[Federal Register: March 17, 1999 (Volume 64, Number 51)]
[Rules and Regulations]
[Page 13253-13303]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17mr99-24]

[[Page 13253]]

_______________________________________________________________________

Part II

Department of Health and Human Services

_______________________________________________________________________

Food and Drug Administration

_______________________________________________________________________

21 CFR Part 201, et al.

Over-The-Counter Human Drugs; Labeling Requirements; Final Rule

[[Page 13254]]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201, 330, 331, 341, 346, 355, 358, 369, and 701

[Docket Nos. 98N-0337, 96N-0420, 95N-0259, and 90P-0201]
RIN 0910-AA79


Over-The-Counter Human Drugs; Labeling Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
establishing a standardized format and standardized content
requirements for the labeling of over-the-counter (OTC) drug products.
This final rule is intended to assist consumers in reading and
understanding OTC drug product labeling so that consumers may use these
products safely and effectively. This final rule will require all OTC
drug products to carry the new, easy-to-read format and the revised
content requirements within prescribed implementation periods.

DATES:
Effective Date: April 16, 1999.

Compliance Dates: For compliance dates see section V of the
SUPPLEMENTARY INFORMATION section of this document.
FOR FURTHER INFORMATION CONTACT: Debra L. Bowen, Food and Drug
Administration, Center for Drug Evaluation and Research (HFD-560), 5600
Fishers Lane, Rockville, MD 20852, 301-827-2222, or email
``BOWEND@cder.fda.gov''.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of February 27, 1997 (62 FR 9024), FDA
proposed to establish a standardized format for the labeling of OTC
drug products that included: (1) Specific headings and subheadings
presented in a standardized order, (2) standardized graphical features
such as Helvetica type style and the use of ``bullet points'' to
introduce key information, and (3) minimum standards for type size and
spacing. The proposal included an extensive list of ``connecting
terms'' that manufacturers may omit from product labeling, and an
expanded list of ``interchangeable terms'' to facilitate the use of
more concise and easy to understand language in OTC drug product
labeling. The agency also proposed to amend several specific warnings,
including the required pregnancy-nursing warning, the ``keep out of
reach of children'' warning, and the accidental overdose/ingestion
warnings, to make these warnings as direct and understandable as
possible. Finally, the agency proposed to preempt State and local rules
that establish different requirements than those in the proposed rule,
to promote a national, standardized format for all OTC drug product
labeling.
    The agency discussed at length its basis for proposing to improve
labeling design (62 FR 9024 at 9027 through 9031). The agency stated
that a standardized labeling format would significantly improve
readability by familiarizing consumers with the types of information in
OTC drug product labeling and the location of that information. In
addition, a standardized appearance and standardized content, including
various ``user-friendly'' visual cues, would help consumers locate and
read important health and safety information and allow quick and
effective product comparisons, thereby helping consumers to select the
most appropriate product.
    The agency reviewed literature studies that confirmed that OTC drug
product labeling often lacks the graphical features and visual cues
needed to ensure readability and comprehension. These and other studies
recommended ways to make labeling easier to read and understand,
described the importance of adherence to directions for use, and
reported on a number of preventable adverse drug reactions from OTC
drug products (see 62 FR 9024 at 9027 and 9028).
    The agency also has benefitted significantly in this proceeding
from the experience it gained in redesigning food labeling under the
Nutrition Labeling and Education Act of 1990 (NLEA) (Pub. L. 101-535,
November 8, 1990). The agency's required nutrition labeling panel
(Sec. 101.9 (21 CFR 101.9)) provides a standardized graphic
presentation for food nutrients, allowing consumers to judge the
significance of the level of a particular nutrient in a product in the
context of a total daily diet. Since its implementation in 1993, the
agency has received praise from consumers and nutritionists, noting the
impact and utility of the standardized food label.
    The agency provided over 7 months for interested persons to comment
on the OTC labeling proposal, which included an extension of the
comment period from June 27, 1997, to October 6, 1997, published in the
Federal Register on June 19, 1997 (62 FR 33379). In addition, the
agency solicited public comment on two labeling studies it conducted.
In the Federal Register of December 30, 1997 (62 FR 67770), the agency
sought comment (until February 13, 1998) on a study entitled
``Evaluation of Revised Formats for Over-the-Counter (OTC) Drugs''
(Study B). Study B consisted of a survey of more than 900 respondents
to evaluate consumer preference for design variations in drug labeling
formats. In the Federal Register of February 13, 1998 (63 FR 7331), the
agency solicited comment (until March 30, 1998) on a second study
entitled ``Evaluation of Proposed Over-the-Counter (OTC) Label Format
Comprehension Study'' (Study A). Study A consisted of a survey of more
than 1,200 consumers on the influence of variations in labeling formats
on the communication of directions for use and required warnings.
    In response to the proposed rule and the publication of Studies A
and B, the agency received more than 1,800 comments from health
professionals and students, professional organizations, trade
associations, manufacturers, consumers, and consumer organizations. An
overwhelming majority of the comments supported the agency's initiative
to standardize the format of OTC drug product labeling and to make the
labeling easier to read and understand by requiring a minimum type
size, user-friendly headings, and other well-accepted visual cues.
    However, a number of specific points in the proposal generated
extensive, and sometimes divergent, comment: (1) Whether pharmacists,
nurses, or other health professionals should be specifically referenced
in certain of the proposed headings; (2) an appropriate minimum type
size for the required labeling information; (3) application of the
proposed labeling format to products traditionally marketed in small
containers and products marketed as both drugs and cosmetics; and (4)
continued reference to Poison Control Centers in the required
accidental ingestion warning. These and other comments are addressed at
length in section IV of this document.
    The agency has considered the information presented in the proposed
rule, the comments received, the results from Studies A and B, and all
other relevant information, and concludes that the standardized format
and content requirements for OTC drug product labeling, as set forth in
this final rule, will enable consumers to better read and understand
the information presented and apply this

[[Page 13255]]

information to the safe and effective use of OTC drug products.
    As discussed in the proposed rule, research on reading behavior and
document simplification shows that the use of less complex terminology,
presented in shorter sentences with an organized or ``chunked''
structure, is likely to improve consumer processing of the information
(Refs. 1, 2, and 3). Research also shows that consumers are more likely
to engage in behavior that they believe they can successfully complete
than in behavior that appears overwhelming (Ref. 4) or that presents a
``cognitive load,'' such as the task of reading densely worded consumer
information (Ref. 5).
    The new OTC drug product labeling is expected to decrease
``cognitive load'' by, among other things, decreasing the memory
demands necessary for processing the information. This, in turn, will
allow consumers to process the information faster. In addition, the new
format offers a more structured, organized, and compact presentation,
which places fewer and less imposing processing demands on the reader.
The consumer's self-perceived ability to read the labeling will
increase significantly and, thereby, result in an improved overall
understanding of the information presented. Finally, the new labeling
is expected to provide clear signals regarding important information,
leading to increased processing and communication of this information.

II. Prototype Labeling Based on This Final Rule

    An outline of the various labeling provisions for OTC drug products
is shown below:
BILLING CODE 4160-01-F
[GRAPHIC] [TIFF OMITTED] TR17MR99.000

BILLING CODE 4160-01-C

[[Page 13256]]

    An example of labeling for a single ingredient antihistamine OTC
drug product, annotated for illustrative purposes, is shown below. FDA
recommends use of the type style and font sizes shown below:
[GRAPHIC] [TIFF OMITTED] TR17MR99.001

    An example of labeling for an antacid OTC drug product, applying
the modified, small package labeling provisions in this final rule and
annotated for illustrative purposes, is shown below. FDA recommends use
of the type style and font sizes shown below:
[GRAPHIC] [TIFF OMITTED] TR17MR99.002

BILLING CODE 4160-01-C

[[Page 13257]]

    Examples of prototype OTC drug product labeling are attached in
Appendix A of this document. The information in these examples is
presented using ordinary package sizes for these types of products.
These examples are for illustrative purposes only and are not intended
to depict specific products. Some are based on proposed monograph
requirements only. Example 1 depicts sample labeling for a single
ingredient antihistamine product, using the format and content
provisions set forth in this final rule. Example 2 depicts labeling for
a combination cough/cold product using the format and content
provisions set forth in this final rule. Example 3 demonstrates how the
same information shown in Example 2 can be presented directly on the
package label for an 8-ounce bottle of syrup, using the small package
modifications specified in the final rule. Example 4 depicts a
toothpaste that is marketed as a standing tube without an outer carton,
using the format and content provisions set forth in this final rule.
Example 5 demonstrates labeling for a drug product that is also
marketed for cosmetic uses using the format and content provisions set
forth in this final rule. Example 5 also demonstrates an acceptable
``similar enclosure'' to a box. Example 6 depicts labeling for a
topical acne product that is marketed in a tube and packaged in a
carton with a riser, in order to provide additional labeling space.
Example 7 depicts labeling for an antacid product, applying the small
package modifications.

III. Summary of Studies A and B

    Studies A and B tested whether the proposed format improves the
readability and understandability of OTC drug product labeling and
investigated consumer preference for certain format variations. The
studies confirm that the new labeling format will increase
communication of OTC drug product information.

A. Study A

    Study A examined the influence of labeling formats and the use of
selective highlighting on the communication of directions for use and
warnings. The study examined two levels of four independent variables
in a factorial design: (1) Labeling format (prototypical existing
format versus proposed new format), (2) drug type (cough-cold versus
pain reliever), (3) the use of highlighting (more versus less emphasis
on graphic design features), and (4) consumer attention (divided versus
focused). Highlighting, label format, and drug type were varied in the
design of the sample product label. Attention (focused or divided) was
varied through instructions given to the respondents. Study
participants were asked to read a food label, then a drug label to test
for divided and focused attention. Half of the participants were told
they would be asked questions about both labels (divided attention);
the other half were told they would be tested only on the drug label
(focused attention) and that the food label was to serve only as
reading practice.
    The study included 1,202 respondents in 8 geographically
distributed shopping malls in the United States, with approximately
equal numbers of respondents from each location. Respondents were asked
to evaluate the presentation of label information on one OTC drug
sample and were asked questions about the labeling to determine their
knowledge, opinions, and willingness to read the labeling.
    Dependent measures were analyzed using a general linear model
analysis of variance. The study demonstrated that the proposed new
format took less time and was easier to read and understand than a
product that did not follow the new format. Study respondents indicated
a general preference for the proposed format and, when their attention
was divided, respondents felt more confident in their ability to use
the proposed format labeling. When more graphical design features were
used, respondents who were instructed to focus on the labeling made
more correct product use decisions, compared to respondents whose
attention was divided. There were no conditions under which a product
with an existing labeling format outperformed the proposed new format.
    The results from Study A suggest that consumers who are presented
with the new labeling format will be: (1) More confident in their
ability to use the information in the labeling, and (2) better able to
make correct product use decisions.

B. Study B

    This study investigated consumer preferences for format and
graphical design variations. The study examined two levels of each of
four independent variables in a factorial design: (1) The order of the
``Warning(s)'' and ``Direction(s)'' section (i.e., warnings before
directions or warnings after directions), (2) the placement of the
``Active ingredients'' section at the top of the labeling versus
bottom, (3) the use of a title as an introduction to the required
information (``Medication Facts'' versus no title), and (4) the use of
dividing lines between sections (thick versus thin lines).
    This study included 904 respondents in 8 geographically distributed
shopping malls in the United States, with approximately equal numbers
of respondents from each location. The respondents were asked to
evaluate 16 labeling variations of either a sample cough-cold or
sunscreen drug product. The respondents were also asked to rank the
randomly ordered labels from most to least preferred, to specify the
reasons for their first and second choices, and to rate a current OTC
drug product that did not follow the new format.
    The study showed that the presence of a title was the most
important factor in determining preference, as participants were more
likely to choose labeling with a title than without. When asked why
they preferred the label ranked as number one, the respondents
indicated that it: (1) Was easy to read, and (2) begins with
``Medication Facts.''
    The agency performed a primary conjoint analysis on the preference
rankings. A conjoint analysis simultaneously weighs multiple variables
and allows for a determination of the relative importance of each
particular attribute of a variable, in addition to the level at which
each attribute is preferred (SPSS Categories, 1994). Results indicated
that, of the four factors examined, title had the greatest impact on
rankings, with a utility range from -1.83 for no title and +1.83 for
the ``Medication Facts'' title. In this primary analysis, the effect of
the other three variables was not significant.
    The agency also performed a secondary analysis of the data, to look
at differences between variables, independent of context. For labeling
with a title, the mean ranks were 6.67 and 10.33 (Z=-20, SD=1.95,
p<0.001), clearly confirming that the presence of a title was the most
important factor in determining preference rankings. The secondary
analysis of the other three format variables showed mean ranks in the
middle range (between 8.18 and 8.82, SDs=0.94 to 1.97). However, as
stated previously, the primary analysis of these three variables showed
that none had a statistically significant influence on preference when
the variable was considered in context. Again, the presence of an
introductory title proved to be the preferred variable.

IV. Summary and Response to Comments

    This section summarizes each section of the final rule and provides
the agency's response to comments.

[[Page 13258]]

A. Scope (Sec. 201.66(a))

    Section 201.66(a) states that the content and format requirements
in Sec. 201.66 apply to the labeling of all OTC drug products. This
would include products marketed under a final OTC drug monograph, an
approved new drug application (NDA) or abbreviated new drug application
(ANDA) under section 505 of the Federal Food, Drug, and Cosmetic Act
(the act) (21 U.S.C. 355), and OTC products for which there is no final
OTC drug monograph or approved drug application. Thus, for example, OTC
drug products that are the subject of tentative final monographs will,
in time, be required to comply with the new labeling requirements.
    The proposed rule stated that the new labeling would apply to
products that are the subject of a final monograph or an approved drug
application. Under both the proposed and the final rule, all OTC drug
products in time would be required to adopt the new labeling. The
revised wording of the scope provision is consistent with and furthers
two central themes of this proceeding. First, the agency has concluded
that consistent, standardized labeling of OTC drug products will
improve the selection and the safe and effective use of all OTC drug
products. Second, all drug products, irrespective of their regulatory
status, must bear labeling that is ``likely to be read and understood
by the ordinary individual under customary conditions of purchase and
use.'' (Section 502 of the act (21 U.S.C. 352(c)).) With all products
following the new format, consumers will be able to readily distinguish
OTC drug products from other categories of products (such as dietary
supplements and foods), make product-to-product comparisons across all
therapeutic classes, and will begin to recognize where to find
information that is critical to the best use of any OTC drug product.
The final rule ensures that by a date certain all OTC drug products
will display the new labeling.
    The agency has chosen an outside implementation date of 6 years for
marketed OTC drug products that are not and do not become the subject
of final OTC monographs (see section V of this document). Because most,
if not all, drug products undergo at least one major labeling revision
every 6 years (see section VIII of this document), the revised scope is
not expected to impose any significant additional burdens.
    1. Several comments asked that Sec. 201.66 include an express
exemption for homeopathic drug products, including those products
listed in the Homeopathic Pharmacopeia of the United States. One
comment recommended that the labeling requirements should apply to
homeopathic drug products to promote their safe use.
    Homeopathic drug products generally are subject to the drug
provisions of the act, including the misbranding provisions in section
502 of the act, and therefore, the agency has concluded that an express
exemption would not be appropriate. However, as emphasized in the
proposed rule, the agency's stated policy is that such products
ordinarily will not be recommended for regulatory action if the product
is a homeopathic drug as described in Compliance Policy Guide 7132.15
entitled ``Conditions Under Which Homeopathic Drugs May Be Marketed''
(62 FR 9024 at 9031), and the product follows the labeling and all
other recommendations outlined in that guidance document. By its terms,
the policy of generally not recommending homeopathic products for
regulatory action will extend to this rule.

B. Definitions (Sec. 201.66(b))

    Section 201.66(b) contains applicable definitions, including
explanations of certain printing, typesetting, and graphics terms
applicable to this rule. The agency has also added definitions for the
terms ``bullet,'' ``title,'' and ``inactive ingredient.'' The
definition for inactive ingredient is identical to the definition in
the agency's good manufacturing practice regulations in 21 CFR
210.3(b)(8).

C. Content Requirements (Sec. 201.66(c))

    Section 201.66(c) contains the content requirements for the
standardized labeling format and states that all information must be
organized under the title, headings, and subheadings set forth in
paragraphs (c)(1) through (c)(8), and it may contain the information
under the heading in paragraph (c)(9), in the order prescribed. This
information must appear on the outside container or wrapper of the
retail package, or the immediate container label if there is no outside
container or wrapper. As discussed below, the agency has amended some
of the headings and subheadings and included additional headings and
subheadings, including the title ``Drug Facts.''
    2. Several comments supported the order for listing information, as
prescribed in Sec. 201.66(c). One comment stated that listing active
ingredients and their purposes first allows consumers to compare
ingredients, avoid certain ingredients for reasons of safety or
personal preference, and helps to ensure that products with different
active ingredients are not used for the same indication.
    Several comments focused on the placement of the inactive
ingredient section, with some suggesting that inactive ingredients
should be listed separately from active ingredients because the
inactive ingredients are of only minor concern to most consumers.
Others were opposed to the separation of active and inactive
ingredients.
    Many comments addressed the relative placement of the
``Directions'' and ``Warnings'' sections. Consumer and professional
groups and industry representatives generally preferred that the
warnings be presented first, to ensure proper self-selection of the
appropriate drug at the point of purchase. A smaller number of comments
favored placing the directions first, based on the idea that this
section would contain the most important information on the proper use
of the product.
    As discussed previously in section III.B of this document, the
primary statistical analysis performed in Study B did not find a
significant respondent preference for the placement of ``Warnings,''
``Directions,'' and ``Active ingredients.'' Therefore, the order for
the placement of information in the final rule is modeled after the
decisionmaking process consumers would be expected to follow, and
should follow, when selecting and using OTC drug products.
    First, consumers need to know what the product is and what it is
intended to do. This information often is not apparent from the
principal display panel (PDP), especially for combination OTC drug
products. This information also is critical to consumers' ability to
select the most appropriate product. Therefore, the agency is requiring
the listing of the active ingredients and their purposes as the first
information presented under the title ``Drug Facts.'' Foremost, the
agency believes that consumers need to be able to identify the active
drug ingredients, to readily access that information, and to associate
the ingredients with their respective purposes.
    Next, the consumer needs to select an appropriate product for its
intended uses. Therefore, this section, entitled ``Use(s),'' follows
the active ingredient and purpose information.
    The ``Warnings'' section, which follows the ``Use(s),'' contains
information that is relevant to both the product selection decision and
to proper use. This section contains information regarding when the
product should absolutely not be used, drug-drug and drug-food
interactions, when to consult

[[Page 13259]]

a doctor or pharmacist before taking the product, possible side
effects, and when to stop use and contact a doctor after taking the
product.
    After a consumer selects an appropriate product, correct
administration and dosing is essential. The ``Directions'' section
contains dosage and administration information necessary for the safe
and effective use of the product. Therefore, this section follows the
``Warnings'' section.
    ``Other information'' is listed in the next section, for products
that need to provide additional information that is important for
complete understanding of the product's use, including information for
consumers who may be allergic to certain ingredients, such as
aspartame, or who restrict the intake of dietary ingredients such as
sodium.
    The ``Inactive ingredients'' section is listed near the conclusion
of the FDA-required information, because some products contain a large
number of inactive ingredients. The location of this section will help
maintain the systematic presentation of the information listed under
the other headings.
    Finally, the agency has included a location for a telephone number.
The telephone number, if provided, would appear after the header
``Questions?'' (or ``Questions or comments?''), does not need to be a
toll-free number, and may include the days of the week and time when
someone is available to respond to questions.
    As described in section III.B in this document, the agency examined
the order of certain headings in Study B, including the relative
placement of the ``Warnings'' and ``Directions'' sections and the
placement of the ``Active ingredients'' section. When all of the design
variables in the study were analyzed simultaneously, the variable
placement of these three headings had little relative impact on
preference or readability ratings of the entire labeling. The agency
selected the order prescribed in Sec. 201.66(c) because it most closely
tracks a logical decisionmaking process that would allow for the best
selection and best use of OTC drug products.
    3. The agency sought comment on whether the new labeling should
apply to the immediate container label even if the product is marketed
with an outer package or wrapper (62 FR 9024 at 9037 and 9038). Several
comments stated that the labeling requirements should not apply to the
immediate container, or should be voluntary for the immediate
container, when there is an outer package, because space is often
especially limited on the container. Some comments supported requiring
certain headings in a mandated order, but not imposing the type size
and other type style requirements. Others, however, emphasized that the
outer carton is often discarded, leaving the immediate container as the
sole source for important warnings and dosage information.
    For products that are sold with an outer package, the agency
encourages manufacturers to try to meet all of the labeling
requirements in this rule on the immediate container as well. If the
immediate container is too small to meet the format requirements of
Sec. 201.66(d)(1) through (d)(9), the agency encourages manufacturers
to include the required information as provided in the small package
format in Sec. 201.66(d)(10). In addition, manufacturers must include
on the immediate container any information that is specifically
required by regulation (including an OTC drug monograph) to appear on
the immediate container, in the manner described in that regulation or
monograph (see, e.g., Sec. 201.314(h)(2) (21 CFR 201.314(h)(2))),
requiring Reye's syndrome warning on the immediate container).
1. Title (Sec. 201.66(c)(1))
    Section 201.66(c)(1) requires the title ``Drug Facts'' as the first
heading in the standardized format. A title provides an important
visual cue for introducing required information. The agency evaluated
the use of a title as a graphical design feature in Study B and
solicited comment on both the design of Study B and the results of the
study. As summarized in section III of this document, respondents in
Study B strongly preferred labeling that contained a title, such as
``Medication Facts,'' and considered such labeling to be more credible
and reliable than labeling without a title. When the agency analyzed
simultaneously the impact of all design variables tested in Study B,
the introductory title had the greatest relative impact on preference
rankings.
    4. The existing regulations governing OTC monograph products allow
manufacturers to use titles such as ``FDA Approved Uses'' and ``FDA
Approved Information'' to introduce required monograph information.
These titles, and the ability to enclose labeling information in a
highlighted ``box,'' are available under FDA's ``exclusivity policy.''
Under the policy, manufacturers may include a specified title and box
if they follow certain precise or ``exclusive'' language provided by
FDA in a final OTC monograph (see Sec. 330.1 (21 CFR 330.1)).
    Most manufacturers, however, have preferred to use ``flexible''
language to describe the uses and other information required under the
OTC drug monographs. Moreover, the proposed rule itself added more
flexibility in selecting language, making it less likely that
manufacturers would avail themselves of the labeling features specified
in Sec. 330.1. The agency therefore solicited comment on whether to
retain the idea of allowing special titles and boxes for manufacturers
who follow precise monograph language (62 FR 9024 at 9039).
    The agency did not receive substantive comments on this issue. The
agency did, however, receive one comment stating that the title ``FDA
Approved Uses'' violated section 301(1) of the act and could create
confusion between products marketed under new drug applications and
similar products marketed under OTC drug monographs. The first issue
was rendered moot by the repeal of section 301(1) of the act under
section 421 of the Food and Drug Administration Modernization Act of
1997 (FDAMA) (Pub. L. 105-115), while the second issue was addressed by
the agency in the rulemaking for Sec. 330.1(c) (see 51 FR 16258 at
16260 and 16261, May 1, 1986).
    The agency agrees, however, that the availability of a title should
not be limited to products marketed under OTC drug monographs. The
agency also finds, based in part on the strong support for a title
under Study B, that consumers would benefit by having a title on all
OTC drug products (rather than only on those few products that chose to
use certain language specified under an OTC drug monograph). The agency
has therefore included a title as part of this final rule to introduce
the required information on all OTC drug products. In addition, the
agency is revoking the titles and boxed labeling provisions from
Sec. 330.1(c).
    5. Several comments contended that a title such as ``Medication
Facts'' was not specifically discussed in the proposed rule and,
therefore, should not be included in this final rule. The comments also
contended that this title has not been shown to actually improve
consumer use of OTC drug products and would take up too much space.
    As discussed, the agency included the title ``Medication Facts'' as
a key variable in Study B and provided ample opportunity for interested
persons to comment on the design and on the results of the study.
    A title on the information panel provides a strong cue to the
consumer that important labeling information follows. This is similar
to the highly

