[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2021 Edition]
[From the U.S. Government Publishing Office]
[[Page i]]
Title 21
Food and Drugs
________________________
Parts 200 to 299
Revised as of April 1, 2021
Containing a codification of documents of general
applicability and future effect
As of April 1, 2021
Published by the Office of the Federal Register
National Archives and Records Administration as a
Special Edition of the Federal Register
[[Page ii]]
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[[Page iii]]
Table of Contents
Page
Explanation................................................. v
Title 21:
Chapter I--Food and Drug Administration, Department
of Health and Human Services (Continued) 3
Finding Aids:
Table of CFR Titles and Chapters........................ 241
Alphabetical List of Agencies Appearing in the CFR...... 261
List of CFR Sections Affected........................... 271
[[Page iv]]
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Cite this Code: CFR
To cite the regulations in
this volume use title,
part and section number.
Thus, 21 CFR 200.5 refers
to title 21, part 200,
section 5.
----------------------------
[[Page v]]
EXPLANATION
The Code of Federal Regulations is a codification of the general and
permanent rules published in the Federal Register by the Executive
departments and agencies of the Federal Government. The Code is divided
into 50 titles which represent broad areas subject to Federal
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name of the issuing agency. Each chapter is further subdivided into
parts covering specific regulatory areas.
Each volume of the Code is revised at least once each calendar year
and issued on a quarterly basis approximately as follows:
Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1
The appropriate revision date is printed on the cover of each
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LEGAL STATUS
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HOW TO USE THE CODE OF FEDERAL REGULATIONS
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To determine whether a Code volume has been amended since its
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EFFECTIVE AND EXPIRATION DATES
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OMB CONTROL NUMBERS
The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires
Federal agencies to display an OMB control number with their information
collection request.
[[Page vi]]
Many agencies have begun publishing numerous OMB control numbers as
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PAST PROVISIONS OF THE CODE
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``[RESERVED]'' TERMINOLOGY
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(a) The incorporation will substantially reduce the volume of
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(b) The matter incorporated is in fact available to the extent
necessary to afford fairness and uniformity in the administrative
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(c) The incorporating document is drafted and submitted for
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What if the material incorporated by reference cannot be found? If
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CFR INDEXES AND TABULAR GUIDES
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this volume.
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that volume.
[[Page vii]]
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Oliver A. Potts,
Director,
Office of the Federal Register
April 1, 2021.
[[Page ix]]
THIS TITLE
Title 21--Food and Drugs is composed of nine volumes. The parts in
these volumes are arranged in the following order: Parts 1-99, 100-169,
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300 to end.
The first eight volumes, containing parts 1-1299, comprise Chapter I--
Food and Drug Administration, Department of Health and Human Services.
The ninth volume, containing part 1300 to end, includes Chapter II--Drug
Enforcement Administration, Department of Justice, and Chapter III--
Office of National Drug Control Policy. The contents of these volumes
represent all current regulations codified under this title of the CFR
as of April 1, 2021.
For this volume, Susannah C. Hurley was Chief Editor. The Code of
Federal Regulations publication program is under the direction of John
Hyrum Martinez, assisted by Stephen J. Frattini.
[[Page 1]]
TITLE 21--FOOD AND DRUGS
(This book contains parts 200 to 299)
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Part
chapter i--Food and Drug Administration, Department of
Health and Human Services (Continued)..................... 200
[[Page 3]]
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF
HEALTH AND HUMAN SERVICES (CONTINUED)
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Editorial Note: Nomenclature changes to chapter I appear at 59 FR
14366, Mar. 28, 1994, and 66 FR 56035, Nov. 6, 2001.
SUBCHAPTER C--DRUGS: GENERAL
Part Page
200 General..................................... 5
201 Labeling.................................... 8
202 Prescription drug advertising............... 107
203 Prescription drug marketing................. 116
205 Guidelines for State licensing of wholesale
prescription drug distributors.......... 129
206 Imprinting of solid oral dosage form drug
products for human use.................. 134
207 Requirements for foreign and domestic
establishment registration and listing
for human drugs, including drugs that
are regulated under a biologics license
application, and animal drugs, and the
national drug code...................... 135
208 Medication Guides for prescription drug
products................................ 151
209 Requirement for authorized dispensers and
pharmacies to distribute a side effects
statement............................... 154
210 Current good manufacturing practice in
manufacturing, processing, packing, or
holding of drugs; general............... 156
211 Current good manufacturing practice for
finished pharmaceuticals................ 158
212 Current good manufacturing practice for
positron emission tomography drugs...... 179
216 Human drug compounding...................... 188
225 Current good manufacturing practice for
medicated feeds......................... 191
226 Current good manufacturing practice for Type
A medicated articles.................... 198
250 Special requirements for specific human
drugs................................... 203
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251 Section 804 importation program............. 211
290 Controlled drugs............................ 235
299 Drugs; official names and established names. 236
[[Page 5]]
SUBCHAPTER C_DRUGS: GENERAL
PART 200_GENERAL--Table of Contents
Subpart A_General Provisions
Sec.
200.5 Mailing of important information about drugs.
200.7 Supplying pharmacists with indications and dosage information.
200.10 Contract facilities (including consulting laboratories) utilized
as extramural facilities by pharmaceutical manufacturers.
200.11 Use of octadecylamine in steam lines of drug establishments.
200.15 Definition of term ``insulin''.
Subpart B [Reserved]
Subpart C_Requirements for Specific Classes of Drugs
200.50 Ophthalmic preparations and dispensers.
200.51 Aqueous-based drug products for oral inhalation.
Subpart D [Reserved]
Subpart E_Prescription Drug Consumer Price Listing
200.200 Prescription drugs; reminder advertisements and reminder
labeling to provide price information to consumers.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360e, 371,
374, 375.
Source: 40 FR 13996, Mar. 27, 1975, unless otherwise noted.
Subpart A_General Provisions
Sec. 200.5 Mailing of important information about drugs.
Manufacturers and distributors of drugs and the Food and Drug
Administration occasionally are required to mail important information
about drugs to physicians and others responsible for patient care. In
the public interest, such mail should be distinctive in appearance so
that it will be promptly recognized and read. The Food and Drug
Administration will make such mailings in accordance with the
specifications set forth in this section. Manufacturers and distributors
of drugs are asked to make such mailings as prescribed by this section
and not to use the distinctive envelopes for ordinary mail.
(a) Use first class mail and No. 10 white envelopes.
(b) The name and address of the agency or the drug manufacturer or
distributor is to appear in the upper left corner of the envelope.
(c) The following statements are to appear in the far left third of
the envelope front, in the type and size indicated, centered in a
rectangular space approximately 3 inches wide and 2\1/4\ inches high
with an approximately \3/8\ inch-wide border in the color indicated:
(1) When the information concerns a significant hazard to health,
the statement:
IMPORTANT
DRUG
WARNING
The statement shall be in three lines, all capitals, and centered.
``Important'' shall be in 36 point Gothic Bold type. ``Drug'' and
``Warning'' shall be in 36 point Gothic Condensed type. The rectangle's
border and the statement therein shall be red.
(2) When the information concerns important changes in drug package
labeling, the statement:
IMPORTANT
PRESCRIBING
INFORMATION
The statement shall be in three lines, all capitals, and centered.
``Important'' shall be in 36 point Gothic Bold type. ``Prescribing'' and
``Information'' shall be in 36 point Gothic Condensed type. The
rectangle's border and the statement therein shall be blue.
(3) When the information concerns a correction of prescription drug
advertising or labeling, the statement:
[[Page 6]]
IMPORTANT
CORRECTION
OF DRUG
INFORMATION
The statement shall be in four lines, all capitals, and centered.
``Important'' shall be in 36 point Gothic Bold type. ``Correction,''
``Of Drug,'' and ``Information'' shall be in 36 point Gothic Condensed
type. The rectangle's border and the statement therein shall be brown.
Sec. 200.7 Supplying pharmacists with indications and dosage
information.
There are presently no regulations under the Federal Food, Drug, and
Cosmetic Act that prevent a manufacturer of prescription drugs from
sending the pharmacist data he needs on indications and dosage in
exercising his important professional function of checking against
possible mistakes in a prescription. The Food and Drug Administration
believes manufacturers should be encouraged to supply such printed
matter to the pharmacist for his professional information. Obviously,
such printed matter should not be displayed to prospective purchasers to
promote over-the-counter sale of prescription drugs.
Sec. 200.10 Contract facilities (including consulting laboratories)
utilized as extramural facilities by pharmaceutical manufacturers.
(a) Section 704(a) of the Federal Food, Drug, and Cosmetic Act
specifically authorizes inspection of consulting laboratories as well as
any factory, warehouse, or establishment in which prescription drugs are
manufactured, processed, packed, or held.
(b) The Food and Drug Administration is aware that many
manufacturers of pharmaceutical products utilize extramural independent
contract facilities, such as testing laboratories, contract packers or
labelers, and custom grinders, and regards extramural facilities as an
extension of the manufacturer's own facility.
(c) The Food and Drug Administration reserves the right to disclose
to the pharmaceutical manufacturer, or to the applicant of a new drug
application (NDA) or to the sponsor of an Investigational New Drug (IND)
Application, any information obtained during the inspection of an
extramural facility having a specific bearing on the compliance of the
manufacturer's, applicant's, or sponsor's product with the Federal Food,
Drug, and Cosmetic Act. The Food and Drug Administration's position is
that by the acceptance of such contract work, the extramural facility
authorizes such disclosures.
(d) The Food and Drug Administration does not consider results of
validation studies of analytical and assay methods and control
procedures to be trade secrets that may be withheld from the drug
manufacturer by the contracted extramural facility.
[40 FR 13996, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Sec. 200.11 Use of octadecylamine in steam lines of drug
establishments.
The Food and Drug Administration will not object to the use of
octadecylamine in steam lines where the steam may be used for
autoclaving surgical instruments and gauze if the octadecylamine in the
steam is not more than 2.4 parts per million.
Sec. 200.15 Definition of term ``insulin.''
For purposes of sections 801 and 802 of the act and this title, the
term insulin means the active principle of the pancreas that affects the
metabolism of carbohydrates in the animal body and which is of value in
the treatment of diabetes mellitus. The term includes synthetic and
biotechnologically derived products that are the same as, or similar to,
naturally occurring insulins in structure, use, and intended effect and
are of value in the treatment of diabetes mellitus.
[63 FR 26698, May 13, 1998]
Subpart B [Reserved]
Subpart C_Requirements for Specific Classes of Drugs
Sec. 200.50 Ophthalmic preparations and dispensers.
(a)(1) Informed medical opinion is in agreement that all
preparations offered
[[Page 7]]
or intended for ophthalmic use, including preparations for cleansing the
eyes, should be sterile. It is further evident that such preparations
purport to be of such purity and quality as to be suitable for safe use
in the eye.
(2) The Food and Drug Administration concludes that all such
preparations, if they are not sterile, fall below their professed
standard of purity or quality and may be unsafe. In a statement of
policy issued on September 1, 1964, the Food and Drug Administration
ruled that liquid preparations offered or intended for ophthalmic use
that are not sterile may be regarded as adulterated within the meaning
of section 501(c) of the Federal Food, Drug, and Cosmetic Act (the act),
and, further, may be deemed misbranded within the meaning of section
502(j) of the act. This ruling is extended to affect all preparations
for ophthalmic use. By this regulation, this ruling is applicable to
ophthalmic preparations that are regulated as drugs. By the regulation
in Sec. 800.10 of this chapter, this ruling is applicable to ophthalmic
preparations that are regulated as medical devices.
(3) The containers of ophthalmic preparations shall be sterile at
the time of filling and closing, and the container or individual carton
shall be so sealed that the contents cannot be used without destroying
the seal. The packaging and labeling of ophthalmic preparations that are
over-the-counter drugs shall also comply with Sec. 211.132 of this
chapter on tamper-resistant packaging requirements.
(b) Liquid ophthalmic preparations packed in multiple-dose
containers should:
(1) Contain one or more suitable and harmless substances that will
inhibit the growth of microorganisms; or
(2) Be so packaged as to volume and type of container and so labeled
as to duration of use and with such necessary warnings as to afford
adequate protection and minimize the hazard of injury resulting from
contamination during use.
(c) Eye cups, eye droppers, and other dispensers intended for
ophthalmic use should be sterile, and may be regarded as falling below
their professed standard of purity or quality if they are not sterile.
These articles, which are regulated as drugs if packaged with the drugs
with which they are to be used, should be packaged so as to maintain
sterility until the package is opened and be labeled, on or within the
retail package, so as to afford adequate directions and necessary
warnings to minimize the hazard of injury resulting from contamination
during use.
[40 FR 13996, Mar. 27, 1975, as amended at 47 FR 50455, Nov. 5, 1982]
Sec. 200.51 Aqueous-based drug products for oral inhalation.
(a) All aqueous-based drug products for oral inhalation must be
manufactured to be sterile.
(b) Manufacturers must also comply with the requirements in Sec.
211.113(b) of this chapter.
[65 FR 34089, May 26, 2000]
Subpart D [Reserved]
Subpart E_Prescription Drug Consumer Price Listing
Sec. 200.200 Prescription drugs; reminder advertisements and
reminder labeling to provide price information to consumers.
(a) Prescription drug reminder advertisements and reminder labeling
intended to provide price information to consumers are exempt from the
requirements of Sec. Sec. 201 .100 and 202.1 of this chapter if all of
the following conditions are met:
(1) The only purpose of the reminder advertisement or reminder
labeling is to provide consumers with information concerning the price
charged for a prescription for a particular drug product, and the
reminder advertisement or reminder labeling contains no representation
or suggestion concerning the drug product's safety, effectiveness, or
indications for use.
(2) The reminder advertisement or reminder labeling contains the
proprietary name of the drug product, if any; the established (generic)
name of the drug product, if any; the drug product's strength if the
product contains a single active ingredient or if the product contains
more than one active ingredient and a relevant strength can be
[[Page 8]]
associated with the product without indicating each active ingredient
(the established name and quantity of each active ingredient are not
required); the dosage form; and the price charged for a prescription for
a specific quantity of the drug product.
(3) The reminder advertisement or reminder labeling may also include
other written, printed, or graphic matter, e.g., identification of
professional or convenience services provided by the pharmacy: Provided,
That such information is neither false nor misleading and contains no
representation or suggestion concerning the drug product's safety,
effectiveness, or indications for use.
(4) The price stated in the reminder advertisement or reminder
labeling as that charged for a prescription shall include all charges to
the consumer including, but not limited to, the cost of the drug
product, professional fees, and handling fees, if any. Mailing fees and
delivery fees, if any, may be stated separately and without repetition.
(b) This exemption from Sec. Sec. 201.100 and 202.1 of this chapter
is applicable to all prescription drug reminder labeling and reminder
advertisements solely intended to provide consumers with information
regarding the price charged for prescriptions including price lists,
catalogs, and other promotional material, whether mailed, posted in a
pharmacy, placed in a newspaper, or aired on radio or television.
(c) Any reminder advertisement or reminder labeling intended to
provide consumers with prescription price information which is not in
compliance with this section shall be the subject of appropriate
regulatory action. Such action may be taken against the product and/or
the responsible person.
[40 FR 58799, Dec. 18, 1975]
PART 201_LABELING--Table of Contents
Subpart A_General Labeling Provisions
Sec.
201.1 Drugs; name and place of business of manufacturer, packer, or
distributor.
201.2 Drugs and devices; National Drug Code numbers.
201.5 Drugs; adequate directions for use.
201.6 Drugs; misleading statements.
201.10 Drugs; statement of ingredients.
201.15 Drugs; prominence of required label statements.
201.16 Drugs; Spanish-language version of certain required statements.
201.17 Drugs; location of expiration date.
201.18 Drugs; significance of control numbers.
201.19 Drugs; use of term ``infant''.
201.20 Declaration of presence of FD&C Yellow No. 5 and/or FD&C Yellow
No. 6 in certain drugs for human use.
201.21 Declaration of presence of phenylalanine as a component of
aspartame in over-the-counter and prescription drugs for human
use.
201.22 Prescription drugs containing sulfites; required warning
statements.
201.23 Required pediatric studies.
201.24 Labeling for systemic antibacterial drug products.
201.25 Bar code label requirements.
201.26 Exceptions or alternatives to labeling requirements for human
drug products held by the Strategic National Stockpile.
Subpart B_Labeling Requirements for Prescription Drugs and/or Insulin
201.50 Statement of identity.
201.51 Declaration of net quantity of contents.
201.55 Statement of dosage.
201.56 Requirements on content and format of labeling for human
prescription drug and biological products.
201.57 Specific requirements on content and format of labeling for human
prescription drug and biological products described in Sec.
201.56(b)(1).
201.58 Waiver of labeling requirements.
Subpart C_Labeling Requirements for Over-the-Counter Drugs
201.60 Principal display panel.
201.61 Statement of identity.
201.62 Declaration of net quantity of contents.
201.63 Pregnancy/breast-feeding warning.
201.64 Sodium labeling.
201.66 Format and content requirements for over-the-counter (OTC) drug
product labeling.
201.70 Calcium labeling.
201.71 Magnesium labeling.
201.72 Potassium labeling.
201.80 Specific requirements on content and format of labeling for human
prescription drug and biological products; older drugs not
described in Sec. 201.56(b)(1).
Subpart D_Exemptions From Adequate Directions for Use
201.100 Prescription drugs for human use.
201.105 Veterinary drugs.
201.115 New drugs or new animal drugs.
[[Page 9]]
201.116 Drugs having commonly known directions.
201.117 Inactive ingredients.
201.119 In vitro diagnostic products.
201.120 Prescription chemicals and other prescription components.
201.122 Drugs for processing, repacking, or manufacturing.
201.125 Drugs for use in teaching, law enforcement, research, and
analysis.
201.127 Drugs; expiration of exemptions.
201.128 Meaning of ``intended uses''.
201.129 Drugs; exemption for radioactive drugs for research use.
Subpart E_Other Exemptions
201.150 Drugs; processing, labeling, or repacking.
201.161 Medical gases.
Subpart F_Labeling Claims for Drugs in Drug Efficacy Study
201.200 Disclosure of drug efficacy study evaluations in labeling and
advertising.
Subpart G_Specific Labeling Requirements for Specific Drug Products
201.300 Notice to manufacturers, packers, and distributors of glandular
preparations.
201.301 Notice to manufacturers, packers, and distributors of estrogenic
hormone preparations.
201.302 Notice to manufacturers, packers, and distributors of drugs for
internal use which contain mineral oil.
201.303 Labeling of drug preparations containing significant proportions
of wintergreen oil.
201.304 Tannic acid and barium enema preparations.
201.305 Isoproterenol inhalation preparations (pressurized aerosols,
nebulizers, powders) for human use; warnings.
201.306 Potassium salt preparations intended for oral ingestion by man.
201.307 Sodium phosphates; package size limitation, warnings, and
directions for over-the-counter sale.
201.308 Ipecac syrup; warnings and directions for use for over-the-
counter sale.
201.309 Acetophenetidin (phenacetin)-containing preparations; necessary
warning statement.
201.310 Phenindione; labeling of drug preparations intended for use by
man.
201.311 [Reserved]
201.312 Magnesium sulfate heptahydrate; label declaration on drug
products.
201.313 Estradiol labeling.
201.314 Labeling of drug preparations containing salicylates.
201.315 Over-the-counter drugs for minor sore throats; suggested
warning.
201.316 Drugs with thyroid hormone activity for human use; required
warning.
201.317 Digitalis and related cardiotonic drugs for human use in oral
dosage forms; required warning.
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.
201.320 Warning statements for drug products containing or manufactured
with chlorofluorocarbons or other ozone-depleting substances.
201.323 Aluminum in large and small volume parenterals used in total
parenteral nutrition.
201.325 Over-the-counter drugs for vaginal contraceptive and spermicide
use containing nonoxynol 9 as the active ingredient; required
warnings and labeling information.
201.326 Over-the-counter drug products containing internal analgesic/
antipyretic active ingredients; required warnings and other
labeling.
201.327 Over-the-counter sunscreen drug products; required labeling
based on effectiveness testing.
201.328 Labeling of medical gas containers.
Appendix A to Part 201--Examples of Graphic Enhancements Used by FDA
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.
Source: 40 FR 13998, Mar. 27, 1975, unless otherwise noted.
Editorial Note: Nomenclature changes to part 201 appear at 69 FR
13717, Mar. 24, 2004.
Subpart A_General Labeling Provisions
Sec. 201.1 Drugs; name and place of business of manufacturer,
packer, or distributor.
(a) A drug or drug product (as defined in Sec. 320.1 of this
chapter) in finished package form is misbranded under section 502 (a)
and (b)(1) of the act if its label does not bear conspicuously the name
and place of business of the manufacturer, packer, or distributor. This
paragraph does not apply to any drug or drug product dispensed in
accordance with section 503(b)(1) of the act.
[[Page 10]]
(b) As used in this section, and for purposes of section 502 (a) and
(b)(1) of the act, the manufacturer of a drug product is the person who
performs all of the following operations that are required to produce
the product: (1) Mixing, (2) granulating, (3) milling, (4) molding, (5)
lyophilizing, (6) tableting, (7) encapsulating, (8) coating, (9)
sterilizing, and (10) filling sterile, aerosol, or gaseous drugs into
dispensing containers.
(c) If no person performs all of the applicable operations listed in
paragraph (b) of this section, no person may be represented as
manufacturer except as follows:
(1) If the person performs more than one half of the applicable
operations listed in paragraph (b) of this section and acknowledges the
contribution of other persons who have performed the remaining
applicable operations by stating on the product label that ``Certain
manufacturing operations have been performed by other firms.''; or
(2) If the person performs at least one applicable operation listed
in paragraph (b) of this section and identifies by appropriate
designation all other persons who have performed the remaining
applicable operations, e.g., ``Made by (Person A), Filled by (Person B),
Sterilized by (Person C)''; or
(3) If the person performs at least one applicable operation listed
in paragraph (b) of this section and the person is listed along with all
other persons who have performed the remaining applicable operations as
``joint manufacturers.'' A list of joint manufacturers shall be
qualified by the phrase ``Jointly Manufactured By ______,'' and the
names of all of the manufacturers shall be printed together in the same
type size and style; or
(4) If the person performs all applicable operations listed in
paragraph (b) of this section except for those operations listed in
paragraph (d) of this section. For purposes of this paragraph, person,
when it identifies a corporation, includes a parent, subsidiary, or
affiliate company where the related companies are under common ownership
and control.
(d) The Food and Drug Administration finds that it is the common
practice in the drug industry to contract out the performance of certain
manufacturing operations listed in paragraph (b) of this section. These
operations include: (1) Soft-gelatin encapsulating, (2) aerosol filling,
(3) sterilizing by irradiation, (4) lyophilizing, and (5) ethylene oxide
sterilization.
(e) A person performs an operation listed in paragraph (b) of this
section only if the operation is performed, including the performance of
the appropriate in-process quality control operations, except laboratory
testing of samples taken during processing, as follows:
(1) By individuals, a majority of whom are employees of the person
and, throughout the performance of the operation, are subject to the
person's direction and control;
(2) On premises that are continuously owned or leased by the person
and subject to the person's direction and control; and
(3) On equipment that is continuously owned or leased by the person.
As used in this paragraph, person, when it identifies a corporation,
includes a parent, subsidiary, or affiliate company where the related
companies are under common ownership and control.
(f) The name of the person represented as manufacturer under
paragraph (b) or (c) of this section must be the same as either (1) the
name of the establishment (as defined in Sec. 207.1 of this chapter)
under which that person is registered at the time the labeled product is
produced or (2) the registered establishment name of a parent,
subsidiary, or affiliate company where the related companies are under
common ownership and control. In addition, the name shall meet the
requirements of paragraph (g) of this section.
(g) The requirement for declaration of the name of the manufacturer,
packer, or distributor shall be deemed to be satisfied, in the case of a
corporate person, only by the actual corporate name, except that the
corporate name may be the name of a parent, subsidiary, or affiliate
company where the related companies are under common ownership and
control. The corporate name may be preceded or followed by the name of
the particular division of
[[Page 11]]
the corporation. ``Company,'' ``Incorporated,'' etc., may be abbreviated
or omitted and ``The'' may be omitted. In the case of an individual,
partnership, or association, the name under which the business is
conducted shall be used.
(h)(1) Except as provided in this section, no person other than the
manufacturer, packer, or distributor may be identified on the label of a
drug or drug product.
(2) The appearance on a drug product label of a person's name
without qualification is a representation that the named person is the
sole manufacturer of the product. That representation is false and
misleading, and the drug product is misbranded under section 502(a) of
the act, if the person is not the manufacturer of the product in
accordance with this section.
(3) If the names of two or more persons appear on the label of a
drug or drug product, the label may identify which of the persons is to
be contacted for further information about the product.
(4) If a trademark appears on the drug or drug product label or
appears as a mark directly on the drug product (e.g., tablet or
capsule), the label may identify the holder or licensee of the
trademark. The label may also state whether the person identified holds
the trademark or is licensee of the trademark.
(5) If the distributor is named on the label, the name shall be
qualified by one of the following phrases: ``Manufactured for ______'',
``Distributed by ______'', ``Manufactured by ______ for ______'',
``Manufactured for _____by _____'', ``Distributor: ______'', ``Marketed
by ______''. The qualifying phrases may be abbreviated.
(6) If the packer is identified on the label, the name shall be
qualified by the phrase ``Packed by ______'' or ``Packaged by ______''.
The qualifying phrases may be abbreviated.
(i) The statement of the place of business shall include the street
address, city, State, and ZIP Code. For a foreign manufacturer, the
statement of the place of business shall include the street address,
city, country, and any applicable mailing code. The street address may
be omitted if it is shown in a current city directory or telephone
directory. The requirement for inclusion of the ZIP Code shall apply to
consumer commodity labels developed or revised after July 1, 1969. In
the case of nonconsumer packages, the ZIP Code shall appear either on
the label or the labeling (including the invoice).
(j) If a person manufactures, packs, or distributes a drug or drug
product at a place other than the person's principal place of business,
the label may state the principal place of business in lieu of the
actual place where such drug or drug product was manufactured or packed
or is to be distributed, unless such statement would be misleading.
(k) Paragraphs (b), (c), (d), (e), and (f) of this section, do not
apply to the labeling of drug components.
(l) A drug product is misbranded under section 502(a) of the act if
its labeling identifies a person as manufacturer, packer, or
distributor, and that identification does not meet the requirements of
this section.
(m) This section does not apply to biological drug products that are
subject to the requirements of section 351 of the Public Health Service
Act, 42 U.S.C. 262.
[45 FR 25775, Apr. 15, 1980; 45 FR 72118, Oct. 31, 1980, as amended at
48 FR 37620, Aug. 19, 1983; 81 FR 60212, Aug. 31, 2016]
Sec. 201.2 Drugs and devices; National Drug Code numbers.
The National Drug Code (NDC) number is requested but not required to
appear on all drug labels and in all drug labeling, including the label
of any prescription drug container furnished to a consumer.
[40 FR 52002, Nov. 7, 1975, as amended at 81 FR 60212, Aug. 31, 2016]
Sec. 201.5 Drugs; adequate directions for use.
Adequate directions for use means directions under which the layman
can use a drug safely and for the purposes for which it is intended.
(Section 201.128 defines ``intended use.'') Directions for use may be
inadequate because, among other reasons, of omission, in whole or in
part, or incorrect specification of:
[[Page 12]]
(a) Statements of all conditions, purposes, or uses for which such
drug is intended, including conditions, purposes, or uses for which it
is prescribed, recommended, or suggested in its oral, written, printed,
or graphic advertising, and conditions, purposes, or uses for which the
drug is commonly used; except that such statements shall not refer to
conditions, uses, or purposes for which the drug can be safely used only
under the supervision of a practitioner licensed by law and for which it
is advertised solely to such practitioner.
(b) Quantity of dose, including usual quantities for each of the
uses for which it is intended and usual quantities for persons of
different ages and different physical conditions.
(c) Frequency of administration or application.
(d) Duration of administration or application.
(e) Time of administration or application (in relation to time of
meals, time of onset of symptoms, or other time factors).
(f) Route or method of administration or application.
(g) Preparation for use, i.e., shaking, dilution, adjustment of
temperature, or, other manipulation or process.
[41 FR 6908, Feb. 13, 1976]
Sec. 201.6 Drugs; misleading statements.
(a) Among representations in the labeling of a drug which render
such drug misbranded is a false or misleading representation with
respect to another drug or a device or a food or cosmetic.
(b) The labeling of a drug which contains two or more ingredients
may be misleading by reason, among other reasons, of the designation of
such drug in such labeling by a name which includes or suggests the name
of one or more but not all such ingredients, even though the names of
all such ingredients are stated elsewhere in the labeling.
[41 FR 6908, Feb. 13, 1976]
Sec. 201.10 Drugs; statement of ingredients.
(a) The ingredient information required by section 502(e) of the
Federal Food, Drug, and Cosmetic Act shall appear together, without any
intervening written, printed, or graphic matter, except the proprietary
names of ingredients, which may be included with the listing of
established names, and such statements that are specifically required
for certain ingredients by the act or regulations in this chapter.
(b) The term ingredient applies to any substance in the drug,
whether added to the formulation as a single substance or in admixture
with other substances.
(c) The labeling of a drug may be misleading by reason (among other
reasons) of:
(1) The order in which the names of the ingredients present in the
drug appear in the labeling, or the relative prominence otherwise given
such names.
(2) Failure to reveal the proportion of, or other fact with respect
to, an ingredient present in such drug, when such proportion or other
fact is material in the light of the representation that such ingredient
is present in such drug.
(3) The employment of a fanciful proprietary name for a drug or
ingredient in such a manner as to imply that the drug or ingredient has
some unique effectiveness or composition when, in fact, the drug or
ingredient is a common substance, the limitations of which are readily
recognized when the drug or ingredient is listed by its established
name.
(4) The featuring in the labeling of inert or inactive ingredients
in a manner that creates an impression of value greater than their true
functional role in the formulation.
(5) Designation of a drug or ingredient by a proprietary name that,
because of similarity in spelling or pronunciation, may be confused with
the proprietary name or the established name of a different drug or
ingredient.
(d)(1) If the drug is in tablet or capsule form or other unit dosage
form, any statement of the quantity of an ingredient contained therein
shall express the quantity of such ingredient in each such unit. If the
drug is not in unit dosage form, any statement of the quantity of an
ingredient contained therein shall express the amount of such ingredient
in a specified unit of
[[Page 13]]
weight or measure of the drug, or the percentage of such ingredient in
such drug. Such statements shall be in terms that are informative to
licensed practitioners, in the case of a prescription drug, and to the
layman, in the case of a nonprescription drug.
(2) A statement of the percentage of an ingredient in a drug shall,
if the term percent is used without qualification, mean percent weight-
in-weight, if the ingredient and the drug are both solids, or if the
ingredient is a liquid and the drug is a solid; percent weight in volume
at 68 [deg]F. (20 [deg]C.), if the ingredient is a solid and the drug is
a liquid; and percent volume in volume at 68 [deg]F. (20 [deg]C.), if
both the ingredient and the drug are liquids, except that alcohol shall
be stated in terms of percent volume of absolute alcohol at 60 [deg]F.
(15.56 [deg]C.).
(e) A derivative or preparation of a substance named in section
502(e) of the act is an article derived or prepared from such substance
by any method, including actual or theoretical chemical action.
(f) If an ingredient is a derivative or preparation of a substance
specifically named in section 502(e) of the act and the established name
of such ingredient does not indicate that it is a derivative or
preparation of the parent substance named in section 502(e) of the act,
the labeling shall, in conjunction with the listing of the established
name of such ingredient, declare that such article is a derivative or
preparation of such parent substance.
(g)(1) If the label or labeling of a prescription drug bears a
proprietary name or designation for the drug or any ingredient thereof,
the established name, if such there be, corresponding to such
proprietary name or designation shall accompany such proprietary name or
designation each time it is featured on the label or in the labeling for
the drug; but, except as provided in this subparagraph, the established
name need not be used with the proprietary name or designation in the
running text of the label or labeling. On any label or page of labeling
in which the proprietary name or designation is not featured but is used
in the running text, the established name shall be used at least once in
the running text in association with such proprietary name or
designation and in the same type size used in such running text:
Provided, however, That if the proprietary name or designation is used
in the running text in larger size type, the established name shall be
used at least once in association with, and in type at least half as
large as the type used for, the most prominent presentation of the
proprietary name or designation in such running text. If any labeling
includes a column with running text containing detailed information as
to composition, prescribing, side effects, or contraindications and the
proprietary name or designation is used in such column but is not
featured above or below the column, the established name shall be used
at least once in such column of running text in association with such
proprietary name or designation and in the same type size used in such
column of running text: Provided, however, That if the proprietary name
or designation is used in such column of running text in larger size
type, the established name shall be used at least once in association
with, and in type at least half as large as the type used for, the most
prominent presentation of the proprietary name or designation in such
column of running text. Where the established name is required to
accompany or to be used in association with the proprietary name or
designation, the established name shall be placed in direct conjunction
with the proprietary name or designation, and the relationship between
the proprietary name or designation and the established name shall be
made clear by use of a phrase such as ``brand of'' preceding the
established name, by brackets surrounding the established name, or by
other suitable means.
(2) The established name shall be printed in letters that are at
least half as large as the letters comprising the proprietary name or
designation with which it is joined, and the established name shall have
a prominence commensurate with the prominence with which such
proprietary name or designation appears, taking into account all
pertinent factors, including typography, layout, contrast, and other
printing features.
[[Page 14]]
(h)(1) In the case of a prescription drug containing two or more
active ingredients, if the label bears a proprietary name or designation
for such mixture and there is no established name corresponding to such
proprietary name or designation, the quantitative ingredient information
required on the label by section 502(e) of the act shall be placed in
direct conjunction with the most prominent display of the proprietary
name or designation. The prominence of the quantitative ingredient
information shall bear a reasonable relationship to the prominence of
the proprietary name.
(2) If the drug is packaged in a container too small to bear the
quantitative ingredient information on the main display panel, the
quantitative ingredient information required by section 502(e) of the
act may appear elsewhere on the label, even though the proprietary name
or designation appears on the main display panel of the label; but side-
or back-panel placement shall in this case be so arranged and printed as
to provide size and prominence of display reasonably related to the size
and prominence of the front-panel display.
