Document ID: FDA-2004-D-0122-0004
Agency: fda
Document Type: Supporting & Related Material
Title: 
Posted Date: 2004-12-23T05:00Z

Guidance for Industry

Labeling OTC Human Drug Products

(Small Entity Compliance Guide)

DRAFT GUIDANCE

Comments and suggestions regarding this draft document should be
submitted within 60 days of publication in the Federal Register of the
notice announcing the availability of the draft guidance.  Submit
comments to the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All
comments should be identified with the docket number listed in the
notice of availability that publishes in the Federal Register.

For questions on the content of the draft document, contact Cazemiro R.
Martin at 301-827-2222.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 2004

OTC

Guidance for Industry

Labeling OTC Human Drug Products 

(Small Entity Compliance Guide)

Additional copies are available from:

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD  20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 2004

OTC

TABLE OF CONTENTS

  TOC \o "1-2"  I.	INTRODUCTION	  PAGEREF _Toc89240247 \h  1 

II.	BACKGROUND	  PAGEREF _Toc89240248 \h  1 

III.	Scope (21 CFR 201.66(a))	  PAGEREF _Toc89240249 \h  2 

IV.	Definitions (21 CFR 201.66(b))	  PAGEREF _Toc89240250 \h  2 

v.	Content Requirements  (21 CFR 201.66(c))	  PAGEREF _Toc89240251 \h  2

VI.	FORMAT LABELING REQUIREMENTS (21 CFR 201.66(d))	  PAGEREF
_Toc89240252 \h  9 

VII.	Standard AND MODIFIED LABELING FORMATS	  PAGEREF _Toc89240253 \h 
15 

VIII.	Topic-Specific Guidance documents	  PAGEREF _Toc89240254 \h  16 

IX.	OTHER fda LABELING REQUIREMENTS	  PAGEREF _Toc89240255 \h  16 

X.	IMPLEMENTATION OF THE OTC LABELING Requirements	  PAGEREF
_Toc89240256 \h  17 

Appendix:  Summary of Labeling Requirements and Relevant contacts	 
PAGEREF _Toc89240257 \h  1 

 Guidance for Industry

Labeling OTC Drug Products

(Small Entity Compliance Guide)

This draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic.  It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public.  You can use an alternative approach if it
satisfies the requirements of the applicable statutes and regulations. 
If you want to discuss an alternative approach, contact the FDA staff
responsible for implementing this guidance.  If you cannot identify the
appropriate FDA staff, call the appropriate number listed on the title
page of this guidance. 

I.	INTRODUCTION

The Food and Drug Administration (FDA) has prepared this guidance in
accordance with section 212 of the Small Business Regulatory Enforcement
Fairness Act.  It is intended to help small businesses better understand
the new over-the-counter (OTC) labeling requirements set forth in 21 CFR
201.66 and prepare new labeling within the prescribed implementation
compliance dates.  To reduce the economic impact on small businesses,
the new requirements provide an additional one-year extension to comply
with 21 CFR 201.66 for OTC drug products with sales of less than $25,000
per year (see Table 3). 

FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities.  Instead, guidances describe the
Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited.  The use of the word should in Agency guidances means that
something is suggested or recommended, but not required.

II.	BACKGROUND

In the Federal Register of March 17, 1999 (64 FR 13254), the Food and
Drug Administration (FDA) published a final regulation (§ 201.66)
establishing standardized content and format for the labeling of OTC
drug products (Drugs Facts regulation).  Standardized labeling for OTC
drug products is intended to make it easier for consumers to read and
understand OTC drug product labeling and use OTC drug products safely
and effectively.

The new Drug Facts labeling regulation in § 201.66 covers all OTC drug
and drug-cosmetic products, whether marketed under a new drug marketing
application (NDA), abbreviated new drug application (ANDA), or OTC drug
monograph (or product not yet the subject of a final OTC drug
monograph).  A copy of § 201.66 can be found at the FDA Dockets
Management Branch Web site. The regulation in § 201.66 provides for
standardized content and format requirements for the labeling of OTC
drug and drug-cosmetic products.  The regulation is divided into two
main parts:  (1)  content requirements in paragraph (c) (i.e., headings,
subheadings, and information in the order listed) and (2)  format
requirements in paragraph (d) (i.e., graphic specifications).  This
guidance document primarily discusses the requirements in paragraphs (c)
and (d).  The sections of the guidance track the sections of the rule
and explain the rule's provisions.

III.	Scope (21 CFR 201.66(a))

This section explains that the content and format requirements apply to
the labeling of all OTC drug products.  This scope includes products
marketed under a final OTC drug monograph, an approved new drug
application (NDA) or abbreviated new drug application (ANDA), and OTC
products for which there is no final OTC drug monograph or approved drug
application.

IV.	Definitions (21 CFR 201.66(b))

This section contains definitions of terms, including an explanation of
certain printing, typesetting, and graphics terms, applicable to this
section of the regulation.

v.	Content Requirements  (21 CFR 201.66(c))

This section requires that all OTC drug product labeling contain the
following information about the product.  The information must be
organized according to the following headings and must be presented in
this order:

(1)  Title				(4)  Use(s)		(7)  Other information

(2)  Active ingredient(s)		(5)  Warnings		(8)  Inactive ingredients

(3)  Purpose(s)				(6)  Directions		(9)  Questions? (optional)

This information must appear on the outside container or wrapper of the
retail package, or on the immediate container label if there is no
outside container or wrapper.

Product trade names and company names cannot appear within the Drug
Facts box or similar enclosure.  (§ 201.66(d)(7))

The following specific information must appear in the Drug Facts
section.

(1)  Title (§ 201.66(c)(1))

If the Drug Facts labeling appears on more than one panel or side of the
labeling, the title Drug Facts (continued) must appear at the top of
each subsequent panel containing such information.  See also the
guidance for industry entitled Labeling OTC Human Drug Products Using a
Column Format for guidance on the title, when a column format is used in
the product's labeling. 