[[Page 13260]]

successful ``Nutrition Facts'' title required on the information panel
for food products (Sec. 101.9). Indeed, respondents in Study B stated
that they preferred a label with a title and that they considered the
information to be more credible and reliable when introduced by a
prominent title.
    The agency does not believe that it must prove that the title alone
improves consumer use of OTC drug products. A number of factors
combined determine consumer use, including format variables,
legibility, readability, comprehension, and consumer motivation. It is
difficult to separate out the influence of each variable. Nevertheless,
it is important to note that when all of the design variables in Study
B were considered simultaneously, the title had the most significant
impact in determining which label consumers preferred. Overall, a title
creates an important, concise visual cue for consumers and serves to
reinforce the importance of the information that follows.
    The agency has decided to use the title ``Drug Facts,'' in place of
the test title ``Medication Facts,'' because the phrase ``Drug Facts''
is short, concise, easy to print in large type, and best signals an OTC
drug product. Consumers may use the term ``Medication'' to refer to
remedies which may not be marketed as drug products. It is also a four
syllable word which requires a higher level of reader comprehension.
Consumers, for example, commonly use the term ``drug store'' to refer
to a pharmacy. The agency therefore concludes that the word ``drug'' in
this title is more precise, readable, comprehensible and, in response
to the comments, will require less labeling space.
    The title will take up one line of text on each panel that it
appears. The previously allowed titles (``FDA APPROVED USES'' and ``FDA
APPROVED INFORMATION'') also took up one line of text. Based in part on
the results of study data and on the agency's experience with other
forms of labeling, the agency concludes that the benefits of having a
title outweigh the minimum space required.
2. Active Ingredient(s) (Sec. 201.66(c)(2))
    Section 201.66(c)(2) requires the heading ``Active ingredient(s),''
followed by the established name and the quantity of each active
ingredient per dosage unit. For products marketed without a discrete
dosage unit, such as topical OTC drug products, the proportion of each
active ingredient must be stated instead of the quantity, unless
otherwise specified in an applicable monograph or approved drug
application.
    This provision incorporates a recent amendment to section 502(e) of
the act under FDAMA. FDAMA amended section 502(e) of the act to require
that the quantity (or the proportion, if determined to be appropriate
by the Secretary of Health and Human Services (the Secretary)) of each
active ingredient appear in the labeling of all OTC drug products
intended for human use. In the proposed rule, the agency provided for
the placement and formatting of the quantity of each active ingredient,
but requested comment on whether to require all products to include
this information. At that time, the agency's regulations encouraged
(but did not require) manufacturers to include the quantity per dosage
unit in the labeling (Sec. 330.1(j)). The vast majority of OTC drug
products already include such information in their labeling. As a
result of the statutory change, this final rule makes clear that the
established name and quantity of each active ingredient must be
included in the required information set forth in Sec. 201.66(c), in
the location and format established by the agency. In an agency
guidance document titled ``National Uniformity for Nonprescription
Drugs--Ingredient Listing for OTC Drugs (April 1998)'' (Ref. 6), the
agency stated that it does not intend to object if manufacturers,
packers, and distributors defer relabeling their products to comply
with the statutory requirement until the earliest applicable
implementation date specified in this final rulemaking document.
    6. Several comments favored placing the active ingredient section
on the PDP, rather than on another panel. The comments argued that
product line extensions (i.e., OTC drug products with the same brand
name that contain different active ingredients) invite the need for
more prominent placement of the active ingredients. According to these
comments, most consumers are able to recognize brand names but are
unable to identify the relevant active ingredients. Placement of the
active ingredients on the PDP would allow consumers to distinguish
products sold under the same brand name.
    This final rule requires the listing of active ingredients as the
very first information within a clearly defined panel, immediately
below a prominent title. This location will enable consumers to quickly
and systematically compare ingredients within products for similar
uses. In addition, because the respective purposes will be listed next
to each active ingredient, consumers will know why the ingredient is in
the product. Regardless of placement on the PDP, such uniform and
prominent placement will help to ensure proper product selection,
especially for product line extensions.
3. Purpose(s) (Sec. 201.66(c)(3))
    Section 201.66(c)(3) requires the heading ``Purpose'' or
``Purposes,'' followed by the general pharmacological category(ies) or
the principal intended actions of the drug or of each active
ingredient, when more than one ingredient is listed. 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. Section 201.66(c)(3) of the final
rule does not differ from the proposal.
4. Use(s) (Sec. 201.66(c)(4))
    Section 201.66(c)(4) requires that all OTC drug product labeling
include the heading ``Use'' or ``Uses'' followed by the indications for
use of the drug product. Section 201.66(c)(4) of the final rule does
not differ from the proposal.
5. Warning(s) (Sec. 201.66(c)(5))
    Section 201.66(c)(5) requires the heading ``Warning'' or
``Warnings'' followed by the specific information and subheadings
listed in Secs. 201.66(c)(5)(i) through (c)(5)(x), as applicable.
    7. Several comments requested that the warning ``For external use
only'' appear immediately following the ``Warnings'' heading, on the
same line of text as the heading. The agency agrees that for topical
drug products not intended for ingestion, this warning should appear
first. The agency, however, believes that the ``Warnings'' heading
should signal the entire warning facts information and, therefore,
disagrees with the request to display this statement on the same line
as the heading. The agency is also specifying that the placement of the
warnings ``For rectal use only'' or ``For vaginal use only,'' where
applicable, immediately follow the ``Warning'' heading.
    8. The proposed rule would have required certain ingredient-
specific warnings, such as the Reye's syndrome warning in
Sec. 201.314(h)(1), to be listed first under the heading. Several
comments recommended that the agency integrate such warnings into the
various subheadings set forth in Sec. 201.66(c)(5). Although the
subheadings provide important visual and organizational cues, the
agency believes that the warnings listed in Sec. 201.66(c)(5)(ii) of
the final rule need to

[[Page 13261]]

be given special prominence and should not be combined or grouped with
other warnings under a subheading. An effective way to ensure that
these special warnings are prominently displayed is to require that
they be listed immediately under the ``Warnings'' heading, with a
subheading that describes the key aspect of the warning. The agency has
incorporated special subheadings for the warnings that will appear in
this section. Some of the subheadings appear in current regulations or
approved drug applications, and others are being added to provide
consumers with signal words that describe the key aspect of the warning
statement.
    9. One comment suggested that the subheading ``Do not use'' include
the word ``if,'' to read ``Do not use if.'' Another suggested listing
allergic reaction warnings under this subheading.
    The agency disagrees with adding ``if'' to this subheading because
conditional words other than ``if'' may be part of certain warnings
(e.g., ``on broken skin''). With respect to allergic reactions, the
agency considers serious allergic reactions (e.g., immediate
hypersensitivity reactions) to be of such importance that it is
requiring these warnings to appear immediately under the ``Warnings''
heading, preceded by the subheading ``Allergy alert.''
    In the labeling examples included in the proposed rule, the agency
showed the prescription monoamine oxidase inhibitor (MAOI) warning
under the ``Do Not Use'' subheading. No comments to the contrary were
received, and the agency concludes that the warning should appear after
this subheading.
    The MAOI warning appears in several places in the cough-cold
monograph (Secs. 341.74(c)(4)(v) and (c)(4)(vi), 341.76(c)(4), and
341.80(c)(1)(i)(D) and (c)(1)(ii)(D) (21 CFR 341.74(c)(4)(v) and
(c)(4)(vi), 341.76(c)(4), and 341.80(c)(1)(i)(D) and (c)(1)(ii)(D)).
The agency has determined that the words ``Drug Interaction
Precaution'' and ``this product,'' which are currently included in
these sections, need not appear when the information appears after the
new ``Do not use'' heading. Therefore, the agency is including the
words ``Drug Interaction Precaution'' and ``this product'' in new
Sec. 330.1(j) in this final rule, which lists connecting terms that can
be deleted from the labeling of OTC drug products. The MAOI warning
would now appear in labeling as follows ``Do not use if you are now
taking a prescription monoamine oxidase inhibitor (MAOI) * * * .''
    10. The agency received numerous comments on the subheading, ``Ask
a doctor before use.'' The agency specifically sought comment on
whether the phrase ``or pharmacist,'' as in ``Ask your doctor or
pharmacist,'' should be included in OTC drug product labeling and, if
so, in what section of the labeling, and for which products (62 FR 9024
at 9039). A majority of the comments supported the inclusion of the
pharmacist in OTC drug product labeling. Other comments suggested
phrases such as ``other health professional,'' ``other healthcare
professional,'' or ``other healthcare practitioner.''
    Those comments favoring the phrase ``or pharmacist'' stated that
pharmacists often are immediately accessible at the time of OTC drug
purchase, are well equipped to provide information regarding benefits
and risks associated with OTC drug products, have extensive training,
and in many instances have immediate access to patient profiles and
prescribing histories. The comments added that when pharmacists do not
have enough information about a person's medical condition, or
otherwise recognize the need to contact a doctor, they are trained to
advise the consumer to speak with a doctor before taking an OTC drug
product. Several comments noted that about 60 percent of OTC drug
products are purchased in retail pharmacies.
    Those supporting phrases such as ``other health professional'' or
``other healthcare professional'' or ``other healthcare practitioner''
stated that for many consumers the primary healthcare provider is a
nurse practitioner, clinical nurse specialist, nurse midwife, physician
assistant, or other healthcare professional, and not a physician. The
comments argued that limiting the reference to ``doctor'' sends the
message that only a ``doctor'' is qualified to know about a drug
product's benefits, risks, side effects, and precautions.
    A few comments stated that a subheading such as ``Ask a doctor or
pharmacist before use'' would equate the role of a pharmacist with that
of a doctor. These comments contended that pharmacists do not have the
same level of knowledge or training regarding patient specific
conditions, symptoms, side effects, and concomitant therapies. Further,
only a physician is trained in medical history-taking, physical
examination, and diagnosis. The comments stated that although a
pharmacist may be qualified to help consumers select OTC drug products,
a phrase such as ``or pharmacist'' is likely to confuse consumers about
the role of their doctor and may seriously and adversely impact health.
    This issue was also presented to the FDA's Nonprescription Drugs
Advisory Committee at its July 14, 1997, meeting. The committee did not
reach consensus whether ``pharmacist'' should be included in the
labeling. However, several presenters suggested a specific consultative
role for the pharmacist when considering drug-drug and drug-food
interactions.
    The agency has determined that warnings for persons with certain
preexisting conditions (e.g., glaucoma) and symptoms (e.g., cough with
fever, rash, or persistent headache) be listed under the subheading,
``Ask a doctor before use if you have,'' and that warnings concerning
drug-drug or drug-food interactions be listed under the subheading,
``Ask a doctor or pharmacist before use if you are.'' However, the
pregnancy/breast-feeding warning in Sec. 201.63 (21 CFR 201.63) will
continue to use the term ``health professional.''
    As stated in the proposed rule, the agency recognizes that
pharmacists are knowledgeable about OTC drug products. Also,
pharmacists are readily accessible to a majority of consumers who
purchase OTC drug products and are a valuable resource for general
questions. Survey studies submitted to the docket for this proceeding
suggest that direct consumer counseling by pharmacists may change
initial OTC drug purchasing decisions and may prevent potential adverse
events (Refs. 7 and 8). In addition, pharmacists are trained to provide
advice about drug-drug and drug-food interactions and often have access
to computer data bases which contain (and frequently update) this
information. Therefore, the agency concludes that warnings concerning
interactions be listed under the subheading, ``Ask a doctor or
pharmacist before use if you are.'' The drug interaction precautions in
21 CFR 331.30(d) and 346.50(c)(7)(ii) have been revised to fit this new
subheading.
    If a consumer has a preexisting disease or clinical symptoms, the
agency concludes that the subheading, ``Ask a doctor before use if you
have,'' should be retained. The agency has decided not to include the
phrase ``or pharmacist'' in this subheading because questions
concerning preexisting diagnoses or clinical symptoms are best answered
by a healthcare provider who is trained and licensed specifically to
make differential diagnoses and to treat disease entities.
    The agency has also decided to use only the term ``doctor'' in this
subheading, rather than a longer list of

[[Page 13262]]

healthcare providers. The agency acknowledges that in addition to
physicians, surgeons, and dentists, other licensed professionals play
important roles in delivering clinical services directly to consumers
and that nurse practitioners and physician's assistants may sometimes
serve as primary medical care providers. However, the agency has
decided not to endeavor to list each specific practitioner who is
licensed and qualified in the clinical practice of medicine and in
disease management. For OTC drug products, the term ``doctor'' in this
subheading is sufficiently broad and inclusive (Ref. 9).
    The agency is retaining the phrase, ``health professional'' in the
revised pregnancy/breast-feeding warning in Sec. 201.63(a), which
requires, when appropriate, the warning, ``If pregnant or breast-
feeding, ask a health professional before use.'' In establishing this
warning (47 FR 54750, December 3, 1982), the agency noted that certain
health professionals (e.g., physicians, nurses, certified nurse
midwives, nurse practitioners, and physician's assistants) may be
familiar with problems related to medication use during pregnancy and
nursing because they receive specific training in this area and they
directly deliver healthcare to women who are pregnant or nursing. As a
consequence, for these specific physiologic conditions, these health
professionals may be appropriately relied upon as sources of
information advising caution concerning drug use while pregnant or
nursing. The agency has amended Sec. 201.63(a) in this final rule by
requiring that the first four words of the warning appear in bold type,
to ensure that this warning is as prominent and conspicuous as the
required subheadings.
    Finally, the agency is including in this final rule a conforming
amendment to the MAOI warning (Secs. 341.74(c)(4)(v) and (c)(4)(vi),
341.76(c)(4), and 341.80(c)(1)(i)(D) and (c)(1)(ii)(D)), substituting
the words ``doctor or pharmacist'' for the words ``health
professional.'' This change is consistent with the respective roles of
pharmacists, doctors, and health professionals in assisting consumers
of OTC drug products.
    11. Several comments recommended consolidating the subheading ``Ask
a doctor before use if you have'' (proposed Sec. 201.66(c)(iii)(A))
with the subheading ``Ask a doctor before use if you are'' (proposed
Sec. 201.66(c)(iii)(B)), to allow greater flexibility in labeling
design.
    The subheading ``Ask a doctor before use if you have''
(Sec. 201.66(c)(5)(iv) in this final rule) cautions consumers about
preexisting conditions when consumers should not use the product before
a doctor is consulted. The subheading ``Ask a doctor or pharmacist
before use if you are'' (Sec. 201.66(c)(5)(v) in this final rule)
cautions consumers about potential drug-drug or drug-food interactions
when consumers should not use the product before a doctor or pharmacist
is consulted. Organizing or ``chunking'' the information under separate
subheadings makes it more likely that the information will be read and
understood by consumers who have certain conditions or are taking other
drugs.
    12. Section 201.66(c)(5)(vi) requires the subheading ``When using
this product,'' followed by any side effects that the consumer may
experience and the substances (e.g., alcohol) or activities (e.g.,
operating machinery, driving a car) to avoid while using the product.
One comment suggested that because this subheading is not parallel in
grammar with the other subheadings, it should read, ``Be aware when
using this product.'' Another comment requested that warnings for drugs
in dispensers pressurized by gaseous propellants be included under this
subheading.
    Although the subheading ``When using this product'' is not
grammatically parallel with the other subheadings, the phrase ``Be
aware'' is implied in the subheading because it appears under the
general heading, ``Warnings.'' Consumers are already cautioned that
they need to read and take note of the warning information that
follows. In addition, the words ``Be aware'' would unnecessarily
lengthen the subheading.
    The agency agrees with the comment that the warnings for drugs in
dispensers pressurized by gaseous propellants (Sec. 369.21 (21 CFR
369.21), 21 CFR 310.201(a)(11) and (a)(18)) would appear under this
subheading.
    13. Section 201.66(c)(5)(vii) requires the subheading ``Stop use
and ask a doctor if,'' followed by any signs of toxicity or other
serious reactions that would necessitate immediately discontinuing use
of the product. This subheading, as proposed, read ``Stop using this
product if,'' followed by the required warnings, followed by ``Ask a
doctor. These may be signs of a serious condition.'' Several comments
raised the concern that the ``Ask a doctor'' portion of this warning
may be de-emphasized within the proposed labeling format. The agency
agrees and has amended the subheading to ensure that consumers are
adequately advised to contact a doctor if they experience certain signs
of toxicity or other reactions.
    The agency has also added to the final rule a ``catch-all''
provision in Sec. 201.66(c)(5)(viii) that directs the placement of any
other required warning that does not fit within the categories listed
in Sec. 201.66(c)(5)(i) through (c)(5)(vii), (c)(5)(ix), and (c)(5)(x),
to appear following the warnings described in (c)(5)(vii).
    14. Many comments disagreed with the proposal to eliminate the
reference to Poison Control Centers in the accidental overdose/
ingestion warning in Sec. 330.1(g), which is incorporated by reference
in Sec. 201.66(c)(5)(x) of the final rule. The comments cited several
factors, including: (1) Medical professionals may lack complete
knowledge about treating an accidental overdose of an OTC drug product;
(2) advising consumers to ``get medical help right away'' is likely to
encourage consumers to proceed immediately to a hospital emergency room
when Poison Control Centers can often help treat such exposures at
home; and (3) Poison Control Centers in appropriate circumstances can
direct consumers to an emergency provider, inform hospital personnel of
a patient's imminent arrival, and provide hospital staff with critical
information. One comment indicated that Poison Control Centers now
serve the entire U.S. population, 24 hours a day, 7 days a week,
providing immediate free advice to consumers and health professionals.
    The agency agrees that Poison Control Centers are a valuable
resource in the event of an accidental overdose or ingestion of an OTC
drug product. Accordingly, the agency is retaining, and adding where
needed, the reference to Poison Control Centers in revised
Sec. 330.1(g), 21 CFR 369.9, 21 CFR 369.20, Secs. 369.21, and
201.314(a) and (g)(1).
6. Directions (Sec. 201.66(c)(6))
    Section 201.66(c)(6) requires the heading ``Directions'' followed
by the applicable directions for use.
    15. One comment suggested that this heading read ``Follow these
directions,'' to give consumers a stronger cue. The agency believes
that the heading ``Directions'' is an implicit instruction to not only
read the directions for use, but also to follow the directions.
Accordingly, the agency prefers the more concise heading.
7. Other Information (Sec. 201.66(c)(7))
    Section 201.66(c)(7) requires the heading ``Other information,''
when appropriate, followed by information that does not fall within any
of the other categories in Sec. 201.66(c), but which is required by or
is made optional under an applicable OTC drug monograph,

[[Page 13263]]

other OTC drug regulation, or an approved drug application.
    16. One comment asked whether information regarding proper storage
of an OTC drug product must appear under this heading. The agency
recognizes that there are space constraints for placement of
information on OTC drug product labeling. For products that include
United States Pharmacopeia (USP) or manufacturer's storage information
in their labeling, this information may be placed under the ``Other
information'' heading or outside the ``Drug Facts'' labeling. However,
if an OTC drug monograph contains storage requirements (e.g., wart
remover drug products in 21 CFR 358.150(c)(3) and corn and callus
remover drug products in 21 CFR 358.550(c)(3)), then that information
must be included in the ``Drug Facts'' labeling under this heading.
    17. Several comments suggested that other required information for
OTC drug products (such as the identification of certain inactive
ingredients and the required tamper-resistant packaging statement)
appear below the ``Other information'' heading. The agency is requiring
inactive ingredients to be listed in a separate section. However,
required information about certain ingredients (e.g., the sodium
content) will appear as the first required statement in the ``Other
information'' section. The required tamper-resistant labeling statement
(now referred to as ``tamper-evident'' labeling (see 63 FR 59463,
November 4, 1998) must be prominently placed to alert consumers about
the product's tamper-evident features (see (21 CFR 211.132(c)). The
agency will continue to allow flexibility as to where this statement
appears in labeling and is not requiring that it be included within the
``Drug Facts'' area. However, if the statement is included in the
``Drug Facts'' area, it should be placed under ``Other information.''
    18. The agency also received comments asking whether a ``sell
copy'' statement or other promotional information, such as a statement
of approval of the American Dental Association, may appear under
``Other information.'' Although promotional copy may be important to
the sale of a drug product, it is generally not necessary for the safe
and effective use of the product. Therefore, this information may not
appear under the ``Other information'' heading or within the ``Drug
Facts'' area, but may appear elsewhere in the labeling (e.g., PDP or
side or end panel) if otherwise permitted by law.
    19. FDA regulations require or will require in the future that
certain information about specific ingredients be included in the
labeling of OTC drug products. Examples include sodium content (21 CFR
201.64), proposed calcium content (Sec. 201.72 (21 CFR 201.72)),
proposed magnesium content (Sec. 201.71), proposed potassium content
(Sec. 201.72), and phenylalanine/aspartame content (21 CFR 201.21(b)).
The agency did not include a separate heading for such dietary
information in the proposed rule. However, the agency requested comment
on the appropriate placement of this information. Several comments
suggested that a separate heading would help ensure appropriate product
selection and reduce health risks associated with certain nutrients.
Other comments disagreed with the need for such a heading, arguing that
this information can be placed in the ``Other information'' section.
    The agency has determined that this information can appropriately
appear after the heading ``Other information.'' This information is
significant for individuals who monitor their intake of certain
nutrients, including persons with hypertension and renal insufficiency,
and for persons who want to increase their intake of certain nutrients
(e.g., calcium). The agency is requiring this important information to
be the first statement under ``Other information'' to draw attention to
it. The information will appear as follows: ``each (insert appropriate
dosage unit) contains:'' [in bold type] (insert name(s) of
ingredient(s) and the quantity of each ingredient), (e.g., sodium 50
mg). The phenylalanine/aspartame content, if applicable, should appear
as the next item of information. 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 (Sec. 201.66(c)(8))
    Section 201.66(c)(8) requires the heading ``Inactive ingredients,''
followed by a listing of the inactive ingredients. If the product is an
OTC drug product that is not also a cosmetic, then the established name
of each inactive ingredient (any ingredient that is not an active
ingredient as defined in Sec. 201.66(b)(2)) shall be listed in
alphabetical order. If the product is both a drug and a cosmetic, then
the inactive ingredients would be listed in accordance with Sec. 701.3
(21 CFR 701.3). However, because Sec. 701.3 includes format
requirements that may not be consistent with this final rule, the
agency has enumerated the paragraphs within Sec. 701.3 that would apply
to the listing of ingredients in OTC drug products that are also
cosmetics. Manufacturers may follow Sec. 701.3(a), which generally
requires the listing of ingredients in descending order of
predominance, or Sec. 701.3(f), which allows ingredients to be grouped
in certain categories. The provisions in Sec. 701.3 in paragraphs (e),
(g), (h), (l), (m), (n), and (o) and 21 CFR 720.8, may also apply, as
appropriate. The names of cosmetic ingredients are to be determined in
the manner described in Sec. 701.3(c).
    This final rule incorporates the recent amendment to section 502(e)
of the act under section 412 of FDAMA. Section 502(e)(iii) of the act,
as amended, authorizes the Secretary to require the listing of the
established name of each inactive ingredient in alphabetical order on
the outside container of the retail package and, if determined to be
appropriate by the Secretary, on the immediate container as well, as
prescribed in regulations issued by the Secretary. Further, the
amendment to section 502(e) of the act provides that if the drug
product is also a cosmetic, then the inactive ingredients need not be
listed in alphabetical order.
    In a guidance document entitled ``National Uniformity for
Nonprescription Drugs--Ingredient Listing for OTC Drugs'' (April 1998),
the agency stated that it would consider whether to provide an
additional opportunity for comment before finalizing provisions
implementing new section 502(e)(1)(iii) of the act. Because the final
rule essentially codifies the provisions of the statute, and because
the final rule requires the listing of inactive ingredients in the same
location as that described in the proposal, an additional opportunity
to comment is not needed at this time. However, the agency recognizes
the possibility that more detailed regulations or guidance on the
listing of inactive ingredients may prove necessary. The agency also
intends to consider whether to consolidate, to the extent permitted
under the act, the requirements for listing inactive ingredients in OTC
drug products with the requirements for OTC drug products that are also
marketed as cosmetics. Either or both of those initiatives, if they
resulted in rulemaking, would provide further opportunities for public
comment.
    Finally, the agency is not requiring at this time the listing of
inactive ingredients on immediate containers when the product is
marketed with an outside retail package that includes the required list
of inactive ingredients.

[[Page 13264]]

9. Questions or Comments? (Sec. 201.66(c)(9))
    Section 201.66(c)(9) identifies where manufacturers may include a
telephone number for consumers. The telephone number would appear after
the header ``Questions?'' (or ``Questions or comments''), is in a
minimum 6-point bold type (but preferably larger), and does not need to
be a toll-free number. It is recommended that the days of the week and
the times when someone is available to respond to questions also be
included. A graphic of a telephone or telephone receiver may appear
before the heading.
    20. Several comments urged the agency to allot space for the
manufacturer's toll-free telephone number in bold Helvetica type. At
least one comment also requested the agency to require a telephone
number in clear braille over-print, to assist those with impaired
eyesight in obtaining usable labeling.
    Many OTC drug products already include a section entitled
``Questions or Comments?'' and provide a telephone number. The agency
considers this information very beneficial because it provides a place
to report concerns after product use and a source to contact when the
product is not purchased in a pharmacy. A telephone number also
provides a contact for the elderly or visually impaired who may not be
able to read the product's labeling, and for individuals who do not use
English as a primary language.
    The agency has allotted space for a telephone number within the
``Drug Facts'' area. While this labeling is not required, the agency
strongly encourages all manufacturers, distributors, and packers to
include a telephone number. The agency also encourages the use of a
point size greater than 6 to display the information, to help those
unable to read 6-point type. Further, the telephone number, if shown,
must appear in bold type. As requested by the comments, a Helvetica
type style may be used. The agency recommends that the days of the week
and the time of the day when a person is available to respond to
questions (e.g., Monday to Friday, 9 a.m. to 5 p.m.) also be included.
Braille labeling is discussed in comment 43 of this document.

