions shall be submitted in three copies in the form of an “Application for Exemption” to the Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. The request shall be clearly identified on the envelope as a “Request for Exemption from 21 CFR 201.66 (OTC Labeling Format)” and shall be directed to Docket No. 98N-0337. A separate request shall be submitted for each OTC drug product. Sponsors of a product marketed under an approved drug application shall also submit a single copy of the exemption request to their application. Decisions on exemptions and deferrals will be maintained in a permanent file in this docket for public review. Exemption and deferral requests shall:
(1) Document why a particular requirement is inapplicable, impracticable, or is contrary to public health or safety; and
(2) Include a representation of the proposed labeling, including any outserts, panel extensions, or other graphical or packaging techniques intended to be used with the product.
(f) Interchangeable terms and connecting terms. The terms listed in § 330.1(i) of this chapter may be used interchangeably in the labeling of OTC drug products, provided such use does not alter the meaning of the labeling that has been established and identified in an applicable OTC drug monograph or by regulation. The terms listed in § 330.1(j) of this chapter may be deleted from the labeling of OTC drug products when the labeling is revised to comply with this section, provided such deletion does not alter the meaning of the labeling that has been established and identified in an applicable OTC drug monograph or by regulation. The terms listed in § 330.1(i) and (j) of this chapter shall not be used to change in any way the specific title, headings, and subheadings required under paragraphs (c)(1) through (c)(9) of this section.
(g) Regulatory action. An OTC drug product that is not in compliance with the format and content requirements in this section is subject to regulatory action.
§ 201.67   Labeling requirements for a nonprescription drug product with an additional condition for nonprescription use (ACNU).
(a) Scope. This section sets forth labeling requirements for a nonprescription drug product with an ACNU.
(b) Definition. The following definition applies to this section:
(1) Additional condition for nonprescription use (ACNU) means one or more FDA-approved conditions that an applicant of a nonprescription drug product must implement to ensure consumers' appropriate self-selection or appropriate actual use, or both, of the nonprescription drug product without the supervision of a practitioner licensed by law to administer such drug, if the applicant demonstrates and FDA determines that labeling alone is insufficient to ensure appropriate self-selection or appropriate actual use, or both.
(2) [Reserved]
(c) General labeling requirements. (1) A nonprescription drug product with an ACNU must comply with applicable labeling requirements for nonprescription drug products under this part, including the format and content requirements for nonprescription drug product labeling under § 201.66 and the statements specified in § 201.130(a) and (b).
(2) A nonprescription drug product with an ACNU may also be approved with additional labeling that supplements the format and content requirements for nonprescription drug product labeling under § 201.66.
(d) Format requirements for the required statement about the ACNU. The statement about the ACNU specified in § 201.130(b)(1) must meet all format requirements as follows:
(1) The statement about the ACNU must appear on the principal display panel (see § 201.60) and the immediate container surface that the consumer is most likely to view when seeking information about the drug product. If the immediate container is a bottle, the statement about the ACNU must appear on the surface that the consumer is most likely to consider the front of the bottle. If the immediate container is a blister card (including a card that contains more than one blister unit), the statement about the ACNU must appear on the blister card surface that the consumer would most likely view when removing the drug product from the blister card. If the blister card contains more than one blister unit ( e.g., perforated blister card where individual blister units can be separated from one another), the statement about the ACNU does not need to be included on each blister unit of a blister card. However, the statement about the ACNU must remain intact and be readable on the blister card when the drug product is removed from each blister unit.
(2) The statement about the ACNU must appear in boldface and black type.
(3) The statement about the ACNU must appear in a yellow background banner. No other information or statements may be included within the yellow background banner.
(4) The statement about the ACNU must be in one of the following font sizes, whichever is greater:
(i) At least 25 percent as large as the font size of the largest printed words on the principal display panel and immediate container; or
(ii) At least 12-point font (1 point = 0.0138 inches).
(5) An applicant may request an exception to the minimum font size requirement specified in paragraph (d)(4) of this section for containers where its size would render compliance with this requirement impractical. FDA may allow such an exception upon request by an applicant if FDA determines an exception is warranted.
(e) Misbranding. A nonprescription drug product with an ACNU is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352) if—
(1) It does not comply with the labeling requirements specified in paragraphs (c) and (d) of this section and § 201.130(a) through (c); or
(2) The ACNU is not implemented by the applicant in accordance with the following, as approved by FDA in the application:
(i) 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; or
(ii) 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.
§ 201.70   Calcium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended for oral ingestion shall contain the calcium content per dosage unit (e.g., tablet, teaspoonful) if the calcium content of a single maximum recommended dose of the product (which may be one or more dosage units) is 20 milligrams or more. OTC drug products intended for oral ingestion include gum and lozenge dosage forms, but do not include dentifrices, mouthwashes, or mouth rinses.
