[Code of Federal Regulations]
[Title 21, Volume 4]
[Revised as of April 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR201.66]
[Page 44-53]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)
PART 201 LABELING--Table of Contents
Subpart C Labeling Requirements for Over-the-Counter Drugs
Sec. 201.66 Format and content requirements for over-the-counter (OTC) drug
product labeling.
(a) Scope. This section sets forth the content and format
requirements for the labeling of all OTC drug products. Where an OTC
drug product is the subject of an applicable monograph or regulation
that contains content and format requirements that conflict with this
section, the content and format requirements in this section must be
followed unless otherwise specifically provided in the applicable
monograph or regulation.
(b) Definitions. The following definitions apply to this section:
(1) Act means the Federal Food, Drug, and Cosmetic Act (secs. 201 et
seq. (21 U.S.C. 321 et seq.)).
(2) Active ingredient means any component that is intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body of humans. The term
includes those components that may undergo chemical change in the
manufacture of the drug product and be present in the drug product in a
modified form intended to furnish the specified activity or effect.
(3) Approved drug application means a new drug (NDA) or abbreviated
new drug (ANDA) application approved under section 505 of the act (21
U.S.C. 355).
(4) Bullet means a geometric symbol that precedes each statement in
a list of statements. For purposes of this section, the bullet style is
limited to solid squares or solid circles, in the format set forth in
paragraph (d)(4) of this section.
(5) Established name of a drug or ingredient thereof means the
applicable official name designated under section 508 of the act (21
U.S.C. 358), or, if there is no designated official name and the drug or
ingredient is recognized in an official compendium, the official title
of the drug or ingredient in such compendium, or, if there is no
designated official name and the drug or ingredient is not recognized in
an official compendium, the common or usual name of the drug or
ingredient.
(6) FDA means the Food and Drug Administration.
(7) Heading means the required statements in quotation marks listed
in paragraphs (c)(2) through (c)(9) of this
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section, excluding subheadings (as defined in paragraph (a)(9) of this
section).
(8) Inactive ingredient means any component other than an active
ingredient.
(9) Subheading means the required statements in quotation marks
listed in paragraphs (c)(5)(ii) through (c)(5)(vii) of this section.
(10) Drug facts labeling means the title, headings, subheadings, and
information required under or otherwise described in paragraph (c) of
this section.
(11) Title means the heading listed at the top of the required OTC
drug product labeling, as set forth in paragraph (c)(1) of this section.
(12) Total surface area available to bear labeling means all
surfaces of the outside container of the retail package or, if there is
no such outside container, all surfaces of the immediate container or
container wrapper except for the flanges at the tops and bottoms of cans
and the shoulders and necks of bottles and jars.
(c) Content requirements. The outside container or wrapper of the
retail package, or the immediate container label if there is no outside
container or wrapper, shall contain the title, headings, subheadings,
and information set forth in paragraphs (c)(1) through (c)(8) of this
section, and may contain the information under the heading in paragraph
(c)(9) of this section, in the order listed.
(1) (Title) ``Drug Facts''. If the drug facts labeling appears on
more than one panel, the title ``Drug Facts (continued)'' shall appear
at the top of each subsequent panel containing such information.
(2) ``Active ingredient'' or ``Active ingredients'' ``(in each
[insert the dosage unit stated in the directions for use (e.g., tablet,
5 mL teaspoonful) or in each gram as stated in Sec. Sec. 333.110 and
333.120 of this chapter])'', followed by the established name of each
active ingredient and the quantity of each active ingredient per dosage
unit. Unless otherwise provided in an applicable OTC drug monograph or
approved drug application, products marketed without discrete dosage
units (e.g., topicals) shall state the proportion (rather than the
quantity) of each active ingredient.
(3) ``Purpose'' or ``Purposes'', followed by the general
pharmacological category(ies) or the principal intended action(s) of the
drug or, where the drug consists of more than one ingredient, the
general pharmacological categories or the principal intended actions of
each active ingredient. When an OTC drug monograph contains a statement
of identity, the pharmacological action described in the statement of
identity shall also be stated as the purpose of the active ingredient.