(2)  Active Ingredient(s) (§ 201.66(c)(2))

An active ingredient is 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. 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.  (§ 201.66(b)(2))

Depending on the type of product (oral or topical), the active
ingredients can be stated in one of two ways:  As the amount "in each":

[for oral dosage forms] use the dosage unit stated in the directions for
use (e.g., tablet, 5 mL teaspoonful), or

[for topical dosage forms marketed with discrete dosage units] use gram,
as stated in §§ 333.110 and 333.120, where the antibiotic active
ingredients are stated as an amount in each gram of the product

Products marketed without discrete dosage units (e.g., topicals) must
state the proportion (rather than the quantity) of each active
ingredient (e.g., 1%), unless otherwise provided in an applicable OTC
drug monograph or approved drug application.  For example, the OTC
anticaries final monograph (21 CFR part 355) lists fluoride active
ingredients as a percent fluoride with an available fluoride ion
concentration of a certain number of parts per million (ppm).  Because
the concentration expressed in ppm may be confusing to consumers, the
available ion concentration must be expressed on the label in fluoride
ion % (i.e., ppm converted to a "%" weight to volume notation of
available fluoride ion).   These anticaries products must list under
this heading the ingredient %, followed by fluoride ion concentration in
percent notation (e.g., Sodium fluoride 0.24% (0.14% W/V fluoride ion)).
 

For OTC drug products that contain both drug and cosmetic ingredients,
the drug ingredients are considered the active ingredients, and the
cosmetic ingredients are considered the inactive ingredients.  (See §§
201.66(b)(2), 201.66(b)(8))

  

(3)  Purpose(s) (§ 201.66(c)(3))

Each active ingredient in the product is to be followed by a description
of the ingredient's purpose, unless this information is specifically
exempted in an OTC drug monograph.  The statement of identity that
appears in an applicable OTC drug monograph shall be stated as the
purpose of the active ingredient.  If there is no statement of identity
or no applicable OTC drug monograph, then FDA recommends that the
following criteria should be used in stating the ingredient's purpose:

 its general pharmacological category(ies), or

 the principal intended action(s) of the drug

If two active ingredients in a product have the same purpose (e.g., two
sunscreen or skin protectant ingredients are present in the product),
then the purpose can be stated only once as long as the purpose is
clearly associated with both active ingredients. (See example in section
VI of this guidance document.)

(4)  Use(s) (§ 201.66(c)(4))

The uses are the specific indications or approved uses for the drug
product.  For drug-cosmetic products, only the drug-related indications
can be included in the Uses section.   

(5)  Warning(s) (§ 201.66(c)(5))

With regard to subject specific warnings described in §§
201.66(c)(5)(ii)(A) through (5)(ii)(G), except for the Reye's syndrome
warning, which must appear first when required, there is no required
order in which these specific warning statements must appear.  The
Agency suggests that manufacturers list the specific warning statements
in the order of importance or impact. 

When applicable, information that must appear under the following
Warning subheadings includes:

Do not use  (§ 201.66(c)(5)(iii)):

Information appearing under this subheading includes situations in which
consumers should not use the product unless a prior diagnosis has been
established by a doctor or for situations in which consumers should not
use the product under any circumstances regardless of whether a doctor
or health professional is consulted.  

FDA recommends that Iin some instances, manufacturers need toshould
convert existing warnings to the new Drug Facts labeling format (see 21
CFR 201.66(a)).  For example, the current warning "Do not use this
product on irritated skin, on any area that is infected or reddened, if
you are a diabetic, or if you have poor blood circulation"“Do not use
this product unless a diagnosis of asthma has been made by a doctor”
would be formatted can be shortened to appear after the Do not use
subheading as follows:  “unless a diagnosis of asthma has been made by
a doctor.”

on irritated skin

on any area that is infected or reddened

if you are a diabetic

if you have poor blood circulation  

 (b)  Ask a doctor before use if you have  (§ 201.66(c)(5)(iv))

Information under this subheading includes all warnings for persons with
certain preexisting conditions (excluding pregnancy) and all warnings
for persons experiencing certain symptoms.  The warnings under this
subheading are intended only for situations where consumers should not
use the product until a doctor is consulted.  Examples of such
situations include:  (1) high blood pressure, heart disease, thyroid
disease, glaucoma, diabetes, and other conditions listed in various OTC
drug monographs or approved drug applications and (2) certain types of
cough (i.e., persistent or chronic cough such as occurs with smoking,
asthma, or emphysema, or if cough is accompanied by excessive phlegm). 
For example, in the new Drug Facts format, these warnings would appear
as follows:

Ask a doctor before use if you have

heart disease

cough that occurs with too much phlegm (mucus) 

chronic cough that lasts as occurs with smoking, asthma, chronic
bronchitis, or emphysema 

(c)  Ask a doctor or pharmacist before use if you are  (§
201.66(c)(5)(v))

Information under this subheading includes all drug-drug and drug-food
interaction warnings.  Examples include:  sedatives or tranquilizers
with antihistamines and a prescription drug for asthma with an OTC
bronchodilator. 

(d)  When using this product (§ 201.66(c)(5)(vi))

Information under this subheading includes all side effects that
consumers may experience and identifies the substances (e.g., alcohol)
that could cause the side effect and the activity (e.g., operating
machinery, driving a car) that should be avoided while using the
product.  This subheading also includes warnings for drugs in dispensers
pressurized by gaseous propellants.  FDA recommends that such
information appear in bulleted text format as follows:

May cause drowsiness [or can appear as:  drowsiness may occur]

Alcohol, sedatives, and tranquilizers may increase the drowsiness effect
[or can               appear as: alcohol, sedatives, and tranquilizers
may increase drowsiness]

Do not puncture or incinerate.  Contents under pressure.  

