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 labeling of a drug which render such drug misbranded is a false or misleading representation with respect to another drug or a device or a food or cosmetic.

(b) The labeling of a drug which contains two or more ingredients may be misleading by reason, among other reasons, of the designation of such drug in such labeling by a name which includes or suggests the name of one or more but not all such ingredients, even though the names of all such ingredients are stated elsewhere in the labeling.

[41 FR 6908, Feb. 13, 1976]

$201.10 Drugs; statement of ingredients.

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

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

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

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

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

(e) A derivative or preparation of a substance named in section 502(e) of the act is an article derived or prepared

from such substance by any method, including actual or theoretical chemical action.

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

(g)(1) If the label or labeling of a prescription drug bears a proprietary name or designation for the drug or any ingredient thereof, the established name, if such there be, corresponding to such proprietary name or designation shall accompany such proprietary name or designation each time it is featured on the label or in the labeling for the drug; but, except as provided in this subparagraph, the established

name need not be used with the proprietary name or designation in the running text of the label or labeling. On any label or page of labeling in which the proprietary name or designation is not featured but is used in the running text, the established name shall be used at least once in the running text in association with such proprietary name or designation and in the same type size used in such running text: Provided, however, That if the proprietary name or designation is used in the running text in larger size type, the established name shall be used at least once in association with, and in type at least half as large as the type used for, the most prominent presentation of the proprietary name or designation in such running text. If any labeling includes a column with running text containing detailed information as to composition, prescribing, side effects, or contraindications and the proprietary name or designation is used in such column but is not featured above or below the column, the established name shall be used at least once in such column of running text in association with such proprietary name or designation and in the same type size used in such column of running text: Provided, however, That if the 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 presentation of the proprietary name or designation in such column of running text. Where the established name is required to accompany or to be used in association with the proprietary name or designation, the established name shall be placed in direct conjunction with the proprietary name or designation, and the relationship between the proprietary name or designation and the established name shall be made clear by use of a phrase such as "brand of" preceding the established name, by brackets surrounding the established name, or by other suitable means.

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

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

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

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

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

(1) The label bears:

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

(iii) An identifying lot or control number; and

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

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

§201.15 Drugs; prominence of required label statements.

(a) A word, statement, or other information required by or under authority of the act to appear on the label may lack that prominence and conspicuousness required by section 502(c) of the act by reason, among other reasons, of: (1) The failure of such word, statement, or information to appear on the part or panel of the label which is presented or displayed under customary conditions of purchase;

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

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

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

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

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

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

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

(2) The use of label space to give greater conspicuousness to any word, statement, or other information than is required by section 502(c) of the act;

or

(3) The use of label space for any representation in a foreign language.

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

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

(3) If the labeling contains any representation in a foreign language, all words, statements, and other information required by or under authority of

version of certain required statements.

An increasing number of medications restricted to prescription use only are being labeled solely in Spanish for distribution in the Commonwealth of Puerto Rico where Spanish is the predominant language. Such labeling is authorized under §201.15(c). Two required warnings, the wording of which is fixed by law in the English language, are presently being translated in various ways, from literal translation to loose interpretation. The statutory nature of these two statements requires that the translation must convey the meaning properly, in order to avoid confusion and dilution of the purposes of the warnings. The Commissioner of Food and Drugs hereby adopts the following Spanish-language versions as the accepted equivalents of the English wording of the following:

(a) Section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act requires the statement "Caution: Federal law prohibits dispensing without prescription." The Spanish version of this shall be: "Precaucion: La ley Federal prohibe su despacho sin prescripcion facultativa."

(b) Section 502(d) of the Federal Food, Drug, and Cosmetic Act requires the statement "Warning-May be habit forming" on habit-forming drugs. The Spanish version of this shall be: "Aviso-Puede formar habito o vicio." [41 FR 6908, Feb. 13, 1976]

$201.17 Drugs; location of expiration date.

When an expiration date of a drug is required, e.g., expiration dating of drug products required by §211.137 of this chapter, it shall appear on the immediate container and also the outer package, if any, unless it is easily legible through such outer package. However, when single-dose containers are packed in individual cartons, the expiration date may properly appear on the

individual carton instead of the immediate product container.