(4) ``Use'' or ``Uses'', followed by the indication(s) for the
specific drug product.
(5) ``Warning'' or ``Warnings'', followed by one or more of the
following, if applicable:
(i) ``For external use only'' [in bold type] for topical drug
products not intended for ingestion, or ``For'' (select one of the
following, as appropriate: ``rectal'' or ``vaginal'') ``use only'' [in
bold type].
(ii) All applicable warnings listed in paragraphs (c)(5)(ii)(A)
through (c)(5)(ii)(G) of this section with the appropriate subheadings
highlighted in bold type:
(A) Reye's syndrome warning for drug products containing salicylates
set forth in Sec. 201.314(h)(1). This warning shall follow the
subheading ``Reye's syndrome:''
(B) Allergic reaction warnings set forth in any applicable OTC drug
monograph or approved drug application for any product that requires a
separate allergy warning. This warning shall follow the subheading
``Allergy alert:''
(C) Flammability warning, with appropriate flammability signal
word(s) (e.g., Sec. Sec. 341.74(c)(5)(iii), 344.52(c), 358.150(c), and
358.550(c) of this chapter). This warning shall follow a subheading
containing the appropriate flammability signal word(s) described in an
applicable OTC drug monograph or approved drug application.
(D) Water soluble gums warning set forth in Sec. 201.319. This
warning shall follow the subheading ``Choking:''
(E) Alcohol warning set forth in Sec. 201.322. This warning shall
follow the subheading ``Alcohol warning:''
[[Page 46]]
(F) Sore throat warning set forth in Sec. 201.315. This warning
shall follow the subheading ``Sore throat warning:''
(G) Warning for drug products containing sodium phosphates set forth
in Sec. 201.307(b)(2)(i) or (b)(2)(ii). This warning shall follow the
subheading ``Dosage warning:''
(iii) ``Do not use'' [in bold type], followed by all
contraindications for use with the product. These contraindications are
absolute and are intended for situations in which consumers should not
use the product unless a prior diagnosis has been established by a
doctor or for situations in which certain consumers should not use the
product under any circumstances regardless of whether a doctor or health
professional is consulted.
(iv) ``Ask a doctor before use if you have'' [in bold type] or, for
products labeled only for use in children under 12 years of age, ``Ask a
doctor before use if the child has'' [in bold type], followed by all
warnings for persons with certain preexisting conditions (excluding
pregnancy) and all warnings for persons experiencing certain symptoms.
The warnings under this heading are those intended only for situations
in which consumers should not use the product until a doctor is
consulted.
(v) ``Ask a doctor or pharmacist before use if you are'' [in bold
type] or, for products labeled only for use in children under 12 years
of age, ``Ask a doctor or pharmacist before use if the child is'' [in
bold type], followed by all drug-drug and drug-food interaction
warnings.
(vi) ``When using this product'' [in bold type], followed by the
side effects that the consumer may experience, and the substances (e.g.,
alcohol) or activities (e.g., operating machinery, driving a car,
warnings set forth in Sec. 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.
(viii) Any required warnings in an applicable OTC drug monograph,
other OTC drug regulations, or approved drug application that do not fit
within one of the categories listed in paragraphs (c)(5)(i) through
(c)(5)(vii), (c)(5)(ix), and (c)(5)(x) of this section.
(ix) The pregnancy/breast-feeding warning set forth in Sec.
201.63(a); the third trimester warning set forth in Sec. 201.63(e) for
products containing aspirin or carbaspirin calcium; the third trimester
warning set forth in approved drug applications for products containing
ketoprofen, naproxen sodium, and ibuprofen (not intended exclusively for
use in children).
(x) The ``Keep out of reach of children'' warning and the accidental
overdose/ingestion warning set forth in Sec. 330.1(g) of this chapter.
(6) ``Directions'', followed by the directions for use described in
an applicable OTC drug monograph or approved drug application.
