Labelling (general) (21 CFR 201.1-201.327)

8 21 CFR Ch. I (4–1–16 Edition) Pt. 201 associated with the product without in dicating each active ingredient (the es tablished name and quantity of each active ingredient are not required); the dosage form; and the price charged for a prescription for a specific quantity of the drug product. (3) The reminder advertisement or re minder labeling may also include other written, printed, or graphic matter, e.g., identification of professional or convenience services provided by the pharmacy: Provided, That such infor mation is neither false nor misleading and contains no representation or sug gestion concerning the drug product’s safety, effectiveness, or indications for use. (4) The price stated in the reminder advertisement or reminder labeling as that charged for a prescription shall in clude all charges to the consumer in cluding, but not limited to, the cost of the drug product, professional fees, and handling fees, if any. Mailing fees and delivery fees, if any, may be stated sep arately and without repetition. (b) This exemption from §§ 201.100 and 202.1 of this chapter is applicable to all prescription drug reminder labeling and reminder advertisements solely in tended to provide consumers with in formation regarding the price charged for prescriptions including price lists, catalogs, and other promotional mate rial, whether mailed, posted in a phar macy, placed in a newspaper, or aired on radio or television. (c) Any reminder advertisement or reminder labeling intended to provide consumers with prescription price in formation which is not in compliance with this section shall be the subject of appropriate regulatory action. Such ac tion may be taken against the product and/or the responsible person. [40 FR 58799, Dec. 18, 1975] PART 201—LABELING Subpart A—General Labeling Provisions Sec. 201.1 Drugs; name and place of business of manufacturer, packer, or distributor. 201.2 Drugs and devices; National Drug Code numbers. 201.5 Drugs; adequate directions for use. 201.6 Drugs; misleading statements. 201.10 Drugs; statement of ingredients. 201.15 Drugs; prominence of required label statements. 201.16 Drugs; Spanish-language version of certain required statements. 201.17 Drugs; location of expiration date. 201.18 Drugs; significance of control num bers. 201.19 Drugs; use of term ‘‘infant’’. 201.20 Declaration of presence of FD&C Yel low No. 5 and/or FD&C Yellow No. 6 in certain drugs for human use. 201.21 Declaration of presence of phenylalanine as a component of aspar tame in over-the-counter and prescrip tion drugs for human use. 201.22 Prescription drugs containing sul fites; required warning statements. 201.23 Required pediatric studies. 201.24 Labeling for systemic antibacterial drug products. 201.25 Bar code label requirements. 201.26 Exceptions or alternatives to labeling requirements for human drug products held by the Strategic National Stockpile. Subpart B—Labeling Requirements for Prescription Drugs and/or Insulin 201.50 Statement of identity. 201.51 Declaration of net quantity of con tents. 201.55 Statement of dosage. 201.56 Requirements on content and format of labeling for human prescription drug and biological products. 201.57 Specific requirements on content and format of labeling for human prescrip tion drug and biological products de scribed in § 201.56(b)(1). 201.58 Waiver of labeling requirements. Subpart C—Labeling Requirements for Over-the-Counter Drugs 201.60 Principal display panel. 201.61 Statement of identity. 201.62 Declaration of net quantity of con tents. 201.63 Pregnancy/breast-feeding warning. 201.64 Sodium labeling. 201.66 Format and content requirements for over-the-counter (OTC) drug product la beling. 201.70 Calcium labeling. 201.71 Magnesium labeling. 201.72 Potassium labeling. 201.80 Specific requirements on content and format of labeling for human prescrip tion drug and biological products; older drugs not described in § 201.56(b)(1). Subpart D—Exemptions From Adequate Directions for Use 201.100 Prescription drugs for human use. 201.105 Veterinary drugs. 201.115 New drugs or new animal drugs. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00018 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 9 Food and Drug Administration, HHS § 201.1 201.116 Drugs having commonly known di rections. 201.117 Inactive ingredients. 201.119 In vitro diagnostic products. 201.120 Prescription chemicals and other prescription components. 201.122 Drugs for processing, repacking, or manufacturing. 201.125 Drugs for use in teaching, law en forcement, research, and analysis. 201.127 Drugs; expiration of exemptions. 201.128 Meaning of ‘‘intended uses’’. 201.129 Drugs; exemption for radioactive drugs for research use. Subpart E—Other Exemptions 201.150 Drugs; processing, labeling, or re packing. 201.161 Carbon dioxide and certain other gases. Subpart F—Labeling Claims for Drugs in Drug Efficacy Study 201.200 Disclosure of drug efficacy study evaluations in labeling and advertising. Subpart G—Specific Labeling Requirements for Specific Drug Products 201.300 Notice to manufacturers, packers, and distributors of glandular prepara tions. 201.301 Notice to manufacturers, packers, and distributors of estrogenic hormone preparations. 201.302 Notice to manufacturers, packers, and distributors of drugs for internal use which contain mineral oil. 201.303 Labeling of drug preparations con taining significant proportions of winter green oil. 201.304 Tannic acid and barium enema prep arations. 201.305 Isoproterenol inhalation prepara tions (pressurized aerosols, nebulizers, powders) for human use; warnings. 201.306 Potassium salt preparations in tended for oral ingestion by man. 201.307 Sodium phosphates; package size limitation, warnings, and directions for over-the-counter sale. 201.308 Ipecac syrup; warnings and direc tions for use for over-the-counter sale. 201.309 Acetophenetidin (phenacetin)-con taining preparations; necessary warning statement. 201.310 Phenindione; labeling of drug prep arations intended for use by man. 201.311 [Reserved] 201.312 Magnesium sulfate heptahydrate; label declaration on drug products. 201.313 Estradiol labeling. 201.314 Labeling of drug preparations con taining salicylates. 201.315 Over-the-counter drugs for minor sore throats; suggested warning. 201.316 Drugs with thyroid hormone activity for human use; required warning. 201.317 Digitalis and related cardiotonic drugs for human use in oral dosage forms; required warning. 201.319 Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (in cluding, but not limited to agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carra geenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil tragacanth, and xanthan gum) as active ingredients; required warnings and direc tions. 201.320 Warning statements for drug prod ucts containing or manufactured with chlorofluorocarbons or other ozone-de pleting substances. 201.323 Aluminum in large and small vol ume parenterals used in total parenteral nutrition. 201.325 Over-the-counter drugs for vaginal contraceptive and spermicide use con taining nonoxynol 9 as the active ingre dient; required warnings and labeling in formation. 201.326 Over-the-counter drug products con taining internal analgesic/antipyretic ac tive ingredients; required warnings and other labeling. 201.327 Over-the-counter sunscreen drug products; required labeling based on ef fectiveness testing. APPENDIX A TO PART 201—EXAMPLES OF GRAPHIC ENHANCEMENTS USED BY FDA AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 360b, 360gg–360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264. SOURCE: 40 FR 13998, Mar. 27, 1975, unless otherwise noted. EDITORIAL NOTE: Nomenclature changes to part 201 appear at 69 FR 13717, Mar. 24, 2004. Subpart A—General Labeling Provisions § 201.1 Drugs; name and place of busi ness 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 sec tion 502 (a) and (b)(1) of the act if its label does not bear conspicuously the name and place of business of the man ufacturer, packer, or distributor. This paragraph does not apply to any drug VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00019 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 10 21 CFR Ch. I (4–1–16 Edition) § 201.1 or drug product dispensed in accord ance 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 re quired to produce the product: (1) Mix ing, (2) granulating, (3) milling, (4) molding, (5) lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9) steri lizing, and (10) filling sterile, aerosol, or gaseous drugs into dispensing con tainers. (c) If no person performs all of the applicable operations listed in para graph (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 ‘‘Cer tain manufacturing operations have been performed by other firms.’’; or (2) If the person performs at least one applicable operation listed in para graph (b) of this section and identifies by appropriate designation all other persons who have performed the re maining 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 para graph (b) of this section and the person is listed along with all other persons who have performed the remaining ap plicable operations as ‘‘joint manufac turers.’’ A list of joint manufacturers shall be qualified by the phrase ‘‘Jointly Manufactured By llllll,’’ and the names of all of the manufacturers shall be printed to gether in the same type size and style; or (4) If the person performs all applica ble 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, in cludes a parent, subsidiary, or affiliate company where the related companies are under common ownership and con trol. (d) The Food and Drug Administra tion finds that it is the common prac tice in the drug industry to contract out the performance of certain manu facturing operations listed in para graph (b) of this section. These oper ations include: (1) Soft-gelatin encap sulating, (2) aerosol filling, (3) steri lizing 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, in cluding the performance of the appro priate in-process quality control oper ations, 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 op eration, are subject to the person’s di rection and control; (2) On premises that are continuously owned or leased by the person and sub ject to the person’s direction and con trol; and (3) On equipment that is continu ously owned or leased by the person. As used in this paragraph, person, when it identifies a corporation, includes a par ent, subsidiary, or affiliate company where the related companies are under common ownership and control. (f) The name of the person rep resented as manufacturer under para graph (b) or (c) of this section must be the same as either (1) the name of the establishment (as defined in § 207.3(b) of this chapter) under which that person is registered at the time the labeled product is produced or (2) the reg istered establishment name of a par ent, subsidiary, or affiliate company where the related companies are under common ownership and control. In ad dition, the name shall meet the re quirements of paragraph (g) of this sec tion. (g) The requirement for declaration of the name of the manufacturer, pack er, or distributor shall be deemed to be satisfied, in the case of a corporate per son, only by the actual corporate name, except that the corporate name may be the name of a parent, sub sidiary, or affiliate company where the related companies are under common ownership and control. The corporate VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00020 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 11 Food and Drug Administration, HHS § 201.5 name may be preceded or followed by the name of the particular division of the corporation. ‘‘Company,’’ ‘‘Incor porated,’’ 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 sec tion, no person other than the manu facturer, 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 quali fication 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 ac cordance with this section. (3) If the names of two or more per sons 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 prod uct. (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 trade mark. (5) If the distributor is named on the label, the name shall be qualified by one of the following phrases: ‘‘Manu factured for llllll’’, ‘‘Distributed by llllll’’, ‘‘Manufactured by llllll for llllll’’, ‘‘Manu factured for lllllby lllll’’, ‘‘Distributor: llllll’’, ‘‘Marketed by llllll’’. 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 llllll’’ or ‘‘Packaged by llllll’’. The quali fying phrases may be abbreviated. (i) The statement of the place of busi ness 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 ad dress may be omitted if it is shown in a current city directory or telephone directory. The requirement for inclu sion of the ZIP Code shall apply to con sumer 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 prin cipal 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 la beling of drug components. (l) A drug product is misbranded under section 502(a) of the act if its la beling identifies a person as manufac turer, packer, or distributor, and that identification does not meet the re quirements of this section. (m) This section does not apply to bi ological drug products that are subject to the requirements of section 351 of the Public Health Service Act, 42 U.S.C. 262. [45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. 31, 1980, as amended at 48 FR 37620, Aug. 19, 1983] § 201.2 Drugs and devices; National Drug Code numbers. The National Drug Code (NDC) num ber is requested but not required to ap pear on all drug labels and in all drug labeling, including the label of any pre scription drug container furnished to a consumer. If the NDC number is shown on a drug label, it shall be displayed as required in § 207.35(b)(3) of this chapter. [40 FR 52002, Nov. 7, 1975] § 201.5 Drugs; adequate directions for use. Adequate directions for use means di rections under which the layman can use a drug safely and for the purposes for which it is intended. (Section VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00021 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 12 21 CFR Ch. I (4–1–16 Edition) § 201.6 201.128 defines ‘‘intended use.’’) Direc tions for use may be inadequate be cause, among other reasons, of omis sion, in whole or in part, or incorrect specification of: (a) Statements of all conditions, pur poses, or uses for which such drug is in tended, including conditions, purposes, or uses for which it is prescribed, rec ommended, or suggested in its oral, written, printed, or graphic adver tising, and conditions, purposes, or uses for which the drug is commonly used; except that such statements shall not refer to conditions, uses, or pur poses 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 quan tities for persons of different ages and different physical conditions. (c) Frequency of administration or application. (d) Duration of administration or ap plication. (e) Time of administration or appli cation (in relation to time of meals, time of onset of symptoms, or other time factors). (f) Route or method of administra tion or application. (g) Preparation for use, i.e., shaking, dilution, adjustment of temperature, or, other manipulation or process. [41 FR 6908, Feb. 13, 1976] § 201.6 Drugs; misleading statements. (a) Among representations in the la beling 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 con tains two or more ingredients may be misleading by reason, among other rea sons, 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 ingredi ents are stated elsewhere in the label ing. [41 FR 6908, Feb. 13, 1976] § 201.10 Drugs; statement of ingredi ents. (a) The ingredient information re quired by section 502(e) of the Federal Food, Drug, and Cosmetic Act shall ap pear together, without any intervening written, printed, or graphic matter, ex cept the proprietary names of ingredi ents, which may be included with the listing of established names, and such statements that are specifically re quired 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 sub stance or in admixture with other sub stances. (c) The labeling of a drug may be misleading by reason (among other rea sons) of: (1) The order in which the names of the ingredients present in the drug ap pear 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 in gredient present in such drug, when such proportion or other fact is mate rial in the light of the representation that such ingredient is present in such drug. (3) The employment of a fanciful pro prietary name for a drug or ingredient in such a manner as to imply that the drug or ingredient has some unique ef fectiveness or composition when, in fact, the drug or ingredient is a com mon substance, the limitations of which are readily recognized when the drug or ingredient is listed by its es tablished name. (4) The featuring in the labeling of inert or inactive ingredients in a man ner that creates an impression of value greater than their true functional role in the formulation. (5) Designation of a drug or ingre dient by a proprietary name that, be cause of similarity in spelling or pro nunciation, 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 cap sule form or other unit dosage form, any statement of the quantity of an in gredient contained therein shall ex press the quantity of such ingredient in VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00022 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 13 Food and Drug Administration, HHS § 201.10 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 prescrip tion 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 qualifica tion, 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 ingre dient 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 vol ume 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 chem ical 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 ingre dient does not indicate that it is a de rivative or preparation of the parent substance named in section 502(e) of the act, the labeling shall, in conjunc tion with the listing of the established name of such ingredient, declare that such article is a derivative or prepara tion of such parent substance. (g)(1) If the label or labeling of a pre scription 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 designa tion 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 propri etary name or designation in the run ning 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 propri etary 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 presen tation of the proprietary name or des ignation in such running text. If any labeling includes a column with run ning text containing detailed informa tion 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 estab lished name shall be used at least once in such column of running text in asso ciation with such proprietary name or designation and in the same type size used in such column of running text: Provided, however, That if the propri etary 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 pres entation of the proprietary name or designation in such column of running text. Where the established name is re quired 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 designa tion, 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 com mensurate with the prominence with VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00023 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 14 21 CFR Ch. I (4–1–16 Edition) § 201.15 which such proprietary name or des ignation appears, taking into account all pertinent factors, including typog raphy, layout, contrast, and other printing features. (h)(1) In the case of a prescription drug containing two or more active in gredients, if the label bears a propri etary name or designation for such mixture and there is no established name corresponding to such propri etary name or designation, the quan titative ingredient information re quired on the label by section 502(e) of the act shall be placed in direct con junction with the most prominent dis play of the proprietary name or des ignation. The prominence of the quan titative ingredient information shall bear a reasonable relationship to the prominence of the proprietary name. (2) If the drug is packaged in a con tainer too small to bear the quan titative ingredient information on the main display panel, the quantitative ingredient information required by sec tion 502(e) of the act may appear else where on the label, even though the proprietary name or designation ap pears on the main display panel of the label; but side- or back-panel place ment shall in this case be so arranged and printed as to provide size and prominence of display reasonably re lated to the size and prominence of the front-panel display. (i) A drug packaged in a container too small or otherwise unable to ac commodate 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 ex empt 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 con tainer, or wrapper has sufficient space to bear such information, or such com plete label information appears on a leaflet with the package. [40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002] § 201.15 Drugs; prominence of required label statements. (a) A word, statement, or other infor mation required by or under authority of the act to appear on the label may lack that prominence and conspicuous ness required by section 502(c) of the act by reason, among other reasons, of: (1) The failure of such word, state ment, or information to appear on the part or panel of the label which is pre sented or displayed under customary conditions of purchase; (2) The failure of such word, state ment, 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 de signed as to render it likely to be, under customary conditions of pur chase, the part or panel displayed; (3) The failure of the label to extend over the area of the container or pack age available for such extension, so as to provide sufficient label space for the prominent placing of such word, state ment, or information; (4) Insufficiency of label space for the prominent placing of such word, state ment, 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, state ment, or information, resulting from the use of label space to give materi ally 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 infor mation appears, insufficient back ground contrast, obscuring designs or vignettes, or crowding with other writ ten, printed, or graphic matter. (b) No exemption depending on insuf ficiency 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00024 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 15 Food and Drug Administration, HHS § 201.19 which is not required by or under au thority 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 rep resentation 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, how ever, That in the case of articles dis tributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant lan guage may be substituted for English. (2) If the label contains any represen tation in a foreign language, all words, statements, and other information re quired 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 rep resentation in a foreign language, all words, statements, and other informa tion required by or under authority of the act to appear on the label or label ing shall appear on the labeling in the foreign language. [41 FR 6908, Feb. 13, 1976] § 201.16 Drugs; Spanish-language version of certain required state ments. An increasing number of medications restricted to prescription use only are being labeled solely in Spanish for dis tribution in the Commonwealth of Puerto Rico where Spanish is the pre dominant language. Such labeling is authorized under § 201.15(c). One re quired warning, the wording of which is fixed by law in the English language, could be translated in various ways, from literal translation to loose inter pretation. 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’’. [67 FR 4906, Feb. 1, 2002] § 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 imme diate container and also the outer package, if any, unless it is easily leg ible through such outer package. How ever, when single-dose containers are packed in individual cartons, the expi ration date may properly appear on the individual carton instead of the imme diate product container. [43 FR 45076, Sept. 29, 1978] § 201.18 Drugs; significance of control numbers. The lot number on the label of a drug should be capable of yielding the com plete 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 die tary foods (§ 105.3(e) of this chapter) de fine 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 label ing, 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 regula tion, where the exact meaning of the term is significant, manufacturers should qualify any reference to ‘‘in fant’’ 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. [40 FR 13998, Mar. 27, 1975, as amended at 42 FR 14091, Mar. 15, 1977; 44 FR 16006, Mar. 16, 1979] VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00025 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 16 21 CFR Ch. I (4–1–16 Edition) § 201.20 § 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, na sally, 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 prod ucts 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 require ments 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 (in cluding bronchial asthma) in certain susceptible persons. Although the over all 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 state ment 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 list ing 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 re quirement 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. [45 FR 60422, Sept. 12, 1980, as amended at 51 FR 41783, Nov. 19, 1986; 52 FR 21509, June 8, 1987; 59 FR 60898, Nov. 29, 1994] EFFECTIVE DATE NOTE: At 53 FR 49138, Dec. 6, 1988, § 201.20(c) was suspended pending fur ther agency action. § 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-a aspartyl-L-phenylalanine), they produce an intensely sweet-tasting sub stance, 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 per form its intended technical function is safe for use as an inactive ingredient in human drug products, provided persons with phenylketonuria, who must re strict carefully their phenylalanine in take, 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 con taining aspartame as an inactive ingre dient shall bear a statement to the fol lowing effect: Phenylketonurics: Con tains Phenylalanine (l)mg Per (Dos age Unit). (c) The package labeling and other labeling providing professional use in formation concerning prescription drugs for human use containing aspar tame as an inactive ingredient shall bear a statement to the following ef fect under the ‘‘Precautions’’ section of the labeling, as required in § 201.57(f)(2): Phenylketonurics: Contains Phenylalanine (l)mg Per (Dosage Unit). (d) Holders of approved new drug ap plications who reformulate their drug products under the provisions of this section shall submit supplements under § 314.70 of this chapter to provide for VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00026 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 17 Food and Drug Administration, HHS § 201.23 the new composition and the labeling changes. (Approved by the Office of Management and Budget under control number 0910–0242) [52 FR 2111, Jan. 20, 1987; 52 FR 12152, Apr. 15, 1987; 53 FR 4135, Feb. 12, 1988] § 201.22 Prescription drugs containing sulfites; required warning state ments. (a) Sulfites are chemical substances that are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation of the ac tive drug ingredient may result in in stability and a loss of potency of the drug product. Examples of specific sul fites used to inhibit this oxidation process include sodium bisulfite, so dium metabisulfite, sodium sulfite, po tassium bisulfite, and potassium metabisulfite. Recent studies have demonstrated that sulfites may cause allergic-type reactions in certain sus ceptible persons, especially asthmatics. The labeling for any prescription drug product to which sulfites have been added as an inactive ingredient, regard less 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 in tended 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 sensi tivity in the general population is un known and probably low. Sulfite sensi tivity is seen more frequently in asth matic 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 epi nephrine for injection for use in aller gic 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 re actions including anaphylactic symp toms or life-threatening or less severe asthmatic episodes in certain suscep tible persons. The alternatives to using epinephrine in a life-threatening situa tion may not be satisfactory. The pres ence 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 ‘‘Warn ings’’ section of the labeling. [51 FR 43904, Dec. 5, 1986] § 201.23 Required pediatric studies. (a) A manufacturer of a marketed drug product, including a biological drug product, that is used in a substan tial number of pediatric patients, or that provides a meaningful therapeutic benefit over existing treatments for pe diatric patients, as defined in §§ 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose label does not pro vide adequate information to support its safe and effective use in pediatric populations for the approved indica tions may be required to submit an ap plication 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 adoles cents, depending upon the known or ap propriate use of the drug product in such subpopulations. The applicant may also be required to develop a pedi atric formulation for a drug product that represents a meaningful thera peutic benefit over existing therapies for pediatric populations for whom a pediatric formulation is necessary, un less the manufacturer demonstrates that reasonable attempts to produce a pediatric formulation have failed. (b) The Food and Drug Administra tion (FDA) may by order, in the form of a letter, after notifying the manu facturer of its intent to require an as sessment of pediatric safety and effec tiveness of a pediatric formulation, and after offering an opportunity for a written response and a meeting, which VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00027 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 18 21 CFR Ch. I (4–1–16 Edition) § 201.24 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 sub stantial number of pediatric patients for the labeled indications and the ab sence of adequate labeling could pose significant risks to pediatric patients; or (2) There is reason to believe that the drug product would represent a mean ingful 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 pedi atric patients. (c)(1) An applicant may request a full waiver of the requirements of para graph (a) of this section if the appli cant 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 sug gesting that the product would be inef fective or unsafe in all pediatric age groups. (2) An applicant may request a par tial waiver of the requirements of para graph (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 thera pies for pediatric patients in that age group, and (B) Is not likely to be used in a sub stantial number of patients in that age group, and (C) The absence of adequate labeling could not pose significant risks to pedi atric 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 sug gesting that the product would be inef fective 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 sec tion have been met. If a waiver is granted on the ground that it is not possible to develop a pediatric formula tion, the waiver will cover only those pediatric age groups requiring that for mulation. If a waiver is granted be cause there is evidence that the prod uct would be ineffective or unsafe in pediatric populations, this information will be included in the product’s label ing. (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 prod uct may be considered misbranded or an unapproved new drug or unlicensed biologic. [63 FR 66668, Dec. 2, 1998] § 201.24 Labeling for systemic anti bacterial drug products. The labeling of all systemic drug products intended for human use indi cated to treat a bacterial infection, ex cept 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-resist ant 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-resist ant 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 sus ceptibility information are available, they VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00028 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 19 Food and Drug Administration, HHS § 201.25 should be considered in selecting or modi fying antibacterial therapy. In the absence of such data, local epidemiology and suscep tibility patterns may contribute to the em piric selection of therapy. (c) In the ‘‘Precautions’’ section, under the ‘‘General’’ subsection, the la beling 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 pro vide 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 anti bacterial drugs including (insert name of anti bacterial 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 prod uct) is prescribed to treat a bacterial infec tion, 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 anti bacterial drug product) or other antibacterial drugs in the future. [68 FR 6081, Feb. 6, 2003] § 201.25 Bar code label requirements. (a) Who is subject to these bar code re quirements? Manufacturers, repackers, relabelers, and private label distribu tors of a human prescription drug prod uct 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 reg istration 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, how ever: (i) The bar code requirement does not apply to the following entities: (A) Prescription drug samples; (B) Allergenic extracts; (C) Intrauterine contraceptive de vices 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 pa tients, but versions of the same drug product that are sold to or used in hos pitals are subject to the bar code re quirements. (2) Biological products; and (3) OTC drug products that are dis pensed pursuant to an order and are commonly used in hospitals. For pur poses of this section, an OTC drug product is ‘‘commonly used in hos pitals’’ 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 ap propriate National Drug Code (NDC) number in a linear bar code that meets European Article Number/Uniform Code Council (EAN.UCC) or Health In dustry Business Communications Council (HIBCC) standards. Addition ally, 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 con ditions 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 Cos metic Act. (d) Can a drug be exempted from the bar code requirement? (1) On our own initia tive, or in response to a written re quest 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 re quest must document why: (i) compliance with the bar code re quirement would adversely affect the VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00029 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 20 21 CFR Ch. I (4–1–16 Edition) § 201.26 safety, effectiveness, purity or potency of the drug or not be technologically feasible, and the concerns underlying the request could not reasonably be ad dressed by measures such as package redesign or use of overwraps; or (ii) an alternative regulatory pro gram 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 Re search, 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 prod uct regulated by the Center for Bio logics Evaluation and Research). [69 FR 9170, Feb. 26, 2004, as amended at 76 FR 12847, Mar. 9, 2011; 80 FR 18090, Apr. 3, 2015] § 201.26 Exceptions or alternatives to labeling requirements for human drug products held by the Strategic National Stockpile. (a) The appropriate FDA Center Di rector may grant an exception or alter native to any provision listed in para graph (f) of this section and not explic itly required by statute, for specified lots, batches, or other units of a human drug product, if the Center Director de termines that compliance with such la beling requirement could adversely af fect the safety, effectiveness, or avail ability of such product that is or will be included in the Strategic National Stockpile. (b)(1)(i) A Strategic National Stock pile official or any entity that manu factures (including labeling, packing, relabeling, or repackaging), distrib utes, or stores a human drug product that is or will be included in the Stra tegic National Stockpile may submit, with written concurrence from a Stra tegic National Stockpile official, a written request for an exception or al ternative 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 ad versely 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 in cludes appropriate information nec essary for the safe and effective use of the product, given the anticipated cir cumstances of use of the product; (v) Provide a draft of the proposed la beling 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 alter native 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 require ments 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 chap ter; however, VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00030 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 21 Food and Drug Administration, HHS § 201.51 (2) You must report any grant of a re quest for an exception or alternative under this section as part of your an nual 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 sec tion to the following provisions of this chapter, to the extent that the require ments in these provisions are not ex plicitly 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. [72 FR 73599, Dec. 28, 2007] Subpart B—Labeling Requirements for Prescription Drugs and/or Insulin § 201.50 Statement of identity. (a) The label of prescription and insu lin-containing drugs in package form shall bear as one of its principal fea tures 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 quan titative ingredient information as pre scribed by § 201.10. (c) The statement of identity of a prescription drug shall also comply with the placement, size and promi nence requirements of § 201.10. [40 FR 13998, Mar. 27, 1975, as amended at 63 FR 26698, May 13, 1998] § 201.51 Declaration of net quantity of contents. (a) The label of a prescription or in sulin-containing drug in package form shall bear a declaration of the net quantity of contents. This shall be ex pressed in the terms of weight, meas ure, 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 ex pressed 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 con tents shall in the case of prescription drugs be expressed in terms of avoirdu pois pound, ounce, and grain or of kilo gram, gram, and subdivisions thereof. A statement of liquid measure of the contents shall in the case of prescrip tion 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 applica ble to such drug, under the provisions VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00031 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 22 21 CFR Ch. I (4–1–16 Edition) § 201.55 of paragraph (a) of this section, shall express with prominence and conspicu ousness 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 dec imal 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 dur ing 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 un reasonably large. In the case of a liquid drug in ampules or vials, intended for injection, the declaration shall be con sidered to express the minimum quan tity