[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 complete manufacturing history of the package. An incorrect lot number may be regarded as causing the article to be misbranded.

§201.19 Drugs; use of term “infant”.

The regulations affecting special dietary foods (§ 105.3(e) of this chapter) define an infant as a child not more than 12 months old. Apart from this, the Food and Drug Administration has not established any definition of the term infant. Some question has arisen whether, for the purposes of drug labeling, an infant means a child up to 1 year of age or a child up to 2 years of age. Until the term is more precisely defined by legislation or formal regulation, where the exact meaning of the term is significant, manufacturers should qualify any reference to "infant" to indicate whether it refers to a Ichild 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]

§201.20 Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow No. 6 in certain drugs for human use.

(a) The label for over-the-counter and prescription drug products intended for human use administered orally, nasally, rectally, or vaginally, or for use in the area of the eye, containing FD&C Yellow No. 5 as a color additive using the names FD&C Yellow No. 5 and tartrazine. The labeling for overthe-counter and prescription drug products shall bear a statement such as "Contains FD&C Yellow No. 5 (tartrazine) as a color additive" or "Contains color additives including FD&C Yellow No. 5 (tartrazine)”. The labels of certain drug products subject to this labeling requirement that are also cosmetics, such as antibacterial mouthwashes and fluoride toothpastes,

need not comply with this requirement provided they comply with the requirements of § 701.3 of this chapter.

(b) For prescription drugs for human use containing FD&C Yellow No. 5 that are administered orally, nasally, vaginally, or rectally, or for use in the area of the eye, the labeling required by $201.100(d) shall bear the warning statement "This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity." This warning statement shall appear in the "Precautions" section of the labeling.

(c) The label for over-the-counter drug products intended for human use administered orally, nasally, rectally, or vaginally containing FD&C Yellow No. 6 shall specifically declare the presence of FD&C Yellow No. 6 by listing the color additive using the name FD&C Yellow No. 6. The labeling for over-the-counter and prescription drug products containing FD&C Yellow No. 6 shall declare the presence of FD&C Yellow No. 6. The labels of certain drug products subject to this labeling requirement that are also cosmetics, such as antibacterial mouthwashes and fluoride toothpastes, need not comply with this requirement provided they comply with the requirements of § 701.3 of this chapter.

[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 further 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-aaspartyl-L-phenylalanine), they produce an intensely sweet-tasting substance, approximately 180 times

as

sweet as sucrose. The Food and Drug Administration has determined that aspartame when used at a level no higher than reasonably required to perform its intended technical function is safe for use as an inactive ingredient in human drug products, provided persons with phenylketonuria, who must restrict carefully their phenylalanine intake, are alerted to the presence of phenylalanine in the drug product and the amount of the ingredient in each dosage unit.

(b) The label and labeling of all overthe-counter human drug products containing aspartame as an inactive ingredient shall bear a statement to the following effect: Phenylketonurics: Contains Phenylalanine (___)mg Per (Dosage Unit).

(c) The package labeling and other labeling providing professional use information concerning prescription drugs for human use containing aspartame as an inactive ingredient shall bear a statement to the following effect under the "Precautions" section of the labeling, as required in §201.57(f)(2): Phenylketonurics: Contains Phenylalanine ____mg Per (Dosage

Unit).

(d) Holders of approved new drug applications who reformulate their drug products under the provisions of this section shall submit supplements under § 314.70 of this chapter to provide for the new composition and the labeling changes.

(Approved by the Office of Management and Budget under control number 0910-0242)

[52 FR 2111, Jan. 20, 1987; 52 FR 12152, April 15, 1987; 53 FR 4135, Feb. 12, 1988]

$201.22 Prescription_drugs containing sulfites; required warning statements.

(a) Sulfites are chemical substances that are added to certain drug products to inhibit the oxidation of the active drug ingredient. Oxidation of the active drug ingredient may result in instability and a loss of potency of the drug product. Examples of specific sulfites used to inhibit this oxidation process include sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, and potassium metabisulfite. Recent studies have demonstrated that sulfites may cause