(7) ``Other information'', followed by additional information that
is not included under paragraphs (c)(2) through (c)(6), (c)(8), and
(c)(9) of this section, but which is required by or is made optional
under an applicable OTC drug monograph, other OTC drug regulation, or is
included in the labeling of an approved drug application.
(i) Required information about certain ingredients in OTC drug
products (e.g., sodium in Sec. 201.64(b), calcium in Sec. 201.70(b),
magnesium in Sec. 201.71(b), and potassium in Sec. 201.72(b)) shall
appear as follows: ``each (insert appropriate dosage unit) contains:''
[in bold type (insert name(s) of ingredient(s) (in alphabetical order)
and the quantity of each ingredient). This information shall be the
first statement under this heading.
(ii) The phenylalanine/aspartame content required by Sec.
201.21(b), if applicable, shall appear as the next item of information.
(iii) Additional information that is authorized to appear under this
heading shall appear as the next item(s) of information. There is no
required order for this subsequent information.
(8) ``Inactive ingredients'', followed by a listing of the
established name of each inactive ingredient. If the product is an OTC
drug product that is not also a cosmetic product, then the inactive
ingredients shall be listed in alphabetical order. If the product is an
OTC drug product that is also a cosmetic product, then the inactive
ingredients
[[Page 47]]
shall be listed as set forth in Sec. 701.3(a) or (f) of this chapter,
the names of cosmetic ingredients shall be determined in accordance with
Sec. 701.3(c) of this chapter, and the provisions in Sec. 701.3(e),
(g), (h), (l), (m), (n), and (o) of this chapter and Sec. 720.8 of this
chapter may also apply, as appropriate. If there is a difference in the
labeling provisions in this Sec. 201.66 and Sec. Sec. 701.3 and 720.8
of this chapter, the labeling provisions in this Sec. 201.66 shall be
used.
(9) ``Questions?'' or ``Questions or comments?'', followed by the
telephone number of a source to answer questions about the product. It
is recommended that the days of the week and times of the day when a
person is available to respond to questions also be included. A graphic
of a telephone or telephone receiver may appear before the heading. The
telephone number must appear in a minimum 6-point bold type.
(d) Format requirements. The title, headings, subheadings, and
information set forth in paragraphs (c)(1) through (c)(9) of this
section shall be presented on OTC drug products in accordance with the
following specifications. In the interest of uniformity of presentation,
FDA strongly reccommends that the Drug Facts labeling be presented using
the graphic specifications set forth in appendix A to part 201.
(1) The title ``Drug Facts'' or ``Drug Facts (continued)'' shall use
uppercase letters for the first letter of the words ``Drug'' and
``Facts.'' All headings and subheadings in paragraphs (c)(2) through
(c)(9) of this section shall use an uppercase letter for the first
letter in the first word and lowercase letters for all other words. The
title, headings, and subheadings in paragraphs (c)(1), (c)(2), and
(c)(4) through (c)(9) of this section shall be left justified.
(2) The letter height or type size for the title ``Drug Facts''
shall appear in a type size larger than the largest type size used in
the Drug Facts labeling. The letter height or type size for the title
``Drug Facts (continued)'' shall be no smaller than 8-point type. The
letter height or type size for the headings in paragraphs (c)(2) through
(c)(9) of this section shall be the larger of either 8-point or greater
type, or 2-point sizes greater than the point size of the text. The
letter height or type size for the subheadings and all other information
described in paragraphs (c)(2) through (c)(9) of this section shall be
no smaller than 6-point type.
(3) The title, heading, subheadings, and information in paragraphs
(c)(1) through (c)(9) of this section shall be legible and clearly
presented, shall have at least 0.5-point leading (i.e., space between
two lines of text), and shall not have letters that touch. The type
style for the title, headings, subheadings, and all other required
information described in paragraphs (c)(2) through (c)(9) of this
section shall be any single, clear, easy-to-read type style, with no
more than 39 characters per inch. The title and headings shall be in
bold italic, and the subheadings shall be in bold type, except that the
word ``(continued)'' in the title ``Drug Facts (continued)'' shall be
regular type. The type shall be all black or one color printed on a
white or other contrasting background, except that the title and the
headings may be presented in a single, alternative, contrasting color
unless otherwise provided in an approved drug application, OTC drug
monograph (e.g., current requirements for bold print in Sec. Sec.