(i) A drug packaged in a container too small or otherwise unable to
accommodate a label with sufficient space to bear the information
required for compliance with section 502(e)(1) (A)(ii) and (B) of the
act shall be exempt from compliance with those clauses: Provided, That:
(1) The label bears:
(i) The proprietary name of the drug;
(ii) The established name, if such there be, of the drug;
(iii) An identifying lot or control number; and
(iv) The name of the manufacturer, packer, or distributor of the
drug; and
(2) All the information required to appear on the label by the act
and the regulations in this chapter appears on the carton or other outer
container or wrapper if such carton, outer container, or wrapper has
sufficient space to bear such information, or such complete label
information appears on a leaflet with the package.
[40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]
Sec. 201.15 Drugs; prominence of required label statements.
(a) A word, statement, or other information required by or under
authority of the act to appear on the label may lack that prominence and
conspicuousness required by section 502(c) of the act by reason, among
other reasons, of:
(1) The failure of such word, statement, or information to appear on
the part or panel of the label which is presented or displayed under
customary conditions of purchase;
(2) The failure of such word, statement, or information to appear on
two or more parts or panels of the label, each of which has sufficient
space therefor, and each of which is so designed as to render it likely
to be, under customary conditions of purchase, the part or panel
displayed;
(3) The failure of the label to extend over the area of the
container or package available for such extension, so as to provide
sufficient label space for the prominent placing of such word,
statement, or information;
(4) Insufficiency of label space for the prominent placing of such
word, statement, or information, resulting from the use of label space
for any word, statement, design, or device which is not required by or
under authority of the act to appear on the label;
(5) Insufficiency of label space for the prominent placing of such
word, statement, or information, resulting from the use of label space
to give materially greater conspicuousness to any other word, statement,
or information, or to any design or device; or
(6) Smallness or style of type in which such word, statement, or
information appears, insufficient background contrast, obscuring designs
or vignettes, or crowding with other written, printed, or graphic
matter.
(b) No exemption depending on insufficiency of label space, as
prescribed in regulations promulgated under section 502 (b) or (e) of
the act, shall apply if such insufficiency is caused by:
(1) The use of label space for any word, statement, design, or
device which is not required by or under authority of the act to appear
on the label;
(2) The use of label space to give greater conspicuousness to any
word,
[[Page 15]]
statement, or other information than is required by section 502(c) of
the act; or
(3) The use of label space for any representation in a foreign
language.
(c)(1) All words, statements, and other information required by or
under authority of the act to appear on the label or labeling shall
appear thereon in the English language: Provided, however, That in the
case of articles distributed solely in the Commonwealth of Puerto Rico
or in a Territory where the predominant language is one other than
English, the predominant language may be substituted for English.
(2) If the label contains any representation in a foreign language,
all words, statements, and other information required by or under
authority of the act to appear on the label shall appear thereon in the
foreign language.
(3) If the labeling contains any representation in a foreign
language, all words, statements, and other information required by or
under authority of the act to appear on the label or labeling shall
appear on the labeling in the foreign language.
[41 FR 6908, Feb. 13, 1976]
Sec. 201.16 Drugs; Spanish-language version of certain required statements.
An increasing number of medications restricted to prescription use
only are being labeled solely in Spanish for distribution in the
Commonwealth of Puerto Rico where Spanish is the predominant language.
Such labeling is authorized under Sec. 201.15(c). One required warning,
the wording of which is fixed by law in the English language, could be
translated in various ways, from literal translation to loose
interpretation. The statutory nature of this warning requires that the
translation convey the meaning properly to avoid confusion and dilution
of the purpose of the warning. Section 503(b)(4) of the Federal Food,
Drug, and Cosmetic Act requires, at a minimum, that the label bear the
statement ``Rx only.'' The Spanish-language version of this must be
``Solamente Rx''.
[67 FR 4906, Feb. 1, 2002]
Sec. 201.17 Drugs; location of expiration date.
When an expiration date of a drug is required, e.g., expiration
dating of drug products required by Sec. 211.137 of this chapter, it
shall appear on the immediate container and also the outer package, if
any, unless it is easily legible through such outer package. However,
when single-dose containers are packed in individual cartons, the
expiration date may properly appear on the individual carton instead of
the immediate product container.
[43 FR 45076, Sept. 29, 1978]
Sec. 201.18 Drugs; significance of control numbers.
The lot number on the label of a drug should be capable of yielding
the complete manufacturing history of the package. An incorrect lot
number may be regarded as causing the article to be misbranded.
Sec. 201.19 Drugs; use of term ``infant''.
The regulations affecting special dietary foods (Sec. 105.3(e) of
this chapter) define an infant as a child not more than 12 months old.
Apart from this, the Food and Drug Administration has not established
any definition of the term infant. Some question has arisen whether, for
the purposes of drug labeling, an infant means a child up to 1 year of
age or a child up to 2 years of age. Until the term is more precisely
defined by legislation or formal regulation, where the exact meaning of
the term is significant, manufacturers should qualify any reference to
``infant'' to indicate whether it refers to a child who is not more than
1 year of age, or a child not more than 2 years of age.
[40 FR 13998, Mar. 27, 1975, as amended at 42 FR 14091, Mar. 15, 1977;
44 FR 16006, Mar. 16, 1979]
Sec. 201.20 Declaration of presence of FD&C Yellow No. 5 and/or
FD&C Yellow No. 6 in certain drugs for human use.
(a) The label for over-the-counter and prescription drug products
intended for human use administered orally, nasally, rectally, or
vaginally, or for use in the area of the eye, containing
[[Page 16]]
FD&C Yellow No. 5 as a color additive using the names FD&C Yellow No. 5
and tartrazine. The labeling for over-the-counter and prescription drug
products shall bear a statement such as ``Contains FD&C Yellow No. 5
(tartrazine) as a color additive'' or ``Contains color additives
including FD&C Yellow No. 5 (tartrazine)''. The labels of certain drug
products subject to this labeling requirement that are also cosmetics,
such as antibacterial mouthwashes and fluoride toothpastes, need not
comply with this requirement provided they comply with the requirements
of Sec. 701.3 of this chapter.
(b) For prescription drugs for human use containing FD&C Yellow No.
5 that are administered orally, nasally, vaginally, or rectally, or for
use in the area of the eye, the labeling required by Sec. 201.100(d)
shall bear the warning statement ``This product contains FD&C Yellow No.
5 (tartrazine) which may cause allergic-type reactions (including
bronchial asthma) in certain susceptible persons. Although the overall
incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general
population is low, it is frequently seen in patients who also have
aspirin hypersensitivity.'' This warning statement shall appear in the
``Precautions'' section of the labeling.
(c) The label for over-the-counter drug products intended for human
use administered orally, nasally, rectally, or vaginally containing FD&C
Yellow No. 6 shall specifically declare the presence of FD&C Yellow No.
6 by listing the color additive using the name FD&C Yellow No. 6. The
labeling for over-the-counter and prescription drug products containing
FD&C Yellow No. 6 shall declare the presence of FD&C Yellow No. 6. The
labels of certain drug products subject to this labeling requirement
that are also cosmetics, such as antibacterial mouthwashes and fluoride
toothpastes, need not comply with this requirement provided they comply
with the requirements of Sec. 701.3 of this chapter.
[45 FR 60422, Sept. 12, 1980, as amended at 51 FR 41783, Nov. 19, 1986;
52 FR 21509, June 8, 1987; 59 FR 60898, Nov. 29, 1994]
Effective Date Note: At 53 FR 49138, Dec. 6, 1988, Sec. 201.20(c)
was suspended pending further agency action.
Sec. 201.21 Declaration of presence of phenylalanine as a
component of aspartame in over-the-counter and prescription drugs
for human use.
(a) Aspartame is the methylester of a dipeptide composed of two
amino acids, phenylalanine and aspartic acid. When these two amino acids
are so combined to form aspartame (1-methyl N-L-[alpha]-aspartyl-L-
phenylalanine), they produce an intensely sweet-tasting substance,
approximately 180 times as sweet as sucrose. The Food and Drug
Administration has determined that aspartame when used at a level no
higher than reasonably required to perform its intended technical
function is safe for use as an inactive ingredient in human drug
products, provided persons with phenylketonuria, who must restrict
carefully their phenylalanine intake, are alerted to the presence of
phenylalanine in the drug product and the amount of the ingredient in
each dosage unit.
(b) The label and labeling of all over-the-counter human drug
products containing aspartame as an inactive ingredient shall bear a
statement to the following effect: Phenylketonurics: Contains
Phenylalanine (_)mg Per (Dosage Unit).
(c) The package labeling and other labeling providing professional
use information concerning prescription drugs for human use containing
aspartame as an inactive ingredient shall bear a statement to the
following effect under the ``Precautions'' section of the labeling, as
required in Sec. 201.57(f)(2): Phenylketonurics: Contains Phenylalanine
(_)mg Per (Dosage Unit).
(d) Holders of approved new drug applications who reformulate their
drug products under the provisions of this section shall submit
supplements under Sec. 314.70 of this chapter to provide for the new
composition and the labeling changes.
(Approved by the Office of Management and Budget under control number
0910-0242)
[52 FR 2111, Jan. 20, 1987; 52 FR 12152, Apr. 15, 1987; 53 FR 4135, Feb.
12, 1988]
[[Page 17]]
Sec. 201.22 Prescription drugs containing sulfites; required
warning statements.
(a) Sulfites are chemical substances that are added to certain drug
products to inhibit the oxidation of the active drug ingredient.
Oxidation of the active drug ingredient may result in instability and a
loss of potency of the drug product. Examples of specific sulfites used
to inhibit this oxidation process include sodium bisulfite, sodium
metabisulfite, sodium sulfite, potassium bisulfite, and potassium
metabisulfite. Recent studies have demonstrated that sulfites may cause
allergic-type reactions in certain susceptible persons, especially
asthmatics. The labeling for any prescription drug product to which
sulfites have been added as an inactive ingredient, regardless of the
amount added, must bear the warning specified in paragraph (b) or (c) of
this section.
(b) The labeling required by Sec. Sec. 201.57 and 201.100(d) for
prescription drugs for human use containing a sulfite, except
epinephrine for injection when intended for use in allergic or other
emergency situations, shall bear the warning statement ``Contains
(insert the name of the sulfite, e.g., sodium metabisulfite), a sulfite
that may cause allergic-type reactions including anaphylactic symptoms
and life-threatening or less severe asthmatic episodes in certain
susceptible people. The overall prevalence of sulfite sensitivity in the
general population is unknown and probably low. Sulfite sensitivity is
seen more frequently in asthmatic than in nonasthmatic people.'' This
statement shall appear in the ``Warnings'' section of the labeling.
(c) The labeling required by Sec. Sec. 201.57 and 201.100(d) for
sulfite-containing epinephrine for injection for use in allergic
emergency situations shall bear the warning statement ``Epinephrine is
the preferred treatment for serious allergic or other emergency
situations even though this product contains (insert the name of the
sulfite, e.g., sodium metabisulfite), a sulfite that may in other
products cause allergic-type reactions including anaphylactic symptoms
or life-threatening or less severe asthmatic episodes in certain
susceptible persons. The alternatives to using epinephrine in a life-
threatening situation may not be satisfactory. The presence of a
sulfite(s) in this product should not deter administration of the drug
for treatment of serious allergic or other emergency situations.'' This
statement shall appear in the ``Warnings'' section of the labeling.
[51 FR 43904, Dec. 5, 1986]
Sec. 201.23 Required pediatric studies.
(a) A manufacturer of a marketed drug product, including a
biological drug product, that is used in a substantial number of
pediatric patients, or that provides a meaningful therapeutic benefit
over existing treatments for pediatric patients, as defined in
Sec. Sec. 314.55(c)(5) and 601.27(c)(5) of this chapter, but whose
label does not provide adequate information to support its safe and
effective use in pediatric populations for the approved indications may
be required to submit an application containing data adequate to assess
whether the drug product is safe and effective in pediatric populations.
The application may be required to contain adequate evidence to support
dosage and administration in some or all pediatric subpopulations,
including neonates, infants, children, and adolescents, depending upon
the known or appropriate use of the drug product in such subpopulations.
The applicant may also be required to develop a pediatric formulation
for a drug product that represents a meaningful therapeutic benefit over
existing therapies for pediatric populations for whom a pediatric
formulation is necessary, unless the manufacturer demonstrates that
reasonable attempts to produce a pediatric formulation have failed.
(b) The Food and Drug Administration (FDA) may by order, in the form
of a letter, after notifying the manufacturer of its intent to require
an assessment of pediatric safety and effectiveness of a pediatric
formulation, and after offering an opportunity for a written response
and a meeting, which may include an advisory committee meeting, require
a manufacturer to submit an application containing the information or
request for approval of a pediatric formulation described in paragraph
(a) of this section within a
[[Page 18]]
time specified in the order, if FDA finds that:
(1) The drug product is used in a substantial number of pediatric
patients for the labeled indications and the absence of adequate
labeling could pose significant risks to pediatric patients; or
(2) There is reason to believe that the drug product would represent
a meaningful therapeutic benefit over existing treatments for pediatric
patients for one or more of the claimed indications, and the absence of
adequate labeling could pose significant risks to pediatric patients.
(c)(1) An applicant may request a full waiver of the requirements of
paragraph (a) of this section if the applicant certifies that:
(i) Necessary studies are impossible or highly impractical because,
e.g., the number of such patients is so small or geographically
dispersed, or
(ii) There is evidence strongly suggesting that the product would be
ineffective or unsafe in all pediatric age groups.
(2) An applicant may request a partial waiver of the requirements of
paragraph (a) of this section with respect to a specified pediatric age
group, if the applicant certifies that:
(i) The product:
(A) Does not represent a meaningful therapeutic benefit over
existing therapies for pediatric patients in that age group, and
(B) Is not likely to be used in a substantial number of patients in
that age group, and
(C) The absence of adequate labeling could not pose significant
risks to pediatric patients; or
(ii) Necessary studies are impossible or highly impractical because,
e.g., the number of patients in that age group is so small or
geographically dispersed, or
(iii) There is evidence strongly suggesting that the product would
be ineffective or unsafe in that age group, or
(iv) The applicant can demonstrate that reasonable attempts to
produce a pediatric formulation necessary for that age group have
failed.
(3) FDA shall grant a full or partial waiver, as appropriate, if the
agency finds that there is a reasonable basis on which to conclude that
one or more of the grounds for waiver specified in paragraphs (c)(2) or
(c)(3) of this section have been met. If a waiver is granted on the
ground that it is not possible to develop a pediatric formulation, the
waiver will cover only those pediatric age groups requiring that
formulation. If a waiver is granted because there is evidence that the
product would be ineffective or unsafe in pediatric populations, this
information will be included in the product's labeling.
(d) If a manufacturer fails to submit a supplemental application
containing the information or request for approval of a pediatric
formulation described in paragraph (a) of this section within the time
specified by FDA, the drug product may be considered misbranded or an
unapproved new drug or unlicensed biologic.
[63 FR 66668, Dec. 2, 1998]
Sec. 201.24 Labeling for systemic antibacterial drug products.
The labeling of all systemic drug products intended for human use
indicated to treat a bacterial infection, except a mycobacterial
infection, must bear the following statements:
(a) At the beginning of the label, under the product name, the
labeling must state:
To reduce the development of drug-resistant bacteria and maintain
the effectiveness of (insert name of antibacterial drug product) and
other antibacterial drugs, (insert name of antibacterial drug product)
should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by bacteria.
(b) In the ``Indications and Usage'' section, the labeling must
state:
To reduce the development of drug-resistant bacteria and maintain
the effectiveness of (insert name of antibacterial drug product) and
other antibacterial drugs, (insert name of antibacterial drug product)
should be used only to treat or prevent infections that are proven or
strongly suspected to be caused by susceptible bacteria. When culture
and susceptibility information are available, they should be considered
in selecting or modifying antibacterial therapy. In the absence of such
data, local epidemiology and susceptibility patterns may contribute to
the empiric selection of therapy.
[[Page 19]]
(c) In the ``Precautions'' section, under the ``General''
subsection, the labeling must state:
Prescribing (insert name of antibacterial drug product) in the
absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient
and increases the risk of the development of drug-resistant bacteria.
(d) In the ``Precautions'' section, under the ``Information for
Patients'' subsection, the labeling must state:
Patients should be counseled that antibacterial drugs including
(insert name of antibacterial drug product) should only be used to treat
bacterial infections. They do not treat viral infections (e.g., the
common cold). When (insert name of antibacterial drug product) is
prescribed to treat a bacterial infection, patients should be told that
although it is common to feel better early in the course of therapy, the
medication should be taken exactly as directed. Skipping doses or not
completing the full course of therapy may (1) decrease the effectiveness
of the immediate treatment and (2) increase the likelihood that bacteria
will develop resistance and will not be treatable by (insert name of
antibacterial drug product) or other antibacterial drugs in the future.
[68 FR 6081, Feb. 6, 2003]
Sec. 201.25 Bar code label requirements.
(a) Who is subject to these bar code requirements? Manufacturers,
repackers, relabelers, and private label distributors of a human
prescription drug product or an over-the-counter (OTC) drug product that
is regulated under the Federal Food, Drug, and Cosmetic Act or the
Public Health Service Act are subject to these bar code requirements
unless they are exempt from the registration and drug listing
requirements in section 510 of the Federal Food, Drug, and Cosmetic Act.
(b) What drugs are subject to these bar code requirements? The
following drug products are subject to the bar code label requirements:
(1) Prescription drug products, however:
(i) The bar code requirement does not apply to the following
entities:
(A) Prescription drug samples;
(B) Allergenic extracts;
(C) Intrauterine contraceptive devices regulated as drugs;
(D) Medical gases;
(E) Radiopharmaceuticals; and
(F) Low-density polyethylene form fill and seal containers that are
not packaged with an overwrap.
(ii) The bar code requirement does not apply to prescription drugs
sold by a manufacturer, repacker, relabeler, or private label
distributor directly to patients, but versions of the same drug product
that are sold to or used in hospitals are subject to the bar code
requirements.
(2) Biological products; and
(3) OTC drug products that are dispensed pursuant to an order and
are commonly used in hospitals. For purposes of this section, an OTC
drug product is ``commonly used in hospitals'' if it is packaged for
hospital use, labeled for hospital use (or uses similar terms), or
marketed, promoted, or sold to hospitals.
(c) What does the bar code look like? Where does the bar code go?
(1) Each drug product described in paragraph (b) of this section must
have a bar code that contains, at a minimum, the appropriate National
Drug Code (NDC) number in a linear bar code that meets European Article
Number/Uniform Code Council (EAN/UCC) or Health Industry Business
Communications Council (HIBCC) standards or another standard or format
that has been approved by the relevant Food and Drug Administration
Center Director. Additionally, the bar code must:
(i) Be surrounded by sufficient blank space so that the bar code can
be scanned correctly; and
(ii) Remain intact under normal conditions of use.
(2) The bar code must appear on the drug's label as defined by
section 201(k) of the Federal Food, Drug, and Cosmetic Act.
(d) Can a drug be exempted from the bar code requirement? (1) On our
own initiative, or in response to a written request from a manufacturer,
repacker, relabeler or private label distributor, we may exempt a drug
product from the bar code label requirements set forth in this section.
The exemption request must document why:
(i) compliance with the bar code requirement would adversely affect
the safety, effectiveness, purity or potency of the drug or not be
technologically
[[Page 20]]
feasible, and the concerns underlying the request could not reasonably
be addressed by measures such as package redesign or use of overwraps;
or
(ii) an alternative regulatory program or method of product use
renders the bar code unnecessary for patient safety.
(2) Requests for an exemption should be sent to the Office of
Compliance, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, Silver Spring, MD
20993-0002 (requests involving a drug product or biological product
regulated by the Center for Drug Evaluation and Research) or to the Food
and Drug Administration, Center for Biologics Evaluation and Research,
Document Control Center, 10903 New Hampshire Ave., Bldg. 71, Rm. G112,
Silver Spring, MD 20993-0002 (requests involving a biological product
regulated by the Center for Biologics Evaluation and Research).
[69 FR 9170, Feb. 26, 2004, as amended at 76 FR 12847, Mar. 9, 2011; 80
FR 18090, Apr. 3, 2015; 81 FR 60212, Aug. 31, 2016]
Sec. 201.26 Exceptions or alternatives to labeling requirements for
human drug products held by the Strategic National Stockpile.
(a) The appropriate FDA Center Director may grant an exception or
alternative to any provision listed in paragraph (f) of this section and
not explicitly required by statute, for specified lots, batches, or
other units of a human drug product, if the Center Director determines
that compliance with such labeling requirement could adversely affect
the safety, effectiveness, or availability of such product that is or
will be included in the Strategic National Stockpile.
(b)(1)(i) A Strategic National Stockpile official or any entity that
manufactures (including labeling, packing, relabeling, or repackaging),
distributes, or stores a human drug product that is or will be included
in the Strategic National Stockpile may submit, with written concurrence
from a Strategic National Stockpile official, a written request for an
exception or alternative described in paragraph (a) of this section to
the Center Director.
(ii) The Center Director may grant an exception or alternative
described in paragraph (a) of this section on his or her own initiative.
(2) A written request for an exception or alternative described in
paragraph (a) of this section must:
(i) Identify the specified lots, batches, or other units of the
human drug product that would be subject to the exception or
alternative;
(ii) Identify the labeling provision(s) listed in paragraph (f) of
this section that are the subject of the exception or alternative
request;
(iii) Explain why compliance with such labeling provision(s) could
adversely affect the safety, effectiveness, or availability of the
specified lots, batches, or other units of a human drug product that are
or will be held in the Strategic National Stockpile;
(iv) Describe any proposed safeguards or conditions that will be
implemented so that the labeling of the product includes appropriate
information necessary for the safe and effective use of the product,
given the anticipated circumstances of use of the product;
(v) Provide a draft of the proposed labeling of the specified lots,
batches, or other units of the human drug product subject to the
exception or alternative; and
(vi) Provide any other information requested by the Center Director
in support of the request.
(c) The Center Director must respond in writing to all requests
under this section.
(d) A grant of an exception or alternative under this section will
include any safeguards or conditions deemed appropriate by the Center
Director so that the labeling of product subject to the exception or
alternative includes the information necessary for the safe and
effective use of the product, given the anticipated circumstances of
use.
(e) If you are a sponsor receiving a grant of a request for an
exception or alternative to the labeling requirements under this
section:
(1) You need not submit a supplement under Sec. 314.70(a) through
(c) or Sec. 601.12(f)(1) through (f)(2) of this chapter; however,
(2) You must report any grant of a request for an exception or
alternative
[[Page 21]]
under this section as part of your annual report under Sec. Sec.
314.70(d) or 601.12(f)(3) of this chapter.
(f) The Center Director may grant an exception or alternative under
this section to the following provisions of this chapter, to the extent
that the requirements in these provisions are not explicitly required by
statute:
(1) Sec. 201.1(h)(1) through (h)(2), (h)(5) through (h)(6), and
(i);
(2) Sec. 201.10(a), (d)(2), (f), (g)(1), and (h)(1);
(3) Sec. 201.17;
(4) Sec. 201.18;
(5) Sec. 201.19;
(6) Sec. 201.20;
(7) Sec. 201.21;
(8) Sec. 201.22;
(9) Sec. 201.24; and
(10) Sec. 312.6.
[72 FR 73599, Dec. 28, 2007]
Subpart B_Labeling Requirements for Prescription Drugs and/or Insulin
Sec. 201.50 Statement of identity.
(a) The label of prescription and insulin-containing drugs in
package form shall bear as one of its principal features a statement of
the identity of the drug.
(b) Such statement of identity shall be in terms of the established
name of the drug. In the case of a prescription drug that is a mixture
and that has no established name, the requirement for statement of
identity shall be deemed to be satisfied by a listing of the
quantitative ingredient information as prescribed by Sec. 201.10.
(c) The statement of identity of a prescription drug shall also
comply with the placement, size and prominence requirements of Sec.
201.10.
[40 FR 13998, Mar. 27, 1975, as amended at 63 FR 26698, May 13, 1998]
Sec. 201.51 Declaration of net quantity of contents.
(a) The label of a prescription or insulin-containing drug in
package form shall bear a declaration of the net quantity of contents.
This shall be expressed in the terms of weight, measure, numerical
count, or a combination of numerical count and weight or measure. The
statement of quantity of drugs in tablet, capsule, ampule, or other unit
dosage form shall be expressed in terms of numerical count; the
statement of quantity for drugs in other dosage forms shall be in terms
of weight if the drug is solid, semi-solid, or viscous, or in terms of
fluid measure if the drug is liquid. When the drug quantity statement is
in terms of the numerical count of the drug units, it shall be augmented
to give the weight or measure of the drug units or the quantity of each
active ingredient in each drug unit or, when quantity does not
accurately reflect drug potency, a statement of the drug potency.
(b) Statements of weight of the contents shall in the case of
prescription drugs be expressed in terms of avoirdupois pound, ounce,
and grain or of kilogram, gram, and subdivisions thereof. A statement of
liquid measure of the contents shall in the case of prescription drugs
be expressed in terms of the U.S. gallon of 231 cubic inches and quart,
pint, fluid-ounce, and fluid-dram subdivisions thereof, or of the liter
and milliliter, or cubic centimeter, and shall express the volume at 68
[deg]F. (20 [deg]C.). A statement of the liquid measure of the contents
in the case of insulin-containing drugs shall be expressed in terms of
the liter and milliliter, or cubic centimeter, and shall express the
volume at 68 [deg]F. (20 [deg]C.).
(c) The declaration shall contain only such fractions as are
generally used in expressing the quantity of the drug. A common fraction
shall be reduced to its lowest terms; a decimal fraction shall not be
carried out to more than three places, except in the case of a statement
of the quantity of an active ingredient in a unit of a drug.
(d) The declaration shall appear as a distinct item on the label
and, in the case of large volume parenterals, may be embossed on the
glass.
(e) The declaration shall accurately reveal the quantity of drug in
the package exclusive of wrappers and other material packed therewith.
(f) A statement of the quantity of a prescription or insulin-
containing drug in terms of weight or measure applicable to such drug,
under the provisions of paragraph (a) of this section, shall
[[Page 22]]
express with prominence and conspicuousness the number of the largest
whole unit, as specified in paragraph (b) of this section, that are
contained in the package. Any remainder shall be expressed in terms of
common or decimal fractions of such unit or in terms of the next smaller
whole unit and common or decimal fractions thereof.
(g) The declaration of net quantity of contents shall express an
accurate statement of the quantity of contents of the package.
Reasonable variations caused by loss or gain of moisture during the
course of good distribution practice or by unavoidable deviations in
good manufacturing practice will be recognized. Variations from stated
quantity of contents shall not be unreasonably large. In the case of a
liquid drug in ampules or vials, intended for injection, the declaration
shall be considered to express the minimum quantity and the variation
above the stated measure shall comply with the excess volume prescribed
by the National Formulary or the U.S. Pharmacopeia for filling of
ampules. In the case of a solid drug in ampules or vials, the
declaration shall be considered to express the accurate net weight.
Variations shall comply with the limitations provided in the U.S.
Pharmacopeia or the National Formulary.
(h) A drug shall be exempt from compliance with the net quantity
declaration required by this section if it is an ointment labeled
``sample'', ``physician's sample'', or a substantially similar statement
and the contents of the package do not exceed 8 grams.
Sec. 201.55 Statement of dosage.
Section 201.100(b)(2) requires that labels for prescription drugs
bear a statement of the recommended or usual dosage. Since the dosage
for some prescription drugs varies within extremely wide limits,
depending upon the conditions being treated, it may not be possible in
all cases to present an informative or useful statement of the
recommended or usual dosage in the space available on the label or
carton of the package. It is the view of the Food and Drug
Administration that when such a situation prevails, compliance with this
requirement would be met by a statement such as ``See package insert for
dosage information'', where the detailed information is contained in
such insert. However, if an informative, realistic, recommended or usual
dosage can readily be set forth on the label, it should appear thereon.
Sec. 201.56 Requirements on content and format of labeling for
human prescription drug and biological products.
(a) General requirements. Prescription drug labeling described in
Sec. 201.100(d) must meet the following general requirements:
(1) The labeling must contain a summary of the essential scientific
information needed for the safe and effective use of the drug.
(2) The labeling must be informative and accurate and neither
promotional in tone nor false or misleading in any particular. In
accordance with Sec. Sec. 314.70 and 601.12 of this chapter, the
labeling must be updated when new information becomes available that
causes the labeling to become inaccurate, false, or misleading.
(3) The labeling must be based whenever possible on data derived
from human experience. No implied claims or suggestions of drug use may
be made if there is inadequate evidence of safety or a lack of
substantial evidence of effectiveness. Conclusions based on animal data
but necessary for safe and effective use of the drug in humans must be
identified as such and included with human data in the appropriate
section of the labeling.
(b) Categories of prescription drugs subject to the labeling content
and format requirements in Sec. Sec. 201.56(d) and 201.57. (1) The
following categories of prescription drug products are subject to the
labeling requirements in paragraph (d) of this section and Sec. 201.57
in accordance with the implementation schedule in paragraph (c) of this
section:
(i) Prescription drug products for which a new drug application
(NDA), biologics license application (BLA), or efficacy supplement was
approved by the Food and Drug Administration (FDA) between June 30, 2001
and June 30, 2006;
(ii) Prescription drug products for which an NDA, BLA, or efficacy
supplement is pending on June 30, 2006; or
[[Page 23]]
(iii) Prescription drug products for which an NDA, BLA, or efficacy
supplement is submitted anytime on or after June 30, 2006.
(2) Prescription drug products not described in paragraph (b)(1) of
this section are subject to the labeling requirements in paragraph (e)
of this section and Sec. 201.80.
(c) Schedule for implementing the labeling content and format
requirements in Sec. Sec. 201.56(d) and 201.57. For products described
in paragraph (b)(1) of this section, labeling conforming to the
requirements in paragraph (d) of this section and Sec. 201.57 must be
submitted according to the following schedule:
(1) For products for which an NDA, BLA, or efficacy supplement is
submitted for approval on or after June 30, 2006, proposed conforming
labeling must be submitted as part of the application.
(2) For products for which an NDA, BLA, or efficacy supplement is
pending on June 30, 2006, or that has been approved any time from June
30, 2005, up to and including June 30, 2006, a supplement with proposed
conforming labeling must be submitted no later than June 30, 2009.
(3) For products for which an NDA, BLA, or efficacy supplement has
been approved anytime from June 30, 2004, up to and including June 29,
2005, a supplement with proposed conforming labeling must be submitted
no later than June 30, 2010.
(4) For products for which an NDA, BLA, or efficacy supplement has
been approved anytime from June 30, 2003, up to and including June 29,
2004, a supplement with proposed conforming labeling must be submitted
no later than June 30, 2011.
(5) For products for which an NDA, BLA, or efficacy supplement has
been approved anytime from June 30, 2002, up to and including June 29,
2003, a supplement with proposed conforming labeling must be submitted
no later than June 30, 2012.
(6) For products for which an NDA, BLA, or efficacy supplement has
been approved anytime from June 30, 2001, up to and including June 29,
2002, a supplement with proposed conforming labeling must be submitted
no later than June 30, 2013.
(d) Labeling requirements for new and more recently approved
prescription drug products. This paragraph applies only to prescription
drug products described in paragraph (b)(1) of this section and must be
implemented according to the schedule specified in paragraph (c) of this
section.
(1) Prescription drug labeling described in Sec. 201.100(d) must
contain the specific information required under Sec. 201.57(a), (b),
and (c) under the following headings and subheadings and in the
following order:
Highlights of Prescribing Information
Product Names, Other Required Information
Boxed Warning
Recent Major Changes
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Full Prescribing Information: Contents
Full Prescribing Information
Boxed Warning
1 Indications and Usage
2 Dosage and Administration
3 Dosage Forms and Strengths
4 Contraindications
5 Warnings and Precautions
6 Adverse Reactions
7 Drug Interactions
8 Use in Specific Populations
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric use
8.5 Geriatric use
9 Drug Abuse and Dependence
9.1 Controlled substance
9.2 Abuse
9.3 Dependence
10 Overdosage
11 Description
12 Clinical Pharmacology
12.1 Mechanism of action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 Nonclinical Toxicology
13.1 Carcinogenesis, mutagenesis, impairment of fertility
13.2 Animal toxicology and/or pharmacology
14 Clinical Studies
15 References
16 How Supplied/Storage and Handling
17 Patient Counseling Information
[[Page 24]]
(2) Additional nonstandard subheadings that are used to enhance
labeling organization, presentation, or ease of use (e.g., for
individual warnings or precautions, or for each drug interaction) must
be assigned a decimal number that corresponds to their placement in
labeling. The decimal numbers must be consistent with the standardized
identifying numbers listed in paragraph (d)(1) of this section (e.g.,
subheadings added to the ``Warnings and Precautions'' section must be
numbered 5.1, 5.2, and so on).
(3) Any reference in Highlights to information appearing in the full
prescribing information must be accompanied by the identifying number
(in parentheses) corresponding to the location of the information in the
full prescribing information.
(4) Omit clearly inapplicable sections, subsections, or specific
information. If sections or subsections required under paragraph (d)(1)
of this section are omitted from the full prescribing information, the
heading ``Full Prescribing Information: Contents'' must be followed by
an asterisk and the following statement must appear at the end of
Contents: ``* Sections or subsections omitted from the full prescribing
information are not listed.''
(5) Any risk information that is required under Sec.
201.57(c)(9)(iv) is considered ``appropriate pediatric
contraindications, warnings, or precautions'' within the meaning of
section 505A(l)(2) of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 355A(l)(2)), whether such information appears in the
``Contraindications,'' ``Warnings and Precautions,'' or ``Use in
Specific Populations'' section of labeling.
(e) Labeling requirements for older prescription drug products. This
paragraph applies only to approved prescription drug products not
described in paragraph (b)(1) of this section.
(1) Prescription drug labeling described in Sec. 201.100(d) must
contain the specific information required under Sec. 201.80 under the
following section headings and in the following order:
Description
Clinical Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Adverse Reactions
Drug Abuse and Dependence
Overdosage
Dosage and Administration
How Supplied
(2) The labeling may contain the following additional section
headings if appropriate and if in compliance with Sec. 201.80(l) and
(m):
Animal Pharmacology and/or Animal Toxicology
Clinical Studies
References
(3) Omit clearly inapplicable sections, subsections, or specific
information.