and the variation above the stated measure shall comply with the excess volume prescribed by the National For mulary or the U.S. Pharmacopeia for filling of ampules. In the case of a solid drug in ampules or vials, the declara tion shall be considered to express the accurate net weight. Variations shall comply with the limitations provided in the U.S. Pharmacopeia or the Na tional Formulary. (h) A drug shall be exempt from com pliance with the net quantity declara tion required by this section if it is an ointment labeled ‘‘sample’’, ‘‘physi cian’s sample’’, or a substantially simi lar statement and the contents of the package do not exceed 8 grams. § 201.55 Statement of dosage. Section 201.100(b)(2) requires that la bels for prescription drugs bear a state ment of the recommended or usual dos age. Since the dosage for some pre scription drugs varies within extremely wide limits, depending upon the condi tions being treated, it may not be pos sible in all cases to present an inform ative or useful statement of the rec ommended 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 de tailed information is contained in such insert. However, if an informative, re alistic, 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 pre scription drug and biological prod ucts. (a) General requirements. Prescription drug labeling described in § 201.100(d) must meet the following general re quirements: (1) The labeling must contain a sum mary of the essential scientific infor mation needed for the safe and effec tive 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 la beling to become inaccurate, false, or misleading. (3) The labeling must be based when ever possible on data derived from human experience. No implied claims or suggestions of drug use may be made if there is inadequate evidence of safe ty 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 sub ject to the labeling content and format re quirements in §§ 201.56(d) and 201.57. (1) The following categories of prescrip tion drug products are subject to the labeling requirements in paragraph (d) of this section and § 201.57 in accord ance 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; VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00032 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 23 Food and Drug Administration, HHS § 201.56 (ii) Prescription drug products for which an NDA, BLA, or efficacy supple ment is pending on June 30, 2006; or (iii) Prescription drug products for which an NDA, BLA, or efficacy supple ment is submitted anytime on or after June 30, 2006. (2) Prescription drug products not de scribed in paragraph (b)(1) of this sec tion are subject to the labeling require ments in paragraph (e) of this section and § 201.80. (c) Schedule for implementing the label ing content and format requirements in §§ 201.56(d) and 201.57. For products de scribed in paragraph (b)(1) of this sec tion, labeling conforming to the re quirements in paragraph (d) of this sec tion and § 201.57 must be submitted ac cording to the following schedule: (1) For products for which an NDA, BLA, or efficacy supplement is sub mitted for approval on or after June 30, 2006, proposed conforming labeling must be submitted as part of the appli cation. (2) For products for which an NDA, BLA, or efficacy supplement is pending on June 30, 2006, or that has been ap proved any time from June 30, 2005, up to and including June 30, 2006, a supple ment with proposed conforming label ing 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 sup plement with proposed conforming la beling 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 sup plement with proposed conforming la beling 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 sup plement with proposed conforming la beling 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 sup plement with proposed conforming la beling 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 de scribed in § 201.100(d) must contain the specific information required under § 201.57(a), (b), and (c) under the fol lowing headings and subheadings and in the following order: Highlights of Prescribing Information Product Names, Other Required Informa tion Boxed Warning Recent Major Changes Indications and Usage Dosage and Administration Dosage Forms and Strengths Contraindications Warnings and Precautions Adverse Reactions Drug Interactions Use in Specific Populations Full Prescribing Information: Contents Full Prescribing Information Boxed Warning 1 Indications and Usage 2 Dosage and Administration 3 Dosage Forms and Strengths 4 Contraindications 5 Warnings and Precautions 6 Adverse Reactions 7 Drug Interactions 8 Use in Specific Populations 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, impair ment of fertility 13.2 Animal toxicology and/or pharma cology 14 Clinical Studies 15 References VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00033 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 24 21 CFR Ch. I (4–1–16 Edition) § 201.57 16 How Supplied/Storage and Handling 17 Patient Counseling Information (2) Additional nonstandard sub headings that are used to enhance la beling organization, presentation, or ease of use (e.g., for individual warn ings or precautions, or for each drug interaction) must be assigned a dec imal number that corresponds to their placement in labeling. The decimal numbers must be consistent with the standardized identifying numbers list ed in paragraph (d)(1) of this section (e.g., subheadings added to the ‘‘Warn ings and Precautions’’ section must be numbered 5.1, 5.2, and so on). (3) Any reference in Highlights to in formation appearing in the full pre scribing information must be accom panied by the identifying number (in parentheses) corresponding to the loca tion of the information in the full pre scribing information. (4) Omit clearly inapplicable sec tions, subsections, or specific informa tion. If sections or subsections required under paragraph (d)(1) of this section are omitted from the full prescribing information, the heading ‘‘Full Pre scribing Information: Contents’’ must be followed by an asterisk and the fol lowing statement must appear at the end of Contents: ‘‘* Sections or sub sections omitted from the full pre scribing information are not listed.’’ (5) Any risk information that is re quired under § 201.57(c)(9)(iv) is consid ered ‘‘appropriate pediatric contra indications, warnings, or precautions’’ within the meaning of section 505A(l)(2) of the Federal Food, Drug, and Cos metic 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 la beling. (e) Labeling requirements for older pre scription drug products. This paragraph applies only to approved prescription drug products not described in para graph (b)(1) of this section. (1) Prescription drug labeling de scribed 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 fol lowing additional section headings if appropriate and if in compliance with § 201.80(l) and (m): Animal Pharmacology and/or Animal Toxi cology Clinical Studies References (3) Omit clearly inapplicable sec tions, subsections, or specific informa tion. (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 informa tion required by § 201.80(a)(1)(i) through (a)(1)(iv) must appear in the ‘‘Descrip tion’’ 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 la beling at the end of prescription drug labeling or accompany the prescription drug labeling must be implemented no later than June 30, 2007. [71 FR 3986, Jan. 24, 2006, as amended at 79 FR 72101, Dec. 4, 2014] § 201.57 Specific requirements on con tent and format of labeling for human prescription drug and bio logical products described in § 201.56(b)(1). The requirements in this section apply only to prescription drug prod ucts 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-ap proved patient labeling at the end of VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00034 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 25 Food and Drug Administration, HHS § 201.57 prescription drug labeling or accom pany the prescription drug labeling, which must be implemented no later than June 30, 2007. (a) Highlights of prescribing informa tion. The following information must appear in all prescription drug label ing: (1) Highlights limitation statement. The verbatim statement ‘‘These highlights do not include all the information needed to use (insert name of drug prod uct) safely and effectively. See full pre scribing 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 Fed eral 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’’ fol lowed by the four-digit year in which FDA initially approved a new molec ular entity, new biological product, or new combination of active ingredients. The statement must be placed on the line immediately beneath the estab lished name or, for biological products, proper name of the product. (4) Boxed warning. A concise sum mary of any boxed warning required by paragraph (c)(1) of this section, not to exceed a length of 20 lines. The sum mary 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 sum mary 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 informa tion for complete boxed warning.’’ (5) Recent major changes. A list of the section(s) of the full prescribing infor mation, limited to the labeling sec tions described in paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this sec tion, that contain(s) substantive label ing 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 head ing(s) and, if appropriate, the sub heading(s) of the labeling section(s) af fected by the change must be listed to gether 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 ap pear in the full prescribing informa tion. A changed section must be listed under this heading in Highlights for at least 1 year after the date of the label ing 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 indi cations, as required under paragraph (c)(2) of this section, with any appro priate 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 (indica tion(s)).’’ (7) Dosage and administration. A con cise summary of the information re quired under paragraph (c)(3) of this section, with any appropriate sub headings, including the recommended dosage regimen, starting dose, dose range, critical differences among popu lation subsets, monitoring rec ommendations, and other clinically significant clinical pharmacologic in formation. (8) Dosage forms and strengths. A con cise summary of the information re quired under paragraph (c)(4) of this section, with any appropriate sub headings (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. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00035 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 26 21 CFR Ch. I (4–1–16 Edition) § 201.57 (9) Contraindications. A concise state ment of each of the product’s contra indications, as required under para graph (c)(5) of this section, with any appropriate subheadings. (10) Warnings and precautions. A con cise 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, rec ommendations for patient monitoring that are critical to safe use of the drug, and measures that can be taken to pre vent or mitigate harm. (11) Adverse reactions. (i) A list of the most frequently occurring adverse re actions, as described in paragraph (c)(7) of this section, along with the criteria used to determine inclusion (e.g., inci dence rate). Adverse reactions impor tant for other reasons (e.g., because they are serious or frequently lead to discontinuation or dosage adjustment) must not be repeated under this head ing in Highlights if they are included elsewhere in Highlights (e.g., Warnings and Precautions, Contraindications). (ii) For drug products other than vac cines, the verbatim statement ‘‘To re port SUSPECTED ADVERSE REAC TIONS, contact (insert name of manu facturer) at (insert manufacturer’s phone number) or FDA at (insert current FDA phone number and Web address for vol untary reporting of adverse reactions).’’ (iii) For vaccines, the verbatim state ment ‘‘To report SUSPECTED AD VERSE REACTIONS, contact (insert name of manufacturer) at (insert manu facturer’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 sum mary of the information required under paragraph (c)(8) of this section, with any appropriate subheadings. (13) Use in specific populations. A con cise summary of the information re quired under paragraph (c)(9) of this section, with any appropriate sub headings. (14) Patient counseling information statement. The verbatim statement ‘‘See 17 for Patient Counseling Infor mation’’ or, if the product has FDA-ap proved patient labeling, the verbatim statement ‘‘See 17 for Patient Coun seling 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: Con tents. 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 identi fying number required under § 201.56(d)(1). Contents must also con tain any additional subheading(s) in cluded in the full prescribing informa tion preceded by the identifying num ber assigned in accordance with § 201.56(d)(2). (c) Full prescribing information. The full prescribing information must con tain the information in the order re quired 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 pre ceded by the identifying number as signed in accordance with § 201.56(d)(2). (1) Boxed warning. Certain contra indications or serious warnings, par ticularly 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 ani mal toxicity may also be the basis of a boxed warning in the absence of clin ical data. The box must contain, in up percase letters, a heading inside the box that includes the word ‘‘WARN ING’’ 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. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00036 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 27 Food and Drug Administration, HHS § 201.57 (2) 1 Indications and usage. This sec tion must state that the drug is indi cated for the treatment, prevention, mitigation, cure, or diagnosis of a rec ognized disease or condition, or of a manifestation of a recognized disease or condition, or for the relief of symp toms associated with a recognized dis ease or condition. (i) This section must include the fol lowing information when the condi tions listed are applicable: (A) If the drug is used for an indica tion only in conjunction with a pri mary mode of therapy (e.g., diet, sur gery, behavior changes, or some other drug), a statement that the drug is in dicated 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 pa tients in a special age group), or if the indication is approved based on a sur rogate endpoint under § 314.510 or § 601.41 of this chapter, a succinct de scription of the limitations of useful ness of the drug and any uncertainty about anticipated clinical benefits, with reference to the ‘‘Clinical Stud ies’’ 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 sus ceptibility tests), the identity of such tests. (D) If information on limitations of use or uncertainty about anticipated clinical benefits is relevant to the rec ommended intervals between doses, to the appropriate duration of treatment when such treatment should be lim ited, or to any modification of dosage, a concise description of the informa tion with reference to the more de tailed 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 refrac tory 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., dem onstration of responsiveness to the drug in a short term trial in a given pa tient), 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 indica tions 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 prepon derance of evidence related to the use or condition shows that the drug is in effective or that the therapeutic bene fits 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 effec tive 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 de rived from adequate and well-con trolled 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 bio logical 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 indi cations listed in this section must be supported by substantial evidence of ef fectiveness. 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 rec ommended dose and, as appropriate: (A) The dosage range, (B) An upper limit beyond which safety and effectiveness have not been established, or beyond which increas ing the dose does not result in increas ing effectiveness, VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00037 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 28 21 CFR Ch. I (4–1–16 Edition) § 201.57 (C) Dosages for each indication and subpopulation, (D) The intervals recommended be tween 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 be cause of drug interactions or in special patient populations (e.g., in children, in geriatric age groups, in groups de fined by genetic characteristics, or in patients with renal or hepatic disease), (I) Important considerations con cerning 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 signifi cant. Information on therapeutic drug concentration monitoring (TDM) must also be included in this section when TDM is necessary. (ii) Dosing regimens must not be im plied or suggested in other sections of the labeling if not included in this sec tion. (iii) Radiation dosimetry information must be stated for both the patient re ceiving a radioactive drug and the per son administering it. (iv) This section must also contain specific direction on dilution, prepara tion (including the strength of the final dosage solution, when prepared accord ing to instructions, in terms of milli grams of active ingredient per milli liter 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 reconsti tuted 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 mat ter and discoloration prior to adminis tration, whenever solution and con tainer 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 respon sible, including: (i) The strength or potency of the dosage form in metric system (e.g., 10 milligram tablets), and, if the apothe cary system is used, a statement of the strength in parentheses after the met ric designation; and (ii) A description of the identifying characteristics of the dosage forms, in cluding 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 out weighs any possible therapeutic ben efit. Those situations include use of the drug in patients who, because of their particular age, sex, concomitant ther apy, 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 pos sibilities 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 con traindications 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 po tential safety hazards (including those that are expected for the pharma cological 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00038 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 29 Food and Drug Administration, HHS § 201.57 mortality and morbidity rates for pa tients experiencing the reaction, if known and necessary for the safe and effective use of the drug, must be ex pressed 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 spe cific warning relating to a use not pro vided 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 com monly prescribed for a disease or con dition and such usage is associated with a clinically significant risk or hazard. (ii) Other special care precautions. This section must contain information re garding any special care to be exer cised by the practitioner for safe and effective use of the drug (e.g., pre cautions 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 ad verse reactions. If appropriate, infor mation must be provided on such fac tors as the range of normal and abnor mal values expected in the particular situation and the recommended fre quency with which tests should be per formed before, during, and after ther apy. (iv) Interference with laboratory tests. This section must briefly note informa tion on any known interference by the product with laboratory tests and ref erence the section where the detailed information is presented (e.g., ‘‘Drug Interactions’’ section). (7) 6 Adverse reactions. This section must describe the overall adverse reac tion profile of the drug based on the en tire safety database. For purposes of prescription drug labeling, an adverse reaction is an undesirable effect, rea sonably associated with use of a drug, that may occur as part of the pharma cological 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 ex posed, 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 com bination of these, as appropriate. With in a category, adverse reactions must be listed in decreasing order of fre quency. If frequency information can not be reliably determined, adverse re actions must be listed in decreasing order of severity. (A) Clinical trials experience. This sec tion must list the adverse reactions identified in clinical trials that oc curred at or above a specified rate ap propriate to the safety database. The rate of occurrence of an adverse reac tion for the drug and comparators (e.g., placebo) must be presented, unless such data cannot be determined or presen tation 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 deter mined (e.g., adverse reactions were ob served 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 occur ring at a rate of less than 1/100, adverse reactions occurring at a rate of less than 1/500) or descriptively identified, VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00039 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 30 21 CFR Ch. I (4–1–16 Edition) § 201.57 if frequency ranges cannot be deter mined. For adverse reactions with sig nificant clinical implications, the list ings must be supplemented with addi tional detail about the nature, fre quency, and severity of the adverse re action and the relationship of the ad verse reaction to drug dose and demo graphic characteristics, if data are available and important. (B) Postmarketing experience. This sec tion of the labeling must list the ad verse 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 label ing applies with other drugs in terms of frequency, severity, or character of ad verse reactions must be based on ade quate and well-controlled studies as de fined in § 314.126(b) of this chapter un less 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 ob served or predicted, with other pre scription or over-the-counter drugs, classes of drugs, or foods (e.g., dietary supplements, grapefruit juice), and spe cific practical instructions for pre venting or managing them. The mecha nism(s) of the interaction, if known, must be briefly described. Interactions that are described in the ‘‘Contra indications’’ or ‘‘Warnings and Pre cautions’’ sections must be discussed in more detail under this section. Details of drug interaction pharmacokinetic studies that are included in the ‘‘Clin ical 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 inter ference of the drug with laboratory tests. (9) 8 Use in specific populations. This section must contain the following sub sections: (i) 8.1 Pregnancy. This subsection of the labeling must contain the following information in the following order under the subheadings ‘‘Pregnancy Ex posure 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 in formation about the registry must be provided following the statement: ‘‘There is a pregnancy exposure reg istry that monitors pregnancy out comes 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 im pairment, 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, regard less of drug exposure. If such informa tion 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 addi tional details in the relevant portion of the ‘‘Data’’ subheading in the ‘‘Preg nancy’’ subsection of the labeling. If data demonstrate that a drug is not systemically absorbed following a par ticular route of administration, the Risk Summary must contain only the following statement: ‘‘(Name of drug) is not absorbed systemically following (route of administration), and mater nal use is not expected to result in fetal exposure to the drug.’’ VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00040 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 31 Food and Drug Administration, HHS § 201.57 (1) Risk statement based on human data. When human data are available that establish the presence or absence of any adverse developmental out come(s) associated with maternal use of the drug, the Risk Summary must summarize the specific developmental outcome(s); their incidence; and the ef fects of dose, duration of exposure, and gestational timing of exposure. If human data indicate that there is an increased risk for a specific adverse de velopmental outcome in infants born to women exposed to the drug during pregnancy, this risk must be quan titatively 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 condi tion 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 indi cated, the risk for the specific outcome must be compared to the rate at which the outcome occurs in the general pop ulation. 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-associ ated 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 devel opmental 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 pharma cology. When the drug has a well-under stood mechanism of action that may result in adverse developmental out come(s), the Risk Summary must ex plain the mechanism of action and the potential associated risks. (C) Clinical considerations. Under the subheading ‘‘Clinical Considerations,’’ the labeling must provide relevant in formation, 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 de livery’’: (1) Disease-associated maternal and/or embryo/fetal risk. If there is a serious known or potential risk to the preg nant woman and/or the embryo/fetus associated with the disease or condi tion 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 preg nancy or if a known adverse reaction occurs with increased frequency or se verity in pregnant women, the labeling must describe the adverse reaction and available intervention(s) for moni toring 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 re action. (4) Fetal/Neonatal adverse reactions. If it is known or anticipated that treat ment of the pregnant woman increases or may increase the risk of an adverse reaction in the fetus or neonate, the la beling must describe the adverse reac tion, the potential severity and revers ibility of the adverse reaction, and available intervention(s) for moni toring 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 ex pected 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00041 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 32 21 CFR Ch. I (4–1–16 Edition) § 201.57 duration of labor and delivery; any in creased risk of adverse reactions, in cluding their potential severity and re versibility; and must provide informa tion about available intervention(s) that can mitigate these effects and/or adverse reactions. The information de scribed under this heading is not re quired for drugs approved for use only during labor and delivery. (D) Data—(1) ‘‘Data’’ subheading. Under the subheading ‘‘Data,’’ the la beling 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 pre sented separately, beneath the head ings ‘‘Human Data’’ and ‘‘Animal Data,’’ and human data must be pre sented first. (3) Description of human data. For human data, the labeling must describe adverse developmental outcomes, ad verse reactions, and other adverse ef fects. To the extent applicable, the la beling must describe the types of stud ies 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 ani mal 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 limi tations of the data. Description of ma ternal and offspring findings must in clude dose-response and severity of ad verse developmental outcomes. Animal doses or exposures must be described in terms of human dose or exposure equivalents and the basis for those cal culations 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 Sum mary,’’ ‘‘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’’ sub section of the labeling. When human data are available, animal data must not be included unless the animal model is specifically known to be pre dictive 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 admin istration), and breastfeeding is not ex pected 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 metabo lite(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 esti mated daily dose for an infant fed ex clusively 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 dem onstrate the presence of the drug and/ or its active metabolite(s) in human milk but the drug and/or its active me tabolite(s) are not expected to be sys temically 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 metabo lite(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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00042 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 33 Food and Drug Administration, HHS § 201.57 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 me tabolite(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 devel opmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for (name of drug) and any potential ad verse effects on the breast-fed child from (name of drug) or from the under lying maternal condition.’’ (B) Clinical considerations. Under ‘‘Clinical Considerations,’’ the fol lowing information must be provided to the extent it is available and rel evant: (1) Minimizing exposure. The labeling must describe ways to minimize expo sure 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 applica ble, 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 miti gating the adverse reaction(s) pre sented 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 reproduc tive 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,’’ ‘‘Contracep tion,’’ 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 pedi atric patient(s) are defined as the pedi atric age group, from birth to 16 years, including age groups often called neo nates, infants, children, and adoles cents. (B) If there is a specific pediatric in dication different from those approved for adults that is supported by ade quate and well-controlled studies in the pediatric population, it must be de scribed under the ‘‘Indications and Usage’’ section, and appropriate pedi atric dosage information must be given under the ‘‘Dosage and Administra tion’’ section. The ‘‘Pediatric use’’ sub section must cite any limitations on the pediatric indication, need for spe cific monitoring, specific hazards asso ciated with use of the drug in any sub sets of the pediatric population (e.g., neonates), differences between pedi atric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. Data summarized in this sub section should be discussed in more de tail, if appropriate, under the ‘‘Clinical Pharmacology’’ or ‘‘Clinical Studies’’ section. As appropriate, this informa tion 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 indica tion also approved for adults that are based on adequate and well-controlled studies in the pediatric population, they must be summarized in the ‘‘Pe diatric use’’ subsection and discussed in more detail, if appropriate, under the ‘‘Clinical Pharmacology’’ and VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00043 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 34 21 CFR Ch. I (4–1–16 Edition) § 201.57 ‘‘Clinical Studies’’ sections. Appro priate pediatric dosage must be given under the ‘‘Dosage and Administra tion’’ section. The ‘‘Pediatric use’’ sub section of the labeling must also cite any limitations on the pediatric use statement, need for specific moni toring, 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 infor mation related to the safe and effective pediatric use of the drug. As appro priate, this information must also be contained in the ‘‘Contraindications’’ and/or ‘‘Warnings and Precautions’’ section(s). (D)(1) When a drug is approved for pe diatric 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 fol lowing statement or a reasonable alter native: The safety and effectiveness of (drug name) have been established in the age groups lll to lll (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 ade quate and well-controlled studies of (drug name) in adults with additional data (insert wording that accurately describes the data sub mitted to support a finding of substantial evi dence of effectiveness in the pediatric popu lation). (2) Data summarized in the preceding prescribed statement in this subsection must be discussed in more detail, if ap propriate, under the ‘‘Clinical Pharma cology’’ or the ‘‘Clinical Studies’’ sec tion. For example, pediatric pharmaco kinetic or pharmacodynamic studies and dose response information should be described in the ‘‘Clinical Pharma cology’’ section. Pediatric dosing in structions must be included in the ‘‘Dosage and Administration’’ section. Any differences between pediatric and adult responses, need for specific moni toring, 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 ap propriate, in the ‘‘Contraindications,’’ ‘‘Warnings and Precautions,’’ and ‘‘Dosage and Administration’’ sections. (E) If the requirements for a finding of substantial evidence to support a pe diatric indication or a pediatric use statement have not been met for a par ticular pediatric population, the ‘‘Pe diatric use’’ subsection must contain an appropriate statement such as ‘‘Safety and effectiveness in pediatric patients below the age of (ll) have not been established.’’ If use of the drug in this pediatric population is as sociated with a specific hazard, the hazard must be described in this sub section, or, if appropriate, the hazard must be stated in the ‘‘Contraindica tions’’ 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 pe diatric 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 neo natal infants, or other pediatric sub groups, is associated with a specific hazard, the hazard must be described in this subsection, or, if appropriate, the hazard must be stated in the ‘‘Contra indications’’ or ‘‘Warnings and Pre cautions’’ section and this subsection must refer to it. (G) If the sponsor believes that none of the statements described in para graphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are appropriate or rel evant 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 para graphs 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 ef fects to neonates or other pediatric subgroups, a special note of this risk must be made, generally in the ‘‘Con traindications’’ or ‘‘Warnings and Pre cautions’’ section. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00044 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 35 Food and Drug Administration, HHS § 201.57 (v) 8.5 Geriatric use. (A) A specific geriatric indication, if any, that is sup ported by adequate and well-controlled studies in the geriatric population must be described under the ‘‘Indica tions and Usage’’ section, and appro priate geriatric dosage must be stated under the ‘‘Dosage and Administra tion’’ section. The ‘‘Geriatric use’’ sub section must cite any limitations on the geriatric indication, need for spe cific monitoring, specific hazards asso ciated 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 per tain to use of the drug in persons 65 years of age and older. Data summa rized in this subsection must be dis cussed in more detail, if appropriate, under ‘‘Clinical Pharmacology’’ or the ‘‘Clinical Studies’’ section. As appro priate, this information must also be contained in the ‘‘Warnings and Pre cautions’’ and/or ‘‘Contraindications’’ section(s). (B) Specific statements on geriatric use of the drug for an indication ap proved for adults generally, as distin guished from a specific geriatric indi cation, must be contained in the ‘‘Geriatric use’’ subsection and must reflect all information available to the sponsor that is relevant to the appro priate use of the drug in elderly pa tients. This information includes de tailed results from controlled studies that are available to the sponsor and pertinent information from well-docu mented studies obtained from a lit erature search. Controlled studies in clude those that are part of the mar keting application and other relevant studies available to the sponsor that have not been previously submitted in the investigational new drug applica tion, new drug application, biologics li cense application, or a supplement or amendment to one of these applica tions (e.g., postmarketing studies or adverse drug reaction reports). The ‘‘Geriatric use’’ subsection must con tain the following statement(s) or rea sonable alternative, as applicable, tak ing 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 sub jects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clin ical experience has not identified dif ferences in responses between the el derly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, re flecting the greater frequency of de creased hepatic, renal, or cardiac func tion, and of concomitant disease or other drug therapy. (2) If clinical studies (including stud ies that are part of marketing applica tions and other relevant studies avail able to the sponsor that have not been submitted in the sponsor’s applica tions) 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 con tain the following statement: Of the total number of subjects in clinical studies of (name of drug), ll percent were 65 and over, while ll 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 ef fectiveness were observed between these sub jects and younger subjects, and other re ported 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 moni toring or dosage adjustment, the VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00045 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 36 21 CFR Ch. I (4–1–16 Edition) § 201.57 ‘‘Geriatric use’’ subsection must con tain a brief description of observed dif ferences or specific monitoring or dos age requirements and, as appropriate, must refer to more detailed discussions in the ‘‘Contraindications,’’ ‘‘Warnings and Precautions,’’ ‘‘Dosage and Admin istration,’’ 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 con tain information on drug/disease and drug/drug interactions that is particu larly relevant to the elderly, who are more likely to have concomitant ill ness and to use concomitant drugs. (2) If a drug is known to be substan tially excreted by the kidney, the ‘‘Geriatric use’’ subsection must in clude the statement: This drug is known to be substantially ex creted by the kidney, and the risk of adverse reactions to this drug may be greater in pa tients with impaired renal function. Because elderly patients are more likely to have de creased 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 ‘‘Geri atric use’’ subsection, or, if appro priate, 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 effec tive 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 para graphs (c)(9)(v)(A) through (c)(9)(v)(E) of this section are appropriate or rel evant 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 state ments if FDA determines that no state ment described in those paragraphs is appropriate or relevant to the drug’s labeling. FDA may permit use of an al ternative statement if the agency de termines that such statement is accu rate and appropriate. (vi) Additional subsections. Additional subsections may be included, as appro priate, 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 in formation, 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 reac tions pertinent to them, and must identify particularly susceptible pa tient populations. This subsection must be based primarily on human data and human experience, but perti nent animal data may also be used. (iii) 9.3 Dependence. This subsection must describe characteristic effects re sulting from both psychological and physical dependence that occur with the drug and must identify the quan tity of the drug over a period of time that may lead to tolerance or depend ence, 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 with drawal 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 fol lowing 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 tox icity or delayed acidosis); VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00046 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 37 Food and Drug Administration, HHS § 201.57 (iii) Concentrations of the drug in biologic fluids associated with toxicity or death; physiologic variables influ encing excretion of the drug, such as urine pH; and factors that influence the dose response relationship of the drug, such as tolerance. The pharmaco kinetic data given in the ‘‘Clinical Pharmacology’’ section also may be referenced here, if applicable to overdoses; (iv) The amount of the drug in a sin gle 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 diure sis, 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 rec ommendations for which data are lack ing 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 es tablished 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 chap ter) 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 quan titative ingredient information as re quired 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 state ment of that fact; (E) The pharmacological or thera peutic class of the drug; (F) For drug products other than bio logical 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, ex ternal 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 re lating to the human clinical pharma cology and actions of the drug in hu mans. 