D. Format Requirements (Sec. 201.66(d))

    Section 201.66(d) prescribes the required format for presenting the
title, headings, subheadings, and information set forth in
Sec. 201.66(c)(1) through (c)(9).
    Although the comments on balance strongly support the conclusion
that a standardized presentation of information will benefit consumers
and health professionals, several comments raised concerns regarding
specific features of the format. These concerns included the need to:
(1) Further improve readability; (2) maintain internal consistency with
respect to periods, spacing, and other type setting features; (3)
increase usable labeling space without decreasing readability; (4)
provide flexibility to accommodate required information on small
packages; and (5) minimize the potential for consumer confusion.
1. Alignment and Punctuation of Headings (Sec. 201.66(d)(1))
    Section 201.66(d)(1) requires that the first letter of each word of
the title in Sec. 201.66(c)(1) appear in uppercase. Section
201.66(d)(1) also requires that only the first letter of the first word
of each heading and subheading set forth in paragraphs (c)(2) through
(c)(9) appear in upper case, and that the title, headings, and
subheadings set forth in paragraphs (c)(1), (c)(2), and (c)(4) through
(c)(9) must be left justified.
    21. Several comments recommended the use of upper case letters only
for the first letter of the first word in each heading and subheading
to be consistent with conventional rules of graphics and labeling
design. The agency agrees that limiting the use of upper case letters
to the first word in the phrases in Sec. 201.66(c)(2) through (c)(9)
will enhance readability. The agency has incorporated this
recommendation into the final rule. The length of the title, however,
is sufficiently short to allow the first letter of both words to appear
in uppercase without compromising readability. However, when the title
appears on additional panels, the term ``(continued)'' will appear in
lowercase letters.
    22. Several comments recommended that all headings be left
justified, rather than centered, to enhance readability. The comments
contended that information that is centered may be missed or
overlooked, particularly when most of the information presented is left
justified. In general, the agency agrees. However, to preserve the
association of each active ingredient with its purpose, the agency has
retained in the final rule the requirement that the heading ``Active
ingredients'' appear immediately adjacent and to the left of the
heading ``Purpose(s)'' (Sec. 201.66(d)(6)).
2. Type Size (Sec. 201.66(d)(2))
    Section 201.66(d)(2) requires that the letter height or type size
for the title ``Drug Facts'' must appear in a type size greater than
the largest type size used within the ``Drug Facts'' area. The type
size for the title ``Drug Facts (continued)'' must appear in no smaller
than 8-point type. The headings in paragraphs (c)(2) through (c)(9)
must appear in 8-point or greater type, or in a type size that is at
least 2-point sizes greater than the text, whichever type size is
larger. Thus, if the required information is presented in 7-point type,
the headings must appear in at least 9-point type. This will ensure
that the headings, which serve as important visual cues, stand out from
the balance of the text, while preserving flexibility for manufacturers
to use larger type sizes to enhance readability. The subheadings and
all of the information described in Sec. 201.66(c)(2) through (c)(9)
must appear in at least 6-point type.
    23. Many comments, particularly from consumers, urged the agency to
adopt the 6-point minimum type size for all required OTC labeling,
except for the manufacturer's name and address. Some comments argued
that anything less than 6-point type is not readable, especially for
elderly consumers. Other comments contended that a 6-point minimum
should be required because, if industry is allowed to use anything less
than 6-point, smaller type size will become the standard. A study (Ref.
7) was submitted demonstrating that many OTC drug products did not
conform with the Nonprescription Drug Manufacturers Association (NDMA)
Readability Guidelines (Ref. 10) recommended for use by the industry
for OTC drug products.
    Manufacturers and several trade associations argued that the 6-
point minimum should be optional, to allow flexibility in fitting all
of the required information into the proposed format. Manufacturers
urged that a 6- point type be used where feasible, but that smaller
types (down to 4.5 point) be permitted when necessary. At least one
comment claimed that if 6-point type is required, the OTC labeling
information would not fit on nearly 33 percent of the branded products
and 95 percent of generic products. Data were not submitted to support
these figures. The comments also noted that the agency has allowed 4.5-
point type for dietary supplements in certain situations.
    Upon careful review of the comments and supportive studies and the
rationale set forth in the proposed rule (see 62 FR 9024 at 9027), the
agency has determined that the type size for required OTC drug product
labeling information must be no smaller than 6-point, under the
conditions set forth in this final rule, including format

[[Page 13265]]

exceptions for small packages as defined in this final rule.
    The proposed rule summarized literature studies that demonstrated
how important type size is in evaluating readability, as well as the
difficulty consumers have in reading OTC drug product labeling because
of small type (see 62 FR 9024 at 9027 to 9029). For example, a survey
of consumers' ability to read OTC drug product labeling printed with
the minimum type sizes recommended by NDMA's Readability Guidelines
demonstrated that a significant portion of the adult population over 20
years of age is not able to read OTC drug product labeling with 4.5-
point minimum type size. Further, only 48 percent of the public who
currently purchase OTC drug products are able to read labels with the
4.5-point minimum type size. People over 51 years of age have the most
trouble reading labels with 4.5-point type size, with only 32 percent
able to read them, and only 63 percent of people under age 51 were able
to read the existing (or tested) labels (62 FR 9024 at 9029).
    Another study evaluated the ability of persons over 60 years of age
to read OTC drug product labeling (Ref. 11). The study found a
significant portion of this population cannot adequately read the print
on certain existing OTC drug products due to small type size (vertical
height) and horizontal letter compression (type style). The study
concluded that to maximally enhance readability for this target
population, OTC drug information should be presented in a minimum
vertical type size of 6.7-point and a letter compression of no more
than 39 characters per inch. Recognizing the space constraints in
existing labeling, the agency chose to require a minimum type size of
6-point and type styles which ensure letter compression of no more than
39 characters per inch.
    Finally, the agency acknowledges that it has allowed 4.5-minimum
type size under certain conditions in dietary supplement labeling for
small packages (see Sec. 101.36(i)(2) (21 CFR 101.36(i)(2)). In these
instances, however, much of the required labeling consists of numerical
information regarding the content of the product. With limited
exception, this information may be presented in a well-defined tabular
format with ample white space to enhance readability. OTC drug product
labeling, on the other hand, consists largely of running text,
including descriptive information essential to the safe and effective
use of the product. This information often occupies one or more full
panels of the product's packaging. It also tends to vary considerably
from product to product, and is no less important on small packages
than it is on larger packages. As a result, OTC drug product labeling
places particularly significant demands on the reader. The agency
therefore believes that while 4.5 point type may be appropriate in
exceptional cases for nutritional information on a dietary supplement
product, it is not an appropriate minimum type size for OTC drug
products.
    The agency recognizes the delicate balance between: (1) The need
for the required information to fit within customary labeling and
packaging constraints, and (2) the need to ensure that the required
information is prominent and readable under customary conditions of
purchase and use. The agency believes it has selected type sizes and
styles that are consistent with the need for readable OTC drug product
labeling by a majority of OTC drug consumers, while at the same time
taking into account the manner in which OTC products are marketed and
the economic impact posed by setting these minimum requirements (see
section VIII of this document).
    24. Some comments suggested a sliding scale for type size based on
package size, similar to the requirements for dietary supplements and
food labeling (Secs. 101.9(j)(13) and 101.36(i)(2)). The agency
generally supports the approach of requiring larger type sizes and more
generous formatting for products marketed in progressively larger
packages. There is, however, less of need to develop such an approach
for OTC drug products than for food products because the range of
package sizes for OTC drug products is much smaller than the range for
food packages. Therefore, the agency has focused in this rulemaking on
developing minimum requirements suitable for typical OTC drug products.
Nevertheless, the agency encourages drug manufacturers to enlarge point
size wherever the package may accommodate larger labeling text. To that
end, the agency has specified in Sec. 201.66(d)(2) the relative
increase in point size for the title and headings when a larger type
size is used for the required text.
3. Font, Leading, Kerning, Contrast, and Highlighting
(Sec. 201.66(d)(3))
    Section 201.66(d)(3) contains font, leading, kerning, contrast, and
highlighting requirements. The agency has determined that at least 0.5-
point leading (i.e., the space between two lines of text) is needed to
ensure readability. While the proposal would have limited type style to
Helvetica, the final rule will allow any single, clear, easy-to-read,
type style. The agency notes that san serif type styles have been
adopted by at least one trade association as the industry standard. The
agency believes that san serif types styles are the most likely to be
considered clear and easy-to-read. The agency also is requiring the
title ``Drug Facts'' and the ``Drug Facts'' part of the ``Drug Facts
(continued)'' title to appear in bold italic print to draw even more
attention to the required information panel and, thereby, contribute to
the goal of ensuring that consumers are appropriately signaled to read
and use the information which follows. The agency is requiring the type
to be all black or one dark color, printed on a white or other light,
neutral color, contrasting background.
    25. Several comments requested that the agency allow the use of any
sans serif type style in OTC drug product labeling.
    The agency is allowing any single, clear, easy-to-read, type style.
Because font styles vary in their stroke weight characteristics (i.e.,
the thickness of the character of each letter is variable). Helvetica
and Univers font styles in particular have consistent and uniform
stroke weight characteristics and are both commonly available. The
agency therefore recommends the use of either one of these font styles.
    26. Several comments requested that only the format layout should
be required and not the graphical features (i.e., type size, leading,
kerning, and highlighting). If graphical features are required, the
comments requested reduced type size and leading.
    Based on the discussion in the proposed rule (62 FR 9024 at 9036),
the agency has determined that both format layout and graphical
features are necessary to ensure that labeling information is conveyed
in a manner that enables the consumer to readily notice and comprehend
such information. The agency has revised the leading requirement from
the proposed 1-point leading to 0.5-point leading in this final rule.
4. Bullets (Sec. 201.66(d)(4))
    Section 201.66(d)(4) specifies the style and format for using
bullet points to introduce and highlight statements of information. The
bullet style is limited to solid squares or solid circles of 5-point
type size and must be presented in the same shape and color throughout
the labeling. The use of a solid circle or square will avoid selection
of an icon that may have an independent meaning, such as an octagon
(stop) or inverted

[[Page 13266]]

triangle (caution). This format provides a valuable visual cue for
introducing each required ``chunk'' of information, without
unnecessarily distracting or confusing the reader. The bullets and
bulleted statements under each heading or subheading must be vertically
aligned, to ensure visual separation and adequate white space between
discrete information chunks. This section also establishes standards
for presenting more than one bulleted statement in the same horizontal
line of text and for the vertical alignment of such additional bulleted
statements.
    27. To increase usable labeling space, several comments requested
that the agency allow more than one bulleted labeling statement per
line and not require that bulleted phrases be separated by at least two
square ``ems'' (two squares of the size of the letter ``M''). The
agency agrees that allowing more than one bulleted statement per line
is an effective way to optimize labeling space. The agency has
incorporated this into the final rule. However, if more than one
bulleted statement appears on the same horizontal line, each statement
must be separated by at least two square ems.
5. Multiple Panels (Sec. 201.66(d)(5))
    The proposed rule would have required that all of the information
presented under the ``Warnings'' heading appear in one continuous
space, on one panel. As described in the following paragraphs,
Sec. 201.66(d)(5) of the final rule provides increased flexibility with
respect to the presentation of the required labeling information on
more than one panel of the retail package.
    28. Several comments requested that the agency allow the warnings
section to appear on more than one panel if: (1) Text or a visual
graphic such as an arrow leads the consumer to the continuation onto
the next adjacent panel, (2) the adjacent panel has an appropriate
heading, and (3) there is no intervening copy or symbols. One comment
noted that the Universal Product Code (UPC) symbol should not be
allowed to interrupt the flow of information in the required OTC drug
product labeling.
    The agency agrees with these comments. Section 201.66(d)(5) of this
final rule provides that the headings, subheadings, and information
required under Sec. 201.66(c), including the warnings section, may
appear on more than one panel. However, appropriate visual cues must be
provided, so that the flow of information is retained. The title ``Drug
Facts (continued)'' must appear on each subsequent panel with a graphic
such as an arrow, directing the consumer to the continuation of the
information on the next panel. The continuation of the required content
and format onto multiple panels must retain the required order and flow
of headings, subheadings, and information. The UPC symbol may appear on
the same panel as some of the information, but must be outside the box
or enclosed. Section 201.66(d)(7) provides that graphical images, such
as the UPC symbol, and information not set forth in paragraphs (c)(1)
through (c)(9) and (d)(1) through (d)(10), may not appear in or
otherwise interrupt the content and format required by these parts of
the final regulation.
6. Active Ingredient, Purpose, and Warning Headings (Sec. 201.66(d)(6))
    Section 201.66(d)(6) establishes the required format for listing
the established name, the quantity or proportion, and the ``purpose''
of each active ingredient. This section also provides that no other
text is permitted to appear on the same line as the ``Warning'' or
``Warnings'' heading.
    29. Several comments recommended that the agency allow products
containing more than one active ingredient with the same purpose to
list the purpose only once, adjacent to the listing of the last active
ingredient. The agency agrees. However, the presentation must allow the
reader to readily associate each active ingredient with its purpose.
The agency has incorporated this recommendation into the final rule.
7. Graphical Images and Interruptions (Sec. 201.66(d)(7))
    Section 201.66(d)(7) requires that graphical images, such as the
UPC symbol, and any information that is not set forth under
Sec. 201.66(c), must not interrupt the required information panel or
panels. The UPC symbol may appear on the same panel as required
information but must be outside the box or enclosure.
8. Required Lines (Sec. 201.66(d)(8))
    Section 201.66(d)(8) sets forth the placement and style of lines
that define the title, headings, subheadings, and information described
in Sec. 201.66(c)(1) through (c)(9). The proposed rule requires a
horizontal line to separate the information under each major heading
(62 FR 9024 at 9036 and 9051). In this final rule, the agency is
including more specific requirements for the use of these hairlines and
is requiring a barline to set off the ``Drug Facts'' labeling from
other information that appears in the labeling.
    Under Sec. 201.66(d)(8), a barline must be used to form a box or
similar enclosure around the information described in Sec. 201.66(c).
Example 7 of the sample labeling in the proposed rule (62 FR 9024 at
9060) depicted the required information surrounded by a hairline
forming a box. Also under Sec. 201.66(d)(8), a horizontal hairline
extending within two spaces on either side of the ``Drug Facts'' box or
similar enclosure must immediately follow the title set forth in
Sec. 201.66(c)(1). A distinctive horizontal barline extending to each
end of the ``Drug Facts'' box or similar enclosure must provide
separation between each of the headings listed in Sec. 201.66(c)(2)
through (c)(9). And, a horizontal hairline extending within two spaces
on either side of the ``Drug Facts'' box or similar enclosure must
immediately precede the subheadings set forth in Sec. 201.66(c)(5),
except the subheadings in Sec. 201.66(c)(5)(ii)(A) through
(c)(5)(ii)(G).
     The placement and style of barlines and hairlines set forth in
Sec. 201.66(d)(8) will highlight the information, making it more
prominent and easier to read and process. Section 330.1(c)(2)
previously provided for the use of a boxed area, in conjunction with
titles such as ``FDA Approved Uses'' and ``FDA Approved Information,''
to set off this information from other OTC labeling information. The
agency has used the box technique to highlight information in several
other notable instances (see, e.g., Sec. 101.9(d)(1)(i)).
9. Directions (Sec. 201.66(d)(9))
    Section 201.66(d)(9) adds the requirement that dosage directions,
when provided for three or more age groups or populations, must be
presented in a table format. The agency displayed this labeling
technique in example 2, 7, and 9 of the proposed rule (62 FR 9024 at
9055, 9060, and 9062 and in the sample cough-cold product used in Study
B.
    30. Several comments requested that the agency allow flexibility in
the arrangement of information under ``Direction(s)'' and not mandate a
table format. One comment added that other formats, e.g., running text,
can adequately convey the information while maximizing text in a
minimal amount of space.
    Study A confirmed that consumers are less likely to make a dosing
error when dosing information for multiple populations is separated
within an easy-to-read table as compared to such information appearing
in a paragraph format. Tables are now widely used in the labeling of
many OTC drug products, including those marketed

[[Page 13267]]

under NDA's and ANDA's. The agency therefore has incorporated into this
final rule a requirement that a table be used when dosing information
is complex, as when separate dosing instructions are presented for
three or more age groups. A text format may be used when there are less
than three dosage directions.
10. Small Packages (Sec. 201.66(d)(10))
    Section 201.66(d)(10) establishes a modified labeling format for
packages that cannot meet the format requirements of paragraphs (d)(1)
through (d)(9).
    31. Several comments urged the agency to adopt a broad, blanket
small package exemption from the proposed content and format
requirements. The comments described small packages as those products
that are marketed in unit doses, convenience sizes, samples, minimal
net content packages, analgesic products with less than 6 square inches
of usable labeling space, uniquely shaped containers (e.g., envelope
packaging, which has a front and back panel only), tubes, roll packs
commonly used for antacids, some ophthalmic products, a number of drug-
cosmetic products, and bottles without an outer carton.
    Many comments suggested graphical flexibility to accommodate
products marketed in small packages, such as: (1) Use of more than one
panel, (2) use of sans serif fonts or more than one font, (3) reduced
type size (to 4.5-point), (4) reduced or no leading, (5) interlined
spacing such that one line's ascenders do not touch the preceding
line's descenders, (6) eliminate hairlines and required bullet spacing,
and (7) consolidate warning information. One comment suggested that
graduated type size requirements could be adopted depending on the
available label space and cited the dietary supplement labeling
provisions in Sec. 101.36(c)(6) (amended and recodified at
Sec. 101.36(i), effective March 23, 1999 (62 FR 49826, September 23,
1997)). Another comment pointed out that the dietary supplement
labeling provisions allow a minimum 4.5-point type size.
    Some comments contended that relying on a subjective standard to
support an exemption would be inefficient. These comments recommended
that a small package be defined as any outer package: (1) Where the
total surface area available to bear labeling is less than 12 square
inches (including the PDP); or (2) where more than 60 percent of the
total surface area available for labeling on the back and side panels
must be used to satisfy the ``content requirements'' in proposed
Sec. 201.66(c); or (3) that is a trial size package, packet, or single
use unit. Some comments proposed that any drug or drug-cosmetic product
that meets this definition be exempt from the new format and content
requirements, but should still bear all required labeling. Some
comments stated that a performance standard, as described in the
proposed rule (62 FR 9024 at 9036), has not been established or
validated and would be impractical to use for small packages at this
time.
    The agency agrees that some manufacturers may have difficulty
providing important drug information, which is prominent and easy to
read, on packages that are irregular (i.e., bottle labels) or small
(i.e., unit does). However, the agency also considers the required OTC
drug labeling information essential for the safe and effective use of
OTC drug products, irrespective of the size or the shape of the
package.
    Because readability is especially dependent on vertical letter
height and letter compression, the agency disagrees that less than 6-
point type or letter compression allowing more than 39 characters per
inch should be permitted (Ref. 11), even on ``small packages.'' As
discussed in response to comment 23 in section IV.D of this document,
the agency considers 6.0 type the minimum allowable for OTC drug
product labeling.
    The agency, however, is including in Sec. 201.66(d)(10) of this
final rule several modifications that may be used with packages that
are too small to meet the format requirements of paragraphs (d)(1)
through (d)(9). Under Sec. 201.66(d)(10), headings may be presented in
a minimum 7-point or greater type size. The leading may be adjusted so
that the ascenders and descenders of the letters do not touch, rather
than the 0.5-point leading required under Sec. 201.66(d)(3). Also,
bulleted statements may continue to the next line of text and need not
be vertically aligned. Finally, the box or similar enclosure required
in Sec. 201.66(d)(8) may be omitted if the headings, subheadings, and
information in Sec. 201.66(c)(1) through (c)(9) are set off from the
rest of the label by color contrast.
    As suggested by the comments, a product will be considered
``small,'' and will be permitted to apply these modifications, if more
than 60 percent of the total surface area available to bear labeling on
the entire outside container or wrapper, or the immediate container
label if there is no outside container or wrapper, would be needed to
present FDA required labeling. This consists of the labeling required
by Sec. 201.66(c)(1) through (c)(9), in accordance with the minimum
specifications in Sec. 201.66(d)(1) through (d)(9) 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. This formula is consistent with the idea that 40 percent
of available labeling space is generally reserved for the UPC symbol
and PDP (see, e.g., 21 CFR 101.1 and Sec. 201.60 (21 CFR 201.60)).
    In determining whether more than 60 percent of the available
surface area is needed, the indications listed under the ``Use(s)''
heading must be limited to the minimum required uses allowed under the
applicable monograph. Also, for purposes of this rule, the ``total
surface area available to bear labeling'' does not include the flanges
at the tops and bottoms of cans and the shoulders and necks of bottles
and jars. All other surface areas are considered to be ``available to
bear labeling.''
    32. Several comments stated that the format under the proposed rule
would require manufacturers to increase the package or container size
of a significant number of OTC drug products. NDMA, for example,
reported that a survey of its members showed 33 percent of branded
products and 95 percent of private label products could not comply with
the proposed format without making some change in package or container
size. Some comments also opposed the mandatory use of alternative
packaging designs, such as extending a single side panel of a package
to increase labeling space, as had been suggested by the agency in the
proposed rule (62 FR 9024 at 9036). According to these comments, the
cost of adding such packaging features, and the additional
environmental waste associated with increasing package size or
configuration, outweighs the need to set a minimum 6.0 type size and
other minimum format requirements. Several comments made general
reference to state ``slack fill'' laws, which prohibit the use of
oversized containers to mislead consumers.
    Other comments, however, encouraged the use of alternative
packaging to ensure that important information is presented in a
readable type size with user-friendly visual cues. They emphasized that
consumers need the information, and need to be able to read and
understand the information, for proper self-selection and self-
medication, and that these concerns support the required use of
alternative packaging to increase available labeling space.
    As discussed in section VIII of this document, the comments that
oppose the required use of alternative packaging

[[Page 13268]]

design greatly overestimated the number of products that would not be
able to accommodate the proposed format within the confines of current
packaging. In addition, the modified format authorized under
Sec. 201.66(d)(10) of the final rule is expected to enable many small
package products to comply without increasing container or package
size.
    For those remaining products that are unable to accommodate the
modified, small package format, a number of design techniques are
available to increase labeling space. As suggested in the proposed
rule, labeling space can be increased by, for example, extending a
single side panel or widening the label affixed to a bottled drug
product (62 FR 9024 at 9036). In a survey described in section VIII of
this document, the agency found that many products are now marketed
with extended panels, peel back or fold out labels, or are otherwise
mounted on cardboard cards or placards. These alternative packaging
techniques often increase labeling space for promoting the sale of the
product and could also be used to accommodate FDA required information.
The agency likewise expects that any packaging changes needed to
conform to this rule will be sufficiently minimal, and can be done in a
manner, as to not render the product misleading under a ``slack fill''
law or similar provision (see, e.g., section 502(i)(1) of the act).
    Thus, products that are unable to meet the labeling format
described in Sec. 201.66(d)(1) through (d)(9), or the modified format
authorized under Sec. 201.66(d)(10), will be expected to be
reconfigured to meet the format requirements of this rule. The agency
will not routinely grant exemptions or deferrals under Sec. 201.66(e)
for products that claim to be too small to meet the requirements of
this rule.
    Finally, the agency is not requiring manufacturers to increase the
size of immediate containers (for those products that are marketed with
outside retail packages) in order for the required format to be applied
to the immediate container (see 62 FR 9024 at 9037). As stated in
response to comment 3 in section IV.C of this document, for products
that are sold with an outer package, the agency is encouraging, but not
requiring, the use of the modified, small package format in
Sec. 201.66(d)(10) on the immediate container.