(e)  Stop use and ask a doctor if   (§ 201.66(c)(vii))

Information under this subheading includes any signs of toxicity or
other reactions that would require a patient to immediately stop using
the product.  For example, the bulleted statement “you get nervous,
dizzy, or sleepless” would appear in this section.

(f)   Any [other] required warnings  (§ 201.66(c)(viii))

This location in the warnings section includes 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 above or below.  There are a limited number of such warnings. 
One such warning is the CFC warning required in certain approved drug
applications, which states:  “Contains CFC-[insert number] and
CFC-[insert number], substances, which harm public health and the
environment by destroying ozone in the upper atmosphere.”

(g)   Pregnancy and related warnings

When applicable, these types of warnings must also be placed in the
Warnings section.  Warnings may include one or more of the following:

The pregnancy/breast-feeding warning in § 201.63(a)

The third trimester warning in § 201.63(e) for products containing
aspirin or carbaspirin calcium

The third trimester warning in approved drug applications for products
containing ketoprofen, naproxen sodium, or ibuprofen (if not intended
exclusively for use in children)

(h)  Keep out of reach of children and the accidental overdose/ingestion
warnings in § 330.1(g)

In a few very special instances, the Keep-out-of-reach-of-children
warning can be omitted (see lipstick with a sunscreen in §
352.52(f)(1)(vi)).  The accidental overdose/ingestion warning can also
be omitted in some instances (see §§ 331.30(f), 332.30(c), 341.74(f)
and 352.52(f)(1)(v)).

(6)  Directions  (§ 201.66(c)(6))

Depending on the product, the directions can appear completely in a
table, as a number of bulleted statements, or as a combination of a
table and bulleted statements.  For example, a table format must be used
when dosage directions are provided for three or more age groups or
populations.  Dosage directions provided for one or two age groups or
populations can be presented using bulleted statements.   (See §§
201.66(d)(4)), 201.66(d)(9)) 

However, a table format can be used for two age groups or populations if
it helps make the presentation of the information clearer and easier to
read.  

FDA recommends that when a combination of a table and bulleted
statements is used, the bulleted statements (e.g., "do not use more than
directed") appear before or after the table.  FDA also recommends that
statements such as "shake well" appear as a separate bulleted statement
within the directions.  For example:

shake well

drink a full glass (8 oz) of liquid with each dose

do not use more than directed



adults and children 12 years and older	2 tablets every 6 hours 

children 6 -12 years	1 tablet every 6 hours 

children under 6 years	ask a doctor

(7)  Other Information   (§ 201.66(c)(7))

Information under this heading must contain information not included
under the other headings or subheadings, but is required or is made
optional under an OTC drug monograph, other OTC drug regulation, or
approved drug application.  

If present and required by the OTC drug regulation to be included in the
OTC drug labeling, certain ingredients in OTC drug products (e.g.,
sodium in § 201.64(c)) must appear as follows:  “each (insert
appropriate dosage unit) contains: [in bold type] (insert name(s) of
ingredient(s) and quantity of each ingredient).”   This statement must
be the first statement under this heading.

Under this heading, phenylalanine/aspartame content required by §
201.21(b), if applicable, must appear as the next bulleted statement as
follows: “Phenylketonurics:  Contains Phenylalanine (insert quantity)
mg per (insert appropriate dosage unit).”   

The tamper-evident statement must be prominently placed on the drug
product package to alert consumers about the product’s tamper-evident
features (21 CFR 211.132).  The tamper-evident statement describes the
tamper-evident feature of the product package and advises consumers
that, if the feature is breached or missing when the product is
purchased, tampering may have occurred.  Tamper-evident packaging with
an appropriate labeling statement will be more likely to protect
consumers because the consumer will be in a better position to detect
tampering when he or she has knowledge that a tamper-evident feature has
been incorporated into the product design.   The Agency allows
flexibility in the placement of this statement on the package and does
not require that it be included within the Drug Facts section.  However,
if included in this section, the statement must appear under the heading
"Other information" (see 21 CFR 201.66(c)(7)).  

The Agency also noted in the final rule preamble for the Drug Facts
regulation that many products are now marketed with "peel back" or "fold
out" labels affixed to the product package and that these labels could
be used to accommodate all of the FDA required information in the Drug
Facts section (64 FR 13254 at 13268; March 17, 1999).  These types of
labels were not in use at the time the tamper-evident requirements
became effective.  Recently, interested parties have inquired whether
the tamper-evident statement may be included in a Drug Facts section
that appears in such "peel back" or "fold out" labels.   We believe that
the goals of the tamper evident statement would likely not be achieved
if the statement only appears in a "peel back" or "fold out" label and
is not clearly visible without peeling back or folding out the label. 

It is important that the consumer view the tamper-evident statement
before purchase and use of the product so that he or she will be better
aware of the tamper-evident features and any signs of tampering.  Once
the consumer opens the tamper-evident package, the tamper-evident
features have been breached.  If the consumer has failed to examine
these features before opening, then the consumer will likely not know if
there were any signs of tampering.  A tamper-evident statement inside a
"peel back" or "fold out" label that is not visible on the outside of
the package is unlikely to be viewed before breach of the tamper evident
feature.  The consumer may not be aware to peel back or unfold this
label to view the tamper-evident statement before opening the package. 
Thus, we recommend that the statement not appear within the Drug Facts
box in a "peel back" or "fold out" label if the statement would not be
clearly visible without peeling back or folding out the label. We
recommend instead in these circumstances that the tamper evident
statement be outside the Drug Facts box in another part of the label
where the statement is clearly visible without further manipulation of
that label.  