341.76 and 341.80 of this chapter), or other OTC drug regulation (e.g.,
the requirement for a box and red letters in Sec. 201.308(c)(1)).
(4) When there is more than one statement, each individual statement
listed under the headings and subheadings in paragraphs (c)(4) through
(c)(7) of this section shall be preceded by a solid square or solid
circle bullet of 5-point type size. Bullets shall be presented in the
same shape and color throughout the labeling. The first bulleted
statement on each horizontal line of text shall be either left justified
or separated from an appropriate heading or subheading by at least two
square ``ems'' (i.e., two squares of the size of the letter ``M''). If
more than one bulleted statement is placed on the same horizontal line,
the end of one bulleted statement shall be separated from the beginning
of the next bulleted statement by at least two square ``ems'' and the
complete additional bulleted statement(s) shall not continue to the next
line of text. Additional bulleted statements appearing
[[Page 48]]
on each subsequent horizontal line of text under a heading or subheading
shall be vertically aligned with the bulleted statements appearing on
the previous line.
(5) The title, headings, subheadings, and information set forth in
paragraphs (c)(1) through (c)(9) of this section may appear on more than
one panel on the outside container of the retail package, or the
immediate container label if there is no outside container or wrapper.
The continuation of the required content and format onto multiple panels
must retain the required order and flow of headings, subheadings, and
information. A visual graphic (e.g., an arrow) shall be used to signal
the continuation of the Drug Facts labeling to the next adjacent panel.
(6) The heading and information required under paragraph (c)(2) of
this section shall appear immediately adjacent and to the left of the
heading and information required under paragraph (c)(3) of this section.
The active ingredients and purposes shall be aligned under the
appropriate headings such that the heading and information required
under paragraph (c)(2) of this section shall be left justified and the
heading and information required under paragraph (c)(3) of this section
shall be right justified. If the OTC drug product contains more than one
active ingredient, the active ingredients shall be listed in
alphabetical order. If more than one active ingredient has the same
purpose, the purpose need not be repeated for each active ingredient,
provided the information is presented in a manner that readily
associates each active ingredient with its purpose (i.e., through the
use of brackets, dot leaders, or other graphical features). The
information described in paragraphs (c)(4) and (c)(6) through (c)(9) of
this section may start on the same line as the required headings. None
of the information described in paragraph (c)(5) of this section shall
appear on the same line as the ``Warning'' or ``Warnings'' heading.
(7) Graphical images (e.g., the UPC symbol) and information not
described in paragraphs (c)(1) through (c)(9) of this section shall not
appear in or in any way interrupt the required title, headings,
subheadings, and information in paragraphs (c)(1) through (c)(9) of this
section. Hyphens shall not be used except to punctuate compound words.
(8) The information described in paragraphs (c)(1) through (c)(9) of
this section shall be set off in a box or similar enclosure by the use
of a barline. A distinctive horizontal barline extending to each end of
the ``Drug Facts'' box or similar enclosure shall provide separation
between each of the headings listed in paragraphs (c)(2) through (c)(9)
of this section. When a heading listed in paragraphs (c)(2) through
(c)(9) of this section appears on a subsequent panel immediately after
the ``Drug Facts (continued)'' title, a horizontal hairline shall follow
the title and immediately precede the heading. A horizontal hairline
extending within two spaces on either side of the ``Drug Facts'' box or
similar enclosure shall immediately follow the title and shall
immediately precede each of the subheadings set forth in paragraph
(c)(5) of this section, except the subheadings in paragraphs
(c)(5)(ii)(A) through (c)(5)(ii)(G) of this section.
(9) The information set forth in paragraph (c)(6) of this section
under the heading ``Directions'' shall appear in a table format when
dosage directions are provided for three or more age groups or
populations. The last line of the table may be the horizontal barline
immediately preceding the heading of the next section of the labeling.