E. Exemptions and Deferrals (Sec. 201.66(e))

    Proposed Sec. 201.66(e) provided that the required labeling
information must be the first information that appears on the back or
side panel of the outside container or wrapper of the retail package
(or the immediate container label if there is no outside container or
wrapper) of all marketed OTC drug products. As explained in the
following paragraphs, the agency has eliminated this requirement to
give manufacturers more flexibility. In addition, the agency has
codified proposed Sec. 201.66(f), Exemptions and deferrals, as
Sec. 201.66(e) and has made several changes to make the exemption
process less burdensome on manufacturers and on the agency.
    33. Several comments recommended that the agency allow the
inclusion of a brand name and product attributes anywhere on the
information panel as long as they do not interrupt the flow of the
required information and as long as the labeling is in compliance with
the type size requirements. Several comments requested that the product
brand name be the first text allowed on the information panel and that
the equivalent of three lines of type be allocated at the top of the
panel for a brand name and product attributes such as: (1) Information
about dosage form, flavor, the absence of certain ingredients,
directions for opening the package, and reference to the importance and
benefits of proper use; (2) references to alternative products that are
available; and (3) information from organizations endorsing the
product. Other comments raised concerns about whether adequate space
would be allowed for guarantee statements, signage, and sell copy.
Another comment suggested that the space for a brand name and product
attributes should be equivalent to the greater of either: (1) Three
lines of the minimum size copy across the width of the information
panel; or (2) 10 percent of the main information panel, at the option
of the manufacturer. The comments maintained that this information is
important to consumers for comparative purposes and for identification
of products with desired features.
    The agency has determined that the required OTC drug product
labeling information need not appear as the first information on the
back or side panel, provided there is adequate space on the outside
container or wrapper for the labeling to conform with Sec. 201.66(c)(1)
through (c)(9) and Sec. 201.66(d)(1) through (d)(10). Accordingly, the
agency is not including proposed Sec. 201.66(e) in this final
monograph. Thus, a brand name and product attributes may appear
anywhere on the labeling outside of the boxed area.
    34. A number of comments suggested that FDA establish an exemption
process other than a citizen petition. The comments contended that the
petition process is too slow and burdensome for both industry and the
agency, and would cause marketing delays. Some comments suggested a
simple notification process when a company is unable to comply with the
final rule. The company would notify the agency, a certain time would
be allowed for the agency to respond with any objections, and, if no
objections were provided, marketing could then proceed.
    Section 201.66(e) in this final rule provides that 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 particular
circumstances presented, one or more specific requirements set forth in
Sec. 201.66(a) through (d), on the basis that the requirement is
inapplicable, impracticable, or would be contrary to public health or
safety.
    The agency agrees that the exemption process need not require a
citizen petition. However, the process should be a matter of public
record and requests for exemptions must be granted by the agency prior
to marketing. Requests for exemptions must be submitted in three copies
in the form of an ``Application for Exemption'' to the agency. The
requests shall be clearly identified on the envelope as a ``Request for
Exemption from 21 CFR 201.66 (OTC Labeling Format)'' and with Docket
No. 98N-0337. A separate request must be submitted for each OTC drug
product. In addition to the three copies of the exemption request
submitted to the agency, manufacturers of a product marketed under an
approved drug application must 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.
    The request for exemption or deferral must: (1) Document why a
particular requirement is inapplicable, impracticable, or would be
contrary to public health or safety, and (2) include a representation
of the proposed label and labeling, including outserts, panel
extensions, or other graphical or packaging intended to be used with
the product.
    35. In the proposed rule, the agency asked for comment on whether
there are particular types of products or packages that should be
granted a regulatory exemption (62 FR 9024 at 9038). At least one
comment, from a trade association, requested that ``drug-cosmetic
products,'' and particularly those that do not have a dosage limitation
(e.g., antidandruff shampoos, anticaries

[[Page 13269]]

toothpastes, antiperspirants, and sunscreens), be exempted from the new
labeling requirements. The comment argued that these products do not
raise serious adverse event concerns, are not used to treat serious
health problems, do not raise serious misuse concerns, do not have the
potential for significant new therapeutic uses in the future, and are
limited in the space available for other information concerning product
attribute labeling. Several comments contended that some drug-cosmetic
products are used primarily for their cosmetic effects, and one comment
argued that most of the required information on these products consists
of ``common-sense'' statements and, therefore, do not need to be
subject to this rule.
    One comment also argued that drug-cosmetic products must include
more mandatory labeling information than other OTC drug products,
leaving even less space on drug-cosmetic products for the required
format. In particular, the comment stated that drug-cosmetic products,
unlike other products, must include a full list of all ingredients (see
Sec. 701.3). According to the comment, the proposed format would force
this information to be listed on more than one panel, making it
difficult for consumers (particularly those who may be allergic to
certain ingredients) to find important ingredient information. This
comment, however, has largely been superseded by the recent amendment
to section 502(e) of the act, which authorizes the agency to require
that all OTC drug products bear a full list of ingredients. The final
format includes a prominent location for the listing of this
information on all OTC drug products, including those that may also be
intended for cosmetic uses.
    The agency also received comments questioning whether the factual
record supports the need to standardize the labeling format for drug-
cosmetic products, especially those without a specified dosage
limitation. One comment noted that the agency failed to include drug-
cosmetic products in its consumer research studies, and that the agency
lacks a factual basis for applying this rule to these products.
    Finally, several comments provided additional reasons why
sunscreens, in particular, should be exempted: (1) The names of
sunscreen active ingredients have little meaning to consumers; and (2)
the prominent display of words such as ``Active ingredients,''
``Uses,'' and ``Warnings'' may discourage the use of traditional
cosmetic products containing a sunscreen or cause manufacturers to
leave out the sunscreen ingredient.
    The agency disagrees and finds no basis for including a broad
exemption because a product is marketed both as a drug and a cosmetic,
because a product does not require a precise dosage limitation, or
because the labeling of the product includes ``common-sense''
statements. When therapeutic claims are made for a product, the drug
provisions of the act apply to ensure the safety and effectiveness of
the drug ingredients, whether or not these products may also be used
for other purposes (see sections 201(g)(1) and (p) (21 U.S.C. 321(g)(1)
and (p)), 502, and 505 of the act). The agency also does not agree that
it lacks a sufficient factual basis for requiring the new format and
content requirements on all OTC drug products.
    The agency does not believe that consumers should be denied the
benefits of the new labeling requirements simply because a product may
have both drug and cosmetic attributes. Moreover, under the approach
suggested by the comment, a manufacturer who markets a standard
sunscreen product for sunscreen (i.e., ``drug'') uses and for
moisturizing (i.e., ``cosmetic'') uses, would not be required to follow
the new labeling requirements, while a manufacturer whose product is
marketed solely as a sunscreen would be required to follow those
requirements. Both products, nevertheless, are regarded as drug
products and share the intended use of sunburn prevention. The agency
is concerned that consumers may be unneccessarily confused if the rule
would allow these products to bear markedly different labeling.
    The agency also disagrees with the comment that products without
dosage limitations do not raise safety issues and, therefore, the
agency lacks a rational basis for applying the new labeling
requirements to such products. While the agency takes steps to ensure
that all OTC drug products are safe for their intended uses, adverse
reactions do occur in the categories of products for which a blanket
exemption has been requested. For example, certain sunscreen
ingredients have the potential to cause photo allergenicity; certain
antidandruff ingredients may promote sunburn or cause even more serious
events if used for prolonged applications; and fluoride-containing
preparations may contribute to fluorosis or may cause acute symptoms in
overdose ingestions. Thus, even products that do not require discrete
dosage limitations contain ingredients that raise safety risks which
the labeling must convey to the consumer.
    The agency also disagrees with the suggestion that the required
labeling in such products consists of nothing more than ``general
common-sense limitations'' such as ``if condition persists, consult a
health professional'' or ``if a rash develops, stop use.'' For example,
a number of acne medications (which are marketed for both drug and
cosmetic uses) contain important warnings for persons who are sensitive
to or have a known allergy to salicylic acid. Dandruff products that
contain coal tar likewise must bear important drug-drug and sunburn
warnings (see 21 CFR 358.750). In any case, the agency does not accept
the argument that ``common-sense'' precautions need not be prominent
and readable. However, the agency will continue to consider whether
required labeling for these products can be simplified and condensed
even more.
    The agency has an ample factual record, discussed elsewhere in this
document and in the proposed rule, to support the conclusion that
current labeling conventions are inadequate. The act requires readable
and understandable labeling, irrespective of a specific showing of
harm. The agency endeavors to require the least amount of information
possible to assure proper self-selection and use. Nevertheless, the
information the agency does require under the act must be prominently
and conspicuously displayed (section 502(c) of the act) and must be
readable and understandable to ensure that all material facts are
provided to consumers (sections 201(n) and 502(a) of the act).
Moreover, improved labeling is needed not only to address potential
safety issues, but also to ensure selection of the most appropriate
product and use of that product in an effective manner.
    With respect to whether sunscreen ingredient names have little
meaning to consumers, the same argument can currently be made for many
OTC drug active ingredients. The new format requires prominent listing
of the active ingredients for all products, together with the purpose
of each active ingredient. The agency believes that this element of the
new format will improve consumer understanding of the names and
purposes of active drug ingredients, including those typically used in
sunscreens. This will assist the consumer and pharmacist in identifying
changes in formulation (and purpose) of many combination OTC drug
products so that medication errors can be avoided and consumers can
appropriately self-select an OTC drug product for their condition(s).
    The agency also emphasizes that with drug-cosmetic products, self-
selection is

[[Page 13270]]

very important because consumers often must choose between a cosmetic
or a drug-cosmetic product. A consumer who has dandruff should select
an antidandruff-conditioner shampoo rather than a conditioner shampoo;
a consumer who wishes to prevent sunburn should select a sunscreen-
moisturizer rather than a moisturizer; a consumer who perspires heavily
should select an antiperspirant-deodorant rather than a deodorant; a
consumer who needs to prevent caries should select a fluoride
toothpaste rather than a nonfluoride toothpaste. This final rule
provides a format for presenting information that will allow consumers
to readily distinguish among seemingly similar products and to readily
access important drug information.
    The agency agrees that there may be limited instances in which a
labeling requirement may discourage manufacturers from marketing
certain products for a drug use (e.g., lipsticks containing sunscreens
or lip balms containing skin protectant ingredients). These products,
when they contain an ingredient intended to provide a therapeutic
effect, do provide significant public health benefits to consumers.
    When developing drug labeling, the agency considers the risks and
benefits of the drug, the intended use, and the need to communicate
limitations or restrictions about the use of the product to the target
population. The quantity and complexity of information which must be
communicated to ensure appropriate product selection, convey the
effectiveness of the drug, communicate risks, and provide complete
directions for use, varies with the drug ingredient, the target
population, the disease or symptoms the product is intended to treat or
prevent, and related information about the conditions which must be
provided for the safe and effective use of the drug.
    In some cases (e.g., lipsticks or lip balms containing sunscreen),
minimal information is needed for the safe and effective use of the
product. Such products may typically be packaged in small amounts, have
a high therapeutic index, carry extremely low risk in actual consumer
use situations, provide a favorable public health benefit, require no
specified dosage limitation, and require few specific warnings and no
general warnings (e.g., pregnancy or overdose warnings). The agency
will identify products with these characteristics and will consider
appropriate exemptions in their respective monographs and drug
marketing applications to the extent possible. In addition, under new
Sec. 201.66(e), FDA, on its own initiative, or in response to a written
request from any manufacturer, packer, or distributer, may exempt or
defer one or more specific requirements set forth in Sec. 201.66 (a)
through (d).
    36. One comment noted that OTC drug product labeling varies among
different countries, particularly for products that are considered
drug-cosmetics in the United States but are regulated as cosmetics in
other countries. The comment contended that these variations make it
difficult to label products intended to be sold in more than one
country. The comment pointed out that FDA is increasingly focused on
international harmonization as a matter of policy. However, requiring
products to meet the new OTC labeling content and format requirements
represents a barrier to trade and harmonization. Another comment
requested that FDA exempt OTC drug products intended for export from
the new labeling requirements.
    The agency disagrees with these comments. As discussed, sound
public policy and the dictates of the act require that drug-cosmetic
products present readable, understandable, prominent, and conspicuous
drug labeling. With respect to export issues, section 802 of the act
(21 U.S.C. 382) sets forth those instances in which exported drug
products are not required to be labeled in accordance with the
requirements for domestic marketing. The agency notes that an OTC drug
product exported in accordance with section 802 of the act would not be
required to meet labeling requirements for domestic marketing (such as
the requirements imposed by this rule), except to the extent that the
import country itself has adopted U.S. requirements (see section
802(b)(1) and (f) of the act).

F. Interchangeable and Connecting Terms (Secs. 201.66(f) and 330.1(i)
and (j))

    Section 201.66(f) permits specific terms codified in Sec. 330.1(i)
(``interchangeable terms'') to be used interchangeably in the labeling
of OTC drug products, provided such use does not alter the meaning of
labeling established in an applicable OTC drug monograph or regulation.
Section 201.66(f) also permits the terms listed in Sec. 330.1(j)
(``connecting terms'') to be deleted from the labeling of OTC drug
products, provided again that such deletion does not alter the meaning
of established labeling. However, the title, headings, and subheadings
listed in Sec. 201.66(c)(1) through (c)(9) cannot be changed through
the use of interchangeable or connecting terms.
    Proposed Sec. 330.1(i) has been modified in the final rule to
include 43 additional interchangeable terms. In addition, two of the
proposed terms were combined and seven others were modified slightly in
this final rule. (See Sec. 330.1(i)(12), (i)(16), (i)(48), (i)(49),
(i)(52), (i)(54), (i)(68), (i)(69), and (i)(72).)
    Although the agency specifically sought recommendations on
additional connecting terms that should be added to the list (62 FR
9024 at 9039), no terms were submitted. Proposed Sec. 330.1(k) has been
redesignated as Sec. 330.1(j) in this final rule and modified to
include seven additional connecting terms based on further analysis of
OTC drug monograph labeling. The agency recognizes that there may be
other connecting terms that can be deleted and that will help required
statements and clauses fit into the new format. The agency encourages
manufacturers, packers, and distributors to submit these terms to the
agency as soon as possible so this list can be further amended before
the implementation dates for this final rule.
    37. One comment requested that an interchangeable term be added to
accommodate products intended for use only in children under 12 years
of age, because the information should be directed to the child's
guardian or care giver.
    The agency agrees that for products intended for use only in
children under 12 years of age the information should be directed to a
care giver, rather than to the child. Accordingly, for such products,
the term ``the child'' may be interchanged with ``you'' or the term
``the child's'' may be interchanged with ``your.''

G. Liable to Regulatory Action (Sec. 201.66(g))

    Section 201.66(g) states that an OTC drug product that is not in
compliance with the format and content requirements is subject to
regulatory action. The wording in Sec. 201.66(g) of the final rule is
changed slightly from the proposal, but the meaning remains the same.

H. Flexibility for Uses (Sec. 330.1(c)(2))

    Section 330.1(c)(2) retains flexibility of labeling for the OTC
drug product's ``Uses'' section by allowing alternative truthful and
nonmisleading statements describing those indications for use that have
been established in an applicable OTC drug monograph. The agency,
however, is shortening and simplifying the previous labeling
requirements in Sec. 330.1(c)(2). This reflects the decision to require
the title ``Drug Facts'' and the boxed or similar enclosure format for
all OTC drug products, in place of the ``Approved Uses'' or ``Approved
Indications'' title and format. The

[[Page 13271]]

agency is consolidating into a new Sec. 330.1(c)(2) the ``exact
language'' requirement currently in Sec. 330.1(c)(2)(vi) for language
(other than indications) established and identified by quotation marks
in an applicable OTC drug monograph or by regulation (e.g.,
Sec. 201.63), except as provided in Sec. 330.1(i) and (j). A number of
comments expressed their support for the existing flexibility policy,
which is being retained in this final rule.

I. Miscellaneous Comments

    38. Several comments requested that OTC drug product labeling
include information on: (1) When to take the drug, e.g., morning or
night, before or after meals; (2) whether the drug can be taken with
liquids; (3) whether analgesics or antibiotics interfere with
effectiveness; and (4) a warning to the elderly that a smaller dosage
may be needed. The comments argued that these facts should be in the
labeling because many consumers may not ask, and some health
professionals do not provide, this information.
    The agency notes that this information is currently included in OTC
drug product labeling when the information is known and when it is
considered to be necessary for the safe and effective use of the
product. For example, labeling for an OTC drug product containing
naproxen sodium includes information on how to reduce the dosage for
the elderly. The labeling for acid reducer products indicates how the
drug should be taken in relation to foods or beverages. In addition,
the warnings section for OTC analgesic products must indicate when
particular drinks (e.g., alcohol) or substances (e.g., caffeine) should
be avoided while taking these products.
    39. Several comments recommended that OTC drug product labeling
should state how long a drug remains in the body.
    The agency believes that information about how long a drug remains
in the body is important. However, it is difficult to state the actual
time that a drug remains in the body in terms meaningful to consumers
because of the variability of metabolism in individuals and because the
time may vary depending on whether the drug is taken with or without
food. Instead, when known and when relevant, the agency requires
labeling that tells consumers when to redose, the maximum number of
doses to take per day, and which drugs or foods to avoid to obtain
maximum effectiveness and safety in the use of their OTC drug products.
    40. Several manufacturers requested that FDA allow voluntary
warnings to appear under the appropriate headings to further protect
consumers from possible misuse of the product. Otherwise, placement of
such information outside of the headings could create the impression
that these warnings are less or more important than the required
warnings.
    The agency encourages manufacturers to discuss with the agency the
addition of voluntary warnings to OTC drug products. As a general
matter, FDA agrees that consumers may be confused if an appropriate
warning were placed outside of the Drug Facts area. Thus, the agency
expects such warnings to appear under the ``Warnings'' heading,
preceded by an appropriate subheading.
    41. In the proposed rule, the agency invited comment on whether
current regulations should be revised to require expiration dating to
appear in a specific location with specific legibility requirements on
both the outer and immediate container packaging, especially for
products marketed in tubes (62 FR 9024 at 9035 to 9036) as requested by
a citizen petition (Ref. 12).
    The agency evaluated the petition and concluded in a letter dated
April 22, 1997 (Ref. 13) that the expiration date should be readily
seen under usual and customary circumstances but did not require that
it be placed in a specific location in the labeling. Comments to the
proposed rule provided no new information for the agency to revise this
conclusion.
    42. Several comments were uncertain about whether the proposed rule
would affect the PDP. This final rule does not affect the PDP
requirements set forth in Sec. 201.60, and 21 CFR 201.61 and 201.62.
    43. Several comments requested that products with multilingual or
braille labeling be exempted from the requirements of the final rule
because space is not available on these labels to follow the
requirements.
    Current regulations (21 CFR 201.15) set forth the requirements for
using foreign languages in labels and labeling. (Although analogous to
multilingual labeling, braille is not specifically addressed in current
regulations.) The regulations provide that ``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: * * * The use of label space for any
representation in a foreign language.'' When multilingual or braille
labeling is used, the agency considers it important that all labeling
on the package be readable and understandable because it is not known
which language the purchaser will use. Therefore, the agency will not
categorically exempt multilingual or braille labeling from the new
format.
    44. Several comments recommended that the agency continue to permit
voluntary use of symbols or pictograms in addition to required warning
language. Some stated that symbols and pictograms may confuse consumers
because they may have different meanings for different people. One
comment recommended that if pictograms are used, USP pictograms should
be adopted.
    The use of symbols and pictograms will remain voluntary, provided
their use is not a substitute for required OTC drug product labeling.
In addition, a symbol or pictogram that directs attention away from
required information, or one that is ambiguous or can be misunderstood
by consumers, may render the product misbranded. The agency is allowing
voluntary use of a telephone or telephone receiver in
Sec. 201.66(c)(9).
    45. One comment recommended field testing new OTC drug labels to:
(1) Assist in the development of criteria that define good OTC drug
labeling; and (2) confirm, with representative consumer groups, that
the new labels are readable, understandable, and cause the desired drug
use behavior.
    The agency agrees. Over the past several years, the agency has
approved OTC drug product labeling, similar to the format required in
this final rule, for new drugs that have moved from prescription to OTC
marketing status. This labeling often is field tested by manufacturers
under OTC usage conditions, and is presented to the agency in
supplemental ``switch'' applications. The agency has incorporated in
this rule content and format elements that have emerged through that
process. Studies A and B (see section III.A and B of this document)
also involved field testing which led to refinements of earlier
labeling prototypes.

J. Reporting Requirements

    Products that are marketed under an OTC drug monograph are not
required to submit labeling to the agency for preapproval. However, if
manufacturers have questions about how to implement the new
requirements, they are encouraged to seek FDA guidance from the
Division of OTC Drug Products.
    Labeling changes to an OTC drug product marketed under a NDA or
ANDA must be made in accordance with Sec. 314.70 (21 CFR 314.70).
Manufacturers of these products are also encouraged to seek agency
guidance.
    46. The agency specifically requested comment on whether labeling
changes

[[Page 13272]]

required by the rule, for products marketed under approved
applications, should be made under Sec. 314.70(b), (c), or (d), and
whether these changes should require agency preapproval (62 FR 9024 at
9042).
    Several comments stated that the changes should be considered
``editorial'' or ``minor.'' The comments contended that the rulemaking
itself takes the place of approving product-specific supplements, and
that the filing of a supplement would impose an unnecessary burden. One
comment favored preapproval supplements as the appropriate mechanism,
because close collaboration between the agency and drug sponsors will
be needed to ensure that final OTC drug product labeling meets the
requirements of the new rule. Another comment argued that the
appropriate process under Sec. 314.70 would vary from product to
product depending upon the nature and extent of the changes needed.
    The agency agrees that it should not single out one process because
the nature and extent of the changes needed to conform to the new
format and content labeling requirements will vary depending on the
product class and uses. The agency expects, however, that the majority
of the changes required by this final rule can be submitted under
Sec. 314.70(d)(3). Section 314.70(d)(3) would cover any labeling
changes that precisely follow Sec. 201.66(c) and (d) and that require
editorial changes specified in Sec. 330.1(i) or (j). All other labeling
changes would be submitted under Sec. 314.70(b)(3) or (c)(2), as
appropriate. However, most changes to required content beyond those
specified in Sec. 330.1(i) or (j) are expected to require preapproval
under Sec. 314.70(b).

K. Implementation Plan

    47. Several comments urged that the time allowed for implementation
of a final regulation on OTC drug labeling be extended to 3 years, with
one comment urging an extension to 4 years. The comments argued that
the number of product lines and stock keeping units (SKU's) involved
creates a tremendous workload, especially in the case of private label
manufacturers who may have to change hundreds of labels and must obtain
approval of changes from their clients. One comment presented data
intended to show that incremental costs to comply with a final rule in
2 years would be $140 million but would drop by half to only $70
million for a 3-year implementation date. No cost data were presented
for a 4-year implementation date.
    The final implementation plan, set forth in section V of this
document, generally retains a 2-year implementation period for
currently marketed products that are the subject of final monographs or
approved drug applications. An additional year is allowed for low
volume products. The economic basis for retaining this implementation
plan is discussed in section VIII of this document. In addition, an
outside date of 6 years from the effective date of this rule, or the
next major labeling revision (whether required or voluntary) after the
rule has been in effect for 2 years, whichever comes first, is set for
all marketed OTC drug products (except those marketed under final
monographs or approved drug applications) to comply with the new format
and content requirements.
    The plan is intended to minimize the economic burden on the
industry while providing consumers with the benefit of more readable
and understandable OTC drug product labeling at the earliest feasible
date. As discussed in section VIII of this document, this
implementation plan provides manufacturers with sufficient time to
design and print new labeling and to deplete existing stock. Products
that do not comply with the format and content requirements in this
final rule on or after the applicable implementation date may be
considered for regulatory action. The agency will review and, as
needed, initiate steps to revise existing statements of enforcement
policy to be consistent with this final rule document.

L. Preemption

    In the proposed rule, the agency tentatively concluded that State
and local laws that would establish different or additional format or
content requirements than those in the proposed rule should be
preempted (62 FR 9024 at 9041 to 9042). The agency is not finalizing
the proposed preemptions sections (proposed Sec. 201.66(h) and (i) as a
result of a recent amendment to the act under FDAMA.
    48. The agency received a significant number of comments supporting
the proposed preemptive effect of the labeling requirements. Several
comments suggested that the agency extend the scope of the preemption
and preempt State requirements on safety and efficacy, dosage form, and
packaging.
    Subsequent to the issuance of the proposed rule, Congress enacted
section 412(a) of FDAMA, which added to the act section 751 (21 U.S.C.
379r), titled ``National Uniformity for Nonprescription Drugs.''
Section 751(a) of the act provides that no State or political
subdivision of a State may establish or continue in effect any
``requirement'' that relates to a nonprescription drug that is
``different from or in addition to, or that is otherwise not identical
with'' a requirement under the act. A ``requirement'' that relates to a
nonprescription drug is defined in section 751(c)(2) of the act as
``any requirement relating to public information or any other form of
public communication relating to a warning of any kind for a drug.''
Similar to the preemption provision in the proposed rule, section
751(b) of the act establishes a process by which a State or political
subdivision may seek an exemption from the preemptive effect of section
751(a) of the act.
    Section 751 of the act also addresses the two issues on which FDA
had specifically requested comment, i.e., the preemptive effect of the
proposed OTC drug product labeling requirements on product liability
lawsuits and the preemptive effect of the proposed labeling
requirements on State initiatives such as California Proposition 65. On
the issue of product liability suits, section 751(e) of the act states
that ``[n]othing in [section 751] shall be construed to modify or
otherwise affect any action or the liability of any person under the
product liability law of any State.'' On the issue of whether the
proposed labeling requirements preempt State initiatives, section
751(d)(2) of the act specifically provides that the national uniformity
requirements in section 751 ``shall not apply to a State requirement
adopted by a State public initiative or referendum enacted prior to
September 1, 1997.''
    This amendment to the act supersedes the agency's proposed
regulation preempting State and local labeling requirements. The
agency, therefore, has removed the preemption provision from this final
rule and will, at this time, rely on the terms of the statute in
addressing preemption issues.