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 under stand dosing or drug interaction infor mation presented in other sections of the labeling. This section must include the following subsections: (A) 12.1 Mechanism of action. This sub section must summarize what is known about the established mechanism(s) of the drug’s action in humans at various levels (e.g., receptor, membrane, tis sue, organ, whole body). If the mecha nism of action is not known, this sub section must contain a statement about the lack of information. (B) 12.2 Pharmacodynamics. This sub section must include a description of any biochemical or physiologic phar macologic effects of the drug or active metabolites related to the drug’s clin ical effect in preventing, diagnosing, mitigating, curing, or treating disease, or those related to adverse effects or toxicity. Exposure-response relation ships (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 con tain a statement about the lack of in formation. Detailed dosing or moni toring recommendations based on pharmacodynamic information that appear in other sections (e.g., ‘‘Warn ings and Precautions’’ or ‘‘Dosage and Administration’’) must not be repeated in this subsection, but the location of such recommendations must be ref erenced. (C) 12.3 Pharmacokinetics. This sub section must describe the clinically significant pharmacokinetics of a drug or active metabolites, (i.e., pertinent absorption, distribution, metabolism, VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00047 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 38 21 CFR Ch. I (4–1–16 Edition) § 201.57 and excretion parameters). Informa tion regarding bioavailability, the ef fect of food, minimum concentration (Cmin), maximum concentration (Cmax), time to maximum concentration (Tmax), area under the curve (AUC), pertinent half-lives (t1/2), time to reach steady state, extent of accumulation, route(s) of elimination, clearance (renal, he patic, total), mechanisms of clearance (e.g., specific enzyme systems), drug/ drug and drug/food (e.g., dietary sup plements, grapefruit juice) pharmaco kinetic interactions (including inhibi tion, induction, and genetic character istics), and volume of distribution (Vd) must be presented if clinically signifi cant. Information regarding nonlin earity 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 me tabolism or interaction) that establish the absence of an effect, including per tinent 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 Spe cific Populations’’) must not be re peated in this subsection, but the loca tion 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 cir cumstances: (A) In vitro data for anti-infective drugs may be included if the data are immediately preceded by the state ment ‘‘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-con trolled 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 sec tion must contain the following sub sections as appropriate: (i) 13.1 Carcinogenesis, mutagenesis, im pairment 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 state ment on these topics must include practical, relevant advice to the pre scriber on the significance of these ani mal findings. Human data suggesting that the drug may be carcinogenic or mutagenic, or suggesting that it im pairs 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 phar macology. Significant animal data nec essary for safe and effective use of the drug in humans that is not incor porated 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. Or dinarily, this section will describe the studies that support effectiveness for the labeled indication(s), including dis cussion of study design, population, endpoints, and results, but must not in clude an encyclopedic listing of all, or even most, studies performed as part of the product’s clinical development pro gram. 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00048 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 39 Food and Drug Administration, HHS § 201.57 information in that section of the la beling, any detailed discussion of the study must appear in this section. (i) For drug products other than bio logical 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 ‘‘In dications and Usage’’ or ‘‘Dosage and Administration’’ section. For biologi cal products, any clinical study that is discussed that relates to an indication for or use of the biological product must constitute or contribute to sub stantial evidence and must not imply or suggest indications or uses or dosing regimens not stated in the ‘‘Indications and Usage’’ or ‘‘Dosage and Adminis tration’’ 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 oth erwise 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 han dling. This section must contain infor mation 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 apothe cary system is used, a statement of the strength in parentheses after the met ric designation; (ii) The units in which the dosage form is ordinarily available for pre scribing by practitioners (e.g., bottles of 100); (iii) Appropriate information to fa cilitate 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-ap proved patient labeling must be ref erenced in this section and the full text of such patient labeling must be re printed immediately following this sec tion or, alternatively, accompany the prescription drug labeling. Any FDA approved patient labeling printed im mediately following this section or ac companying the labeling is subject to the type size requirements in para graph (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 fol lowing specifications: (1) All headings and subheadings re quired 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 high lighting. (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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00049 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 40 21 CFR Ch. I (4–1–16 Edition) § 201.58 minimum of 8 points, except for label ing information that is on or within the package from which the drug is to be dispensed, which must be a min imum 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 pre cede 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 para graph (a) of this section, not including the information required under para graph (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 (81⁄2 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 sec tion heading must be in bold print. Each subheading within a section must be indented and not bolded. [71 FR 3988, Jan. 24, 2006, as amended at 79 FR 72101, Dec. 4, 2014] § 201.58 Waiver of labeling require ments. An applicant may ask the Food and Drug Administration to waive any re quirement under §§ 201.56, 201.57, and 201.80. A waiver request must be sub mitted in writing to the Director (or the Director’s designee), Center for Drug Evaluation and Research, Food and Drug Administration, Central Doc ument Room, 5901–B Ammendale Rd., Beltsville, MD 20705–1266, or, if applica ble, the Director (or the Director’s des ignee), 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 Direc tor’s designee. [71 FR 3996, Jan. 24, 2006, as amended at 74 FR 13112, Mar. 26, 2009; 80 FR 18090, Apr. 3, 2015] Subpart C—Labeling Require ments for Over-the-Counter Drugs SOURCE: 41 FR 6908, Feb. 13, 1976, unless otherwise noted. § 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 with out obscuring designs, vignettes, or crowding. Where packages bear alter nate principal display panels, informa tion required to be placed on the prin cipal display panel shall be duplicated on each principal display panel. For the purpose of obtaining uniform type size in declaring the quantity of con tents for all packages of substantially the same size, the term area of the prin cipal display panel means the area of the side or surface that bears the prin cipal display panel, which area shall be: (a) In the case of a rectangular pack age where one entire side properly can be considered to be the principal dis play 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 con tainer times the circumference; and (c) In the case of any other shape of container, 40 percent of the total sur face of the container: Provided, how ever, That where such container pre sents an obvious ‘‘principal display panel’’ such as the top of a triangular or circular package, the area shall con sist of the entire top surface. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00050 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 41 Food and Drug Administration, HHS § 201.62 In determining the area of the prin cipal display panel, exclude tops, bot toms, flanges at the tops and bottoms of cans, and shoulders and necks of bot tles or jars. In the case of cylindrical or nearly cylindrical containers, infor mation required by this part to appear on the principal display panel shall ap pear within that 40 percent of the cir cumference which is most likely to be displayed, presented, shown, or exam ined under customary conditions of dis play for retail sale. § 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 fea tures 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 require ment shall be deemed to be satisfied by a prominent and conspicuous state ment of the general pharmacological action(s) of the mixture or of its prin cipal 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 des ignation and shall employ terms de scriptive of general pharmacological category(ies) or principal intended ac tion(s); for example, ‘‘antacid,’’ ‘‘an algesic,’’ ‘‘decongestant,’’ ‘‘antihis taminic,’’ 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 regula tions in this part. (c) The statement of identity shall be presented in bold face type on the prin cipal display panel, shall be in a size reasonably related to the most promi nent 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 dec laration of the net quantity of con tents. 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 tab let, capsule, ampule, or other unit form and the quantity of devices shall be ex pressed 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 cus tom 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 infor mation 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 pack age form shall be expressed in terms of linear measure augmented by a state ment of its width. (2) Whenever the Commissioner de termines for a specific packaged drug that an existing practice of declaring net quantity of contents by weight, measure, numerical count, or a com bination of these does not facilitate value comparisons by consumers, he shall by regulation designate the ap propriate term or terms to be used for such article. (b) Statements of weight of the con tents shall be expressed in terms of av oirdupois pound and ounce. A state ment 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00051 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 42 21 CFR Ch. I (4–1–16 Edition) § 201.62 at 68 °F (20 °C). See also paragraph (p) of this section. (c) The declaration may contain com mon 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 let tering used in the declaration, from other printed label information appear ing 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 in formation 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 exag gerate the amount of the drug in the container. It shall be placed on the principal display panel within the bot tom 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 mar keted 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 con tainer is waived. (3) The principal display panel of a drug marketed on a display card to which the immediate container is af fixed may be considered to be the dis play panel of the card, and the type size of the net quantity of contents statement is governed by the dimen sions 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: Pro vided, 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 con tents that will be expelled when the in structions for use as shown on the con tainer are followed. The propellant is included in the net quantity declara tion. (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 mold ed on a glass or plastic surface is per missible 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 min imum 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 prin cipal display panel of the package and VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00052 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 43 Food and Drug Administration, HHS § 201.62 shall be uniform for all packages of substantially the same size by com plying with the following type speci fications: (1) Not less than one-sixteenth inch in height on packages the principal dis play 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 dis play 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 prin cipal 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 dis play 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. Where the declaration is blown, em bossed, or molded on a glass or plastic surface rather than by printing, typ ing, or coloring, the lettering sizes specified in paragraphs (h) (1) through (4) of this section shall be increased by one-sixteenth of an inch. (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 ap plicable (1 pound or 1 pint or more) fol lowed in parentheses by a declaration in pounds for weight units, with any re mainder 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 remain der in terms of fluid ounces or common or decimal fractions of the pint or quart (see examples set forth in para graphs (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 re spective 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 con tents in terms of fluid measure or nu merical count is optional. It is suffi cient 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 re mainder 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 dec imal 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 11⁄2 pounds weight shall be expressed as ‘‘Net wt. 24 oz (1 lb 8 oz),’’ or ‘‘Net wt. 24 oz (11⁄2 lb)’’ or ‘‘Net wt. 24 oz (1.5 lb)’’. (2) A declaration of three-fourths pound avoirdupois weight shall be ex pressed 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 13⁄4 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 21⁄2 gallons liquid measure shall be expressed as ‘‘Net contents 2 gal 2 qt,’’ ‘‘Net contents 2.5 gallons,’’ or ‘‘Net contents 21⁄2 gal’’ but not as ‘‘2 gal 4 pt’’. (l) For quantities, the following ab breviations and none other may be em ployed. Periods and plural forms are optional: Gallon gal quart qt pint pt ounce oz VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00053 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 44 21 CFR Ch. I (4–1–16 Edition) § 201.63 pound lb grain gr kilogram kg gram g milligram mg microgram mcg liter l milliliter ml cubic centimeter cc yard yd feet or foot ft inch in meter m centimeter cm millimeter mm fluid fl square sq weight wt (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 pa rentheses 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 ad hesive 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 (21⁄2 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 dec laration 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 pro hibit supplemental statements at loca tions other than the principal display panel(s) describing in nondeceptive terms the net quantity of contents, provided that such supplemental state ments 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 quan tity of contents as provided for in para graphs (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 quan tity of contents in terms of the metric system of weight or measure is not re garded 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 dis play 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 dur ing 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 un reasonably large. (r) A drug shall be exempt from com pliance with the net quantity declara tion required by this section if it is an ointment labeled ‘‘sample,’’ ‘‘physi cian’s sample,’’ or a substantially simi lar 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, un less specifically exempted, shall con tain a general warning under the head ing ‘‘Warning’’ (or ‘‘Warnings’’ if it ap pears with additional warning state ments) as follows: ‘‘If pregnant or breast-feeding, ask a health profes sional before use.’’ [first four words of this statement in bold type] In addi tion 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 nurs ing has been established for a par ticular drug product in a new drug ap plication (NDA) or for a product cov ered 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 sec tion, unless otherwise stated in the NDA or in the final OTC drug mono graph. (c) The following OTC drugs are ex empt from the provisions of paragraph (a) of this section: VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00054 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 45 Food and Drug Administration, HHS § 201.64 1 See § 201 .66(b)(4) of this chapter for defini tion of bullet symbol. (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 Administra tion will grant an exemption from paragraph (a) of this section where ap propriate upon petition under the pro visions of § 10.30 of this chapter. Deci sions with respect to requests for ex emptions shall be maintained in a per manent file for public review by the Di vision of Dockets Management (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 para graph (a) of this section. The warning shall be as follows: ‘‘It is especially important not to use’’ (se lect ‘‘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 de livery.’’ [47 FR 54757, Dec. 3, 1982, as amended at 55 FR 27784, July 5, 1990; 59 FR 14364, Mar. 28, 1994; 64 FR 13286, Mar. 17, 1999; 68 FR 24879, May 9, 2003] § 201.64 Sodium labeling. (a) The labeling of over-the-counter (OTC) drug products intended for oral ingestion shall contain the sodium con tent per dosage unit (e.g., tablet, tea spoonful) 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 in gestion include gum and lozenge dosage forms, but do not include dentifrices, mouthwashes, or mouth rinses. (b) The sodium content shall be ex pressed in milligrams per dosage unit and shall include the total amount of sodium regardless of the source, i.e., from both active and inactive ingredi ents. The sodium content shall be rounded-off to the nearest whole num ber. 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 con tain 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 so dium-restricted diet’’. The warnings in §§ 201.64(c), 201.70(c), 201.71(c), and 201.72(c) may be combined, if applica ble, provided the ingredients are listed in alphabetical order, e g., a calcium or sodium restricted diet. (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 max imum 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 prod ucts intended for oral ingestion if the amount of sodium in the labeled max imum 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 max imum 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 so dium, and low sodium shall be in print size and style no larger than the prod uct’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 para graph that contains sodium bicarbon ate, 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 de livered for introduction into interstate VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00055 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 46 21 CFR Ch. I (4–1–16 Edition) § 201.66 commerce after April 22, 1997, is mis branded 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 ini tially introduced or initially delivered for introduction into interstate com merce after the following dates is mis branded 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 prod ucts 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 con tent shall be expressed in milligrams or grams. If less than 1 gram, milli grams should be used. The sodium con tent shall be rounded-off to the nearest whole number if expressed in milli grams (or nearest tenth of a gram if ex pressed 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 so dium phosphate as an active ingredient intended for rectal administration and that is not labeled as required by this paragraph and that is initially intro duced or initially delivered for intro duction into interstate commerce after November 29, 2005, is misbranded under sections 201(n) and 502(a) and (f) of the act. [61 FR 17806, Apr. 22, 1996, as amended at 62 FR 19925, Apr. 24, 1997; 64 FR 13286, Mar. 17, 1999; 69 FR 13724, Mar. 24, 2004; 69 FR 69280, Nov. 29, 2004] § 201.66 Format and content require ments 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 sub ject of an applicable monograph or reg ulation that contains content and for mat requirements that conflict with this section, the content and format re quirements in this section must be fol lowed unless otherwise specifically pro vided in the applicable monograph or regulation. (b) Definitions. The following defini tions 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 com ponent that is intended to furnish pharmacological activity or other di rect effect in the diagnosis, cure, miti gation, treatment, or prevention of dis ease, 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 sec tion, the bullet style is limited to solid squares or solid circles, in the format set forth in paragraph (d)(4) of this sec tion. (5) Established name of a drug or in gredient 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 com pendium, or, if there is no designated official name and the drug or ingre dient is not recognized in an official compendium, the common or usual name of the drug or ingredient. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00056 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 47 Food and Drug Administration, HHS § 201.66 (6) FDA means the Food and Drug Administration. (7) Heading means the required state ments in quotation marks listed in paragraphs (c)(2) through (c)(9) of this section, excluding subheadings (as de fined in paragraph (a)(9) of this sec tion). (8) Inactive ingredient means any com ponent 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 infor mation required under or otherwise de scribed in paragraph (c) of this section. (11) Title means the heading listed at the top of the required OTC drug prod uct labeling, as set forth in paragraph (c)(1) of this section. (12) Total surface area available to bear labeling means all surfaces of the out side 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, head ings, subheadings, and information set forth in paragraphs (c)(1) through (c)(8) of this section, and may contain the in formation under the heading in para graph (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 (con tinued)’’ shall appear at the top of each subsequent panel containing such in formation. (2) ‘‘Active ingredient’’ or ‘‘Active in gredients’’ ‘‘(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 in gredient and the quantity of each ac tive ingredient per dosage unit. Unless otherwise provided in an applicable OTC drug monograph or approved drug application, products marketed with out discrete dosage units (e.g., topicals) shall state the proportion (rather than the quantity) of each ac tive ingredient. (3) ‘‘Purpose’’ or ‘‘Purposes’’, fol lowed 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 prod uct. (5) ‘‘Warning’’ or ‘‘Warnings’’, fol lowed by one or more of the following, if applicable: (i) ‘‘For external use only’’ [in bold type] for topical drug products not in tended 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 ap propriate 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 applica tion 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 ap propriate flammability signal word(s) (e.g., §§ 341.74(c)(5)(iii), 344.52(c), 358.150(c), and 358.550(c) of this chap ter). This warning shall follow a sub heading containing the appropriate flammability signal word(s) described VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00057 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 48 21 CFR Ch. I (4–1–16 Edition) § 201.66 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 bleed ing 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 con taining sodium phosphates set forth in § 201.307(b)(2)(i) or (b)(2)(ii). This warn ing shall follow the subheading ‘‘Dos age warning:’’ (H) Sexually transmitted diseases (STDs) warning for vaginal contracep tive and spermicide drug products con taining 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], fol lowed by all contraindications for use with the product. These contraindica tions are absolute and are intended for situations in which consumers should not use the product unless a prior diag nosis has been established by a doctor or for situations in which certain con sumers 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 la beled only for use in children under 12 years of age, ‘‘Ask a doctor before use if the child has’’ [in bold type], fol lowed by all warnings for persons with certain preexisting conditions (exclud ing pregnancy) and all warnings for persons experiencing certain symp toms. 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 be fore 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 activi ties (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 appli cation whose packaging does not in clude 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 ap plicable 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 aspi rin or carbaspirin calcium; the third trimester warning set forth in ap proved drug applications for products containing ketoprofen, naproxen so dium, and ibuprofen (not intended ex clusively for use in children). (x) The ‘‘Keep out of reach of chil dren’’ warning and the accidental over dose/ingestion warning set forth in § 330.1(g) of this chapter. (6) ‘‘Directions’’, followed by the di rections for use described in an appli cable OTC drug monograph or approved drug application. (7) ‘‘Other information’’, followed by additional information that is not in cluded under paragraphs (c)(2) through (c)(6), (c)(8), and (c)(9) of this section, but which is required by or is made op tional under an applicable OTC drug VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00058 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 49 Food and Drug Administration, HHS § 201.66 monograph, other OTC drug regulation, or is included in the labeling of an ap proved drug application. (i) Required information about cer tain 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 dos age unit) contains:’’ [in bold type (in sert name(s) of ingredient(s) (in alpha betical 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 appli cable, shall appear as the next item of information. (iii) Additional information that is authorized to appear under this head ing 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 alphabet ical 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 cos metic 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 head ing. The telephone number must ap pear 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 presen tation, FDA strongly reccommends that the Drug Facts labeling be pre sented 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 let ter height or type size for the headings in paragraphs (c)(2) through (c)(9) of this section shall be the larger of ei ther 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 informa tion 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, sub headings, and all other required infor mation 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 con trasting background, except that the VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00059 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 50 21 CFR Ch. I (4–1–16 Edition) § 201.66 title and the headings may be pre sented in a single, alternative, con trasting color unless otherwise pro vided in an approved drug application, OTC drug monograph (e.g., current re quirements for bold print in §§ 341.76 and 341.80 of this chapter), or other OTC drug regulation (e.g., the require ment 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 sub headings 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 head ing 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 con tinue to the next line of text. Addi tional 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 para graphs (c)(1) through (c)(9) of this sec tion may appear on more than one panel on the outside container of the retail package, or the immediate con tainer label if there is no outside con tainer or wrapper. The continuation of the required content and format onto multiple panels must retain the re quired order and flow of headings, sub headings, 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 re quired under paragraph (c)(2) of this section shall appear immediately adja cent and to the left of the heading and information required under paragraph (c)(3) of this section. The active ingre dients and purposes shall be aligned under the appropriate headings such that the heading and information re quired 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 para graphs (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 ‘‘Warn ings’’ 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 simi lar enclosure by the use of a barline. A distinctive horizontal barline extend ing to each end of the ‘‘Drug Facts’’ box or similar enclosure shall provide separation between each of the head ings 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 subse quent panel immediately after the ‘‘Drug Facts (continued)’’ title, a hori zontal 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00060 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 51 Food and Drug Administration, HHS § 201.66 immediately precede each of the sub headings 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 para graph (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, sub headings, and information in para graphs (c)(1) through (c)(9) of this sec tion, 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, cos metic products, other than information required to appear on a principle dis play panel, requires more than 60 per cent 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 sur face 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 re quired 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 sub heading need not be vertically aligned. (v) Paragraph (d)(8) of this section shall apply except that the box or simi lar 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: VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00061 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 52 21 CFR Ch. I (4–1–16 Edition) § 201.66 (ii) The following sample label illus trates the provisions in paragraphs (c) and (d) of this section: VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00062 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 M R 9 9 .0 0 3 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 53 Food and Drug Administration, HHS § 201.66 (iii) The following sample label illus trates the provisions in paragraphs (c) and (d) of this section, including para graph (d)(10) of this section, which per mits modifications for small packages: VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00063 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 M R 9 9 .0 0 4 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 54 21 CFR Ch. I (4–1–16 Edition) § 201.66 (iv) The following sample label illus trates the provisions in paragraphs (c) and (d) of this section for a drug prod uct marketed with cosmetic claims: VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00064 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 M R 9 9 .0 0 5 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 55 Food and Drug Administration, HHS § 201.66 (e) Exemptions and deferrals. FDA on its own initiative or in response to a written request from any manufac turer, packer, or distributor, may ex empt or defer, based on the cir cumstances presented, one or more spe cific requirements set forth in this sec tion on the basis that the requirement is inapplicable, impracticable, or con trary to public health or safety. Re quests for exemptions shall be sub mitted 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 iden tified on the envelope as a ‘‘Request for Exemption from 21 CFR 201.66 (OTC La beling Format)’’ and shall be directed to Docket No. 98N–0337. A separate re quest shall be submitted for each OTC drug product. Sponsors of a product marketed under an approved drug ap plication 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 re quests shall: (1) Document why a particular re quirement is inapplicable, impracti cable, 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 in tended to be used with the product. (f) Interchangeable terms and con necting terms. The terms listed in § 330.1(i) of this chapter may be used VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00065 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 M R 9 9 .0 0 6 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 56 21 CFR Ch. I (4–1–16 Edition) § 201.70 1 See § 201.66(b)(4) of this chapter for defini tion of bullet symbol. interchangeably in the labeling of OTC drug products, provided such use does not alter the meaning of the labeling that has been established and identi fied in an applicable OTC drug mono graph or by regulation. The terms list ed 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 mean ing of the labeling that has been estab lished 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. [64 FR 13286, Mar. 17, 1999, as amended at 65 FR 8, Jan. 3, 2000; 65 FR 48904, Aug. 10, 2000; 69 FR 13733, Mar. 24, 2004; 72 FR 71785, Dec. 19, 2007; 73 FR 403, Jan. 3, 2008; 74 FR 19407, Apr. 29, 2009; 76 FR 44487, July 26, 2011] § 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 in gestion include gum and lozenge dosage forms, but do not include dentifrices, mouthwashes, or mouth rinses. (b) The calcium content shall be ex pressed in milligrams or grams per dos age unit and shall include the total amount of calcium regardless of the source, i.e., from both active and inac tive ingredients. If the dosage unit con tains less than 1 gram of calcium, mil ligrams should be used. The calcium content per dosage unit shall be round ed-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 infor mation’’ as stated in § 201.66(c)(7). (c) The labeling of OTC drug products intended for oral ingestion shall con tain 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 re stricted diet. (d) Any product subject to this para graph that is not labeled as required by this paragraph and that is initially in troduced or initially delivered for in troduction into interstate commerce after the following dates is misbranded under sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and Cos metic 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. [69 FR 13733, Mar. 24, 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 loz enge 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00066 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 57 Food and Drug Administration, HHS § 201.72 1 See § 201.66(b)(4) of this chapter for defini tion of bullet symbol. 