For example, the above-mentioned statements would appear under this
heading as follows:

  

Other information

each tablet contains:  calcium 10 mg,  magnesium 10 mg,  and sodium 15
mg

Phenylketonurics:  Contains phenylalanine 10 mg per tablet

[insert storage information] 

[if applicable, insert tamper-evident statement]

(8)  Inactive ingredients  (§ 201.66(c)(8))

This section contains a list of inactive ingredients, using their
established names.  For OTC drug products (not cosmetic product), the
established names of inactive ingredients must be listed in alphabetical
order (§ 201.66(c)(8)).  For example:  Inactive ingredients colloidal
silicon dioxide, FD&C blue #1 lake, hydroxypropyl methylcellulose,
lactose, magnesium stearate, polyethylene glycol, povidone, propylene
glycol, titanium dioxide.

For an OTC product that is a drug-cosmetic product, the inactive
ingredients must be listed in order of predominance in the product
formulation (§ 201.66(c)(8)).  For example:  Inactive ingredients
water, sorbitan isostearate, sorbitol, triethanolamine, stearic acid,
barium sulfate, benzyl alcohol, dimethicone, methylparaben, aloe
extract, carbomer, disodium EDTA.

Note:  For ingredients that may be contained in the product, see section
VI(5) of this guidance document.

Questions? or Questions or comments? (§ 201.66(c)(9))

If this heading is included in the Drug Facts box (see 21 CFR
201.66(c)(9)), the telephone number or a source to answer questions
about the product must be included in this section.  FDA recommends that
the days of the week and times of the day when a person is available to
respond to questions also be included.  While this heading and
subsequent information are not required, the Agency recommends all
manufacturers, distributors, and repackers include this heading and
subsequent information within the Drug Facts box.

Although not permitted to appear in or otherwise interrupt the required
Drug Facts labeling information, brand names or product attributes can
appear in the telephone number and/or in the Web site address.  However,
if the telephone number appears as letters of the brand name or product
attribute, FDA recommends that the manufacturer also include the
numerical representation of the telephone number in this section. 

VI.	FORMAT LABELING REQUIREMENTS (21 CFR 201.66(d))

This section addresses the manner in which the title, headings,
subheadings, and other information set forth in § 201.66(c) must be
presented in the labeling of OTC drug products.  Sample annotated
graphics appear in Appendix A to part 201.

(1)  Use of bold type and mathematical notation

Where FDA regulations require bold print for specific information, FDA
recommends that manufacturers not use bold print for other information
in that immediate area (unless required by regulation to do so) because
this practice might reduce the emphasis on the FDA bold print
information. 

For easier understanding, fractions (e.g., 1/2) may be expressed in text
format (i.e., one-half) when used within the Drug Facts box or similar
enclosure.  The text must be in the same single, clear, easy-to-read
type style and type size used for the other text included in the Drug
Facts box.   However, if fractions are expressed in mathematical
notation, each component of the numerical notation must be no smaller
than 6-point type. 

Bulleted Statements

Bullets are a visual cue adopted by the Agency to aid in the
presentation of OTC drug or drug-cosmetic product labeling information. 
Bullets are a solid square or solid circle in a 5-point type size,
presented in the same shape and color throughout the labeling.  Under §
201.66(d)(4), bullets are required to be used in the following ways:

   

When there is more than one statement listed under the headings Uses,
Warnings, Directions, or Other information, or any subheadings under
these headings, each individual statement is preceded by a bullet (see
all examples below).

The first bulleted statement on each horizontal line of text is either
left justified or separated from an appropriate heading or subheading by
at least 2 square ems (i.e., 2 squares the size of the capital letter M
in the font being used).

If more than one bulleted statement is placed on the same horizontal
line, the end of one bulleted statement is separated from the beginning
of the next bulleted statement by at least 2 square ems and the complete
additional bulleted statements does not continue to the next line of
text. 

Note: If the modified format is used, additional bulleted statements can
continue to the next line of text.

Additional bulleted statements on each subsequent horizontal line of
text under a heading or subheading are vertically aligned with the
bulleted statements appearing on the previous line (see example 2.b.
below).  This requirement does not apply when the modified labeling
format (as described in section VII below) in § 201.66 (d)(10) is used
(see example 2.c. below).

If necessary, because of space constraints when using the standard
labeling format, the Agency would allow a single bulleted statement to
appear on the same line as a heading (except the heading Warnings) or a
subheading (see example 2.e. below).  If a bulleted statement is placed
on the same line as a heading or subheading, additional bulleted
statements that appear under the heading or subheading can either be
left justified (see example 2.e below) or aligned with the first
bulleted statement. 

If the size of the text is greater than 6-point type, FDA will allow in
its discretion that bullets be greater than 5-point type. 

   ● temporarily relieves pain and itching due to:

           ● insect bites   ● minor skin irritations

           ● rashes due to poison ivy, oak, and sumac

     ● dries the oozing and weeping of:

           ● poison ivy    ● poison oak    ● poison sumac

Note:  Align major bulleted statements and sub-bulleted statements.

b.  Ask a doctor before use if you have

     ● heart disease	  ●  glaucoma	    ●  high blood pressure

     ● thyroid disease	  ●  diabetes

     ● trouble urinating due to an enlarged prostate gland

     ● a breathing problem such as emphysema or chronic bronchitis

Note:  Multiple bulleted statements on same line are aligned with the
previous line of bulleted statements.  Any bulleted statements not able
to fit entirely on a multi-bulleted line must be left justified.

c.  [Modified format] Ask a doctor before use if you have  ● heart
disease  ● glaucoma

     ● high blood pressure  ● thyroid disease  ● diabetes  ●
trouble urinating due to an 

     enlarged prostate gland  ● a breathing problem such as emphysema
or chronic bronchitis 

Note:  No bullet alignment is required in the modified format; bulleted
statements can continue to the next line of text.

d.   Ask a doctor or pharmacist before use if you are taking a
prescription drug for:

      ● anticoagulation (blood thinning)  ● gout   ● diabetes  
● arthritis

Note:  Multiple bulleted statements are not required to appear on same
line as subheading.

e.  Directions  ● shake well

     ● adults and children 2 years and over: apply to affected area
not more than 3 to 4 times daily

     ● children under 2 years: ask a doctor

Note:  Bullets can appear on same line as headings and subheadings. 
However, no bulleted statements or text can appear on the same line as
the Warning heading.