M. Comments on Studies A and B

    49. Two comments stated that it is generally accepted by industry
and by experts in label readability that a format that includes a
standard order of information, standard headings, bullet points, and
interchangeable terms is superior to the ``old'' format. However, the
comments maintained that the results of Studies A and B should be given
little or no weight in FDA's deliberations because these studies
covered only a small segment of all label readability issues.
    The agency agrees that a number of format variables can affect
readability,

[[Page 13273]]

and that Studies A and B did not evaluate all format variables that
affect readability. The agency has been mindful of the limitations of
these studies in its deliberations. Indeed, all of the significant
conclusions in this proceeding have been informed by data gathered from
a variety of sources. In addition to the two studies, the agency has
considered and relied upon information provided by comments,
information gathered from the leading literature on label design,
graphics, and readability, and information drawn from the agency's own
expertise in drug labeling.
    50. The comments requested that the agency provide an extension to
the comment period for Studies A and B. The comments also requested
that the agency provide its analyses of the studies for public comment.
    The agency provided two 45-day comment periods for these studies
(see section I of this document). In order to facilitate public
comment, the agency also made available in electronic format all of the
data collected for these studies, including full tabulations of the
data organized along key variables. The agency's summary analyses for
these studies are contained in this document and an expanded review
will be placed on file in the Dockets Management Branch (Ref. 14).
    In light of the opportunities for comment already provided on the
design and outcome of the studies, and the extent to which the agency
in the end relied on the studies, the agency disagrees that there is a
need for one more opportunity for comment.
    51. One comment stated that the data from Study A are irrelevant to
whether the proposed new OTC labeling is necessary for ``drug-cosmetic
products,'' because no such product was evaluated in the study. The
comment contended that consumer research concerning OTC analgesic and
cough-cold drug products is not relevant to drug-cosmetic products. The
comment urged the agency to undertake consumer research relevant to
drug-cosmetic labeling, taking into account the differences between OTC
drug products and OTC drug-cosmetic products.
    For several recent prescription-to-OTC switches of drug-cosmetic
products, the agency has observed labeling comprehension results
similar to that seen in Study A. The results of several of these
studies have been presented and discussed at open public advisory
committee meetings (e.g., Rogaine). Given this experience, the agency
believes that the findings from Study A can be applied to all OTC drug
products, including those marketed as drug-cosmetics.
    Study A evaluated the influence of label format, comparing the
existing style formats to the proposed new format. This comparison
demonstrated that the new format takes less time to read and helps
people make better product use decisions. This comparison also found
that consumers preferred the new format to the existing format. The
agency believes that these findings would not differ if the product
were marketed as a drug-cosmetic because the drug information would
appear in the ``Drug Facts'' labeling format (see also comment 35
section IV.E of this document).
    Study A also evaluated how the amount of information affected the
time it takes to find information needed to answer specific questions.
This was done by examining two drug types, a three-ingredient cough-
cold product and a single-ingredient analgesic. The study demonstrated
that the greater the amount of information, the longer it takes to find
relevant information in the labeling. Again, although a drug-cosmetic
was not evaluated in Study A, there is no reason to expect the results
to be different if the product were a multi-ingredient drug-cosmetic
versus a single ingredient drug-cosmetic.
    Finally, Study A evaluated the influence of highlighting, or
graphic design emphasis, on communication of important OTC drug product
labeling information. The results showed that more, compared to less,
highlighting helped participants make correct product use decisions
when there is a large amount of information in the labeling. Labeling
with more highlighting was also considered more useful. The agency
considers the use of highlighting equally applicable to drug-cosmetic
products that contain a large amount of information in the labeling.
    52. One comment maintained that Study B is flawed in design and
rationale because of its complexity and its intention to use consumer
preferences as indicators of important labeling elements. The comment
stated that the order of information should not be determined by
consumer preference.
    The agency carefully designed the protocol for Study B and
solicited public comment on the design prior to initiating the study.
The agency agrees, however, that consumer preference should not be the
sole determinant of labeling design or information (Ref. 15). Thus, the
final order and placement of label information in this rule is intended
to follow a logical decisionmaking process that assists the consumer in
the appropriate selection and use of OTC drug products.
    However, Study B clearly indicated that the presence of a title for
OTC labeling information was the most important factor in determining
preference rankings. Consumers are the ultimate users of the OTC drug
product labeling. They stated that they preferred the title because it
drew their attention to the required information and made the required
information appear more credible. The agency considers such unequivocal
consumer input very important and useful in the design of OTC drug
product labeling format.
    53. One comment stated that because inactive ingredients were not
included in Study B and because the terms for the active ingredients
were not authentic, there was no way to determine whether these
omissions or fabrications would have any impact on consumer label
preference.
    The agency used fabricated names for the active ingredients to
reduce the influence of preconceived knowledge about specific OTC drug
products. Because new drug ingredients are novel to consumers when
these products first enter the marketplace, use of novel names for
active ingredients would simulate this condition. The agency has no
reason to believe that not including inactive ingredients or using
fabricated names for the active ingredients influenced consumer
preference in Study B.

V. Final Implementation Plan

    The applicable implementation dates vary according to the
regulatory status of the product. Any product that does not comply with
this final rule as of the applicable implementation date may be
considered for regulatory action. The agency will review and, as
needed, initiate steps to revise existing statements of enforcement
policy to ensure consistency with this implementation plan.

A. Products in the OTC Drug Review

    Products marketed under final OTC drug monographs must comply with
this rule as of April 16, 2001. Products for which a final monograph
becomes effective on or after April 16, 1999, must comply with this
rule as of: (1) The applicable implementation date for that final
monograph, (2) the next major revision to any part of the label or
labeling after April 16, 2001, or (3) April 18, 2005, whichever occurs
first.
    Combination drug products in which all of the active ingredients
are the subject of a final monograph or monographs must comply with
this rule as of April 16, 2001. Combination

[[Page 13274]]

products in which one or more active ingredients are the subject of a
final monograph, and one or more ingredients are still under review as
of the effective date of this rule, must comply with this rule as of
the implementation date for the last applicable final monograph for the
combination, or as of April 16, 2001, whichever is earlier. Combination
products in which none of the active ingredients is the subject of a
final monograph or monographs as of the effective date of this rule,
must comply with this rule as of: (1) The implementation date of the
last applicable final monograph for the combination, (2) the next major
revision to any part of the label or labeling after April 16, 2001, or
(3) April 18, 2005, whichever comes first.

B. Products Marketed under NDA's and ANDA's

    Products that are the subject of an approved drug application (NDA
or ANDA) before April 16, 1999, must comply with this rule as of April
16, 2001. Products that become the subject of an approved marketing
application (NDA or ANDA) on or after April 16, 1999, must immediately
comply with this rule.

C. Additional Provisions

    Any OTC drug product not described in section V.A. and B of this
document must comply with this rule as of: (1) The next major revision
to any part of the label or labeling after April 16, 2001, or (2) April
18, 2005, whichever occurs first.
    Products (including combinations) marketed under a final OTC drug
monograph or monographs, or under an approved drug application (NDA or
ANDA), with annual sales of less than $25,000, must comply with this
rule as of April 16, 2002. This is intended to provide marketed
products with a low level of distribution an additional year to come
into compliance with this final rule.
    Finally, irrespective of the regulatory status of the product, the
agency strongly encourages all manufacturers, distributors, and packers
of OTC drug products to voluntarily implement the new content and
format requirements as soon as possible, particularly when existing
labeling is exhausted and relabeling would occur in the normal course
of business. The agency also encourages sponsors of products marketed
under NDA's and ANDA's to submit any required labeling supplements as
soon as possible, to ensure timely review.
    Provided below is a chart that summarizes the time periods within
which the various categories of marketed OTC drug products must be in
compliance with this final rule. Unless otherwise stated, all time
periods begin on the effective date of this final rule.

                                         Table 1.--Implementation Charts
----------------------------------------------------------------------------------------------------------------
                        Products                                               Time Periods
----------------------------------------------------------------------------------------------------------------
Single entity and combination products subject to drug   Within 2 years (or within 3 years if annual sales of
 marketing applications approved before April 16, 1999.   the product are less than $25,000).
----------------------------------------------------------------------------------------------------------------
Single entity and combination products subject to drug   Immediately upon approval of the application.
 marketing applications approved on or after April 16,
 1999.
----------------------------------------------------------------------------------------------------------------
Single entity products subject to an OTC drug monograph  Within 2 years (or within 3 years if annual sales of
 finalized before April 16, 1999.                         the product are less than $25,000).
----------------------------------------------------------------------------------------------------------------
Single entity products subject to an OTC drug monograph  Within the period specified in the final monograph.
 finalized on or after April 16, 1999.                    However, if a monograph has not been finalized as of
                                                          April 16, 2001, then the product must comply as of the
                                                          first major labeling revision after April 16, 2001 or
                                                          within 6 years, whichever occurs first.
----------------------------------------------------------------------------------------------------------------
Combination products subject to an OTC drug monograph    Within 2 years (or within 3 years if annual sales of
 or monographs in which all applicable monographs were    the product are less than $25,000).
 finalized before April 16, 1999.
----------------------------------------------------------------------------------------------------------------
Combination products subject to an OTC drug monograph    Within the period specified in the last applicable
 or monographs in which at least one applicable           monograph to be finalized, or within 2 years (or 3
 monograph was finalized before April 16, 1999 and at     years if annual sales of the product are less than
 least one applicable monograph was finalized on or       $25,000), whichever occurs first.
 after April 16, 1999.
----------------------------------------------------------------------------------------------------------------
Combination products subject to an OTC drug monograph    Within the period specified in the last applicable
 or monographs in which all applicable monographs are     monograph to be finalized. However, if the last
 finalized on or after April 16, 1999.                    monograph is not finalized as of April 16, 2001, then
                                                          the product must comply as of the first major labeling
                                                          revision after April 16, 2001 or within 6 years,
                                                          whichever occurs first.
----------------------------------------------------------------------------------------------------------------
All other single entity and combination OTC drug         If a monograph has not been finalized as of April 16,
 products (e.g., products in the OTC Drug Review that     2001, then the product must comply as of the first
 are not yet the subject of proposed OTC drug             major labeling revision after April 16, 2001 or within
 monographs).                                             6 years, whichever occurs first.
----------------------------------------------------------------------------------------------------------------

VI. The Paperwork Reduction Act of 1995

    This final rule contains information collections that are subject
to review by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title,
description, and respondent description of the information collection
provisions are shown below with an estimate of the annual reporting
burden. Included in the estimate is the time for reviewing
instructions, gathering and maintaining the data needed, and completing
and reviewing the collection of information.
    With respect to this collection of information, FDA invited
comments on: (1) Whether the proposed collection of information is
necessary for proper performance of FDA's functions, including whether
the information will

[[Page 13275]]

have practical utility; (2) the accuracy of FDA's estimate of the
burden of the proposed collection of information, including the
validity of the methodology and assumptions used; (3) ways to enhance
the quality, utility, and clarity of the information to be collected;
and (4) ways to minimize the burden of the collection of information on
respondents, including through the use of automated collection
techniques, when appropriate, and other forms of information
technology. FDA received no comments concerning the proposed burden
estimates of this rulemaking under the Paperwork Reduction Act of 1995
(62 FR 9024 at 9044).
    Regarding OMB's concerns about various label formats informing
consumers about purchasing and using OTC drug products in a manner that
will improve their health, FDA discussed this subject in the February
27, 1997 (62 FR 9024 at 9031) proposal. The agency points out that the
required label format (i.e., the order for the placement of
information) is modeled after the decisionmaking process consumers
would be expected to follow, and should follow, when selecting and
using OTC drug products. This new required labeling format should help
consumers to more efficiently and better use OTC drug products.
    OMB, in its notice of action did state that it wished to allow the
industry and the public to consider the notice of proposed rulemaking,
specifically its concerns about the utility of various label formats to
inform consumers about purchasing and using OTC drug products in a
manner that will improve their health. FDA has met with the industry on
numerous occasions over the past 4 years to discuss various aspects of
the new labeling formats and believes that the industry and public
sector has had ample opportunity to express their views and be aware of
the reporting burdens established by this final rule. Throughout the
preamble, the agency has addressed numerous comments received
concerning information collection. The agency adds that many
manufacturers of OTC drug products have begun on their own initiative
implementing the labeling format provided in this rule as part of their
routine labeling redesign practice.
    Title: Over-the-Counter Human Drugs; Final Rule for Labeling
Requirements.
    Description: FDA is amending its regulations governing labeling
requirements for human drug products to establish a standardized format
and standardized content requirements for the labeling of all marketed
OTC drug products. The rule requires that the outside container or
wrapper of the retail package (or the immediate container label if
there is no outside container or wrapper) of all OTC drug products
include uniform headings and subheadings, presented in a standardized
order, with minimum standards for type size and other graphical
features. FDA is issuing these requirements because it has determined
that the design and format of labeling information varies considerably
among OTC drug products and consumers may have difficulty reading and
understanding the information presented on OTC drug product labeling.
The rule is intended to enable consumers to better read and understand
OTC drug product labeling and to apply this information to the safe and
effective use of OTC drug products.
    FDA's legal authority to modify and simplify the manner in which
certain information is presented in OTC drug product labeling derives
from sections 201, 502, 503, 505, and 701 of the act. Regulating the
order, appearance, and format of OTC drug product labeling is
consistent with FDA's authority to ensure that drug labeling conveys
all material information to the consumer (sections 201(n) and 502(a) of
the act), and that labeling communicates this information in a manner
that is ``likely to be read and understood by the ordinary individual
under customary conditions of purchase and use'' (section 502(c) of the
act).
    FDA concludes that the labeling statements required under this rule
are not subject to review by the OMB because they are ``originally
supplied by the Federal government to the recipient for the purpose of
disclosure to the public'' (5 CFR 1320.3(c)(2)) and therefore do not
constitute a ``collection of information'' under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501 et seq.).
     Section 201.66 requires all OTC manufacturers to format labeling
as set forth in subsections (c) and (d). FDA has learned from the
industry that OTC manufacturers routinely redesign the labeling of OTC
products as part of their usual and customary business practice. This
rule provides varied timeframes for implementing the OTC labeling
requirements. Therefore, the majority of respondents will be able to
format OTC labeling in accordance with Sec. 201.66 as part of their
routine redesign practice, creating no additional paperwork or economic
burden. However, of the 39,310 SKU's currently marketed under a final
monograph, FDA has determined that approximately 32 percent, or 12,573
products, may necessitate labeling format changes sooner than provided
under their usual and customary practice of label redesign. FDA has
estimated that of the 400 respondents who produce OTC products,
including the 12,573 products described above, each may be required to
respond approximately 31.4 times to this rule outside of their usual
and customary practice. Each response is estimated to take, on the
average, 4 hours, for a total of 50,292 hours per year. This burden is
expected to be a one-time burden.
    Although the usual and customary practice of label redesign will
minimize the burden for the remainig 68 percent of SKU's currently
marketed, or 26,737 products, additional time may be necessary for each
company to make the format changes under this rule. FDA has estimated
that of the 400 respondents who produce OTC products, each may be
required to respond approximately 66.8 times to bring the 26,737
products into compliance with this rule. FDA estimates that for this
group, each response will take an average of 2.5 hours for a total of
66,842 hours. This is expected to be a one time burden. The chart
reflects this group on the second line.
    Section 201.66(c) and (d) will also trigger the requirement that
OTC manufacturers with approved or pending new drug applications
(NDA's) and abbreviated new drug applications (ANDA's) must submit to
FDA supplements and amendments regarding labeling changes under 21 CFR
314.60(a), Sec. 314.70, 21 CFR 314.96(a), and 21 CFR 314.97. In the
proposed rule, the agency attributed this paperwork burden to these
specific NDA and ANDA regulations. For the final rule, the agency has
redesignated the burden under Sec. 201.66(c) and (d). Based on its
records and experience, FDA estimates that approximately 61 respondents
hold applications (41 NDA holders and 20 ANDA holders) for which
supplements and amendments will be required. FDA expects that
approximately 522 submissions (350 to NDA's and 172 to ANDA's) will be
required regarding labeling changes under Sec. 201.66(c) and (d), which
averages to 8.5 submissions per respondent. Based on information and
experience, FDA further estimates that each submission will take an
average of 2 hours to prepare, for a total of 1,040 hours annually.
This burden is also expected to be a one-time burden.
    Under Sec. 201.66(e), respondents subject to this rule will be
required to submit requests in writing for exemptions and deferrals
from the specific requirements of Sec. 201.66. Based on its experience
with exemption and deferral requests under similar provisions, FDA
estimates that

[[Page 13276]]

approximately 16 percent of the total number of respondents, or 25
manufacturers, packers, or distributors, could be expected to submit
such requests on the average of one time per year. Such requests may
take an average 24 hours each for a total of 2,400 hours annually.
    The agency estimates that approximately 59,329 SKU's are moving
towards publication of a final monograph. The burden associated with
label reformatting for these products is not included below. The burden
below will be adjusted after these products become final.

                                  Table 2.--Estimated Annual Reporting Burden<SUP>1</SUP>
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               No. of       Frequency per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
201.66<SUP>2</SUP>                               400              31.43       12,573               4          50,292
201.66                                400              66.8        26,737               2.5        66,842
201.66(c) and (d)<SUP>2</SUP>                     61               8.5           522               2           1,044
201.66(e)                              25               4             100              24           2,400
Total                                                                                             120,578
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operation and maintenance costs associated with this collection of
  information.
\2\ One-time burden.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VIII. Analysis of Impacts

A. Background and Summary

    FDA has examined the impacts of the final rule under Executive
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act (2 U.S.C. 1501 et seq.). Executive Order
12866 directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Under the Regulatory
Flexibility Act, if a rule has a significant impact on a substantial
number of small entities, an agency must analyze regulatory options
that would minimize any significant impact of the rule on small
entities. Title II of the Unfunded Mandates Reform Act requires that
agencies prepare a written assessment and economic analysis before
proposing any rule that may result in an expenditure in any 1 year by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100 million (adjusted annually for inflation).
    The agency believes that this final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The final rule is a significant regulatory action as defined by the
Executive Order due to the novel policy issues it raises. It is also an
economically significant regulatory action because of its substantial
benefits. With respect to the Regulatory Flexibility Act, the following
analysis constitutes the agency's Final Regulatory Flexibility
Analysis. Because the rule does not impose any mandates on State,
local, or tribal governments, or the private sector, that will result
in an expenditure in any 1 year of $100 million or more, FDA is not
required to perform a cost-benefit analysis according to the Unfunded
Mandates Reform Act.
    The standardized format and easier-to-read labels established by
this rule will have a positive effect on the nation's public health by
enhancing the ability of consumers to find, read, and understand
important safety and use information. The expected benefits of the rule
will include: (1) Improved drug effectiveness for labeled indications,
(2) reduced adverse drug reactions, and (3) more efficient consumer
search activities. The health benefits that will result from improved
drug effectiveness could not be quantified, but FDA believes that they
are substantial. With respect to the anticipated reduction in adverse
drug events, the agency finds that if the rule prevents just 5 percent
of the hospitalizations associated with the unintended consequences of
self-medication, the economic savings could be $39 million annually in
direct benefits and $52 million annually from indirect benefits. In
addition, by reducing consumer search time, the uniform format could
lead to consumer time savings valued at from $19 million to $38 million
per year. The total benefits of this rule range from $110.5 million to
$129.6 million per year.
    The costs of the product redesign and relabeling imposed by this
rule will be incurred by the manufacturers of OTC drug products. FDA
estimates that the required labeling redesign will cost about $19.4
million. In addition, the minimum print size and other format changes
will require a small percentage of products (estimated at 6.4 percent)
to increase the size of their label and/or package. These size-related
adjustments will add about $38 million in one-time costs and $11.5
million in annually recurring costs. Overall, therefore, the agency
estimates that the one-time costs of this rule will amount to about $58
million and the annual recurring costs about $11.5 million.

B. Benefits of Regulation

    The purpose of this final rule is to establish a standardized
format for the labeling of all OTC drug products so that the labeling
will be easier to read and understand, and will provide consistent
information in like situations. Thus, the final rule will enhance the
safe and effective use of OTC drug products by improving the ability of
consumers to find, read, and understand important safety and use
information. As discussed in section III.A of this document, the agency
conducted a study (Study A) to examine the influence on comprehension
of the new versus the previously used OTC labeling format. That study
supports the conclusion that the new format will take less time to read
and will help consumers make a greater number of correct product use
decisions when such decisions require a simple search for information
in the product labeling. The study found that individuals like a format
with strong visual cues and consider information easier to use when
presented in easy to read ``chunks.'' Especially when attention is
divided, individuals felt more confident in their ability to use such a
format.

