"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, features.

and other printing

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

(2) If the drug is packaged in a container too small to bear the quantitative ingredient information on the main display panel, the quantitative ingredient information required by section 502(e) of the act may appear elsewhere on the label, even though the proprietary name or designation appears on the main display panel of the label; but side- or 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 FR. 6375, June 20, 1963]

§ 1.105 Prescription-drug advertise

ments.

(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 ingredi

ent 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) An advertisement for a prescription drug covered by an approved newdrug application shall not recommend nor suggest any use that is not in the labeling accepted in the approved newdrug application. 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.

(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 a prescription drug not subject to the new-drug provisions

or the certification provisions, an advertisement may recommend use of the drug only for those purposes for which the article is generally recognized as safe and effective by medical experts or for those purposes for which the article is generally recognized as safe by medical experts and for which there exists substantial evidence, consisting of adequate and well-controlled investigations, including clinical investigations, by medical experts, on the basis of which it can fairly and responsibly be concluded that the drug is effective for such purposes. 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.

(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 compliance with section 502(n) of the act and the applicable regulations thereunder shall cause stocks of such drug in possession of the person responsible for issuing or causing the issuance of the advertisement, and stocks of the drug distributed by such person and still in the channels of commerce, to be misbranded under section 502 (n) of the act.

(1) Brochures, mailing pieces, detailing pieces, file cards, bulletins, price lists, catalogs, house organs, literature reprints, and similar pieces of printed matter concerning a drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor, including reference publications for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug, are regarded as labeling not subject to section 502(n) of the act but subject to the "full disclosure" labeling requirement of § 1.106(b) or (c), as well as the labeling requirements of § 1.104.

(Sec. 502 (e), (n), 52 Stat. 1050, 1051; 21 U.S.C. 352) [28 F.R. 6376, June 20, 1963, as amended at 28 F.R. 10994, Oct. 15, 1963]

NOTE: In § 1.105, the provisions of paragraph (h) were stayed at 28 F.R. 9837, Sept. 10, 1963.

for

use.

directions (a) Adequate "Adequate directions for use" means directions under which the layman can use a drug or device safely and for the purposes for which it is intended. Directions for use may be inadequate because (among other reasons) of omission, in whole or in part, or incorrect specification of:

(1) Statements of all conditions, purposes, or uses for which such drug or device is intended, including conditions, purposes, or uses for which it is prescribed, recommended, or suggested in its oral, written, printed, or graphic advertising, and conditions, purposes, or uses for which the drug or device is commonly used; except that such statements shall not refer to conditions, uses, or purposes for which the drug or device can be safely used only under the supervision of a practitioner licensed by law and for which it is advertised solely to such practitioner.

(2) Quantity of dose (including usual quantities for each of the uses for which it is intended and usual quantities for persons of different ages and different physical conditions).

(3) Frequency of administration or application.

(4) Duration of administration or application.

(5) Time of administration or application (in relation to time of meals, time of onset of symptoms, or other time factors).

(6) Route or method of administration or application.

(7) Preparation for use (shaking, dilution, adjustment of temperature, or other manipulation or process).

(b) Exemption for prescription drugs. A drug subject to the requirements of section 503 (b) (1) of the act shall be exempt from section 502 (f) (1) if all the following conditions are met:

(1) The drug is:

(1) (a) 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

(b) In the possession of a retail, hospital, or clinic pharmacy, or a public health agency, regularly and lawfully engaged in dispensing prescription drugs; or

(c) In the possession of a practitioner licensed by law to administer or prescribe such drugs; and

(ii) It is to be dispensed in accordance with section 503(b).

(2) The label of the drug bears: (i) The statement "Caution: Federal law prohibits dispensing without prescription"; and

(ii) The recommended or usual dosage; and

(iii) The route of administration, if it is not for oral use; and

(iv) The quantity or proportion of each active ingredient, as well as the information required by section 502 (d) and (e); and

(v) If it is for other than oral use, the names of all inactive ingredients, except that:

(a) Flavorings and perfumes may be designated as such without naming their components.