(3)  Number of Label Panels/Column Format/Graphic

See separate guidance for industry entitled Labeling OTC Human Drug
Products Using a Column Format.

(4)   Active ingredient(s) and Purpose(s)

When there is more than one active ingredient, they are listed in
alphabetical order. Furthermore, when more than one active ingredient
has the same purpose, the purpose does not need to be repeated for each
ingredient if the information is presented in a manner that readily
associates each active ingredient with its purpose (by using brackets,
dot leaders, or other graphical features).  Examples include:

Active ingredients (in each tablet)                                     
                                            Purpose  

Acetaminophen 500 mg
........................................................................
Pain reliever/fever reducer

Pseudoephedrine HCl 30 mg
........................................................................
...Nasal decongestant

Triprolidine HCl 1.25
mg......................................................................
....................Antihistamine

Active ingredients                                                      
                                                     Purpose

Homosalate 6%  }

Oxybenzone 3%
}…………...........................................................
.................................Sunscreen

Padimate O 2%  }

Note:  Active ingredients with the same pharmacological activity can be
bracketed together to avoid repetitive listing of purpose.

Inactive ingredients:  "contains one or more of these ingredients"
labeling

There may be circumstances when manufacturers, repackers, and
distributors who market OTC drug products use multiple suppliers for
some products to maintain an uninterrupted supply of the product to
their customers.  In such cases, the specific inactive ingredients in
the products may vary slightly from supplier to supplier: some inactive
ingredients may be present in products coming from all suppliers while
other inactive ingredients may not be present. In order to have one
label for all products, FDA recommends that the ingredients that may (or
may not) be contained in each individual product be listed on the
labeling in the following manner. 

The Agency believes that this type of inactive ingredient labeling can
be accomplished best by placing those ingredients that may (or may not)
be contained in an OTC drug product in the inactive ingredient listing,
as set forth in § 201.66(c)(8), with an asterisk placed next to those
ingredients (e.g.,  acacia*, dextrose*, sucrose, xanthum gum*).  The
asterisk would then be reprinted at the bottom or end of the inactive
ingredient section in the Drug Facts box, with the notation “*
contains one or more of these ingredients” (if more than one
ingredient may (or may not) be in the product), or “* may contain this
ingredient” (if only one ingredient may (or may not) be in the
product), whichever is appropriate.  

FDA recommends that for product labeling using the standard labeling
format set forth in § 201.66, the statement (“* contains one or more
of these ingredients,” or  “* may contain this ingredient,”
whichever is appropriate) should be left justified at the end of the
inactive ingredient section.  For product labeling that uses the
modified format set forth in § 201.66(d)(10), the appropriate statement
should appear at the end of the inactive ingredient section with 2
square ems between the last inactive ingredient and the statement.  The
type size of these statements must be at least 6-point type (see 21 CFR
201.66(d)(2)).

Listing too many alternative ingredients could be misleading and could
cause consumer confusion.  To avoid such confusion, sponsors may wish to
consider using a second set of labels for products with a lengthy list
of different inactive ingredients.  Additionally, to provide consumers
with the opportunity to learn if an ingredient is in the lot number of
the product, the Agency recommends that the optional information in §
201.66(c)(9) (Questions? or Questions or comments? followed by the
telephone number of a source to answer questions about the product) be
included in labeling.

Sponsors are also reminded to follow all applicable current good
manufacturing practice regulations in 21 CFR part 211 for finished
pharmaceuticals so that manufacturers maintain appropriate records
showing which lot numbers of the product contain which inactive
ingredients.

(6)  HEADINGS: Uses, Warnings, Directions, Other Information, Inactive
Ingredients, and Questions — Information on Same Line as Heading

The information under any of these headings, except Warning(s), may
start on the same line as the heading.

None of the information under the heading Warning(s) can appear on the
same line as this heading (§ 201.66(d)(6)).  However, information under
any of the subheadings that appear under the heading Warning(s) can
start on the same line as the subheading.

(7)  Graphical Images/Pictograms

Graphical images (e.g., the American Dental Association seal, Good
Housekeeping seal, the Universal Product Code (UPC) symbol) cannot
appear in, or in any way interrupt, the information required in the Drug
Facts labeling (§ 201.66(d)(7)).  Below are examples of the possible
placement of the UPC graphic image:

Drug

Facts

Labeling

        (DF)	

	

DF	

	

DF

	

	

	

	

UPC

	

UPC	

	

A pictogram is a pictorial representation of some object used to
symbolize information.  The use of pictograms is voluntary in product
labeling.  If used, pictograms must not appear within the Drug Facts
labeling (see § 201.66(d)(7)).  The only allowed exception is the use
of a telephone or telephone receiver before the Questions heading (see§
201.66(c)(9)).  A pictogram that directs attention away from required
information, that is ambiguous, or that can be misunderstood by
consumers may render a product misbranded. 

Note:  product trade name and company name cannot appear in or in any
way interrupt the information required in the Drug Facts labeling.

(8)  Barlines/Hairlines  

All of the Drug Facts information must be set off in a box or similar
enclosure by the use of a barline (§ 201.66(d)(8)).  FDA recommends
size 2.5-point type.

A distinctive horizontal barline (recommended size 2.5-point type)
extending to each end of the Drug Facts box or similar enclosure must
separate each of the headings in the Drug Facts labeling (§
201.66(d)(8)). 

A horizontal hairline (recommended size 0.5-point type) extending within
two spaces on either side of the Drug Facts box or similar enclosure
must immediately follow the title Drug Facts (§ 201.66(d)(8)).