(4) The labeling may contain a ``Product Title'' section preceding
the ``Description'' section and containing only the information required
by Sec. 201.80(a)(1)(i), (a)(1)(ii), (a)(1)(iii), and (a)(1)(iv) and
Sec. 201.100(e). The information required by Sec. 201.80(a)(1)(i)
through (a)(1)(iv) must appear in the ``Description'' section of the
labeling, whether or not it also appears in a ``Product Title.''
(5) The labeling must contain the date of the most recent revision
of the labeling, identified as such, placed prominently immediately
after the last section of the labeling.
(6) The requirement in Sec. 201.80(f)(2) to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or
accompany the prescription drug labeling must be implemented no later
than June 30, 2007.
[71 FR 3986, Jan. 24, 2006, as amended at 79 FR 72101, Dec. 4, 2014]
Sec. 201.57 Specific requirements on content and format of labeling
for human prescription drug and biological products described in
Sec. 201.56(b)(1).
The requirements in this section apply only to prescription drug
products described in Sec. 201.56(b)(1) and must be implemented
according to the schedule specified in Sec. 201.56(c), except for the
requirement in paragraph (c)(18) of this section to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or
accompany the prescription drug labeling,
[[Page 25]]
which must be implemented no later than June 30, 2007.
(a) Highlights of prescribing information. The following information
must appear in all prescription drug labeling:
(1) Highlights limitation statement. The verbatim statement ``These
highlights do not include all the information needed to use (insert name
of drug product) safely and effectively. See full prescribing
information for (insert name of drug product).''
(2) Drug names, dosage form, route of administration, and controlled
substance symbol. The proprietary name and the established name of the
drug, if any, as defined in section 502(e)(3) of the Federal Food, Drug,
and Cosmetic Act (the act) or, for biological products, the proper name
(as defined in Sec. 600.3 of this chapter) including any appropriate
descriptors. This information must be followed by the drug's dosage form
and route of administration. For controlled substances, the controlled
substance symbol designating the schedule in which the controlled
substance is listed must be included as required by Sec. 1302.04 of
this chapter.
(3) Initial U.S. approval. The verbatim statement ``Initial U.S.
Approval'' followed by the four-digit year in which FDA initially
approved a new molecular entity, new biological product, or new
combination of active ingredients. The statement must be placed on the
line immediately beneath the established name or, for biological
products, proper name of the product.
(4) Boxed warning. A concise summary of any boxed warning required
by paragraph (c)(1) of this section, not to exceed a length of 20 lines.
The summary must be preceded by a heading, in upper-case letters,
containing the word ``WARNING'' and other words that are appropriate to
identify the subject of the warning. The heading and the summary must be
contained within a box and bolded. The following verbatim statement must
be placed immediately following the heading of the boxed warning: ``See
full prescribing information for complete boxed warning.''
(5) Recent major changes. A list of the section(s) of the full
prescribing information, limited to the labeling sections described in
paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this section,
that contain(s) substantive labeling changes that have been approved by
FDA or authorized under Sec. 314.70(c)(6) or (d)(2), or Sec.
601.12(f)(1) through (f)(3) of this chapter. The heading(s) and, if
appropriate, the subheading(s) of the labeling section(s) affected by
the change must be listed together with each section's identifying
number and the date (month/year) on which the change was incorporated in
labeling. These labeling sections must be listed in the order in which
they appear in the full prescribing information. A changed section must
be listed under this heading in Highlights for at least 1 year after the
date of the labeling change and must be removed at the first printing
subsequent to the 1 year period.
(6) Indications and usage. A concise statement of each of the
product's indications, as required under paragraph (c)(2) of this
section, with any appropriate subheadings. Major limitations of use
(e.g., lack of effect in particular subsets of the population, or second
line therapy status) must be briefly noted. If the product is a member
of an established pharmacologic class, the concise statement under this
heading in Highlights must identify the class in the following manner:
``(Drug) is a (name of class) indicated for (indication(s)).''
(7) Dosage and administration. A concise summary of the information
required under paragraph (c)(3) of this section, with any appropriate
subheadings, including the recommended dosage regimen, starting dose,
dose range, critical differences among population subsets, monitoring
recommendations, and other clinically significant clinical pharmacologic
information.
(8) Dosage forms and strengths. A concise summary of the information
required under paragraph (c)(4) of this section, with any appropriate
subheadings (e.g., tablets, capsules, injectable, suspension), including
the strength or potency of the dosage form in metric system (e.g., 10-
milligram tablets) and whether the product is scored.
[[Page 26]]
(9) Contraindications. A concise statement of each of the product's
contraindications, as required under paragraph (c)(5) of this section,
with any appropriate subheadings.
(10) Warnings and precautions. A concise summary of the most
clinically significant information required under paragraph (c)(6) of
this section, with any appropriate subheadings, including information
that would affect decisions about whether to prescribe a drug,
recommendations for patient monitoring that are critical to safe use of
the drug, and measures that can be taken to prevent or mitigate harm.
(11) Adverse reactions. (i) A list of the most frequently occurring
adverse reactions, as described in paragraph (c)(7) of this section,
along with the criteria used to determine inclusion (e.g., incidence
rate). Adverse reactions important for other reasons (e.g., because they
are serious or frequently lead to discontinuation or dosage adjustment)
must not be repeated under this heading in Highlights if they are
included elsewhere in Highlights (e.g., Warnings and Precautions,
Contraindications).
(ii) For drug products other than vaccines, the verbatim statement
``To report SUSPECTED ADVERSE REACTIONS, contact (insert name of
manufacturer) at (insert manufacturer's phone number) or FDA at (insert
current FDA phone number and Web address for voluntary reporting of
adverse reactions).''
(iii) For vaccines, the verbatim statement ``To report SUSPECTED
ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert
manufacturer's phone number) or VAERS at (insert the current VAERS phone
number and Web address for voluntary reporting of adverse reactions).''
(iv) For manufacturers with a Web site for voluntary reporting of
adverse reactions, the Web address of the direct link to the site.
(12) Drug interactions. A concise summary of the information
required under paragraph (c)(8) of this section, with any appropriate
subheadings.
(13) Use in specific populations. A concise summary of the
information required under paragraph (c)(9) of this section, with any
appropriate subheadings.
(14) Patient counseling information statement. The verbatim
statement ``See 17 for Patient Counseling Information'' or, if the
product has FDA-approved patient labeling, the verbatim statement ``See
17 for Patient Counseling Information and (insert either FDA-approved
patient labeling or Medication Guide).''
(15) Revision date. The date of the most recent revision of the
labeling, identified as such, placed at the end of Highlights.
(b) Full prescribing information: Contents. Contents must contain a
list of each heading and subheading required in the full prescribing
information under Sec. 201.56(d)(1), if not omitted under Sec.
201.56(d)(4), preceded by the identifying number required under Sec.
201.56(d)(1). Contents must also contain any additional subheading(s)
included in the full prescribing information preceded by the identifying
number assigned in accordance with Sec. 201.56(d)(2).
(c) Full prescribing information. The full prescribing information
must contain the information in the order required under paragraphs
(c)(1) through (c)(18) of this section, together with the headings,
subheadings, and identifying numbers required under Sec. 201.56(d)(1),
unless omitted under Sec. 201.56(d)(4). If additional subheadings are
used within a labeling section, they must be preceded by the identifying
number assigned in accordance with Sec. 201.56(d)(2).
(1) Boxed warning. Certain contraindications or serious warnings,
particularly those that may lead to death or serious injury, may be
required by the FDA to be presented in a box. The boxed warning
ordinarily must be based on clinical data, but serious animal toxicity
may also be the basis of a boxed warning in the absence of clinical
data. The box must contain, in uppercase letters, a heading inside the
box that includes the word ``WARNING'' and conveys the general focus of
the information in the box. The box must briefly explain the risk and
refer to more detailed information in the ``Contraindications'' or
``Warnings and Precautions'' section, accompanied by the identifying
number for the section or subsection containing the detailed
information.
[[Page 27]]
(2) 1 Indications and usage. This section must state that the drug
is indicated for the treatment, prevention, mitigation, cure, or
diagnosis of a recognized disease or condition, or of a manifestation of
a recognized disease or condition, or for the relief of symptoms
associated with a recognized disease or condition.
(i) This section must include the following information when the
conditions listed are applicable:
(A) If the drug is used for an indication only in conjunction with a
primary mode of therapy (e.g., diet, surgery, behavior changes, or some
other drug), a statement that the drug is indicated as an adjunct to
that mode of therapy.
(B) If evidence is available to support the safety and effectiveness
of the drug or biological product only in selected subgroups of the
larger population (e.g., patients with mild disease or patients in a
special age group), or if the indication is approved based on a
surrogate endpoint under Sec. 314.510 or Sec. 601.41 of this chapter,
a succinct description of the limitations of usefulness of the drug and
any uncertainty about anticipated clinical benefits, with reference to
the ``Clinical Studies'' section for a discussion of the available
evidence.
(C) If specific tests are necessary for selection or monitoring of
the patients who need the drug (e.g., microbe susceptibility tests), the
identity of such tests.
(D) If information on limitations of use or uncertainty about
anticipated clinical benefits is relevant to the recommended intervals
between doses, to the appropriate duration of treatment when such
treatment should be limited, or to any modification of dosage, a concise
description of the information with reference to the more detailed
information in the ``Dosage and Administration'' section.
(E) If safety considerations are such that the drug should be
reserved for specific situations (e.g., cases refractory to other
drugs), a statement of the information.
(F) If there are specific conditions that should be met before the
drug is used on a long term basis (e.g., demonstration of responsiveness
to the drug in a short term trial in a given patient), a statement of
the conditions; or, if the indications for long term use are different
from those for short term use, a statement of the specific indications
for each use.
(ii) If there is a common belief that the drug may be effective for
a certain use or if there is a common use of the drug for a condition,
but the preponderance of evidence related to the use or condition shows
that the drug is ineffective or that the therapeutic benefits of the
product do not generally outweigh its risks, FDA may require that this
section state that there is a lack of evidence that the drug is
effective or safe for that use or condition.
(iii) Any statements comparing the safety or effectiveness of the
drug with other agents for the same indication must, except for
biological products, be supported by substantial evidence derived from
adequate and well-controlled studies as defined in Sec. 314.126(b) of
this chapter unless this requirement is waived under Sec. 201.58 or
Sec. 314.126(c) of this chapter. For biological products, such
statements must be supported by substantial evidence.
(iv) For drug products other than biological products, all
indications listed in this section must be supported by substantial
evidence of effectiveness based on adequate and well-controlled studies
as defined in Sec. 314.126(b) of this chapter unless the requirement is
waived under Sec. 201.58 or Sec. 314.126(c) of this chapter.
Indications or uses must not be implied or suggested in other sections
of the labeling if not included in this section.
(v) For biological products, all indications listed in this section
must be supported by substantial evidence of effectiveness. Indications
or uses must not be implied or suggested in other sections of the
labeling if not included in this section.
(3) 2 Dosage and administration. (i) This section must state the
recommended dose and, as appropriate:
(A) The dosage range,
(B) An upper limit beyond which safety and effectiveness have not
been established, or beyond which increasing the dose does not result in
increasing effectiveness,
[[Page 28]]
(C) Dosages for each indication and subpopulation,
(D) The intervals recommended between doses,
(E) The optimal method of titrating dosage,
(F) The usual duration of treatment when treatment duration should
be limited,
(G) Dosing recommendations based on clinical pharmacologic data
(e.g., clinically significant food effects),
(H) Modification of dosage needed because of drug interactions or in
special patient populations (e.g., in children, in geriatric age groups,
in groups defined by genetic characteristics, or in patients with renal
or hepatic disease),
(I) Important considerations concerning compliance with the dosage
regimen,
(J) Efficacious or toxic concentration ranges and therapeutic
concentration windows of the drug or its metabolites, if established and
clinically significant. Information on therapeutic drug concentration
monitoring (TDM) must also be included in this section when TDM is
necessary.
(ii) Dosing regimens must not be implied or suggested in other
sections of the labeling if not included in this section.
(iii) Radiation dosimetry information must be stated for both the
patient receiving a radioactive drug and the person administering it.
(iv) This section must also contain specific direction on dilution,
preparation (including the strength of the final dosage solution, when
prepared according to instructions, in terms of milligrams of active
ingredient per milliliter of reconstituted solution, unless another
measure of the strength is more appropriate), and administration of the
dosage form, if needed (e.g., the rate of administration of parenteral
drug in milligrams per minute; storage conditions for stability of the
reconstituted drug, when important; essential information on drug
incompatibilities if the drug is mixed in vitro with other drugs or
diluents; and the following verbatim statement for parenterals:
``Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and
container permit.'')
(4) 3 Dosage forms and strengths. This section must contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible, including:
(i) The strength or potency of the dosage form in metric system
(e.g., 10 milligram tablets), and, if the apothecary system is used, a
statement of the strength in parentheses after the metric designation;
and
(ii) A description of the identifying characteristics of the dosage
forms, including shape, color, coating, scoring, and imprinting, when
applicable. The National Drug Code number(s) for the drug product must
not be included in this section.
(5) 4 Contraindications. This section must describe any situations
in which the drug should not be used because the risk of use (e.g.,
certain potentially fatal adverse reactions) clearly outweighs any
possible therapeutic benefit. Those situations include use of the drug
in patients who, because of their particular age, sex, concomitant
therapy, disease state, or other condition, have a substantial risk of
being harmed by the drug and for whom no potential benefit makes the
risk acceptable. Known hazards and not theoretical possibilities must be
listed (e.g., if severe hypersensitivity to the drug has not been
demonstrated, it should not be listed as a contraindication). If no
contraindications are known, this section must state ``None.''
(6) 5 Warnings and precautions. (i) General. This section must
describe clinically significant adverse reactions (including any that
are potentially fatal, are serious even if infrequent, or can be
prevented or mitigated through appropriate use of the drug), other
potential safety hazards (including those that are expected for the
pharmacological class or those resulting from drug/drug interactions),
limitations in use imposed by them (e.g., avoiding certain concomitant
therapy), and steps that should be taken if they occur (e.g., dosage
modification). The frequency of all clinically significant adverse
reactions and the approximate
[[Page 29]]
mortality and morbidity rates for patients experiencing the reaction, if
known and necessary for the safe and effective use of the drug, must be
expressed as provided under paragraph (c)(7) of this section. In
accordance with Sec. Sec. 314.70 and 601.12 of this chapter, the
labeling must be revised to include a warning about a clinically
significant hazard as soon as there is reasonable evidence of a causal
association with a drug; a causal relationship need not have been
definitely established. A specific warning relating to a use not
provided for under the ``Indications and Usage'' section may be required
by FDA in accordance with sections 201(n) and 502(a) of the act if the
drug is commonly prescribed for a disease or condition and such usage is
associated with a clinically significant risk or hazard.
(ii) Other special care precautions. This section must contain
information regarding any special care to be exercised by the
practitioner for safe and effective use of the drug (e.g., precautions
not required under any other specific section or subsection).
(iii) Monitoring: Laboratory tests. This section must identify any
laboratory tests helpful in following the patient's response or in
identifying possible adverse reactions. If appropriate, information must
be provided on such factors as the range of normal and abnormal values
expected in the particular situation and the recommended frequency with
which tests should be performed before, during, and after therapy.
(iv) Interference with laboratory tests. This section must briefly
note information on any known interference by the product with
laboratory tests and reference the section where the detailed
information is presented (e.g., ``Drug Interactions'' section).
(7) 6 Adverse reactions. This section must describe the overall
adverse reaction profile of the drug based on the entire safety
database. For purposes of prescription drug labeling, an adverse
reaction is an undesirable effect, reasonably associated with use of a
drug, that may occur as part of the pharmacological action of the drug
or may be unpredictable in its occurrence. This definition does not
include all adverse events observed during use of a drug, only those
adverse events for which there is some basis to believe there is a
causal relationship between the drug and the occurrence of the adverse
event.
(i) Listing of adverse reactions. This section must list the adverse
reactions that occur with the drug and with drugs in the same
pharmacologically active and chemically related class, if applicable.
The list or lists must be preceded by the information necessary to
interpret the adverse reactions (e.g., for clinical trials, total number
exposed, extent and nature of exposure).
(ii) Categorization of adverse reactions. Within a listing, adverse
reactions must be categorized by body system, by severity of the
reaction, or in order of decreasing frequency, or by a combination of
these, as appropriate. Within a category, adverse reactions must be
listed in decreasing order of frequency. If frequency information cannot
be reliably determined, adverse reactions must be listed in decreasing
order of severity.
(A) Clinical trials experience. This section must list the adverse
reactions identified in clinical trials that occurred at or above a
specified rate appropriate to the safety database. The rate of
occurrence of an adverse reaction for the drug and comparators (e.g.,
placebo) must be presented, unless such data cannot be determined or
presentation of comparator rates would be misleading. If adverse
reactions that occurred below the specified rate are included, they must
be included in a separate listing. If comparative rates of occurrence
cannot be reliably determined (e.g., adverse reactions were observed
only in the uncontrolled trial portion of the overall safety database),
adverse reactions must be grouped within specified frequency ranges as
appropriate to the safety database for the drug (e.g., adverse reactions
occurring at a rate of less than 1/100, adverse reactions occurring at a
rate of less than 1/500) or descriptively identified,
[[Page 30]]
if frequency ranges cannot be determined. For adverse reactions with
significant clinical implications, the listings must be supplemented
with additional detail about the nature, frequency, and severity of the
adverse reaction and the relationship of the adverse reaction to drug
dose and demographic characteristics, if data are available and
important.
(B) Postmarketing experience. This section of the labeling must list
the adverse reactions, as defined in paragraph (c)(7) of this section,
that are identified from domestic and foreign spontaneous reports. This
listing must be separate from the listing of adverse reactions
identified in clinical trials.
(iii) Comparisons of adverse reactions between drugs. For drug
products other than biological products, any claim comparing the drug to
which the labeling applies with other drugs in terms of frequency,
severity, or character of adverse reactions must be based on adequate
and well-controlled studies as defined in Sec. 314.126(b) of this
chapter unless this requirement is waived under Sec. 201.58 or Sec.
314.126(c) of this chapter. For biological products, any such claim must
be based on substantial evidence.
(8) 7 Drug interactions. (i) This section must contain a description
of clinically significant interactions, either observed or predicted,
with other prescription or over-the-counter drugs, classes of drugs, or
foods (e.g., dietary supplements, grapefruit juice), and specific
practical instructions for preventing or managing them. The mechanism(s)
of the interaction, if known, must be briefly described. Interactions
that are described in the ``Contraindications'' or ``Warnings and
Precautions'' sections must be discussed in more detail under this
section. Details of drug interaction pharmacokinetic studies that are
included in the ``Clinical Pharmacology'' section that are pertinent to
clinical use of the drug must not be repeated in this section.
(ii) This section must also contain practical guidance on known
interference of the drug with laboratory tests.
(9) 8 Use in specific populations. This section must contain the
following subsections:
(i) 8.1 Pregnancy. This subsection of the labeling must contain the
following information in the following order under the subheadings
``Pregnancy Exposure Registry,'' ``Risk Summary,'' ``Clinical
Considerations,'' and ``Data'':
(A) Pregnancy exposure registry. If there is a scientifically
acceptable pregnancy exposure registry for the drug, contact information
needed to enroll in the registry or to obtain information about the
registry must be provided following the statement: ``There is a
pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to (name of drug) during pregnancy.''
(B) Risk summary. The Risk Summary must contain risk statement(s)
based on data from all relevant sources (human, animal, and/or
pharmacologic) that describe, for the drug, the risk of adverse
developmental outcomes (i.e., structural abnormalities, embryo-fetal
and/or infant mortality, functional impairment, alterations to growth).
When multiple data sources are available, the statements must be
presented in the following order: Human, animal, pharmacologic. The
source(s) of the data must be stated. The labeling must state the
percentage range of live births in the United States with a major birth
defect and the percentage range of pregnancies in the United States that
end in miscarriage, regardless of drug exposure. If such information is
available for the population(s) for which the drug is labeled, it must
also be included. When use of a drug is contraindicated during
pregnancy, this information must be stated first in the Risk Summary.
When applicable, risk statements as described in paragraphs
(c)(9)(i)(B)(1) and (2) of this section must include a cross-reference
to additional details in the relevant portion of the ``Data'' subheading
in the ``Pregnancy'' subsection of the labeling. If data demonstrate
that a drug is not systemically absorbed following a particular route of
administration, the Risk Summary must contain only the following
statement: ``(Name of drug) is not absorbed systemically following
(route of administration), and maternal use is not expected to result in
fetal exposure to the drug.''
[[Page 31]]
(1) Risk statement based on human data. When human data are
available that establish the presence or absence of any adverse
developmental outcome(s) associated with maternal use of the drug, the
Risk Summary must summarize the specific developmental outcome(s); their
incidence; and the effects of dose, duration of exposure, and
gestational timing of exposure. If human data indicate that there is an
increased risk for a specific adverse developmental outcome in infants
born to women exposed to the drug during pregnancy, this risk must be
quantitatively compared to the risk for the same outcome in infants born
to women who were not exposed to the drug but who have the disease or
condition for which the drug is indicated to be used. When risk
information is not available for women with the disease or condition for
which the drug is indicated, the risk for the specific outcome must be
compared to the rate at which the outcome occurs in the general
population. The Risk Summary must state when there are no human data or
when available human data do not establish the presence or absence of
drug-associated risk.
(2) Risk statement based on animal data. When animal data are
available, the Risk Summary must summarize the findings in animals and
based on these findings, describe, for the drug, the potential risk of
any adverse developmental outcome(s) in humans. This statement must
include: The number and type(s) of species affected, timing of exposure,
animal doses expressed in terms of human dose or exposure equivalents,
and outcomes for pregnant animals and offspring. When animal studies do
not meet current standards for nonclinical developmental toxicity
studies, the Risk Summary must so state. When there are no animal data,
the Risk Summary must so state.
(3) Risk statement based on pharmacology. When the drug has a well-
understood mechanism of action that may result in adverse developmental
outcome(s), the Risk Summary must explain the mechanism of action and
the potential associated risks.
(C) Clinical considerations. Under the subheading ``Clinical
Considerations,'' the labeling must provide relevant information, to the
extent it is available, under the headings ``Disease-associated maternal
and/or embryo/fetal risk,'' ``Dose adjustments during pregnancy and the
postpartum period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal
adverse reactions,'' and ``Labor or delivery'':
(1) Disease-associated maternal and/or embryo/fetal risk. If there
is a serious known or potential risk to the pregnant woman and/or the
embryo/fetus associated with the disease or condition for which the drug
is indicated to be used, the labeling must describe the risk.
(2) Dose adjustments during pregnancy and the postpartum period. If
there are pharmacokinetic data that support dose adjustment(s) during
pregnancy and the postpartum period, a summary of this information must
be provided.
(3) Maternal adverse reactions. If use of the drug is associated
with a maternal adverse reaction that is unique to pregnancy or if a
known adverse reaction occurs with increased frequency or severity in
pregnant women, the labeling must describe the adverse reaction and
available intervention(s) for monitoring or mitigating the reaction. The
labeling must describe, if known, the effect of dose, timing, and
duration of exposure on the risk to the pregnant woman of experiencing
the adverse reaction.
(4) Fetal/Neonatal adverse reactions. If it is known or anticipated
that treatment of the pregnant woman increases or may increase the risk
of an adverse reaction in the fetus or neonate, the labeling must
describe the adverse reaction, the potential severity and reversibility
of the adverse reaction, and available intervention(s) for monitoring or
mitigating the reaction. The labeling must describe, if known, the
effect of dose, timing, and duration of exposure on the risk.
(5) Labor or delivery. If the drug is expected to affect labor or
delivery, the labeling must provide information about the effect of the
drug on the pregnant woman and the fetus or neonate; the effect of the
drug on the
[[Page 32]]
duration of labor and delivery; any increased risk of adverse reactions,
including their potential severity and reversibility; and must provide
information about available intervention(s) that can mitigate these
effects and/or adverse reactions. The information described under this
heading is not required for drugs approved for use only during labor and
delivery.
(D) Data--(1) ``Data'' subheading. Under the subheading ``Data,''
the labeling must describe the data that are the basis for the Risk
Summary and Clinical Considerations.
(2) Human and animal data headings. Human and animal data must be
presented separately, beneath the headings ``Human Data'' and ``Animal
Data,'' and human data must be presented first.
(3) Description of human data. For human data, the labeling must
describe adverse developmental outcomes, adverse reactions, and other
adverse effects. To the extent applicable, the labeling must describe
the types of studies or reports, number of subjects and the duration of
each study, exposure information, and limitations of the data. Both
positive and negative study findings must be included.
(4) Description of animal data. For animal data, the labeling must
describe the following: Types of studies, animal species, dose, duration
and timing of exposure, study findings, presence or absence of maternal
toxicity, and limitations of the data. Description of maternal and
offspring findings must include dose-response and severity of adverse
developmental outcomes. Animal doses or exposures must be described in
terms of human dose or exposure equivalents and the basis for those
calculations must be included.
(ii) 8.2 Lactation. This subsection of the labeling must contain the
following information in the following order under the subheadings
``Risk Summary,'' ``Clinical Considerations,'' and ``Data'':
(A) Risk summary. When relevant human and/or animal lactation data
are available, the Risk Summary must include a cross-reference to the
``Data'' subheading in the ``Lactation'' subsection of the labeling.
When human data are available, animal data must not be included unless
the animal model is specifically known to be predictive for humans. When
use of a drug is contraindicated during breastfeeding, this information
must be stated first in the Risk Summary.
(1) Drug not absorbed systemically. If data demonstrate that the
drug is not systemically absorbed by the mother, the Risk Summary must
contain only the following statement: ``(Name of drug) is not absorbed
systemically by the mother following (route of administration), and
breastfeeding is not expected to result in exposure of the child to
(name of drug).''
(2) Drug absorbed systemically. If the drug is absorbed
systemically, the Risk Summary must describe the following to the extent
relevant information is available:
(i) Presence of drug in human milk. The Risk Summary must state
whether the drug and/or its active metabolite(s) are present in human
milk. If there are no data to assess this, the Risk Summary must so
state. If studies demonstrate that the drug and/or its active
metabolite(s) are not detectable in human milk, the Risk Summary must
state the limits of the assay used. If studies demonstrate the presence
of the drug and/or its active metabolite(s) in human milk, the Risk
Summary must state the concentration of the drug and/or its active
metabolite(s) in human milk and the actual or estimated daily dose for
an infant fed exclusively with human milk. The actual or estimated
amount of the drug and/or its active metabolite(s) ingested by the
infant must be compared to the labeled infant or pediatric dose, if
available, or to the maternal dose. If studies demonstrate the presence
of the drug and/or its active metabolite(s) in human milk but the drug
and/or its active metabolite(s) are not expected to be systemically
bioavailable to the breast-fed child, the Risk Summary must describe the
disposition of the drug and/or its active metabolite(s). If only animal
lactation data are available, the Risk Summary must state only whether
or not the drug and/or its active metabolite(s) were detected in animal
milk and specify the animal species.
(ii) Effects of drug on the breast-fed child. The Risk Summary must
include
[[Page 33]]
information, on the known or predicted effects on the child from
exposure to the drug and/or its active metabolite(s) through human milk
or from contact with breast or nipple skin (for topical products). The
Risk Summary also must include information on systemic and/or local
adverse reactions. If there are no data to assess the effects of the
drug and/or its active metabolite(s) on the breast-fed child, the Risk
Summary must so state.
(iii) Effects of drug on milk production. The Risk Summary must
describe the effects of the drug and/or its active metabolite(s) on milk
production. If there are no data to assess the effects of the drug and/
or its active metabolite(s) on milk production, the Risk Summary must so
state.
(3) Risk and benefit statement. For drugs absorbed systemically,
unless breastfeeding is contraindicated during drug therapy, the
following risk and benefit statement must appear at the end of the Risk
Summary: ``The developmental and health benefits of breastfeeding should
be considered along with the mother's clinical need for (name of drug)
and any potential adverse effects on the breast-fed child from (name of
drug) or from the underlying maternal condition.''
(B) Clinical considerations. Under ``Clinical Considerations,'' the
following information must be provided to the extent it is available and
relevant:
(1) Minimizing exposure. The labeling must describe ways to minimize
exposure in the breast-fed child if: The drug and/or its active
metabolite(s) are present in human milk in clinically relevant
concentrations; the drug does not have an established safety profile in
infants; and the drug is used either intermittently, in single doses, or
for short courses of therapy. When applicable, the labeling must also
describe ways to minimize a breast-fed child's oral intake of topical
drugs applied to the breast or nipple skin.
(2) Monitoring for adverse reactions. The labeling must describe
available intervention(s) for monitoring or mitigating the adverse
reaction(s) presented in the Risk Summary.
(C) Data. Under the subheading ``Data,'' the labeling must describe
the data that are the basis for the Risk Summary and Clinical
Considerations.
(iii) 8.3 Females and males of reproductive potential. When
pregnancy testing and/or contraception are required or recommended
before, during, or after drug therapy and/or when there are human and/or
animal data that suggest drug-associated fertility effects, this
subsection of labeling must contain this information under the
subheadings ``Pregnancy Testing,'' ``Contraception,'' and
``Infertility,'' in that order.
(iv) 8.4 Pediatric use. (A) Pediatric population(s)/pediatric
patient(s): For the purposes of paragraphs (c)(9)(iv)(B) through
(c)(9)(iv)(H) of this section, the terms pediatric population(s) and
pediatric patient(s) are defined as the pediatric age group, from birth
to 16 years, including age groups often called neonates, infants,
children, and adolescents.
(B) If there is a specific pediatric indication different from those
approved for adults that is supported by adequate and well-controlled
studies in the pediatric population, it must be described under the
``Indications and Usage'' section, and appropriate pediatric dosage
information must be given under the ``Dosage and Administration''
section. The ``Pediatric use'' subsection must cite any limitations on
the pediatric indication, need for specific monitoring, specific hazards
associated with use of the drug in any subsets of the pediatric
population (e.g., neonates), differences between pediatric and adult
responses to the drug, and other information related to the safe and
effective pediatric use of the drug. Data summarized in this subsection
should be discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' or ``Clinical Studies'' section. As appropriate, this
information must also be contained in the ``Contraindications'' and/or
``Warnings and Precautions'' section(s).
(C) If there are specific statements on pediatric use of the drug
for an indication also approved for adults that are based on adequate
and well-controlled studies in the pediatric population, they must be
summarized in the ``Pediatric use'' subsection and discussed in more
detail, if appropriate, under the ``Clinical Pharmacology'' and
[[Page 34]]
``Clinical Studies'' sections. Appropriate pediatric dosage must be
given under the ``Dosage and Administration'' section. The ``Pediatric
use'' subsection of the labeling must also cite any limitations on the
pediatric use statement, need for specific monitoring, specific hazards
associated with use of the drug in any subsets of the pediatric
population (e.g., neonates), differences between pediatric and adult
responses to the drug, and other information related to the safe and
effective pediatric use of the drug. As appropriate, this information
must also be contained in the ``Contraindications'' and/or ``Warnings
and Precautions'' section(s).
(D)(1) When a drug is approved for pediatric use based on adequate
and well-controlled studies in adults with other information supporting
pediatric use, the ``Pediatric use'' subsection of the labeling must
contain either the following statement or a reasonable alternative:
The safety and effectiveness of (drug name) have been established in
the age groups ___ to ___ (note any limitations, e.g., no data for
pediatric patients under 2, or only applicable to certain indications
approved in adults). Use of (drug name) in these age groups is supported
by evidence from adequate and well-controlled studies of (drug name) in
adults with additional data (insert wording that accurately describes
the data submitted to support a finding of substantial evidence of
effectiveness in the pediatric population).
(2) Data summarized in the preceding prescribed statement in this
subsection must be discussed in more detail, if appropriate, under the
``Clinical Pharmacology'' or the ``Clinical Studies'' section. For
example, pediatric pharmacokinetic or pharmacodynamic studies and dose
response information should be described in the ``Clinical
Pharmacology'' section. Pediatric dosing instructions must be included
in the ``Dosage and Administration'' section. Any differences between
pediatric and adult responses, need for specific monitoring, dosing
adjustments, and any other information related to safe and effective use
of the drug in pediatric patients must be cited briefly in the
``Pediatric use'' subsection and, as appropriate, in the
``Contraindications,'' ``Warnings and Precautions,'' and ``Dosage and
Administration'' sections.
(E) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for a particular pediatric population, the ``Pediatric use''
subsection must contain an appropriate statement such as ``Safety and
effectiveness in pediatric patients below the age of (__) have not been
established.'' If use of the drug in this pediatric population is
associated with a specific hazard, the hazard must be described in this
subsection, or, if appropriate, the hazard must be stated in the
``Contraindications'' or ``Warnings and Precautions'' section and this
subsection must refer to it.
(F) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for any pediatric population, this subsection must contain the
following statement: ``Safety and effectiveness in pediatric patients
have not been established.'' If use of the drug in premature or neonatal
infants, or other pediatric subgroups, is associated with a specific
hazard, the hazard must be described in this subsection, or, if
appropriate, the hazard must be stated in the ``Contraindications'' or
``Warnings and Precautions'' section and this subsection must refer to
it.
(G) If the sponsor believes that none of the statements described in
paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are
appropriate or relevant to the labeling of a particular drug, the
sponsor must provide reasons for omission of the statements and may
propose alternative statement(s). FDA may permit use of an alternative
statement if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling and that
the alternative statement is accurate and appropriate.
(H) If the drug product contains one or more inactive ingredients
that present an increased risk of toxic effects to neonates or other
pediatric subgroups, a special note of this risk must be made, generally
in the ``Contraindications'' or ``Warnings and Precautions'' section.
[[Page 35]]
(v) 8.5 Geriatric use. (A) A specific geriatric indication, if any,
that is supported by adequate and well-controlled studies in the
geriatric population must be described under the ``Indications and
Usage'' section, and appropriate geriatric dosage must be stated under
the ``Dosage and Administration'' section. The ``Geriatric use''
subsection must cite any limitations on the geriatric indication, need
for specific monitoring, specific hazards associated with the geriatric
indication, and other information related to the safe and effective use
of the drug in the geriatric population. Unless otherwise noted,
information contained in the ``Geriatric use'' subsection must pertain
to use of the drug in persons 65 years of age and older. Data summarized
in this subsection must be discussed in more detail, if appropriate,
under ``Clinical Pharmacology'' or the ``Clinical Studies'' section. As
appropriate, this information must also be contained in the ``Warnings
and Precautions'' and/or ``Contraindications'' section(s).