[[Page 13277]]

    Both the variability and the presentation of existing OTC drug
product labeling make it difficult for consumers to select the most
appropriate OTC drug product and to use the product safely and
effectively. For consumers to gain the greatest benefit from these
products, relevant information must be easy to find, readable, readily
understood, noted, and acted upon. Despite the critical importance of
safety and use information, OTC drug product labeling is often printed
in small type with a crowded layout and minimal white space. Although
the OTC drug industry has developed voluntary labeling standards
encouraging a minimum 6-point type size, many OTC drug product labels
fail to meet this standard. Moreover, the placement of the information
varies, making it harder for consumers to find and compare similar
information on competing products.
    The revised labeling will produce at least three important
benefits: (1) The new label will enhance the therapeutic value of OTC
drug products by helping consumers select appropriate products and
adhere to proper dosage regimens; (2) consumers will find it easier to
avoid ingredients or products that in some circumstances cause adverse
events such as allergic reactions, adverse drug interactions, or other
unintended outcomes, ranging from minor discomfort to hospitalization;
and (3) consumers will increase the economic efficiency of their OTC
drug purchases by more quickly locating and identifying key elements of
product information, such as appropriate ingredients, uses, and
warnings.
1. Improved Product Selection and Use
    The number of consumers relying on self-diagnosis and self-
treatment has increased rapidly over the past decade, due in part to
the rising cost of health care and the increasing number of drug
products switched from prescription to OTC status. Consumers, however,
are faced with a growing number of choices for purchase decisions and
often find it difficult to determine the product that is best for their
particular condition. The absence of uniform and easily readable
product information complicates product comparisons and can result in
less than optimal health outcomes. Moreover, even informed product
selections can produce disappointing results if directions for use are
misread. Inappropriate product selections or illegible dosage
directions can postpone relief from aches or pains, or permit other
discomforts to persist longer than necessary. Study A suggests that the
standardized labeling format will reduce such incorrect product use
decisions. Although FDA cannot quantify the value of the health
improvements that would result, the agency is confident that the more
informed OTC drug selection and use produced by this rule will increase
consumer satisfaction and, at times, reduce health care costs for
additional or supplemental medications, doctor visits, and
hospitalizations.
2. Savings From Reduced Adverse Drug Reactions
    Although adverse events associated with some OTC drug products are
not systematically tracked and recorded, substantial documentation does
exist for the more serious events. Numerous studies in the literature
have documented drug-related hospitalizations (60 FR 44182 at 44232,
August 24, 1995). One comprehensive review of 36 articles focused
specifically on adverse drug reactions (ADR's) as the primary cause of
hospitalization. This study counted the number of events attributed to
the unintended consequences of drug therapy, excluding admissions due
to overdose, intentional poisoning, attempted suicides, drug abuse or
intoxication, and found that the percentage of hospitalizations due to
ADR's ranged from 0.2 to 22 percent, with a mean of 5.5 percent (Ref.
16). Of those studies that distinguished between prescription and OTC
drugs, the reported OTC share ranged from between 4 (Ref. 17) and 18
percent (Refs. 18 and 19). Thus, FDA estimates that unintended OTC
drug-related hospitalizations may account for about 0.55 percent (5.5
percent x 10 percent), or 170,500 of the nation's 31 million annual
hospital admissions. Investigators have determined that between 48 and
55 percent of all hospital admissions related to adverse reactions are
preventable (60 FR 44182 at 44232). (A recent study of in-hospital
adverse drug reactions also found that almost 50 percent were
preventable.) (Ref. 20). Consequently, on the assumption that 50
percent of the hospitalizations attributable to OTC drug adverse
reactions are preventable and that the cost of an average hospital stay
is $9,191 (Ref. 21), FDA finds that $784 million (170,500 x 50 percent
x $9,191) is spent annually on hospitalizations due to potentially
avoidable OTC drug ADR's.
    The realized benefits of the rule will depend on the degree to
which consumers are better able to read and understand OTC drug product
labeling and to act on that information to make choices that would
reduce drug side effects, drug interactions, allergic reactions, and
other unintended consequences of self-medicating. If the improved
labeling format and larger print size contributed to the avoidance of
only 5 percent of these hospitalizations, the economic savings would
amount to $39 million annually.
    The indirect benefits from reduced drug-related illnesses include
avoided costs due to lost work time or reduced productivity. Roughly 58
percent of adverse drug reaction admissions were for patients aged 20
to 59. The remaining 42 percent of admissions were for patients under
20 years (<10 percent) and over 59 years old (Refs. 17, 18, and 22). To
calculate productivity losses, the agency assumed 56 hours per
admission for the patients aged 20 to 59 years (40 hours of lost work
per hospitalization plus 16 additional hours for recovery and followup
doctor visits) and 14 hours for the remaining group (to account for
lost volunteer time or for time away from work for the care givers of
dependent patients). Using the average hourly production workers
earnings plus 30 percent for fringe benefits of $15.96, the estimated
value of lost productivity is $44.2 million patients for aged 20 to 60
and $8 million for the remaining patients or their care givers (Ref.
23). These estimates may somewhat overstate the value of lost
productivity for the 20 to 59 age group because all patients are
assumed to be employed. On the other hand, indirect benefits for the
remaining age groups are understated because many of these patients are
in the workforce and for those who are not, data are inadequate to
measure their contribution to society.
    Although less severe adverse incidents have not been systematically
tracked and recorded, they likely occur frequently, as over 5 billion
OTC drug products are purchased annually. The crowded format and small
print size found on many of these products obscures important
directions and warnings that might otherwise be heeded by consumers.
For example, certain OTC drug products contain warnings about not
driving or operating heavy equipment when using those products. Some
consumers inadvertently overdose because they are unaware that a
particular ingredient was also contained in a multi-symptom product. In
the case of combination products with multiple active ingredients,
especially in the cough/cold category, consumers often treat symptoms
that are not present, raising the likelihood of an adverse drug event.
The new label format will establish a consistent order of presentation
and group similar information (such as ingredients, warnings, and
directions) together under relevant headings so that

[[Page 13278]]

it will be easier for consumers to find and read this information, thus
helping to reduce the number of adverse event occurrences.
3. Savings From More Efficient Product Search
    By facilitating product comparisons, easier-to-read labeling will
reduce those suboptimal purchases that result from inappropriate price-
quality relationships and competitive inefficiencies. For example, the
uniform format will reduce consumer search and transaction costs,
because all products will display information in the same order. In
turn, consumers will find it easier to purchase more economical items
by comparing products with similar ingredients and uses. Although FDA
could not assign an economic value to this expected efficiency gain,
Study A found that the time required to read the complete safety and
use information in the proposed format was reduced by a statistically
significant 10 seconds compared to traditional formats. The total time
saved searching for specific information components, such as
ingredients and their therapeutic benefits, or for conducting product
comparisons, should be even greater at the point of purchase.
    According to A.C. Nielsen (Nielsen), a recognized provider of
market research business information and analysis, consumers purchased
5.6 billion units of OTC drug products in 1995. (This figure excludes
dandruff shampoos and facial makeup and lipstick with sunscreen.) If 10
percent of these purchases represent first time or annual evaluations
of purchase decisions, 0.6 billion product decisions are made annually.
If consumers save only the reported 10 seconds per purchase decision,
they would save 1.6 million hours annually. Using 1997 average hourly
production worker earnings of $12.28, the approximate economic value of
this time savings is $19.1 million per year (Ref. 23). If consumers
compare two products, the additional time could double, with a value of
$38 million per year.
4. Summary of Expected Benefits
    In summary, FDA expects revised OTC drug product labeling to
generate substantial benefits, many of which the agency could not
quantify. While the majority of the costs attributed to this rule are
one-time costs associated with labeling redesign and packaging
reconfiguration, the benefits from improved labeling will accrue
annually. Better informed product selection and use will raise the
likelihood that OTC drugs will produce desired health outcomes. The
standardized format and easier-to-read labeling is expected to reduce
the number of ADR's associated with OTC drug products. A 5 percent
decrease, for example, would reduce annual hospital costs by about $39
million and reduce annual productivity losses by $59 million. Finally,
FDA expects that easier-to-read information will lead to more efficient
marketing transactions, because product and price comparisons will be
simpler and faster, permitting consumers to obtain comparable results
in less time. The value of the reduced search time could range from $19
to $38 million annually. The total benefits of this rule range from
$110 million to $129 million annually.

C. Costs of Regulation

    For its analysis of the proposed rule, FDA determined that the cost
of revising labeling for thousands of OTC drug products would be
substantial, involving numerous levels of review and verification, in
addition to extensive graphic redesign. The agency found, however, that
regulatory costs would be moderated by the standard business practice
of periodic redesign. Because a majority of the labeling would undergo
design changes even in the absence of a new rule, FDA estimated the
costs of redesign by counting only the value of the label-years that
would be lost, after adjusting for the length of the traditional
labeling cycle. The regulatory cost was calculated as the product of
the number of SKU's, which are the individual products, packages, and
sizes affected; the number of years of labeling life lost; and the
value of each year of labeling life lost (see 62 FR 9024 at 9045
through 9049). As explained below, upon review of the comments, FDA has
concluded that its methodology for estimating the cost of a labeling
change was sound. The agency has, however, refined its earlier cost
estimates, based on the comments and other supplemental information,
and has added costs for increasing the size of certain packages and
labeling.
1. Number of Products Affected
    Once the rule is fully effective, a new OTC drug product labeling
design will be required for each SKU. For its initial analysis, FDA
based its estimate of the size of the affected OTC drug market on data
from Nielsen. According to Nielsen, OTC drug products in 1995 accounted
for $18.7 billion in sales in grocery stores, drug stores, and mass
merchandise outlets. FDA allocated the products in Nielsen's inventory
into review categories based on their monograph review status. This
categorization indicated that almost 30,000 brand name SKU's were
regulated under the OTC drug monograph review process. The breakdown of
these branded SKU's by monograph review status showed: 10,910 under a
final monograph (including products switched from prescription to OTC
status), 8,241 scheduled to become final before this final rule, and
the remaining 8,488 scheduled to become final after this final rule is
published. (The latter figure was subject to greater uncertainty
because of incomplete coverage of products with sunscreens in the
Nielsen data base.) (See Table 3 of this document.)

                            Table 3.--Number of Estimated SKU's by Regulatory Status
----------------------------------------------------------------------------------------------------------------
                                                          Brand name            Private              Total
----------------------------------------------------------------------------------------------------------------
Marketed under final monograph                             10,910              28,400              39,310
Under review, scheduled for final monograph                 8,241              21,300              29,541
Remaining                                                   8,488              21,300              29,788
Total                                                      27,639              71,000              98,639
----------------------------------------------------------------------------------------------------------------

    Because the Nielsen data base did not break out SKU's for private
label store brands, FDA estimated the number of private label SKU's
using data on the number of retail chains likely to market private
label brands (Ref. 24) and Nielsen data on the average number of SKU's
carried by firms that relabel generic OTC drug products. The agency
estimated 71,000 private label SKU's (62 FR 9024 at 9046 to 9047) and
assumed the same regulatory status distribution as for branded SKU's.
    While this rule will ultimately affect all OTC drug products, the
implementation dates for the labeling changes will vary according to
the

[[Page 13279]]

regulatory status of the product. For its analysis of the proposed
rule, FDA assumed that products currently covered by a final OTC drug
monograph or marketing application, or about 39,310 SKU's, would incur
labeling design costs. A second group of up to 29,541 SKU's was thought
to be potentially affected, depending on the timing of the publication
of their final OTC drug monographs. The agency assumed that monographs
for the remaining 29,788 SKU's would become final only after
publication of the final rule. Because products marketed under this
latter group of OTC drug monographs would require labeling changes
regardless of the final rule, no design-related costs were assigned to
this group of products. Although FDA received no comments questioning
this SKU allocation, the agency has now determined that the 29,541
SKU's in the review category will not be finalized before this rule is
published. As a result, only those 39,310 SKU's currently covered by
final OTC drug monographs are expected to incur incremental labeling
design costs.
2. Original Agency Estimate
    a. Cost of labeling redesign. FDA's previous analysis (62 FR 9024
at 9045 to 9049) found that redesign cost estimates varied from $2,700
to $10,000 per SKU for branded products and from $500 to $1,500 per SKU
for private label products. These costs included the drafting of
language, art work, review, and implementation and generally included
redesign of the PDP. FDA assumed that the PDP accounted for 50 percent
of the cost to redesign branded product labeling and reduced the
estimated redesign costs by one-half, on the presumption that the rule
would not affect the PDP. To derive an average cost, the agency
weighted the affected share of private label and branded SKU's at 80
and 20 percent, respectively, based on FDA's estimate of 71,000 private
label SKU's and an analysis of Nielsen sales data covering the
remaining 27,639 branded SKU's. Because the analysis found that a
substantial proportion of the branded products were regional and/or low
sales volume items, FDA assumed that the redesign costs for regional
and low sales volume branded products would be similar to that for
private label products. Using the midpoints of the cost ranges, and
reducing the cost for branded products by 50 percent to account for the
PDP adjustment, the analysis calculated an average redesign cost of
$1,500 per SKU. However, as described in section VIII.E.3 of this
document, based on additional information, the agency's final analysis
eliminates the PDP adjustment.
    b. Methodology. The agency's assessment of the proposed rule found
that frequent labeling redesigns are recognized as a cost of doing
business in the OTC drug industry. Thus, labeling that would normally
be redesigned within the implementation period was assumed to incur no
additional costs. To represent the distribution of typical labeling
replacement intervals, the agency had estimated that the labeling for
20 percent of the affected SKU's would be redesigned at least every 2
years, 40 percent every 3 years, and 40 percent every 6 years. Both the
number of OTC drug products requiring redesign and the market value of
the labeling were assumed to be evenly distributed over their labeling
lifetimes. That is, for labeling with a 6-year lifetime, one-sixth
would be redesigned in year 1, one-sixth in year 2, and so on. FDA then
measured the economic cost of the proposed labeling redesign
requirement as the lost value of the remaining life-years of the
existing labeling designs. For example, given a 2-year phase-in period,
product labeling with a remaining 3-year lifetime would lose the value
of 1 year of labeling-life.\1\
---------------------------------------------------------------------------

    \1\ Mathematically, the following formula was used to calculate
the costs:
    Cost<INF>yx</INF> = <greek-S>jN<INF>x</INF>A<INF>x</INF>(1/x),
where j = 1 to (x-y)
    Total Cost<INF>y</INF> = Cost<INF>y6</INF> + Cost<INF>y3</INF> +
Cost<INF>y2</INF>
    where:
    x = life of labeling in years (2, 3, or 6),
    y = implementation period in years,
    N<INF>x</INF> = number of SKU's with labeling life of x years,
and
    A<INF>x</INF> = amortized annual value of labeling with a life
of x years.
    (A<INF>x</INF> is equivalent to the annuity value to pay off an
initial investment, i.e., A<INF>x</INF> = C x { I / [1 - (1/ (1 +
I)<SUP>x</SUP>)]}; where C = the average weighted cost to redesign a
labeling ($1,500); I = the discount rate (7%); and x = the life of a
labeling in years (2, 3, or 6).)
---------------------------------------------------------------------------

    FDA found that, with a 2-year implementation period, the cost of
the proposed requirements would be $19.7 million. To reduce the
economic impact on small entities, the agency proposed an additional 1
year extension for OTC drug products with sales of less than $25,000
per year. Based on the Nielsen data, this extension applied to about 40
percent of OTC drug products, but only about 1 percent of OTC drug
retail sales. With this added deferral, FDA estimated the cost of the
proposed rule at $14.2 million.
3. Response to Comments
    A number of comments from the OTC drug industry asserted that the
agency understated the cost of the proposed rule. These comments stated
that: (1) FDA's estimated average cost to redesign labeling was too
low, (2) FDA's methodology to calculate the economic impact of the
proposal was inappropriate, and (3) FDA incorrectly assumed that
package and label sizes would not need to be increased. The following
section addresses each of these issues while focusing primarily on the
comments and alternative economic analysis submitted by NDMA. Appendix
G of NDMA's comment provides a full description of its explanatory data
and methodology (Ref. 25).
    NDMA stated that the cost to comply with the proposed rule,
assuming a 2-year implementation period, would be a minimum of $140
million, even without changes to package and label sizes. NDMA
subsequently recommended the use of a net present value approach, which
reduced its cost estimate to $114 million. Further, FDA had proposed an
additional implementation year for SKU's with annual sales below
$25,000. This adjustment reduces NDMA's cost estimate (assuming no
package or label size changes) to $86 million, substantially less than
the originally stated $140 million figure, but still far above FDA's
estimate of $14.2 million.
    a. Cost of redesigning drug label. NDMA agreed that FDA
``approached the very complex task of assessing the economic costs
resulting from the proposed rule in a rational, data-based manner'' and
that ``many of the parameters that FDA used as a basis to determine
label design costs were supported by reliable market research data.''
For example, NDMA accepted FDA estimates for both the number and life
cycle of the affected drug labels. Nevertheless, NDMA asserted that the
agency had understated the cost of redesigning a label for the
following reasons: (1) FDA's unit cost estimate was based on a small,
nonrandom sample; (2) FDA was incorrect in eliminating PDP redesign
from the cost of relabeling branded OTC drug products; and (3) FDA did
not consider either the cost of scrapping label inventory or the
administrative burden that would be incurred by firms in developing
compliance strategies.
    i. Unit cost estimate (without scrap). NDMA reports that it
developed a cost estimate by surveying 74 member firms regarding the
average cost of redesigning an OTC drug product label. The survey (Ref.
25) requested information on minor and major label changes. Thirty-four
firms responded, of which 31 were brand label manufacturers and 3 were
private label manufacturers. The reported cost per SKU to redesign a
label ranged from $500 to $420,000. Excluding three extreme outliers,

[[Page 13280]]

NDMA projected an average cost (omitting scrap) of $15,154 per SKU to
redesign a branded label and $1,261 for a private label. Assuming a 20/
80 market split for branded and private label products, NDMA calculated
a weighted average cost per SKU of $4,039, roughly double the earlier
FDA estimate (without a PDP adjustment) of $2,070.
    To validate its estimate, NDMA cited a cost model that had been
developed by the Research Triangle Institute (RTI) to estimate the
regulatory impact of the NLEA. The RTI model assumed that the cost of
changing a food product label was a function of administrative,
analytical, marketing, printing, and label inventory costs. Printing
costs depended on the type of printing process, the frequency of
redesign, the number of SKU's affected, the complexity of the label
changes, and the length of the compliance period (Ref. 26). NDMA
estimated, based on responses from 21 member firms, that about 50
percent of the industry's SKU's are printed using lithography, 47
percent by flexography, 1 percent by gravure, and the remaining by
other methods. Applying these proportions to the RTI model for complex
printing tasks with four or more color changes, NDMA derived a label
printing cost of $3,458 per SKU for an average OTC drug product and
concluded that this result verified its estimate of $4,039 per SKU
(without scrap).
    The agency agrees that the cost data used in FDA's economic
analysis of the proposed rule were not drawn from a random sample,
although they were supplied by sources familiar with the OTC drug
industry, including smaller and private label manufacturers. FDA notes,
however, that the survey underlying the NDMA cost estimates was
likewise not based on a random sample of manufacturers. While NDMA
member firms include a range of large, small, brand-label, and private-
label manufacturers, many smaller firms do not belong to NDMA. Indeed,
NDMA indicates that its 74 members (which may represent less than 20
percent of all OTC drug manufacturers), account for 90 to 95 percent of
all OTC drug sales. A survey limited to this membership necessarily
over-represents large manufacturers of nationally branded products and
under-represents smaller manufacturers of regionally branded products.
    Following review of the survey data provided by NDMA, FDA concludes
that NDMA's figures overstate the industry average cost of redesigning
OTC drug labels. For example, the survey reports unreasonably large
differentials between branded and private label manufacturers, with
survey costs for branded SKU's from 3 to 40 times greater than those
for private label SKU's. For graphics development (directions for
studio, draft/mock-ups, review, and concurrence), the average SKU cost
reported was $6,215 for branded and $291 for private label products.
Assuming an hourly wage rate of $40 for branded and private product
personnel, manufacturers of branded products spend 155 hours per SKU on
this function compared to 7 hours by private labelers. For separations
(color mock-ups created and reviewed), the survey reported the per SKU
cost for branded and private label companies at $3,210 and $82,
respectively, almost a 40-fold difference. The agency acknowledges that
large manufactures of nationally branded products involve more
personnel in decision making and may use higher quality packaging
materials. Nevertheless, in view of the substantial degree of market
competition in this industry, private labelers typically package goods
to resemble the competing national brand. Moreover, while questioning
the size of the reported range, FDA could not review the basis for
NDMA's estimates, because the supporting data, such as the number of
labor hours or labor costs used in its calculations, were not
submitted.
    Furthermore, while the proposed rule required manufacturers to
reformat the information panels, the NDMA survey instructed respondents
to include the cost of changing all labeling, including certain
promotional materials. Thus, some manufacturers may have reported costs
for developing new product identities, advertising campaigns, etc.
Also, survey respondents were asked to estimate the cost to redesign
only one SKU, which ignores both learning curve and economy of scale
effects. For the most part, the same industry personnel are responsible
for copy and layout decisions for numerous product lines and SKU's.
Moreover, FDA does not agree that the RTI model necessarily validates
NDMA's redesign cost estimate. The portion of the RTI model used by
NDMA was developed to estimate the cost of printing food labels, which
are often considerably larger than OTC drug labels.
    NDMA's recent estimate also differs from the average cost of $7,900
per SKU submitted by the Cosmetic, Toiletry, and Fragrance Association
to change a drug-cosmetic label (Ref. 27). OTC drug-cosmetics are
generally considered to have more expensive labeling than OTC drugs
alone, because they compete with other elaborately packaged cosmetic
products.
    To finalize its estimate of the average cost of redesigning an OTC
drug label, FDA considered several approaches. First, the agency
maintained its initial estimating methodology, but adjusted the
estimated unit cost per SKU. Based on all available information, FDA
concludes that the cost of redesigning nationally branded products
manufactured by large companies ranges from $5,000 to $15,000 per SKU.
The cost to redesign regional or low sales volume brands of smaller
manufacturers is considerably less, ranging from about $1,000 to $8,000
per SKU. The cost to redesign labels for private label brands is
smaller still, but approximates FDA's original estimate of $1,000 and
NDMA's survey estimate of $1,261 per SKU. Accordingly, to calculate a
final estimate, the agency divided OTC drug products into three
classes: (1) Branded products manufactured by large NDMA member
companies, with a midpoint cost estimate of $10,000 per SKU; (2)
branded products manufactured by smaller companies, with a mid-point
cost estimate of $4,500 per SKU; and (3) private label products,
assumed to cost $1,261 per SKU, as reported by NDMA.
    The agency used its original estimate of the SKU distribution,
which indicated that about 30 percent of all OTC drug SKU's are
branded, and the NDMA member survey to determine costing weights to
apply to each industry sector. Respondents to NDMA's survey reported
that they account for about 4,000 branded SKU's, which amount to 15
percent of all branded SKU's. As these survey respondents comprise
almost half of NDMA's membership, FDA assumed that branded products of
all NDMA members may account for about 30 percent of all branded SKU's,
or approximately 10 percent of all affected SKU's (30 percent branded x
30 percent NDMA members). The remaining branded products, therefore,
account for 20 percent of all affected SKU's, and the private label
products account for the remaining 70 percent. This calculation results
in a weighted average cost of $2,783 (without scrap) to redesign a
label (i.e., ($10,000 x 10 percent)+($4,500 x 20 percent)+($1,261 x 70
percent)), a figure higher than the prior FDA estimates but below the
NDMA survey estimate of $4,039.
    A second approach was developed by the Eastern Research Group, Inc.
(ERG), a private economics consulting firm under contract to FDA. ERG
developed its model based on data collected during site visits to
several large and small drug

[[Page 13281]]

companies and through discussions with other industry consultants (Ref.
28). ERG assumed a more complex distribution of various types of SKU's
among firms of different sizes and included specific cost variables for
regulatory affairs, art/graphics, manufacturing changes, and inventory
losses by firm size (by employment), firm type (branded or private
label), and type of label changed (carton, container, etc.). Under
ERG's model, the estimated weighted average cost of label redesign
(without scrap) is $1,210 per SKU (Ref. 28).
    Because the OTC industry is so diverse and the relevant cost data
are so limited, no single model or single estimate can be viewed as
definitive. Nevertheless, the agency continues to believe that its
overall approach represents a rational basis for estimating the
redesign costs associated with this rule. The agency in its proposed
analysis arrived at an estimate of $2,070 per SKU (without a PDP
adjustment). That figure, when revised to take into account certain
data from the NDMA survey, is increased to $2,783 per SKU. ERG employed
a more complex model and arrived at a figure of $1,210 (or half that of
FDA), while NDMA arrived at a weighted average of $4,039 (or twice that
of FDA). Given this spread, and given the agency's concerns about
NDMA's methodology and input data, the agency is adopting the revised
figure of $2,783 as its base average cost estimate. The agency
acknowledges that it has adopted a conservative figure, relative to
that derived by ERG. However, nothing in the ERG model, or in the NDMA
model, suggests that FDA should discard its methodology or its
assumptions for estimating unit costs.
    ii. Principal display panel. In its original analysis, FDA assumed
that the PDP need not be altered and therefore adjusted its unit cost
estimate for branded products downward by 50 percent. NDMA argued that
this correction was inappropriate as it failed to account for many
commonly used labeling and packaging configurations. NDMA pointed out
that, with the exception of labels with separate front and back panels,
all PDP's must be reprinted when the information panel is changed.
Based on a poll of 7-member companies, NDMA estimated that about 90
percent of all OTC drug SKU's require the PDP to be reprinted when
changes are made to the information panel.
    The fact that the PDP needs to be reprinted when the information
panel is changed does not mean that it has to be redesigned. For the
majority of labels, the PDP and information labeling are printed as a
single label, with one printing plate required for each of the colors
used. For many products, only one or two colors will be changed on the
information panel to accommodate the new requirements; consequently,
only those plates would need to be redesigned, the others could be
reused or simply copied at significantly reduced cost. Nevertheless,
the agency acknowledges that many manufacturers would, at the time of
redesigning the information panel, also make incremental changes to the
PDP. Therefore, the agency has adopted the NDMA position and eliminated
any downward PDP adjustment from its calculation of the cost of the
final rule.
    iii. Scrap. NDMA also argued that the cost of scrapping unused
inventory should be included as a regulatory cost. Based on its survey,
it estimated that scrap labeling inventory adds about $1,000 to the
weighted redesign cost per SKU ($2,968 per SKU for higher cost firms
and $576 per SKU for lower cost firms), raising its average unit cost
estimate to about $5,000. NDMA declared this a conservative estimate
that would underestimate the cost of scrap label inventory if the
implementation date were less than 2 years.
    FDA agrees that some scrap label inventory loss is inevitable when
label changes are made, but notes that the longer the implementation
period the easier it is for manufacturers to minimize the cost. The
final rule allows either a 2- or 3-year implementation phase (depending
on sales volume), which is sufficient time to minimize inventory
losses. Because the NDMA survey question failed to state the length of
the phase-in period, the survey response cannot be considered reliable.
Nonetheless, because a better estimate of the average scrap cost is not
available, FDA accepts NDMA's figures, but adjusts the weighting to 10
percent for the higher cost firms and 90 percent for the lower cost
firms, for a weighted average of $800. This weighting is based on the
assumption that both small brand name manufacturers and private label
manufacturers have less expensive labels and smaller inventories than
large brand-name companies. The consideration of scrap, therefore,
raises FDA's weighted average design cost estimate to approximately
$3,600 per SKU.
    iv. Administrative costs. NDMA suggested that the agency also
include administrative costs in its calculation of the cost to redesign
the label. NDMA provided no estimate of these costs, but noted that
there would be a burden to manufacturers to manage the additional
required redesign of labels.
    FDA agrees that the rule will impose administrative costs, but
concludes that these costs are adequately accounted for in the previous
estimates. OTC drugs are highly regulated products and manufacturers
are expected to have regulatory personnel on staff or consultants
available to address compliance matters. The complexity of the rule is
not unusual compared to other OTC drug regulations and the requirements
will be clear to graphics design and regulatory personnel. Moreover,
the rule is expected to receive widespread publicity when issued and
most OTC drug firms belong to trade associations or have access to
trade publications that provide additional sources of information.
Because the rule permits a 2- to 3-year implementation period, FDA
continues to believe that managing the label changes will not impose
burdens beyond the costs included in the agency's estimate.
    b. Methodology for calculating economic impact. NDMA disagreed with
the methodology the agency used to calculate the economic impact of the
proposed rule for two reasons: (1) FDA treated the cost to redesign as
a financed rather than an expensed cost and calculated the impact using
an amortized cost rather than a net present value, and (2) FDA treated
label redesign as an accelerated change rather than an additional
change.
    i. Economic versus accounting costs. NDMA asserted that FDA used an
incorrect valuation method to assess the economic impact of the rule,
because the agency's valuation of amortized lost label life incorrectly
implies that the costs of label redesign are financed costs, rather
than sunk costs expensed in the year they incur. According to NDMA, the
proper approach is not to amortize, but to calculate the net present
value of the incremental costs of label redesign.
    FDA does not agree that the amortization of lost label life is
inappropriate. Executive Order 12866 charges Federal agencies to
determine the economic cost of its rules, but such costs are not
necessarily identical to financial costs, as interpreted by accounting
convention. According to the U.S. Office of Management and Budget (Ref.
29), the preferred measure for economic analyses is ``the opportunity
cost' of the resources used or the benefits forgone as a result of the
regulatory action.'' Whether firms expense label design costs in the
year they occur is largely irrelevant to the proper calculation of
economic costs, i.e., the opportunity cost of the rule.

