§ 1.103 Drugs and devices; forms of making required statements.

(a) A word, statement, or other information required by or under authority of the act to appear on the label may lack that prominence and conspicuousness required by section 502(c) of the act by reason (among other reasons) of:

(1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;

(2) The failure of such word, statement, or information to appear on two or more parts or panels of the label, each of which has sufficient space therefor, and each of which is so designed as to render it likely to be, under customary conditions of purchase, the part or panel displayed;

(3) The failure of the label to extend over the area of the container or package available for such extension, so as to provide sufficient label space for the prominent placing of such word, statement, or information;

(4) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;

(5) Insufficiency of label space (for the prominent placing of such word, statement, or information) resulting from the use of label space to give materially greater conspicuousness to any other word, statement, or information, or to any design or device; or

(6) Smallness or style of type in which such word, statement, or information appears, insufficient background contrast, obscuring designs or vignettes, or crowding with other written, printed, or graphic matter.

(b) No exemption depending on insufficiency of label space, as prescribed in regulations promulgated under section 502 (b) or (e) of the act, shall apply if such insufficiency is caused by:

(1) The use of label space for any word, statement, design, or device which is not required by or under authority of the act to appear on the label;

(2) The use of label space to give greater conspicuousness to any word,

statement, or other information than is required by section 502 (c) of the act; or (3) The use of label space for any representation in a foreign language.

(c) (1) All words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear thereon in the English language: Provided, however, That in the case of articles distributed solely in the Commonwealth of Puerto Rico or in a Territory where the predominant language is one other than English, the predominant language may be substituted for English.

(2) If the label contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label shall appear thereon in the foreign language.

(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of the act to appear on the label or labeling shall appear on the labeling in the foreign language.

(Sec. 502, 52 Stat. 1050, as amended; 21 U.S.C. 352) [20 F.R. 9531, Dec. 20, 1955, as amended at 28 F.R. 5719. June 12, 1963]

§ 1.104 Drugs; statement of ingredients.

(a) The ingredient information required by section 502(e) of the Federal Food, Drug, and Cosmetic Act shall appear together, without any intervening written, printed, or graphic matter, except the proprietary names of ingredients, which may be included with the listing of established names, and such statements as "Warning-May be habit forming" that are specifically required for certain ingredients by the act or regulations in this chapter.

(b) The term "ingredient" applies to any substance in the drug, whether added to the formulation as a single substance or in admixture with other substances.

(c) The labeling of a drug may be misleading by reason (among other reasons) of:

(1) The order in which the names of the ingredients present in the drug appear in the labeling, or the relative prominence otherwise given such names.

(2) Failure to reveal the proportion of, or other fact with respect to, an ingredient present in such drug, when such proportion or other fact is material

in the light of the representation that such ingredient is present in such drug. (3) The employment of a fanciful proprietary name for a drug or ingredient in such a manner as to imply that the drug or ingredient has some unique effectiveness or composition when, in fact, the drug or ingredient is a common substance, the limitations of which are readily recognized when the drug or ingredient is listed by its established name.

(4) The featuring in the labeling of inert or inactive ingredients in a manner that creates an impression of value greater than their true functional role in the formulation.

(5) Designation of a drug or ingredient by a proprietary name that, because of similarity in spelling or pronunciation, may be confused with the proprietary name or the established name of a different drug or ingredient.

(d) (1) If the drug is in tablet or capsule form or other unit dosage form, any statement of the quantity of an ingredient contained therein shall express the quantity of such ingredient in each such unit. If the drug is not in unit dosage form, any statement of the quantity of an ingredient contained therein shall express the amount of such ingredient in a specified unit of weight or measure of the drug, or the percentage of such ingredient in such drug. Such statements shall be in terms that are informative to licensed practitioners, in the case of a prescription drug, and to the layman, in the case of a nonprescription drug.

(2) A statement of the percentage of an ingredient in a drug shall, if the term "percent" is used without qualification, mean percent weight-in-weight, if the ingredient and the drug are both solids, or if the ingredient is a liquid and the drug is a solid; percent weight in volume at 68° F. (20° C.), if the ingredient is a solid and the drug is a liquid; and percent volume in volume at 68° F. (20° C.), if both the ingredient and the drug are liquids, except that alcohol shall be stated in terms of percent volume of absolute alcohol at 60° F. (15.56° C.).

(e) A derivative or preparation of a substance named in section 502(e) of the act is an article derived or prepared from such substance by any method, including actual or theoretical chemical action.

(f) If an ingredient is a derivative or preparation of a substance specifically named in section 502(e) of the act and

the established name of such ingredient does not indicate that it is a derivative or preparation of the parent substance named in section 502(e) of the act, the labeling shall, in conjunction with the listing of the established name of such ingredient, declare that such article is a derivative or preparation of such parent substance.

(g) (1) If the label or labeling of a prescription drug bears a proprietary name or designation for the drug or any ingredient thereof, the established name, if such there be, corresponding to such proprietary name or designation, shall accompany each appearance of such proprietary name or designation. The established name shall be placed in direct conjunction with the proprietary name or designation, and the relationship between the proprietary name or designation and the established name shall be made clear by use of a phrase such as "brand of," preceding the established name, or by brackets surrounding the established name.