(B) Specific statements on geriatric use of the drug for an
indication approved for adults generally, as distinguished from a
specific geriatric indication, must be contained in the ``Geriatric
use'' subsection and must reflect all information available to the
sponsor that is relevant to the appropriate use of the drug in elderly
patients. This information includes detailed results from controlled
studies that are available to the sponsor and pertinent information from
well-documented studies obtained from a literature search. Controlled
studies include those that are part of the marketing application and
other relevant studies available to the sponsor that have not been
previously submitted in the investigational new drug application, new
drug application, biologics license application, or a supplement or
amendment to one of these applications (e.g., postmarketing studies or
adverse drug reaction reports). The ``Geriatric use'' subsection must
contain the following statement(s) or reasonable alternative, as
applicable, taking into account available information:
(1) If clinical studies did not include sufficient numbers of
subjects aged 65 and over to determine whether elderly subjects respond
differently from younger subjects, and other reported clinical
experience has not identified such differences, the ``Geriatric use''
subsection must include the following statement:
Clinical studies of (name of drug) did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
(2) If clinical studies (including studies that are part of
marketing applications and other relevant studies available to the
sponsor that have not been submitted in the sponsor's applications)
included enough elderly subjects to make it likely that differences in
safety or effectiveness between elderly and younger subjects would have
been detected, but no such differences (in safety or effectiveness) were
observed, and other reported clinical experience has not identified such
differences, the ``Geriatric use'' subsection must contain the following
statement:
Of the total number of subjects in clinical studies of (name of
drug), __ percent were 65 and over, while __ percent were 75 and over.
(Alternatively, the labeling may state the total number of subjects
included in the studies who were 65 and over and 75 and over.) No
overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
(3) If evidence from clinical studies and other reported clinical
experience available to the sponsor indicates that use of the drug in
elderly patients is associated with differences in safety or
effectiveness, or requires specific monitoring or dosage adjustment, the
[[Page 36]]
``Geriatric use'' subsection must contain a brief description of
observed differences or specific monitoring or dosage requirements and,
as appropriate, must refer to more detailed discussions in the
``Contraindications,'' ``Warnings and Precautions,'' ``Dosage and
Administration,'' or other sections.
(C)(1) If specific pharmacokinetic or pharmacodynamic studies have
been carried out in the elderly, they must be described briefly in the
``Geriatric use'' subsection and in detail under the ``Clinical
Pharmacology'' section. The ``Clinical Pharmacology'' and ``Drug
Interactions'' sections ordinarily contain information on drug/disease
and drug/drug interactions that is particularly relevant to the elderly,
who are more likely to have concomitant illness and to use concomitant
drugs.
(2) If a drug is known to be substantially excreted by the kidney,
the ``Geriatric use'' subsection must include the statement:
This drug is known to be substantially excreted by the kidney, and
the risk of adverse reactions to this drug may be greater in patients
with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
(D) If use of the drug in the elderly appears to cause a specific
hazard, the hazard must be described in the ``Geriatric use''
subsection, or, if appropriate, the hazard must be stated in the
``Contraindications'' or ``Warnings and Precautions'' section, and the
``Geriatric use'' subsection must refer to those sections.
(E) Labeling under paragraphs (c)(9)(v)(A) through (c)(9)(v)(C) of
this section may include statements, if they are necessary for safe and
effective use of the drug, and reflect good clinical practice or past
experience in a particular situation, e.g., for a sedating drug, it
could be stated that:
Sedating drugs may cause confusion and over-sedation in the elderly;
elderly patients generally should be started on low doses of (name of
drug) and observed closely.
(F) If the sponsor believes that none of the requirements described
in paragraphs (c)(9)(v)(A) through (c)(9)(v)(E) of this section are
appropriate or relevant to the labeling of a particular drug, the
sponsor must provide reasons for omission of the statements and may
propose an alternative statement. FDA may permit omission of the
statements if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling. FDA may
permit use of an alternative statement if the agency determines that
such statement is accurate and appropriate.
(vi) Additional subsections. Additional subsections may be included,
as appropriate, if sufficient data are available concerning the use of
the drug in other specified subpopulations (e.g., renal or hepatic
impairment).
(10) 9 Drug abuse and dependence. This section must contain the
following information, as appropriate:
(i) 9.1 Controlled substance. If the drug is controlled by the Drug
Enforcement Administration, the schedule in which it is controlled must
be stated.
(ii) 9.2 Abuse. This subsection must state the types of abuse that
can occur with the drug and the adverse reactions pertinent to them, and
must identify particularly susceptible patient populations. This
subsection must be based primarily on human data and human experience,
but pertinent animal data may also be used.
(iii) 9.3 Dependence. This subsection must describe characteristic
effects resulting from both psychological and physical dependence that
occur with the drug and must identify the quantity of the drug over a
period of time that may lead to tolerance or dependence, or both.
Details must be provided on the adverse effects of chronic abuse and the
effects of abrupt withdrawal. Procedures necessary to diagnose the
dependent state and the principles of treating the effects of abrupt
withdrawal must be described.
(11) 10 Overdosage. This section must be based on human data. If
human data are unavailable, appropriate animal and in vitro data may be
used. The following specific information must be provided:
(i) Signs, symptoms, and laboratory findings associated with an
overdosage of the drug;
(ii) Complications that can occur with the drug (for example, organ
toxicity or delayed acidosis);
[[Page 37]]
(iii) Concentrations of the drug in biologic fluids associated with
toxicity or death; physiologic variables influencing excretion of the
drug, such as urine pH; and factors that influence the dose response
relationship of the drug, such as tolerance. The pharmacokinetic data
given in the ``Clinical Pharmacology'' section also may be referenced
here, if applicable to overdoses;
(iv) The amount of the drug in a single dose that is ordinarily
associated with symptoms of overdosage and the amount of the drug in a
single dose that is likely to be life threatening;
(v) Whether the drug is dialyzable; and
(vi) Recommended general treatment procedures and specific measures
for support of vital functions (e.g., proven antidotes, gastric lavage,
forced diuresis, or as per Poison Control Center). Such recommendations
must be based on data available for the specific drug or experience with
pharmacologically related drugs. Unqualified recommendations for which
data are lacking for the specific drug or class of drugs must not be
stated.
(12) 11 Description. (i) This section must contain:
(A) The proprietary name and the established name, if any, as
defined in section 502(e)(2) of the act, of the drug or, for biological
products, the proper name (as defined in Sec. 600.3 of this chapter)
and any appropriate descriptors;
(B) The type of dosage form(s) and the route(s) of administration to
which the labeling applies;
(C) The same qualitative and/or quantitative ingredient information
as required under Sec. 201.100(b) for drug labels or Sec. Sec. 610.60
and 610.61 of this chapter for biological product labels;
(D) If the product is sterile, a statement of that fact;
(E) The pharmacological or therapeutic class of the drug;
(F) For drug products other than biological products, the chemical
name and structural formula of the drug; and
(G) If the product is radioactive, a statement of the important
nuclear physical characteristics, such as the principal radiation
emission data, external radiation, and physical decay characteristics.
(ii) If appropriate, other important chemical or physical
information, such as physical constants or pH, must be stated.
(13) 12 Clinical pharmacology. (i) This section must contain
information relating to the human clinical pharmacology and actions of
the drug in humans. Pharmacologic information based on in vitro data
using human biomaterials or pharmacologic animal models, or relevant
details about in vivo study designs or results (e.g., drug interaction
studies), may be included in this section if essential to understand
dosing or drug interaction information presented in other sections of
the labeling. This section must include the following subsections:
(A) 12.1 Mechanism of action. This subsection must summarize what is
known about the established mechanism(s) of the drug's action in humans
at various levels (e.g., receptor, membrane, tissue, organ, whole body).
If the mechanism of action is not known, this subsection must contain a
statement about the lack of information.
(B) 12.2 Pharmacodynamics. This subsection must include a
description of any biochemical or physiologic pharmacologic effects of
the drug or active metabolites related to the drug's clinical effect in
preventing, diagnosing, mitigating, curing, or treating disease, or
those related to adverse effects or toxicity. Exposure-response
relationships (e.g., concentration-response, dose-response) and time
course of pharmacodynamic response (including short-term clinical
response) must be included if known. If this information is unknown,
this subsection must contain a statement about the lack of information.
Detailed dosing or monitoring recommendations based on pharmacodynamic
information that appear in other sections (e.g., ``Warnings and
Precautions'' or ``Dosage and Administration'') must not be repeated in
this subsection, but the location of such recommendations must be
referenced.
(C) 12.3 Pharmacokinetics. This subsection must describe the
clinically significant pharmacokinetics of a drug or active metabolites,
(i.e., pertinent absorption, distribution, metabolism,
[[Page 38]]
and excretion parameters). Information regarding bioavailability, the
effect of food, minimum concentration (Cmin), maximum
concentration (Cmax), time to maximum concentration
(Tmax), area under the curve (AUC), pertinent half-lives
(t1/2), time to reach steady state, extent of accumulation,
route(s) of elimination, clearance (renal, hepatic, total), mechanisms
of clearance (e.g., specific enzyme systems), drug/drug and drug/food
(e.g., dietary supplements, grapefruit juice) pharmacokinetic
interactions (including inhibition, induction, and genetic
characteristics), and volume of distribution (Vd) must be
presented if clinically significant. Information regarding nonlinearity
in pharmacokinetic parameters, changes in pharmacokinetics over time,
and binding (plasma protein, erythrocyte) parameters must also be
presented if clinically significant. This section must also include the
results of pharmacokinetic studies (e.g., of metabolism or interaction)
that establish the absence of an effect, including pertinent human
studies and in vitro data. Dosing recommendations based on clinically
significant factors that change the product's pharmacokinetics (e.g.,
age, gender, race, hepatic or renal dysfunction, concomitant therapy)
that appear in other sections (e.g., ``Warnings and Precautions,''
``Dosage and Administration'' or ``Use in Specific Populations'') must
not be repeated in this subsection, but the location of such
recommendations must be referenced.
(ii) Data that demonstrate activity or effectiveness in in vitro or
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be
included under this section only under the following circumstances:
(A) In vitro data for anti-infective drugs may be included if the
data are immediately preceded by the statement ``The following in vitro
data are available but their clinical significance is unknown.''
(B) For other classes of drugs, in vitro and animal data that have
not been shown by adequate and well-controlled studies, as defined in
Sec. 314.126(b) of this chapter, to be necessary for the safe and
effective use may be included in this section only if a waiver is
granted under Sec. 201.58 or Sec. 314.126(c) of this chapter.
(14) 13 Nonclinical toxicology. This section must contain the
following subsections as appropriate:
(i) 13.1 Carcinogenesis, mutagenesis, impairment of fertility. This
subsection must state whether long term studies in animals have been
performed to evaluate carcinogenic potential and, if so, the species and
results. If results from reproduction studies or other data in animals
raise concern about mutagenesis or impairment of fertility in either
males or females, this must be described. Any precautionary statement on
these topics must include practical, relevant advice to the prescriber
on the significance of these animal findings. Human data suggesting that
the drug may be carcinogenic or mutagenic, or suggesting that it impairs
fertility, as described in the ``Warnings and Precautions'' section,
must not be included in this subsection of the labeling.
(ii) 13.2 Animal toxicology and/or pharmacology. Significant animal
data necessary for safe and effective use of the drug in humans that is
not incorporated in other sections of labeling must be included in this
section (e.g., specifics about studies used to support approval under
Sec. 314.600 or Sec. 601.90 of this chapter, the absence of chronic
animal toxicity data for a drug that is administered over prolonged
periods or is implanted in the body).
(15) 14 Clinical studies. This section must discuss those clinical
studies that facilitate an understanding of how to use the drug safely
and effectively. Ordinarily, this section will describe the studies that
support effectiveness for the labeled indication(s), including
discussion of study design, population, endpoints, and results, but must
not include an encyclopedic listing of all, or even most, studies
performed as part of the product's clinical development program. If a
specific important clinical study is mentioned in any section of the
labeling required under Sec. Sec. 201.56 and 201.57 because the study
is essential to an understandable presentation of the
[[Page 39]]
information in that section of the labeling, any detailed discussion of
the study must appear in this section.
(i) For drug products other than biological products, any clinical
study that is discussed in prescription drug labeling that relates to an
indication for or use of the drug must be adequate and well-controlled
as described in Sec. 314.126(b) of this chapter and must not imply or
suggest indications or uses or dosing regimens not stated in the
``Indications and Usage'' or ``Dosage and Administration'' section. For
biological products, any clinical study that is discussed that relates
to an indication for or use of the biological product must constitute or
contribute to substantial evidence and must not imply or suggest
indications or uses or dosing regimens not stated in the ``Indications
and Usage'' or ``Dosage and Administration'' section.
(ii) Any discussion of a clinical study that relates to a risk from
the use of the drug must also refer to the other sections of the
labeling where the risk is identified or discussed.
(16) 15 References. When prescription drug labeling must summarize
or otherwise rely on a recommendation by an authoritative scientific
body, or on a standardized methodology, scale, or technique, because the
information is important to prescribing decisions, the labeling may
include a reference to the source of the information.
(17) 16 How supplied/storage and handling. This section must contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible. The
information must include, as appropriate:
(i) The strength or potency of the dosage form in metric system
(e.g., 10 milligram tablets) and, if the apothecary system is used, a
statement of the strength in parentheses after the metric designation;
(ii) The units in which the dosage form is ordinarily available for
prescribing by practitioners (e.g., bottles of 100);
(iii) Appropriate information to facilitate identification of the
dosage forms, such as shape, color, coating, scoring, imprinting, and
National Drug Code number; and
(iv) Special handling and storage conditions.
(18) 17 Patient counseling information. This section must contain
information necessary for patients to use the drug safely and
effectively (e.g., precautions concerning driving or the concomitant use
of other substances that may have harmful additive effects). Any FDA-
approved patient labeling must be referenced in this section and the
full text of such patient labeling must be reprinted immediately
following this section or, alternatively, accompany the prescription
drug labeling. Any FDA-approved patient labeling printed immediately
following this section or accompanying the labeling is subject to the
type size requirements in paragraph (d)(6) of this section, except for a
Medication Guide to be detached and distributed to patients in
compliance with Sec. 208.24 of this chapter. Medication Guides for
distribution to patients are subject to the type size requirements set
forth in Sec. 208.20 of this chapter.
(d) Format requirements. All labeling information required under
paragraphs (a), (b), and (c) of this section must be printed in
accordance with the following specifications:
(1) All headings and subheadings required by paragraphs (a) and (c)
of this section must be highlighted by bold type that prominently
distinguishes the headings and subheadings from other labeling
information. Reverse type is not permitted as a form of highlighting.
(2) A horizontal line must separate the information required by
paragraphs (a), (b), and (c) of this section.
(3) The headings listed in paragraphs (a)(5) through (a)(13) of this
section must be presented in the center of a horizontal line.
(4) If there are multiple subheadings listed under paragraphs (a)(4)
through (a)(13) of this section, each subheading must be preceded by a
bullet point.
(5) The labeling information required by paragraphs (a)(1) through
(a)(4), (a)(11)(ii) through (a)(11)(iv), and (a)(14) of this section
must be in bold print.
(6) The letter height or type size for all labeling information,
headings, and subheadings set forth in paragraphs (a), (b), and (c) of
this section must be a
[[Page 40]]
minimum of 8 points, except for labeling information that is on or
within the package from which the drug is to be dispensed, which must be
a minimum of 6 points.
(7) The identifying numbers required by Sec. 201.56(d) and
paragraphs (c)(1) through (c)(18) of this section must be presented in
bold print and must precede the heading or subheading by at least two
square em's (i.e., two squares of the size of the letter ``m'' in 8
point type).
(8) The information required by paragraph (a) of this section, not
including the information required under paragraph (a)(4) of this
section, must be limited in length to an amount that, if printed in 2
columns on a standard sized piece of typing paper (8\1/2\ by 11 inches),
single spaced, in 8 point type with \1/2\-inch margins on all sides and
between columns, would fit on one-half of the page.
(9) Sections or subsections of labeling that are identified as
containing recent major changes under paragraph (a)(5) of this section
must be highlighted in the full prescribing information by the inclusion
of a vertical line on the left edge of the new or modified text.
(10) For the information required by paragraph (b) of this section,
each section heading must be in bold print. Each subheading within a
section must be indented and not bolded.
[71 FR 3988, Jan. 24, 2006, as amended at 79 FR 72101, Dec. 4, 2014]
Sec. 201.58 Waiver of labeling requirements.
An applicant may ask the Food and Drug Administration to waive any
requirement under Sec. Sec. 201.56, 201.57, and 201.80. A waiver
request must be submitted in writing to the Director (or the Director's
designee), Center for Drug Evaluation and Research, Food and Drug
Administration, Central Document Room, 5901-B Ammendale Rd., Beltsville,
MD 20705-1266, or, if applicable, the Director (or the Director's
designee), Food and Drug Administration, Center for Biologics Evaluation
and Research, Document Control Center, 10903 New Hampshire Ave., Bldg.
71, Rm. G112, Silver Spring, MD 20993-0002. The waiver must be granted
or denied in writing by the Director or the Director's designee.
[71 FR 3996, Jan. 24, 2006, as amended at 74 FR 13112, Mar. 26, 2009; 80
FR 18090, Apr. 3, 2015]
Subpart C_Labeling Requirements for Over-the-Counter Drugs
Source: 41 FR 6908, Feb. 13, 1976, unless otherwise noted.
Sec. 201.60 Principal display panel.
The term principal display panel, as it applies to over-the-counter
drugs in package form and as used in this part, means the part of a
label that is most likely to be displayed, presented, shown, or examined
under customary conditions of display for retail sale. The principal
display panel shall be large enough to accommodate all the mandatory
label information required to be placed thereon by this part with
clarity and conspicuousness and without obscuring designs, vignettes, or
crowding. Where packages bear alternate principal display panels,
information required to be placed on the principal display panel shall
be duplicated on each principal display panel. For the purpose of
obtaining uniform type size in declaring the quantity of contents for
all packages of substantially the same size, the term area of the
principal display panel means the area of the side or surface that bears
the principal display panel, which area shall be:
(a) In the case of a rectangular package where one entire side
properly can be considered to be the principal display panel side, the
product of the height times the width of that side;
(b) In the case of a cylindrical or nearly cylindrical container, 40
percent of the product of the height of the container times the
circumference; and
(c) In the case of any other shape of container, 40 percent of the
total surface of the container: Provided, however, That where such
container presents an obvious ``principal display panel'' such as the
top of a triangular or circular package, the area shall consist of the
entire top surface.
[[Page 41]]
In determining the area of the principal display panel, exclude tops,
bottoms, flanges at the tops and bottoms of cans, and shoulders and
necks of bottles or jars. In the case of cylindrical or nearly
cylindrical containers, information required by this part to appear on
the principal display panel shall appear within that 40 percent of the
circumference which is most likely to be displayed, presented, shown, or
examined under customary conditions of display for retail sale.
Sec. 201.61 Statement of identity.
(a) The principal display panel of an over-the-counter drug in
package form shall bear as one of its principal features a statement of
the identity of the commodity.
(b) Such statement of identity shall be in terms of the established
name of the drug, if any there be, followed by an accurate statement of
the general pharmacological category(ies) of the drug or the principal
intended action(s) of the drug. In the case of an over-the-counter drug
that is a mixture and that has no established name, this requirement
shall be deemed to be satisfied by a prominent and conspicuous statement
of the general pharmacological action(s) of the mixture or of its
principal intended action(s) in terms that are meaningful to the layman.
Such statements shall be placed in direct conjunction with the most
prominent display of the proprietary name or designation and shall
employ terms descriptive of general pharmacological category(ies) or
principal intended action(s); for example, ``antacid,'' ``analgesic,''
``decongestant,'' ``antihistaminic,'' etc. The indications for use shall
be included in the directions for use of the drug, as required by
section 502(f)(1) of the act and by the regulations in this part.
(c) The statement of identity shall be presented in bold face type
on the principal display panel, shall be in a size reasonably related to
the most prominent printed matter on such panel, and shall be in lines
generally parallel to the base on which the package rests as it is
designed to be displayed.
Sec. 201.62 Declaration of net quantity of contents.
(a) The label of an over-the-counter drug in package form shall bear
a declaration of the net quantity of contents. This shall be expressed
in the terms of weight, measure, numerical count, or a combination or
numerical count and weight, measure, or size. The statement of quantity
of drugs in tablet, capsule, ampule, or other unit form and the quantity
of devices shall be expressed in terms of numerical count; the statement
of quantity for drugs in other dosage forms shall be in terms of weight
if the drug is solid, semisolid, or viscous, or in terms of fluid
measure if the drug is liquid. The drug quantity statement shall be
augmented when necessary to give accurate information as to the strength
of such drug in the package; for example, to differentiate between
several strengths of the same drug ``100 tablets, 5 grains each'' or
``100 capsules, 125 milligrams each'' or ``100 capsules, 250 milligrams
each'': Provided, That:
(1) In the case of a firmly established, general consumer usage and
trade custom of declaring the quantity of a drug in terms of linear
measure or measure of area, such respective term may be used. Such term
shall be augmented when necessary for accuracy of information by a
statement of the weight, measure, or size of the individual units or of
the entire drug; for example, the net quantity of adhesive tape in
package form shall be expressed in terms of linear measure augmented by
a statement of its width.
(2) Whenever the Commissioner determines for a specific packaged
drug that an existing practice of declaring net quantity of contents by
weight, measure, numerical count, or a combination of these does not
facilitate value comparisons by consumers, he shall by regulation
designate the appropriate term or terms to be used for such article.
(b) Statements of weight of the contents shall be expressed in terms
of avoirdupois pound and ounce. A statement of liquid measure of the
contents shall be expressed in terms of the U.S. gallon of 231 cubic
inches and quart, pint, and fluid-ounce subdivisions thereof, and shall
express the volume
[[Page 42]]
at 68 [deg]F (20 [deg]C). See also paragraph (p) of this section.
(c) The declaration may contain common or decimal fractions. A
common fraction shall be in terms of halves, quarters, eights,
sixteenths, or thirty-seconds; except that if there exists a firmly
established, general consumer usage and trade custom of employing
different common fractions in the net quantity declaration of a
particular commodity, they may be employed. A common fraction shall be
reduced to its lowest terms; a decimal fraction shall not be carried out
to more than two places. A statement that includes small fractions of an
ounce shall be deemed to permit smaller variations than one which does
not include such fractions.
(d) The declaration shall be located on the principal display panel
of the label, and with respect to packages bearing alternate principal
panels it shall be duplicated on each principal display panel.
(e) The declaration shall appear as a distinct item on the principal
display panel, shall be separated, by at least a space equal to the
height of the lettering used in the declaration, from other printed
label information appearing above or below the declaration and, by at
least a space equal to twice the width of the letter ``N'' of the style
of type used in the quantity of contents statement, from other printed
label information appearing to the left or right of the declaration. It
shall not include any term qualifying a unit of weight, measure, or
count, such as ``giant pint'' and ``full quart'', that tends to
exaggerate the amount of the drug in the container. It shall be placed
on the principal display panel within the bottom 30 percent of the area
of the label panel in lines generally parallel to the base on which the
package rests as it is designed to be displayed: Provided, That:
(1) On packages having a principal display panel of 5 square inches
or less the requirement for placement within the bottom 30 percent of
the area of the label panel shall not apply when the declaration of net
quantity of contents meets the other requirements of this part; and
(2) In the case of a drug that is marketed with both outer and inner
retail containers bearing the mandatory label information required by
this part and the inner container is not intended to be sold separately,
the net quantity of contents placement requirement of this section
applicable to such inner container is waived.
(3) The principal display panel of a drug marketed on a display card
to which the immediate container is affixed may be considered to be the
display panel of the card, and the type size of the net quantity of
contents statement is governed by the dimensions of the display card.
(f) The declaration shall accurately reveal the quantity of drug or
device in the package exclusive of wrappers and other material packed
therewith: Provided, That in the case of drugs packed in containers
designed to deliver the drug under pressure, the declaration shall state
the net quantity of the contents that will be expelled when the
instructions for use as shown on the container are followed. The
propellant is included in the net quantity declaration.
(g) The declaration shall appear in conspicuous and easily legible
boldface print or type in distinct contrast (by typography, layout,
color, embossing, or molding) to other matter on the package; except
that a declaration of net quantity blown, embossed, or molded on a glass
or plastic surface is permissible when all label information is so
formed on the surface. Requirements of conspicuousness and legibility
shall include the specifications that:
(1) The ratio of height to width of the letter shall not exceed a
differential of 3 units to 1 unit, i.e., no more than 3 times as high as
it is wide.
(2) Letter heights pertain to upper case or capital letters. When
upper and lower case or all lower case letters are used, it is the lower
case letter ``o'' or its equivalent that shall meet the minimum
standards.
(3) When fractions are used, each component numeral shall meet one-
half the minimum height standards.
(h) The declaration shall be in letters and numerals in a type size
established in relationship to the area of the principal display panel
of the package and
[[Page 43]]
shall be uniform for all packages of substantially the same size by
complying with the following type specifications:
(1) Not less than one-sixteenth inch in height on packages the
principal display panel of which has an area of 5 square inches or less.
(2) Not less than one-eighth inch in height on packages the
principal display panel of which has an area of more than five but not
more than 25 square inches.
(3) Not less than three-sixteenths inch in height on packages the
principal display panel of which has an area of more than 25 but not
more than 100 square inches.
(4) Not less than one-fourth inch in height on packages the
principal display panel of which has an area of more than 100 square
inches, except not less than one-half inch in height if the area is more
than 400 square inches.
Where the declaration is blown, embossed, or molded on a glass or
plastic surface rather than by printing, typing, or coloring, the
lettering sizes specified in paragraphs (h) (1) through (4) of this
section shall be increased by one-sixteenth of an inch.
(i) On packages containing less than 4 pounds or 1 gallon and
labeled in terms of weight or fluid measure:
(1) The declaration shall be expressed both in ounces, with
identification by weight or by liquid measure and, if applicable (1
pound or 1 pint or more) followed in parentheses by a declaration in
pounds for weight units, with any remainder in terms of ounces or common
or decimal fractions of the pound (see examples set forth in paragraphs
(k) (1) and (2) of this section), or in the case of liquid measure, in
the largest whole units (quarts, quarts and pints, or pints, as
appropriate) with any remainder in terms of fluid ounces or common or
decimal fractions of the pint or quart (see examples set forth in
paragraphs (k) (3) and (4) of this section). If the net weight of the
package is less than 1 ounce avoirdupois or the net fluid measure is
less than 1 fluid ounce, the declaration shall be in terms of common or
decimal fractions of the respective ounce and not in terms of drams.
(2) The declaration may appear in more than one line. The term net
weight shall be used when stating the net quantity of contents in terms
of weight. Use of the terms net or net contents in terms of fluid
measure or numerical count is optional. It is sufficient to distinguish
avoirdupois ounce from fluid ounce through association of terms; for
example, ``Net wt. 6 oz'' or ``6 oz net wt.,'' and ``6 fl oz'' or ``net
contents 6 fl oz''.
(j) On packages containing 4 pounds or 1 gallon or more and labeled
in terms of weight or fluid measure, the declaration shall be expressed
in pounds for weight units with any remainder in terms of ounces or
common or decimal fractions of the pound; in the case of fluid measure,
it shall be expressed in the largest whole unit (gallons, followed by
common or decimal fractions of a gallon or by the next smaller whole
unit or units (quarts or quarts and pints)) with any remainder in terms
of fluid ounces or common or decimal fractions of the pint or quart; see
paragraph (k)(5) of this section.
(k) Examples:
(1) A declaration of 1\1/2\ pounds weight shall be expressed as
``Net wt. 24 oz (1 lb 8 oz),'' or ``Net wt. 24 oz (1\1/2\ lb)'' or ``Net
wt. 24 oz (1.5 lb)''.
(2) A declaration of three-fourths pound avoirdupois weight shall be
expressed as ``Net wt. 12 oz''.
(3) A declaration of 1 quart liquid measure shall be expressed as
``Net contents 32 fl oz (1 qt)'' or ``32 fl oz (1 qt)''.
(4) A declaration of 1\3/4\ quarts liquid measure shall be expressed
as ``Net contents 56 fl oz (1 qt 1 pt 8 oz)'' or ``Net contents 56 fl oz
(1 qt 1.5 pt),'' but not in terms of quart and ounce such as ``Net 56 fl
oz (1 qt 24 oz).''
(5) A declaration of 2\1/2\ gallons liquid measure shall be
expressed as ``Net contents 2 gal 2 qt,'' ``Net contents 2.5 gallons,''
or ``Net contents 2\1/2\ gal'' but not as ``2 gal 4 pt''.
(l) For quantities, the following abbreviations and none other may
be employed. Periods and plural forms are optional:
Gallon gal
quart qt
pint pt
ounce oz
[[Page 44]]
pound lb
grain gr
kilogram kg
gram g
milligram mg
microgram mcg
liter l
milliliter ml
cubic centimeter cc
yard yd
feet or foot ft
inch in
meter m
centimeter cm
millimeter mm
fluid fl
square sq
weight wt
(m) On packages labeled in terms of linear measure, the declaration
shall be expressed both in terms of inches and, if applicable (1 foot or
more), the largest whole units (yards, yards and feet, feet). The
declaration in terms of the largest whole units shall be in parentheses
following the declaration in terms of inches and any remainder shall be
in terms of inches or common or decimal fractions of the foot or yard;
if applicable, as in the case of adhesive tape, the initial declaration
in linear inches shall be preceded by a statement of the width. Examples
of linear measure are ``86 inches (2 yd 1 ft 2 in),'' ``90 inches (2\1/
2\ yd),'' ``30 inches (2.5 ft),'' `` \3/4\ inch by 36 in (1 yd),'' etc.
(n) On packages labeled in terms of area measure, the declaration
shall be expressed both in terms of square inches and, if applicable (1
square foot or more), the largest whole square unit (square yards,
square yards and square feet, square feet). The declaration in terms of
the largest whole units shall be in parentheses following the
declaration in terms of square inches and any remainder shall be in
terms of square inches or common or decimal fractions of the square foot
or square yard; for example, ``158 sq inches (1 sq ft 14 sq in).''
(o) Nothing in this section shall prohibit supplemental statements
at locations other than the principal display panel(s) describing in
nondeceptive terms the net quantity of contents, provided that such
supplemental statements of net quantity of contents shall not include
any term qualifying a unit of weight, measure, or count that tends to
exaggerate the amount of the drug contained in the package; for example,
``giant pint'' and ``full quart.'' Dual or combination declarations of
net quantity of contents as provided for in paragraphs (a) and (i) of
this section are not regarded as supplemental net quantity statements
and shall be located on the principal display panel.
(p) A separate statement of net quantity of contents in terms of the
metric system of weight or measure is not regarded as a supplemental
statement and an accurate statement of the net quantity of contents in
terms of the metric system of weight or measure may also appear on the
principal display panel or on other panels.
(q) The declaration of net quantity of contents shall express an
accurate statement of the quantity of contents of the package.
Reasonable variations caused by loss or gain of moisture during the
course of good distribution practice or by unavoidable deviations in
good manufacturing practice will be recognized. Variations from stated
quantity of contents shall not be unreasonably large.
(r) A drug shall be exempt from compliance with the net quantity
declaration required by this section if it is an ointment labeled
``sample,'' ``physician's sample,'' or a substantially similar statement
and the contents of the package do not exceed 8 grams.
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] In
addition to the written warning, a symbol that conveys the intent of the
warning may be used in labeling.
(b) Where a specific warning relating to use during pregnancy or
while nursing has been established for a particular drug product in a
new drug application (NDA) or for a product covered by an OTC drug final
monograph in part 330 of this chapter, the specific warning shall be
used in place of the warning in paragraph (a) of this section, unless
otherwise stated in the NDA or in the final OTC drug monograph.
(c) The following OTC drugs are exempt from the provisions of
paragraph (a) of this section:
[[Page 45]]
(1) Drugs that are intended to benefit the fetus or nursing infant
during the period of pregnancy or nursing.
(2) Drugs that are labeled exclusively for pediatric use.
(d) The Food and Drug Administration will grant an exemption from
paragraph (a) of this section where appropriate upon petition under the
provisions of Sec. 10.30 of this chapter. Decisions with respect to
requests for exemptions shall be maintained in a permanent file for
public review by the Division of Dockets Management (HFA-305), Food and
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
(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.''
[47 FR 54757, Dec. 3, 1982, as amended at 55 FR 27784, July 5, 1990; 59
FR 14364, Mar. 28, 1994; 64 FR 13286, Mar. 17, 1999; 68 FR 24879, May 9,
2003]
Sec. 201.64 Sodium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended
for oral ingestion shall contain the sodium content per dosage unit
(e.g., tablet, teaspoonful) if the sodium content of a single maximum
recommended dose of the product (which may be one or more dosage units)
is 5 milligrams or more. OTC drug products intended for oral ingestion
include gum and lozenge dosage forms, but do not include dentifrices,
mouthwashes, or mouth rinses.
(b) The sodium content shall be expressed in milligrams per dosage
unit and shall include the total amount of sodium regardless of the
source, i.e., from both active and inactive ingredients. The sodium
content shall be rounded-off to the nearest whole number. The sodium
content per dosage unit shall follow the heading ``Other information''
as stated in Sec. 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion
shall contain the following statement under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) if the
amount of sodium present in the labeled maximum daily dose of the
product is more than 140 milligrams: ``Ask a doctor before use if you
have [in bold type] [bullet] \1\ a sodium-restricted diet''. The
warnings in Sec. Sec. 201.64(c), 201.70(c), 201.71(c), and 201.72(c)
may be combined, if applicable, provided the ingredients are listed in
alphabetical order, e g., a calcium or sodium restricted diet.
---------------------------------------------------------------------------
\1\ See Sec. 201 .66(b)(4) of this chapter for definition of bullet
symbol.
---------------------------------------------------------------------------
(d) The term sodium free may be used in the labeling of OTC drug
products intended for oral ingestion if the amount of sodium in the
labeled maximum daily dose is 5 milligrams or less and the amount of
sodium per dosage unit is 0 milligram (when rounded-off in accord with
paragraph (b) of this section).