[[Page 13282]]

 Moreover, FDA's calculation yields results that are identical to those
obtained through a net present value approach. To derive its results,
FDA estimated a net present value and then, for ease of exposition,
converted this figure into an equivalent stream of annual costs.
    ii. Additive versus accelerated costs. The primary reason that
NDMA's methodology produces substantially higher costs than FDA's
estimate is that NDMA's approach assumes a ``market driven'' label
cycle that is independent of the design changes required by the rule.
For example, if the average lifetime of a particular label type is 3
years and a design change costs $3,000 per SKU, both FDA and NDMA agree
that a 2-year phase-in would allow two-thirds of the labels to be
replaced under normal business conditions without additional costs
(assuming no package size changes). FDA's methodology, however, also
assumed that the remaining one-third of the labels lose only 1-year of
their expected lifetime, so that the economic cost (ignoring any
discounting adjustment) would be $1,000 per SKU (1/3 x $3,000) for one-
third of these SKU's. This approach, however, implicitly assumes that
the label design cycle would resume at a 3-year interval, so that the
next voluntary label redesign, on average, would not occur until 3
years after the mandated change.
    In contrast, NDMA argues that voluntary label redesign occurs in
response to external ``market driven'' factors that would be
independent of this mandated change. According to NDMA, such redesigns
are to change product attribute copy; change graphics; add litigation-
driven warnings; delete ``new'' flags after 6 months; add multilingual
labeling; change labeling information, such as manufacturer,
distributor, or inactive ingredient; or add or change SKU's in a
product line. NDMA contends that, because the mandated changes required
by this rule would not affect the underlying ``market driven'' design
cycle, the full cost of the redesign, rather than just the value of the
remaining life of the former label, measures the economic cost of the
regulation.
    With respect to the previous numerical example, NDMA's methodology
implies that those labels that were redesigned in year 2 for regulatory
reasons would, on average, be redesigned again in year 3 for ``market
driven'' reasons. (FDA would assume that the labels that had to be
redesigned in year 2 would not, on average, be redesigned again until
year 5.) NDMA's methodology, therefore, would calculate the economic
cost at about $3,000 per affected SKU, compared to FDA's estimate of
about $1,000.
    The agency does not dispute the theoretical possibility of NDMA's
argument. If ``market driven'' reasons for label adjustments always
compelled an immediate response, companies could not coordinate
voluntary label updates with mandatory label redesign; the regulatory
cost for each affected label, therefore, would be the full cost of the
design change. However, FDA does not agree that such abrupt shifts in
marketing strategies are the industry norm. Many of the examples of
``market driven'' label changes NDMA cited are for exactly the kind of
incremental adjustments that would be deferred and consolidated in a
major redesign effort. For example, the demand for most changes to
product attribute copy or graphics mounts gradually in response to
shifting advertising and marketing styles. Once changed, such
modifications postpone the need for future change. Revisions for
litigation-driven warnings are less common events that would be
expected to have a small effect on industry averages. According to the
RTI study (Ref. 26), line copy changes or changes affecting just one
color are minor changes that, in most cases, are made without the
assistance of a label artist and cost one-sixth the cost of a four-or-
more color change. Such minor adjustments would not be expected to
alter the underlying design cycle.
    The agency finds it more likely that the demand for most major
label changes is a steadily increasing function of the time that has
elapsed since the last labeling revision and that manufacturers
continually refine marketing techniques and strategies. As most
companies will find it cost-effective to complete these incremental
labeling changes concurrently with the mandatory redesign required by
this rule, FDA's revised analysis maintains the assumption that the
current labeling change cycle will continue unaltered. Moreover, it is
important to note that the agency's decision not to exclude PDP design
costs is based on its finding that incremental style modifications
accompany mandated changes. If firms would not bundle incremental style
changes with the mandated changes, the PDP design costs should be
subtracted from the regulatory cost estimate.
    c. Cost of increasing size of packages and/or labels. Several
comments objected to FDA's assumption that the proposed rule would
require few changes to the size or configuration of OTC drug packages
or labels. NDMA reported that its survey indicated that 33 percent of
branded and 95 percent of private label SKU's could not accommodate the
proposed label format. NDMA estimated that exemption petitions would be
filed for 33,500 SKU's, that 32,600 SKU's would alter package
configuration at a cost of over $1 billion, and that about 15,500 SKU's
would be removed from the market. While not including administrative
costs for feasibility studies to determine cost-effective packaging and
labeling configurations, NDMA stated that they would be large. One
manufacturer suggested that a new packaging line to accommodate a label
change for just one product line would result in a one-time equipment
expenditure of about $2.5 million (including equipment, installation,
validation, depreciation of old equipment, facility renovation, and
inventory loss) and recurring costs of almost $500,000 for the more
expensive labeling.
    The previously mentioned projections greatly overestimate the
percentage of SKU's that will not be able to accommodate the new format
and the cost of increasing the size of the labeling, where necessary.
In particular, the assertion that 95 percent of private label SKU's
could not accommodate the proposal requirements is difficult to
understand, as the vast majority of private label OTC drug products are
packaged almost identically to the leading branded products for
competitive reasons. Moreover, the agency carefully reviewed labels
submitted as examples of those that would not fit the proposed format
and found that many could, in fact, accommodate the final rule without
a change in label or package size.
    FDA also questions the methodology for calculating the costs of
package size changes. Although details of these calculations were not
submitted, it appears that NDMA estimated the cost of purchasing or
modifying equipment by multiplying the unit costs by the number of
affected SKU's, with no allowance for multiple SKU's packaged on a
given production line, or for the widespread usage of contract
packagers. Although agreeing that such factors should be considered
when determining costs, NDMA nonetheless assumed substantial equipment
requirements for each SKU. Moreover, NDMA does not differentiate
between the costs of branded and private label manufacturers. Most
private label products are manufactured by firms that produce hundreds
of SKU's on the same equipment, as most packaging machines can
accommodate a spectrum of changes with only minor modification or
retooling. As firms will choose the most cost-effective means of
implementing

[[Page 13283]]

package changes, only in rare cases, or when equipment is already
obsolete, should the rule lead to the purchase of new equipment.
    For some small SKU's, the impact of this rule will be moderated by
the more flexible leading and formatting provisions in the final rule
and the modified small package format allowed in 201.66(d)(10). FDA
further believes that any reduced consumer choice, should a small
package product not be able to meet the new requirements, will be
relatively insignificant because most manufacturers offer products in
more than one package size.
    To respond fully to the estimates offered by NDMA, FDA asked its
economics consultant, ERG, to survey (Ref. 28) all of the OTC drug
products found on the shelves in three retail outlets in the Boston
area. These outlets included: (1) A large pharmacy chain, (2) an
independent pharmacy, and (3) a convenience store. ERG examined each of
the 2,689 distinct SKU's found on the store shelves, and recorded data
on the package size and type, the available labeling space, and the
font size. ERG then compared these data to generic mock-ups of the
revised monographs to estimate the percent of the SKU's that might need
to increase the size of either the label or package. ERG also estimated
the amount of the additional space needed to accommodate the new format
for those SKU's that lacked sufficient labeling surface area, using an
expansion factor to derive estimates for SKU's for which no adequate
mock-ups were available.
    The results of the survey are shown by type of package in Table 4
of this document. The vast majority of SKU's, 92 percent, have
sufficient labeling space to accommodate the revised format. Of these,
16 percent will require some reconfiguration of the current information
presentation, such as moving, reducing, or eliminating certain
marketing information. Another 1.7 percent of the SKU's would increase
the size of their label to accommodate the new format and 6.4 percent
either would not fit or were indeterminate (too close to call) and,
thus, might require a new packaging configuration. (SKU's were judged
indeterminate when the available labeling area was within 5 square
centimeters of the required area.)

     Table 4.--Findings for 6.0-Point Font, Condensed Type Allowed<SUP>1</SUP>
------------------------------------------------------------------------
                                                            Percent of
                    Labeling outcome                           SKU's
------------------------------------------------------------------------
Revised label can fit using existing area allotted for         75.9
 regulatory information
Revised label fits if area allotted for regulatory             16.0
 information is increased
Revised label fits if expanded on existing container            1.7
Revised label will not fit                                      4.5
Indeterminate                                                   1.9
Total                                                         100
------------------------------------------------------------------------
\1\ Horizontal width of the characters reduced by approximately 20
  percent while the vertical height of the characters is unchanged.

    To evaluate the estimate of reconfiguration costs (i.e., changes to
the size of the labeling or packaging) presented in the comments, ERG
considered several options for packaging changes, including adding a
carton (if not already present), adding a fifth panel, increasing the
size of the packaging, or switching to a nonstandard form of labeling
such as peel-back or accordion labels (Ref. 28). Where applicable, the
costs for changing a container size included container inventory loss,
adjustment of the packaging line, and stability testing. The estimated
packaging change costs varied with the option chosen (for example,
adjustment or retooling of existing machinery versus the purchase of
new equipment), although the lower cost options had a higher
probability of selection. ERG also considered the recurring annual
costs that would be associated with the need for larger labels or
packages. A detailed description of ERG's assumptions, calculations,
and unit costs is presented in the full report.
4. Total Incremental Costs
    The costs of labeling redesign apply only to products covered by
final OTC drug monographs or applications. Currently there are about
39,310 SKU's in this category (see Table 3 of this document). No
redesign costs are assigned to the remaining 59,330 SKU's because the
6-year implementation period for these products will allow
manufacturers to incorporate the design changes in their usual redesign
cycle. Using a weighted average cost to redesign a label of $3,600 per
SKU and assuming labels are redesigned voluntarily every 2, 3, or 6
years, the total incremental costs for redesigning labeling using the
methodology discussed earlier is $19.4 million.
    Reconfiguration costs apply to those products that cannot
accommodate the small package format allowed in Sec. 201.66(d)(10).
These costs include the one-time cost to increase labeling size (the
label or package, where applicable) to accommodate a minimum 6.0
condensed font, plus the recurring cost of producing larger labeling.
Because these costs are applied to this rule regardless of the
monograph status of the product, all 98,639 SKU's are potentially
subject to label reconfiguration costs; 39,310 within 2 years of the
effective date of this final rule, the remaining 59,330 within 6 years
of the effective date of this final rule. The estimated reconfiguration
costs amount to $38.1 million in one-time costs and $11.5 million in
annual recurring costs. The latter reflects the incremental increases
in labeling or packaging materials to accommodate the format
requirements.
    Table 5 of this document presents FDA's estimate of the one-time
and annual recurring costs and the total annualized cost by compliance
activity. The total one-time costs of $57.5 million include $19.4
million for label redesign and $38.1 million for packaging changes. The
annual costs are $11.5 million. The total annualized cost to industry
(using a 7 percent discount rate) is estimated at $18.4 million. The
cost to individual firms will vary with the number of SKU's, the type
of changes needed, and the timing of the changes.

[[Page 13284]]

                Table 5.--Total Industry Compliance Costs
------------------------------------------------------------------------
                             One-Time         Annual           Total
        Activity            ($Million)      ($Million)      Annualized
------------------------------------------------------------------------
Label redesign                 19.4            NA               1.4
Packaging                      38.1            11.5            17.0
Total                          57.5            11.5            18.4
------------------------------------------------------------------------

    These estimates may overstate the costs attributable to this rule.
First, reconfiguration costs will be reduced to the extent that
companies opt to eliminate some smaller packaging sizes within a
product line. In these instances, however, consumers will bear some of
the added costs. Second, the recent amendment to section 502(e) of the
act under FDAMA requires that OTC drug manufacturers list the inactive
ingredients in their labeling. The ERG retail outlet survey (Ref. 28)
found that about 7 percent of the SKU's currently do not include
inactive ingredients on their labels. Some of these products may need
larger label or package sizes irrespective of this rule.

D. Small Business Impact

    Manufacturers and those entities that engage in the relabeling of
OTC drug products will be required to redesign the labeling of their
products to comply with this rule. Census data provide aggregate
industry statistics on the number of manufacturers for Standardized
Industrial Classification Code 2834, Pharmaceutical Preparations, by
establishment size, but do not distinguish between manufacturers of
prescription and OTC drugs. Over 92 percent of the roughly 700
establishments and over 87 percent of the 650 firms in this sector have
fewer than 500 employees. The Small Business Administration (SBA)
considers firms with fewer than 750 employees in this industry to be
small, but the U.S. Census size categories do not correspond to the SBA
designation. An alternative data source, IMS, identified roughly 400
firms as manufacturers of OTC drug products. Using the SBA size
designation of 750 employees, about 70 percent of the 400 affected
manufacturing firms would be considered small.
    This regulation will affect the information content and format
associated with OTC drug product labeling. Firms that manufacture or
relabel OTC drug products will need to change the information panel for
each affected product and may need to increase the size of the
packaging or labeling for a few SKU's. These costs will be mitigated,
however, by the several year implementation period, which will permit
many of these changes to be coordinated with those labeling changes
conducted in the normal course of business. OTC drug products subject
to new drug and ANDA's will need to submit revised labeling to the
agency in accordance with Sec. 314.70. This is a standard procedure
that companies routinely follow for labeling changes. The final rule
will not require new reporting and recordkeeping activities. Therefore,
no additional professional skills are necessary.
    The economic impact of this rule on small firms is particularly
difficult to measure, because published financial data do not
distinguish between firms manufacturing mostly OTC drugs and firms
manufacturing mostly prescription drugs. ERG adopted Census data on
firm size and revenue for SIC 2834, Pharmaceutical Preparations, and
assumed 400 manufacturers of OTC drug products to derive the figures in
Table 6 of this document. These data indicate that if 90 percent of the
OTC drug product firms meet the SBA size criteria for small businesses,
the annualized industry cost attributed to small businesses would
amount to $12.3 million out of the total $18.4 million. If revenues of
small OTC drug product manufacturers are similar to those of all small
manufacturers in SIC 2834, these costs represent only 0.17 percent of
small business OTC drug revenues.

                                         Table 6.--Small Business Impact
----------------------------------------------------------------------------------------------------------------
                                                          OTC Manufacturing Total      OTC Small Business Total
----------------------------------------------------------------------------------------------------------------
Firms                                                              400                          357
Establishments                                                     478                          374
Employees                                                       86,849                       18,942
Average employees per firm                                         217                           53
Percentage of total small business employment                       NA                         100%
Receipts ($000)                                            $42,363,000                   $7,411,000
Receipts per firm ($000)                                      $106,000                      $21,000
Total SKU's affected                                            98,639                       65,792
As percentage of all SKU's                                        100%                           66.7%
Total annualized compliance costs ($ millions)                     $18.4                        $12.3
Total annualized compliance costs as percentage of                   0.0004                       0.0017
 annual revenues
----------------------------------------------------------------------------------------------------------------

    These calculations, however, assume that small businesses can
finance the one-time outlays over time. In fact, some small firms may
have difficulty raising the funds. FDA finds that, on average, the
incremental one-time cost per SKU is about $600 ($57.5 million <divide>
98,639 SKU's). If a small firm manufactures 10 or 20 SKU's, it might
need to raise from $6,000 to $12,000 within the permitted
implementation period. In view of the figures developed for Table 6 of
this document, which imply that the annual revenue per SKU averages
about $100,000 for small businesses, such one-time outlays should be
manageable for most small firms.
    The agency has taken a number of steps to minimize the impact on
small entities, including: (1) A 2- to 6- year implementation period to
allow the sale of existing product inventories and to permit
coordination of required labeling changes with routine industry-
initiated labeling changes, (2) a modified format for small packages,
(3) an additional phase-in year for OTC drug products covered by a
final monograph or an

[[Page 13285]]

approved drug application if yearly sales are less than $25,000, and
(4) coordination of the FDAMA requirement for listing inactive
ingredients with the implementation of this rule. These provisions will
provide additional flexibility and cost savings for small entities.

E. Alternatives

    The major regulatory alternatives considered included various
implementation periods and graphics features, including font sizes and
print types. As shown in Table 7 of this document, redesign costs for
the 39,310 SKU's with a final monograph decrease substantially with
longer implementation periods for products covered by final monographs
or approved drug applications. One-time costs for a 1-year
implementation period would be about $59.1 million. A 2-year
implementation period reduces this figure to $27 million and a 3-year
period to $11.9 million. The selected alternative, which includes the
2-year implementation period, but permits a third year for products
with low volume sales, reduces these redesign costs to $19.4 million.
The agency believes this implementation period will provide substantial
relief to industry while achieving important consumer safety and use
goals in a timely manner.

       Table 7.--Effect of Implementation Period on Redesign Costs
------------------------------------------------------------------------
                                                  Redesign Cost With 1
   Implementation                                Additional Year for Low
  Period for Final        Cost ($ Millions)        Volume Products ($
     Monographs                                         Millions)
------------------------------------------------------------------------
1 year                            59.1                      46.9
2 years                           27.0                      19.4
3 years                           11.9                       8.9
------------------------------------------------------------------------

    FDA also considered alternative requirements for minimum font sizes
and print types. Table 8 of this document presents, for several
alternatives, ERG's estimates of the percent of SKU's with current
labels too small to fit, the one-time costs for labeling
reconfiguration, and the recurring label, carton, and container costs,
under varied font size and print requirements. The annualized cost for
a minimum 6.0 font but not condensed type (i.e., the horizontal width
of the characters reduced approximately 10 to 20 percent while the
vertical height of the characters is unchanged) requirement would be
$25 million. The final rule allows condensed print, which reduces this
cost to $17 million. The agency considered but rejected labeling with
smaller than 6-point type size because of the readability issues
associated with such labeling.

                                        Table 8.--Effect of Print Requirements on Labeling Reconfiguration Costs
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                        Recurring Incremental
                                                    Percent of SKU's That      One-Time Packaging         Label, Carton and         Total Annualized
     Minimum Font Size, Print Type Required           Cannot Fit or Are        Reconfiguration ($      Container Materials ($       Packaging Cost ($
                                                        Indeterminate               Millions)                 Millions)                 Millions)
--------------------------------------------------------------------------------------------------------------------------------------------------------
6.0, not condensed                                            9.5                      45.9                      18.3                      25.0
6.0, condensed allowed                                        6.4                      38.1                      11.5                      17.0
4.5, not condensed                                            3.4                      21.0                       5.1                       8.2
4.5, condensed allowed                                        2.3                      14.0                       3.4                       5.4
--------------------------------------------------------------------------------------------------------------------------------------------------------

    This final rule has been determined to be a major rule for purposes
of 5 U.S.C. 801 et. seq., subtitle E of the Small Business Regulatory
Enforcement Fairness Act of 1996 (Pub. L. 104-121). FDA is submitting
the information and reports as required by the statute.

IX. References

    The following references are on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
    1. Miller, G. A., ``The Magical Number Seven, Plus or Minus Two:
Some limits on Our Capacity for Processing Information,''
Psychological Review, 101(2):343-352, 1994.
    2. Shiffrin, R. M., and R. M. Nosofsky, ``Seven Plus or Minus
Two: A Commentary On Capacity Limitations,'' Psychological Review,
101(2):357-361, 1994.
    3. Allen, P. A., and L. C. Crozier, ``Age and Ideal Chunk
Size,'' Journal of Gerontology: Psychological Sciences, 47(1):47-51,
1992.
    4. Wood, R., and A. Bandura, ``Impact of Conceptions of Ability
on Self-Regulatory Mechanisms and Complex Decision Making,'' Journal
of Personality and Social Psychology, 56(3): 407-415, 1989.
    5. Chandler, P., and J. Sweller, ``Cognitive Load Theory and the
Format of Instruction,'' Cognition and Instruction, 8(4):293-332,
1991.
    6. Food and Drug Administration, ``National Uniformity for
Nonprescription Drugs--Ingredient Listing for OTC Drugs,'' April
1998, Docket No. 98D-0149, Dockets Management Branch.
    7. Comment No. 718, Docket No. 96P-0318, Dockets Management
Branch.
    8. Comment No. 684, Docket No. 96P-0318, Dockets Management
Branch.
    9. Webster's Ninth New Collegiate Dictionary, p. 371, 1990.
    10. Nonprescription Drug Manufacturers Association, ``Label
Readability Guidelines,'' May 1996, in OTC vol. 28FR, Docket No.
96N-0420, Dockets Management Branch.
    11. Watanabe, R. K., ``The Ability of the Geriatric Population
to Read Labels on Over-the-Counter Medication Containers,'' Journal
of the American Optometric Association, 65:32-37, 1994.
    12. Comment No. CP1, Docket No. 96P-0318, Dockets Management
Branch.
    13. Letter from R. G. Chesemore, FDA, to B. Nakutin, dated April
22, 1997, coded PDN1, Docket No. 96P-0318, Dockets Management
Branch.
    14. Food and Drug Administration ``Consumer Comprehension and
Preference for Variation in the Proposed Over-the-Counter Drug
Labeling Format,'' in OTC vol. 28FR, Docket No. 96N-0420, Dockets
Management Branch.
    15. Levy, A. S., S. B. Fein, and R. E. Schucker, ``More
Effective Nutrition Label Formats Are Not Necessarily More
Preferred,'' Journal of the American Dietetic Association,
92(10):1230-1234, 1992.
    16. Einarson, T. R., ``Drug-Related Hospital Admissions,'' The
Annals of Pharmacotherapy, 27:832-840, 1993.
    17. Ives, T. J., E. J. Bentz, and R. E. Gwyther, ``Drug-Related
Admissions to a Family Medicine Inpatient Service,'' Archives of
Internal Medicine, 147:1117-1120, 1987.
    18. Caranasos, G. J., R. Stewart, and L. E. Cluff, ``Drug-
induced Illness Leading to

[[Page 13286]]

Hospitalization,'' Journal of the American Medical Association,
228:713-7171, 1974.
    19. Mitchell, A. A. et al., ``Adverse Drug Reactions in Children
Leading to Hospital Admission,'' Pediatrics, 82:24-29, 1988.
    20. Classen, D. C. et al., ``Adverse Drug Events in Hospitalized
Patients,'' Journal of the American Medical Association, 277(4):301-
306, 1997.
    21. Agency for Health Care Policy and Research, ``National
Medical Expenditure Survey: Annual Expenses and Sources of Payment
for Health Care Services Research Findings 14,'' p. 7, 1995.
    22. McKenney, J. M., and W. L. Harrison, ``Drug-related Hospital
Admissions,'' American Journal of Hospital Pharmacists, 33:792-795,
1976.
    23. U.S. Department of Commerce, ``Statistical Abstract of the
United States 1998,'' The National Data Book, Table 683, 118:426,
1998.
    24. U.S. Department of Commerce, ``1992 Census of Retail Trade;
Establishment and Firm Size,'' Table 3, pp. 56, 57, and 68, 1992.
    25. Comment No. 716, Supplement No. 2 (attachment 1, appendix
G), Docket No. 96N-0420, Dockets Management Branch.
    26. Research Triangle Institute, ``Compliance Cost of Food
Labeling Regulations: Final Report (January, 1991),'' FDA contract
number 223-87-2097, Docket Nos. 90N-0134 and 90N-0135, Dockets
Management Branch.
    27. Comment No. C717, Docket No. 96N-0420, Dockets Management
Branch.
    28. Eastern Research Group, Inc., ``Cost Impacts of the Over-
the-Counter Pharmaceutical Labeling Rule,'' in OTC vol. 28FR, Docket
No. 96N-0420, Dockets Management Branch.
    29. Office of Management and Budget, ``Economic Analysis of
Federal Regulations Under Executive Order 12866,'' 1996.