1 See § 201.66(b)(4) of this chapter for defini tion of bullet symbol. amount of magnesium regardless of the source, i.e., from both active and inac tive ingredients. If the dosage unit con tains less than 1 gram of magnesium, milligrams should be used. The magne sium 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 infor mation’’ as stated in § 201.66(c)(7). (c) The labeling of OTC drug products intended for oral ingestion shall con tain the following statement under the heading ‘‘Warning’’ (or ‘‘Warnings’’ if it appears with additional warning statements) if the amount of magne sium 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 applica ble, provided the ingredients are listed in alphabetical order, e.g., a magne sium or potassium-restricted diet. (d) Any product subject to this para graph that is not labeled as required by this paragraph and that is initially in troduced or initially delivered for in troduction into interstate commerce after the following dates is misbranded under sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and Cos metic 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. [69 FR 13734, Mar. 24, 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 loz enge 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 inac tive ingredients. If the dosage unit con tains less than 1 gram of potassium, milligrams should be used. The potas sium content shall be rounded-off to the nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). The po tassium content per dosage unit shall follow the heading ‘‘Other informa tion’’ as stated in § 201.66(c)(7). (c) The labeling of OTC drug products intended for oral ingestion shall con tain 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. (d) Any product subject to this para graph that is not labeled as required by this paragraph and that is initially in troduced or initially delivered for in troduction into interstate commerce after the following dates is misbranded under sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and Cos metic 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 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00067 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 58 21 CFR Ch. I (4–1–16 Edition) § 201.80 OTC drug monograph, or subject to drug marketing applications approved before April 23, 2004. [69 FR 13734, Mar. 24, 2004] § 201.80 Specific requirements on con tent and format of labeling for human prescription drug and bio logical products; older drugs not described in § 201.56(b)(1). Each section heading listed in § 201.56(d), if not omitted under § 201.56(d)(3), shall contain the fol lowing information in the following order: (a) Description. (1) Under this section heading, the labeling shall contain: (i) The proprietary name and the es tablished name, if any, as defined in section 502(e)(2) of the act, of the drug; (ii) The type of dosage form and the route of administration to which the labeling applies; (iii) The same qualitative and/or quantitative ingredient information as required under § 201.100(b) for labels; (iv) If the product is sterile, a state ment of that fact; (v) The pharmacological or thera peutic class of the drug; (vi) The chemical name and struc tural formula of the drug; (vii) If the product is radioactive, a statement of the important nuclear physical characteristics, such as the principal radiation emission data, ex ternal radiation, and physical decay characteristics. (2) If appropriate, other important chemical or physical information, such as physical constants, or pH, shall be stated. (b) Clinical Pharmacology. (1) Under this section heading, the labeling shall contain a concise factual summary of the clinical pharmacology and actions of the drug in humans. The summary may include information based on in vitro and/or animal data if the infor mation is essential to a description of the biochemical and/or physiological mode of action of the drug or is other wise pertinent to human therapeutics. Pharmacokinetic information that is important to safe and effective use of the drug is required, if known, e.g., de gree and rate of absorption, pathways of biotransformation, percentage of dose as unchanged drug and metabo lites, rate or half-time of elimination, concentration in body fluids associated with therapeutic and/or toxic effects, degree of binding to plasma proteins, degree of uptake by a particular organ or in the fetus, and passage across the blood brain barrier. Inclusion of phar macokinetic information is restricted to that which relates to clinical use of the drug. If the pharmacological mode of action of the drug is unknown or if important metabolic or pharmaco kinetic data in humans are unavail able, the labeling shall contain a state ment about the lack of information. (2) Data that demonstrate activity or effectiveness in in vitro or animal tests and that have not been shown by ade quate and well-controlled clinical stud ies to be pertinent to clinical use may be included under this section of the la beling only under the following cir cumstances: (i) In vitro data for anti-infective drugs may be included if the data are immediately preceded by the state ment ‘‘The following in vitro data are available but their clinical significance is unknown.’’ (ii) For other classes of drugs, in vitro and animal data that have not been shown by adequate and well-con trolled clinical studies, as defined in § 314.126(b) of this chapter, to be perti nent to clinical use may be used only if a waiver is granted under § 201.58 or § 314.126(c) of this chapter. (c) Indications and Usage. (1) Under this section heading, the labeling shall state that: (i) The drug is indicated in the treat ment, prevention, or diagnosis of a rec ognized disease or condition, e.g., peni cillin is indicated for the treatment of pneumonia due to susceptible pneumococci; and/or (ii) The drug is indicated for the treatment, prevention, or diagnosis of an important manifestation of a dis ease or condition, e.g., chlorothiazide is indicated for the treatment of edema in patients with congestive heart fail ure; and/or (iii) The drug is indicated for the re lief of symptoms associated with a dis ease or syndrome, e.g., chlorpheniramine is indicated for the symptomatic relief of nasal congestion VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00068 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 59 Food and Drug Administration, HHS § 201.80 in patients with vasomotor rhinitis; and/or (iv) The drug, if used for a particular indication only in conjuction with a primary mode of therapy, e.g., diet, surgery, or some other drug, is an ad junct to the mode of therapy. (2)(i) For drug products other than biological products, all indications list ed in this section must be supported by substantial evidence of effectiveness based on adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless the requirement is waived under § 201.58 or § 314.126(c) of this chapter. Indications or uses must not be implied or suggested in other sections of labeling if not included in this section. (ii) For biological products, all indi cations listed in this section must be supported by substantial evidence of ef fectiveness. Indications or uses must not be implied or suggested in other sections of labeling if not included in this section. (3) This section of the labeling shall also contain the following additional information: (i) If evidence is available to support the safety and effectiveness of the drug only in selected subgroups of the larger population with a disease, syndrome, or symptom under consideration, e.g., patients with mild disease or patients in a special age group, the labeling shall describe the available evidence and state the limitations of usefulness of the drug. The labeling shall also identify specific tests needed for selec tion or monitoring of the patients who need the drug, e.g., microbe suscepti bility tests. Information on the approx imate kind, degree, and duration of im provement to be anticipated shall be stated if available and shall be based on substantial evidence derived from adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless the requirement is waived under § 201.58 or § 314.126(c) of this chapter. If the information is relevant to the rec ommended intervals between doses, the usual duration of treatment, or any modification of dosage, it shall be stat ed in the ‘‘Dosage and Administration’’ section of the labeling and referenced in this section. (ii) If safety considerations are such that the drug should be reserved for certain situations, e.g., cases refrac tory to other drugs, this information shall be stated in this section. (iii) If there are specific conditions that should be met before the drug is used on a long-term basis, e.g., dem onstration of responsiveness to the drug in a short-term trial, the labeling shall identify the conditions; or, if the indications for long-term use are dif ferent from those for short-term use, the labeling shall identify the specific indications for each use. (iv) If there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the prepon derance of evidence related to the use or condition shows that the drug is in effective, the Food and Drug Adminis tration may require that the labeling state that there is a lack of evidence that the drug is effective for that use or condition. (v) Any statements comparing the safety or effectiveness, either greater or less, of the drug with other agents for the same indication shall be sup ported by adequate and well-controlled studies as defined in § 314.126(b) of this chapter unless this requirement is waived under § 201.58 or § 314.126(c) of this chapter. (d) Contraindications. Under this sec tion heading, the labeling shall de scribe those situations in which the drug should not be used because the risk of use clearly outweighs any pos sible benefit. These situations include administration of the drug to patients known to have a hypersensitivity to it; use of the drug in patients who, be cause of their particular age, sex, con comitant therapy, disease state, or other condition, have a substantial risk of being harmed by it; or contin ued use of the drug in the face of an un acceptably hazardous adverse reaction. Known hazards and not theoretical pos sibilities shall be listed, e.g., if hyper sensitivity to the drug has not been demonstrated, it should not be listed as a contraindication. If no contraindica tions are known, this section of the la beling shall state ‘‘None known.’’ (e) Warnings. Under this section head ing, the labeling shall describe serious VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00069 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 60 21 CFR Ch. I (4–1–16 Edition) § 201.80 adverse reactions and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur. The labeling shall be re vised to include a warning as soon as there is reasonable evidence of an asso ciation of a serious hazard with a drug; a causal relationship need not have been proved. A specific warning relat ing to a use not provided for under the ‘‘Indications and Usage’’ section of the labeling may be required by the Food and Drug Administration if the drug is commonly prescribed for a disease or condition, and there is lack of substan tial evidence of effectivenes for that disease or condition, and such usage is associated with serious risk or hazard. Special problems, particularly those that may lead to death or serious in jury, may be required by the Food and Drug Administration to be placed in a prominently displayed box. The boxed warning ordinarily shall be based on clinical data, but serious animal tox icity may also be the basis of a boxed warning in the absence of clinical data. If a boxed warning is required, its loca tion will be specified by the Food and Drug Administration. The frequency of these serious adverse reactions and, if known, the approximate mortality and morbidity rates for patients sustaining the reaction, which are important to safe and effective use of the drug, shall be expressed as provided under the ‘‘Adverse Reactions’’ section of the la beling. (f) Precautions. Under this section heading, the labeling shall contain the following subsections as appropriate for the drug: (1) General. This subsection of the la beling shall contain information re garding any special care to be exer cised by the practitioner for safe and effective use of the drug, e.g., pre cautions not required under any other specific section or subsection of the la beling. (2) Information for patients. This sub section must contain information nec essary for patients to use the drug safe ly and effectively (e.g., precautions concerning driving or the concomitant use of other substances that may have harmful additive effects). Any FDA-ap proved patient labeling must be ref erenced in this section and the full text of such patient labeling must be re printed immediately following the last section of labeling or, alternatively, accompany the prescription drug label ing. The type size requirement for the Medication Guide set forth in § 208.20 of this chapter does not apply to the Medication Guide that is reprinted in or accompanying the prescription drug labeling unless such Medication Guide is to be detached and distributed to pa tients in compliance with § 208.24 of this chapter. (3) Laboratory tests. This subsection of the labeling shall identify any labora tory tests that may be helpful in fol lowing the patient’s response or in identifying possible adverse reactions. If appropriate, information shall be provided on such factors as the range of normal and abnormal values ex pected in the particular situation and the recommended frequency with which tests should be done before, dur ing, and after therapy. (4)(i) Drug interactions. This sub section of the labeling shall contain specific practical guidance for the phy sician on preventing clinically signifi cant drug/drug and drug/food inter actions that may occur in vivo in pa tients taking the drug. Specific drugs or classes of drugs with which the drug to which the labeling applies may interact in vivo shall be identified, and the mechanism(s) of the interaction shall be briefly described. Information in this subsection of the labeling shall be limited to that pertaining to clin ical use of the drug in patients. Drug interactions supported only by animal or in vitro experiments may not ordi narily be included, but animal or in vitro data may be used if shown to be clinically relevant. Drug incompati bilities, i.e., drug interactions that may occur when drugs are mixed in vitro, as in a solution for intravenous administration, shall be discussed under the ‘‘Dosage and Administra tion’’ section of the labeling rather than under this subsection of the label ing. (ii) Drug/laboratory test interactions. This subsection of the labeling shall contain practical guidance on known interference of the drug with labora tory tests. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00070 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 61 Food and Drug Administration, HHS § 201.80 (5) Carcinogenesis, mutagenesis, impair ment of fertility. This subsection of the labeling shall state whether long-term studies in animals have been performed to evaluate carcinogenic potential and, if so, the species and results. If repro duction studies or other data in ani mals reveal a problem or potential problem concerning mutagenesis or im pairment of fertility in either males or females, the information shall be de scribed. Any precautionary statement on these topics shall include practical, relevant advice to the physician on the significance of these animal findings. If there is evidence from human data that the drug may be carcinogenic or muta genic or that it impairs fertility, this information shall be included under the ‘‘Warnings’’ section of the labeling. Also, under ‘‘Precautions,’’ the label ing shall state: ‘‘See ‘Warnings’ section for information on carcinogenesis, mutagenesis, and impairment of fer tility.’’ (6) Pregnancy. This subsection of the labeling may be omitted only if the drug is not absorbed systemically and the drug is not known to have a poten tial for indirect harm to the fetus. For all other drugs, this subsection of the labeling shall contain the following in formation: (i) Teratogenic effects. Under this heading the labeling shall identify one of the following categories that applies to the drug, and the labeling shall bear the statement required under the cat egory: (a) If adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling shall state: ‘‘Studies in pregnant women have not shown that (name of drug) increases the risk of fetal abnormalities if adminis tered during the first (second, third, or all) trimester(s) of pregnancy. If this drug is used during pregnancy, the pos sibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, (name of drug) should be used during pregnancy only if clearly needed.’’ The labeling shall also contain a description of the human studies. If animal reproduction studies are available and they fail to demonstrate a risk to the fetus, the la beling shall also state: ‘‘Reproduction studies have been performed in (kinds of animal(s)) at doses up to (x) times the human dose and have revealed no evi dence of impaired fertility or harm to the fetus due to (name of drug).’’ The labeling shall also contain a descrip tion of available data on the effect of the drug on the later growth, develop ment, and functional maturation of the child. (b) If animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women, the labeling shall state: ‘‘ Re production studies have been per formed in (kind(s) of animal(s)) at doses up to (x) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to (name of drug). There are, however, no adequate and well-controlled studies in pregnant women. Because animal re production studies are not always pre dictive of human response, this drug should be used during pregnancy only if clearly needed.’’ If animal reproduc tion studies have shown an adverse ef fect (other than decrease in fertility), but adequate and well-controlled stud ies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters), the labeling shall state: ‘‘Reproduction studies in (kind(s) of animal(s)) have shown (describe findings) at (x) times the human dose. Studies in pregnant women, however, have not shown that (name of drug) increases the risk of abnormalities when adminis tered during the first (second, third, or all) trimester(s) of pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is re mote, if the drug is used during preg nancy. Nevertheless, because the stud ies in humans cannot rule out the pos sibility of harm, (name of drug) should be used during pregnancy only if clear ly needed.’’ The labeling shall also con tain a description of the human studies and a description of available data on the effect of the drug on the later growth, development, and functional maturation of the child. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00071 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 62 21 CFR Ch. I (4–1–16 Edition) § 201.80 (c) If animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks, the labeling shall state: ‘‘ (Name of drug) has been shown to be teratogenic (or to have an embryocidal effect or other adverse ef fect) in (name(s) of species) when given in doses (x) times the human dose. There are no adequate and well-con trolled studies in pregnant women. (Name of drug) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.’’ The labeling shall contain a de scription of the animal studies. If there are no animal reproduction studies and no adequate and well-controlled studies in humans, the labeling shall state: ‘‘Animal reproduction studies have not been conducted with (name of drug). It is also not known whether (name of drug) can cause fetal harm when ad ministered to a pregnant woman or can affect reproduction capacity. (Name of drug) should be given to a pregnant woman only if clearly needed.’’ The la beling shall contain a description of any available data on the effect of the drug on the later growth, development, and functional maturation of the child. (d) If there is positive evidence of human fetal risk based on adverse reac tion data from investigational or mar keting experience or studies in hu mans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threatening situation or seri ous disease for which safer drugs can not be used or are ineffective), the la beling shall state: ‘‘ See ‘Warnings’ sec tion.’’ Under the ‘‘Warnings’’ section, the labeling states: ‘‘(Name of drug) can cause fetal harm when administered to a pregnant woman. (Describe the human data and any pertinent animal data.) If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.’’ (e) If studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing ex perience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit (for example, safer drugs or other forms of therapy are available), the la beling shall state: ‘‘ See ‘Contraindica tions’ section.’’ Under ‘‘Contraindica tions,’’ the labeling shall state: ‘‘(Name of drug) may (can) cause fetal harm when administered to a pregnant woman. (Describe the human data and any pertinant animal data.) (Name of drug) is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be ap prised of the potential hazard to the fetus.’’ (ii) Nonteratogenic effects. Under this heading the labeling shall contain other information on the drug’s effects on reproduction and the drug’s use dur ing pregnancy that is not required spe cifically by one of the pregnancy cat egories, if the information is relevant to the safe and effective use of the drug. Information required under this heading shall include nonteratogenic effects in the fetus or newborn infant (for example, withdrawal symptoms or hypoglycemia) that may occur because of a pregnant woman’s chronic use of the drug for a preexisting condition or disease. (7) Labor and delivery. If the drug has a recognized use during labor or deliv ery (vaginal or abdominal delivery), whether or not the use is stated in the indications section of the labeling, this subsection of the labeling shall de scribe the available information about the effect of the drug on the mother and the fetus, on the duration of labor or delivery, on the possibility that for ceps delivery or other intervention or resuscitation of the newborn will be necessary, and the effect of the drug on the later growth, development, and functional maturation of the child. If any information required under this subsection is unknown, this subsection of the labeling shall state that the in formation is unknown. (8) Nursing mothers. (i) If a drug is ab sorbed systemically, this subsection of VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00072 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 63 Food and Drug Administration, HHS § 201.80 the labeling shall contain, if known, in formation about excretion of the drug in human milk and effects on the nurs ing infant. Pertinent adverse effects observed in animal offspring shall be described. (ii) If a drug is absorbed systemically and is known to be excreted in human milk, this subsection of the labeling shall contain one of the following statements, as appropriate. If the drug is associated with serious adverse reac tions or if the drug has a known tumorigenic potential, the labeling shall state: ‘‘Because of the potential for serious adverse reactions in nursing infants from (name of drug) (or, ‘‘Be cause of the potential for tumorigenicity shown for (name of drug) in (animal or human) studies), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the im portance of the drug to the mother.’’ If the drug is not associated with serious adverse reactions and does not have a known tumorigenic potential, the la beling shall state: ‘‘Caution should be exercised when (name of drug) is admin istered to a nursing woman.’’ (iii) If a drug is absorbed system ically and information on excretion in human milk is unknown, this sub section of the labeling shall contain one of the following statements, as ap propriate. If the drug is associated with serious adverse reactions or has a known tumorigenic potential, the la beling shall state: ‘‘It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the po tential for serious adverse reactions in nursing infants from (name of drug) (or, ‘‘Because of the potential for tumorigenicity shown for (name of drug) in (animal or human) studies), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the im portance of the drug to the mother.’’ If the drug is not associated with serious adverse reactions and does not have a known tumorigenic potential, the la beling shall state: ‘‘It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exer cised when (name of drug) is adminis tered to a nursing woman.’’ (9) Pediatric use. (i) Pediatric popu lation(s)/pediatric patient(s): For the purposes of paragraphs (f)(9)(ii) through (f)(9)(viii) of this section, the terms pediatric population(s) and pedi atric patient(s) are defined as the pedi atric age group, from birth to 16 years, including age groups often called neo nates, infants, children, and adoles cents. (ii) If there is a specific pediatric in dication (i.e., an indication different from those approved for adults) that is supported by adequate and well-con trolled studies in the pediatric popu lation, it shall be described under the ‘‘Indications and Usage’’ section of the labeling, and appropriate pediatric dos age information shall be given under the ‘‘Dosage and Administration’’ sec tion of the labeling. The ‘‘Pediatric use’’ subsection shall cite any limita tions on the pediatric indication, need for specific monitoring, specific haz ards associated with use of the drug in any subsets of the pediatric population (e.g., neonates), differences between pe diatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. Data summarized in this sub section of the labeling should be dis cussed in more detail, if appropriate, under the ‘‘Clinical Pharmacology’’ or ‘‘Clinical Studies’’ section. As appro priate, this information shall also be contained in the ‘‘Contraindications,’’ ‘‘Warnings,’’ and elsewhere in the ‘‘Precautions’’ sections. (iii) If there are specific statements on pediatric use of the drug for an indi cation also approved for adults that are based on adequate and well-controlled studies in the pediatric population, they shall be summarized in the ‘‘Pe diatric use’’ subsection of the labeling and discussed in more detail, if appro priate, under the ‘‘Clinical Pharma cology’’ and ‘‘Clinical Studies’’ sec tions. Appropriate pediatric dosage shall be given under the ‘‘Dosage and Administration’’ section of the label ing. The ‘‘Pediatric use’’ subsection of the labeling shall also cite any limita tions on the pediatric use statement, need for specific monitoring, specific hazards associated with use of the drug VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00073 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 64 21 CFR Ch. I (4–1–16 Edition) § 201.80 in any subsets of the pediatric popu lation (e.g., neonates), differences be tween pediatric and adult responses to the drug, and other information related to the safe and effective pediatric use of the drug. As appropriate, this infor mation shall also be contained in the ‘‘Contraindications,’’ ‘‘Warnings,’’ and elsewhere in the ‘‘Precautions’’ sec tions. (iv) FDA may approve a drug for pe diatric use based on adequate and well controlled studies in adults, with other information supporting pediatric use. In such cases, the agency will have concluded that the course of the dis ease and the effects of the drug, both beneficial and adverse, are sufficiently similar in the pediatric and adult popu lations to permit extrapolation from the adult efficacy data to pediatric pa tients. The additional information sup porting pediatric use must ordinarily include data on the pharmacokinetics of the drug in the pediatric population for determination of appropriate dos age. Other information, such as data from pharmacodynamic studies of the drug in the pediatric population, data from other studies supporting the safe ty or effectiveness of the drug in pedi atric patients, pertinent premarketing or postmarketing studies or experi ence, may be necessary to show that the drug can be used safely and effec tively in pediatric patients. When a drug is approved for pediatric use based on adequate and well-controlled studies in adults with other information sup porting pediatric use, the ‘‘Pediatric use’’ subsection of the labeling shall contain either the following statement, or a reasonable alternative: ‘‘The safe ty and effectiveness of (drug name) have been established in the age groups l to l (note any limitations, e.g., no data for pediatric patients under 2, or only applicable to certain indications ap proved in adults). Use of (drug name) in these age groups is supported by evi dence from adequate and well-con trolled studies of (drug name) in adults with additional data (insert wording that accurately describes the data sub mitted to support a finding of substan tial evidence of effectiveness in the pe diatric population).’’ Data summarized in the preceding prescribed statement in this subsection of the labeling shall be discussed in more detail, if appro priate, under the ‘‘Clinical Pharma cology’’ or the ‘‘Clinical Studies’’ sec tion. For example, pediatric pharmaco kinetic or pharmacodynamic studies and dose-response information should be described in the ‘‘Clinical Pharma cology’’ section. Pediatric dosing in structions shall be included in the ‘‘Dosage and Administration’’ section of the labeling. Any differences be tween pediatric and adult responses, need for specific monitoring, dosing ad justments, and any other information related to safe and effective use of the drug in pediatric patients shall be cited briefly in the ‘‘Pediatric use’’ sub section and, as appropriate, in the ‘‘Contraindications,’’ ‘‘Warnings,’’ ‘‘Precautions,’’ and ‘‘Dosage and Ad ministration’’ sections. (v) If the requirements for a finding of substantial evidence to support a pe diatric indication or a pediatric use statement have not been met for a par ticular pediatric population, the ‘‘Pe diatric use’’ subsection of the labeling shall contain an appropriate statement such as ‘‘Safety and effectiveness in pe diatric patients below the age of (l) have not been established.’’ If use of the drug in this pediatric population is associated with a specific hazard, the hazard shall be described in this sub section of the labeling, or, if appro priate, the hazard shall be stated in the ‘‘Contraindications’’ or ‘‘Warnings’’ section of the labeling and this sub section shall refer to it. (vi) If the requirements for a finding of substantial evidence to support a pe diatric indication or a pediatric use statement have not been met for any pediatric population, this subsection of the labeling shall contain the following statement: ‘‘Safety and effectiveness in pediatric patients have not been estab lished.’’ If use of the drug in premature or neonatal infants, or other pediatric subgroups, is associated with a specific hazard, the hazard shall be described in this subsection of the labeling, or, if appropriate, the hazard shall be stated in the ‘‘Contraindications’’ or ‘‘Warn ings’’ section of the labeling and this subsection shall refer to it. (vii) If the sponsor believes that none of the statements described in para graphs (f)(9)(ii) through (f)(9)(vi) of this VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00074 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 65 Food and Drug Administration, HHS § 201.80 section is appropriate or relevant to the labeling of a particular drug, the sponsor shall provide reasons for omis sion of the statements and may pro pose alternative statement(s). FDA may permit use of an alternative state ment if FDA determines that no state ment described in those paragraphs is appropriate or relevant to the drug’s labeling and that the alternative state ment is accurate and appropriate. (viii) If the drug product contains one or more inactive ingredients that present an increased risk of toxic ef fects to neonates or other pediatric subgroups, a special note of this risk shall be made, generally in the ‘‘Con traindications,’’ ‘‘Warnings,’’ or ‘‘Pre cautions’’ section. (10) Geriatric use. (i) A specific geri atric indication, if any, that is sup ported by adequate and well-controlled studies in the geriatric population shall be described under the ‘‘Indica tions and Usage’’ section of the label ing, and appropriate geriatric dosage shall be stated under the ‘‘Dosage and Administration’’ section of the label ing. The ‘‘Geriatric use’’ subsection shall cite any limitations on the geri atric indication, need for specific moni toring, specific hazards associated with the geriatric indication, and other in formation related to the safe and effec tive use of the drug in the geriatric population. Unless otherwise noted, in formation contained in the ‘‘Geriatric use’’ subsection of the labeling shall pertain to use of the drug in persons 65 years of age and older. Data summa rized in this subsection of the labeling shall be discussed in more detail, if ap propriate, under ‘‘Clinical Pharma cology’’ or the ‘‘Clinical Studies’’ sec tion. As appropriate, this information shall also be contained in ‘‘Contra indications,’’ ‘‘Warnings,’’ and else where in ‘‘Precautions.’’ (ii) Specific statements on geriatric use of the drug for an indication ap proved for adults generally, as distin guished from a specific geriatric indi cation, shall be contained in the ‘‘Geriatric use’’ subsection and shall reflect all information available to the sponsor that is relevant to the appro priate use of the drug in elderly pa tients. This information includes de tailed results from controlled studies that are available to the sponsor and pertinent information from well-docu mented studies obtained from a lit erature search. Controlled studies in clude those that are part of the mar keting application and other relevant studies available to the sponsor that have not been previously submitted in the investigational new drug applica tion, new drug application, biological license application, or a supplement or amendment to one of these applica tions (e.g., postmarketing studies or adverse drug reaction reports). The ‘‘Geriatric use’’ subsection shall con tain the following statement(s) or rea sonable alternative, as applicable, tak ing into account available information: (A) If clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether elderly subjects respond differently from younger subjects, and other reported clinical experience has not identified such differences, the ‘‘Geriatric use’’ subsection shall include the following statement: ‘‘Clinical studies of (name of drug) did not include sufficient numbers of subjects aged 65 and over to determine whether they re spond 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 car diac function, and of concomitant disease or other drug therapy.’’ (B) If clinical studies (including stud ies that are part of marketing applica tions and other relevant studies avail able to the sponsor that have not been submitted in the sponsor’s applica tions) included enough elderly subjects to make it likely that differences in safety or effectiveness between elderly and younger subjects would have been detected, but no such differences (in safety or effectiveness) were observed, and other reported clinical experience has not identified such differences, the ‘‘Geriatric use’’ subsection shall con tain the following statement: Of the total number of subjects in clinical studies of (name of drug), l percent were 65 and over, while l percent were 75 and over. (Alternatively, the labeling may state the total number of subjects included in the VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00075 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 66 21 CFR Ch. I (4–1–16 Edition) § 201.80 studies who were 65 and over and 75 and over.) No overall differences in safety or ef fectiveness were observed between these sub jects and younger subjects, and other re ported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. (C) If evidence from clinical studies and other reported clinical experience available to the sponsor indicates that use of the drug in elderly patients is associated with differences in safety or effectiveness, or requires specific moni toring or dosage adjustment, the ‘‘Geriatric use’’ subsection of the label ing shall contain a brief description of observed differences or specific moni toring or dosage requirements and, as appropriate, shall refer to more de tailed discussions in the ‘‘Contra indications,’’ ‘‘Warnings,’’ ‘‘Dosage and Administration,’’ or other sections of the labeling. (iii)(A) If specific pharmacokinetic or pharmacodynamic studies have been carried out in the elderly, they shall be described briefly in the ‘‘Geriatric use’’ subsection of the labeling and in detail under the ‘‘Clinical Pharmacology’’ section. The ‘‘Clinical Pharmacology’’ section and ‘‘Drug interactions’’ sub section of the ‘‘Precautions’’ section ordinarily contain information on drug-disease and drug-drug inter actions that is particularly relevant to the elderly, who are more likely to have concomitant illness and to utilize concomitant drugs. (B) If a drug is known to be substan tially excreted by the kidney, the ‘‘Geriatric use’’ subsection shall in clude the statement: ‘‘This drug is known to be substantially ex creted by the kidney, and the risk of toxic reactions to this drug may be greater in pa tients with impaired renal function. Because elderly patients are more likely to have de creased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.’’ (iv) If use of the drug in the elderly appears to cause a specific hazard, the hazard shall be described in the ‘‘Geri atric use’’ subsection of the labeling, or, if appropriate, the hazard shall be stated in the ‘‘Contraindications,’’ ‘‘Warnings,’’ or ‘‘Precautions’’ section of the labeling, and the ‘‘Geriatric use’’ subsection shall refer to those sections. (v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of this sec tion may include statements, if they would be useful in enhancing safe use of the drug, that reflect good clinical practice or past experience in a par ticular situation, e.g., for a sedating drug, it could be stated that: ‘‘Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of (name of drug) and observed closely.’’ (vi) If the sponsor believes that none of the requirements described in para graphs (f)(10)(i) through (f)(10)(v) of this section is appropriate or relevant to the labeling of a particular drug, the sponsor shall provide reasons for omis sion of the statements and may pro pose an alternative statement. FDA may permit omission of the statements if FDA determines that no statement described in those paragraphs is appro priate or relevant to the drug’s label ing. FDA may permit use of an alter native statement if the agency deter mines that such statement is accurate and appropriate. (g) Adverse Reactions. An adverse re action is an undesirable effect, reason ably associated with the use of the drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. (1) This section of the labeling shall list the adverse reactions that occur with the drug and with drugs in the same pharmacologically active and chemically related class, if applicable. (2) In this listing, adverse reactions may be categorized by organ system, by severity of the reaction, by fre quency, or by toxicological mecha nism, or by a combination of these, as appropriate. If frequency information from adequate clinical studies is avail able, the categories and the adverse re actions within each category shall be listed in decreasing order of frequency. An adverse reaction that is signifi cantly more severe than the other re actions listed in a category, however, shall be listed before those reactions, regardless of its frequency. If frequency information from adequate clinical studies is not available, the categories VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00076 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 67 Food and Drug Administration, HHS § 201.80 and adverse reactions within each cat egory shall be listed in decreasing order of severity. The approximate fre quency of each adverse reaction shall be expressed in rough estimates or or ders of magnitude essentially as fol lows: ‘‘The most frequent adverse reac tion(s) to (name of drug) is (are) (list re actions). This (these) occur(s) in about (e.g., one-third of patients; one in 30 patients; less than one-tenth of pa tients). Less frequent adverse reactions are (list reactions), which occur in ap proximately (e.g., one in 100 patients). Other adverse reactions, which occur rarely, in approximately (e.g., one in 1,000 patients), are (list reactions).’’ Per cent figures may not ordinarily be used unless they are documented by ade quate and well-controlled studies as de fined in § 314.126(b) of this chapter, they are shown to reflect general experi ence, and they do not falsely imply a greater degree of accuracy than actu ally exists. (3) The ‘‘Warnings’’ section of the la beling or, if appropriate, the ‘‘Contra indications’’ section of the labeling shall identify any potentially fatal ad verse reaction. (4) Any claim comparing the drug to which the labeling applies with other drugs in terms of frequency, severity, or character of adverse reactions shall be based on adequate and well-con trolled studies as defined in § 314.126(b) of this chapter unless this requirement is waived under § 201.58 or § 314.126(c) of this chapter. (h) Drug Abuse and Dependence. Under this section heading, the labeling shall contain the following subsections, as appropriate for the drug: (1) Controlled Substance. If the drug is controlled by the Drug Enforcement Administration, the schedule in which it is controlled shall be stated. (2) Abuse. This subsection of the la beling shall be based primarily on human data and human experience, but pertinent animal data may also be used. This subsection shall state the types of abuse that can occur with the drug and the adverse reactions perti nent to them. Particularly susceptible patient populations shall be identified. (3) Dependence. This subsection of the labeling shall describe characteristic effects resulting from both psycho logical and physical dependence that occur with the drug and shall identify the quantity of the drug over a period of time that may lead to tolerance or dependence, or both. Details shall be provided on the adverse effects of chronic abuse and the effects of abrupt withdrawal. Procedures necessary to diagnose the dependent state shall be provided, and the principles of treating the effects of abrupt withdrawal shall be described. (i) Overdosage. Under this section heading, the labeling shall describe the signs, symptoms, and laboratory find ings of acute overdosage and the gen eral principles of treatment. This sec tion shall be based on human data, when available. If human data are un available, appropriate animal and in vitro data may be used. Specific infor mation shall be provided about the fol lowing: (1) Signs, symptoms, and laboratory findings associated with an overdosage of the drug. (2) Complications that can occur with the drug (for example, organ toxicity or delayed acidosis). (3) Oral LD50 of the drug in animals; concentrations of the drug in biologic fluids associated with toxicity and/or death; physiologic variables influ encing excretion of the drug, such as urine pH; and factors that influence the dose response relationship of the drug, such as tolerance. The pharmaco kinetic data given in the ‘‘Clinical Pharmacology’’ section also may be referenced here, if applicable to overdoses. (4) The amount of the drug in a single dose that is ordinarily associated with symptoms of overdosage and the amount of the drug in a single dose that is likely to be life-threatening. (5) Whether the drug is dialyzable. (6) Recommended general treatment procedures and specific measures for support of vital functions, such as proven antidotes, gastric lavage, and forced diuresis. Unqualified rec ommendations for which data are lack ing with the specific drug or class of drugs, especially treatment using an other drug (for example, central nerv ous system stimulants, respiratory stimulants) may not be stated unless VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00077 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 68 21 CFR Ch. I (4–1–16 Edition) § 201.80 specific data or scientific rationale ex ists to support safe and effective use. (j) Dosage and Administration. This section of the labeling shall state the recommended usual dose, the usual dosage range, and, if appropriate, an upper limit beyond which safety and ef fectiveness have not been established; dosages shall be stated for each indica tion when appropriate. Dosing regi mens must not be implied or suggested in other sections of labeling if not in cluded in this section. This section shall also state the intervals rec ommended between doses, the optimal method of titrating dosage, the usual duration of treatment, and any modi fication of dosage needed in special pa tient populations, e.g., in children, in geriatric age groups, or in patients with renal or hepatic disease. Specific tables or monographs may be included to clarify dosage schedules. Radiation dosimetry information shall be stated for both the patient receiving a radio active drug and the person admin istering it. This section shall also con tain specific direction on dilution, preparation (including the strength of the final dosage solution, when pre pared according to instructions, in terms of milligrams active ingredient per milliliter of reconstituted solution, unless another measure of the strength is more appropriate), and administra tion of the dosage form, if needed, e.g., the rate of administration of paren teral drug in milligrams per minute; storage conditions for stability of the drug or reconstituted drug, when im portant; essential information on drug incompatibilities if the drug is mixed in vitro with other drugs; and the fol lowing statement for parenterals: ‘‘Parenteral drug products should be inspected visually for particulate mat ter and discoloration prior to adminis tration, whenever solution and con tainer permit.’’ (k) How Supplied. This section of the labeling shall contain information on the available dosage forms to which the labeling applies and for which the manufacturer or distributor is respon sible. The information shall ordinarily include: (1) The strength of the dosage form, e.g., 10-milligram tablets, in metric system and, if the apothecary system is used, a statement of the strength is placed in parentheses after the metric designation; (2) The units in which the dosage form is ordinarily available for pre scribing by practitioners, e.g., bottles of 100; (3) Appropriate information to facili tate identification of the dosage forms, such as shape, color, coating, scoring, and National Drug Code; and (4) Special handling and storage con ditions. (l) Animal Pharmacology and/or Animal Toxicology. In most cases, the labeling need not include this section. Signifi cant animal data necessary for safe and effective use of the drug in humans shall ordinarily be included in one or more of the other sections of the label ing, as appropriate. Commonly for a drug that has been marketed for a long time, and in rare cases for a new drug, chronic animal toxicity studies have not been performed or completed for a drug that is administered over pro longed periods or is implanted in the body. The unavailability of such data shall be stated in the appropriate sec tion of the labeling for the drug. If the pertinent animal data cannot be appro priately incorporated into other sec tions of the labeling, this section may be used. (m) ‘‘Clinical Studies’’ and ‘‘Ref erences’’. These sections may appear in labeling in the place of a detailed dis cussion of a subject that is of limited interest but nonetheless important. A reference to a specific important clin ical study may be made in any section of the format required under §§ 201.56 and 201.57 if the study is essential to an understandable presentation of the available information. References may appear in sections of the labeling for mat, other than the ‘‘Clinical Studies’’ or ‘‘References’’ section, in rare cir cumstances only. A clinical study or reference may be cited in prescription drug labeling only under the following conditions: (1)(i) If the clinical study is cited in the labeling in place of a detailed dis cussion of data and information con cerning an indication for use of the drug, the clinical study must con stitute an adequate and well-controlled study as described in § 314.126(b) of this VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00078 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 69 Food and Drug Administration, HHS § 201.100 chapter, except for biological products, and must not imply or suggest indica tions or uses or dosing regimens not stated in the ‘‘Indications and Usage’’ or ‘‘Dosage and Administration’’ sec tion. (ii) When prescription drug labeling must summarize or otherwise rely on a recommendation by an authoritative scientific body, or on a standardized methodology, scale, or technique, be cause the information is important to prescribing decisions, the labeling may include a reference to the source of the information. (2) If the clinical study or reference is cited in the labeling in the place of a detailed discussion of data and infor mation concerning a risk or risks from the use of the drug, the risk or risks shall also be identified or discussed in the appropriate section of the labeling for the drug. [44 FR 37462, June 26, 1979, as amended at 55 FR 11576, Mar. 29, 1990; 59 FR 64249, Dec. 13, 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396, Dec. 1, 1998. Redesignated and amended at 71 FR 3988, 3996, Jan. 24, 2006; 79 FR 72103, Dec. 4, 2014] Subpart D—Exemptions From Adequate Directions for Use § 201.100 Prescription drugs for human use. A drug subject to the requirements of section 503(b)(1) of the act shall be ex empt from section 502(f)(1) if all the following conditions are met: (a) The drug is: (1)(i) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of prescription drugs; or (ii) In the possession of a retail, hos pital, or clinic pharmacy, or a public health agency, regularly and lawfully engaged in dispensing prescription drugs; or (iii) In the possession of a practi tioner licensed by law to administer or prescribe such drugs; and (2) It is to be dispensed in accordance with section 503(b) (b) The label of the drug bears: (1) The statement ‘‘Rx only’’ and (2) The recommended or usual dosage and (3) The route of administration, if it is not for oral use; and (4) The quantity or proportion of each active ingredient, as well as the information required by section 502 (d) and (e); and (5) If it is for other than oral use, the names of all inactive ingredients, ex cept that: (i) Flavorings and perfumes may be designated as such without naming their components. (ii) Color additives may be des ignated as coloring without naming specific color components unless the naming of such components is required by a color additive regulation pre scribed in subchapter A of this chapter. (iii) Trace amounts of harmless sub stances added solely for individual product identification need not be named. If it is intended for administra tion by parenteral injection, the quan tity or proportion of all inactive ingre dients, except that ingredients added to adjust the pH or to make the drug isotonic may be declared by name and a statement of their effect; and if the vehicle is water for injection it need not be named. (6) An identifying lot or control num ber from which it is possible to deter mine the complete manufacturing his tory of the package of the drug. (7) A statement directed to the phar macist specifying the type of container to be used in dispensing the drug prod uct to maintain its identity, strength, quality, and purity. Where there are standards and test procedures for de termining that the container meets the requirements for specified types of con tainers as defined in an official com pendium, such terms may be used. For example, ‘‘Dispense in tight, light-re sistant container as defined in the Na tional Formulary’’. Where standards and test procedures for determining the types of containers to be used in dispensing the drug product are not in cluded in an official compendium, the specific container or types of con tainers known to be adequate to main tain the identity, strength, quality, and purity of the drug products shall be described. For example, ‘‘Dispense VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00079 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 70 21 CFR Ch. I (4–1–16 Edition) § 201.100 in containers which (statement of spec ifications which clearly enable the dis pensing pharmacist to select an ade quate container)’’: Provided, however, That in the case of containers too small or otherwise unable to accommo date a label with sufficient space to bear all such information, but which are packaged within an outer container from which they are removed for dis pensing or use, the information re quired by paragraph (b) (2), (3), (5), and (7) of this section may be contained in other labeling on or within the package from which it is to be dispensed; the in formation referred to in paragraph (b)(1) of this section may be placed on such outer container only; and the in formation required by paragraph (b)(6) of this section may be on the crimp of the dispensing tube. The information required by this paragraph (b)(7) is not required for prescription drug products packaged in unit-dose, unit-of-use, on other packaging format in which the manufacturer’s original package is de signed and intended to be dispensed to patients without repackaging. (c)(1) Labeling on or within the pack age from which the drug is to be dis pensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and fre quency and duration of administration, and any relevant hazards, contra indications, side effects, and pre cautions under which practitioners li censed by law to administer the drug can use the drug safely and for the pur poses for which it is intended, includ ing all purposes for which it is adver tised or represented; and (2) If the article is subject to section 505 of the act, the labeling bearing such information is the labeling authorized by the approved new drug application or required as a condition for the cer tification or the exemption from cer tification requirements applicable to preparations of insulin or antibiotic drugs. (d) Any labeling, as defined in section 201(m) of the act, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, pack er, or distributor of the drug, that fur nishes or purports to furnish informa tion for use or which prescribes, rec ommends, or suggests a dosage for the use of the drug (other than dose infor mation required by paragraph (b)(2) of this section and § 201.105(b)(2) contains: (1) Adequate information for such use, including indications, effects, dos ages, routes, methods, and frequency and duration of administration and any relevant warnings, hazards, contra indications, side effects, and pre cautions, under which practitioners li censed by law to administer the drug can use the drug safely and for the pur poses for which it is intended, includ ing all conditions for which it is adver tised or represented; and if the article is subject to section 505 of the act, the parts of the labeling providing such in formation are the same in language and emphasis as labeling approved or permitted, under the provisions of sec tion 505, and any other parts of the la beling are consistent with and not con trary to such approved or permitted la beling; and (2) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed. (3) The information required, and in the format specified, by §§ 201.56, 201.57, and 201.80. (e) All labeling described in para graph (d) of this section bears con spicuously the name and place of busi ness of the manufacturer, packer, or distributor, as required for the label of the drug under § 201.1. (f) Reminder labeling which calls at tention to the name of the drug prod uct but does not include indications or dosage recommendations for use of the drug product is exempted from the pro visions of paragraph (d) of this section. This reminder labeling shall contain only the proprietary name of the drug product, if any; the established name of the drug product, if any; the estab lished name of each active ingredient in the drug product; and, optionally, information relating to quantitative ingredient statements, dosage form, quantity of package contents, price, the name and address of the manufac turer, packer, or distributor or other written, printed, or graphic matter containing no representation or sug gestion relating to the drug product. If VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00080 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 71 Food and Drug Administration, HHS § 201.105 the Commissioner finds that there is evidence of significant incidence of fa talities or serious injury associated with the use of a particular prescrip tion drug, he may withdraw this ex emption by so notifying the manufac turer, packer, or distributor of the drug by letter. Reminder labeling, other than price lists and catalogs sole ly intended to convey price informa tion including, but not limited to, those subject to the requirements of § 200.200 of this chapter, is not per mitted for a prescription drug product whose labeling contains a boxed warn ing relating to a serious hazard associ ated with the use of the drug product. Reminder labeling which is intended to provide consumers with information concerning the price charged for a pre scription for a particular drug product shall meet all of the conditions con tained in § 200.200 of this chapter. Re minder labeling, other than that sub ject to the requirements of § 200.200 of this chapter, is not permitted for a drug for which an announcement has been published pursuant to a review of the labeling claims for the drug by the National Academy of Sciences/National Research Council (NAS/NRC), Drug Ef ficacy Study Group, and for which no claim has been evaluated as higher than ‘‘possibly effective.’’ If the Com missioner finds the circumstances are such that reminder labeling may be misleading to prescribers of drugs sub ject to NAS/NRC evaluation, such re minder labeling will not be allowed and the manufacturer, packer, or dis tributor will be notified either in the publication of the conclusions on the effectiveness of the drug or by letter. [40 FR 13998, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975; 42 FR 15674, Mar. 22, 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659, Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR 25777, Apr. 15, 1980; 63 FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999; 67 FR 4906, Feb. 1, 2002; 71 FR 3996, Jan. 24, 2006] § 201.105 Veterinary drugs. A drug subject to the requirements of section 503(f)(1) of the act shall be ex empt from section 502(f)(1) of the act if all the following conditions are met: (a) The drug is: (1)(i) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale distribution of drugs that are to be used only by or on the prescription or other order of a licensed veterinarian; or (ii) In the possession of a retail, hos pital, or clinic pharmacy, or other per son authorized under State law to dis pense veterinary prescription drugs, who is regularly and lawfully engaged in dispensing drugs that are to be used only by or on the prescription or other order of a licensed veterinarian; or (iii) In the possession of a licensed veterinarian for use in the course of his professional practice; and (2) To be dispensed in accordance with section 503(f) of the act. (b) The label of the drug bears: (1) The statement ‘‘Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian’’; and (2) The recommended or usual dos age; and (3) The route of administration, if it is not for oral use; and (4) The quantity or proportion of each active ingredient as well as the information required by section 502(e) of the act; and (5) If it is for other than oral use, the names of all inactive ingredients, ex cept that: (i) Flavorings and perfumes may be designated as such without naming their components. (ii) Color additives may be des ignated as coloring without naming specific color components unless the naming of such components is required by a color additive regulation pre scribed in subchapter A of this chapter. (iii) Trace amounts of harmless sub stances added solely for individual product identification need not be named. If it is intended for administration by parenteral injection, the quantity or proportion of all inactive ingredients, except that ingredients added to adjust the pH or to make the drug isotonic may be declared by name and a state ment of their effect; and if the vehicle is water for injection, it need not be named. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00081 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 72 21 CFR Ch. I (4–1–16 Edition) § 201.105 (6) An identifying lot or control num ber from which it is possible to deter mine the complete manufacturing his tory of the package of the drug; Provided, however, That in the case of containers too small or otherwise un able to accommodate a label with suffi cient space to bear all such informa tion, but which are packaged within an outer container from which they are removed for dispensing or use, the in formation required by paragraphs (b) (2), (3), and (5) of this section may be contained in other labeling on or with in the package from which it is to be so dispensed, and the information referred to in paragraph (b)(1) of this section may be placed on such outer container only, and the information required by paragraph (b)(6) of this section may be on the crimp of the dispensing tube. (c)(1) Labeling on or within the pack age from which the drug is to be dis pensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and fre quency and duration of administration, and any relevant hazards, contra indications, side effects, and pre cautions under which veterinarians li censed by law to administer the drug can use the drug safely and for the pur poses for which it is intended, includ ing all purposes for which it is adver tised or represented; and (2) If the article is subject to section 512 or 572 of the act, the labeling bear ing such information is the labeling au thorized by the approved new animal drug application or contained in the index listing: Provided, however, That the information required by paragraph (c)(1) of this section may be omitted from the dispensing package if, but only if, the article is a drug for which directions, hazards, warnings, and use information are commonly known to veterinarians licensed by law to admin ister the drug. Upon written request, stating reasonable grounds therefore, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso. (d) Any labeling, as defined in section 201(m) of the act, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, pack er, or distributor of the drug, that fur nishes or purports to furnish informa tion for use or which prescribes, rec ommends, or suggests a dosage for the use of the drug (other than dose infor mation required by paragraph (b)(2) of this section and § 201.100(b)(2)) contains: (1) Adequate information for such use, including indications, effects, dos ages, routes, methods, and frequency and duration of administration, and any relevant warnings, hazards, con traindications, side effects, and pre cautions, and including information relevant to compliance with the new animal drug provisions of the act, under which veterinarians licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all con ditions for which it is advertised or represented; and if the article is sub ject to section 512 or 572 of the act, the parts of the labeling providing such in formation are the same in language and emphasis as labeling approved, per mitted, or indexed under the provisions of section 512 or 572, and any other parts of the labeling are consistent with and not contrary to such ap proved, permitted, or indexed labeling; and (2) The same information concerning the ingredients of the drug as appears on the label and labeling on or within the package from which the drug is to be dispensed; Provided, however, That the informa tion required by paragraphs (d) (1) and (2) of this section is not required on the so-called reminder-piece labeling which calls attention to the name of the drug but does not include indications or dos age recommendations for use of the drug. (e) All labeling, except labels and cartons, bearing information for use of the drug also bears the date of the issuance or the date of the latest revi sion of such labeling. (f) A prescription drug intended for both human and veterinary use shall comply with paragraphs (e) and (f) of this section and § 201.100. [40 FR 13998, Mar. 27, 1975, as amended at 42 FR 15674, Mar. 22, 1977; 57 FR 54300, Nov. 18, 1992; 72 FR 69119, Dec. 6, 2007] VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00082 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 73 Food and Drug Administration, HHS § 201.120 § 201.115 New drugs or new animal drugs. A new drug shall be exempt from sec tion 502(f)(1) of the act: (a) To the extent to which such ex emption is claimed in an approved ap plication with respect to such drug under section 505 or 512 of the act or an index listing with respect to such drug under section 572 of the act; or (b) If no application under section 505 or 512 of the act is approved and no re quest for addition to the index is grant ed under section 572 with respect to such drug but it complies with section 505(i), 512(j), or 572(g) of the act and regulations thereunder. No exemption shall apply to any other drug which would be a new drug if its labeling bore representations for its in tended uses. [40 FR 13998, Mar. 27, 1975, as amended at 72 FR 69119, Dec. 6, 2007] § 201.116 Drugs having commonly known directions. A drug shall be exempt from section 502(f)(1) of the act insofar as adequate directions for common uses thereof are known to the ordinary individual. [41 FR 6910, Feb. 13, 1976] § 201.117 Inactive ingredients. A harmless drug that is ordinarily used as an inactive ingredient, such as a coloring, emulsifier, excipient, fla voring, lubricant, preservative, or sol vent, in the preparation of other drugs shall be exempt from section 502(f)(1) of the act. This exemption shall not apply to any substance intended for a use which results in the preparation of a new drug, unless an approved new-drug application provides for such use. § 201.119 In vitro diagnostic products. (a) ‘‘In vitro diagnostic products’’ are those reagents, instruments and sys tems intended for use in the diagnosis of disease or in the determination of the state of health in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are in tended for use in the collection, prepa ration and examination of specimens taken from the human body. These products are drugs or devices as defined in section 201(g) and 201(h), respec tively, of the Federal Food, Drug, and Cosmetic Act (the act) or are a com bination of drugs and devices, and may also be a biological product subject to section 351 of the Public Health Service Act. (b) A product intended for use in the diagnosis of disease and which is an in vitro diagnostic product as defined in paragraph (a) of this section shall be deemed to be in compliance with the requirements of this section and sec tion 502(f)(1) of the act if it meets the requirements of § 809.10 of this chapter. [41 FR 6910, Feb. 13, 1976] § 201.120 Prescription chemicals and other prescription components. A drug prepared, packaged, and pri marily sold as a prescription chemical or other component for use by reg istered pharmacists in compounding prescriptions or for dispensing in dos age unit form upon prescriptions shall be exempt from section 502(f)(1) of the act if all the following conditions are met: (a) The drug is an official liquid acid or official liquid alkali, or is not a liq uid solution, emulsion, suspension, tab let, capsule, or other dosage unit form; and (b) The label of the drug bears: (1) The statement ‘‘For prescription compounding’’; and (2) If in substantially all dosage forms in which it may be dispensed it is subject to section 503(b)(1) of the act, the statement ‘‘Rx only’’; or (3) If it is not subject to section 503(b)(1) of the act and is by custom among retail pharmacists sold in or from the interstate package for use by consumers, ‘‘adequate directions for use’’ in the conditions for which it is so sold. Provided, however, That the informa tion referred to in paragraph (b)(3) of this section may be contained in the labeling on or within the package from which it is to be dispensed. (c) This exemption shall not apply to any substance intended for use in compounding which results in a new VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00083 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 74 21 CFR Ch. I (4–1–16 Edition) § 201.122 drug, unless an approved new-drug ap plication covers such use of the drug in compounding prescriptions. [40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002] § 201.122 Drugs for processing, repack ing, or manufacturing. A drug in a bulk package, except tab lets, capsules, or other dosage unit forms, intended for processing, repack ing, or use in the manufacture of an other drug shall be exempt from sec tion 502(f)(1) of the act if its label bears the statement ‘‘Caution: For manufac turing, processing, or repacking’’; and if in substantially all dosage forms in which it may be dispensed it is subject to section 503(b)(1) of the act, the state ment ‘‘Rx only’’, or if in substantially all dosage forms in which it may be dispensed it is subject to section 503(f)(1) of the act, the statement ‘‘Caution: Federal law restricts this drug to use by or on the order of a li censed veterinarian’’. This exemption and the exemption under § 201.120 may be claimed for the same article. How ever, the exemption shall not apply to a substance intended for a use in manu facture, processing, or repacking which causes the finished article to be a new drug or new animal drug, unless: (a) An approved new drug application or new animal drug application or a new animal drug index listing covers the production and delivery of the drug substance to the application or index listing holder by persons named in the application or in the request for deter mination of eligibility for indexing, and, for a new drug substance, the ex port of it by such persons under § 314.410 of this chapter; or (b) If no application is approved with respect to such new drug or new animal drug, and it is not listed in the index, the label statement ‘‘Caution: For manufacturing, processing, or repack ing’’ is immediately supplemented by the words ‘‘in the preparation of a new drug or new animal drug limited by Federal law to investigational use’’, and the delivery is made for use only in the manufacture of such new drug or new animal drug limited to investiga tional use as provided in part 312 or § 511.1 or § 516.125 of this chapter; or (c) A new drug application or new animal drug application or a request for addition to the index covering the use of the drug substance in the pro duction and marketing of a finished drug product has been submitted but not yet approved, disapproved, granted, or denied, the bulk drug is not ex ported, and the finished drug product is not further distributed after it is man ufactured until after the new drug ap plication or new animal drug applica tion is approved or the request for ad dition to the index is granted. [41 FR 6911, Feb. 13, 1976, as amended at 41 FR 15844, Apr. 15, 1976; 50 FR 7492, Feb. 22, 1985; 55 FR 11576, Mar. 29, 1990; 57 FR 54301, Nov. 18, 1992; 67 FR 4906, Feb. 1, 2002; 72 FR 69119, Dec. 6, 2007] § 201.125 Drugs for use in teaching, law enforcement, research, and analysis. A drug subject to § 201.100 or § 201.105, shall be exempt from section 502(f)(1) of the act if shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry, or medicine not involving clinical use, or engaged in law enforcement, or in research not in volving clinical use, or in chemical analysis, or physical testing, and is to be used only for such instruction, law enforcement, research, analysis, or testing. [41 FR 6911, Feb. 13, 1976] § 201.127 Drugs; expiration of exemp tions. (a) If a shipment or delivery, or any part thereof, of a drug which is exempt under the regulations in this section is made to a person in whose possession the article is not exempt, or is made for any purpose other than those speci fied, such exemption shall expire, with respect to such shipment or delivery or part thereof, at the beginning of that shipment or delivery. The causing of an exemption to expire shall be considered an act which results in such drug being misbranded unless it is disposed of under circumstances in which it ceases to be a drug or device. (b) The exemptions conferred by §§ 201.117, 201.119, 201.120, 201.122, and 201.125 shall continue until the drugs are used for the purposes for which VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00084 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 75 Food and Drug Administration, HHS § 201.150 they are exempted, or until they are relabeled to comply with section 502(f)(1) of the act. If, however, the drug is converted, compounded, or manufactured into a dosage form lim ited to prescription dispensing, no ex emption shall thereafter apply to the article unless the dosage form is la beled as required by section 503(b) and §§ 201.100 or 201.105. [41 FR 6911, Feb. 13, 1976] § 201.128 Meaning of ‘‘intended uses’’. The words intended uses or words of similar import in §§ 201.5, 201.115, 201.117, 201.119, 201.120, and 201.122 refer to the objective intent of the persons legally responsible for the labeling of drugs. The intent is determined by such persons’ expressions or may be shown by the circumstances sur rounding the distribution of the arti cle. This objective intent may, for ex ample, be shown by labeling claims, ad vertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither la beled nor advertised. The intended uses of an article may change after it has been introduced into interstate com merce by its manufacturer. If, for ex ample, a packer, distributor, or seller intends an article for different uses than those intended by the person from whom he received the drug, such pack er, distributor, or seller is required to supply adequate labeling in accordance with the new intended uses. But if a manufacturer knows, or has knowledge of facts that would give him notice, that a drug introduced into interstate commerce by him is to be used for con ditions, purposes, or uses other than the ones for which he offers it, he is re quired to provide adequate labeling for such a drug which accords with such other uses to which the article is to be put. [41 FR 6911, Feb. 13, 1976] § 201.129 Drugs; exemption for radio active drugs for research use. A radioactive drug intended for ad ministration to human research sub jects during the course of a research project intended to obtain basic re search information regarding metabo lism (including kinetics, distribution, and localization) of a radioactively la beled drug or regarding human physi ology, pathophysiology, or bio chemistry (but not intended for imme diate therapeutic, diagnostic, or simi lar purposes), under the conditions set forth in § 361.1 of this chapter, shall be exempt from section 502(f)(1) of the act if the packaging, label, and labeling are in compliance with § 361.1(f) of this chapter. [41 FR 6911, Feb. 13, 1976] Subpart E—Other Exemptions § 201.150 Drugs; processing, labeling, or repacking. (a) Except as provided by paragraphs (b) and (c) of this section, a shipment or other delivery of a drug which is, in accordance with the practice of the trade, to be processed, labeled, or re packed in substantial quantity at an establishment other than that where originally processed or packed, shall be exempt, during the time of introduc tion into and movement in interstate commerce and the time of holding in such establishment, from compliance with the labeling and packaging re quirements of sections 501(b) and 502 (b), (d), (e), (f), and (g) of the act if: (1) The person who introduced such shipment or delivery into interstate commerce is the operator of the estab lishment where such drug is to be proc essed, labeled, or repacked; or (2) In case such person is not such op erator, such shipment or delivery is made to such establishment under a written agreement, signed by and con taining the post-office addresses of such person and such operator, and containing such specifications for the processing, labeling, or repacking, as the case may be, of such drug in such establishment as will insure, if such specifications are followed, that such drug will not be adulterated or mis branded within the meaning of the act upon completion of such processing, la beling, or repacking. Such person and such operator shall each keep a copy of such agreement until 2 years after the final shipment or delivery of such drug VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00085 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 76 21 CFR Ch. I (4–1–16 Edition) § 201.161 from such establishment, and shall make such copies available for inspec tion at any reasonable hour to any offi cer or employee of the Department who requests them. (b) An exemption of a shipment or other delivery of a drug under para graph (a)(1) of this section shall, at the beginning of the act of removing such shipment or delivery, or any part thereof, from such establishment, be come void ab initio if the drug com prising such shipment, delivery, or part is adulterated or misbranded within the meaning of the act when so re moved. (c) An exemption of a shipment or other delivery of a drug under para graph (a)(2) of this section shall be come void ab initio with respect to the person who introduced such shipment or delivery into interstate commerce upon refusal by such person to make available for inspection a copy of the agreement, as required by such para graph (a)(2) of this section. (d) An exemption of a shipment or other delivery of a drug under para graph (a)(2) of this section shall expire: (1) At the beginning of the act of re moving such shipment or delivery, or any part thereof, from such establish ment if the drug comprising such ship ment, delivery, or part is adulterated or misbranded within the meaning of the act when so removed; or (2) Upon refusal by the operator of the establishment where such drug is to be processed, labeled, or repacked, to make available for inspection a copy of the agreement, as required by such clause. [41 FR 6911, Feb. 13, 1976, as amended at 64 FR 400, Jan. 5, 1999] § 201.161 Carbon dioxide and certain other gases. (a) Carbon dioxide, cyclopropane, ethylene, helium, and nitrous oxide gases intended for drug use are exempt ed from the requirements of § 201.100(b) (2), (3), and (c)(1) provided the labeling bears, in addition to any other infor mation required by the Federal Food, Drug, and Cosmetic Act, the following: (1) The warning statement ‘‘Warn ing—Administration of (name of gas) may be hazardous or contraindicated. For use only by or under the super vision of a licensed practitioner who is experienced in the use and administra tion of (name of gas) and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the haz ards, contraindications, and side ef fects and the precautions to be taken’’; and (2) Any needed directions concerning the conditions for storage and warn ings against the inherent dangers in the handling of the specific compressed gas. (b) This labeling exemption does not apply to mixtures of any one or more of these gases with oxygen or with each other. (c) Regulatory action may be initi ated with respect to any article shipped within the jurisdiction of the Act contrary to the provisions of this section after 60 days following publica tion of this section in the FEDERAL REGISTER. Subpart F—Labeling Claims for Drugs in Drug Efficacy Study § 201.200 Disclosure of drug efficacy study evaluations in labeling and advertising. (a)(1) The National Academy of Sciences—National Research Council, Drug Efficacy Study Group, has com pleted an exhaustive review of labeling claims made for drugs marketed under new-drug and antibiotic drug proce dures between 1938 and 1962. The results are compiled in ‘‘Drug Efficacy Study, A Report to the Commissioner of Food and Drugs from the National Academy of Sciences (1969).’’ As the report notes, this review has made ‘‘an audit of the state of the art of drug usage that has been uniquely extensive in scope and uniquely intensive in time’’ and is ap plicable to more than 80 percent of the currently marketed drugs. The report further notes that the quality of the evidence of efficacy, as well as the quality of the labeling claims, is poor. Labeling and other promotional claims have been evaluated as ‘‘effective,’’ ‘‘probably effective,’’ ‘‘possibly effec tive,’’ ‘‘ineffective,’’ ‘‘ineffective as a fixed combination,’’ and ‘‘effective but,’’ and a report for each drug in the VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00086 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 77 Food and Drug Administration, HHS § 201.200 study has been submitted to the Com missioner. (2) The Food and Drug Administra tion is processing the reports, seeking voluntary action on the part of the drug manufacturers and distributors in the elimination or modification of un supported promotional claims, and ini tiating administrative actions as nec essary to require product and labeling changes. (3) Delays have been encountered in bringing to the attention of the pre scribers of prescription items the con clusions of the expert panels that re viewed the promotional claims. (b) The Commissioner of Food and Drugs concludes that: (1) The failure to disclose in the la beling of a drug and in other pro motional material the conclusions of the Academy experts that a claim is ‘‘ineffective,’’ ‘‘possibly effective,’’ ‘‘probably effective,’’ or ‘‘ineffective as a fixed combination,’’ while labeling and promotional material bearing any such claim are being used, is a failure to disclose facts that are material in light of the representations made and causes the drug to be misbranded. (2) The Academy classification of a drug as other than ‘‘effective’’ for a claim for which such drug is rec ommended establishes that there is a material weight of opinion among qualified experts contrary to the rep resentation made or suggested in the labeling, and failure to reveal this fact causes such labeling to be misleading. (c) Therefore, after publication in the FEDERAL REGISTER of a Drug Efficacy Study Implementation notice on a pre scription drug, unless exempted or oth erwise provided for in the notice, all package labeling (other than the im mediate container or carton label, un less such labeling contains information required by § 201.100(c)(1) in lieu of a package insert), promotional labeling, and advertisements shall include, as part of the information for practi tioners under which the drug can be safely and effectively used, an appro priate qualification of all claims evalu ated as other than ‘‘effective’’ by a panel of the National Academy of Sciences—National Research Council, Drug Efficacy Study Group, if such claims continue to be included in ei ther the labeling or advertisements. However, this qualifying information will be required in advertisements only if promotional material is included therein for claims evaluated as less than ‘‘effective’’ or if such claims are included in the indications section of the portion of the advertisement con taining the information required in brief summary by § 202.1(e)(1) of this chapter. When, however, the Food and Drug Administration classification of such claim is ‘‘effective’’ (for example, on the basis of revision of the language of the claim or submission or existence of adequate data), such qualification is not necessary. When the Food and Drug Administration classification of the claim, as stated in the implementation notice, differs from that of the Acad emy but is other than ‘‘effective,’’ the qualifying statement shall refer to this classification in lieu of the Academy’s classification. (d) For new drugs and antibiotics, supplements to provide for revised la beling in accord with paragraph (c) of this section shall be submitted under the provisions of § 314.70 and § 514.8 of this chapter within 90 days after publi cation of the implementation notice in the FEDERAL REGISTER or by May 15, 1972, for those drugs for which notices have been published and such labeling shall be put into use as soon as possible but not later than the end of the time period allowed for submitting supple ments to provide for revised labeling. (e) Qualifying information required in drug labeling by paragraph (c) of this section in order to advise pre scribers of a drug of the findings made by a panel of the Academy in evalu ating a claim as other than ‘‘effective’’ shall be at least of the same size and color and degree of prominence as other printing in the labeling and shall be presented in a prominent box using one of the following formats and proce dures: (1) In drug labeling the box state ment may entirely replace the indica tions section and be in the following format: INDICATIONS Based on a review of this drug by the Na tional Academy of Sciences—National Re search Council and/or other information, VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00087 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 78 21 CFR Ch. I (4–1–16 Edition) § 201.200 FDA has classified the indication(s) as fol lows: Effective: (list or state in paragraph form). ‘‘Probably’’ effective: (list or state in para graph form). ‘‘Possibly’’ effective: (list or state in para graph form). Final classification of the less-than-effec tive indications requires further investiga tion. (2) Or the indication(s) for which the drug has been found effective may ap pear outside the boxed statement and be followed immediately by the fol lowing boxed statement: Based on a review of this drug by the National Academy of Sciences—Na tional Research Council and/or other information, FDA has classified the other indication(s) as follows: ‘‘Probably’’ effective: (list or state in paragraph form). ‘‘Possibly’’ effective: (list or state in paragraph form). Final classification of the less-than effective indications requires further investigation. (3) In drug labeling (other than that which is required by § 201.100(c)(1)) which may contain a promotional mes sage, the promotional message shall be keyed to the boxed statement by the same means as those provided for ad vertisements in paragraph (f)(2) of this section. (f) Qualifying information required in prescription drug advertising by para graph (c) of this section shall contain a prominent boxed statement of the ad vertised indication(s) and of the limita tions of effectiveness using the same format, language, and emphasis as that required in labeling by paragraph (e) of this section. (1) The boxed statement shall appear in (or next to) the information required in brief summary by § 202.1(e)(1) of this chapter and shall have prominence at least equal to that provided for other information presented in the brief sum mary and shall have type size, cap tions, color, and other physical charac teristics comparable to the informa tion required in the brief summary. (2) Less-than-effective indication(s) in the promotional message of an ad vertisement which is a single page or less shall be keyed to the boxed state ment by asterisk, by an appropriate statement, or by other suitable means providing adequate emphasis on the boxed statement. On each page where less-than-effective indication(s) appear in a mutiple page advertisement, an as terisk shall be placed after the most prominent mention of the indi cation(s); if the degree of prominence does not vary, an asterisk shall be placed after the first mention of the in dication. The asterisk shall refer to a notation at the bottom of the page which shall state ‘‘This drug has been evaluated as probably effective (or pos sibly effective whichever is appro priate) for this indication’’ and ‘‘See Brief Summary’’ or ‘‘See Prescribing Information,’’ the latter legend to be used only if the advertisement carries the required information for profes sional use as set forth in § 201.100(c)(1). (3) For less-than-effective indications which are included in the advertise ment only as a part of the information required in brief summary, the disclo sure information shall appear in this portion of the advertisement in the same manner as is specified for label ing in paragraph (e) of this section. (g) The Commissioner may find cir cumstances are such that, while the elimination of claims evaluated as other than effective will generally eliminate the need for disclosure about such claims, there will be instances in which the change in the prescribing or promotional profile of the drug is so substantial as to require a disclosure of the reason for the change so that the purchaser or prescriber is not misled by being left unaware through the sponsor’s silence that a basic change has taken place. The Food and Drug Administration will identify these situ ations in direct correspondence with the drug promoters, after which the failure to make the disclosure will be regarded as misleading and appropriate action will be taken. [40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990] VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00088 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 79 Food and Drug Administration, HHS § 201.301 Subpart G—Specific Labeling Re quirements for Specific Drug Products § 201.300 Notice to manufacturers, packers, and distributors of glan dular preparations. (a) Under date of December 4, 1941, in a notice to manufacturers of glandular preparations, the Food and Drug Ad ministration expressed the opinion that preparations of inert glandular materials intended for medicinal use should, in view of the requirement of section 201(n) of the Federal Food, Drug, and Cosmetic Act (52 Stat. 1041; 21 U.S.C. 321(n)), be labeled with a statement of the material fact that there is no scientific evidence that the articles contain any therapeutic or physiologically active constituents. Numerous preparations of such inert glandular materials were subsequently marketed with disclaimers of the type suggested. The term inert glandular ma terials means preparations incapable of exerting an action or effect of some significant or measurable benefit in one way or another, i.e., in the diag nosis, cure, mitigation, treatment, or prevention of disease, or in affecting the structure or any function of the body. (b) Manufacturers have heretofore taken advantage of § 201.100 permitting omission of directions for use when the label bears the prescription legend. Section 201.100(c) requires that the la beling of the drug, which may include brochures readily available to licensed practitioners, bear information as to the use of the drug by practitioners li censed by law to administer it. Obvi ously, information adequate for the use of an inert glandular preparation is not available to practitioners licensed by law. (c) The Department of Health and Human Services is of the opinion that inert glandular materials may not be exempted from the requirements of section 502(f)(1) of the act that they bear adequate directions for use; and, accordingly, that their labeling must include among other things, represen tations as to the conditions for which such articles are intended to be used or as to the structure or function of the human body that they are intended to affect. Since any such representations offering these articles for use as drugs would be false or misleading, such arti cles will be considered to be mis branded if they are distributed for use as drugs. (d) The amended regulations provide also that in the case of drugs intended for parenteral administration there shall be no exemption from the require ment that their labelings bear ade quate directions for use. Such inert glandular materials for parenteral use are therefore subject to the same com ment as applies to those intended for oral administration. § 201.301 Notice to manufacturers, packers, and distributors of estro genic hormone preparations. Some drug preparations fabricated wholly or in part from estradiol and la beled as to potency in terms of inter national units or in terms of inter national units of estrone activity have been marketed. The international unit of the estrus-producing hormone was established by the International Con ference on the Standardization of Sex Hormones at London, England, on Au gust 1, 1932. This unit was defined as ‘‘the specific estrus-producing activity contained in 0.1 gamma ( = 0.0001 mg.) of the standard’’ hydroxyketonic hor mone found in urine (estrone). The International Conference declared that it did not recommend the determina tion of the activity of nonhydroxyketonic forms of estrogenic hormones in units of estrone because of the varying ratios between the activity of such nonhydroxyketonic estrogenic hormones and estrone, when measured by different methods on test animals. There is no international unit for measuring the activity of estradiol and no accepted relationship between its activity and that of estrone, either in test animals or in humans. The dec laration of potency of estradiol in terms of international units or in terms of international units of estrone activity is therefore considered mis leading, within the meaning of 21 U.S.C. 352(a). The declaration of the es tradiol content of an estrogenic hor mone preparation in terms of weight is considered appropriate. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00089 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 80 21 CFR Ch. I (4–1–16 Edition) § 201.302 § 201.302 Notice to manufacturers, packers, and distributors of drugs for internal use which contain min eral oil. (a) In the past few years research studies have altered medical opinion as to the usefulness and harmfulness of mineral oil in the human body. These studies have indicated that when min eral oil is used orally near mealtime it interferes with absorption from the di gestive tract of provitamin A and the fat-soluble vitamins A, D, and K, and consequently interferes with the utili zation of calcium and phosphorus, with the result that the user is left liable to deficiency diseases. When so used in pregnancy it predisposes to hemor rhagic disease of the newborn. (b) There is accumulated evidence that the indiscriminate administration of mineral oil to infants may be fol lowed by aspiration of the mineral oil and subsequent ‘‘lipoid pneumonia.’’ (c) In view of these facts, the Depart ment of Health and Human Services will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act a drug for oral ad ministration consisting in whole or in part of mineral oil, the labeling of which encourages its use in pregnancy or indicates or implies that such drug is for administration to infants. (d) It is also this Department’s view that the act requires the labelings of such drugs to bear a warning against consumption other than at bedtime and against administration to infants. The following form of warning is sug gested: ‘‘Caution: To be taken only at bedtime. Do not use at any other time or administer to infants, except upon the advice of a physician.’’ (e) This statement of interpretation does not in any way exempt mineral oil or preparations containing mineral oil from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act. § 201.303 Labeling of drug prepara tions containing significant propor tions of wintergreen oil. (a) Because methyl salicylate (win tergreen oil) manifests no toxicity in the minute amounts in which it is used as a flavoring, it is mistakenly re garded by the public as harmless even when taken in substantially larger amounts. Actually, it is quite toxic when taken in quantities of a teaspoon ful or more. Wintergreen oil and prep arations containing it have caused a number of deaths through accidental misuse by both adults and children. Children are particularly attracted by the odor and are likely to swallow these products when left within reach. (b) To safeguard against fatalities from this cause, the Department of Health and Human Services will regard as misbranded under the provisions of the Federal Food, Drug, and Cosmetic Act any drug containing more than 5 percent methyl salicylate (wintergreen oil), the labeling of which fails to warn that use otherwise than as directed therein may be dangerous and that the article should be kept out of reach of children to prevent accidental poi soning. (c) This statement of interpretation in no way exempts methyl salicylate (wintergreen oil) or its preparations from complying in all other respects with the requirements of the Federal Food, Drug, and Cosmetic Act. § 201.304 Tannic acid and barium enema preparations. (a) It has become a widespread prac tice for tannic acid to be added to bar ium enemas to improve X-ray pictures. Tannic acid is capable of causing di minished liver function and severe liver necrosis when absorbed in suffi cient amounts. The medical literature reports a number of deaths associated with the addition of tannic acid to bar ium enemas. There is a lack of sci entific evidence to establish the condi tions, if any, under which tannic acid is safe and effective for use in enemas. Tannic acid for rectal use to enhance X-ray visualization is regarded as a new drug within the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act. (b) In view of the hazards involved when tannic acid is used in barium en emas, any shipments of tannic acid la beled to come within the exemptions under 502(f) of the Act containing such phrases as: ‘‘Caution: For manufac turing, processing, or repackaging,’’ ‘‘For prescription compounding,’’ or ‘‘Diagnostic reagent—For professional VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00090 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 81 Food and Drug Administration, HHS § 201.305 use only’’ will be regarded by the Com missioner of Food and Drugs as mis branded within the meaning of section 502(f) of the Federal Food, Drug, and Cosmetic Act unless the label and the labeling bear conspicuously a warning to the effect: ‘‘Warning— Not for use in enemas.’’ (c) Any tannic acid intended for use by man and found within the jurisdic tion of the Federal Food, Drug, and Cosmetic Act labeled contrary to this section after 60 days from the date of its publication in the FEDERAL REG ISTER may be made the subject of regu latory proceedings. § 201.305 Isoproterenol inhalation preparations (pressurized aerosols, nebulizers, powders) for human use; warnings. (a) Accumulating reports have been received by the Food and Drug Admin istration and have appeared in the medical literature of severe paradox ical bronchoconstriction associated with repeated, excessive use of isoproterenol inhalation preparations in the treatment of bronchial asthma and other chronic bronchopulmonary disorders. The cause of this paradoxical reaction is unknown; it has been ob served, however, that patients have not responded completely to other forms of therapy until use of the isoproterenol inhalation preparation was discon tinued. In addition, sudden unexpected deaths have been associated with the excessive use of isoproterenol inhala tion preparations. The mechanism of these deaths and their relationship, if any, to the cases of severe paradoxical bronchospasm are not clear. Cardiac arrest was noted in several of these cases of sudden death. (b) On the basis of the above informa tion and after discussion with and con currence of the Respiratory and Anes thetic Drugs Advisory Committee for Food and Drug Administration, the Commissioner of Food and Drugs con cludes that in order for the labeling of such drugs to bear adequate informa tion for their safe use, as required by § 201.100, such labeling must include the following: Warning: Occasional patients have been re ported to develop severe paradoxical airway resistance with repeated, excessive use of isoproterenol inhalation preparations. The cause of this refractory state is unknown. It is advisable that in such instances the use of this preparation be discontinued imme diately and alternative therapy instituted, since in the reported cases the patients did not respond to other forms of therapy until the drug was withdrawn. Deaths have been reported following exces sive use of isoproterenol inhalation prepara tions and the exact cause is unknown. Car diac arrest was noted in several instances. (c)(1) The Commissioner also con cludes that in view of the manner in which these preparations are self-ad ministered for relief of attacks of bron chial asthma and other chronic bron chopulmonary disorders, it is necessary for the protection of users that warn ing information to patients be included as a part of the label and as part of any instructions to patients included in the package dispensed to the patient as fol lows: Warning: Do not exceed the dose prescribed by your physician. If difficulty in breathing persists, contact your physician imme diately. (2) The warning on the label may be accomplished (i) by including it on the immediate container label with a statement directed to pharmacists not to remove the label or (ii) by including in the package a printed warning with instructions to pharmacists to place the warning on the container prior to dispensing. (d) The marketing of isoproterenol inhalation preparations may be contin ued if all the following conditions are met: (1) Within 30 days following the date of publication of this section in the FEDERAL REGISTER: (i) The label and labeling of such preparations shipped within the juris diction of the act are in accordance with paragraphs (b) and (c) of this sec tion. (ii) The holder of an approved new drug application for such preparation submits a supplement to his new-drug application to provide for appropriate labeling changes as described in para graphs (b) and (c) of this section. (2) Within 90 days following the date of publication of this section in the FEDERAL REGISTER, the manufacturer, VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00091 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 82 21 CFR Ch. I (4–1–16 Edition) § 201.306 packer, or distributor of any drug con taining isoproterenol intended for in halation for which a new-drug approval is not in effect submits a new-drug ap plication containing satisfactory infor mation of the kinds required by § 314.50 of this chapter, including appropriate labeling as described in paragraphs (b) and (c) of this section. (3) The applicant submits additional information required for the approval of the application as may be specified in a written communication from the Food and Drug Administration. (e) After 270 days following expira tion of said 90 days, regulatory pro ceedings based on section 505(a) of the Federal Food, Drug, and Cosmetic Act may be initiated with regard to any such drug shipped within the jurisdic tion of the act for which an approved new-drug application is not in effect. [40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990] § 201.306 Potassium salt preparations intended for oral ingestion by man. (a) The Food and Drug Administra tion will initiate no regulatory action with respect to the continued mar keting of coated tablets containing po tassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet provided all the following conditions are met: (1) Within 30 days from the date of publication of this statement of policy in the FEDERAL REGISTER: (i) The labeling of the drug bears the prescription caution statement quoted in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; (ii) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the ‘‘full disclosure’’ labeling re quirements of § 201.100 of this chapter, including the following warning state ment: Warning—There have been several reports, published and unpublished, concerning non specific small-bowel lesions consisting of ste nosis, with or without ulceration, associated with the administration of enteric-coated thiazides with potassium salts. These lesions may occur with enteric-coated potassium tablets alone or when they are used with nonenteric-coated thiazides, or certain other oral diuretics. These small-bowel lesions have caused obstruction, hemorrhage, and perforation. Surgery was frequently required and deaths have occurred. Based on a large survey of physicians and hospitals, both United States and foreign, the incidence of these lesions is low, and a causal relation ship in man has not been definitely estab lished. Available information tends to impli cate enteric-coated potassium salts, al though lesions of this type also occur spon taneously. Therefore, coated potassium-con taining formulations should be administered only when indicated, and should be discon tinued immediately if abdominal pain, dis tention, nausea, vomiting, or gastro intestinal bleeding occur. Coated potassium tablets should be used only when adequate dietary supplementation is not practicable. (Although the warning statement in cludes references to enteric-coated po tassium salt preparations, it applies to any capsule or coated tablet of a potas sium salt intended for oral ingestion without prior dilution with an ade quate volume of liquid to preclude gas trointestinal injury.) (iii) Any other labeling or additional advertising for the drug conforms to the labeling described in paragraph (a)(1)(ii) of this section, in accordance with §§ 202.1 and 201.100 of this chapter. (2) Within 90 days from the date of publication of this statement of policy in the FEDERAL REGISTER, the manu facturer, packer, or distributor of the drug shall submit a new-drug applica tion containing satisfactory informa tion of the kind required by § 314.50 of this chapter, with appropriate labeling as described in this paragraph. (b) The Food and Drug Administra tion may initiate regulatory pro ceedings after 30 days from the date of publication of this section, with re spect to the marketing of uncoated tablets containing potassium chloride or other potassium salts which supply 100 milligrams or more of potassium per tablet or with respect to liquid preparations containing potassium chloride or other potassium salts which supply 20 milligrams or more of potas sium per milliliter, labeled or intended for human use, unless all the following conditions are met: (1) The labeling of the drug bears the prescription statement quoted in sec tion 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; and VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00092 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 83 Food and Drug Administration, HHS § 201.307 (2) The labeling on or within the package from which the drug is to be dispensed bears adequate information for its use by practitioners in accord with the ‘‘full disclosure’’ labeling re quirements of § 201.100 of this chapter, including a recommendation that pa tients be directed to dissolve any such tablets in an appropriate amount of liquid and to dilute any such liquid preparations adequately to assure against gastrointestinal injury associ ated with the oral ingestion of con centrated potassium salt preparations. [40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990; 67 FR 4906, Feb. 1, 2002] § 201.307 Sodium phosphates; package size limitation, warnings, and direc tions for over-the-counter sale. (a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that multiple container sizes of sodium phosphates oral solution available in the marketplace have caused consumer confusion and appear to have been in volved in several consumer deaths. So dium phosphates oral solution has been marketed in 45-milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and 90-mL container sizes of sodium phosphates oral solution are often rec ommended and prescribed by physi cians for bowel cleansing prior to sur gery and diagnostic procedures of the colon. Sodium phosphates oral solution (adult dose 20 mL to 45 mL) is also used as an over-the-counter (OTC) laxative for the relief of occasional constipa tion. Accidental overdosing and deaths have occurred because the 240-mL con tainer was mistakenly used instead of the 45-mL or 90-mL container. The Food and Drug Administration is lim iting the amount of sodium phosphates oral solution to not more than 90 mL (3 ounces (oz)) per OTC container because of the serious health risks associated with the ingestion of larger than in tended doses of this product. Further, because an overdose of either oral or rectal enema sodium phosphates can cause an electrolyte imbalance, addi tional warning and direction state ments are required for the safe use of any OTC laxative drug product con taining sodium phosphates. (b) Any OTC drug product for lax ative or bowel cleansing use containing sodium phosphates as an active ingre dient when marketed as described in paragraph (a) of this section is mis branded within the meaning of section 502 of the Federal Food, Drug, and Cos metic Act unless packaged and labeled as follows: (1) Package size limitation for so dium phosphates oral solution: Con tainer shall not contain more than 90 mL (3 oz). (2) Warnings. The following sentences shall appear in boldface type as the first statement under the heading ‘‘Warnings.’’ (i) Oral dosage forms. ‘‘Taking more than the recommended dose in 24 hours can be harmful.’’ (ii) Rectal enema dosage forms. ‘‘Using more than one enema in 24 hours can be harmful.’’ (3) Directions—(i) The labeling of all orally or rectally administered OTC drug products containing sodium phosphates shall contain the following directions in boldface type imme diately preceding the dosage informa tion: ‘‘Do not’’ (‘‘take’’ or ‘‘use’’) ‘‘more unless directed by a doctor. See Warnings.’’ (ii) For products containing dibasic sodium phosphate/monobasic sodium phosphate identified in § 334.16(d) mar keted as a solution. Adults and chil dren 12 years of age and over: Oral dos age is dibasic sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate 9.1 to 20.2 g (20 to 45 mL di basic sodium phosphate/monobasic so dium phosphate oral solution) as a sin gle daily dose. ‘‘Do not take more than 45 mL (9 teaspoonfuls or 3 tablespoon fuls) in a 24-hour period.’’ Children 10 and 11 years of age: Oral dosage is diba sic sodium phosphate 1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g (10 to 20 mL dibasic sodium phos phate/monobasic sodium phosphate oral solution) as a single daily dose. ‘‘Do not take more than 20 mL (4 tea spoonfuls) in a 24-hour period.’’ Chil dren 5 to 9 years of age: Oral dosage is dibasic sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to 5.05 g (5 to 10 mL dibasic sodium phos phate/monobasic sodium phosphate oral solution) as a single daily dose. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00093 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 84 21 CFR Ch. I (4–1–16 Edition) § 201.308 ‘‘Do not take more than 10 mL (2 tea spoonfuls) in a 24-hour period.’’ Chil dren under 5 years of age: ask a doctor. (c) After June 22, 1998, for package size limitation and September 18, 1998, for labeling in accord with paragraph (b) of this section, any such OTC drug product initially introduced or ini tially delivered for introduction into interstate commerce, or any such drug product that is repackaged or relabeled after these dates regardless of the date the product was manufactured, ini tially introduced, or initially delivered for introduction into interstate com merce, that is not in compliance with this section is subject to regulatory ac tion. [63 FR 27843, May 21, 1998] § 201.308 Ipecac syrup; warnings and directions for use for over-the counter sale. (a) It is estimated that each year about 500,000 accidental poisonings occur in the United States and result in approximately 1,500 deaths, of which over 400 are children. In the emergency treatment of these poisonings, ipecac syrup is considered the emetic of choice. The immediate availability of this drug for use in such situations is critical, since rapid treatment may be the difference between life and death. The restriction of this drug to prescrip tion sale limits its availability in emergencies. On the other hand, it is the consensus of informed medical opinion that ipecac syrup should be used only under medical supervision in the emergency treatment of poisonings. In view of these facts, the question of whether ipecac syrup la beled as an emergency treatment for use in poisonings should be available over the counter has been controver sial. (b) In connection with its study of this problem, the Food and Drug Ad ministration has obtained the views of medical authorities. It is the unani mous recommendation of the American Academy of Pediatrics, the American Association of Poison Control Centers, the American Medical Association, and the Medical Advisory Board of the Food and Drug Administration that ip ecac syrup in 1 fluid ounce containers be permitted to be sold without pre scription so that it will be readily available in the household for emer gency treatment of poisonings, under medical supervision, and that the drug be appropriately packaged and labeled for this purpose. (c) In view of the above recommenda tions, the Commissioner of Food and Drugs has determined that it is in the interest of the public health for ipecac syrup to be available for sale without prescription, provided that it is pack aged in a quantity of 1 fluid ounce (30 milliliters), and its label bears, in addi tion to other required label informa tion, the following, in a prominent and conspicuous manner: (1) A statement conspicuously boxed and in red letters, to the effect: ‘‘For emergency use to cause vomiting in poisoning. Before using, call physician, the Poison Control Center, or hospital emergency room immediately for ad vice.’’ (2) A warning to the effect: ‘‘Warn ing—Keep out of reach of children. Do not use in unconscious persons. Ordi narily, this drug should not be used if strychnine, corrosives such as alkalies (lye) and strong acids, or petroleum distillates such as kerosine, gasoline, coal oil, fuel oil, paint thinner, or cleaning fluid have been ingested.’’ (3) Usual dosage: 1 tablespoon (15 mil liliters) in persons over 1 year of age. § 201.309 Acetophenetidin (phen acetin)-containing preparations; necessary warning statement. (a) In 1961, the Food and Drug Admin istration, pursuant to its statutory re sponsibility for the safety and effec tiveness of drugs shipped in interstate commerce, began an active investiga tion of reports of possible toxic effects and renal damage due to misuse of the drug acetophenetidin. This study led to the decision that there was probable cause to conclude that misuse and pro longed use of the drug were in fact re sponsible for kidney lesions and dis ease. The Commissioner of Food and Drugs, in December 1963, appointed an ad hoc Advisory Committee of Inquiry on Possible Nephrotoxicity Associated With the Abuse of Acetophenetidin (Phenacetin)-Containing Preparations. This committee, composed of scientists VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00094 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 85 Food and Drug Administration, HHS § 201.314 in the fields of pharmacology and med icine, on April 23, 1964, submitted its findings and conclusions in the matter and recommended that all acetophe netidin (phenacetin)-containing prep arations bear a warning as provided in section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act. (b) On the basis of the studies made by the Food and Drug Administration and the report of the Advisory Com mittee, the Commissioner of Food and Drugs has concluded that it is nec essary for the protection of users that the label and labeling of all acetophe netidin (phenacetin)-containing prep arations bear a warning statement to the following effect: ‘‘Warning—This medication may damage the kidneys when used in large amounts or for a long period of time. Do not take more than the recommended dosage, nor take regularly for longer than 10 days without consulting your physician.’’ § 201.310 Phenindione; labeling of drug preparations intended for use by man. (a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that phenindione, a synthetic anticoagulant drug, has caused a number of cases of agranulocytosis (with two fatalities). There are also reports implicating the drug in cases of hepatitis and hyper sensitivity reactions. In view of the po tentially serious effects found to be as sociated with preparations of this drug intended for use by man, the Commis sioner of Food and Drugs will regard such preparations as misbranded with in the meaning of section 502(f) (1) and (2) of the Federal Food, Drug, and Cos metic Act, unless the label and label ing on or within the package from which the drug is to be dispensed, and any other labeling furnishing or pur porting to furnish information for use of the drug, bear a conspicuous warn ing statement to the following effect: ‘‘Warning: Agranulocytosis and hepa titis have been associated with the use of phenindione. Patients should be in structed to report promptly prodromal symptoms such as marked fatigue, chill, fever, and sore throat. Periodic blood studies and liver function tests should be performed. Use of the drug should be discontinued if leukopenia occurs or if evidence of hyper sensitivity, such as dermatitis or fever, appears.’’ (b) Regulatory action may be initi ated with respect to preparations of phenindione intended for use by man found within the jurisdiction of the act on or after November 25, 1961, unless such preparations are labeled in ac cordance with paragraph (a) of this sec tion. § 201.311 [Reserved] § 201.312 Magnesium sulfate hepta hydrate; label declaration on drug products. Magnesium sulfate heptahydrate should be listed on the label of a drug product as epsom salt, which is its common or usual name. § 201.313 Estradiol labeling. The article presently recognized in The National Formulary under the heading ‘‘Estradiol’’ and which is said to be ‘‘17-cis-beta estradiol’’ is the same substance formerly recognized in the United States Pharmacopeia under the designation ‘‘Alpha Estradiol.’’ The substance should no longer be referred to in drug labeling as ‘‘Alpha Estra diol.’’ The Food and Drug Administra tion would not object to label ref erences to the article as simply ‘‘Es tradiol’’; nor would it object if the label of a preparation containing this substance referred to the presence of ‘‘Estradiol (formerly known as Alpha Estradiol).’’ § 201.314 Labeling of drug prepara tions containing salicylates. (a) The label of any oral drug prepa ration intended for sale without pre scription and which contains any salic ylate ingredient (including aspirin, sal icylamide, other salicylates, and com binations) must conspicuously bear, on a clearly contrasting background, the warning statement: ‘‘Keep out of reach of children [highlighted in bold type]. In case of overdose, get medical help or contact a Poison Control Center right away,’’ or ‘‘Keep out of reach of chil dren [highlighted in bold type],’’ except that if the article is an aspirin prepara tion, it shall bear the first of these VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00095 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 86 21 CFR Ch. I (4–1–16 Edition) § 201.314 warning statements. Such a warning statement is required for compliance with section 502(f)(2) of the Federal Food, Drug, and Cosmetic Act and is intended to guard against accidental poisonings. Safety closures that pre vent access to the drug by young chil dren are also recommended to guard against accidental poisonings. (b) Effervescent preparations and preparations containing para aminosalicylate as the only salicylate ingredient are exempted from this la beling requirement. (c) Aspirin tablets sold as such and containing no other active ingredients, except tablets which cannot be readily subdivided into a child’s dose because of their coating or size, should always bear dosage directions for each age group down to 3 years of age, with a statement such as ‘‘For children under 3 years of age, consult your physician.’’ It is recommended that: (1) Aspirin tablets especially made for pediatric use be produced only in 11⁄4-grain size to reduce the hazard of errors in dosage; (2) By June 1, 1967, manufacturers and distributors of 11⁄4-grain size aspi rin tablets discontinue the distribution of such tablets in retail containers con taining more than 36 tablets, to reduce the hazard of accidental poisoning; (3) The flavoring of 5-grain aspirin tablets or other ‘‘adult aspirin tablets’’ be discontinued; and (4) Labeling giving undue emphasis to the pleasant flavor of flavored aspi rin tablets be discontinued. (d) Salicylate preparations other than aspirin tablets sold as such may, at the option of the distributor, be la beled for use by adults only. If their la beling and advertising clearly offer them for administration to adults only. (e)(1) It is the obligation of the dis tributor who labels a salicylate prepa ration for administration to children to make certain that the article is suitable for such use and labeled with adequate directions for use in the age group for which it is offered, but in no case should such an article bear direc tions for use in children under 3 years of age. If the directions provide for ad ministration to children as young as 3 years of age, the label should bear the statement, ‘‘For children under 3 years of age consult your physician.’’ How ever, if the directions provide for ad ministration to children only of an age greater than 3 years (for example, the dosage instructions provide for admin istration of the article to children only down to age 6), the label should bear a statement such as, ‘‘For younger chil dren consult your physician.’’ (2) A statement such as, ‘‘For chil dren under 3 years of age consult your physician’’ or ‘‘For younger children consult your physician’’ is not required on the label of an article clearly of fered for administration to adults only. (f) If the labeling or advertising of a salicylate preparation offers it for use in arthritis or rheumatism, the label and labeling should clearly state that the beneficial effects claimed are lim ited to: ‘‘For the temporary relief of minor aches and pains of arthritis and rheumatism.’’ The qualifying phrase ‘‘for the temporary relief of minor aches and pains’’ should appear with the same degree of prominence and conspicuousness as the phrase ‘‘arthri tis and rheumatism’’. The label and la beling should bear in juxtaposition with such directions for use con spicuous warning statements to the ef fect: ‘‘Caution: If pain persists for more than 10 days, or redness is present, or in conditions affecting children under 12 years of age, consult a physician im mediately.’’ The salicylate dosage should not exceed 60 grains in a 24-hour period or 10 grains in a 4-hour period. If the article contains other analgesics, the salicylate dosage should be appro priately reduced. (g)(1) The label of any drug con taining more than 5 percent methyl sa licylate (wintergreen oil) should bear a conspicuous warning such as: ‘‘Do not use otherwise than as directed.’’ These drug products must also include the ‘‘Keep out of reach of children’’ warn ing and the accidental ingestion warn ing as required in § 330.1(g) of this chap ter. (2) If the preparation is a counter irritant or rubefacient, it should also bear a caution such as, ‘‘Caution: Dis continue use if excessive irritation of the skin develops. Avoid getting into the eyes or on mucous membranes.’’ (See also § 201.303.) VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00096 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 87 Food and Drug Administration, HHS § 201.316 (h)(1) The labeling of orally or rec tally administered over-the-counter drug products containing aspirin or nonaspirin salicylates as active ingre dients subject to this paragraph is re quired to prominently bear the fol lowing warning: ‘‘Reye’s syndrome [subheading in bold type]: Children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behav ior with nausea and vomiting occur, consult a doctor because these symp toms could be an early sign of Reye’s syndrome, a rare but serious illness.’’ (2) This warning statement shall ap pear on the immediate container label ing. In cases where the immediate con tainer is not the retail package, the re tail package also must bear the warn ing statement. In addition, the warning statement shall appear on any labeling that contains warnings and, in such cases, the warning statement shall be the first warning statement under the heading ‘‘Warnings.’’ (3) Over-the-counter drug products subject to this paragraph and labeled solely for use by children (pediatric products) shall not recommend the product for use in treating flu or chick en pox. (4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of this section that is not labeled as required by these paragraphs and that is initially intro duced or initially delivered for intro duction into interstate commerce after the following dates is misbranded under sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and Cos metic Act. (i) Compliance by October 18, 2004, for OTC drug products containing aspirin and nonaspirin salicylates as an active ingredient and marketed under a new drug application or abbreviated new drug application. (ii) Compliance by April 19, 2004, for OTC antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as an active ingredient and have annual sales greater than $25,000. (iii) Compliance by April 18, 2005, for OTC antidiarrheal and overindulgence drug products that contain bismuth subsalicylate as an active ingredient and have annual sales less than $25,000. (iv) Compliance dates for all other OTC drug products containing aspirin and nonaspirin salicylates as an active ingredient and marketed under an OTC drug monograph (for internal analge sic, antipyretic, and antirheumatic drug products, or for menstrual drug products) will be established when the final monographs for those products are published in a future issue of the FEDERAL REGISTER. In the interim, these products should continue to be labeled with the previous Reye’s syn drome warning that appears in para graph (h)(1) of this section. [40 FR 13998, Mar. 27, 1985, as amended at 51 FR 8182, Mar. 7, 1986; 53 FR 21637, June 9, 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR 18869, Apr. 17, 2003] § 201.315 Over-the-counter drugs for minor sore throats; suggested warn ing. The Food and Drug Administration has studied the problem of the labeling of lozenges or troches containing a local anesthetic, chewing gum con taining aspirin, various mouth washes and gargles and other articles sold over the counter for the relief of minor irri tations of the mouth or throat. It will not object to the labeling of suitable articles of this type ‘‘For the tem porary relief of minor sore throats’’, provided this is immediately followed in the labeling with a warning state ment in prominent type essentially as follows: ‘‘Warning—Severe or per sistent sore throat or sore throat ac companied by high fever, headache, nausea, and vomiting may be serious. Consult physician promptly. Do not use more than 2 days or administer to children under 3 years of age unless di rected by physician.’’ § 201.316 Drugs with thyroid hormone activity for human use; required warning. (a) Drugs with thyroid hormone ac tivity have been promoted for, and con tinue to be dispensed and prescribed for, use in the treatment of obesity, al though their safety and effectiveness for that use have never been estab lished. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00097 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 88 21 CFR Ch. I (4–1–16 Edition) § 201.317 (b) Drugs for human use with thyroid hormone activity are misbranded with in the meaning of section 502 of the Federal Food, Drug, and Cosmetic Act unless their labeling bears the fol lowing boxed warning at the beginning of the ‘‘Warnings’’ section: Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal re quirements are ineffective for weight re duction. Larger doses may produce seri ous or even life-threatening manifesta tions of toxicity, particularly when given in association with sympatho mimetic amines such as those used for their anorectic effects. [43 FR 22009, May 23, 1978] § 201.317 Digitalis and related cardiotonic drugs for human use in oral dosage forms; required warn ing. (a) Digitalis and related cardiotonic drugs for human use in oral dosage forms have been promoted for, and con tinue to be dispensed and prescribed for, use in the treatment of obesity, al though their safety and effectiveness for that use have never been estab lished. (b) Digitalis and related cardiotonic drugs for human use in oral dosage forms are misbranded within the mean ing of section 502 of the Federal Food, Drug, and Cosmetic Act unless their la beling bears the following boxed warn ing at the beginning of the ‘‘Warnings’’ section: Digitalis alone or with other drugs has been used in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs in the treatment of obesity is dangerous. (c) This section does not apply to dig oxin products for oral use, which shall be labeled according to the require ments of § 310.500 of this chapter. [43 FR 22009, May 23, 1978] § 201.319 Water-soluble gums, hydro philic gums, and hydrophilic mucilloids (including, but not lim ited to agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil tragacanth, and xan than gum) as active ingredients; re quired warnings and directions. (a) Reports in the medical literature and data accumulated by the Food and Drug Administration indicate that esophageal obstruction and asphyxia tion have been associated with the in gestion of water-soluble gums, hydro philic gums, and hydrophilic mucilloids including, but not limited to, agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B–1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil, tragacanth, and xan than gum. Esophageal obstruction and asphyxiation due to orally-adminis tered drug products containing water soluble gums, hydrophilic gums, and hydrophilic mucilloids as active ingre dients are significant health risks when these products are taken without adequate fluid or when they are used by individuals with esophageal nar rowing or dysfunction, or with dif ficulty in swallowing. Additional label ing is needed for the safe and effective use of any OTC drug product for human use containing a water-soluble gum, hydrophilic gum, or hydrophilic mucilloid as an active ingredient when marketed in a dry or incompletely hy drated form to include, but not limited to, the following dosage forms: Cap sules, granules, powders, tablets, and wafers. Granular dosage forms con taining psyllium are not generally rec ognized as safe and effective as OTC laxatives (see § 310.545(a)(12)(i)(B) of this chapter) and may not be marketed without an approved new drug applica tion because the warnings and direc tions in paragraph (b) of this section have been found inadequate for these products. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00098 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 89 Food and Drug Administration, HHS § 201.320 (b) Any drug products for human use containing a water-soluble gum, hydro philic gum, or hydrophilic mucilloid as an active ingredient in an oral dosage form when marketed in a dry or incom pletely hydrated form as described in paragraph (a) of this section are mis branded within the meaning of section 502 of the Federal Food, Drug, and Cos metic Act unless their labeling bears the following warnings (under the sub heading ‘‘Choking’’) and directions: ‘‘ ‘Choking’ [highlighted in bold type]: Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swal lowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention;’’ and ‘‘ ‘Directions’ [highlighted in bold type]:’’ (Select one of the following, as appropriate: ‘‘Take’’ or ‘‘Mix’’) ‘‘this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product with out enough liquid may cause choking. See choking warning.’’ (c) After February 28, 1994, any such OTC drug product initially introduced or initially delivered for introduction into interstate commerce, or any such drug product that is repackaged or re labeled after this date regardless of the date the product was manufactured, initially introduced, or initially deliv ered for introduction into interstate commerce, that is not in compliance with this section is subject to regu latory action. [58 FR 45201, Aug. 26, 1993, as amended at 64 FR 13292, Mar. 17, 1999; 72 FR 14674, Mar. 29, 2007] § 201.320 Warning statements for drug products containing or manufac tured with chlorofluorocarbons or other ozone-depleting substances. (a)(1) All drug products containing or manufactured with chlorofluorocarbons, halons, carbon tetrachloride, methyl chloride, or any other class I substance designated by the Environmental Protection Agency (EPA) shall, except as provided in para graph (b) or (c) of this section, bear the following warning statement: Warning: Contains [or Manufactured with, if applicable] [insert name of substance], a sub stance which harms public health and the environment by destroying ozone in the upper atmosphere. (2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and under stood by consumers under normal con ditions of purchase. (b)(1) For prescription drug products for human use, the following alter native warning statement may be used: NOTE: The indented statement below is re quired by the Federal government’s Clean Air Act for all products containing or manu factured with chlorofluorocarbons (CFC’s) [or name of other class I substance, if appli cable]: This product contains [or is manufactured with, if applicable] [insert name of substance], a substance which harms the environment by destroying ozone in the upper atmosphere. Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any ques tions about alternatives, consult with your physician. (2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and under stood by consumers under normal con ditions of purchase. (3) If the warning statement in para graph (b)(1) of this section is used, the following warning statement must be placed on the package labeling in tended to be read by the physician (physician package insert) after the ‘‘How supplied’’ section, which de scribes special handling and storage conditions on the physician labeling: NOTE: The indented statement below is re quired by the Federal government’s Clean VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00099 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 90 21 CFR Ch. I (4–1–16 Edition) § 201.323 Air Act for all products containing or manu factured with chlorofluorocarbons (CFC’s) [or name of other class I substance, if appli cable]: WARNING: Contains [or Manufactured with, if applicable] [insert name of substance], a sub stance which harms public health and the environment by destroying ozone in the upper atmosphere. A notice similar to the above WARNING has been placed in the information for the patient [or patient information leaflet, if ap plicable] of this product under the Environ mental Protection Agency’s (EPA’s) regula tions. The patient’s warning states that the patient should consult his or her physician if there are questions about alternatives. (c)(1) For over-the-counter drug prod ucts for human use, the following al ternative warning statement may be used: NOTE: The indented statement below is re quired by the Federal government’s Clean Air Act for all products containing or manu factured with chlorofluorocarbons (CFC’s) [or other class I substance, if applicable]: WARNING: Contains [or Manufactured with, if applicable] [insert name of substance], a sub stance which harms public health and envi ronment by destroying ozone in the upper at mosphere. CONSULT WITH YOUR PHYSICIAN OR HEALTH PROFESSIONAL IF YOU HAVE ANY QUESTION ABOUT THE USE OF THIS PRODUCT. (2) The warning statement shall be clearly legible and conspicuous on the product, its immediate container, its outer packaging, or other labeling in accordance with the requirements of 40 CFR part 82 and appear with such prominence and conspicuousness as to render it likely to be read and under stood by consumers under normal con ditions of purchase. (d) This section does not replace or relieve a person from any requirements imposed under 40 CFR part 82. [61 FR 20100, May 3, 1996] § 201.323 Aluminum in large and small volume parenterals used in total parenteral nutrition. (a) The aluminum content of large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy must not exceed 25 micrograms per liter (μg/L). (b) The package insert of LVP’s used in TPN therapy must state that the drug product contains no more than 25 μg/L of aluminum. This information must be contained in the ‘‘Pre cautions’’ section of the labeling of all large volume parenterals used in TPN therapy. (c) Except as provided in paragraph (d) of this section, the maximum level of aluminum present at expiry must be stated on the immediate container label of all small volume parenteral (SVP) drug products and pharmacy bulk packages (PBPs) used in the prep aration of TPN solutions. The alu minum content must be stated as fol lows: ‘‘Contains no more than ll μg/L of aluminum.’’ The immediate con tainer label of all SVP’s and PBP’s that are lyophilized powders used in the preparation of TPN solutions must contain the following statement: ‘‘When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than ll μg/L.’’ This max imum level of aluminum must be stat ed as the highest of: (1) The highest level for the batches produced during the last 3 years; (2) The highest level for the latest five batches, or (3) The maximum historical level, but only until completion of produc tion of the first five batches after July 26, 2004. (d) If the maximum level of alu minum is 25 μg/L or less, instead of stating the exact amount of aluminum as required in paragraph (c) of this sec tion, the immediate container label may state: ‘‘Contains no more than 25 μg/L of aluminum.’’ If the SVP or PBP is a lyophilized powder, the immediate container label may state: ‘‘When re constituted in accordance with the package insert instructions, the con centration of aluminum will be no more than 25 μg/L’’. (e) The package insert for all LVP’s, all SVP’s, and PBP’s used in TPN must contain a warning statement. This warning must be contained in the ‘‘Warnings’’ section of the labeling. The warning must state: WARNING: This product contains alu minum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is im paired. Premature neonates are particularly VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00100 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 91 Food and Drug Administration, HHS § 201.325 at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain alu minum. Research indicates that patients with im paired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 μg/kg/day accumulate aluminum at levels associated with central nervous system and bone tox icity. Tissue loading may occur at even lower rates of administration. (f) Applicants and manufacturers must use validated assay methods to determine the aluminum content in parenteral drug products. The assay methods must comply with current good manufacturing practice require ments. Applicants must submit to the Food and Drug Administration valida tion of the method used and release data for several batches. Manufactur ers of parenteral drug products not subject to an approved application must make assay methodology avail able to FDA during inspections. Hold ers of pending applications must sub mit an amendment under § 314.60 or § 314.96 of this chapter. [65 FR 4110, Jan. 26, 2000, as amended at 67 FR 70691, Nov. 26, 2002; 68 FR 32981, June 3, 2003] § 201.325 Over-the-counter drugs for vaginal contraceptive and spermicide use containing nonoxynol 9 as the active ingre dient; required warnings and label ing information. (a) Studies indicate that use of vag inal contraceptive drug products con taining nonoxynol 9 does not protect against infection from the human im munodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), or against the trans mission of other sexually transmitted diseases (STDs). Studies also indicate that use of vaginal contraceptive drug products containing nonoxynol 9 can increase vaginal irritation, such as the disruption of the vaginal epithelium, and also can cause epithelial disruption when used in the rectum. These effects may increase the risk of transmission of the AIDS virus (HIV) from an in fected partner. Therefore, consumers should be warned that these products do not protect against the trans mission of the AIDS virus (HIV) or other STDs, that use of these products can increase vaginal and rectal irrita tion, which may increase the risk of getting the AIDS virus (HIV) from an HIV infected partner, and that the products are not for rectal use. Con sumers should also be warned that these products should not be used by persons who have HIV/AIDS or are at high risk for HIV/AIDS. (b) The labeling of OTC vaginal con traceptive and spermicide drug prod ucts containing nonoxynol 9 as the ac tive ingredient, whether subject to the ongoing OTC drug review or an ap proved drug application, must contain the following warnings under the head ing ‘‘Warnings,’’ in accordance with 21 CFR 201.66. (1) ‘‘[bullet] For vaginal use only [bullet] Not for rectal (anal) use’’ [both warnings in bold type]. (2) ‘‘Sexually transmitted diseases (STDs) alert [in bold type]: This prod uct does not [word ‘‘not’’ in bold type] protect against HIV/AIDS or other STDs and may increase the risk of get ting HIV from an infected partner’’. (3) ‘‘Do not use’’ [in bold type] if you or your sex partner has HIV/AIDS. If you do not know if you or your sex partner is infected, choose another form of birth control’’. (4) ‘‘When using this product [in bold type] [optional, bullet] you may get vaginal irritation (burning, itching, or a rash)’’. (5) ‘‘Stop use and ask a doctor if [in bold type] [optional, bullet] you or your partner get burning, itching, a rash, or other irritation of the vagina or penis’’. (c) The labeling of this product states under the ‘‘Other information’’ section of the Drug Facts labeling in accord ance with § 201.66(c)(7), ‘‘[bullet] when used correctly every time you have sex, latex condoms greatly reduce, but do not eliminate, the risk of catching or spreading HIV, the virus that causes AIDS. (d) The labeling of this product in cludes the following statements either on the outside container or wrapper of the retail package, under the ‘‘Other information’’ section of the Drug Facts labeling in accordance with § 201.66(c)(7), or in a package insert: VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00101 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 92 21 CFR Ch. I (4–1–16 Edition) § 201.326 (1) ‘‘[bullet] studies have raised safe ty concerns that products containing the spermicide nonoxynol 9 can irritate the vagina and rectum. Sometimes this irritation has no symptoms. This irri tation may increase the risk of getting HIV/AIDS from an infected partner’’. (2) ‘‘[bullet] you can use nonoxynol 9 for birth control with or without a dia phragm or condom if you have sex with only one partner who is not infected with HIV and who has no other sexual partners or HIV risk factors’’. (3) ‘‘[bullet] use a latex condom with out nonoxynol 9 if you or your sex partner has HIV/AIDS, multiple sex partners, or other HIV risk factors’’. (4) ‘‘[bullet] ask a health professional if you have questions about your best birth control and STD prevention methods’’. (e) Any drug product subject to this section that is not labeled as required and that is initially introduced or ini tially delivered for introduction into interstate commerce after June 19, 2008, is misbranded under section 502 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 352), is a new drug under section 505 of the act (21 U.S.C. 355), and is subject to regulatory action. [72 FR 71785, Dec. 19, 2007] § 201.326 Over-the-counter drug prod ucts containing internal analgesic/ antipyretic active ingredients; re quired warnings and other labeling. (a) Labeling. The labeling for all over the-counter (OTC) drug products con taining any internal analgesic/anti pyretic active ingredients (including, but not limited to, acetaminophen, as pirin, carbaspirin calcium, choline sa licylate, ibuprofen, ketoprofen, magne sium salicylate, naproxen sodium, and sodium salicylate) alone or in combina tion must bear the following labeling in accordance with §§ 201.60, 201.61, and 201.66. (1) Acetaminophen—(i) Statement of identity. The statement of identity ap pears in accord with §§ 201.61 and 299.4 of this chapter. The ingredient name ‘‘acetaminophen’’ must appear high lighted (e.g., fluorescent or color con trast) or in bold type, be in lines gen erally parallel to the base on which the package rests as it is designed to be displayed, and be in one of the fol lowing sizes, whichever is greater: (A) At least one-quarter as large as the size of the most prominent printed matter on the principal display panel (PDP), or (B) At least as large as the size of the ‘‘Drug Facts’’ title, as required in § 201.66(d)(2). The presence of acetami nophen must appear as part of the es tablished name of the drug, as defined in § 299.4 of this chapter. Combination products containing acetaminophen and a nonanalgesic ingredient(s) (e.g., cough-cold) must include the name ‘‘acetaminophen’’ and the name(s) of the other active ingredient(s) in the product on the PDP in accord with this paragraph. Only the name ‘‘acetami nophen’’ must appear highlighted or in bold type, and in a prominent print size, as described in this paragraph. (ii) Active Ingredient and Purpose Headings. The information required under § 201.66(c)(2) and (c)(3) of this chapter must be included under these headings. The information under these headings, but not the headings, may appear highlighted. (iii) For products labeled for adults only. The labeling of the product states the following warnings under the head ing ‘‘Warnings’’: (A) The liver warning states ‘‘Liver warning [heading in bold type]: This product contains acetaminophen. Se vere liver damage may occur if you take [bullet] more than [insert max imum number of daily dosage units] in 24 hours, which is the maximum daily amount [optional: ‘for this product’] [bullet] with other drugs containing ac etaminophen [bullet] 3 or more alco holic drinks every day while using this product’’. This ‘‘Liver’’ warning must be the first warning under the ‘‘Warn ings’’ heading. For products that con tain both acetaminophen and aspirin, this ‘‘Liver’’ warning must appear after the ‘‘Reye’s syndrome’’ and ‘‘Allergy alert’’ warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B) and before the ‘‘Stom ach bleeding’’ warning in paragraph (a)(2)(iii)(A) of this section. If there is an outer and immediate container of a retail package, this warning must ap pear on both the outer and immediate containers. If the immediate container VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00102 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 93 Food and Drug Administration, HHS § 201.326 is a blister card, the warning must ap pear on the blister card and remain in tact and readable when drug product is removed from the blister card. The warning does not need to be included on each blister unit. (B) ‘‘Do not use with any other drug containing acetaminophen (prescrip tion or nonprescription). If you are not sure whether a drug contains acetami nophen, ask a doctor or pharmacist.’’ (C) ‘‘Ask a doctor before use if you have liver disease’’. (D) ‘‘Ask a doctor or pharmacist be fore use if you are taking the blood thinning drug warfarin’’ except on the labeling of combination products that contain acetaminophen and NSAID(s). (iv) For products labeled only for chil dren under 12 years of age. (A) Warnings. The labeling of the product states the following warnings under the heading ‘‘Warnings’’: (1) The liver warning states ‘‘Liver warning [heading in bold type]: This product contains acetaminophen. Se vere liver damage may occur if your child takes [bullet] more than 5 doses in 24 hours, which is the maximum daily amount [optional: ‘for this prod uct’] [bullet] with other drugs con taining acetaminophen’’. This ‘‘Liver’’ warning must be the first warning under the ‘‘Warnings’’ heading. If there is an outer and immediate container of a retail package, this warning must ap pear on both the outer and immediate containers. If the immediate container is a blister card, the warning must ap pear on the blister card and remain in tact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit. (2) ‘‘Do not use with any other drug containing acetaminophen (prescrip tion or nonprescription). If you are not sure whether a drug contains acetami nophen, ask a doctor or pharmacist.’’ (3) ‘‘Ask a doctor before use if your child has liver disease’’. (4) ‘‘Ask a doctor or pharmacist be fore use if your child is taking the blood thinning drug warfarin’’ except on the labeling of combination prod ucts that contain acetaminophen and NSAID(s). (B) Directions. The labeling of the product contains the following infor mation under the heading ‘‘Direc tions’’: ‘‘this product does not contain directions or complete warnings for adult use’’ [in bold type]. (v) For products labeled for adults and children under 12 years of age. The label ing of the product states all of the warnings in paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of this section with the following modifica tions: (A) The liver warning states ‘‘Liver warning [heading in bold type]: This product contains acetaminophen. Se vere liver damage may occur if [bullet] adult takes more than [insert max imum number of daily dosage units] in 24 hours, which is the maximum daily amount [optional: ‘for this product’] [bullet] child takes more than 5 doses in 24 hours [bullet] taken with other drugs containing acetaminophen [bul let] adult has 3 or more alcoholic drinks everyday while using this prod uct.’’ If there is an outer and imme diate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not re quired to be included on each blister unit. (B) ‘‘Ask a doctor before use if the user has liver disease.’’ (C) ‘‘Do not use with any other drug containing acetaminophen (prescrip tion or nonprescription). If you are not sure whether a drug contains acetami nophen, ask a doctor or pharmacist.’’ (D) ‘‘Ask a doctor or pharmacist be fore use if the user is taking the blood thinning drug warfarin’’ except on the labeling of combination products that contain acetaminophen and NSAID(s). (2) Nonsteroidal anti-inflammatory an algesic/antipyretic active ingredients—in cluding, but not limited to, aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicy late, naproxen sodium, and sodium salicy late. (i) Statement of identity. The state ment of identity appears in accord with §§ 201.61 and 299.4 of this chapter. The VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00103 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 94 21 CFR Ch. I (4–1–16 Edition) § 201.326 word ‘‘(NSAID)’’ must appear high lighted (e.g., fluorescent or color con trast) or in bold type, be in lines gen erally parallel to the base on which the package rests as it is designed to be displayed, and be in one of the fol lowing sizes, whichever is greater: (A) At least one-quarter as large as the size of the most prominent printed matter on the PDP, or (B) At least as large as the size of the ‘‘Drug Facts’’ title, as required in § 201.66(d)(2). The word ‘‘(NSAID)’’ must appear as part of the established name of the drug, as defined in § 299.4 of this chapter, or after the general pharma cological (principal intended) action of the NSAID ingredient. Combination products containing an NSAID and a nonanalgesic ingredient(s) (e.g., cough cold) must include the name of the NSAID ingredient and the word ‘‘(NSAID)’’ in accordance with this paragraph, and the name(s) of the other active ingredient(s) in the prod uct on the PDP. Only the word ‘‘(NSAID)’’ needs to appear highlighted or in bold type, and in a prominent print size, as described in this para graph. (ii) Active Ingredient and Purpose Headings. The information required under § 201.66(c)(2) and (c)(3) of this chapter must be included under these headings. The active ingredient(s) sec tion of the product’s labeling, as de fined in § 201.66(c)(2), contains the term ‘‘(NSAID*)’’ after the NSAID active in gredient with an asterisk statement at the end of the active ingredient(s) sec tion that defines the term ‘‘NSAID’’ and states ‘‘* nonsteroidal anti-inflam matory drug.’’ The information under these headings may appear highlighted. However, the headings ‘‘Active Ingre dient’’ and ‘‘Purpose’’ may not appear highlighted. (iii) For products labeled for adults only. The labeling of the product states the following warnings under the head ing ‘‘Warnings’’: (A) The stomach bleeding warning states ‘‘Stomach bleeding warning [heading in bold type]: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you [bullet] are age 60 or older [bullet] have had stomach ulcers or bleeding problems [bullet] take a blood thinning (anticoagulant) or steroid drug [bullet] take other drugs con taining prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others) [bullet] have 3 or more alco holic drinks every day while using this product [bullet] take more or for a longer time than directed’’. This ‘‘Stomach bleeding’’ warning must ap pear after the ‘‘Reye’s syndrome’’ and ‘‘Allergy alert’’ warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For products that contain both acetamino phen and aspirin, the acetaminophen ‘‘Liver’’ warning in paragraph (a)(1)(iii) of this section must appear before the ‘‘Stomach bleeding’’ warning in this paragraph. If there is an outer and im mediate container of a retail package, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not re quired to be included on each blister unit. (B) ‘‘Ask a doctor before use if [bul let] stomach bleeding warning applies to you [bullet] you have a history of stomach problems, such as heartburn [bullet] you have high blood pressure, heart disease, liver cirrhosis, or kidney disease [bullet] you are taking a diu retic’’. (C) ‘‘Stop use and ask a doctor if [bullet] you experience any of the fol lowing signs of stomach bleeding:’’ [add the following as second level of state ments: ‘‘[bullet] feel faint [bullet] vomit blood [bullet] have bloody or black stools [bullet] have stomach pain that does not get better’’]. (iv) For products labeled only for chil dren under 12 years of age. (A) Warnings. The labeling of the product states the following warnings under the heading ‘‘Warnings’’: (1) The stomach bleeding warning states ‘‘Stomach bleeding warning [heading in bold type]: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if your child [bullet] has had stomach ulcers or bleeding problems [bullet] takes a blood thinning (anti coagulant) or steroid drug [bullet] VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00104 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 95 Food and Drug Administration, HHS § 201.326 takes other drugs containing prescrip tion or nonprescription NSAIDs (aspi rin, ibuprofen, naproxen, or others) [bullet] takes more or for a longer time than directed’’. The ‘‘Stomach bleed ing’’ warning must appear after the ‘‘Reye’s syndrome’’ and ‘‘Allergy alert’’ warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and immediate container of a retail pack age, this warning must appear on both the outer and immediate containers. If the immediate container is a blister card, the warning must appear on the blister card and remain intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit. (2) ‘‘Ask a doctor before use if [bul let] stomach bleeding warning applies to your child [bullet] child has a his tory of stomach problems, such as heartburn [bullet] child has not been drinking fluids [bullet] child has lost a lot of fluid due to vomiting or diarrhea [bullet] child has high blood pressure, heart disease, liver cirrhosis, or kidney disease [bullet] child is taking a diu retic’’. (3) ‘‘Stop use and ask a doctor if [bul let] child experiences any of the fol lowing signs of stomach bleeding:’’ [add the following as second level of state ments: [bullet] feels faint [bullet] vom its blood [bullet] has bloody or black stools [bullet] has stomach pain that does not get better’’]. (B) Directions. The labeling of the product contains the following infor mation under the heading ‘‘Direc tions’’: ‘‘this product does not contain directions or complete warnings for adult use’’ [in bold type]. (v) For products labeled for adults and children under 12 years of age. The label ing of the product states all of the warnings in paragraphs (a)(2)(iii)(A) through (a)(2)(iii)(C) of this section with the following modifications: (A) The Stomach bleeding warning states ‘‘Stomach bleeding warning [heading in bold type]: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if the user [bullet] has had stomach ulcers or bleeding problems [bullet] takes a blood thinning (anti coagulant) or steroid drug [bullet] takes other drugs containing prescrip tion or nonprescription NSAIDs (aspi rin, ibuprofen, naproxen, or others) [bullet] takes more or for a longer time than directed [bullet] is age 60 or older [bullet] has 3 or more alcoholic drinks everyday while using this product’’. The ‘‘Stomach bleeding’’ warning must appear after the ‘‘Reye’s syndrome‘‘ and ‘‘Allergy alert’’ warnings in § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and immediate con tainer of a retail package, this warning must appear on both the outer and im mediate containers. If the immediate container is a blister card, the warning must appear on the blister card and re main intact and readable when drug product is removed from the blister card. The warning is not required to be included on each blister unit. (B) The labeling states ‘‘Ask a doctor before use if [bullet] stomach bleeding warning applies to user [bullet] user has history of stomach problems, such as heartburn [bullet] user has high blood pressure, heart disease, liver cir rhosis, or kidney disease [bullet] user takes a diuretic [bullet] user has not been drinking fluids [bullet] user has lost a lot of fluid due to vomiting or di arrhea’’. (C) The labeling states ‘‘Stop use and ask a doctor if [bullet] user experiences any of the following signs of stomach bleeding:’’ [add the following as second level of statements: [bullet] feels faint [bullet] vomits blood [bullet] has bloody or black stools [bullet] has stomach pain that does not get bet ter’’]. (b) New warnings information state ment. The labeling of any drug product subject to this section that is initially introduced or initially delivered for in troduction into interstate commerce before or on April 29, 2010, must bear on its PDP, as defined in § 201.60, the statement ‘‘See new warnings informa tion’’. This statement must appear highlighted (e.g., fluorescent or color contrast) or in bold type, be in lines generally parallel to the base on which the package rests as it is designed to be displayed, and be in one of the fol lowing sizes, whichever is greater: (1) At least one-quarter as large as the size of the most prominent printed matter on the PDP, or VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00105 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 96 21 CFR Ch. I (4–1–16 Edition) § 201.327 (2) At least as large as the size of the ‘‘Drug Facts’’ title, as required in § 201.66(d)(2). The new warnings infor mation statement must remain on the PDP of the drug product for at least 1 year from the date the product is ini tially introduced into interstate com merce. (c) Requirements to supplement ap proved application. Holders of approved applications for OTC drug products that contain internal analgesic/anti pyretic active ingredients that are sub ject to the requirements of paragraph (a) of this section must submit supple ments under § 314.70(c) of this chapter to include the required information in the product’s labeling. Such labeling may be put into use without advance approval of FDA provided it includes at least the exact information included in paragraph (a) of this section. [74 FR 19407, Apr. 29, 2009, as amended at 74 FR 31180, June 30, 2009; 74 FR 61514, Nov. 25, 2009] § 201.327 Over-the-counter sunscreen drug products; required labeling based on effectiveness testing. The following provisions apply to sunscreen products containing amino benzoic acid, avobenzone, cinoxate, dioxybenzone, ensulizole, homosalate, meradimate, octinoxate, octisalate, octocrylene, oxybenzone, padimate O, sulisobenzone, titanium dioxide, trolamine salicylate, or zinc oxide, alone or in combination. The provi sions do not apply to sunscreen prod ucts marketed under approved new drug applications or abbreviated new drug applications. (a) Principal display panel. In addition to the statement of identity in para graph (b) of this section, the following labeling shall be prominently placed on the principal display panel: (1) Effectiveness claim—(i) For products that pass the broad spectrum test in para graph (j) of this section. (A) The labeling states ‘‘Broad Spectrum SPF [insert numerical SPF value resulting from testing under paragraph (i) of this sec tion]’’. (B) Prominence. The Broad Spectrum SPF statement shall appear as contin uous text with no intervening text or graphic. The entire text shall appear in the same font style, size, and color with the same background color. (ii) For sunscreen products that do not pass the broad spectrum test in paragraph (j) of this section. The labeling states ‘‘SPF [insert numerical SPF value re sulting from testing under paragraph (i) of this section]’’. The entire text shall appear in the same font style, size, and color with the same back ground color. (2) Water resistance statements—(i) For products that provide 40 minutes of water resistance according to the test in para graph (i)(7)(i) of this section. The label ing states ‘‘Water Resistant (40 min utes)’’. (ii) For products that provide 80 min utes of water resistance according to the test in paragraph (i)(7)(ii) of this section. The labeling states ‘‘Water Resistant (80 minutes)’’. (b) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies the drug as a ‘‘sunscreen.’’ (c) Indications. The labeling of the product states, under the heading ‘‘Uses,’’ the phrases listed in this para graph (c), as appropriate. Other truth ful and nonmisleading statements, de scribing only the uses that have been established and listed in this paragraph (c), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Fed eral Food, Drug, and Cosmetic Act (the FD&C Act) relating to misbranding and the prohibition in section 301(d) of the FD&C Act against the introduction or delivery for introduction into inter state commerce of unapproved new drugs in violation of section 505(a) of the FD&C Act. (1) For all sunscreen products, the following indication statement must be included under the heading ‘‘Uses’’: ‘‘[Bullet] helps prevent sunburn’’. See § 201.66(b)(4) of this chapter for defini tion of bullet. (2) For sunscreen products with a Broad Spectrum SPF value of 15 or higher according to the tests in para graphs (i) and (j) of this section, the la beling may include the following state ment in addition to the indication in § 201.327(c)(1): ‘‘[Bullet] if used as di rected with other sun protection meas ures (see Directions [in bold italic VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00106 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 97 Food and Drug Administration, HHS § 201.327 font]), decreases the risk of skin cancer and early skin aging caused by the sun’’. (3) Any labeling or promotional ma terials that suggest or imply that the use, alone, of any sunscreen reduces the risk of or prevents skin cancer or early skin aging will cause the product to be misbranded under section 502 of the FD&C Act (21 U.S.C. 352). (d) Warnings. The labeling of the product contains the following warn ings under the heading ‘‘Warnings’’. (1) For all sunscreen products. (i) The labeling states ‘‘Do not use [bullet] on damaged or broken skin’’. (ii) The labeling states ‘‘When using this product [bullet] keep out of eyes. Rinse with water to remove.’’ (iii) The labeling states ‘‘Stop use and ask a doctor if [bullet] rash oc curs’’. (2) For sunscreen products that are broad spectrum with SPF values of at least 2 but less than 15 according to the SPF test in paragraph (i) of this section or that do not pass the broad spectrum test in paragraph (j) of this section. The first statement under the heading ‘‘Warn ings’’ states ‘‘Skin Cancer/Skin Aging Alert [in bold font]; Spending time in the sun increases your risk of skin can cer and early skin aging. This product has been shown only to help prevent sunburn, not [in bold font] skin cancer or early skin aging.’’ (e) Directions. The labeling of the product contains the following state ments, as appropriate, under the head ing ‘‘Directions.’’ More detailed direc tions applicable to a particular product formulation may also be included. (1) For all sunscreen products. (i) As an option, the labeling may state ‘‘For sunscreen use:’’. (ii) The labeling states ‘‘[bullet] apply [select one of the following: ‘Lib erally’ or ‘generously’] [and, as an op tion: ‘And evenly’] 15 minutes before sun exposure’’. (iii) As an option, the labeling may state ‘‘[bullet] apply to all skin ex posed to the sun’’. (iv) The labeling states ‘‘[bullet] chil dren under 6 months of age: Ask a doc tor’’. (2) For sunscreen products with a Broad Spectrum SPF value of 15 or higher ac cording to the tests in paragraphs (i) and (j) of this section. The labeling states ‘‘[bullet] Sun Protection Measures. [in bold font] Spending time in the sun in creases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with a Broad Spectrum SPF value of 15 or higher and other sun protection measures in cluding: [Bullet] limit time in the sun, especially from 10 a.m.–2 p.m. [bullet] wear long-sleeved shirts, pants, hats, and sunglasses’’. (3) For products that satisfy the water resistance test in paragraph (i)(7) of this section. The labeling states ‘‘[bullet] re apply: [Bullet] after [select one of the following determined by water resist ance test: ‘40 minutes of’ or ‘80 minutes of’] swimming or sweating [bullet] im mediately after towel drying [bullet] at least every 2 hours’’. (4) For products that do not satisfy the water resistance test in paragraph (i)(7) of this section. The labeling states ‘‘[bul let] reapply at least every 2 hours [bul let] use a water resistant sunscreen if swimming or sweating’’. (f) Other information. The labeling of the product contains the following statement under the heading ‘‘Other information:’’ ‘‘[bullet] protect the product in this container from exces sive heat and direct sun’’. (g) False and misleading claims. There are claims that would be false and/or misleading on sunscreen products. These claims include but are not lim ited to the following: ‘‘Sunblock,’’ ‘‘sweatproof,’’ and ‘‘waterproof.’’ These or similar claims will cause the prod uct to be misbranded under section 502 of the FD&C Act (21 U.S.C. 352). (h) Labeling of products containing a combination of sunscreen and skin pro tectant active ingredients. Statements of identity, indications, warnings, and di rections for use, respectively, applica ble to each ingredient in the product may be combined to eliminate duplica tive words or phrases so that the re sulting information is clear and under standable. Labeling provisions in § 347.50(e) of this chapter shall not apply to these products. (i) SPF test procedure—(1) UV source (solar simulator). (i) Emission spectrum. A single port or multiport solar simu lator should be filtered so that it pro vides a continuous emission spectrum VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00107 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 98 21 CFR Ch. I (4–1–16 Edition) § 201.327 from 290 to 400 nanometers (nm) with a limit of 1,500 Watts per square meter (W/m2) on total irradiance for all wave lengths between 250 and 1,400 nm. (A) The solar simulator should have the following percentage of erythema effective radiation in each specified range of wavelengths: SOLAR SIMULATOR EMISSION SPECTRUM Wavelength range (nm) Percent erythemal contribution 1 <290 ......................................................... <0.1 290–300 ................................................... 1.0–8.0 290–310 ................................................... 49.0–65.0 290–320 ................................................... 85.0–90.0 290–330 ................................................... 91.5–95.5 290–340 ................................................... 94.0–97.0 290–400 ................................................... 99.9–100.0 1 Calculation of erythema action spectrum described in § 201.327(i)(1)(ii) of this section. (B) In addition, UVA II (320–340 nm) irradiance should equal or exceed 20 percent of the total UV (290–400 nm) ir radiance. UVA I (340–400 nm) irradiance should equal or exceed 60 percent of the total UV irradiance. (ii) Erythema action spectrum. (A) Cal culate the erythema action spectrum weighting factor (Vi) at each wave length λ: (1) Vi (λ) = 1.0 (250 <λ ≤298 nm) (2) Vi (λ) = 100.094* (298·λ) (298 <λ ≤328 nm) (3) Vi (λ) = 100.015* (140·λ) (328 <λ ≤400 nm) (B) Calculate the erythema-effective UV dose (E) delivered by a solar simu lator as follows: Where Vi(λ) = erythema action spectrum weighting factor at each wavelength λ I(λ) = irradiance (Watts per square meter) at each wavelength λ t = exposure time (seconds) Erythema-effective dose (E) is ex pressed as effective Joules per square meter (J/m2-eff). (C) The emission spectrum must be determined using a handheld radiom eter with a response weighted to match the spectrum in ISO 17166 CIE S 007/E entitled ‘‘Erythemal reference action spectrum and standard erythema dose,’’ dated 1999 (First edition, 1999– 12–15; corrected and reprinted 2000–11– 15), which is incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy from the ISO Copyright Office, Case Postale 56, CH–1211, Geneva 20, Switzer land, telephone +41–22–749–01–11 or fax +41–22–74–09–47. http://www.iso.org. You may inspect a copy at the Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993, call 301–796–2090, or at the National Archives and Records Administration (NARA). For informa tion on the availability of this mate rial at NARA, call 202–741–6030, or go to: http://www/archives.gov/ federallregister/ codeloflfederallregulations/ ibrllocations.html. The solar simulator output should be measured before and after each phototest or, at a minimum, at the beginning and end of each test day. This radiometer should be cali brated using side-by-side comparison with the spectroradiometer (using the weighting factors determined accord ing to paragraph (i)(1)(ii)(A) of this sec tion) at the time of the annual spectroradiometric measurement of the solar simulator as described in paragraph (i)(1)(iv) of this section. (iii) Operation. A solar simulator should have no significant time-related fluctuations (within 20 percent) in radi ation emissions after an appropriate warm-up time and demonstrate good beam uniformity (within 20 percent) in the exposure plane. The delivered dose to the UV exposure site must be within 10 percent of the expected dose. (iv) Periodic measurement. To ensure that the solar simulator delivers the appropriate spectrum of UV radiation, the emission spectrum of the solar sim ulator should be measured at least an nually with an appropriate and accu rately calibrated spectroradiometer system (results should be traceable to the National Institute for Standards and Technology). In addition, the solar simulator must be recalibrated if there is any change in the lamp bulb or the optical filtering components (i.e., fil ters, mirrors, lenses, collimating de vices, or focusing devices). Daily solar simulator radiation intensity should be monitored with a broadband radiom eter with a response weighted to match the erythema action spectrum in ISO 17166 CIE S 007/E entitled ‘‘Erythemal VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00108 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 JN 1 1 .0 0 2 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 99 Food and Drug Administration, HHS § 201.327 reference action spectrum and standard erythema dose,’’ which is incorporated by reference in paragraph (i)(1)(ii)(C) of this section. If a lamp must be replaced due to failure or aging during a phototest, broadband device readings consistent with those obtained for the original calibrated lamp will suffice until measurements can be performed with the spectroradiometer at the ear liest possible opportunity. (2) SPF standard—(i) Preparation. The SPF standard should be a formulation containing 7-percent padimate O and 3 percent oxybenzone. COMPOSITION OF THE PADIMATE O/OXYBENZONE SPF STANDARD Ingredients Percent by weight Part A: Lanolin ........................................................ 4.50 Cocoa butter ............................................... 2.00 Glyceryl monostearate ............................... 3.00 Stearic acid ................................................. 2.00 Padimate O ................................................ 7.00 Oxybenzone ............................................... 3.00 Part B: Purified water USP ..................................... 71.60 Sorbitol solution .......................................... 5.00 Triethanolamine, 99 percent ...................... 1.00 Methylparaben ............................................ 0.30 Propylparaben ............................................ 0.10 Part C: Benzyl alcohol ............................................ 0.50 Part D: Purified water USP ..................................... QS 1 1 Quantity sufficient to make 100 grams. Step 1. Add the ingredients of Part A into a suitable stainless steel kettle equipped with a propeller agitator. Mix at 77 to 82 °C until uniform. Step 2. Add the water of Part B into a suitable stainless steel kettle equipped with a propeller agitator and begin mixing at 77 to 82 °C. Add the re maining ingredients of Part B and mix until uniform. Step 3. Add the batch of Step 1 to the batch of Step 2 and mix at 77 to 82 °C until smooth and uniform. Slowly cool the batch to 49 to 54 °C. Step 4. Add the benzyl alcohol of Part C to the batch of Step 3 at 49 to 54 °C. Mix until uniform. Continue to cool batch to 35 to 41 °C. Step 5. Add sufficient water of Part D to the batch of Step 4 at 35 to 41 °C to obtain 100 grams of SPF standard. Mix until uniform. Cool batch to 27 to 32 °C. (ii) HPLC assay. Use the following high performance liquid chroma tography (HPLC) procedure to verify the concentrations of padimate O and oxybenzone in the SPF standard: (A) Instrumentation. (1) Equilibrate a suitable liquid chromatograph to the following or equivalent conditions: (i) Column .. C–18, 250 millimeters (mm) length, 4.6 mm inner diameter (5 mi crons) (ii) Mobile Phase. 85:15:0.5 methanol: water: acetic acid (iii) Flow Rate. 1.5 milliliters (mL) per minute (iv) Tem perature. Ambient (v) Detector UV spectrophotometer at 308 nanometers (vi) Attenu ation. As needed (2) Use HPLC grade reagents for mo bile phase. (B) Preparation of the HPLC reference standard. (1) Weigh 0.50 gram (g) of oxybenzone USP reference standard into a 250-mL volumetric flask. Dis solve and dilute to volume with isopropanol. Mix well. (2) Weigh 0.50 g of padimate O USP reference standard into a 250-mL volu metric flask. Dissolve and dilute to volume with isopropanol. Mix well. (3) Pipet 3.0 mL of the oxybenzone so lution and 7.0 mL of the padimate O so lution into a 100-mL volumetric flask. Dilute to volume with isopropanol and mix well. (C) HPLC system suitability. (1) Make three replicate 10-microliter injections of the HPLC reference standard (de scribed in paragraph (i)(2)(ii)(B) of this section). The relative standard devi ation in peak areas should not be more than 2.0 percent for either oxybenzone or padimate O. (2) Calculate the resolution (R) be tween the oxybenzone and padimate O peaks from one chromatogram as fol lows: Where to = retention time for oxybenzone tp = retention time for padimate O Wo = oxybenzone peak width at baseline Wp = padimate O peak width at baseline VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00109 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 JN 1 1 .0 0 3 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 100 21 CFR Ch. I (4–1–16 Edition) § 201.327 If the resolution (R) is less than 3.0, ad just the mobile phase or replace the column. (D) SPF standard assay—(1) The SPF standard is diluted to the same con centration as the HPLC reference standard according to the following steps: (i) Step 1. Weigh 1.0 g of the SPF standard (described in paragraph (i)(2)(i) of this section) into a 50-mL volumetric flask. (ii) Step 2. Add approximately 30 mL of isopropanol and heat with swirling until contents are evenly dispersed. (iii) Step 3. Cool to room temperature (15 to 30 °C) and dilute to volume with isopropanol. Mix well. (iv) Step 4. Pipet 5.0 mL of the prepa ration into a 50-mL volumetric flask and dilute to volume with isopropanol. Mix well. (2)(i) Inject 10-microliter of diluted SPF standard from paragraph (i)(2)(D)(1) of this section and calculate the amount of oxybenzone and padimate O as follows: (ii) The percent of oxybenzone and padimate O in the SPF standard should be between 95 and 105. (3) Test subjects—(i) Number of subjects. A test panel should include enough subjects to produce a minimum of 10 valid test results. A maximum of three subjects may be rejected from this panel based on paragraph (i)(5)(v)) of this section. (ii) Medical history. (A) Obtain a med ical history from each subject with em phasis on the effects of sunlight on the subject’s skin. Determine that each subject is in good general health with skin type I, II, or III as follows: (1) Always burns easily; never tans (sensitive). (2) Always burns easily; tans mini mally (sensitive). (3) Burns moderately; tans gradually (light brown) (normal). (4) Burns minimally; always tans well (moderate brown) (normal). (5) Rarely burns; tans profusely (dark brown) (insensitive). (6) Never burns; deeply pigmented (insensitive). (B) Skin type is based on first 30 to 45 minutes of sun exposure after a winter season of no sun exposure. Determine that each subject is not taking topical or systemic medication that is known to alter responses to UV radiation. De termine that each subject has no his tory of sensitivities to topical products and/or abnormal responses to sunlight, such as a phototoxic or photoallergic response. (iii) Physical examination. Conduct a physical examination to determine the presence of sunburn, suntan, scars, ac tive dermal lesions, and uneven skin tones on the areas of the back to be tested. A suitable source of low power UVA, such as a Woods lamp, is helpful in this process. If any of these condi tions are present, the subject is not qualified to participate in the study. The presence of nevi, blemishes, or moles will be acceptable if, in the phy sician’s judgment, they will neither compromise the study nor jeopardize a subject’s safety. Subjects with dysplastic nevi should not be enrolled. Excess hair on the back is acceptable if the hair is clipped. Shaving is unac ceptable because it may remove a sig nificant portion of the stratum corneum and temporarily alter the skin’s response to UV radiation. (iv) Informed consent. Obtain legally effective written informed consent from all test subjects. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00110 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 JN 1 1 .0 0 4 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 101 Food and Drug Administration, HHS § 201.327 (4) Sunscreen application. (i) Test site. Test sites are locations on each sub ject’s back, between the beltline and the shoulder blades (scapulae) and lat eral to the midline, where skin re sponses to UV radiation are deter mined. Responses on unprotected skin (no test material applied) and pro tected skin (sunscreen test product(s) or SPF standard applied) are deter mined at separate unprotected and pro tected test sites, respectively. Test sites should be randomly located in a blinded manner. Each test site should be a minimum of 30 square centimeters and outlined with indelible ink. (ii) Test subsite. Test subsites are the locations to which UV radiation is ad ministered within a test site. At least five test subsites should receive UV doses within each test site. Test subsites should be at least 0.5 square centimeters (cm2) in area and should be separated from each other by at least 0.8 cm. Each test subsite should be out lined with indelible ink. (iii) Applying test materials. Apply the sunscreen test product and the SPF standard at 2 milligrams per square centimeter (mg/cm2) to their respective test sites. Use a finger cot compatible with the sunscreen to spread the prod uct as evenly as possible. (iv) Waiting period. Wait at least 15 minutes after applying a sunscreen product before exposing the test sites to UV radiation as described in para graph (i)(5)) of this section. For water resistant sunscreen products, proceed with the water resistance testing pro cedure described in paragraph (i)(7) of this section after waiting at least 15 minutes. (5) UV exposure—(i) Definition of mini mal erythema dose (MED). The minimal erythema dose (MED) is the smallest UV dose that produces perceptible red ness of the skin (erythema) with clear ly defined borders at 16 to 24 hours after UV exposure. The MED for unpro tected skin (MEDu) is determined on a test site that does not have sunscreen applied. The MED for protected skin (MEDp) is determined on a test site that has sunscreen applied. An MEDp is determined for the SPF standard (ssMEDp). An MEDp is determined for the sunscreen test product (tpMEDp). (ii) UV exposure for initial MEDu. For each test subject, administer a series of UV radiation doses expressed as J/m2 eff (as determined according to para graph (a)(2) of this section) to the test subsites within an unprotected test site using an accurately calibrated solar simulator. Select doses that are a geometric series represented by 1.25n (i.e., each dose is 25 percent greater than the previous dose). (iii) UV exposure for final MEDu, ssMEDp, and tpMEDp. For each subject, determine the final MEDu, ssMEDp, and tpMEDp by administering a series of five UV doses to the appropriate test sites. The middle dose (X) in each of these dose series (i.e., the third dose) should equal the initial MEDu times the expected SPF. Note that the ex pected SPF equals 1 and 16.3 for the final MEDu and ssMEDp, respectively. The remaining UV doses in the series depend upon the expected SPF value of the sunscreen test product(s). For products with an expected SPF less than 8, administer UV doses that increase by 25 percent with each suc cessive dose (i.e., 0.64X, 0.80X, 1.00X, 1.25X, and 1.56X). For products with an expected SPF from 8 to 15, administer UV doses that increase by 20 percent with each successive dose (i.e., 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X). For prod ucts with an expected SPF higher than 15, administer UV doses that increase by 15 percent with each successive dose (i.e., 0.76X, 0.87X, 1.00X, 1.15X, and 1.32X). (iv) Evaluation of test subsites. In order that the person who evaluates the test subsites is not biased, he/she should not be the same person who ap plied the sunscreen drug product to the test site or administered the UV doses. After UV doses are administered, all immediate responses should be re corded. These may include an imme diate darkening or tanning, typically grayish or purplish in color, which fades in 30 to 60 minutes; an immediate reddening at the subsite, due to heat ing of the skin, which fades rapidly; and an immediate generalized heat re sponse, spreading beyond the subsite, which fades in 30 to 60 minutes. After the immediate responses are noted, each subject should shield the exposed area from further UV radiation until VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00111 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 102 21 CFR Ch. I (4–1–16 Edition) § 201.327 the MED is determined. Determine the MED 16 to 24 hours after UV exposure. Because erythema is evaluated 16 to 24 hours after UV exposure, the final MEDu, ssMEDp, and tpMEDp are typi cally determined the day following de termination of the initial MEDu. Evalu ate the erythema responses of each test subsite using either tungsten or warm white fluorescent lighting that pro vides at least 450 lux of illumination at the test site. For the evaluation, the test subject should be in the same posi tion as when the test site was irradi ated. (v) Invalid test data. Reject test data for a test subject if erythema is not present on either the unprotected or protected test sites; or erythema is present at all subsites; or the responses are inconsistent with the series of UV doses administered; or the subject was noncompliant (e.g., the subject with draws from the test due to illness or work conflicts or does not shield the exposed testing sites from further UV radiation until the MED is deter mined). (6) Determination of SPF. (i) Calculate an SPF value for each test subject (SPFi) as follows: (ii) Calculate the mean and the standard deviation (s) from the SPFi values. Calculate the standard error (SE), which equals s/√n (where n equals the number of subjects who pro vided valid test results). Obtain the t value from Student’s t distribution table corresponding to the upper 5-per cent point with n—1 degrees of free dom. Determine the labeled SPF value, which equals the largest whole number less than In order for the SPF determination of a test product to be considered valid, the SPF value of the SPF standard should fall within the standard devi ation range of the expected SPF (i.e., 16.3 ±3.43). (7) Determination of water resistance. The following procedure should be per formed in an indoor fresh water pool, whirlpool, and/or hot tub maintained at 23 to 32 °C. Fresh water is clean drinking water that meets the stand ards in 40 CFR part 141. The pool and air temperature and the relative hu midity should be recorded. (i) Water resistance (40 minutes). The labeled SPF should be determined after 40 minutes of water immersion using the following procedure: (A) Step 1: Apply the sunscreen as de scribed in paragraph (d) of this section. (B) Step 2: Perform moderate activ ity in water for 20 minutes. (C) Step 3: Rest out of water for 15 minutes. Do not towel test site(s). (D) Step 4: Perform moderate activ ity in water for 20 minutes. (E) Step 5: Allow test sites to dry completely without toweling. (F) Step 6: Apply the SPF standard as described in paragraph (d) of this section. Step 1. Expose test sites to UV doses as described in paragraph (e) of this section. (ii) Water resistance (80 minutes). The labeled SPF should be determined after 80 minutes of water immersion using the following procedure: (A) Step 1: Apply the sunscreen as de scribed in paragraph (d) of this section. (B) Step 2: Perform moderate activ ity in water for 20 minutes. (C) Step 3: Rest out of water for 15 minutes. Do not towel test site(s). (D) Step 4: Perform moderate activ ity in water for 20 minutes. (E) Step 5: Rest out of water for 15 minutes. Do not towel test site(s). (F) Step 6: Perform moderate activ ity in water for 20 minutes. (G) Step 7: Rest out of water for 15 minutes. Do not towel test site(s). (H) Step 8: Perform moderate activ ity in water for 20 minutes. (I) Step 9: Allow test sites to dry completely without toweling. (J) Step 10: Apply the SPF standard as described in paragraph (d) of this section. (K) Step 11: Expose test sites to UV doses as described in paragraph (e) of this section. (j) Broad spectrum test procedure—(1) UV Spectrometry. (i) Plate. Use optical VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00112 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 JN 1 1 .0 0 5 < /G P H > E R 1 7 JN 1 1 .0 0 9 < /G P H > E R 1 7 JN 1 1 .0 1 2 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 103 Food and Drug Administration, HHS § 201.327 grade polymethylmethacrylate (PMMA) plates suitable for UV trans mittance measurements. The plate should be roughened on one side to a three dimensional surface topography measure (Sa) between 2 and 7 microm eters and must have a rectangular ap plication area of at least 16 square cen timeters (with no side shorter than 4 cm). (ii) Sample holder. The sample holder should hold the PMMA plate in a hori zontal position to avoid flowing of the sunscreen drug product from one edge of the PMMA plate to the other. It should be mounted as close as possible to the input optics of the spectrometer to maximize capture of forward scat tered radiation. The sample holder should be a thin, flat plate with a suit able aperture through which UV radi ation can pass. The PMMA plate should be placed on the upper surface of the sample holder with the roughened side facing up. (iii) Light source. The light source should produce a continuous spectral distribution of UV radiation from 290 to 400 nanometers. (iv) Input optics. Unless the spectrom eter is equipped with an integrating sphere, an ultraviolet radiation dif fuser should be placed between the sample and the input optics of the spectrometer. The diffuser will be con structed from any UV radiation trans parent material (e.g., Teflon ® or quartz). The diffuser ensures that the radiation received by the spectrometer is not collimated. The spectrometer input slits should be set to provide a bandwidth that is less than or equal to 1 nanometer. (v) Dynamic range of the spectrometer. The dynamic range of the spectrometer should be sufficient to measure trans mittance accurately through a highly absorbing sunscreen product at all ter restrial solar UV wavelengths (290 to 400 nm). (2) Sunscreen product application to PMMA plate. The accuracy of the test depends upon the application of a pre cisely controlled amount of sunscreen product with a uniform distribution over the PMMA plate. The product is applied at 0.75 mg per square centi meter to the roughened side of the PMMA plate. The sunscreen product should be applied in a series of small dots over the entire PMMA plate and then spread evenly using a gloved fin ger. Spreading should be done with a very light spreading action for approxi mately 30 seconds followed by spread ing with greater pressure for approxi mately 30 seconds. The plate should then be allowed to equilibrate for 15 minutes in the dark before the pre-irra diation described in paragraph (c) of this section. (3) Sunscreen product pre-irradiation. To account for lack of photostability, apply the sunscreen product to the PMMA plate as described in paragraph (b) of this section and then irradiate with a solar simulator described in sec tion 352.70(b) of this chapter. The irra diation dose should be 4 MEDs which is equivalent to an erythemal effective dose of 800 J/m2 (i.e., 800 J/m2-eff). (4) Calculation of mean transmittance values. After pre-irradiation described in paragraph (c) of this section, mean transmittance values should be deter mined for each wavelength λ over the full UV spectrum (290 to 400 nano meters). The transmittance values should be measured at 1 nanometer in tervals. Measurements of spectral irra diance transmitted for each wave length λ through control PMMA plates coated with 15 microliters of glycerin (no sunscreen product) should be ob tained from at least 5 different loca tions on the PMMA plate [C1(λ), C2(λ), C3(λ), C4(λ), and C5(λ)]. In addition, a minimum of 5 measurements of spec tral irradiance transmitted for each wavelength λ through the PMMA plate covered with the sunscreen product will be similarly obtained after pre-ir radiation of the sunscreen product [P1(λ), P2(λ), P3(λ), P4(λ), and P5(λ)]. The mean transmittance for each wavelength, is the ratio of the mean of the C(λ) val ues to the mean of the P(λ) values, as follows: Where n ≥5 VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00113 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 JN 1 1 .0 1 0 < /G P H > E R 1 7 JN 1 1 .0 0 6 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 104 21 CFR Ch. I (4–1–16 Edition) Pt. 201, App. A (5) Calculation of mean absorbance val ues. (i) Mean transmittance values, are converted into mean absorbance values, at each wavelength by taking the nega tive logarithm of the mean transmit tance value as follows: (ii) The calculation yields 111 monochromatic absorbance values in 1 nanometer increments from 290 to 400 nanometers. (6) Number of plates. For each sun screen product, mean absorbance val ues should be determined from at least three individual PMMA plates. Because paragraph (d) of this section requires at least 5 measurements per plate, there should be a total of at least 15 measurements. (7) Calculation of the critical wave length. The critical wavelength is iden tified as the wavelength at which the integral of the spectral absorbance curve reaches 90 percent of the integral over the UV spectrum from 290 to 400 nm. The following equation defines the critical wavelength: Where λc = critical wavelength A(λ) = mean absorbance at each wavelength dλ = wavelength interval between measure ments A mean critical wavelength of 370 nm or greater is classified as broad spec trum protection. [76 FR 35660, June 17, 2011, as amended at 76 FR 38975, July 5, 2011] APPENDIX A TO PART 201—EXAMPLES OF GRAPHIC ENHANCEMENTS USED BY FDA I. SECTION 201.66 STANDARD LABELING FORMAT A. Overall 1. The ‘‘Drug Facts’’ labeling is set off in a box or similar enclosure by the use of a barline with all black type printed on a white, color contrasting background. B. Typeface and size 1. ‘‘Drug Facts’’ is set in 14 point Helvetica Bold Italic, left justified. 2. ‘‘Drug Facts (continued)’’ is set in 8 point Helvetica Bold Italic for the words ‘‘Drug Facts’’ and 8 point Helvetica Regular for the word ‘‘(continued)’’ and is left justi fied. 3. The headings (e.g., ‘‘Directions’’) are set in 8 point Helvetica Bold Italic, left justified. 4. The subheadings (e.g., ‘‘Ask a doctor or pharmacist before use if you are’’) are set in 6 point Helvetica Bold, left justified. 5. The information is set in 6 point Helvetica Regular with 6.5 point leading, left justified. 6. The heading ‘‘Purpose’’ is right justified. 7. The bullet is a 5-point solid square. 8. Two em spacing separates bullets when more than one bullet is on the same line. 9. A table format is used for 3 or more dos age directions. 10. A graphic appears at the bottom of the first panel leading the reader to the next panel. C. Barlines and hairlines 1. A 2.5-point horizontal barline extends to each end of the ‘‘Drug Facts’’ box (or similar enclosure), providing separation between each of the headings. 2. A 0.5-point horizontal hairline extends within 2 spaces on either side of the ‘‘Drug Facts’’ box (or similar enclosure), imme diately following the title and immediately preceding the subheadings. 3. A 0.5-point horizontal hairline follows the title, immediately preceding the head ing, when a heading appears on a subsequent panel immediately after the ‘‘Drug Facts (continued)’’ title. D. Box or Enclosure 1. All information is enclosed by a 2.5-point barline. II. SECTION 201.66 MODIFIED LABELING FORMAT A. Overall 1. The ‘‘Drug Facts’’ labeling is presented in all black type printed on a white color contrasting background. B. Typeface and size 1. ‘‘Drug Facts’’ is set in 9 point Helvetica Bold Italic, left justified. 2. The headings (e.g., ‘‘Directions’’) are set in 8 point Helvetica Bold Italic, left justified. 3. The subheadings (e.g., ‘‘Ask a doctor or pharmacist before use if you are’’) are set in 6 point Helvetica Bold, left justified. VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00114 Fmt 8010 Sfmt 8002 Y:\SGML\238073.XXX 238073 ER 1 7 JN 1 1 .0 1 0 < /G P H > E R 1 7 JN 1 1 .0 1 1 < /G P H > E R 1 7 JN 1 1 .0 0 8 < /G P H > E R 1 7 JN 1 1 .0 0 7 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 105 Food and Drug Administration, HHS Pt. 201, App. A 4. The information is set in 6 point Helvetica Regular with 6.5 point leading, left justified. 5. The heading ‘‘Purpose’’ is right justified. 6. The bullet is a 5-point solid square. 7. Bulleted information may start on same line as headings (except for the ‘‘Warnings’’ heading) and subheadings, with 2 em spacing separating bullets, and need not be vertically aligned. C. Barlines and hairlines 1. A 2.5-point horizontal barline extends to each end of the ‘‘Drug Facts’’ box (or similar enclosure), providing separation between each of the headings. 2. A 0.5-point horizontal hairline extends within 2 spaces on either side of the ‘‘Drug Facts’’ box (or similar enclosure), imme diately following the title and immediately preceding the subheadings. D. Box or Enclosure 1. All information is set off by color con trast. No barline is used. III. EXAMPLES OF § 201.66 STANDARD LABELING AND MODIFIED LABELING FORMATS A. SECTION 201.66 STANDARD LABELING FORMAT VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00115 Fmt 8010 Sfmt 8006 Y:\SGML\238073.XXX 238073 ER 1 7 M R 9 9 .0 0 7 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R 106 21 CFR Ch. I (4–1–16 Edition) Pt. 202 B. SECTION 201.66 MODIFIED LABELING FORMAT PART 202—PRESCRIPTION DRUG ADVERTISING AUTHORITY: 21 U.S.C. 321, 331, 352, 355, 360b, 371. § 202.1 Prescription-drug advertise ments. (a)(1) The ingredient information re quired by section 502(n) of the Federal Food, Drug, and Cosmetic Act shall ap pear together, without any intervening written, printed, or graphic matter, ex cept the proprietary names of ingredi ents, which may be included with the listing of established names. (2) The order of listing of ingredients in the advertisement shall be the same as the order of listing of ingredients on the label of the product, and the infor mation presented in the advertisement concerning the quantity of each such ingredient shall be the same as the cor responding information on the label of the product. (3) The advertisement shall not em ploy a fanciful proprietary name for the drug or any ingredient in such a manner as to imply that the drug or in gredient 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 advertisement shall not fea ture inert or inactive ingredients in a manner that creates an impression of value greater than their true func tional role in the formulation. (5) The advertisement shall not des ignate a drug or ingredient by a propri etary 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. (b)(1) If an advertisement for a pre scription 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 designa tion shall accompany such proprietary name or designation each time it is featured in the advertisement for the drug; but, except as provided below in this subparagraph, the established name need not be used with the propri etary name or designation in the run ning text of the advertisement. On any page of an advertisement 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 the running text: Pro vided, however, That if the proprietary VerDate Sep<11>2014 13:32 Jun 07, 2016 Jkt 238073 PO 00000 Frm 00116 Fmt 8010 Sfmt 8010 Y:\SGML\238073.XXX 238073 ER 1 7 M R 9 9 .0 0 8 < /G P H > js ta llw o rt h o n D S K 7 T P T V N 1 P R O D w ith C F R