(e) The term very low sodium may be used in the labeling of OTC drug
products intended for oral ingestion if the amount of sodium in the
labeled maximum daily dose is 35 milligrams or less.
(f) The term low sodium may be used in the labeling of OTC drug
products intended for oral ingestion if the amount of sodium in the
labeled maximum daily dose is 140 milligrams or less.
(g) The term salt is not synonymous with the term sodium and shall
not be used interchangeably or substituted for the term sodium.
(h) The terms sodium free, very low sodium, and low sodium shall be
in print size and style no larger than the product's statement of
identity and shall not be unduly prominent in print size or style
compared to the statement of identity.
(i) Any product subject to this paragraph that contains sodium
bicarbonate, sodium phosphate, or sodium biphosphate as an active
ingredient for oral ingestion and that is not labeled as required by
this paragraph and that is initially introduced or initially delivered
for introduction into interstate
[[Page 46]]
commerce after April 22, 1997, is misbranded under sections 201(n) and
502 (a) and (f) of the Federal Food, Drug, and Cosmetic Act (the act).
(j) Any product subject to paragraphs (a) through (h) of this
section that is not labeled as required and that is initially introduced
or initially delivered for introduction into interstate commerce after
the following dates is misbranded under sections 201(n) and 502(a) and
(f) of the Federal Food, Drug, and Cosmetic Act.
(1) As of the date of approval of the application for any single
entity and combination products subject to drug marketing applications
approved on or after April 23, 2004.
(2) Septemeber 24, 2005, for all OTC drug products subject to any
OTC drug monograph, not yet the subject of any OTC drug monograph, or
subject to drug marketing applications approved before April 23, 2004.
(k) The labeling of OTC drug products intended for rectal
administration containing dibasic sodium phosphate and/or monobasic
sodium phosphate shall contain the sodium content per delivered dose if
the sodium content is 5 milligrams or more. The sodium content shall be
expressed in milligrams or grams. If less than 1 gram, milligrams should
be used. The sodium content shall be rounded-off to the nearest whole
number if expressed in milligrams (or nearest tenth of a gram if
expressed in grams). The sodium content per delivered dose shall follow
the heading ``Other information'' as stated in Sec. 201.66(c)(7). Any
product subject to this paragraph that contains dibasic sodium phosphate
and/or monobasic sodium phosphate as an active ingredient intended for
rectal administration and that is not labeled as required by this
paragraph and that is initially introduced or initially delivered for
introduction into interstate commerce after November 29, 2005, is
misbranded under sections 201(n) and 502(a) and (f) of the act.
[61 FR 17806, Apr. 22, 1996, as amended at 62 FR 19925, Apr. 24, 1997;
64 FR 13286, Mar. 17, 1999; 69 FR 13724, Mar. 24, 2004; 69 FR 69280,
Nov. 29, 2004]
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.
[[Page 47]]
(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.
(12) Total surface area available to bear labeling means all
surfaces of the outside container of the retail package or, if there is
no such outside container, all surfaces of the immediate container or
container wrapper except for the flanges at the tops and bottoms of cans
and the shoulders and necks of bottles and jars.
(c) Content requirements. The outside container or wrapper of the
retail package, or the immediate container label if there is no outside
container or wrapper, shall contain the title, headings, subheadings,
and information set forth in paragraphs (c)(1) through (c)(8) of this
section, and may contain the information under the heading in paragraph
(c)(9) of this section, in the order listed.
(1) (Title) ``Drug Facts''. If the drug facts labeling appears on
more than one panel, the title ``Drug Facts (continued)'' shall appear
at the top of each subsequent panel containing such information.
(2) ``Active ingredient'' or ``Active ingredients'' ``(in each
[insert the dosage unit stated in the directions for use (e.g., tablet,
5 mL teaspoonful) or in each gram as stated in Sec. Sec. 333.110 and
333.120 of this chapter])'', followed by the established name of each
active ingredient and the quantity of each active ingredient per dosage
unit. Unless otherwise provided in an applicable OTC drug monograph or
approved drug application, products marketed without discrete dosage
units (e.g., topicals) shall state the proportion (rather than the
quantity) of each active ingredient.
(3) ``Purpose'' or ``Purposes'', followed by the general
pharmacological category(ies) or the principal intended action(s) of the
drug or, where the drug consists of more than one ingredient, the
general pharmacological categories or the principal intended actions of
each active ingredient. When an OTC drug monograph contains a statement
of identity, the pharmacological action described in the statement of
identity shall also be stated as the purpose of the active ingredient.
(4) ``Use'' or ``Uses'', followed by the indication(s) for the
specific drug product.
(5) ``Warning'' or ``Warnings'', followed by one or more of the
following, if applicable:
(i) ``For external use only'' [in bold type] for topical drug
products not intended for ingestion, or ``For'' (select one of the
following, as appropriate: ``rectal'' or ``vaginal'') ``use only'' [in
bold type].
(ii) All applicable warnings listed in paragraphs (c)(5)(ii)(A)
through (c)(5)(ii)(G) of this section with the appropriate subheadings
highlighted in bold type:
(A) Reye's syndrome warning for drug products containing salicylates
set forth in Sec. 201.314(h)(1). This warning shall follow the
subheading ``Reye's syndrome:''
(B) Allergic reaction and asthma alert warnings. 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:'' The asthma
alert warning set forth in Sec. Sec. 341.76(c)(5) and 341.76(c)(6) of
this chapter. This warning shall follow the subheading ``Asthma alert:''
(C) Flammability warning, with appropriate flammability signal
word(s) (e.g., Sec. Sec. 341.74(c)(5)(iii), 344.52(c), 358.150(c), and
358.550(c) of this chapter). This warning shall follow a subheading
containing the appropriate flammability signal word(s) described
[[Page 48]]
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) Liver warning set forth in Sec. 201.326(a)(1)(iii) and/or
stomach bleeding warning set forth in Sec. 201.326(a)(2)(iii). The
liver warning shall follow the subheading ``Liver warning:'' and the
stomach bleeding warning shall follow the subheading ``Stomach bleeding
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:''
(H) Sexually transmitted diseases (STDs) warning for vaginal
contraceptive and spermicide drug products containing nonoxynol 9 set
forth in Sec. 201.325(b)(2). This warning shall follow the subheading
``Sexually transmitted diseases (STDs) alert:''
(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. For all OTC drug products
under an approved drug application whose packaging does not include a
toll-free number through which consumers can report complaints to the
manufacturer or distributor of the drug product, the following text
shall immediately follow the subheading: ``[Bullet] side effects occur.
You may report side effects to FDA at 1-800-FDA-1088.'' The telephone
number must appear in a minimum 6-point bold letter height or type size.
(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
[[Page 49]]
monograph, other OTC drug regulation, or is included in the labeling of
an approved drug application.
(i) Required information about certain ingredients in OTC drug
products (e.g., sodium in Sec. 201.64(b), calcium in Sec. 201.70(b),
magnesium in Sec. 201.71(b), and potassium in Sec. 201.72(b)) shall
appear as follows: ``each (insert appropriate dosage unit) contains:''
[in bold type (insert name(s) of ingredient(s) (in alphabetical order)
and the quantity of each ingredient). This information shall be the
first statement under this heading.
(ii) The phenylalanine/aspartame content required by Sec.
201.21(b), if applicable, shall appear as the next item of information.
(iii) Additional information that is authorized to appear under this
heading shall appear as the next item(s) of information. There is no
required order for this subsequent information.
(8) ``Inactive ingredients'', followed by a listing of the
established name of each inactive ingredient. If the product is an OTC
drug product that is not also a cosmetic product, then the inactive
ingredients shall be listed in alphabetical order. If the product is an
OTC drug product that is also a cosmetic product, then the inactive
ingredients shall be listed as set forth in Sec. 701.3(a) or (f) of
this chapter, the names of cosmetic ingredients shall be determined in
accordance with Sec. 701.3(c) of this chapter, and the provisions in
Sec. 701.3(e), (g), (h), (l), (m), (n), and (o) of this chapter and
Sec. 720.8 of this chapter may also apply, as appropriate. If there is
a difference in the labeling provisions in this Sec. 201.66 and
Sec. Sec. 701.3 and 720.8 of this chapter, the labeling provisions in
this Sec. 201.66 shall be used.
(9) ``Questions?'' or ``Questions or comments?'', followed by the
telephone number of a source to answer questions about the product. It
is recommended that the days of the week and times of the day when a
person is available to respond to questions also be included. A graphic
of a telephone or telephone receiver may appear before the heading. The
telephone number must appear in a minimum 6-point bold type.
(d) Format requirements. The title, headings, subheadings, and
information set forth in paragraphs (c)(1) through (c)(9) of this
section shall be presented on OTC drug products in accordance with the
following specifications. In the interest of uniformity of presentation,
FDA strongly reccommends that the Drug Facts labeling be presented using
the graphic specifications set forth in appendix A to part 201.
(1) The title ``Drug Facts'' or ``Drug Facts (continued)'' shall use
uppercase letters for the first letter of the words ``Drug'' and
``Facts.'' All headings and subheadings in paragraphs (c)(2) through
(c)(9) of this section shall use an uppercase letter for the first
letter in the first word and lowercase letters for all other words. The
title, headings, and subheadings in paragraphs (c)(1), (c)(2), and
(c)(4) through (c)(9) of this section shall be left justified.
(2) The letter height or type size for the title ``Drug Facts''
shall appear in a type size larger than the largest type size used in
the Drug Facts labeling. The letter height or type size for the title
``Drug Facts (continued)'' shall be no smaller than 8-point type. The
letter height or type size for the headings in paragraphs (c)(2) through
(c)(9) of this section shall be the larger of either 8-point or greater
type, or 2-point sizes greater than the point size of the text. The
letter height or type size for the subheadings and all other information
described in paragraphs (c)(2) through (c)(9) of this section shall be
no smaller than 6-point type.
(3) The title, heading, subheadings, and information in paragraphs
(c)(1) through (c)(9) of this section shall be legible and clearly
presented, shall have at least 0.5-point leading (i.e., space between
two lines of text), and shall not have letters that touch. The type
style for the title, headings, subheadings, and all other required
information described in paragraphs (c)(2) through (c)(9) of this
section shall be any single, clear, easy-to-read type style, with no
more than 39 characters per inch. The title and headings shall be in
bold italic, and the subheadings shall be in bold type, except that the
word ``(continued)'' in the title ``Drug Facts (continued)'' shall be
regular type. The type shall be all black or one color printed on a
white or other contrasting background, except that the
[[Page 50]]
title and the headings may be presented in a single, alternative,
contrasting color unless otherwise provided in an approved drug
application, OTC drug monograph (e.g., current requirements for bold
print in Sec. Sec. 341.76 and 341.80 of this chapter), or other OTC
drug regulation (e.g., the requirement for a box and red letters in
Sec. 201.308(c)(1)).
(4) When there is more than one statement, each individual statement
listed under the headings and subheadings in paragraphs (c)(4) through
(c)(7) of this section shall be preceded by a solid square or solid
circle bullet of 5-point type size. Bullets shall be presented in the
same shape and color throughout the labeling. The first bulleted
statement on each horizontal line of text shall be either left justified
or separated from an appropriate heading or subheading by at least two
square ``ems'' (i.e., two squares of the size of the letter ``M''). If
more than one bulleted statement is placed on the same horizontal line,
the end of one bulleted statement shall be separated from the beginning
of the next bulleted statement by at least two square ``ems'' and the
complete additional bulleted statement(s) shall not continue to the next
line of text. Additional bulleted statements appearing on each
subsequent horizontal line of text under a heading or subheading shall
be vertically aligned with the bulleted statements appearing on the
previous line.
(5) The title, headings, subheadings, and information set forth in
paragraphs (c)(1) through (c)(9) of this section may appear on more than
one panel on the outside container of the retail package, or the
immediate container label if there is no outside container or wrapper.
The continuation of the required content and format onto multiple panels
must retain the required order and flow of headings, subheadings, and
information. A visual graphic (e.g., an arrow) shall be used to signal
the continuation of the Drug Facts labeling to the next adjacent panel.
(6) The heading and information required under paragraph (c)(2) of
this section shall appear immediately adjacent and to the left of the
heading and information required under paragraph (c)(3) of this section.
The active ingredients and purposes shall be aligned under the
appropriate headings such that the heading and information required
under paragraph (c)(2) of this section shall be left justified and the
heading and information required under paragraph (c)(3) of this section
shall be right justified. If the OTC drug product contains more than one
active ingredient, the active ingredients shall be listed in
alphabetical order. If more than one active ingredient has the same
purpose, the purpose need not be repeated for each active ingredient,
provided the information is presented in a manner that readily
associates each active ingredient with its purpose (i.e., through the
use of brackets, dot leaders, or other graphical features). The
information described in paragraphs (c)(4) and (c)(6) through (c)(9) of
this section may start on the same line as the required headings. None
of the information described in paragraph (c)(5) of this section shall
appear on the same line as the ``Warning'' or ``Warnings'' heading.
(7) Graphical images (e.g., the UPC symbol) and information not
described in paragraphs (c)(1) through (c)(9) of this section shall not
appear in or in any way interrupt the required title, headings,
subheadings, and information in paragraphs (c)(1) through (c)(9) of this
section. Hyphens shall not be used except to punctuate compound words.
(8) The information described in paragraphs (c)(1) through (c)(9) of
this section shall be set off in a box or similar enclosure by the use
of a barline. A distinctive horizontal barline extending to each end of
the ``Drug Facts'' box or similar enclosure shall provide separation
between each of the headings listed in paragraphs (c)(2) through (c)(9)
of this section. When a heading listed in paragraphs (c)(2) through
(c)(9) of this section appears on a subsequent panel immediately after
the ``Drug Facts (continued)'' title, a horizontal hairline shall follow
the title and immediately precede the heading. A horizontal hairline
extending within two spaces on either side of the ``Drug Facts'' box or
similar enclosure shall immediately follow the title and shall
[[Page 51]]
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:
[[Page 52]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.003
(ii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section:
[[Page 53]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.004
(iii) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section, including para-graph (d)(10) of
this section, which permits modifications for small packages:
[[Page 54]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.005
(iv) The following sample label illustrates the provisions in
paragraphs (c) and (d) of this section for a drug product marketed with
cosmetic claims:
[[Page 55]]
[GRAPHIC] [TIFF OMITTED] TR17MR99.006
(e) Exemptions and deferrals. FDA on its own initiative or in
response to a written request from any manufacturer, packer, or
distributor, may exempt or defer, based on the circumstances presented,
one or more specific requirements set forth in this section on the basis
that the requirement is inapplicable, impracticable, or contrary to
public health or safety. Requests for exemptions shall be submitted in
three copies in the form of an ``Application for Exemption'' to the Food
and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD
20852. The request shall be clearly identified on the envelope as a
``Request for Exemption from 21 CFR 201.66 (OTC Labeling Format)'' and
shall be directed to Docket No. 98N-0337. A separate request shall be
submitted for each OTC drug product. Sponsors of a product marketed
under an approved drug application shall also submit a single copy of
the exemption request to their application. Decisions on exemptions and
deferrals will be maintained in a permanent file in this docket for
public review. Exemption and deferral requests shall:
(1) Document why a particular requirement is inapplicable,
impracticable, or is contrary to public health or safety; and
(2) Include a representation of the proposed labeling, including any
outserts, panel extensions, or other graphical or packaging techniques
intended to be used with the product.
(f) Interchangeable terms and connecting terms. The terms listed in
Sec. 330.1(i) of this chapter may be used
[[Page 56]]
interchangeably in the labeling of OTC drug products, provided such use
does not alter the meaning of the labeling that has been established and
identified in an applicable OTC drug monograph or by regulation. The
terms listed in Sec. 330.1(j) of this chapter may be deleted from the
labeling of OTC drug products when the labeling is revised to comply
with this section, provided such deletion does not alter the meaning of
the labeling that has been established and identified in an applicable
OTC drug monograph or by regulation. The terms listed in Sec. 330.1(i)
and (j) of this chapter shall not be used to change in any way the
specific title, headings, and subheadings required under paragraphs
(c)(1) through (c)(9) of this section.
(g) Regulatory action. An OTC drug product that is not in compliance
with the format and content requirements in this section is subject to
regulatory action.
[64 FR 13286, Mar. 17, 1999, as amended at 65 FR 8, Jan. 3, 2000; 65 FR
48904, Aug. 10, 2000; 69 FR 13733, Mar. 24, 2004; 72 FR 71785, Dec. 19,
2007; 73 FR 403, Jan. 3, 2008; 74 FR 19407, Apr. 29, 2009; 76 FR 44487,
July 26, 2011]
Sec. 201.70 Calcium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended
for oral ingestion shall contain the calcium content per dosage unit
(e.g., tablet, teaspoonful) if the calcium content of a single maximum
recommended dose of the product (which may be one or more dosage units)
is 20 milligrams or more. OTC drug products intended for oral ingestion
include gum and lozenge dosage forms, but do not include dentifrices,
mouthwashes, or mouth rinses.
(b) The calcium content shall be expressed in milligrams or grams
per dosage unit and shall include the total amount of calcium regardless
of the source, i.e., from both active and inactive ingredients. If the
dosage unit contains less than 1 gram of calcium, milligrams should be
used. The calcium content per dosage unit shall be rounded-off to the
nearest 5 milligrams (or nearest tenth of a gram if over 1 gram). The
calcium content per dosage unit shall follow the heading ``Other
information'' as stated in Sec. 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion
shall contain the following statement under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) if the
amount of calcium present in the labeled maximum daily dose of the
product is more than 3.2 grams: ``Ask a doctor before use if you have
[in bold type] [bullet] \1\ kidney stones [bullet] a calcium-restricted
diet''. The warnings in Sec. Sec. 201.64(c), 201.70(c), 201.71(c), and
201.72(c) may be combined, if applicable, provided the ingredients are
listed in alphabetical order, e.g., a calcium or sodium restricted diet.
---------------------------------------------------------------------------
\1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet
symbol.
---------------------------------------------------------------------------
(d) Any product subject to this paragraph that is not labeled as
required by this paragraph and that is initially introduced or initially
delivered for introduction into interstate commerce after the following
dates is misbranded under sections 201(n) and 502(a) and (f) of the
Federal Food, Drug, and Cosmetic Act.
(1) As of the date of approval of the application for any single
entity and combination products subject to drug marketing applications
approved on or after April 23, 2004.
(2) September 24, 2005, for all OTC drug products subject to any OTC
drug monograph, not yet the subject of any OTC drug monograph, or
subject to drug marketing applications approved before April 23, 2004.
[69 FR 13733, Mar. 24, 2004]
Sec. 201.71 Magnesium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended
for oral ingestion shall contain the magnesium content per dosage unit
(e.g., tablet, teaspoonful) if the magnesium content of a single maximum
recommended dose of the product (which may be one or more dosage units)
is 8 milligrams or more. OTC drug products intended for oral ingestion
include gum and lozenge dosage forms, but do not include dentifrices,
mouthwashes, or mouth rinses.
(b) The magnesium content shall be expressed in milligrams or grams
per dosage unit and shall include the total
[[Page 57]]
amount of magnesium regardless of the source, i.e., from both active and
inactive ingredients. If the dosage unit contains less than 1 gram of
magnesium, milligrams should be used. The magnesium content shall be
rounded-off to the nearest 5 milligrams (or nearest tenth of a gram if
over 1 gram). The magnesium content per dosage unit shall follow the
heading ``Other information'' as stated in Sec. 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion
shall contain the following statement under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) if the
amount of magnesium present in the labeled maximum daily dose of the
product is more than 600 milligrams: ``Ask a doctor before use if you
have [in bold type] [bullet] \1\ kidney disease [bullet] a magnesium-
restricted diet''. The warnings in Sec. Sec. 201.64(c), 201.70(c),
201.71(c), and 201.72(c) may be combined, if applicable, provided the
ingredients are listed in alphabetical order, e.g., a magnesium or
potassium-restricted diet.
---------------------------------------------------------------------------
\1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet
symbol.
---------------------------------------------------------------------------
(d) Any product subject to this paragraph that is not labeled as
required by this paragraph and that is initially introduced or initially
delivered for introduction into interstate commerce after the following
dates is misbranded under sections 201(n) and 502(a) and (f) of the
Federal Food, Drug, and Cosmetic Act.
(1) As of the date of approval of the application for any single
entity and combination products subject to drug marketing applications
approved on or after April 23, 2004.
(2) September 24. 2005, for all OTC drug products subject to any OTC
drug monograph, not yet the subject of any OTC drug monograph, or
subject to drug marketing applications approved before April 23, 2004.
[69 FR 13734, Mar. 24, 2004]
Sec. 201.72 Potassium labeling.
(a) The labeling of over-the-counter (OTC) drug products intended
for oral ingestion shall contain the potassium content per dosage unit
(e.g., tablet, teaspoonful) if the potassium content of a single maximum
recommended dose of the product (which may be one or more dosage units)
is 5 milligrams or more. OTC drug products intended for oral ingestion
include gum and lozenge dosage forms, but do not include dentifrices,
mouthwashes, or mouth rinses.
(b) The potassium content shall be expressed in milligrams or grams
per dosage unit and shall include the total amount of potassium
regardless of the source, i.e., from both active and inactive
ingredients. If the dosage unit contains less than 1 gram of potassium,
milligrams should be used. The potassium content shall be rounded-off to
the nearest 5 milligrams (or nearest tenth of a gram if over 1 gram).
The potassium content per dosage unit shall follow the heading ``Other
information'' as stated in Sec. 201.66(c)(7).
(c) The labeling of OTC drug products intended for oral ingestion
shall contain the following statement under the heading ``Warning'' (or
``Warnings'' if it appears with additional warning statements) if the
amount of potassium present in the labeled maximum daily dose of the
product is more than 975 milligrams: ``Ask a doctor before use if you
have [in bold type] [bullet] \1\ kidney disease [bullet] a potassium-
restricted diet''. The warnings in Sec. Sec. 201.64(c), 201.70(c),
201.71(c), and 201.72(c) may be combined, if applicable, provided the
ingredients are listed in alphabetical order, e.g., a magnesium or
potassium-restricted diet.
---------------------------------------------------------------------------
\1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet
symbol.
---------------------------------------------------------------------------
(d) Any product subject to this paragraph that is not labeled as
required by this paragraph and that is initially introduced or initially
delivered for introduction into interstate commerce after the following
dates is misbranded under sections 201(n) and 502(a) and (f) of the
Federal Food, Drug, and Cosmetic Act.
(1) As of the date of approval of the application for any single
entity and combination products subject to drug marketing applications
approved on or after April 23, 2004.
(2) September 24, 2005, for all OTC drug products subject to any OTC
drug monograph, not yet the subject of any
[[Page 58]]
OTC drug monograph, or subject to drug marketing applications approved
before April 23, 2004.
[69 FR 13734, Mar. 24, 2004]
Sec. 201.80 Specific requirements on content and format of labeling
for human prescription drug and biological products; older drugs not
described in Sec. 201.56(b)(1).
Each section heading listed in Sec. 201.56(d), if not omitted under
Sec. 201.56(d)(3), shall contain the following information in the
following order:
(a) Description. (1) Under this section heading, the labeling shall
contain:
(i) The proprietary name and the established name, if any, as
defined in section 502(e)(2) of the act, of the drug;
(ii) The type of dosage form and the route of administration to
which the labeling applies;
(iii) The same qualitative and/or quantitative ingredient
information as required under Sec. 201.100(b) for labels;
(iv) If the product is sterile, a statement of that fact;
(v) The pharmacological or therapeutic class of the drug;
(vi) The chemical name and structural formula of the drug;
(vii) If the product is radioactive, a statement of the important
nuclear physical characteristics, such as the principal radiation
emission data, external radiation, and physical decay characteristics.
(2) If appropriate, other important chemical or physical
information, such as physical constants, or pH, shall be stated.
(b) Clinical Pharmacology. (1) Under this section heading, the
labeling shall contain a concise factual summary of the clinical
pharmacology and actions of the drug in humans. The summary may include
information based on in vitro and/or animal data if the information is
essential to a description of the biochemical and/or physiological mode
of action of the drug or is otherwise pertinent to human therapeutics.
Pharmacokinetic information that is important to safe and effective use
of the drug is required, if known, e.g., degree and rate of absorption,
pathways of biotransformation, percentage of dose as unchanged drug and
metabolites, rate or half-time of elimination, concentration in body
fluids associated with therapeutic and/or toxic effects, degree of
binding to plasma proteins, degree of uptake by a particular organ or in
the fetus, and passage across the blood brain barrier. Inclusion of
pharmacokinetic information is restricted to that which relates to
clinical use of the drug. If the pharmacological mode of action of the
drug is unknown or if important metabolic or pharmacokinetic data in
humans are unavailable, the labeling shall contain a statement about the
lack of information.
(2) Data that demonstrate activity or effectiveness in in vitro or
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be
included under this section of the labeling only under the following
circumstances:
(i) In vitro data for anti-infective drugs may be included if the
data are immediately preceded by the statement ``The following in vitro
data are available but their clinical significance is unknown.''
(ii) For other classes of drugs, in vitro and animal data that have
not been shown by adequate and well-controlled clinical studies, as
defined in Sec. 314.126(b) of this chapter, to be pertinent to clinical
use may be used only if a waiver is granted under Sec. 201.58 or Sec.
314.126(c) of this chapter.
(c) Indications and Usage. (1) Under this section heading, the
labeling shall state that:
(i) The drug is indicated in the treatment, prevention, or diagnosis
of a recognized disease or condition, e.g., penicillin is indicated for
the treatment of pneumonia due to susceptible pneumococci; and/or
(ii) The drug is indicated for the treatment, prevention, or
diagnosis of an important manifestation of a disease or condition, e.g.,
chlorothiazide is indicated for the treatment of edema in patients with
congestive heart failure; and/or
(iii) The drug is indicated for the relief of symptoms associated
with a disease or syndrome, e.g., chlorpheniramine is indicated for the
symptomatic relief of nasal congestion
[[Page 59]]
in patients with vasomotor rhinitis; and/or
(iv) The drug, if used for a particular indication only in
conjuction with a primary mode of therapy, e.g., diet, surgery, or some
other drug, is an adjunct to the mode of therapy.
(2)(i) For drug products other than biological products, all
indications listed in this section must be supported by substantial
evidence of effectiveness based on adequate and well-controlled studies
as defined in Sec. 314.126(b) of this chapter unless the requirement is
waived under Sec. 201.58 or Sec. 314.126(c) of this chapter.
Indications or uses must not be implied or suggested in other sections
of labeling if not included in this section.
(ii) For biological products, all indications listed in this section
must be supported by substantial evidence of effectiveness. Indications
or uses must not be implied or suggested in other sections of labeling
if not included in this section.
(3) This section of the labeling shall also contain the following
additional information:
(i) If evidence is available to support the safety and effectiveness
of the drug only in selected subgroups of the larger population with a
disease, syndrome, or symptom under consideration, e.g., patients with
mild disease or patients in a special age group, the labeling shall
describe the available evidence and state the limitations of usefulness
of the drug. The labeling shall also identify specific tests needed for
selection or monitoring of the patients who need the drug, e.g., microbe
susceptibility tests. Information on the approximate kind, degree, and
duration of improvement to be anticipated shall be stated if available
and shall be based on substantial evidence derived from adequate and
well-controlled studies as defined in Sec. 314.126(b) of this chapter
unless the requirement is waived under Sec. 201.58 or Sec. 314.126(c)
of this chapter. If the information is relevant to the recommended
intervals between doses, the usual duration of treatment, or any
modification of dosage, it shall be stated in the ``Dosage and
Administration'' section of the labeling and referenced in this section.
(ii) If safety considerations are such that the drug should be
reserved for certain situations, e.g., cases refractory to other drugs,
this information shall be stated in this section.
(iii) If there are specific conditions that should be met before the
drug is used on a long-term basis, e.g., demonstration of responsiveness
to the drug in a short-term trial, the labeling shall identify the
conditions; or, if the indications for long-term use are different from
those for short-term use, the labeling shall identify the specific
indications for each use.
(iv) If there is a common belief that the drug may be effective for
a certain use or if there is a common use of the drug for a condition,
but the preponderance of evidence related to the use or condition shows
that the drug is ineffective, the Food and Drug Administration may
require that the labeling state that there is a lack of evidence that
the drug is effective for that use or condition.
(v) Any statements comparing the safety or effectiveness, either
greater or less, of the drug with other agents for the same indication
shall be supported by adequate and well-controlled studies as defined in
Sec. 314.126(b) of this chapter unless this requirement is waived under
Sec. 201.58 or Sec. 314.126(c) of this chapter.
(d) Contraindications. Under this section heading, the labeling
shall describe those situations in which the drug should not be used
because the risk of use clearly outweighs any possible benefit. These
situations include administration of the drug to patients known to have
a hypersensitivity to it; use of the drug in patients who, because of
their particular age, sex, concomitant therapy, disease state, or other
condition, have a substantial risk of being harmed by it; or continued
use of the drug in the face of an unacceptably hazardous adverse
reaction. Known hazards and not theoretical possibilities shall be
listed, e.g., if hypersensitivity to the drug has not been demonstrated,
it should not be listed as a contraindication. If no contraindications
are known, this section of the labeling shall state ``None known.''
(e) Warnings. Under this section heading, the labeling shall
describe serious
[[Page 60]]
adverse reactions and potential safety hazards, limitations in use
imposed by them, and steps that should be taken if they occur. The
labeling shall be revised to include a warning as soon as there is
reasonable evidence of an association of a serious hazard with a drug; a
causal relationship need not have been proved. A specific warning
relating to a use not provided for under the ``Indications and Usage''
section of the labeling may be required by the Food and Drug
Administration if the drug is commonly prescribed for a disease or
condition, and there is lack of substantial evidence of effectivenes for
that disease or condition, and such usage is associated with serious
risk or hazard. Special problems, particularly those that may lead to
death or serious injury, may be required by the Food and Drug
Administration to be placed in a prominently displayed box. The boxed
warning ordinarily shall be based on clinical data, but serious animal
toxicity may also be the basis of a boxed warning in the absence of
clinical data. If a boxed warning is required, its location will be
specified by the Food and Drug Administration. The frequency of these
serious adverse reactions and, if known, the approximate mortality and
morbidity rates for patients sustaining the reaction, which are
important to safe and effective use of the drug, shall be expressed as
provided under the ``Adverse Reactions'' section of the labeling.
(f) Precautions. Under this section heading, the labeling shall
contain the following subsections as appropriate for the drug:
(1) General. This subsection of the labeling shall contain
information regarding any special care to be exercised by the
practitioner for safe and effective use of the drug, e.g., precautions
not required under any other specific section or subsection of the
labeling.
(2) Information for patients. This subsection must contain
information necessary for patients to use the drug safely and
effectively (e.g., precautions concerning driving or the concomitant use
of other substances that may have harmful additive effects). Any FDA-
approved patient labeling must be referenced in this section and the
full text of such patient labeling must be reprinted immediately
following the last section of labeling or, alternatively, accompany the
prescription drug labeling. The type size requirement for the Medication
Guide set forth in Sec. 208.20 of this chapter does not apply to the
Medication Guide that is reprinted in or accompanying the prescription
drug labeling unless such Medication Guide is to be detached and
distributed to patients in compliance with Sec. 208.24 of this chapter.
(3) Laboratory tests. This subsection of the labeling shall identify
any laboratory tests that may be helpful in following the patient's
response or in identifying possible adverse reactions. If appropriate,
information shall be provided on such factors as the range of normal and
abnormal values expected in the particular situation and the recommended
frequency with which tests should be done before, during, and after
therapy.
(4)(i) Drug interactions. This subsection of the labeling shall
contain specific practical guidance for the physician on preventing
clinically significant drug/drug and drug/food interactions that may
occur in vivo in patients taking the drug. Specific drugs or classes of
drugs with which the drug to which the labeling applies may interact in
vivo shall be identified, and the mechanism(s) of the interaction shall
be briefly described. Information in this subsection of the labeling
shall be limited to that pertaining to clinical use of the drug in
patients. Drug interactions supported only by animal or in vitro
experiments may not ordinarily be included, but animal or in vitro data
may be used if shown to be clinically relevant. Drug incompatibilities,
i.e., drug interactions that may occur when drugs are mixed in vitro, as
in a solution for intravenous administration, shall be discussed under
the ``Dosage and Administration'' section of the labeling rather than
under this subsection of the labeling.
(ii) Drug/laboratory test interactions. This subsection of the
labeling shall contain practical guidance on known interference of the
drug with laboratory tests.
[[Page 61]]
(5) Carcinogenesis, mutagenesis, impairment of fertility. This
subsection of the labeling shall state whether long-term studies in
animals have been performed to evaluate carcinogenic potential and, if
so, the species and results. If reproduction studies or other data in
animals reveal a problem or potential problem concerning mutagenesis or
impairment of fertility in either males or females, the information
shall be described. Any precautionary statement on these topics shall
include practical, relevant advice to the physician on the significance
of these animal findings. If there is evidence from human data that the
drug may be carcinogenic or mutagenic or that it impairs fertility, this
information shall be included under the ``Warnings'' section of the
labeling. Also, under ``Precautions,'' the labeling shall state: ``See
`Warnings' section for information on carcinogenesis, mutagenesis, and
impairment of fertility.''
(6) Pregnancy. This subsection of the labeling may be omitted only
if the drug is not absorbed systemically and the drug is not known to
have a potential for indirect harm to the fetus. For all other drugs,
this subsection of the labeling shall contain the following information:
(i) Teratogenic effects. Under this heading the labeling shall
identify one of the following categories that applies to the drug, and
the labeling shall bear the statement required under the category:
(a) If adequate and well-controlled studies in pregnant women have
failed to demonstrate a risk to the fetus in the first trimester of
pregnancy (and there is no evidence of a risk in later trimesters), the
labeling shall state: ``Studies in pregnant women have not shown that
(name of drug) increases the risk of fetal abnormalities if administered
during the first (second, third, or all) trimester(s) of pregnancy. If
this drug is used during pregnancy, the possibility of fetal harm
appears remote. Because studies cannot rule out the possibility of harm,
however, (name of drug) should be used during pregnancy only if clearly
needed.'' The labeling shall also contain a description of the human
studies. If animal reproduction studies are available and they fail to
demonstrate a risk to the fetus, the labeling shall also state:
``Reproduction studies have been performed in (kinds of animal(s)) at
doses up to (x) times the human dose and have revealed no evidence of
impaired fertility or harm to the fetus due to (name of drug).'' The
labeling shall also contain a description of available data on the
effect of the drug on the later growth, development, and functional
maturation of the child.