List of Subjects

21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 330

    Over-the-counter drugs.

21 CFR Parts 331, 341, 346, 355, and 358

    Labeling, Over-the-counter drugs.

21 CFR Part 369

    Labeling, Medical devices, Over-the-counter drugs.

21 CFR Part 701

    Cosmetics, Labeling, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR parts 201, 330, 331, 341, 346,
355, 358, 369, and 701 are amended as follows:

PART 201--LABELING

    1. The authority citation for 21 CFR part 201 continues to read as
follows:

    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.

    2. Section 201.63 is amended by revising the section heading, the
first sentence in paragraph (a), and paragraph (e) to read as follows:

Sec. 201.63  Pregnancy/breast-feeding warning.

    (a) The labeling for all over-the-counter (OTC) drug products that
are intended for systemic absorption, unless specifically exempted,
shall contain a general warning under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) as
follows: ``If pregnant or breast-feeding, ask a health professional
before use.'' [first four words of this statement in bold type] * * *
* * * * *
    (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 paragraph (a) of this
section. The warning shall be as follows:
    ``It is especially important not to use'' (select ``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
delivery.''
    3. Section 201.64 is amended by revising the last sentence in
paragraph (b) to read as follows:

Sec. 201.64  Sodium labeling.

* * * * *
    (b) * * * The sodium content per dosage unit shall follow the
heading ``Other information'' as stated in Sec. 201.66(c)(7).
 * * * * *
    4. Section 201.66 is added to subpart C to read as follows:

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 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.

[[Page 13287]]

    (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 Secs. 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) 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:''
    (B) 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:''
    (C) Flammability warning, with appropriate flammability signal word
(e.g., Secs. 358.150(c) and 358.550(c) of this chapter). This warning
shall follow a subheading containing the appropriate flammability
signal word 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:''
    (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(c)) shall appear as follows:
``each (insert appropriate dosage unit) contains:'' [in bold type]
(insert name(s) of ingredient(s) 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.

[[Page 13288]]

    (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 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
Secs. 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, headings, subheadings, and information in paragraphs
(c)(1) through (c)(9) of this section shall be legible and clearly
presented, shall not appear in reverse type, 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 dark color, printed on a white or other light, neutral color,
contrasting background, except that the title and the headings may be
presented in a single, alternative, contrasting dark color unless
otherwise provided in an approved drug application, OTC drug monograph
(e.g., current requirements for bold print in Secs. 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 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

[[Page 13289]]

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 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:
BILLING CODE 4160-01-F
[GRAPHIC] [TIFF OMITTED] TR17MR99.003

BILLING CODE 4160-01-C

[[Page 13290]]

    (ii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section:
[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:
[GRAPHIC] [TIFF OMITTED] TR17MR99.005

BILLING CODE 4160-01-C

[[Page 13291]]

    (iv) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section for a drug product marketed with
cosmetic claims:
[GRAPHIC] [TIFF OMITTED] TR17MR99.006

BILLING CODE 4160-01-C
    (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 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.
    5. Section 201.314 is amended by revising the first two sentences
in paragraph (a) and by revising paragraphs (g)(1) and (h)(1) to read
as follows:

Sec. 201.314  Labeling of drug preparations containing salicylates.

    (a) The label of any oral drug preparation intended for sale
without prescription and which contains any salicylate ingredient
(including aspirin, salicylamide, other salicylates, and combinations)
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 children
[highlighted in bold type],'' except that if the article is an aspirin
preparation, it shall bear the first of these warning statements. * * *
* * * * *
    (g)(1) The label of any drug containing more than 5 percent methyl
salicylate

[[Page 13292]]

(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'' warning and the accidental
ingestion warning as required in Sec. 330.1(g) of this chapter.
* * * * *
    (h)(1) The labeling of orally or rectally administered over-the-
counter aspirin and aspirin-containing drug products subject to this
paragraph is required to prominently bear a warning. The warning shall
be as follows: ``Children and teenagers should not use this medicine
for chicken pox or flu symptoms before a doctor is consulted about Reye
syndrome, a rare but serious illness reported to be associated with
aspirin.''
* * * * *
    6. Section 201.319 is amended by revising paragraph (b) to read as
follows:

Sec. 201.319  Water-soluble gums, hydrophilic 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 xanthan gum) as active ingredients; required warnings
and directions.

* * * * *
    (b) Any drug products for human use containing a water-soluble gum,
hydrophilic gum, or hydrophilic mucilloid as an active ingredient in an
oral dosage form when marketed in a dry or incompletely hydrated form
as described in paragraph (a) of this section are misbranded within the
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act
unless their labeling bears the following warnings (under the
subheading ``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 swallowing. 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 without enough liquid may cause
choking. See choking warning.''
* * * * *
    7. Appendix A is added to part 201 to read as follows:

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 justified.
    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 dosage 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),
immediately following the title and immediately preceding the
subheadings.
    3. A 0.5-point horizontal hairline follows the title,
immediately preceding the heading, 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.
    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),
immediately following the title and immediately preceding the
subheadings.

D. Box or Enclosure

    1. All information is set off by color contrast. No barline is
used.

BILLING CODE 4160-01-F

[[Page 13293]]

III. Examples of Sec. 201.66 Standard Labeling and Modified Labeling
Formats

A. Section 201.66 Standard Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.007

B. Section 201.66 Modified Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.008

BILLING CODE 4160-01-C

[[Page 13294]]

PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED

    8. The authority citation for 21 CFR part 330 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    9. Section 330.1 is amended by revising paragraphs (c)(1), (c)(2),
(i), and (j), and by removing the first three sentences in paragraph
(g) and adding two sentences in their place to read as follows:

Sec. 330.1  General conditions for general recognition as safe,
effective, and not misbranded.

* * * * *
    (c)(1) The product is labeled in compliance with chapter V of the
Federal Food, Drug, and Cosmetic Act (the act) and subchapter C et seq.
of this chapter, including the format and content requirements in
Sec. 201.66 of this chapter. An OTC drug product that is not in
compliance with chapter V and subchapter C, including Sec. 201.66 of
this chapter, is subject to regulatory action. For purposes of
Sec. 201.61(b) of this chapter, the statement of identity of the
product shall be the term or phrase used in the applicable OTC drug
monograph established in this part.
    (2) The ``Uses'' section of the label and labeling of the product
shall contain the labeling describing the ``Indications'' that have
been established in an applicable OTC drug monograph or alternative
truthful and nonmisleading statements describing only those indications
for use that have been established in an applicable monograph, subject
to the provisions of section 502 of the act relating to misbranding and
the prohibition in section 301(d) of the act against the introduction
or delivery for introduction into interstate commerce of unapproved new
drugs in violation of section 505(a) of the act. Any other labeling
under this subchapter and subchapter C et seq. of this chapter shall be
stated in the exact language where exact language has been established
and identified by quotation marks in an applicable OTC drug monograph
or by regulation (e.g., Sec. 201.63 of this chapter), except as
provided in paragraphs (i) and (j) of this section.
* * * * *
    (g) The labeling for all drugs contains the general warning: ``Keep
out of reach of children.'' [highlighted in bold type]. The labeling of
drugs shall also state as follows: For drugs used by oral
administration, ``In case of overdose, get medical help or contact a
Poison Control Center right away''; for drugs used topically, rectally,
or vaginally and not intended for oral ingestion, ``If swallowed, get
medical help or contact a Poison Control Center right away''; and for
drugs used topically and intended for oral use, ``If more than used
for'' (insert intended use, e.g., pain) ``is accidentally swallowed,
get medical help or contact a Poison Control Center right away.'' * * *
* * * * *
    (i) The following terms may be used 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
monograph or by regulation. The following terms shall not be used to
change in any way the title, headings, and subheadings required under
Sec. 201.66(c)(1) through (c)(9) of this chapter:
    (1) ``Abdominal'' or ``stomach'' (in context only).
    (2) ``Administer'' or ``give''.
    (3) ``Aggravate(s)'' or ``make(s) worse''.
    (4) ``Application of this product'' or ``applying''.
    (5) ``Are uncertain'' or ``do not know''.
    (6) ``Ask'' or ``consult'' or ``contact''.
    (7) ``Asking'' or ``consulting''.
    (8) ``Assistance'' or ``help'' or ``aid''.
    (9) ``Associated with'' or ``due to'' or ``caused by''.
    (10) ``Avoid contact with eyes'' or ``do not get into eyes''.
    (11) ``Avoid inhaling'' or ``do not inhale''.
    (12) ``Before a doctor is consulted'' or ``without first consulting
your doctor'' or ``consult your doctor before''.
    (13) ``Beverages'' or ``drinks''.
    (14) ``Clean'' or ``cleanse''.
    (15) ``Consulting'' or ``advising''.
    (16) ``Continue(s)'' or ``persist(s)'' or ``is persistent'' or
``do(es) not go away'' or ``last(s)''.
    (17) ``Daily'' or ``every day''.
    (18) ``Develop(s)'' or ``begin(s)'' or ``occur(s)''.
    (19) ``Difficulty'' or ``trouble''.
    (20) ``Difficulty in urination'' or ``trouble urinating''.
    (21) ``Discard'' or ``throw away''.
    (22) ``Discontinue'' or ``stop'' or ``quit''.
    (23) ``Doctor'' or ``physician''.
    (24) ``Drowsiness'' or ``the drowsiness effect''.
    (25) ``Drowsiness may occur'' or ``you may get drowsy''.
    (26) ``Enlargement of the'' or ``an enlarged''.
    (27) ``Especially in children'' or especially children''.
    (28) ``Exceed'' or ``use more than'' or ``go beyond''.
    (29) ``Exceed recommended dosage'' or ``use more than directed''.
    (30) ``Excessive'' or ``too much''.
    (31) ``Excitability may occur'' or ``you may get excited''.
    (32) ``Experience'' or ``feel''.
    (33) ``For relief of'' or ``relieves''.
    (34) ``For temporary reduction of'' or ``temporarily reduces''.
    (35) ``For the temporary relief of'' or ``temporarily relieves''.
    (36) ``For the treatment of'' or ``treats''.
    (37) ``Frequently'' or ``often''.
    (38) ``Give to'' or ``use in''.
    (39) ``Immediately'' or ``right away'' or ``directly''.
    (40) ``Immediately'' or ``as soon as''.
    (41) ``Immediately following'' or ``right after''.
    (42) ``Improve(s)'' or ``get(s) better'' or ``make(s) better''.
    (43) ``Increased'' or ``more''.
    (44) ``Increase your risk of'' or ``cause''.
    (45) ``Indication(s)'' or ``Use(s)''.
    (46) ``Inhalation'' or ``puff''.
    (47) ``In persons who'' or ``if you'' or ``if the child''.
    (48) ``Instill'' or ``put''.
    (49) ``Is (are) accompanied by'' or ``you also have'' (in context
only) or ``(optional: that) occur(s) with''.
    (50) ``Longer'' or ``more''.
    (51) ``Lung'' or ``pulmonary''.
    (52) ``Medication(s)'' or ``medicine(s)'' or ``drug(s)''.
    (53) ``Nervousness, dizziness, or sleeplessness occurs'' or ``you
get nervous, dizzy, or sleepless''.
    (54) ``Not to exceed'' or ``do not exceed'' or ``not more than''.
    (55) ``Obtain(s)'' or ``get(s)''.
    (56) ``Passages'' or ``passageways'' or ``tubes''.
    (57) ``Perforation of'' or ``hole in''.
    (58) ``Persistent'' or ``that does not go away'' or ``that
continues'' or ``that lasts''.
    (59) ``Per day'' or ``daily''.
    (60) ``Presently'' or ``now''.
    (61) ``Produce(s)'' or ``cause(s)''.
    (62) ``Prompt(ly)'' or ``quick(ly)'' or ``right away''.
    (63) ``Reduce'' or ``minimize''.
    (64) ``Referred to as'' or ``of''.
    (65) ``Sensation'' or ``feeling''.
    (66) ``Solution'' or ``liquid''.
    (67) ``Specifically'' or ``definitely''.
    (68) ``Take'' or ``use'' or ``give''.
    (69) ``Tend(s) to recur'' or ``reoccur(s)'' or ``return(s)'' or
``come(s) back''.
    (70) ``To avoid contamination'' or ``avoid contamination'' or ``do
not contaminate''.
    (71) ``To help'' or ``helps''.
    (72) ``Unless directed by a doctor'' or ``except under the advice
of a doctor'' or ``unless told to do so by a doctor''.

[[Page 13295]]

    (73) ``Use caution'' or ``be careful''.
    (74) ``Usually'' or ``generally'' (in context only).
    (75) ``You'' (``Your'') or ``the child'' (``the child's'').
    (76) ``You also have'' or ``occurs with''.
    (77) ``When practical'' or ``if possible''.
    (78) ``Whether'' or ``if''.
    (79) ``Worsen(s)'' or ``get(s) worse'' or ``make(s) worse''.
    (j) The following connecting terms may be deleted from the labeling
of OTC drug products, provided such deletion does not alter the meaning
of the labeling that has been established and identified in an
applicable monograph or by regulation. The following terms shall not be
used to change in any way the specific title, headings, and subheadings
required under Sec. 201.66(c)(1) through (c)(9) of this chapter:
    (l) ``And''.
    (2) ``As may occur with''.
    (3) ``Associated'' or ``to be associated''.
    (4) ``Consult a doctor''.
    (5) ``Discontinue use''.
    (6) ``Drug Interaction Precaution''.
    (7) ``Due to''.
    (8) ``Except under the advice and supervision of a physician''.
    (9) ``If this occurs''.
    (10) ``In case of''.
    (11) ``Notice''.
    (12) ``Or''.
    (13) ``Occurring with''.
    (14) ``Or as directed by a doctor''.
    (15) ``Such as''.
    (16) ``Such as occurs with''.
    (17) ``Tends to''.
    (18) ``This product''.
    (19) ``Unless directed by a doctor''.
    (20) ``While taking this product'' or ``before taking this
product''.
    (21) ``Within''.
* * * * *

PART 331--ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE

    10. The authority citation for 21 CFR part 331 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    11. Section 331.30 is amended by revising paragraph (d) to read as
follows:

Sec. 331.30  Labeling of antacid products.

* * * * *
    (d) Drug interaction precaution. The labeling of the product
contains the following statement ``Ask a doctor or pharmacist before
use if you are [bullet]\1\ presently taking a prescription drug.
Antacids may interact with certain prescription drugs.''
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter.
---------------------------------------------------------------------------

* * * * *

PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    12. The authority citation for 21 CFR part 341 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    13. Section 341.74 is amended by revising paragraphs (c)(4)(v) and
(c)(4)(vi) to read as follows:

Sec. 341.74  Labeling of antitussive drug products.

* * * * *
    (c) * * *
    (4) * * *
    (v) For products containing dextromethorphan or dextromethorphan
hydrobromide as identified in Sec. 341.14(a)(3) and (a)(4) when labeled
for adults or for adults and children under 12 years of age. Drug
interaction precaution. ``Do not use if you are now taking a
prescription monoamine oxidase inhibitor (MAOI) (certain drugs for
depression, psychiatric, or emotional conditions, or Parkinson's
disease), or for 2 weeks after stopping the MAOI drug. If you do not
know if your prescription drug contains an MAOI, ask a doctor or
pharmacist before taking this product.''
    (vi) For products containing dextromethorphan or dextromethorphan
hydrobromide as identified in Sec. 341.14(a)(3) and (a)(4) when labeled
only for children under 12 years of age. Drug interaction precaution.
``Do not give to a child who is taking a prescription monoamine oxidase
inhibitor MAOI) (certain drugs for depression, psychiatric, or
emotional conditions, or Parkinson's disease), or for 2 weeks after
stopping the MAOI drug. If you do not know if your child's prescription
drug contains an MAOI, ask a doctor or pharmacist before giving this
product.''
* * * * *
    14. Section 341.76 is amended by revising paragraph (c)(4) to read
as follows:

Sec. 341.76  Labeling of bronchodilator drug products.

* * * * *
    (c) * * *
    (4) Drug interaction precaution. ``Do not use if you are now taking
a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for
depression, psychiatric, or emotional conditions, or Parkinson's
disease), or for 2 weeks after stopping the MAOI drug. If you do not
know if your prescription drug contains an MAOI, ask a doctor or
pharmacist before taking this product.''
* * * * *
    15. Section 341.80 is amended by revising paragraphs (c)(1)(i)(D)
and (c)(1)(ii)(D) to read as follows:

Sec. 341.80  Labeling of nasal decongestant drug products.

* * * * *
    (c) * * *
    (1) * * *
    (i) * * *
    (D) Drug interaction precaution. ``Do not use if you are now taking
a prescription monoamine oxidase inhibitor (MAOI) (certain drugs for
depression, psychiatric, or emotional conditions, or Parkinson's
disease), or for 2 weeks after stopping the MAOI drug. If you do not
know if your prescription drug contains an MAOI, ask a doctor or
pharmacist before taking this product.''
    (ii) * * *
    (D) Drug interaction precaution. ``Do not give to a child who is
taking a prescription monoamine oxidase inhibitor (MAOI) (certain drugs
for depression, psychiatric, or emotional conditions, or Parkinson's
disease), or for 2 weeks after stopping the MAOI drug. If you do not
know if your child's prescription drug contains an MAOI, ask a doctor
or pharmacist before giving this product.''
* * * * *

PART 346--ANORECTAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    16. The authority citation for 21 CFR part 346 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    17. Section 346.50 is amended by revising paragraph (c)(7)(ii) to
read as follows:

Sec. 346.50  Labeling of anorectal drug products.

* * * * *
    (c) * * *
    (7) * * *
    (ii) ``Ask a doctor or pharmacist before use if you are [bullet]\1\
presently taking a prescription drug for high blood pressure or
depression.''
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter.
---------------------------------------------------------------------------

* * * * *

[[Page 13296]]

PART 355--ANTICARIES DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    18. The authority citation for 21 CFR part 355 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    19. Section 355.50 is amended by revising paragraphs (c)(1) and
(c)(2) to read as follows:

Sec. 355.50  Labeling of anticaries drug products.

* * * * *
    (c) * * *
    (1) For all fluoride dentifrice (gel, paste, and powder) products.
``Keep out of reach of children under 6 years of age. [highlighted in
bold type] If more than used for brushing is accidentally swallowed,
get medical help or contact a Poison Control Center right away.'' These
warnings shall be used in place of the general warning statements
required by Sec. 330.1(g) of this chapter.
    (2) For all fluoride rinse and preventive treatment gel products.
``Keep out of reach of children. [highlighted in bold type] If more
than used for'' (select appropriate word: ``brushing'' or ``rinsing'')
``is accidentally swallowed, get medical help or contact a Poison
Control Center right away.'' These warnings shall be used in place of
the general warning statements required by Sec. 330.1(g) of this
chapter.
* * * * *

PART 358--MISCELLANEOUS EXTERNAL DRUG PRODUCTS FOR OVER-THE-COUNTER
HUMAN USE

    20. The authority citation for 21 CFR part 358 continues to read as
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    21. Section 358.650 is amended in paragraph (d)(1) by revising the
information in the brackets to read as follows:

Sec. 358.650  Labeling of pediculicide drug products.

* * * * *
    (d) * * *
    (1) * * * [statement in boldface type].
* * * * *

PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND
DEVICES FOR OVER-THE-COUNTER SALE

    22. The authority citation for 21 CFR part 369 continues to read as
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371.

    23. Section 369.9 is revised to read as follows:

Sec. 369.9  General warnings re accidental ingestion by children.

    Section 369.20 includes under certain items, but not all medicines,
the statement: ``Keep this and all medicines out of children's reach.
In case of overdose, get medical help or contact a Poison Control
Center right away,'' or ``Keep out of reach of children.'' However, in
view of the possibility of accidental ingestion of drugs, it is not
only suggested but is recommended that one of these statements be used
on the label of all drug products.

Sec. 369.20  Drugs; recommended warning and caution statements.
[Amended]

    24. Section 369.20 is amended as follows:

    a. The entry ``NUX VOMICA AND STRYCHNINE PREPARATIONS.'' is revised
to read as follows:
NUX VOMICA AND STRYCHNINE PREPARATIONS.
    ``Do not use more than the recommended dosage. Keep out of reach of
children. In case of overdose, get medical help or contact a Poison
Control Center right away.''
    b. The entry beginning ``SALICYLATES, INCLUDING ASPIRIN'' is
revised to read as follows:
SALICYLATES, INCLUDING ASPIRIN AND SALICYLAMIDE (EXCEPT METHYL
SALICYLATE, EFFERVESCENT SALICYLATE PREPARATIONS, AND PREPARATIONS OF
AMINOSALICYLIC ACID AND ITS SALTS). (See also Sec. 201.314 of this
chapter.)
    ``Keep out of reach of children. In case of overdose, get medical
help or contact a Poison Control Center right away;'' or ``Keep out of
reach of children.''
    If the article is an aspirin preparation, it should bear the first
of the above two warning statements. In either case, the above
information should appear on the label.
    Caution--For children under 3 years of age, consult your physician;
or
    Caution--For younger children, consult your physician.
    One of the two immediately preceding caution statements is required
on the label of all aspirin tablets, but such a statement is not
required on the labels of other salicylates clearly offered for
administration to adults only.
    If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
    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 immediately.
    c. The entry ``SALICYLATES: METHYL SALICYLATE (WINTERGREEN OIL).''
is revised to read as follows:
SALICYLATES: METHYL SALICYLATE (WINTERGREEN OIL). (See also
Secs. 201.303 and 201.314 of this chapter.)
    ``Do not use otherwise than as directed. Keep out of reach of
children to avoid accidental poisoning. If swallowed, get medical help
or contact a Poison Control Center right away.''
    If the preparation is a counter-irritant or rubefacient the
statement:
    Caution--Discontinue use if excessive irritation of the skin
develops. Avoid getting into the eyes or on mucous membranes.
    If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
    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 immediately.
    d. The entry ``ZINC STEARATE DUSTING POWDERS.'' is revised to read
as follows:
ZINC STEARATE DUSTING POWDERS.
    ``Keep out of reach of children; avoid inhaling. If swallowed, get
medical help or contact a Poison Control Center right away.''

Sec. 369.21  Drugs; warning and caution statements required by
regulations. [Amended]

    25. Section 369.21 is amended as follows:

    a. The entry ```COUGH-DUE-TO-COLD' PREPARATIONS (CARBETAPENTANE
CITRATE).'' is revised to read as follows:
``COUGH-DUE-TO-COLD'' PREPARATIONS (CARBETAPENTANE CITRATE). (See
Sec. 310.201(a)(20) of this chapter.)
    ``Keep out of reach of children. In case of overdose, get medical
help or contact a Poison Control Center right away.''
    b. The entry ``SODIUM GENTISATE.'' is revised to read as follows:
SODIUM GENTISATE. (See Secs. 201.314 and 310.301(a)(2) of this
chapter.)
    Warning--Do not give to children under 6 years of age or use for
prolonged period unless directed by physician.
    ``Keep out of reach of children. In case of overdose, get medical
help or contact a Poison Control Center right away.''
    If offered for use in arthritis or rheumatism, in juxtaposition
therewith, the statement:
    Caution--If pain persists for more than 10 days, or redness is
present, or

[[Page 13297]]

in conditions affecting children under 12 years of age, consult a
physician immediately.

PART 701--COSMETIC LABELING

    26. The authority citation for 21 CFR part 701 continues to read as
follows:

    Authority:  21 U.S.C. 321, 352, 361, 362, 363, 371, 374; 15
U.S.C. 1454, 1455.

    27. Section 701.3 is amended by revising paragraph (d) to read as
follows:

Sec. 701.3   Designation of ingredients.

* * * * *
    (d) Where a cosmetic product is also an over-the-counter drug
product, the declaration shall declare the active drug ingredients as
set forth in Sec. 201.66(c)(2) and (d) of this chapter, and the
declaration shall declare the cosmetic ingredients as set forth in
Sec. 201.66(c)(8) and (d) of this chapter.
* * * * *

    Dated: January 4, 1999.
Jane E. Henney
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
    Note: The following Appendix A to the preamble will not appear
in the Code of Federal Regulations.

BILLING CODE 4160-01-F

Appendix A to Preamble--Examples of Prototype OTC Drug Product Labeling
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[FR Doc. 99-6296 Filed 3-11-99; 11:59 am]
BILLING CODE 4160-01-C