(10) If the title, headings, subheadings, and information in
paragraphs (c)(1) through (c)(9) of this section, printed in accordance
with the specifications in paragraphs (d)(1) through (d)(9) of this
section, and any other FDA required information for drug products, and,
as appropriate, cosmetic products, other than information required to
appear on a principle display panel, requires more than 60 percent of
the total surface area available to bear labeling, then the Drug Facts
labeling shall be printed in accordance with the specifications set
forth in paragraphs (d)(10)(i) through (d)(10)(v) of this section. In
determining whether more than 60 percent of the total surface area
available to bear labeling is required, the indications for use listed
under the ``Use(s)'' heading, as set
[[Page 49]]
forth in paragraph (c)(4) of this section, shall be limited to the
minimum required uses reflected in the applicable monograph, as provided
in Sec. 330.1(c)(2) of this chapter.
(i) Paragraphs (d)(1), (d)(5), (d)(6), and (d)(7) of this section
shall apply.
(ii) Paragraph (d)(2) of this section shall apply except that the
letter height or type size for the title ``Drug Facts (continued)''
shall be no smaller than 7-point type and the headings in paragraphs
(c)(2) through (c)(9) of this section shall be the larger of either 7-
point or greater type, or 1-point size greater than the point size of
the text.
(iii) Paragraph (d)(3) of this section shall apply except that less
than 0.5-point leading may be used, provided the ascenders and
descenders do not touch.
(iv) Paragraph (d)(4) of this section shall apply except that if
more than one bulleted statement is placed on the same horizontal line,
the additional bulleted statements may continue to the next line of
text, and except that the bullets under each heading or subheading need
not be vertically aligned.
(v) Paragraph (d)(8) of this section shall apply except that the box
or similar enclosure required in paragraph (d)(8) of this section may be
omitted if the Drug Facts labeling is set off from the rest of the
labeling by use of color contrast.
(11)(i) The following labeling outlines the various provisions in
paragraphs (c) and (d) of this section:
[GRAPHIC] [TIFF OMITTED] TR17MR99.003
(ii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section:
[[Page 50]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.004
(iii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section, including paragraph (d)(10) of
this section, which permits modifications for small packages:
[[Page 51]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.005
(iv) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section for a drug product marketed with
cosmetic claims:
[[Page 52]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.006
(e) Exemptions and deferrals. FDA on its own initiative or in
response to a written request from any manufacturer, packer, or
distributor, may exempt or defer, based on the circumstances presented,
one or more specific requirements set forth in this section on the basis
that the requirement is inapplicable, impracticable, or contrary to
public health or safety. Requests for exemptions shall be submitted in
three copies in the form of an ``Application for Exemption'' to the Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. The request shall be clearly identified on the envelope as a
``Request for Exemption from 21 CFR 201.66 (OTC Labeling Format)'' and
shall be directed to Docket No. 98N-0337. A separate request shall be
submitted for each OTC drug product. Sponsors of a product marketed
under an approved drug application shall also submit a single copy of
the exemption request to their application. Decisions on exemptions and
deferrals will be maintained in a permanent file in this docket for
public review. Exemption and deferral requests shall:
(1) Document why a particular requirement is inapplicable,
impracticable, or is contrary to public health or safety; and
(2) Include a representation of the proposed labeling, including any
outserts, panel extensions, or other graphical or packaging techniques
intended to be used with the product.
(f) Interchangeable terms and connecting terms. The terms listed in
Sec. 330.1(i) of this chapter may be used
[[Page 53]]
interchangeably in the labeling of OTC drug products, provided such use
does not alter the meaning of the labeling that has been established and
identified in an applicable OTC drug monograph or by regulation. The
terms listed in Sec. 330.1(j) of this chapter may be deleted from the
labeling of OTC drug products when the labeling is revised to comply
with this section, provided such deletion does not alter the meaning of
the labeling that has been established and identified in an applicable
OTC drug monograph or by regulation. The terms listed in Sec. 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]
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