When a heading appears on a subsequent panel after the Drug Facts
(continued) title, a horizontal hairline (recommended size 0.5-point
type), rather than a barline, must follow the title and immediately
precede the heading (§ 201.66(d)(8)).

A horizontal hairline (recommended size 0.5-point type) extending within
two spaces on either side of the Drug Facts box or similar enclosure
must immediately precede each of the subheadings in the Warning(s)
section except for the subheadings in paragraphs (c)(5)(ii)(A) through
(c)(5)(ii)(G). The specific subheadings in these paragraphs are not
preceded by any horizontal hairlines. 

When a table is used as the last item of information in the Directions
section, the last line of the table may be the horizontal barline that
immediately precedes the heading of the next section of the labeling (§
201.66(d)(9)).

Examples of the use of barlines and hairlines appear in Appendix A to
part 201.  See also the guidance for industry entitled Labeling OTC
Human Drug Products Using a Column Format for additional information
when a column format is used in the labeling.

VII.	Standard AND MODIFIED LABELING FORMATS 

The regulation contains a formula that allows use of a modified labeling
format, which is described in § 201.66(d)(10).  When the required Drug
Facts content information in paragraph (c) printed as specified in
paragraph (d), plus any other FDA required information for drug or
drug-cosmetic products (other than information required to appear on the
principle display panel), requires more than 60 percent of the total
surface area available to bear labeling, the Drug Facts labeling must
appear in the modified labeling format.  In determining whether more
than 60 percent available labeling space is required, the indications
for use listed under the Uses(s) heading must be limited to the minimum
required uses reflected in the applicable monograph (see §
330.1(c)(2)).  Table 1 describes selected format requirements used in
the standard and modified labeling formats.

Table  1. — Comparison of Standard and Modified Labeling Formats

           Labeling Element           Standard Format			Modified Format

≥ 8-point  or 2-point type  greater than point size of text	≥
7-point or 1-point type greater than point size of text

Subheadings 	No smaller than 6-point type	No smaller than 6-point type

Bulleted text	No smaller than 6-point type	No smaller than 6-point type

Leading	Minimum 0.5-point type 	Less than 0.5-point type can be used,
provided the ascenders and descenders do not touch

Bullets	Minimum 5-point type

Vertical alignment	Minimum 5-point type

No alignment required

If you need assistance in making content or format conversions of
existing labeling to the new required labeling, you should contact the
Division of OTC Drug Products for guidance (see Appendix for contact
information).

VIII.	Topic-Specific Guidance documents

The Agency has developed several guidance documents to help
manufacturers, packers, and distributors implement the final rule
establishing standardized content and format requirements for the
labeling of all OTC drug products.  Currently available guidances
include:

ANDA labeling:  guidance for industry entitled Labeling OTC Human Drug
Products —Updating Labeling in ANDAs 

Column format:  guidance for industry entitled Labeling OTC Human Drug
Products —Using a Column Format 

IX.	OTHER fda LABELING REQUIREMENTS

In addition to the standardized content and format regulations, there
are other labeling requirements that may be applicable to the product
and that manufacturers, packers, and distributors are required to
follow.  The general labeling requirements in 21 CFR part 201 specify
what information must be included on a drug product's labeling and how
the information should be presented, among other things.  The Federal
Food, Drug, and Cosmetic Act (the Act) defines labeling in broad terms,
such that labeling means all labels and "other written, printed, or
graphic matter (1) upon any article or any of its containers or
wrappers, or (2) accompanying such article" (see section 201(m) of the
Act (21 U.S.C. 321(m)).  This definition does not require labeling to be
physically attached to a drug.  For example, an outer carton, a brochure
about the product, or a package insert is considered labeling.  Table 2
summarizes some of the other labeling requirements that may be
applicable in addition to the standardized content and format
requirements in 21 CFR 201.66.

Table 2.— General Labeling Requirements in 21 CFR Parts 201 and 211

Paragraph	Description of Paragraph

201.1 	Name and place of business of manufacturer, packer, or
distributor

201.5	Adequate directions for use

  201.17	Location of expiration dates

  201.18	Control numbers

  201.60	Principle Display Panel

  201.61	Statement of Identity

Established name of drug

Statement of general pharmacological category(ies) or the principal
intended actions

Bold type

Size related to the most  prominent printed matter

  201.62	Declaration of net quantity of contents

  201.63	Pregnancy/breast feeding warnings

   211.132(c) 	Tamper-evident labeling 

X.	IMPLEMENTATION OF THE OTC LABELING Requirements

Applicable implementation dates vary according to the regulatory status
of the OTC drug product (see Table 3 below).

FDA has granted a stay of compliance for implementation of the Drug
Facts Rule until further notice (67 FR 16304) for OTC drug products that
contain no more than two doses of an OTC drug product and, because of
their limited surface area available to bear labeling, qualify for the
labeling modifications set forth in § 201.66(d)(10).  

Table 3.— Implementation Chart

                                Products	                               
  Time periods*

Subject to NDA/ANDA:

Single entity products approved before May 16, 1999.	By May 2002 (or by
May 16, 2003, if annual sales of the product are less than $25,000).

Single entity products approved on or after May 16, 1999.	Immediately
upon approval of the application.

Combination products approved before May 16, 1999.	By May 2002 (or by
May 16, 2003, if annual sales of the product are less than $25,000).

Combination products approved on or after May 16, 1999.	Immediately upon
approval of the application.

Subject to OTC Drug Monograph(s):

Single entity products finalized before May 16, 1999.	By May 16, 2002
(or by May 16, 2003, if annual sales of the product are less than
$25,000).

Single entity products finalized on or after May 16, 1999.	Within the
period specified in the final monograph.  However, if a monograph has
not been finalized as of May 16, 2002, then the product must comply as
of the first major labeling revision after May 16, 2002, or May 16,
2005, whichever occurs first.

Combination products in which all applicable monographs were finalized
before May 16, 1999.	By May 16, 2002 (or by May 16, 2003, if annual
sales of the product are less than $25,000).