(b) If animal reproduction studies have failed to demonstrate a risk
to the fetus and there are no adequate and well-controlled studies in
pregnant women, the labeling shall state: `` Reproduction studies have
been performed in (kind(s) of animal(s)) at doses up to (x) times the
human dose and have revealed no evidence of impaired fertility or harm
to the fetus due to (name of drug). There are, however, no adequate and
well-controlled studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, this drug should be
used during pregnancy only if clearly needed.'' If animal reproduction
studies have shown an adverse effect (other than decrease in fertility),
but adequate and well-controlled studies in pregnant women have failed
to demonstrate a risk to the fetus during the first trimester of
pregnancy (and there is no evidence of a risk in later trimesters), the
labeling shall state: ``Reproduction studies in (kind(s) of animal(s))
have shown (describe findings) at (x) times the human dose. Studies in
pregnant women, however, have not shown that (name of drug) increases
the risk of abnormalities when administered during the first (second,
third, or all) trimester(s) of pregnancy. Despite the animal findings,
it would appear that the possibility of fetal harm is remote, if the
drug is used during pregnancy. Nevertheless, because the studies in
humans cannot rule out the possibility of harm, (name of drug) should be
used during pregnancy only if clearly needed.'' The labeling shall also
contain a description of the human studies and a description of
available data on the effect of the drug on the later growth,
development, and functional maturation of the child.
[[Page 62]]
(c) If animal reproduction studies have shown an adverse effect on
the fetus, if there are no adequate and well-controlled studies in
humans, and if the benefits from the use of the drug in pregnant women
may be acceptable despite its potential risks, the labeling shall state:
`` (Name of drug) has been shown to be teratogenic (or to have an
embryocidal effect or other adverse effect) in (name(s) of species) when
given in doses (x) times the human dose. There are no adequate and well-
controlled studies in pregnant women. (Name of drug) should be used
during pregnancy only if the potential benefit justifies the potential
risk to the fetus.'' The labeling shall contain a description of the
animal studies. If there are no animal reproduction studies and no
adequate and well-controlled studies in humans, the labeling shall
state: ``Animal reproduction studies have not been conducted with (name
of drug). It is also not known whether (name of drug) can cause fetal
harm when administered to a pregnant woman or can affect reproduction
capacity. (Name of drug) should be given to a pregnant woman only if
clearly needed.'' The labeling shall contain a description of any
available data on the effect of the drug on the later growth,
development, and functional maturation of the child.
(d) If there is positive evidence of human fetal risk based on
adverse reaction data from investigational or marketing experience or
studies in humans, but the potential benefits from the use of the drug
in pregnant women may be acceptable despite its potential risks (for
example, if the drug is needed in a life-threatening situation or
serious disease for which safer drugs cannot be used or are
ineffective), the labeling shall state: `` See `Warnings' section.''
Under the ``Warnings'' section, the labeling states: ``(Name of drug)
can cause fetal harm when administered to a pregnant woman. (Describe
the human data and any pertinent animal data.) If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the
fetus.''
(e) If studies in animals or humans have demonstrated fetal
abnormalities or if there is positive evidence of fetal risk based on
adverse reaction reports from investigational or marketing experience,
or both, and the risk of the use of the drug in a pregnant woman clearly
outweighs any possible benefit (for example, safer drugs or other forms
of therapy are available), the labeling shall state: `` See
`Contraindications' section.'' Under ``Contraindications,'' the labeling
shall state: ``(Name of drug) may (can) cause fetal harm when
administered to a pregnant woman. (Describe the human data and any
pertinant animal data.) (Name of drug) is contraindicated in women who
are or may become pregnant. If this drug is used during pregnancy, or if
the patient becomes pregnant while taking this drug, the patient should
be apprised of the potential hazard to the fetus.''
(ii) Nonteratogenic effects. Under this heading the labeling shall
contain other information on the drug's effects on reproduction and the
drug's use during pregnancy that is not required specifically by one of
the pregnancy categories, if the information is relevant to the safe and
effective use of the drug. Information required under this heading shall
include nonteratogenic effects in the fetus or newborn infant (for
example, withdrawal symptoms or hypoglycemia) that may occur because of
a pregnant woman's chronic use of the drug for a preexisting condition
or disease.
(7) Labor and delivery. If the drug has a recognized use during
labor or delivery (vaginal or abdominal delivery), whether or not the
use is stated in the indications section of the labeling, this
subsection of the labeling shall describe the available information
about the effect of the drug on the mother and the fetus, on the
duration of labor or delivery, on the possibility that forceps delivery
or other intervention or resuscitation of the newborn will be necessary,
and the effect of the drug on the later growth, development, and
functional maturation of the child. If any information required under
this subsection is unknown, this subsection of the labeling shall state
that the information is unknown.
(8) Nursing mothers. (i) If a drug is absorbed systemically, this
subsection of
[[Page 63]]
the labeling shall contain, if known, information about excretion of the
drug in human milk and effects on the nursing infant. Pertinent adverse
effects observed in animal offspring shall be described.
(ii) If a drug is absorbed systemically and is known to be excreted
in human milk, this subsection of the labeling shall contain one of the
following statements, as appropriate. If the drug is associated with
serious adverse reactions or if the drug has a known tumorigenic
potential, the labeling shall state: ``Because of the potential for
serious adverse reactions in nursing infants from (name of drug) (or,
``Because of the potential for tumorigenicity shown for (name of drug)
in (animal or human) studies), a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.'' If the drug is not associated
with serious adverse reactions and does not have a known tumorigenic
potential, the labeling shall state: ``Caution should be exercised when
(name of drug) is administered to a nursing woman.''
(iii) If a drug is absorbed systemically and information on
excretion in human milk is unknown, this subsection of the labeling
shall contain one of the following statements, as appropriate. If the
drug is associated with serious adverse reactions or has a known
tumorigenic potential, the labeling shall state: ``It is not known
whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from (name of drug) (or, ``Because of the
potential for tumorigenicity shown for (name of drug) in (animal or
human) studies), a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.'' If the drug is not associated with serious
adverse reactions and does not have a known tumorigenic potential, the
labeling shall state: ``It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk, caution
should be exercised when (name of drug) is administered to a nursing
woman.''
(9) Pediatric use. (i) Pediatric population(s)/pediatric patient(s):
For the purposes of paragraphs (f)(9)(ii) through (f)(9)(viii) of this
section, the terms pediatric population(s) and pediatric patient(s) are
defined as the pediatric age group, from birth to 16 years, including
age groups often called neonates, infants, children, and adolescents.
(ii) If there is a specific pediatric indication (i.e., an
indication different from those approved for adults) that is supported
by adequate and well-controlled studies in the pediatric population, it
shall be described under the ``Indications and Usage'' section of the
labeling, and appropriate pediatric dosage information shall be given
under the ``Dosage and Administration'' section of the labeling. The
``Pediatric use'' subsection shall cite any limitations on the pediatric
indication, need for specific monitoring, specific hazards associated
with use of the drug in any subsets of the pediatric population (e.g.,
neonates), differences between pediatric and adult responses to the
drug, and other information related to the safe and effective pediatric
use of the drug. Data summarized in this subsection of the labeling
should be discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' or ``Clinical Studies'' section. As appropriate, this
information shall also be contained in the ``Contraindications,''
``Warnings,'' and elsewhere in the ``Precautions'' sections.
(iii) If there are specific statements on pediatric use of the drug
for an indication also approved for adults that are based on adequate
and well-controlled studies in the pediatric population, they shall be
summarized in the ``Pediatric use'' subsection of the labeling and
discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' and ``Clinical Studies'' sections. Appropriate pediatric
dosage shall be given under the ``Dosage and Administration'' section of
the labeling. The ``Pediatric use'' subsection of the labeling shall
also cite any limitations on the pediatric use statement, need for
specific monitoring, specific hazards associated with use of the drug
[[Page 64]]
in any subsets of the pediatric population (e.g., neonates), differences
between pediatric and adult responses to the drug, and other information
related to the safe and effective pediatric use of the drug. As
appropriate, this information shall also be contained in the
``Contraindications,'' ``Warnings,'' and elsewhere in the
``Precautions'' sections.
(iv) FDA may approve a drug for pediatric use based on adequate and
well-controlled studies in adults, with other information supporting
pediatric use. In such cases, the agency will have concluded that the
course of the disease and the effects of the drug, both beneficial and
adverse, are sufficiently similar in the pediatric and adult populations
to permit extrapolation from the adult efficacy data to pediatric
patients. The additional information supporting pediatric use must
ordinarily include data on the pharmacokinetics of the drug in the
pediatric population for determination of appropriate dosage. Other
information, such as data from pharmacodynamic studies of the drug in
the pediatric population, data from other studies supporting the safety
or effectiveness of the drug in pediatric patients, pertinent
premarketing or postmarketing studies or experience, may be necessary to
show that the drug can be used safely and effectively in pediatric
patients. When a drug is approved for pediatric use based on adequate
and well-controlled studies in adults with other information supporting
pediatric use, the ``Pediatric use'' subsection of the labeling shall
contain either the following statement, or a reasonable alternative:
``The safety and effectiveness of (drug name) have been established in
the age groups _ to _ (note any limitations, e.g., no data for pediatric
patients under 2, or only applicable to certain indications approved in
adults). Use of (drug name) in these age groups is supported by evidence
from adequate and well-controlled studies of (drug name) in adults with
additional data (insert wording that accurately describes the data
submitted to support a finding of substantial evidence of effectiveness
in the pediatric population).'' Data summarized in the preceding
prescribed statement in this subsection of the labeling shall be
discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' or the ``Clinical Studies'' section. For example,
pediatric pharmacokinetic or pharmacodynamic studies and dose-response
information should be described in the ``Clinical Pharmacology''
section. Pediatric dosing instructions shall be included in the ``Dosage
and Administration'' section of the labeling. Any differences between
pediatric and adult responses, need for specific monitoring, dosing
adjustments, and any other information related to safe and effective use
of the drug in pediatric patients shall be cited briefly in the
``Pediatric use'' subsection and, as appropriate, in the
``Contraindications,'' ``Warnings,'' ``Precautions,'' and ``Dosage and
Administration'' sections.
(v) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for a particular pediatric population, the ``Pediatric use''
subsection of the labeling shall contain an appropriate statement such
as ``Safety and effectiveness in pediatric patients below the age of (_)
have not been established.'' If use of the drug in this pediatric
population is associated with a specific hazard, the hazard shall be
described in this subsection of the labeling, or, if appropriate, the
hazard shall be stated in the ``Contraindications'' or ``Warnings''
section of the labeling and this subsection shall refer to it.
(vi) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for any pediatric population, this subsection of the labeling
shall contain the following statement: ``Safety and effectiveness in
pediatric patients have not been established.'' If use of the drug in
premature or neonatal infants, or other pediatric subgroups, is
associated with a specific hazard, the hazard shall be described in this
subsection of the labeling, or, if appropriate, the hazard shall be
stated in the ``Contraindications'' or ``Warnings'' section of the
labeling and this subsection shall refer to it.
(vii) If the sponsor believes that none of the statements described
in paragraphs (f)(9)(ii) through (f)(9)(vi) of this
[[Page 65]]
section is appropriate or relevant to the labeling of a particular drug,
the sponsor shall provide reasons for omission of the statements and may
propose alternative statement(s). FDA may permit use of an alternative
statement if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling and that
the alternative statement is accurate and appropriate.
(viii) If the drug product contains one or more inactive ingredients
that present an increased risk of toxic effects to neonates or other
pediatric subgroups, a special note of this risk shall be made,
generally in the ``Contraindications,'' ``Warnings,'' or ``Precautions''
section.
(10) Geriatric use. (i) A specific geriatric indication, if any,
that is supported by adequate and well-controlled studies in the
geriatric population shall be described under the ``Indications and
Usage'' section of the labeling, and appropriate geriatric dosage shall
be stated under the ``Dosage and Administration'' section of the
labeling. The ``Geriatric use'' subsection shall cite any limitations on
the geriatric indication, need for specific monitoring, specific hazards
associated with the geriatric indication, and other information related
to the safe and effective use of the drug in the geriatric population.
Unless otherwise noted, information contained in the ``Geriatric use''
subsection of the labeling shall pertain to use of the drug in persons
65 years of age and older. Data summarized in this subsection of the
labeling shall be discussed in more detail, if appropriate, under
``Clinical Pharmacology'' or the ``Clinical Studies'' section. As
appropriate, this information shall also be contained in
``Contraindications,'' ``Warnings,'' and elsewhere in ``Precautions.''
(ii) Specific statements on geriatric use of the drug for an
indication approved for adults generally, as distinguished from a
specific geriatric indication, shall be contained in the ``Geriatric
use'' subsection and shall reflect all information available to the
sponsor that is relevant to the appropriate use of the drug in elderly
patients. This information includes detailed results from controlled
studies that are available to the sponsor and pertinent information from
well-documented studies obtained from a literature search. Controlled
studies include those that are part of the marketing application and
other relevant studies available to the sponsor that have not been
previously submitted in the investigational new drug application, new
drug application, biological license application, or a supplement or
amendment to one of these applications (e.g., postmarketing studies or
adverse drug reaction reports). The ``Geriatric use'' subsection shall
contain the following statement(s) or reasonable alternative, as
applicable, taking into account available information:
(A) If clinical studies did not include sufficient numbers of
subjects aged 65 and over to determine whether elderly subjects respond
differently from younger subjects, and other reported clinical
experience has not identified such differences, the ``Geriatric use''
subsection shall include the following statement:
``Clinical studies of (name of drug) did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.''
(B) If clinical studies (including studies that are part of
marketing applications and other relevant studies available to the
sponsor that have not been submitted in the sponsor's applications)
included enough elderly subjects to make it likely that differences in
safety or effectiveness between elderly and younger subjects would have
been detected, but no such differences (in safety or effectiveness) were
observed, and other reported clinical experience has not identified such
differences, the ``Geriatric use'' subsection shall contain the
following statement:
Of the total number of subjects in clinical studies of (name of
drug), _ percent were 65 and over, while _ percent were 75 and over.
(Alternatively, the labeling may state the total number of subjects
included in the
[[Page 66]]
studies who were 65 and over and 75 and over.) No overall differences in
safety or effectiveness were observed between these subjects and younger
subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
(C) If evidence from clinical studies and other reported clinical
experience available to the sponsor indicates that use of the drug in
elderly patients is associated with differences in safety or
effectiveness, or requires specific monitoring or dosage adjustment, the
``Geriatric use'' subsection of the labeling shall contain a brief
description of observed differences or specific monitoring or dosage
requirements and, as appropriate, shall refer to more detailed
discussions in the ``Contraindications,'' ``Warnings,'' ``Dosage and
Administration,'' or other sections of the labeling.
(iii)(A) If specific pharmacokinetic or pharmacodynamic studies have
been carried out in the elderly, they shall be described briefly in the
``Geriatric use'' subsection of the labeling and in detail under the
``Clinical Pharmacology'' section. The ``Clinical Pharmacology'' section
and ``Drug interactions'' subsection of the ``Precautions'' section
ordinarily contain information on drug-disease and drug-drug
interactions that is particularly relevant to the elderly, who are more
likely to have concomitant illness and to utilize concomitant drugs.
(B) If a drug is known to be substantially excreted by the kidney,
the ``Geriatric use'' subsection shall include the statement:
``This drug is known to be substantially excreted by the kidney, and
the risk of toxic reactions to this drug may be greater in patients with
impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection,
and it may be useful to monitor renal function.''
(iv) If use of the drug in the elderly appears to cause a specific
hazard, the hazard shall be described in the ``Geriatric use''
subsection of the labeling, or, if appropriate, the hazard shall be
stated in the ``Contraindications,'' ``Warnings,'' or ``Precautions''
section of the labeling, and the ``Geriatric use'' subsection shall
refer to those sections.
(v) Labeling under paragraphs (f)(10)(i) through (f)(10)(iii) of
this section may include statements, if they would be useful in
enhancing safe use of the drug, that reflect good clinical practice or
past experience in a particular situation, e.g., for a sedating drug, it
could be stated that:
``Sedating drugs may cause confusion and over-sedation in the
elderly; elderly patients generally should be started on low doses of
(name of drug) and observed closely.''
(vi) If the sponsor believes that none of the requirements described
in paragraphs (f)(10)(i) through (f)(10)(v) of this section is
appropriate or relevant to the labeling of a particular drug, the
sponsor shall provide reasons for omission of the statements and may
propose an alternative statement. FDA may permit omission of the
statements if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling. FDA may
permit use of an alternative statement if the agency determines that
such statement is accurate and appropriate.
(g) Adverse Reactions. An adverse reaction is an undesirable effect,
reasonably associated with the use of the drug, that may occur as part
of the pharmacological action of the drug or may be unpredictable in its
occurrence.
(1) This section of the labeling shall list the adverse reactions
that occur with the drug and with drugs in the same pharmacologically
active and chemically related class, if applicable.
(2) In this listing, adverse reactions may be categorized by organ
system, by severity of the reaction, by frequency, or by toxicological
mechanism, or by a combination of these, as appropriate. If frequency
information from adequate clinical studies is available, the categories
and the adverse reactions within each category shall be listed in
decreasing order of frequency. An adverse reaction that is significantly
more severe than the other reactions listed in a category, however,
shall be listed before those reactions, regardless of its frequency. If
frequency information from adequate clinical studies is not available,
the categories
[[Page 67]]
and adverse reactions within each category shall be listed in decreasing
order of severity. The approximate frequency of each adverse reaction
shall be expressed in rough estimates or orders of magnitude essentially
as follows: ``The most frequent adverse reaction(s) to (name of drug) is
(are) (list reactions). This (these) occur(s) in about (e.g., one-third
of patients; one in 30 patients; less than one-tenth of patients). Less
frequent adverse reactions are (list reactions), which occur in
approximately (e.g., one in 100 patients). Other adverse reactions,
which occur rarely, in approximately (e.g., one in 1,000 patients), are
(list reactions).'' Percent figures may not ordinarily be used unless
they are documented by adequate and well-controlled studies as defined
in Sec. 314.126(b) of this chapter, they are shown to reflect general
experience, and they do not falsely imply a greater degree of accuracy
than actually exists.
(3) The ``Warnings'' section of the labeling or, if appropriate, the
``Contraindications'' section of the labeling shall identify any
potentially fatal adverse reaction.
(4) Any claim comparing the drug to which the labeling applies with
other drugs in terms of frequency, severity, or character of adverse
reactions shall be based on adequate and well-controlled studies as
defined in Sec. 314.126(b) of this chapter unless this requirement is
waived under Sec. 201.58 or Sec. 314.126(c) of this chapter.
(h) Drug Abuse and Dependence. Under this section heading, the
labeling shall contain the following subsections, as appropriate for the
drug:
(1) Controlled Substance. If the drug is controlled by the Drug
Enforcement Administration, the schedule in which it is controlled shall
be stated.
(2) Abuse. This subsection of the labeling shall be based primarily
on human data and human experience, but pertinent animal data may also
be used. This subsection shall state the types of abuse that can occur
with the drug and the adverse reactions pertinent to them. Particularly
susceptible patient populations shall be identified.
(3) Dependence. This subsection of the labeling shall describe
characteristic effects resulting from both psychological and physical
dependence that occur with the drug and shall identify the quantity of
the drug over a period of time that may lead to tolerance or dependence,
or both. Details shall be provided on the adverse effects of chronic
abuse and the effects of abrupt withdrawal. Procedures necessary to
diagnose the dependent state shall be provided, and the principles of
treating the effects of abrupt withdrawal shall be described.
(i) Overdosage. Under this section heading, the labeling shall
describe the signs, symptoms, and laboratory findings of acute
overdosage and the general principles of treatment. This section shall
be based on human data, when available. If human data are unavailable,
appropriate animal and in vitro data may be used. Specific information
shall be provided about the following:
(1) Signs, symptoms, and laboratory findings associated with an
overdosage of the drug.
(2) Complications that can occur with the drug (for example, organ
toxicity or delayed acidosis).
(3) Oral LD50 of the drug in animals; concentrations of
the drug in biologic fluids associated with toxicity and/or death;
physiologic variables influencing excretion of the drug, such as urine
pH; and factors that influence the dose response relationship of the
drug, such as tolerance. The pharmacokinetic data given in the
``Clinical Pharmacology'' section also may be referenced here, if
applicable to overdoses.
(4) The amount of the drug in a single dose that is ordinarily
associated with symptoms of overdosage and the amount of the drug in a
single dose that is likely to be life-threatening.
(5) Whether the drug is dialyzable.
(6) Recommended general treatment procedures and specific measures
for support of vital functions, such as proven antidotes, gastric
lavage, and forced diuresis. Unqualified recommendations for which data
are lacking with the specific drug or class of drugs, especially
treatment using another drug (for example, central nervous system
stimulants, respiratory stimulants) may not be stated unless
[[Page 68]]
specific data or scientific rationale exists to support safe and
effective use.
(j) Dosage and Administration. This section of the labeling shall
state the recommended usual dose, the usual dosage range, and, if
appropriate, an upper limit beyond which safety and effectiveness have
not been established; dosages shall be stated for each indication when
appropriate. Dosing regimens must not be implied or suggested in other
sections of labeling if not included in this section. This section shall
also state the intervals recommended between doses, the optimal method
of titrating dosage, the usual duration of treatment, and any
modification of dosage needed in special patient populations, e.g., in
children, in geriatric age groups, or in patients with renal or hepatic
disease. Specific tables or monographs may be included to clarify dosage
schedules. Radiation dosimetry information shall be stated for both the
patient receiving a radioactive drug and the person administering it.
This section shall also contain specific direction on dilution,
preparation (including the strength of the final dosage solution, when
prepared according to instructions, in terms of milligrams active
ingredient per milliliter of reconstituted solution, unless another
measure of the strength is more appropriate), and administration of the
dosage form, if needed, e.g., the rate of administration of parenteral
drug in milligrams per minute; storage conditions for stability of the
drug or reconstituted drug, when important; essential information on
drug incompatibilities if the drug is mixed in vitro with other drugs;
and the following statement for parenterals: ``Parenteral drug products
should be inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container permit.''
(k) How Supplied. This section of the labeling shall contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible. The
information shall ordinarily include:
(1) The strength of the dosage form, e.g., 10-milligram tablets, in
metric system and, if the apothecary system is used, a statement of the
strength is placed in parentheses after the metric designation;
(2) The units in which the dosage form is ordinarily available for
prescribing by practitioners, e.g., bottles of 100;
(3) Appropriate information to facilitate identification of the
dosage forms, such as shape, color, coating, scoring, and National Drug
Code; and
(4) Special handling and storage conditions.
(l) Animal Pharmacology and/or Animal Toxicology. In most cases, the
labeling need not include this section. Significant animal data
necessary for safe and effective use of the drug in humans shall
ordinarily be included in one or more of the other sections of the
labeling, as appropriate. Commonly for a drug that has been marketed for
a long time, and in rare cases for a new drug, chronic animal toxicity
studies have not been performed or completed for a drug that is
administered over prolonged periods or is implanted in the body. The
unavailability of such data shall be stated in the appropriate section
of the labeling for the drug. If the pertinent animal data cannot be
appropriately incorporated into other sections of the labeling, this
section may be used.
(m) ``Clinical Studies'' and ``References''. These sections may
appear in labeling in the place of a detailed discussion of a subject
that is of limited interest but nonetheless important. A reference to a
specific important clinical study may be made in any section of the
format required under Sec. Sec. 201.56 and 201.57 if the study is
essential to an understandable presentation of the available
information. References may appear in sections of the labeling format,
other than the ``Clinical Studies'' or ``References'' section, in rare
circumstances only. A clinical study or reference may be cited in
prescription drug labeling only under the following conditions:
(1)(i) If the clinical study is cited in the labeling in place of a
detailed discussion of data and information concerning an indication for
use of the drug, the clinical study must constitute an adequate and
well-controlled study as described in Sec. 314.126(b) of this
[[Page 69]]
chapter, except for biological products, and must not imply or suggest
indications or uses or dosing regimens not stated in the ``Indications
and Usage'' or ``Dosage and Administration'' section.
(ii) When prescription drug labeling must summarize or otherwise
rely on a recommendation by an authoritative scientific body, or on a
standardized methodology, scale, or technique, because the information
is important to prescribing decisions, the labeling may include a
reference to the source of the information.
(2) If the clinical study or reference is cited in the labeling in
the place of a detailed discussion of data and information concerning a
risk or risks from the use of the drug, the risk or risks shall also be
identified or discussed in the appropriate section of the labeling for
the drug.
[44 FR 37462, June 26, 1979, as amended at 55 FR 11576, Mar. 29, 1990;
59 FR 64249, Dec. 13, 1994; 62 FR 45325, Aug. 27, 1997; 63 FR 66396,
Dec. 1, 1998. Redesignated and amended at 71 FR 3988, 3996, Jan. 24,
2006; 79 FR 72103, Dec. 4, 2014]
Subpart D_Exemptions From Adequate Directions for Use
Sec. 201.100 Prescription drugs for human use.
A drug subject to the requirements of section 503(b)(1) of the act
shall be exempt from section 502(f)(1) if all the following conditions
are met:
(a) The drug is:
(1)(i) In the possession of a person (or his agents or employees)
regularly and lawfully engaged in the manufacture, transportation,
storage, or wholesale distribution of prescription drugs; or
(ii) In the possession of a retail, hospital, or clinic pharmacy, or
a public health agency, regularly and lawfully engaged in dispensing
prescription drugs; or
(iii) In the possession of a practitioner licensed by law to
administer or prescribe such drugs; and
(2) It is to be dispensed in accordance with section 503(b)
(b) The label of the drug bears:
(1) The statement ``Rx only'' and
(2) The recommended or usual dosage and
(3) The route of administration, if it is not for oral use; and
(4) The quantity or proportion of each active ingredient, as well as
the information required by section 502 (d) and (e); and
(5) If it is for other than oral use, the names of all inactive
ingredients, except that:
(i) Flavorings and perfumes may be designated as such without naming
their components.
(ii) Color additives may be designated as coloring without naming
specific color components unless the naming of such components is
required by a color additive regulation prescribed in subchapter A of
this chapter.
(iii) Trace amounts of harmless substances added solely for
individual product identification need not be named. If it is intended
for administration by parenteral injection, the quantity or proportion
of all inactive ingredients, except that ingredients added to adjust the
pH or to make the drug isotonic may be declared by name and a statement
of their effect; and if the vehicle is water for injection it need not
be named.
(6) An identifying lot or control number from which it is possible
to determine the complete manufacturing history of the package of the
drug.
(7) A statement directed to the pharmacist specifying the type of
container to be used in dispensing the drug product to maintain its
identity, strength, quality, and purity. Where there are standards and
test procedures for determining that the container meets the
requirements for specified types of containers as defined in an official
compendium, such terms may be used. For example, ``Dispense in tight,
light-resistant container as defined in the National Formulary''. Where
standards and test procedures for determining the types of containers to
be used in dispensing the drug product are not included in an official
compendium, the specific container or types of containers known to be
adequate to maintain the identity, strength, quality, and purity of the
drug products shall be described. For example, ``Dispense
[[Page 70]]
in containers which (statement of specifications which clearly enable
the dispensing pharmacist to select an adequate container)'': Provided,
however, That in the case of containers too small or otherwise unable to
accommodate a label with sufficient space to bear all such information,
but which are packaged within an outer container from which they are
removed for dispensing or use, the information required by paragraph (b)
(2), (3), (5), and (7) of this section may be contained in other
labeling on or within the package from which it is to be dispensed; the
information referred to in paragraph (b)(1) of this section may be
placed on such outer container only; and the information required by
paragraph (b)(6) of this section may be on the crimp of the dispensing
tube. The information required by this paragraph (b)(7) is not required
for prescription drug products packaged in unit-dose, unit-of-use, on
other packaging format in which the manufacturer's original package is
designed and intended to be dispensed to patients without repackaging.
(c)(1) Labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use, including
indications, effects, dosages, routes, methods, and frequency and
duration of administration, and any relevant hazards, contraindications,
side effects, and precautions under which practitioners licensed by law
to administer the drug can use the drug safely and for the purposes for
which it is intended, including all purposes for which it is advertised
or represented; and
(2) If the article is subject to section 505 of the act, the
labeling bearing such information is the labeling authorized by the
approved new drug application or required as a condition for the
certification or the exemption from certification requirements
applicable to preparations of insulin or antibiotic drugs.
(d) Any labeling, as defined in section 201(m) of the act, whether
or not it is on or within a package from which the drug is to be
dispensed, distributed by or on behalf of the manufacturer, packer, or
distributor of the drug, that furnishes or purports to furnish
information for use or which prescribes, recommends, or suggests a
dosage for the use of the drug (other than dose information required by
paragraph (b)(2) of this section and Sec. 201.105(b)(2) contains:
(1) Adequate information for such use, including indications,
effects, dosages, routes, methods, and frequency and duration of
administration and any relevant warnings, hazards, contraindications,
side effects, and precautions, under which practitioners licensed by law
to administer the drug can use the drug safely and for the purposes for
which it is intended, including all conditions for which it is
advertised or represented; and if the article is subject to section 505
of the act, the parts of the labeling providing such information are the
same in language and emphasis as labeling approved or permitted, under
the provisions of section 505, and any other parts of the labeling are
consistent with and not contrary to such approved or permitted labeling;
and
(2) The same information concerning the ingredients of the drug as
appears on the label and labeling on or within the package from which
the drug is to be dispensed.
(3) The information required, and in the format specified, by
Sec. Sec. 201.56, 201.57, and 201.80.
(e) All labeling described in paragraph (d) of this section bears
conspicuously the name and place of business of the manufacturer,
packer, or distributor, as required for the label of the drug under
Sec. 201.1.
(f) Reminder labeling which calls attention to the name of the drug
product but does not include indications or dosage recommendations for
use of the drug product is exempted from the provisions of paragraph (d)
of this section. This reminder labeling shall contain only the
proprietary name of the drug product, if any; the established name of
the drug product, if any; the established name of each active ingredient
in the drug product; and, optionally, information relating to
quantitative ingredient statements, dosage form, quantity of package
contents, price, the name and address of the manufacturer, packer, or
distributor or other written, printed, or graphic matter containing no
representation or suggestion relating to the drug product. If
[[Page 71]]
the Commissioner finds that there is evidence of significant incidence
of fatalities or serious injury associated with the use of a particular
prescription drug, he may withdraw this exemption by so notifying the
manufacturer, packer, or distributor of the drug by letter. Reminder
labeling, other than price lists and catalogs solely intended to convey
price information including, but not limited to, those subject to the
requirements of Sec. 200.200 of this chapter, is not permitted for a
prescription drug product whose labeling contains a boxed warning
relating to a serious hazard associated with the use of the drug
product. Reminder labeling which is intended to provide consumers with
information concerning the price charged for a prescription for a
particular drug product shall meet all of the conditions contained in
Sec. 200.200 of this chapter. Reminder labeling, other than that
subject to the requirements of Sec. 200.200 of this chapter, is not
permitted for a drug for which an announcement has been published
pursuant to a review of the labeling claims for the drug by the National
Academy of Sciences/National Research Council (NAS/NRC), Drug Efficacy
Study Group, and for which no claim has been evaluated as higher than
``possibly effective.'' If the Commissioner finds the circumstances are
such that reminder labeling may be misleading to prescribers of drugs
subject to NAS/NRC evaluation, such reminder labeling will not be
allowed and the manufacturer, packer, or distributor will be notified
either in the publication of the conclusions on the effectiveness of the
drug or by letter.
[40 FR 13998, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975;
42 FR 15674, Mar. 22, 1977; 43 FR 37989, Aug. 25, 1978; 44 FR 20659,
Apr. 6, 1979; 44 FR 37467, June 26, 1979; 45 FR 25777, Apr. 15, 1980; 63
FR 26698, May 13, 1998; 64 FR 400, Jan. 5, 1999; 67 FR 4906, Feb. 1,
2002; 71 FR 3996, Jan. 24, 2006]
Sec. 201.105 Veterinary drugs.
A drug subject to the requirements of section 503(f)(1) of the act
shall be exempt from section 502(f)(1) of the act if all the following
conditions are met:
(a) The drug is:
(1)(i) In the possession of a person (or his agents or employees)
regularly and lawfully engaged in the manufacture, transportation,
storage, or wholesale distribution of drugs that are to be used only by
or on the prescription or other order of a licensed veterinarian; or
(ii) In the possession of a retail, hospital, or clinic pharmacy, or
other person authorized under State law to dispense veterinary
prescription drugs, who is regularly and lawfully engaged in dispensing
drugs that are to be used only by or on the prescription or other order
of a licensed veterinarian; or
(iii) In the possession of a licensed veterinarian for use in the
course of his professional practice; and
(2) To be dispensed in accordance with section 503(f) of the act.
(b) The label of the drug bears:
(1) The statement ``Caution: Federal law restricts this drug to use
by or on the order of a licensed veterinarian''; and
(2) The recommended or usual dosage; and
(3) The route of administration, if it is not for oral use; and
(4) The quantity or proportion of each active ingredient as well as
the information required by section 502(e) of the act; and
(5) If it is for other than oral use, the names of all inactive
ingredients, except that:
(i) Flavorings and perfumes may be designated as such without naming
their components.
(ii) Color additives may be designated as coloring without naming
specific color components unless the naming of such components is
required by a color additive regulation prescribed in subchapter A of
this chapter.
(iii) Trace amounts of harmless substances added solely for
individual product identification need not be named.
If it is intended for administration by parenteral injection, the
quantity or proportion of all inactive ingredients, except that
ingredients added to adjust the pH or to make the drug isotonic may be
declared by name and a statement of their effect; and if the vehicle is
water for injection, it need not be named.