(2) The established name shall be printed in letters that are at least half as large as the letters comprising the proprietary name or designation with which it is joined, and the established name shall have a prominence commensurate with the prominence with which such proprietary name or designation appears, taking into account all pertinent factors, including typography, layout, contrast, and other printing features.

(h) (1) In the case of a prescription drug containing two or more active ingredients, if the label bears a proprietary name or designation for such mixture and there is no established name corresponding to such proprietary name or designation, the quantitative ingredient information required on the label by section 502(e) of the act shall be placed in direct conjunction with the most prominent display of the proprietary name or designation. The prominence of the quantitative ingredient information shall bear a reasonable relationship to the prominence of the proprietary name.

(2) If the drug is packaged in a container too small to bear the quantitative ingredient information on the main display panel, the quantitative ingredient information required by section 502(e) of the act may appear elsewhere on the label, even though the proprietary name or designation appears on the main dis

play panel of the label; but side- or backpanel placement shall in this case be so arranged and printed as to provide size and prominence of display reasonably related to the size and prominence of the front-panel display.

(i) A drug packaged in a container too small or otherwise unable to accommodate a label with sufficient space to bear the information required for compliance with section 502(e) (1) (A) (ii) and (B) of the act shall be exempt from compliance with those clauses: Provided, That:

(1) The label bears:

(i) The proprietary name of the drug; (ii) The established name, if such there be, of the drug;

(iii) An identifying lot or control number; and

(iv) The name of the manufacturer, packer, or distributor of the drug; and

(2) All the information required to appear on the label by the act and the regulations in this chapter appears on the carton or other outer container or wrapper if such carton, outer container, or wrapper has sufficient space to bear such information, or such complete label information appears on a leaflet with the package.

[28 F.R. 6375, June 20, 1963]

(a) (1) The ingredient information required by section 502 (n) of the Federal Food, Drug, and Cosmetic Act shall appear together, without any intervening written, printed, or graphic matter, except the proprietary names of ingredients, which may be included with the listing of established names.

(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 information presented in the advertisement concerning the quantity of each such ingredient shall be the same as the corresponding information on the label of the product.

(3) The advertisement shall not employ a fanciful proprietary name for the drug or any ingredient in such a manner as to imply that the drug or ingredient has some unique effectiveness or composition, when, in fact, the drug or ingredient is a common substance, the limitations of which are readily recognized when the drug or ingredient is listed by its established name.

(4) The advertisement shall not feature inert or inactive ingredients in a manner that creates an impression of value greater than their true functional role in the formulation.

(5) The advertisement shall not designate a drug or ingredient by a proprietary name that, because of similarity in spelling or pronunciation, may be confused with the proprietary name or the established name of a different drug or ingredient.

(b) (1) If an advertisement for a prescription drug bears a proprietary name or designation for the drug or any ingredient thereof, the established name, if such there be, corresponding to such proprietary name or designation, shall accompany each appearance of such proprietary name or designation. The established name shall be placed in direct conjunction with the proprietary name or designation, and the relationship between the proprietary name or designation and the established name shall be made clear by use of a phrase such as "brand of," preceding the established name, or by brackets surrounding the established name.

(2) The established name shall be printed in letters that are at least half as large as the letters comprising the proprietary name or designation with which it is joined, and the established name shall have a prominence commensurate with the prominence with which such proprietary name or designation appears, taking into account all pertinent factors, including typography, layout, contrast, and other printing features.

(c) In the case of a prescription drug containing two or more active ingredients, if the advertisement bears a proprietary name or designation for such mixture and there is no established name corresponding to such proprietary name or designation, the quantitative ingredient information required in the advertisement by section 502(n) of the act shall be placed in direct conjunction with the most prominent display of the proprietary name or designation. The prominence of the quantitative ingredient information shall bear a reasonable relationship to the prominence of the proprietary name.

(d) (1) If the advertisement employs one proprietary name or designation to refer to a combination of active ingredients present in more than one preparation (the individual preparations differing from each other as to quantities of

active ingredients and/or the form of the finished preparation) and there is no established name corresponding to such proprietary name or designation, a listing showing the established names of the active ingredients shall be placed in direct conjunction with the most prominent display of such proprietary name or designation. The prominence of this listing of active ingredients shall bear a reasonable relationship to the prominence of the proprietary name and the relationship between such proprietary name or designation, and the listing of active ingredients shall be made clear by use of such phrase as “brand of,” preceding the listing of active ingredients.

(2) The advertisement shall prominently display the name of at least one specific dosage form and shall have the quantitative ingredient information required by section 502(n) of the act in direct conjunction with such display. If other dosage forms are listed in the advertisement, the quantitative ingredient information for such dosage forms shall appear in direct conjunction and in equal prominence with the most prominent listing of the names of such dosage forms.