Combination products in which at least one applicable monograph was
finalized before May 16, 1999, and at least one applicable monograph is
finalized on or after May 16, 1999.	Within the period specified in the
last applicable monograph to be finalized, or by May 16, 2002 (or by May
16, 2003, if annual sales of the product are less than $25,000),
whichever occurs first, unless the last applicable monograph to be
finalized specifies a later date.

Combination products in which all applicable monographs are finalized on
or after May 16, 1999.	Within the period specified in the last
applicable monograph to be finalized.  However, if the last monograph is
not finalized as of May 16, 2002, then the product must comply as of the
first major labeling revision after May 16, 2002, or by May 16, 2005,
whichever occurs first.

All other single entity and combination OTC drug products (e.g.,
products in the OTC drug review that are not yet the subject of proposed
OTC drug monographs).	If a monograph has not been finalized as of May
16, 2002, then the product must comply as of the first major labeling
revision after May 16, 2002, or by May 16, 2005, whichever occurs first.

* Time delayed until further notice for OTC drug products that contain
no more than two doses of an OTC drug product and, because of their
limited total surface area available to bear labeling, qualify for the
labeling modifications set forth in § 201.66(d)(10).

The Appendix to this draft guidance document is provided for quick
reference to certain content and format requirements associated with key
labeling elements.  If you have questions on whether a particular FDA
requirement applies to your drug or drug-cosmetic product, please
contact the relevant office listed in the Appendix.

Appendix:  Summary of Labeling Requirements and Relevant contacts

Table I.  Labeling Content:  21 CFR 201.66(c)(1) through (c)(9)

      Paragraph

	

Description of Paragraph	

Comments

(c)(1)	Drug Facts, Drug Facts (continued)	Title to be used is Drug Facts
(on subsequent panels use Drug Facts (continued)

(c)(2)	Active ingredient, established name, quantity	For drug-cosmetic
products, the drug ingredients are considered the active ingredients,
and the cosmetic ingredients are considered the inactive ingredients.
See 21 CFR 201.66(b)(2), 21 CFR 201.66(b)(8),

 21 CFR 201.66(c)(8), and 21 CFR 701.3(a) and (f).  

(c)(3)	Purpose(s)	If there is no statement of identity or no applicable
OTC drug monograph, the ingredient purpose is stated based on its
general pharmacological category(ies), or the principal intended
action(s) of the drug.

(c)(4)	Use(s)	The use(s) is/are the specific indication(s) or approved
use(s) for the drug product. For drug-cosmetic products, the use in the
Drug Facts labeling is attributed only to the drug component.  See 21
CFR 201.66(c)(4).

(c)(5)	Warning(s)	Warning(s) information appears in a specific order,
under the heading Warnings, as applicable.  Most warnings follow
specific subheadings, as described below in (c)(5)(i) through (c)(5)(x).

(c)(5)(i)	For external/rectal/ vaginal use only	Appears in bold type. 
In some instances, the external-use-only warning can be omitted.  For
example, OTC lip protectant drug products may omit this warning (21 CFR
347.50(e)(1)(iii)). 

(c)(5)(ii)	All applicable warnings	Appear with subheadings highlighted
in bold type.

(c)(5)(ii)(A)	

Reye’s syndrome warning 	When this warning is required, it is the
first warning of the warnings listed in paragraphs (c)(5)(ii)(A) through
 (c)(5)(ii)(G) to appear in this location in the Warnings labeling.

(c)(5)(ii)(B)	Allergic reaction warnings 	Subheading Allergy alert is
used.

(c)(5)(ii)(C)	Flammability warning, with appropriate signal   word	The
appropriate flammability signal word in an approved drug application or
OTC drug monograph is used.

(c)(5)(ii)(D)	Water soluble gum          warning, Choking	The subheading
Choking is used.

(c)(5)(ii)(E)	 Alcohol warning 	Subheading Alcohol warning is used.

(c)(5)(ii)(F)	 Sore throat warning	Subheading Sore throat warning is
used.

(c)(5)(ii)(G)	

 Dosage warning	The warnings in § 201.307(b)(2)(i) or (b)(2)(ii) for
drug products containing sodium phosphates.  The subheading Dosage
warning is used.

(c)(5)(iii)	 Do not use followed by all contraindications	Subheading
used for all absolute contraindications and involve several different
types of situations.

(c)(5)(iv)	 Ask a doctor before use if you have	Subheading used for
certain preexisting conditions or when experiencing certain symptoms.  

(c)(5)(v)	 Ask a doctor or pharmacist before use if you are	Subheading
used for all drug-drug and drug-food interactions.

(c)(5)(vi)	When using this product	Subheading used for all side effects
that the consumer may experience; identifies substances or activities
that should be avoided while using the product.

(c)(5)(vii)	Stop use and ask a doctor if	Subheading used for any signs
of toxicity or other reactions that would necessitate immediately
discontinuing use of product.

(c)(5)(viii)	Any required warnings	Location used to include any other
required warnings that do not fit within §§ 201.66(c)(5)(i) through
(c)(5)(vii),(c)(5)(ix), and (e)(5)(x).

(c)(5)(ix)	The pregnancy/breast     feeding warning	General warning and
other related warnings.

(c)(5)(x)	Keep out of reach of children	General warning and accidental
overdose/ingestion warning in § 330.1(g).

(c)(6)	Directions	Described in an applicable OTC drug monograph or
approved drug application.

(c)(7)	Other information and additional information not included in
(c)(2) – (c)(6), (c)(8), (c)(9) of this section.	Subheading used for
additional information that is not included under the other subheadings,
but which is required or is made optional under an OTC drug
monograph(s), other OTC drug regulation(s), or approved drug
application.