[[Page 72]]
(6) An identifying lot or control number from which it is possible
to determine the complete manufacturing history of the package of the
drug;
Provided, however, That in the case of containers too small or otherwise
unable to accommodate a label with sufficient space to bear all such
information, but which are packaged within an outer container from which
they are removed for dispensing or use, the information required by
paragraphs (b) (2), (3), and (5) of this section may be contained in
other labeling on or within the package from which it is to be so
dispensed, and the information referred to in paragraph (b)(1) of this
section may be placed on such outer container only, and the information
required by paragraph (b)(6) of this section may be on the crimp of the
dispensing tube.
(c)(1) Labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use, including
indications, effects, dosages, routes, methods, and frequency and
duration of administration, and any relevant hazards, contraindications,
side effects, and precautions under which veterinarians licensed by law
to administer the drug can use the drug safely and for the purposes for
which it is intended, including all purposes for which it is advertised
or represented; and
(2) If the article is subject to section 512 or 572 of the act, the
labeling bearing such information is the labeling authorized by the
approved new animal drug application or contained in the index listing:
Provided, however, That the information required by paragraph (c)(1) of
this section may be omitted from the dispensing package if, but only if,
the article is a drug for which directions, hazards, warnings, and use
information are commonly known to veterinarians licensed by law to
administer the drug. Upon written request, stating reasonable grounds
therefore, the Commissioner will offer an opinion on a proposal to omit
such information from the dispensing package under this proviso.
(d) Any labeling, as defined in section 201(m) of the act, whether
or not it is on or within a package from which the drug is to be
dispensed, distributed by or on behalf of the manufacturer, packer, or
distributor of the drug, that furnishes or purports to furnish
information for use or which prescribes, recommends, or suggests a
dosage for the use of the drug (other than dose information required by
paragraph (b)(2) of this section and Sec. 201.100(b)(2)) contains:
(1) Adequate information for such use, including indications,
effects, dosages, routes, methods, and frequency and duration of
administration, and any relevant warnings, hazards, contraindications,
side effects, and precautions, and including information relevant to
compliance with the new animal drug provisions of the act, under which
veterinarians licensed by law to administer the drug can use the drug
safely and for the purposes for which it is intended, including all
conditions for which it is advertised or represented; and if the article
is subject to section 512 or 572 of the act, the parts of the labeling
providing such information are the same in language and emphasis as
labeling approved, permitted, or indexed under the provisions of section
512 or 572, and any other parts of the labeling are consistent with and
not contrary to such approved, permitted, or indexed labeling; and
(2) The same information concerning the ingredients of the drug as
appears on the label and labeling on or within the package from which
the drug is to be dispensed;
Provided, however, That the information required by paragraphs (d) (1)
and (2) of this section is not required on the so-called reminder-piece
labeling which calls attention to the name of the drug but does not
include indications or dosage recommendations for use of the drug.
(e) All labeling, except labels and cartons, bearing information for
use of the drug also bears the date of the issuance or the date of the
latest revision of such labeling.
(f) A prescription drug intended for both human and veterinary use
shall comply with paragraphs (e) and (f) of this section and Sec.
201.100.
[40 FR 13998, Mar. 27, 1975, as amended at 42 FR 15674, Mar. 22, 1977;
57 FR 54300, Nov. 18, 1992; 72 FR 69119, Dec. 6, 2007]
[[Page 73]]
Sec. 201.115 New drugs or new animal drugs.
A new drug shall be exempt from section 502(f)(1) of the act:
(a) To the extent to which such exemption is claimed in an approved
application with respect to such drug under section 505 or 512 of the
act or an index listing with respect to such drug under section 572 of
the act; or
(b) If no application under section 505 or 512 of the act is
approved and no request for addition to the index is granted under
section 572 with respect to such drug but it complies with section
505(i), 512(j), or 572(g) of the act and regulations thereunder.
No exemption shall apply to any other drug which would be a new drug if
its labeling bore representations for its intended uses.
[40 FR 13998, Mar. 27, 1975, as amended at 72 FR 69119, Dec. 6, 2007]
Sec. 201.116 Drugs having commonly known directions.
A drug shall be exempt from section 502(f)(1) of the act insofar as
adequate directions for common uses thereof are known to the ordinary
individual.
[41 FR 6910, Feb. 13, 1976]
Sec. 201.117 Inactive ingredients.
A harmless drug that is ordinarily used as an inactive ingredient,
such as a coloring, emulsifier, excipient, flavoring, lubricant,
preservative, or solvent, in the preparation of other drugs shall be
exempt from section 502(f)(1) of the act. This exemption shall not apply
to any substance intended for a use which results in the preparation of
a new drug, unless an approved new-drug application provides for such
use.
Sec. 201.119 In vitro diagnostic products.
(a) ``In vitro diagnostic products'' are those reagents, instruments
and systems intended for use in the diagnosis of disease or in the
determination of the state of health in order to cure, mitigate, treat,
or prevent disease or its sequelae. Such products are intended for use
in the collection, preparation and examination of specimens taken from
the human body. These products are drugs or devices as defined in
section 201(g) and 201(h), respectively, of the Federal Food, Drug, and
Cosmetic Act (the act) or are a combination of drugs and devices, and
may also be a biological product subject to section 351 of the Public
Health Service Act.
(b) A product intended for use in the diagnosis of disease and which
is an in vitro diagnostic product as defined in paragraph (a) of this
section shall be deemed to be in compliance with the requirements of
this section and section 502(f)(1) of the act if it meets the
requirements of Sec. 809.10 of this chapter.
[41 FR 6910, Feb. 13, 1976]
Sec. 201.120 Prescription chemicals and other prescription components.
A drug prepared, packaged, and primarily sold as a prescription
chemical or other component for use by registered pharmacists in
compounding prescriptions or for dispensing in dosage unit form upon
prescriptions shall be exempt from section 502(f)(1) of the act if all
the following conditions are met:
(a) The drug is an official liquid acid or official liquid alkali,
or is not a liquid solution, emulsion, suspension, tablet, capsule, or
other dosage unit form; and
(b) The label of the drug bears:
(1) The statement ``For prescription compounding''; and
(2) If in substantially all dosage forms in which it may be
dispensed it is subject to section 503(b)(1) of the act, the statement
``Rx only''; or
(3) If it is not subject to section 503(b)(1) of the act and is by
custom among retail pharmacists sold in or from the interstate package
for use by consumers, ``adequate directions for use'' in the conditions
for which it is so sold.
Provided, however, That the information referred to in paragraph (b)(3)
of this section may be contained in the labeling on or within the
package from which it is to be dispensed.
(c) This exemption shall not apply to any substance intended for use
in compounding which results in a new
[[Page 74]]
drug, unless an approved new-drug application covers such use of the
drug in compounding prescriptions.
[40 FR 13998, Mar. 27, 1975, as amended at 67 FR 4906, Feb. 1, 2002]
Sec. 201.122 Drugs for processing, repacking, or manufacturing.
A drug in a bulk package, except tablets, capsules, or other dosage
unit forms, intended for processing, repacking, or use in the
manufacture of another drug shall be exempt from section 502(f)(1) of
the act if its label bears the statement ``Caution: For manufacturing,
processing, or repacking''; and if in substantially all dosage forms in
which it may be dispensed it is subject to section 503(b)(1) of the act,
the statement ``Rx only'', or if in substantially all dosage forms in
which it may be dispensed it is subject to section 503(f)(1) of the act,
the statement ``Caution: Federal law restricts this drug to use by or on
the order of a licensed veterinarian''. This exemption and the exemption
under Sec. 201.120 may be claimed for the same article. However, the
exemption shall not apply to a substance intended for a use in
manufacture, processing, or repacking which causes the finished article
to be a new drug or new animal drug, unless:
(a) An approved new drug application or new animal drug application
or a new animal drug index listing covers the production and delivery of
the drug substance to the application or index listing holder by persons
named in the application or in the request for determination of
eligibility for indexing, and, for a new drug substance, the export of
it by such persons under Sec. 314.410 of this chapter; or
(b) If no application is approved with respect to such new drug or
new animal drug, and it is not listed in the index, the label statement
``Caution: For manufacturing, processing, or repacking'' is immediately
supplemented by the words ``in the preparation of a new drug or new
animal drug limited by Federal law to investigational use'', and the
delivery is made for use only in the manufacture of such new drug or new
animal drug limited to investigational use as provided in part 312 or
Sec. 511.1 or Sec. 516.125 of this chapter; or
(c) A new drug application or new animal drug application or a
request for addition to the index covering the use of the drug substance
in the production and marketing of a finished drug product has been
submitted but not yet approved, disapproved, granted, or denied, the
bulk drug is not exported, and the finished drug product is not further
distributed after it is manufactured until after the new drug
application or new animal drug application is approved or the request
for addition to the index is granted.
[41 FR 6911, Feb. 13, 1976, as amended at 41 FR 15844, Apr. 15, 1976; 50
FR 7492, Feb. 22, 1985; 55 FR 11576, Mar. 29, 1990; 57 FR 54301, Nov.
18, 1992; 67 FR 4906, Feb. 1, 2002; 72 FR 69119, Dec. 6, 2007]
Sec. 201.125 Drugs for use in teaching, law enforcement, research,
and analysis.
A drug subject to Sec. 201.100 or Sec. 201.105, shall be exempt
from section 502(f)(1) of the act if shipped or sold to, or in the
possession of, persons regularly and lawfully engaged in instruction in
pharmacy, chemistry, or medicine not involving clinical use, or engaged
in law enforcement, or in research not involving clinical use, or in
chemical analysis, or physical testing, and is to be used only for such
instruction, law enforcement, research, analysis, or testing.
[41 FR 6911, Feb. 13, 1976]
Sec. 201.127 Drugs; expiration of exemptions.
(a) If a shipment or delivery, or any part thereof, of a drug which
is exempt under the regulations in this section is made to a person in
whose possession the article is not exempt, or is made for any purpose
other than those specified, such exemption shall expire, with respect to
such shipment or delivery or part thereof, at the beginning of that
shipment or delivery. The causing of an exemption to expire shall be
considered an act which results in such drug being misbranded unless it
is disposed of under circumstances in which it ceases to be a drug or
device.
(b) The exemptions conferred by Sec. Sec. 201.117, 201.119,
201.120, 201.122, and 201.125 shall continue until the drugs are used
for the purposes for which
[[Page 75]]
they are exempted, or until they are relabeled to comply with section
502(f)(1) of the act. If, however, the drug is converted, compounded, or
manufactured into a dosage form limited to prescription dispensing, no
exemption shall thereafter apply to the article unless the dosage form
is labeled as required by section 503(b) and Sec. Sec. 201.100 or
201.105.
[41 FR 6911, Feb. 13, 1976]
Sec. 201.128 Meaning of ``intended uses''.
The words intended uses or words of similar import in Sec. Sec.
201.5, 201.115, 201.117, 201.119, 201.120, and 201.122 refer to the
objective intent of the persons legally responsible for the labeling of
drugs. The intent is determined by such persons' expressions or may be
shown by the circumstances surrounding the distribution of the article.
This objective intent may, for example, be shown by labeling claims,
advertising matter, or oral or written statements by such persons or
their representatives. It may be shown by the circumstances that the
article is, with the knowledge of such persons or their representatives,
offered and used for a purpose for which it is neither labeled nor
advertised. The intended uses of an article may change after it has been
introduced into interstate commerce by its manufacturer. If, for
example, a packer, distributor, or seller intends an article for
different uses than those intended by the person from whom he received
the drug, such packer, distributor, or seller is required to supply
adequate labeling in accordance with the new intended uses. But if a
manufacturer knows, or has knowledge of facts that would give him
notice, that a drug introduced into interstate commerce by him is to be
used for conditions, purposes, or uses other than the ones for which he
offers it, he is required to provide adequate labeling for such a drug
which accords with such other uses to which the article is to be put.
[41 FR 6911, Feb. 13, 1976]
Effective Date Note: At 82 FR 2217, Jan. 9, 2017, Sec. 201.128 was
revised, effective Feb. 8, 2017. This effective date was delayed to Mar.
21, 2017, at 82 FR 9501, Feb. 7, 2017, and was then further delayed to
Mar. 19, 2018 at 82 FR 14319, Mar. 20, 2017. At 83 FR 11639, Mar. 16,
2018, the effective date for this revision was delayed indefinitely. For
the convenience of the user, the revised text is set forth as follows:
Sec. 201.128 Meaning of ``intended uses''.
The words intended uses or words of similar import in Sec. Sec.
201.5, 201.115, 201.117, 201.119, 201.120, 201.122, and 1100.5 of this
chapter refer to the objective intent of the persons legally responsible
for the labeling of drugs. The intent is determined by such persons'
expressions or may be shown by the circumstances surrounding the
distribution of the article. This objective intent may, for example, be
shown by labeling claims, advertising matter, or oral or written
statements by such persons or their representatives. It may be shown,
for example, by circumstances in which the article is, with the
knowledge of such persons or their representatives, offered and used for
a purpose for which it is neither labeled nor advertised. The intended
uses of an article may change after it has been introduced into
interstate commerce by its manufacturer. If, for example, a packer,
distributor, or seller intends an article for different uses than those
intended by the person from whom he received the drug, such packer,
distributor, or seller is required to supply adequate labeling in
accordance with the new intended uses. And if the totality of the
evidence establishes that a manufacturer objectively intends that a drug
introduced into interstate commerce by him is to be used for conditions,
purposes, or uses other than ones for which it is approved (if any), he
is required, in accordance with section 502(f) of the Federal Food,
Drug, and Cosmetic Act, or, as applicable, duly promulgated regulations
exempting the drug from the requirements of section 502(f)(1), to
provide for such drug adequate labeling that accords with such other
intended uses.
Sec. 201.129 Drugs; exemption for radioactive drugs for research use.
A radioactive drug intended for administration to human research
subjects during the course of a research project intended to obtain
basic research information regarding metabolism (including kinetics,
distribution, and localization) of a radioactively labeled drug or
regarding human physiology, pathophysiology, or biochemistry (but not
intended for immediate therapeutic, diagnostic, or similar purposes),
under the conditions set forth in Sec. 361.1 of this chapter, shall be
exempt from section 502(f)(1) of the act if the packaging, label, and
labeling
[[Page 76]]
are in compliance with Sec. 361.1(f) of this chapter.
[41 FR 6911, Feb. 13, 1976]
Subpart E_Other Exemptions
Sec. 201.150 Drugs; processing, labeling, or repacking.
(a) Except as provided by paragraphs (b) and (c) of this section, a
shipment or other delivery of a drug which is, in accordance with the
practice of the trade, to be processed, labeled, or repacked in
substantial quantity at an establishment other than that where
originally processed or packed, shall be exempt, during the time of
introduction into and movement in interstate commerce and the time of
holding in such establishment, from compliance with the labeling and
packaging requirements of sections 501(b) and 502 (b), (d), (e), (f),
and (g) of the act if:
(1) The person who introduced such shipment or delivery into
interstate commerce is the operator of the establishment where such drug
is to be processed, labeled, or repacked; or
(2) In case such person is not such operator, such shipment or
delivery is made to such establishment under a written agreement, signed
by and containing the post-office addresses of such person and such
operator, and containing such specifications for the processing,
labeling, or repacking, as the case may be, of such drug in such
establishment as will insure, if such specifications are followed, that
such drug will not be adulterated or misbranded within the meaning of
the act upon completion of such processing, labeling, or repacking. Such
person and such operator shall each keep a copy of such agreement until
2 years after the final shipment or delivery of such drug from such
establishment, and shall make such copies available for inspection at
any reasonable hour to any officer or employee of the Department who
requests them.
(b) An exemption of a shipment or other delivery of a drug under
paragraph (a)(1) of this section shall, at the beginning of the act of
removing such shipment or delivery, or any part thereof, from such
establishment, become void ab initio if the drug comprising such
shipment, delivery, or part is adulterated or misbranded within the
meaning of the act when so removed.
(c) An exemption of a shipment or other delivery of a drug under
paragraph (a)(2) of this section shall become void ab initio with
respect to the person who introduced such shipment or delivery into
interstate commerce upon refusal by such person to make available for
inspection a copy of the agreement, as required by such paragraph (a)(2)
of this section.
(d) An exemption of a shipment or other delivery of a drug under
paragraph (a)(2) of this section shall expire:
(1) At the beginning of the act of removing such shipment or
delivery, or any part thereof, from such establishment if the drug
comprising such shipment, delivery, or part is adulterated or misbranded
within the meaning of the act when so removed; or
(2) Upon refusal by the operator of the establishment where such
drug is to be processed, labeled, or repacked, to make available for
inspection a copy of the agreement, as required by such clause.
[41 FR 6911, Feb. 13, 1976, as amended at 64 FR 400, Jan. 5, 1999]
Sec. 201.161 Medical gases.
(a) Oxygen, nitrogen, carbon dioxide, helium, and nitrous oxide
gases intended for drug use, and medically appropriate combinations of
any of these gases intended for drug use, are exempted from the
requirements of Sec. 201.100(b)(2) and (3), and (c)(1), provided that,
where applicable, the requirements of Sec. Sec. 201.328 and
211.94(e)(2) of this chapter are met and the labeling bears, in addition
to any other information required by the Federal Food, Drug, and
Cosmetic Act, the following:
(1)(i) In the case of oxygen, a warning statement providing that
uninterrupted use of high concentrations of oxygen over a long duration,
without monitoring its effect on oxygen content of arterial blood, may
be harmful; that oxygen should not be used on patients who have stopped
breathing unless used in conjunction with resuscitative equipment; and,
in the case of oxygen that may be provided without a prescription for
use in the
[[Page 77]]
event of depressurization or other environmental oxygen deficiency, or
for oxygen deficiency or for use in emergency resuscitation when
administered by properly trained personnel, a warning statement
providing that oxygen may be used for emergency use only when
administered by properly trained personnel for oxygen deficiency and
resuscitation, and that for all other medical applications a
prescription is required.
(ii) In the case of nitrogen, carbon dioxide, helium, nitrous oxide,
and medically appropriate combinations of any of the gases listed in
paragraph (a) of this section, a warning statement providing that the
administration of the gas or gas combination (as applicable) may be
hazardous or contraindicated; and that the gas or gas combination (as
applicable) should be used only by or under the supervision of a
licensed practitioner who is experienced in the use and administration
of the gas or gas combination (as applicable) and is familiar with the
indications, effects, dosages, methods, and frequency and duration of
administration, and with the hazards, contraindications, and side
effects and the precautions to be taken.
(2) Any needed directions concerning the conditions for storage and
warnings against the inherent dangers in the handling of the specific
compressed gas.
(b) [Reserved]
[81 FR 81696, Nov. 18, 2016]
Subpart F_Labeling Claims for Drugs in Drug Efficacy Study
Sec. 201.200 Disclosure of drug efficacy study evaluations in
labeling and advertising.
(a)(1) The National Academy of Sciences--National Research Council,
Drug Efficacy Study Group, has completed an exhaustive review of
labeling claims made for drugs marketed under new-drug and antibiotic
drug procedures between 1938 and 1962. The results are compiled in
``Drug Efficacy Study, A Report to the Commissioner of Food and Drugs
from the National Academy of Sciences (1969).'' As the report notes,
this review has made ``an audit of the state of the art of drug usage
that has been uniquely extensive in scope and uniquely intensive in
time'' and is applicable to more than 80 percent of the currently
marketed drugs. The report further notes that the quality of the
evidence of efficacy, as well as the quality of the labeling claims, is
poor. Labeling and other promotional claims have been evaluated as
``effective,'' ``probably effective,'' ``possibly effective,''
``ineffective,'' ``ineffective as a fixed combination,'' and ``effective
but,'' and a report for each drug in the study has been submitted to the
Commissioner.
(2) The Food and Drug Administration is processing the reports,
seeking voluntary action on the part of the drug manufacturers and
distributors in the elimination or modification of unsupported
promotional claims, and initiating administrative actions as necessary
to require product and labeling changes.
(3) Delays have been encountered in bringing to the attention of the
prescribers of prescription items the conclusions of the expert panels
that reviewed the promotional claims.
(b) The Commissioner of Food and Drugs concludes that:
(1) The failure to disclose in the labeling of a drug and in other
promotional material the conclusions of the Academy experts that a claim
is ``ineffective,'' ``possibly effective,'' ``probably effective,'' or
``ineffective as a fixed combination,'' while labeling and promotional
material bearing any such claim are being used, is a failure to disclose
facts that are material in light of the representations made and causes
the drug to be misbranded.
(2) The Academy classification of a drug as other than ``effective''
for a claim for which such drug is recommended establishes that there is
a material weight of opinion among qualified experts contrary to the
representation made or suggested in the labeling, and failure to reveal
this fact causes such labeling to be misleading.
(c) Therefore, after publication in the Federal Register of a Drug
Efficacy Study Implementation notice on a prescription drug, unless
exempted or otherwise provided for in the notice, all
[[Page 78]]
package labeling (other than the immediate container or carton label,
unless such labeling contains information required by Sec.
201.100(c)(1) in lieu of a package insert), promotional labeling, and
advertisements shall include, as part of the information for
practitioners under which the drug can be safely and effectively used,
an appropriate qualification of all claims evaluated as other than
``effective'' by a panel of the National Academy of Sciences--National
Research Council, Drug Efficacy Study Group, if such claims continue to
be included in either the labeling or advertisements. However, this
qualifying information will be required in advertisements only if
promotional material is included therein for claims evaluated as less
than ``effective'' or if such claims are included in the indications
section of the portion of the advertisement containing the information
required in brief summary by Sec. 202.1(e)(1) of this chapter. When,
however, the Food and Drug Administration classification of such claim
is ``effective'' (for example, on the basis of revision of the language
of the claim or submission or existence of adequate data), such
qualification is not necessary. When the Food and Drug Administration
classification of the claim, as stated in the implementation notice,
differs from that of the Academy but is other than ``effective,'' the
qualifying statement shall refer to this classification in lieu of the
Academy's classification.
(d) For new drugs and antibiotics, supplements to provide for
revised labeling in accord with paragraph (c) of this section shall be
submitted under the provisions of Sec. 314.70 and Sec. 514.8 of this
chapter within 90 days after publication of the implementation notice in
the Federal Register or by May 15, 1972, for those drugs for which
notices have been published and such labeling shall be put into use as
soon as possible but not later than the end of the time period allowed
for submitting supplements to provide for revised labeling.
(e) Qualifying information required in drug labeling by paragraph
(c) of this section in order to advise prescribers of a drug of the
findings made by a panel of the Academy in evaluating a claim as other
than ``effective'' shall be at least of the same size and color and
degree of prominence as other printing in the labeling and shall be
presented in a prominent box using one of the following formats and
procedures:
(1) In drug labeling the box statement may entirely replace the
indications section and be in the following format:
Indications
Based on a review of this drug by the National Academy of Sciences--
National Research Council and/or other information, FDA has classified
the indication(s) as follows:
Effective: (list or state in paragraph form).
``Probably'' effective: (list or state in paragraph form).
``Possibly'' effective: (list or state in paragraph form).
Final classification of the less-than-effective indications requires
further investigation.
(2) Or the indication(s) for which the drug has been found effective
may appear outside the boxed statement and be followed immediately by
the following boxed statement:
Based on a review of this drug by the National Academy of Sciences--
National Research Council and/or other information, FDA has classified
the other indication(s) as follows:
``Probably'' effective: (list or state in paragraph form).
``Possibly'' effective: (list or state in paragraph form).
Final classification of the less-than-effective indications requires
further investigation.
(3) In drug labeling (other than that which is required by Sec.
201.100(c)(1)) which may contain a promotional message, the promotional
message shall be keyed to the boxed statement by the same means as those
provided for advertisements in paragraph (f)(2) of this section.
(f) Qualifying information required in prescription drug advertising
by paragraph (c) of this section shall contain a prominent boxed
statement of the advertised indication(s) and of the limitations of
effectiveness using the same format, language, and emphasis as that
required in labeling by paragraph (e) of this section.
[[Page 79]]
(1) The boxed statement shall appear in (or next to) the information
required in brief summary by Sec. 202.1(e)(1) of this chapter and shall
have prominence at least equal to that provided for other information
presented in the brief summary and shall have type size, captions,
color, and other physical characteristics comparable to the information
required in the brief summary.
(2) Less-than-effective indication(s) in the promotional message of
an advertisement which is a single page or less shall be keyed to the
boxed statement by asterisk, by an appropriate statement, or by other
suitable means providing adequate emphasis on the boxed statement. On
each page where less-than-effective indication(s) appear in a mutiple
page advertisement, an asterisk shall be placed after the most prominent
mention of the indi- cation(s); if the degree of prominence does not
vary, an asterisk shall be placed after the first mention of the
indication. The asterisk shall refer to a notation at the bottom of the
page which shall state ``This drug has been evaluated as probably
effective (or possibly effective whichever is appropriate) for this
indication'' and ``See Brief Summary'' or ``See Prescribing
Information,'' the latter legend to be used only if the advertisement
carries the required information for professional use as set forth in
Sec. 201.100(c)(1).
(3) For less-than-effective indications which are included in the
advertisement only as a part of the information required in brief
summary, the disclosure information shall appear in this portion of the
advertisement in the same manner as is specified for labeling in
paragraph (e) of this section.
(g) The Commissioner may find circumstances are such that, while the
elimination of claims evaluated as other than effective will generally
eliminate the need for disclosure about such claims, there will be
instances in which the change in the prescribing or promotional profile
of the drug is so substantial as to require a disclosure of the reason
for the change so that the purchaser or prescriber is not misled by
being left unaware through the sponsor's silence that a basic change has
taken place. The Food and Drug Administration will identify these
situations in direct correspondence with the drug promoters, after which
the failure to make the disclosure will be regarded as misleading and
appropriate action will be taken.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Subpart G_Specific Labeling Requirements for Specific Drug Products
Sec. 201.300 Notice to manufacturers, packers, and distributors
of glandular preparations.
(a) Under date of December 4, 1941, in a notice to manufacturers of
glandular preparations, the Food and Drug Administration expressed the
opinion that preparations of inert glandular materials intended for
medicinal use should, in view of the requirement of section 201(n) of
the Federal Food, Drug, and Cosmetic Act (52 Stat. 1041; 21 U.S.C.
321(n)), be labeled with a statement of the material fact that there is
no scientific evidence that the articles contain any therapeutic or
physiologically active constituents. Numerous preparations of such inert
glandular materials were subsequently marketed with disclaimers of the
type suggested. The term inert glandular materials means preparations
incapable of exerting an action or effect of some significant or
measurable benefit in one way or another, i.e., in the diagnosis, cure,
mitigation, treatment, or prevention of disease, or in affecting the
structure or any function of the body.
(b) Manufacturers have heretofore taken advantage of Sec. 201.100
permitting omission of directions for use when the label bears the
prescription legend. Section 201.100(c) requires that the labeling of
the drug, which may include brochures readily available to licensed
practitioners, bear information as to the use of the drug by
practitioners licensed by law to administer it. Obviously, information
adequate for the use of an inert glandular preparation is not available
to practitioners licensed by law.
(c) The Department of Health and Human Services is of the opinion
that inert glandular materials may not be exempted from the requirements
of
[[Page 80]]
section 502(f)(1) of the act that they bear adequate directions for use;
and, accordingly, that their labeling must include among other things,
representations as to the conditions for which such articles are
intended to be used or as to the structure or function of the human body
that they are intended to affect. Since any such representations
offering these articles for use as drugs would be false or misleading,
such articles will be considered to be misbranded if they are
distributed for use as drugs.
(d) The amended regulations provide also that in the case of drugs
intended for parenteral administration there shall be no exemption from
the requirement that their labelings bear adequate directions for use.
Such inert glandular materials for parenteral use are therefore subject
to the same comment as applies to those intended for oral
administration.
Sec. 201.301 Notice to manufacturers, packers, and distributors
of estrogenic hormone preparations.
Some drug preparations fabricated wholly or in part from estradiol
and labeled as to potency in terms of international units or in terms of
international units of estrone activity have been marketed. The
international unit of the estrus-producing hormone was established by
the International Conference on the Standardization of Sex Hormones at
London, England, on August 1, 1932. This unit was defined as ``the
specific estrus-producing activity contained in 0.1 gamma ( = 0.0001
mg.) of the standard'' hydroxyketonic hormone found in urine (estrone).
The International Conference declared that it did not recommend the
determination of the activity of nonhydroxyketonic forms of estrogenic
hormones in units of estrone because of the varying ratios between the
activity of such nonhydroxyketonic estrogenic hormones and estrone, when
measured by different methods on test animals. There is no international
unit for measuring the activity of estradiol and no accepted
relationship between its activity and that of estrone, either in test
animals or in humans. The declaration of potency of estradiol in terms
of international units or in terms of international units of estrone
activity is therefore considered misleading, within the meaning of 21
U.S.C. 352(a). The declaration of the estradiol content of an estrogenic
hormone preparation in terms of weight is considered appropriate.
Sec. 201.302 Notice to manufacturers, packers, and distributors of
drugs for internal use which contain mineral oil.
(a) In the past few years research studies have altered medical
opinion as to the usefulness and harmfulness of mineral oil in the human
body. These studies have indicated that when mineral oil is used orally
near mealtime it interferes with absorption from the digestive tract of
provitamin A and the fat-soluble vitamins A, D, and K, and consequently
interferes with the utilization of calcium and phosphorus, with the
result that the user is left liable to deficiency diseases. When so used
in pregnancy it predisposes to hemorrhagic disease of the newborn.
(b) There is accumulated evidence that the indiscriminate
administration of mineral oil to infants may be followed by aspiration
of the mineral oil and subsequent ``lipoid pneumonia.''
(c) In view of these facts, the Department of Health and Human
Services will regard as misbranded under the provisions of the Federal
Food, Drug, and Cosmetic Act a drug for oral administration consisting
in whole or in part of mineral oil, the labeling of which encourages its
use in pregnancy or indicates or implies that such drug is for
administration to infants.
(d) It is also this Department's view that the act requires the
labelings of such drugs to bear a warning against consumption other than
at bedtime and against administration to infants. The following form of
warning is suggested: ``Caution: To be taken only at bedtime. Do not use
at any other time or administer to infants, except upon the advice of a
physician.''
(e) This statement of interpretation does not in any way exempt
mineral oil or preparations containing mineral oil from complying in all
other respects with the requirements of the Federal Food, Drug, and
Cosmetic Act.
[[Page 81]]
Sec. 201.303 Labeling of drug preparations containing significant
proportions of wintergreen oil.
(a) Because methyl salicylate (wintergreen oil) manifests no
toxicity in the minute amounts in which it is used as a flavoring, it is
mistakenly regarded by the public as harmless even when taken in
substantially larger amounts. Actually, it is quite toxic when taken in
quantities of a teaspoonful or more. Wintergreen oil and preparations
containing it have caused a number of deaths through accidental misuse
by both adults and children. Children are particularly attracted by the
odor and are likely to swallow these products when left within reach.
(b) To safeguard against fatalities from this cause, the Department
of Health and Human Services will regard as misbranded under the
provisions of the Federal Food, Drug, and Cosmetic Act any drug
containing more than 5 percent methyl salicylate (wintergreen oil), the
labeling of which fails to warn that use otherwise than as directed
therein may be dangerous and that the article should be kept out of
reach of children to prevent accidental poisoning.
(c) This statement of interpretation in no way exempts methyl
salicylate (wintergreen oil) or its preparations from complying in all
other respects with the requirements of the Federal Food, Drug, and
Cosmetic Act.
Sec. 201.304 Tannic acid and barium enema preparations.
(a) It has become a widespread practice for tannic acid to be added
to barium enemas to improve X-ray pictures. Tannic acid is capable of
causing diminished liver function and severe liver necrosis when
absorbed in sufficient amounts. The medical literature reports a number
of deaths associated with the addition of tannic acid to barium enemas.
There is a lack of scientific evidence to establish the conditions, if
any, under which tannic acid is safe and effective for use in enemas.
Tannic acid for rectal use to enhance X-ray visualization is regarded as
a new drug within the meaning of section 201(p) of the Federal Food,
Drug, and Cosmetic Act.
(b) In view of the hazards involved when tannic acid is used in
barium enemas, any shipments of tannic acid labeled to come within the
exemptions under 502(f) of the Act containing such phrases as:
``Caution: For manufacturing, processing, or repackaging,'' ``For
prescription compounding,'' or ``Diagnostic reagent--For professional
use only'' will be regarded by the Commissioner of Food and Drugs as
misbranded within the meaning of section 502(f) of the Federal Food,
Drug, and Cosmetic Act unless the label and the labeling bear
conspicuously a warning to the effect: ``Warning-- Not for use in
enemas.''
(c) Any tannic acid intended for use by man and found within the
jurisdiction of the Federal Food, Drug, and Cosmetic Act labeled
contrary to this section after 60 days from the date of its publication
in the Federal Register may be made the subject of regulatory
proceedings.
Sec. 201.305 Isoproterenol inhalation preparations (pressurized
aerosols, nebulizers, powders) for human use; warnings.
(a) Accumulating reports have been received by the Food and Drug
Administration and have appeared in the medical literature of severe
paradoxical bronchoconstriction associated with repeated, excessive use
of isoproterenol inhalation preparations in the treatment of bronchial
asthma and other chronic bronchopulmonary disorders. The cause of this
paradoxical reaction is unknown; it has been observed, however, that
patients have not responded completely to other forms of therapy until
use of the isoproterenol inhalation preparation was discontinued. In
addition, sudden unexpected deaths have been associated with the
excessive use of isoproterenol inhalation preparations. The mechanism of
these deaths and their relationship, if any, to the cases of severe
paradoxical bronchospasm are not clear. Cardiac arrest was noted in
several of these cases of sudden death.
(b) On the basis of the above information and after discussion with
and concurrence of the Respiratory and Anesthetic Drugs Advisory
Committee for Food and Drug Administration, the
[[Page 82]]
Commissioner of Food and Drugs concludes that in order for the labeling
of such drugs to bear adequate information for their safe use, as
required by Sec. 201.100, such labeling must include the following:
Warning: Occasional patients have been reported to develop severe
paradoxical airway resistance with repeated, excessive use of
isoproterenol inhalation preparations. The cause of this refractory
state is unknown. It is advisable that in such instances the use of this
preparation be discontinued immediately and alternative therapy
instituted, since in the reported cases the patients did not respond to
other forms of therapy until the drug was withdrawn.
Deaths have been reported following excessive use of isoproterenol
inhalation preparations and the exact cause is unknown. Cardiac arrest
was noted in several instances.