(e) A brief summary relating to side effects, contraindications, and effectiveness shall be presented in any prescription-drug advertisement that provides any information regarding indications or dosage recommendations. This summary shall fairly show the effectiveness of the drug in the conditions for which it is recommended in the advertisement, together with a showing of those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and any other use or uses for which the dosage form advertised is commonly prescribed. A fair balance shall be made in presenting the information on effectiveness and that on side effects and contraindications; such fair balance shall be achieved even if small size of the advertisement limits the total amount of information presented.

(f) (1) An advertisement for a prescription drug covered by a new-drug application approved after October 10, 1962, or any approved supplement thereto, shall not recommend nor suggest any use that is not in the labeling accepted in the approved new-drug application or such supplement. The advertisement shall present information from the approved new-drug application labeling

concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and any other use or uses for which the dosage form advertised is commonly prescribed.

(2) If a prescription drug was covered by a new-drug application or a supplement thereto that became effective prior to October 10, 1962, an advertisement may recommend or suggest:

(i) Uses contained in the labeling accepted in such new-drug application and any effective or approved supplement thereto.

(ii) Additional uses contained in labeling in commercial use on October 9, 1962, to the extent that such uses did not cause the drug to be an unapproved "new drug" as "new drug" was defined in section 201(p) of the act as then in force and to the extent that such uses would be permitted were the drug subject to paragraph (h) of this section.

(iii) Additional uses contained in labeling in current commercial use to the extent that such uses do not cause the drug to be an unapproved "new drug," as defined in section 201(p) of the act, as amended.

The advertisement shall present information from such labeling concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and for any other use or uses for which the dosage form advertised is commonly prescribed.

(g) An advertisement for a prescription drug subject to certification shall not recommend nor suggest any use that is not in the labeling covered by the certification or covered by the applicable certification regulations or regulations providing for exemption from certification. The advertisement shall present information from such labeling covered by the certification, or the applicable certification regulations or regulations providing for exemption from certification, concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and any other use or uses for which the dosage form advertised is commonly prescribed.

(h) In the case of an advertisement for a prescription drug other than a drug the labeling of which causes it to be an unapproved "new drug" and other

than drugs covered by paragraphs (f) and (g) of this section, an advertisement may recommend and suggest the drug cnly for those uses contained in the labeling thereof:

(1) For which the drug is generally recognized as safe and effective among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs; or

(2) For which there exists substantial evidence of safety and effectiveness, consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the safety and effectiveness of the drug involved, on the basis of which it can fairly and responsibly be concluded by such experts that the drug is safe and effective for such uses; or

(3) For which there exists substantial clinical experience, adequately documented in medical literature or by other data (to be supplied to the Food and Drug Administration, if requested), on the basis of which it can fairly and responsibly be concluded by qualified experts that the drug is safe and effective for such uses; or

(4) For which safety is supported under any of the preceding clauses in subparagraphs (1), (2), and (3) of this paragraph and effectiveness is supported under any other of such clauses.

The advertisement shall present information concerning those side effects and contraindications that are pertinent with respect to the uses recommended or suggested in the advertisement and for any other use or uses for which the dosage form advertised is commonly prescribed.

(i) The information concerning side effects and contraindications in an advertisement for a prescription drug shall appear in reasonably close association with the information concerning effectiveness and shall have the same relative degree of prominence as the information concerning effectiveness, taking into account all pertinent factors, including typography, layout, contrast, and other printing features.

(j) (1) No advertisement concerning a particular prescription drug may be disseminated without prior approval by the Food and Drug Administration if:

(i) The sponsor or the Food and Drug Administration has received information that has not been widely publicized in medical literature that the use of the

drug may cause fatalities or serious damage;

(ii) The Commissioner (or in his absence the officer acting as Commissioner), after evaluating the reliability of such information, has notified the sponsor that the information must be a part of the advertisements for the drug; and

(iii) The sponsor has failed within a reasonable time as specified in such notification to present to the Food and Drug Administration a program, adequate in light of the nature of the information, for assuring that such information will be publicized promptly and adequately to the medical profession in subsequent advertisements.

If the Commissioner finds that the program presented is not being followed, he will notify the sponsor that prior approval of all advertisements for the particular drug will be required. Nothing in this paragraph is to be construed as limiting the Commissioner's or the Secretary's rights, as authorized by law, to issue publicity, to suspend any newdrug application, to decertify any antibiotic, or to recomend any regulatory action.

(2) Within a reasonable time after information concerning the possibility that a drug may cause fatalities or serious damage has been widely publicized in medical literature, the Food and Drug Administration shall notify the sponsor of the drug by mail that prior approval of advertisements for the drug is no longer necessary.

(3) Dissemination of an advertisement not in compliance with this paragraph shall be deemed to be an act that causes the drug to be misbranded under section 502(n) of the act.

(4) Any advertisement may be submitted to the Food and Drug Administration prior to publication for comment. If the advertiser is notified that the submitted advertisement is not in violation and, at some subsequent time, the Food and Drug Administration changes its opinion, the advertiser will be so notified and will be given a reasonable time for correction before any regulatory action is taken under this section. Notification to the advertiser that a proposed advertisement is or is not considered to be in violation shall be in written form.

(k) An advertisement issued or caused to be issued by the manufacturer, packer, or distributor of the drug promoted by the advertisement and which is not in