(b) Color additives may be designated as coloring without naming specific color components unless the naming of such components is required by a color additive regulation prescribed in Part 8 of this chapter.

(c) Trace amounts of harmless substances added solely for individual product identification need not be named. If it is intended for administration by parenteral injection, the quantity or proportion of all inactive ingredients, except that ingredients added to adjust the pH or to make the drug isotonic may be declared by name and a statement of their effect; and if the vehicle is water for injection it need not be named.

(vi) An identifying lot or control number from which it is possible to determine the complete manufacturing history of the package of the drug;

Provided, however, That in the case of containers too small or otherwise unable to accommodate a label with sufficient space to bear all such information, but which are packaged within an outer container from which they are removed for dispensing or use, the information required by subdivisions (ii), (iii) and (v) of this subparagraph may be contained in other labeling on or within the package from which it is to be dispensed, and the information referred to in subdivision (i) of this subparagraph may be placed on such outer container only, and the information required by subdivision (vi) of this subparagraph may be on the crimp of the dispensing tube.

CROSS-REFERENCE: See § 1.108 for the Spanish-language version of the required labeling statement in § 1.106 (b) (2) (i), (c) (2) (1), (d) (2) (1), (k) (2) (11), and (1).

(3) (i) Labeling on or within the package from which the drug is to be dispensed bears adequate information for its use, including indications, effects, dosages, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all purposes for which it is advertised or represented; and

(ii) If the article is subject to section 505, 506, or 507 of the act, the labeling bearing such information is the labeling authorized by the effective new-drug application or required as a condition for the certification or the exemption from certification requirements applicable to preparations of insulin or antibiotic drugs: Provided, however, That the information required by subdivision (i) of this subparagraph 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 practitioners licensed by law to administer the drug. Upon written request, stating reasonable grounds therefor, the Commissioner will offer an opinion on a proposal to omit such information from the dispensing package under this proviso.

(4) Any labeling, as defined in section 201 (m) of the act, whether or not it is on or within a package from which the drug is to be dispensed, distributed by or on behalf of the manufacturer, packer, or distributor of the drug, that furnishes or purports to furnish information for use or which prescribes, recommends, or suggests a dosage for the use of the drug (other than dose information required by subparagraph (2) (ii) of this paragraph and paragraph (c) (2) (ii) of this section) contains:

(i) Adequate information for such use, including indications, effects, dosages, routes, methods, and frequency and duration of administration and any relevant hazards, contraindications, side effects, and precautions, under which practitioners licensed by law to administer the drug can use the drug safely and for the purposes for which it is intended, including all conditions for which it is advertised or represented;

and if the article is subject to section 505, 506, or 507 of the act, the labeling providing such information is substantially the same as the labeling authorized by the effective new-drug application or required as a condition for its certification or exemption from certification; and

(ii) 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 information required by subdivisions (i) and (ii) of this subparagraph 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 dosage recommendations for use of the drug.

(5) All labeling, except labels and cartons, bearing information for use of the drug also bears the date of the issuance or the date of the latest revision of such labeling.

(c) Exemption for veterinary drugs. A drug intended for veterinary use which, because of toxicity or other potentiality for harmful effect, or the method of its use, is not safe for animal use except under the supervision of a licensed veterinarian, and hence for which "adequate directions for use” cannot be prepared, shall be exempt from section 502(f) (1) of the act if all the following conditions are met:

(1) The drug is:

(i) In the possession of a person (or his agents or employees) regularly and lawfully engaged in the manufacture, transportation, storage, or wholesale or retail distribution of veterinary drugs and is to be sold only to or on the prescription or other order of a licensed veterinarian for use in the course of his professional practice; or

(ii) In the possession of a licensed veterinarian for use in the course of his professional practice.

(2) The label of the drug bears:

(1) The statement "Caution: Federal law restricts this drug to sale by or on the order of a licensed veterinarian"; and

(ii) The recommended or usual dosage; and

(iii) The route of administration, if it is not for oral use; and

(iv) The quantity or proportion of each active ingredient as well as the in