(b) The calcium content shall be expressed in milligrams or grams per dosage unit and shall include the total amount of calcium regardless of the source, i.e., from both active and inactive ingredients. If the dosage unit contains less than 1 gram of calcium, milligrams should be used. The calcium content per dosage unit shall be rounded-off to the nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). The calcium content per dosage unit shall follow the heading “Other information” as stated in § 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion shall contain the following statement under the heading “Warning” (or “Warnings” if it appears with additional warning statements) if the amount of calcium present in the labeled maximum daily dose of the product is more than 3.2 grams: “Ask a doctor before use if you have [in bold type] [bullet] 1 kidney stones [bullet] a calcium-restricted diet”. The warnings in §§ 201.64(c), 201.70(c), 201.71(c), and 201.72(c) may be combined, if applicable, provided the ingredients are listed in alphabetical order, e.g., a calcium or sodium restricted diet.
1 See § 201.66(b)(4) of this chapter for definition of bullet symbol.
(d) Any product subject to this paragraph that is not labeled as required by this paragraph 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.
(1) As of the date of approval of the application for any single entity and combination products subject to drug marketing applications approved on or after April 23, 2004.
(2) September 24, 2005, for all OTC drug products subject to any OTC drug monograph, not yet the subject of any OTC drug monograph, or subject to drug marketing applications approved before April 23, 2004.
§ 201.71   Magnesium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended for oral ingestion shall contain the magnesium content per dosage unit (e.g., tablet, teaspoonful) if the magnesium content of a single maximum recommended dose of the product (which may be one or more dosage units) is 8 milligrams or more. OTC drug products intended for oral ingestion include gum and lozenge dosage forms, but do not include dentifrices, mouthwashes, or mouth rinses.
(b) The magnesium content shall be expressed in milligrams or grams per dosage unit and shall include the total amount of magnesium regardless of the source, i.e., from both active and inactive ingredients. If the dosage unit contains less than 1 gram of magnesium, milligrams should be used. The magnesium content shall be rounded-off to the nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). The magnesium content per dosage unit shall follow the heading “Other information” as stated in § 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion shall contain the following statement under the heading “Warning” (or “Warnings” if it appears with additional warning statements) if the amount of magnesium present in the labeled maximum daily dose of the product is more than 600 milligrams: “Ask a doctor before use if you have [in bold type] [bullet] 1 kidney disease [bullet] a magnesium-restricted diet”. The warnings in §§ 201.64(c), 201.70(c), 201.71(c), and 201.72(c) may be combined, if applicable, provided the ingredients are listed in alphabetical order, e.g., a magnesium or potassium-restricted diet.
1 See § 201.66(b)(4) of this chapter for definition of bullet symbol.
(d) Any product subject to this paragraph that is not labeled as required by this paragraph 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.
(1) As of the date of approval of the application for any single entity and combination products subject to drug marketing applications approved on or after April 23, 2004.
(2) September 24. 2005, for all OTC drug products subject to any OTC drug monograph, not yet the subject of any OTC drug monograph, or subject to drug marketing applications approved before April 23, 2004.
§ 201.72   Potassium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended for oral ingestion shall contain the potassium content per dosage unit (e.g., tablet, teaspoonful) if the potassium content of a single maximum recommended dose of the product (which may be one or more dosage units) is 5 milligrams or more. OTC drug products intended for oral ingestion include gum and lozenge dosage forms, but do not include dentifrices, mouthwashes, or mouth rinses.
(b) The potassium content shall be expressed in milligrams or grams per dosage unit and shall include the total amount of potassium regardless of the source, i.e., from both active and inactive ingredients. If the dosage unit contains less than 1 gram of potassium, milligrams should be used. The potassium content shall be rounded-off to the nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). The potassium content per dosage unit shall follow the heading “Other information” as stated in § 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion shall contain the following statement under the heading “Warning” (or “Warnings” if it appears with additional warning statements) if the amount of potassium present in the labeled maximum daily dose of the product is more than 975 milligrams: “Ask a doctor before use if you have [in bold type] [bullet] 1 kidney disease [bullet] a potassium-restricted diet”. The warnings in §§ 201.64(c), 201.70(c), 201.71(c), and 201.72(c) may be combined, if applicable, provided the ingredients are listed in alphabetical order, e.g., a magnesium or potassium-restricted diet.
1 See § 201.66(b)(4) of this chapter for definition of bullet symbol.
(d) Any product subject to this paragraph that is not labeled as required by this paragraph 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.
(1) As of the date of approval of the application for any single entity and combination products subject to drug marketing applications approved on or after April 23, 2004.
(2) September 24, 2005, for all OTC drug products subject to any OTC drug monograph, not yet the subject of any OTC drug monograph, or subject to drug marketing applications approved before April 23, 2004.