(c)(7)(i)	certain ingredients 

(e.g. Na)	For example, see § 201.64(b)

(c)(7)(ii)	Phenylalanine	See § CFR 201.21(b)

(c)(7)(iii)	additional information	For example: storage conditions,
tamper-evident statement

(c)(8)	Inactive ingredients	List of each inactive ingredient, using its
established name

(c)(9)	Questions?  (or Questions or Comments?)	Optional subheading used
to provide a telephone number of a source to answer questions about the
product.

Table II.  Labeling Format: 21 CFR 201.66(d)(1) through (d)(9)

Paragraph

	

Description of Paragraph

(d)(1)	Drug Facts: first letter of words uppercase

“	Headings, subheadings: first letter of first word uppercase

“	Left justification

      (d)(2) 	Drug Facts type size greater than largest type size used
in Drug Facts labeling

“	Heading 8-pt or 2-pt type sizes greater than text point size

    “    	≥ 6-pt type size for information in Drug Facts

“	Subheadings ≥ 6-pt type size

   “    	Drug Facts (continued):  type size no smaller than 8-pt type

(d)(3)	Letters do not touch

“	 ≥ 0.5 pt leading  (space between lines)

“	No more than 39 characters per inch

“	Bold Italic headings and title

“	Bold subheading, except the phrase “(continued)”

“	Contrasting dark color for title and heading

(d)(4)	Bullet: solid circle or square 5-pt type, same shape and color,
left justified or separated from heading or subheading by at least two
square ems

“	Bullet on same lines:  end of statement separated from bulleted
statement by two em spaces 

“	Bullet on same lines:  additional bulleted statement does not
continue on next line

“	Vertical alignment of bulleted statements

(d)(5)	Appear on more than one panel

“	Visual graphic signals continuation

(d)(6)	Left justification of information required by (c)(2)

“	Right justification of information required by (c)(3)

“	Alphabetical order of active ingredients

“	Information required by (c)(4), (c)(6) - (c)(9) may start on same
line as required headings

“	None of information required in (c)(5) shall appear on same line as
Warnings

 (d)(7)	Graphical images should not interrupt the heading, subheading
and information.  Hyphens should not be used except to punctuate
compound words.

(d)(8)	Enclosed box using barline

“	Horizontal barline separates headings listed in (c)(2) - (c)(9)

          “ 	Horizontal hairline immediately follows the title "Drug
Facts (continued)", and immediately precedes a heading or subsequent
text that follows after this title.

“	Horizontal hairline extending within 2 spaces on either side of the
Drug Facts box shall immediately follow the title and precede the
subheadings set forth in (c)(5) [except (c)(5) (ii) A – G]

(d)(9)	Directions in table format when dosage instructions are provided
for three or more age groups or populations

“	Horizontal barline preceding the next heading may end the table

For additional information, contact the relevant office or division. 

Office of Compliance (HFD-310)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

301-827-8958 or 301-827-8959

or

.

0

8

C

X

Y

Z

z

|

~

ž

Ÿ

¢

A

C

K

U

V

h

i

j

x

y

{

␃愁Ĥᰀ{

|

‰

Š

£

¤

¥

¦

§

¨

«

¬

·

¸

Ñ

Ò

Ó

Ô

Õ

Ö

Ú

Û

á

ð

ñ

ó

ô

õ

᣿

ᆰ

萑ː葠ː



摫3

kdä

ì

w

ì

kd>

w

kdë

w

ì

眀



ਁ氃愀϶ΖༀDivision of OTC Drug Products (HFD-560)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

301-827-2222

or

Office of Cosmetics and Colors (HFS-105)

Center for Food Safety and Applied Nutrition

Food and Drug Administration

200 C Street, SW.

Washington, DC 20204

202-205-4061

 This guidance has been prepared by the Division of Over-the-Counter
(OTC) Drug Products in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration. 

 Products with both drug and cosmetic attributes.  For example, a
sunscreen product intended for sunscreen (i.e., drug) uses and for
moisturizing (i.e., cosmetic) uses.

 See http://www.fda.gov/cder/otc/label/label-fr-reg.htm.

See Appendix A(I) to this draft guidance document for a general summary
of content labeling requirements set forth in § 201.66(c).

 Title means the heading listed at the top of the required OTC drug
product labeling, as set forth in § 201.66(c)(1).

 The word (continued) appears in regular type.

 Warning statements for drug products containing or manufactured with
chlorofluorocarbons or other ozone-depleting substances (see §
201.320).

 See Appendix A(II) to this draft guidance document for a general
summary of content labeling requirements set forth in § 201.66(c).

 A barline is a distinctive horizontal line that extends to each end of
the Drug Facts box or similar enclosure and provides separation between
each of the headings listed in § 201.66(c)(2) through (c)(9) (§
201.66(d)(8)).  A hairline is a distinctive horizontal line that extends
within two spaces on either side of the Drug Facts box or similar
enclosure (§ 201.66(d)(8)).  This line immediately follows the title
Drug Facts and the title Drug Facts (continued) on subsequent panels and
immediately precedes each of the subheadings set forth in §
201.66(c)(5), except the subheadings in § 201.66(c)(5)(ii)(A) through
(c)(5)(ii)(G).

 A draft guidance has been issued on EXEMPTIONS AND DEFERRALS (§
201.66(e)).  Once finalized, this guidance will contain the Agency's
recommendations on this topic. 

 PAGE   

  FILENAME \p  J:\!GUIDANC\5204dft.doc 

  DATE \@ "M/d/yyyy"  11/29/2004 

  FILENAME \p  J:\!GUIDANC\5204dft.doc 

  DATE \@ "M/d/yyyy"  11/29/2004 

Contains Nonbinding Recommendations

Draft — Not for Implementation

  FILENAME \p  J:\!GUIDANC\5204dft.doc 

  DATE \@ "M/d/yyyy"  11/29/2004 

 PAGE   13 

  FILENAME \p  J:\!GUIDANC\5204dft.doc 

  DATE \@ "M/d/yyyy"  11/29/2004