(c)(1) The Commissioner also concludes that in view of the manner in
which these preparations are self-administered for relief of attacks of
bronchial asthma and other chronic bronchopulmonary disorders, it is
necessary for the protection of users that warning information to
patients be included as a part of the label and as part of any
instructions to patients included in the package dispensed to the
patient as follows:
Warning: Do not exceed the dose prescribed by your physician. If
difficulty in breathing persists, contact your physician immediately.
(2) The warning on the label may be accomplished (i) by including it
on the immediate container label with a statement directed to
pharmacists not to remove the label or (ii) by including in the package
a printed warning with instructions to pharmacists to place the warning
on the container prior to dispensing.
(d) The marketing of isoproterenol inhalation preparations may be
continued if all the following conditions are met:
(1) Within 30 days following the date of publication of this section
in the Federal Register:
(i) The label and labeling of such preparations shipped within the
jurisdiction of the act are in accordance with paragraphs (b) and (c) of
this section.
(ii) The holder of an approved new-drug application for such
preparation submits a supplement to his new-drug application to provide
for appropriate labeling changes as described in paragraphs (b) and (c)
of this section.
(2) Within 90 days following the date of publication of this section
in the Federal Register, the manufacturer, packer, or distributor of any
drug containing isoproterenol intended for inhalation for which a new-
drug approval is not in effect submits a new-drug application containing
satisfactory information of the kinds required by Sec. 314.50 of this
chapter, including appropriate labeling as described in paragraphs (b)
and (c) of this section.
(3) The applicant submits additional information required for the
approval of the application as may be specified in a written
communication from the Food and Drug Administration.
(e) After 270 days following expiration of said 90 days, regulatory
proceedings based on section 505(a) of the Federal Food, Drug, and
Cosmetic Act may be initiated with regard to any such drug shipped
within the jurisdiction of the act for which an approved new-drug
application is not in effect.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990]
Sec. 201.306 Potassium salt preparations intended for oral
ingestion by man.
(a) The Food and Drug Administration will initiate no regulatory
action with respect to the continued marketing of coated tablets
containing potassium chloride or other potassium salts which supply 100
milligrams or more of potassium per tablet provided all the following
conditions are met:
(1) Within 30 days from the date of publication of this statement of
policy in the Federal Register:
(i) The labeling of the drug bears the prescription caution
statement quoted in section 503(b)(4) of the Federal Food, Drug, and
Cosmetic Act;
(ii) The labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use by practitioners in
accord with the ``full disclosure'' labeling requirements of Sec.
201.100 of this chapter, including the following warning statement:
[[Page 83]]
Warning--There have been several reports, published and unpublished,
concerning nonspecific small-bowel lesions consisting of stenosis, with
or without ulceration, associated with the administration of enteric-
coated thiazides with potassium salts. These lesions may occur with
enteric-coated potassium tablets alone or when they are used with
nonenteric-coated thiazides, or certain other oral diuretics. These
small-bowel lesions have caused obstruction, hemorrhage, and
perforation. Surgery was frequently required and deaths have occurred.
Based on a large survey of physicians and hospitals, both United States
and foreign, the incidence of these lesions is low, and a causal
relationship in man has not been definitely established. Available
information tends to implicate enteric-coated potassium salts, although
lesions of this type also occur spontaneously. Therefore, coated
potassium-containing formulations should be administered only when
indicated, and should be discontinued immediately if abdominal pain,
distention, nausea, vomiting, or gastrointestinal bleeding occur. Coated
potassium tablets should be used only when adequate dietary
supplementation is not practicable.
(Although the warning statement includes references to enteric-coated
potassium salt preparations, it applies to any capsule or coated tablet
of a potassium salt intended for oral ingestion without prior dilution
with an adequate volume of liquid to preclude gastrointestinal injury.)
(iii) Any other labeling or additional advertising for the drug
conforms to the labeling described in paragraph (a)(1)(ii) of this
section, in accordance with Sec. Sec. 202.1 and 201.100 of this
chapter.
(2) Within 90 days from the date of publication of this statement of
policy in the Federal Register, the manufacturer, packer, or distributor
of the drug shall submit a new-drug application containing satisfactory
information of the kind required by Sec. 314.50 of this chapter, with
appropriate labeling as described in this paragraph.
(b) The Food and Drug Administration may initiate regulatory
proceedings after 30 days from the date of publication of this section,
with respect to the marketing of uncoated tablets containing potassium
chloride or other potassium salts which supply 100 milligrams or more of
potassium per tablet or with respect to liquid preparations containing
potassium chloride or other potassium salts which supply 20 milligrams
or more of potassium per milliliter, labeled or intended for human use,
unless all the following conditions are met:
(1) The labeling of the drug bears the prescription statement quoted
in section 503(b)(4) of the Federal Food, Drug, and Cosmetic Act; and
(2) The labeling on or within the package from which the drug is to
be dispensed bears adequate information for its use by practitioners in
accord with the ``full disclosure'' labeling requirements of Sec.
201.100 of this chapter, including a recommendation that patients be
directed to dissolve any such tablets in an appropriate amount of liquid
and to dilute any such liquid preparations adequately to assure against
gastrointestinal injury associated with the oral ingestion of
concentrated potassium salt preparations.
[40 FR 13998, Mar. 27, 1975, as amended at 55 FR 11576, Mar. 29, 1990;
67 FR 4906, Feb. 1, 2002]
Sec. 201.307 Sodium phosphates; package size limitation, warnings,
and directions for over-the-counter sale.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that multiple container sizes of
sodium phosphates oral solution available in the marketplace have caused
consumer confusion and appear to have been involved in several consumer
deaths. Sodium phosphates oral solution has been marketed in 45-
milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and 90-mL
container sizes of sodium phosphates oral solution are often recommended
and prescribed by physicians for bowel cleansing prior to surgery and
diagnostic procedures of the colon. Sodium phosphates oral solution
(adult dose 20 mL to 45 mL) is also used as an over-the-counter (OTC)
laxative for the relief of occasional constipation. Accidental
overdosing and deaths have occurred because the 240-mL container was
mistakenly used instead of the 45-mL or 90-mL container. The Food and
Drug Administration is limiting the amount of sodium phosphates oral
solution to not more than 90 mL (3 ounces (oz)) per OTC container
because of the serious health risks associated with the ingestion of
larger than intended doses of this product. Further,
[[Page 84]]
because an overdose of either oral or rectal enema sodium phosphates can
cause an electrolyte imbalance, additional warning and direction
statements are required for the safe use of any OTC laxative drug
product containing sodium phosphates.
(b) Any OTC drug product for laxative or bowel cleansing use
containing sodium phosphates as an active ingredient when marketed as
described in paragraph (a) of this section is misbranded within the
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act
unless packaged and labeled as follows:
(1) Package size limitation for sodium phosphates oral solution:
Container shall not contain more than 90 mL (3 oz).
(2) Warnings. The following sentences shall appear in boldface type
as the first statement under the heading ``Warnings.''
(i) Oral dosage forms. ``Taking more than the recommended dose in 24
hours can be harmful.''
(ii) Rectal enema dosage forms. ``Using more than one enema in 24
hours can be harmful.''
(3) Directions--(i) The labeling of all orally or rectally
administered OTC drug products containing sodium phosphates shall
contain the following directions in boldface type immediately preceding
the dosage information: ``Do not'' (``take'' or ``use'') ``more unless
directed by a doctor. See Warnings.''
(ii) For products containing dibasic sodium phosphate/monobasic
sodium phosphate identified in Sec. 334.16(d) marketed as a solution.
Adults and children 12 years of age and over: Oral dosage is dibasic
sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate
9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/monobasic sodium
phosphate oral solution) as a single daily dose. ``Do not take more than
45 mL (9 teaspoonfuls or 3 tablespoonfuls) in a 24-hour period.''
Children 10 and 11 years of age: Oral dosage is dibasic sodium phosphate
1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g (10 to 20 mL
dibasic sodium phosphate/monobasic sodium phosphate oral solution) as a
single daily dose. ``Do not take more than 20 mL (4 teaspoonfuls) in a
24-hour period.'' Children 5 to 9 years of age: Oral dosage is dibasic
sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to
5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 10 mL (2
teaspoonfuls) in a 24-hour period.'' Children under 5 years of age: ask
a doctor.
(c) After June 22, 1998, for package size limitation and September
18, 1998, for labeling in accord with paragraph (b) of this section, any
such OTC drug product initially introduced or initially delivered for
introduction into interstate commerce, or any such drug product that is
repackaged or relabeled after these dates regardless of the date the
product was manufactured, initially introduced, or initially delivered
for introduction into interstate commerce, that is not in compliance
with this section is subject to regulatory action.
[63 FR 27843, May 21, 1998]
Sec. 201.308 Ipecac syrup; warnings and directions for use for
over-the-counter sale.
(a) It is estimated that each year about 500,000 accidental
poisonings occur in the United States and result in approximately 1,500
deaths, of which over 400 are children. In the emergency treatment of
these poisonings, ipecac syrup is considered the emetic of choice. The
immediate availability of this drug for use in such situations is
critical, since rapid treatment may be the difference between life and
death. The restriction of this drug to prescription sale limits its
availability in emergencies. On the other hand, it is the consensus of
informed medical opinion that ipecac syrup should be used only under
medical supervision in the emergency treatment of poisonings. In view of
these facts, the question of whether ipecac syrup labeled as an
emergency treatment for use in poisonings should be available over the
counter has been controversial.
(b) In connection with its study of this problem, the Food and Drug
Administration has obtained the views of medical authorities. It is the
unanimous recommendation of the American
[[Page 85]]
Academy of Pediatrics, the American Association of Poison Control
Centers, the American Medical Association, and the Medical Advisory
Board of the Food and Drug Administration that ipecac syrup in 1 fluid
ounce containers be permitted to be sold without prescription so that it
will be readily available in the household for emergency treatment of
poisonings, under medical supervision, and that the drug be
appropriately packaged and labeled for this purpose.
(c) In view of the above recommendations, the Commissioner of Food
and Drugs has determined that it is in the interest of the public health
for ipecac syrup to be available for sale without prescription, provided
that it is packaged in a quantity of 1 fluid ounce (30 milliliters), and
its label bears, in addition to other required label information, the
following, in a prominent and conspicuous manner:
(1) A statement conspicuously boxed and in red letters, to the
effect: ``For emergency use to cause vomiting in poisoning. Before
using, call physician, the Poison Control Center, or hospital emergency
room immediately for advice.''
(2) A warning to the effect: ``Warning--Keep out of reach of
children. Do not use in unconscious persons. Ordinarily, this drug
should not be used if strychnine, corrosives such as alkalies (lye) and
strong acids, or petroleum distillates such as kerosine, gasoline, coal
oil, fuel oil, paint thinner, or cleaning fluid have been ingested.''
(3) Usual dosage: 1 tablespoon (15 milliliters) in persons over 1
year of age.
Sec. 201.309 Acetophenetidin (phenacetin)-containing preparations;
necessary warning statement.
(a) In 1961, the Food and Drug Administration, pursuant to its
statutory responsibility for the safety and effectiveness of drugs
shipped in interstate commerce, began an active investigation of reports
of possible toxic effects and renal damage due to misuse of the drug
acetophenetidin. This study led to the decision that there was probable
cause to conclude that misuse and prolonged use of the drug were in fact
responsible for kidney lesions and disease. The Commissioner of Food and
Drugs, in December 1963, appointed an ad hoc Advisory Committee of
Inquiry on Possible Nephrotoxicity Associated With the Abuse of
Acetophenetidin (Phenacetin)-Containing Preparations. This committee,
composed of scientists in the fields of pharmacology and medicine, on
April 23, 1964, submitted its findings and conclusions in the matter and
recommended that all acetophenetidin (phenacetin)-containing
preparations bear a warning as provided in section 502(f)(2) of the
Federal Food, Drug, and Cosmetic Act.
(b) On the basis of the studies made by the Food and Drug
Administration and the report of the Advisory Committee, the
Commissioner of Food and Drugs has concluded that it is necessary for
the protection of users that the label and labeling of all
acetophenetidin (phenacetin)-containing preparations bear a warning
statement to the following effect: ``Warning--This medication may damage
the kidneys when used in large amounts or for a long period of time. Do
not take more than the recommended dosage, nor take regularly for longer
than 10 days without consulting your physician.''
Sec. 201.310 Phenindione; labeling of drug preparations intended
for use by man.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that phenindione, a synthetic
anticoagulant drug, has caused a number of cases of agranulocytosis
(with two fatalities). There are also reports implicating the drug in
cases of hepatitis and hypersensitivity reactions. In view of the
potentially serious effects found to be associated with preparations of
this drug intended for use by man, the Commissioner of Food and Drugs
will regard such preparations as misbranded within the meaning of
section 502(f) (1) and (2) of the Federal Food, Drug, and Cosmetic Act,
unless the label and labeling on or within the package from which the
drug is to be dispensed, and any other labeling furnishing or purporting
to furnish information for use of the drug, bear a conspicuous warning
statement to the following effect: ``Warning: Agranulocytosis and
hepatitis have been associated with the use
[[Page 86]]
of phenindione. Patients should be instructed to report promptly
prodromal symptoms such as marked fatigue, chill, fever, and sore
throat. Periodic blood studies and liver function tests should be
performed. Use of the drug should be discontinued if leukopenia occurs
or if evidence of hypersensitivity, such as dermatitis or fever,
appears.''
(b) Regulatory action may be initiated with respect to preparations
of phenindione intended for use by man found within the jurisdiction of
the act on or after November 25, 1961, unless such preparations are
labeled in accordance with paragraph (a) of this section.
Sec. 201.311 [Reserved]
Sec. 201.312 Magnesium sulfate heptahydrate; label declaration
on drug products.
Magnesium sulfate heptahydrate should be listed on the label of a
drug product as epsom salt, which is its common or usual name.
Sec. 201.313 Estradiol labeling.
The article presently recognized in The National Formulary under the
heading ``Estradiol'' and which is said to be ``17-cis-beta estradiol''
is the same substance formerly recognized in the United States
Pharmacopeia under the designation ``Alpha Estradiol.'' The substance
should no longer be referred to in drug labeling as ``Alpha Estradiol.''
The Food and Drug Administration would not object to label references to
the article as simply ``Estradiol''; nor would it object if the label of
a preparation containing this substance referred to the presence of
``Estradiol (formerly known as Alpha Estradiol).''
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. Such a warning statement is
required for compliance with section 502(f)(2) of the Federal Food,
Drug, and Cosmetic Act and is intended to guard against accidental
poisonings. Safety closures that prevent access to the drug by young
children are also recommended to guard against accidental poisonings.
(b) Effervescent preparations and preparations containing para-
aminosalicylate as the only salicylate ingredient are exempted from this
labeling requirement.
(c) Aspirin tablets sold as such and containing no other active
ingredients, except tablets which cannot be readily subdivided into a
child's dose because of their coating or size, should always bear dosage
directions for each age group down to 3 years of age, with a statement
such as ``For children under 3 years of age, consult your physician.''
It is recommended that:
(1) Aspirin tablets especially made for pediatric use be produced
only in 1\1/4\-grain size to reduce the hazard of errors in dosage;
(2) By June 1, 1967, manufacturers and distributors of 1\1/4\-grain
size aspirin tablets discontinue the distribution of such tablets in
retail containers containing more than 36 tablets, to reduce the hazard
of accidental poisoning;
(3) The flavoring of 5-grain aspirin tablets or other ``adult
aspirin tablets'' be discontinued; and
(4) Labeling giving undue emphasis to the pleasant flavor of
flavored aspirin tablets be discontinued.
(d) Salicylate preparations other than aspirin tablets sold as such
may, at the option of the distributor, be labeled for use by adults
only. If their labeling and advertising clearly offer them for
administration to adults only.
(e)(1) It is the obligation of the distributor who labels a
salicylate preparation for administration to children to make certain
that the article is suitable for such use and labeled with adequate
directions for use in the age group for which it is offered, but in no
[[Page 87]]
case should such an article bear directions for use in children under 3
years of age. If the directions provide for administration to children
as young as 3 years of age, the label should bear the statement, ``For
children under 3 years of age consult your physician.'' However, if the
directions provide for administration to children only of an age greater
than 3 years (for example, the dosage instructions provide for
administration of the article to children only down to age 6), the label
should bear a statement such as, ``For younger children consult your
physician.''
(2) A statement such as, ``For children under 3 years of age consult
your physician'' or ``For younger children consult your physician'' is
not required on the label of an article clearly offered for
administration to adults only.
(f) If the labeling or advertising of a salicylate preparation
offers it for use in arthritis or rheumatism, the label and labeling
should clearly state that the beneficial effects claimed are limited to:
``For the temporary relief of minor aches and pains of arthritis and
rheumatism.'' The qualifying phrase ``for the temporary relief of minor
aches and pains'' should appear with the same degree of prominence and
conspicuousness as the phrase ``arthritis and rheumatism''. The label
and labeling should bear in juxtaposition with such directions for use
conspicuous warning statements to the effect: ``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.'' The salicylate dosage should not exceed 60 grains in a
24-hour period or 10 grains in a 4-hour period. If the article contains
other analgesics, the salicylate dosage should be appropriately reduced.
(g)(1) The label of any drug containing more than 5 percent methyl
salicylate (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.
(2) If the preparation is a counterirritant or rubefacient, it
should also bear a caution such as, ``Caution: Discontinue use if
excessive irritation of the skin develops. Avoid getting into the eyes
or on mucous membranes.'' (See also Sec. 201.303.)
(h)(1) The labeling of orally or rectally administered over-the-
counter drug products containing aspirin or nonaspirin salicylates as
active ingredients subject to this paragraph is required to prominently
bear the following warning: ``Reye's syndrome [subheading in bold type]:
Children and teenagers who have or are recovering from chicken pox or
flu-like symptoms should not use this product. When using this product,
if changes in behavior with nausea and vomiting occur, consult a doctor
because these symptoms could be an early sign of Reye's syndrome, a rare
but serious illness.''
(2) This warning statement shall appear on the immediate container
labeling. In cases where the immediate container is not the retail
package, the retail package also must bear the warning statement. In
addition, the warning statement shall appear on any labeling that
contains warnings and, in such cases, the warning statement shall be the
first warning statement under the heading ``Warnings.''
(3) Over-the-counter drug products subject to this paragraph and
labeled solely for use by children (pediatric products) shall not
recommend the product for use in treating flu or chicken pox.
(4) Any product subject to paragraphs (h)(1), (h)(2), and (h)(3) of
this section that is not labeled as required by these paragraphs and
that is initially introduced or initially delivered for introduction
into interstate commerce after the following dates is misbranded under
sections 201(n) and 502(a) and (f) of the Federal Food, Drug, and
Cosmetic Act.
(i) Compliance by October 18, 2004, for OTC drug products containing
aspirin and nonaspirin salicylates as an active ingredient and marketed
under a new drug application or abbreviated new drug application.
(ii) Compliance by April 19, 2004, for OTC antidiarrheal and
overindulgence drug products that contain bismuth subsalicylate as an
active ingredient
[[Page 88]]
and have annual sales greater than $25,000.
(iii) Compliance by April 18, 2005, for OTC antidiarrheal and
overindulgence drug products that contain bismuth subsalicylate as an
active ingredient and have annual sales less than $25,000.
(iv) Compliance dates for all other OTC drug products containing
aspirin and nonaspirin salicylates as an active ingredient and marketed
under an OTC drug monograph (for internal analgesic, antipyretic, and
antirheumatic drug products, or for menstrual drug products) will be
established when the final monographs for those products are published
in a future issue of the Federal Register. In the interim, these
products should continue to be labeled with the previous Reye's syndrome
warning that appears in paragraph (h)(1) of this section.
[40 FR 13998, Mar. 27, 1985, as amended at 51 FR 8182, Mar. 7, 1986; 53
FR 21637, June 9, 1988; 53 FR 24830, June 30, 1988; 64 FR 13291, Mar.
17, 1999; 65 FR 8, Jan. 3, 2000; 68 FR 18869, Apr. 17, 2003]
Sec. 201.315 Over-the-counter drugs for minor sore throats;
suggested warning.
The Food and Drug Administration has studied the problem of the
labeling of lozenges or troches containing a local anesthetic, chewing
gum containing aspirin, various mouth washes and gargles and other
articles sold over the counter for the relief of minor irritations of
the mouth or throat. It will not object to the labeling of suitable
articles of this type ``For the temporary relief of minor sore
throats'', provided this is immediately followed in the labeling with a
warning statement in prominent type essentially as follows: ``Warning--
Severe or persistent sore throat or sore throat accompanied by high
fever, headache, nausea, and vomiting may be serious. Consult physician
promptly. Do not use more than 2 days or administer to children under 3
years of age unless directed by physician.''
Sec. 201.316 Drugs with thyroid hormone activity for human use;
required warning.
(a) Drugs with thyroid hormone activity have been promoted for, and
continue to be dispensed and prescribed for, use in the treatment of
obesity, although their safety and effectiveness for that use have never
been established.
(b) Drugs for human use with thyroid hormone activity are misbranded
within the meaning of section 502 of the Federal Food, Drug, and
Cosmetic Act unless their labeling bears the following boxed warning at
the beginning of the ``Warnings'' section:
------------------------------------------------------------------
Drugs with thyroid hormone activity, alone or together
with other therapeutic agents, have been used for the
treatment of obesity. In euthyroid patients, doses within
the range of daily hormonal requirements are ineffective for
weight reduction. Larger doses may produce serious or even
life-threatening manifestations of toxicity, particularly
when given in association with sympatho mimetic amines such
as those used for their anorectic effects.
------------------------------------------------------------------
[43 FR 22009, May 23, 1978]
Sec. 201.317 Digitalis and related cardiotonic drugs for human
use in oral dosage forms; required warning.
(a) Digitalis and related cardiotonic drugs for human use in oral
dosage forms have been promoted for, and continue to be dispensed and
prescribed for, use in the treatment of obesity, although their safety
and effectiveness for that use have never been established.
(b) Digitalis and related cardiotonic drugs for human use in oral
dosage forms are misbranded within the meaning of section 502 of the
Federal Food, Drug, and Cosmetic Act unless their labeling bears the
following boxed warning at the beginning of the ``Warnings'' section:
------------------------------------------------------------------
Digitalis alone or with other drugs has been used in the
treatment of obesity. This use of digoxin or other digitalis
glycosides is unwarranted. Moreover, since they may cause
potentially fatal arrhythmias or other adverse effects, the
use of these drugs in the treatment of obesity is dangerous.
------------------------------------------------------------------
[[Page 89]]
(c) This section does not apply to digoxin products for oral use.
[43 FR 22009, May 23, 1978, as amended at 85 FR 72907, Nov. 16, 2020]
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.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that esophageal obstruction and
asphyxiation have been associated with the ingestion of 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. Esophageal obstruction and asphyxiation due to orally-
administered drug products containing water-soluble gums, hydrophilic
gums, and hydrophilic mucilloids as active ingredients are significant
health risks when these products are taken without adequate fluid or
when they are used by individuals with esophageal narrowing or
dysfunction, or with difficulty in swallowing. Additional labeling is
needed for the safe and effective use of any OTC drug product for human
use containing a water-soluble gum, hydrophilic gum, or hydrophilic
mucilloid as an active ingredient when marketed in a dry or incompletely
hydrated form to include, but not limited to, the following dosage
forms: Capsules, granules, powders, tablets, and wafers. Granular dosage
forms containing psyllium are not generally recognized as safe and
effective as OTC laxatives (see Sec. 310.545(a)(12)(i)(B) of this
chapter) and may not be marketed without an approved new drug
application because the warnings and directions in paragraph (b) of this
section have been found inadequate for these products.
(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.''
(c) After February 28, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce, or any such drug product that is repackaged or relabeled after
this date regardless of the date the product was manufactured, initially
introduced, or initially delivered for introduction into interstate
commerce, that is not in compliance with this section is subject to
regulatory action.
[58 FR 45201, Aug. 26, 1993, as amended at 64 FR 13292, Mar. 17, 1999;
72 FR 14674, Mar. 29, 2007]
Sec. 201.320 Warning statements for drug products containing
or manufactured with chlorofluorocarbons or other ozone-depleting
substances.
(a)(1) All drug products containing or manufactured with
chlorofluorocarbons, halons, carbon
[[Page 90]]
tetrachloride, methyl chloride, or any other class I substance
designated by the Environmental Protection Agency (EPA) shall, except as
provided in paragraph (b) or (c) of this section, bear the following
warning statement:
Warning: Contains [or Manufactured with, if applicable] [insert name
of substance], a substance which harms public health and the environment
by destroying ozone in the upper atmosphere.
(2) The warning statement shall be clearly legible and conspicuous
on the product, its immediate container, its outer packaging, or other
labeling in accordance with the requirements of 40 CFR part 82 and
appear with such prominence and conspicuousness as to render it likely
to be read and understood by consumers under normal conditions of
purchase.
(b)(1) For prescription drug products for human use, the following
alternative warning statement may be used:
Note: The indented statement below is required by the Federal
government's Clean Air Act for all products containing or manufactured
with chlorofluorocarbons (CFC's) [or name of other class I substance, if
applicable]:
This product contains [or is manufactured with, if applicable]
[insert name of substance], a substance which harms the environment by
destroying ozone in the upper atmosphere.
Your physician has determined that this product is likely to help
your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO
DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about
alternatives, consult with your physician.
(2) The warning statement shall be clearly legible and conspicuous
on the product, its immediate container, its outer packaging, or other
labeling in accordance with the requirements of 40 CFR part 82 and
appear with such prominence and conspicuousness as to render it likely
to be read and understood by consumers under normal conditions of
purchase.
(3) If the warning statement in paragraph (b)(1) of this section is
used, the following warning statement must be placed on the package
labeling intended to be read by the physician (physician package insert)
after the ``How supplied'' section, which describes special handling and
storage conditions on the physician labeling:
Note: The indented statement below is required by the Federal
government's Clean Air Act for all products containing or manufactured
with chlorofluorocarbons (CFC's) [or name of other class I substance, if
applicable]:
Warning: Contains [or Manufactured with, if applicable] [insert name
of substance], a substance which harms public health and the environment
by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the
information for the patient [or patient information leaflet, if
applicable] of this product under the Environmental Protection Agency's
(EPA's) regulations. The patient's warning states that the patient
should consult his or her physician if there are questions about
alternatives.
(c)(1) For over-the-counter drug products for human use, the
following alternative warning statement may be used:
Note: The indented statement below is required by the Federal
government's Clean Air Act for all products containing or manufactured
with chlorofluorocarbons (CFC's) [or other class I substance, if
applicable]:
Warning: Contains [or Manufactured with, if applicable] [insert name
of substance], a substance which harms public health and environment by
destroying ozone in the upper atmosphere.
CONSULT WITH YOUR PHYSICIAN OR HEALTH PROFESSIONAL IF YOU HAVE ANY
QUESTION ABOUT THE USE OF THIS PRODUCT.
(2) The warning statement shall be clearly legible and conspicuous
on the product, its immediate container, its outer packaging, or other
labeling in accordance with the requirements of 40 CFR part 82 and
appear with such prominence and conspicuousness as to render it likely
to be read and understood by consumers under normal conditions of
purchase.
(d) This section does not replace or relieve a person from any
requirements imposed under 40 CFR part 82.
[61 FR 20100, May 3, 1996]
Sec. 201.323 Aluminum in large and small volume parenterals used
in total parenteral nutrition.
(a) The aluminum content of large volume parenteral (LVP) drug
products used in total parenteral nutrition
[[Page 91]]
(TPN) therapy must not exceed 25 micrograms per liter ([micro]g/L).
(b) The package insert of LVP's used in TPN therapy must state that
the drug product contains no more than 25 [micro]g/L of aluminum. This
information must be contained in the ``Precautions'' section of the
labeling of all large volume parenterals used in TPN therapy.
(c) Except as provided in paragraph (d) of this section, the maximum
level of aluminum present at expiry must be stated on the immediate
container label of all small volume parenteral (SVP) drug products and
pharmacy bulk packages (PBPs) used in the preparation of TPN solutions.
The aluminum content must be stated as follows: ``Contains no more than
__ [micro]g/L of aluminum.'' The immediate container label of all SVP's
and PBP's that are lyophilized powders used in the preparation of TPN
solutions must contain the following statement: ``When reconstituted in
accordance with the package insert instructions, the concentration of
aluminum will be no more than __ [micro]g/L.'' This maximum level of
aluminum must be stated as the highest of:
(1) The highest level for the batches produced during the last 3
years;
(2) The highest level for the latest five batches, or
(3) The maximum historical level, but only until completion of
production of the first five batches after July 26, 2004.
(d) If the maximum level of aluminum is 25 [micro]g/L or less,
instead of stating the exact amount of aluminum as required in paragraph
(c) of this section, the immediate container label may state: ``Contains
no more than 25 [micro]g/L of aluminum.'' If the SVP or PBP is a
lyophilized powder, the immediate container label may state: ``When
reconstituted in accordance with the package insert instructions, the
concentration of aluminum will be no more than 25 [micro]g/L''.
(e) The package insert for all LVP's, all SVP's, and PBP's used in
TPN must contain a warning statement. This warning must be contained in
the ``Warnings'' section of the labeling. The warning must state:
WARNING: This product contains aluminum that may be toxic. Aluminum
may reach toxic levels with prolonged parenteral administration if
kidney function is impaired. Premature neonates are particularly at risk
because their kidneys are immature, and they require large amounts of
calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function,
including premature neonates, who receive parenteral levels of aluminum
at greater than 4 to 5 [micro]g/kg/day accumulate aluminum at levels
associated with central nervous system and bone toxicity. Tissue loading
may occur at even lower rates of administration.
(f) Applicants and manufacturers must use validated assay methods to
determine the aluminum content in parenteral drug products. The assay
methods must comply with current good manufacturing practice
requirements. Applicants must submit to the Food and Drug Administration
validation of the method used and release data for several batches.
Manufacturers of parenteral drug products not subject to an approved
application must make assay methodology available to FDA during
inspections. Holders of pending applications must submit an amendment
under Sec. 314.60 or Sec. 314.96 of this chapter.
[65 FR 4110, Jan. 26, 2000, as amended at 67 FR 70691, Nov. 26, 2002; 68
FR 32981, June 3, 2003]
Sec. 201.325 Over-the-counter drugs for vaginal contraceptive
and spermicide use containing nonoxynol 9 as the active ingredient;
required warnings and labeling information.
(a) Studies indicate that use of vaginal contraceptive drug products
containing nonoxynol 9 does not protect against infection from the human
immunodeficiency virus (HIV), the virus that causes acquired
immunodeficiency syndrome (AIDS), or against the transmission of other
sexually transmitted diseases (STDs). Studies also indicate that use of
vaginal contraceptive drug products containing nonoxynol 9 can increase
vaginal irritation, such as the disruption of the vaginal epithelium,
and also can cause epithelial disruption when used in the rectum. These
effects may increase the risk of transmission
[[Page 92]]
of the AIDS virus (HIV) from an infected partner. Therefore, consumers
should be warned that these products do not protect against the
transmission of the AIDS virus (HIV) or other STDs, that use of these
products can increase vaginal and rectal irritation, which may increase
the risk of getting the AIDS virus (HIV) from an HIV infected partner,
and that the products are not for rectal use. Consumers should also be
warned that these products should not be used by persons who have HIV/
AIDS or are at high risk for HIV/AIDS.
(b) The labeling of OTC vaginal contraceptive and spermicide drug
products containing nonoxynol 9 as the active ingredient, whether
subject to the ongoing OTC drug review or an approved drug application,
must contain the following warnings under the heading ``Warnings,'' in
accordance with 21 CFR 201.66.
(1) ``[bullet] For vaginal use only [bullet] Not for rectal (anal)
use'' [both warnings in bold type].
(2) ``Sexually transmitted diseases (STDs) alert [in bold type]:
This product does not [word ``not'' in bold type] protect against HIV/
AIDS or other STDs and may increase the risk of getting HIV from an
infected partner''.
(3) ``Do not use'' [in bold type] if you or your sex partner has
HIV/AIDS. If you do not know if you or your sex partner is infected,
choose another form of birth control''.
(4) ``When using this product [in bold type] [optional, bullet] you
may get vaginal irritation (burning, itching, or a rash)''.
(5) ``Stop use and ask a doctor if [in bold type] [optional, bullet]
you or your partner get burning, itching, a rash, or other irritation of
the vagina or penis''.
(c) The labeling of this product states under the ``Other
information'' section of the Drug Facts labeling in accordance with
Sec. 201.66(c)(7), ``[bullet] when used correctly every time you have
sex, latex condoms greatly reduce, but do not eliminate, the risk of
catching or spreading HIV, the virus that causes AIDS.
(d) The labeling of this product includes the following statements
either on the outside container or wrapper of the retail package, under
the ``Other information'' section of the Drug Facts labeling in
accordance with Sec. 201.66(c)(7), or in a package insert:
(1) ``[bullet] studies have raised safety concerns that products
containing the spermicide nonoxynol 9 can irritate the vagina and
rectum. Sometimes this irritation has no symptoms. This irritation may
increase the risk of getting HIV/AIDS from an infected partner''.
(2) ``[bullet] you can use nonoxynol 9 for birth control with or
without a diaphragm or condom if you have sex with only one partner who
is not infected with HIV and who has no other sexual partners or HIV
risk factors''.
(3) ``[bullet] use a latex condom without nonoxynol 9 if you or your
sex partner has HIV/AIDS, multiple sex partners, or other HIV risk
factors''.
(4) ``[bullet] ask a health professional if you have questions about
your best birth control and STD prevention methods''.
(e) Any drug product subject to this section that is not labeled as
required and that is initially introduced or initially delivered for
introduction into interstate commerce after June 19, 2008, is misbranded
under section 502 of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 352), is a new drug under section 505 of the act (21 U.S.C.
355), and is subject to regulatory action.
[72 FR 71785, Dec. 19, 2007]
Sec. 201.326 Over-the-counter drug products containing
internal analgesic/antipyretic active ingredients; required
warnings and other labeling.
(a) Labeling. The labeling for all over-the-counter (OTC) drug
products containing any internal analgesic/antipyretic active
ingredients (including, but not limited to, acetaminophen, aspirin,
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen,
magnesium salicylate, naproxen sodium, and sodium salicylate) alone or
in combination must bear the following labeling in accordance with
Sec. Sec. 201.60, 201.61, and 201.66.
(1) Acetaminophen--(i) Statement of identity. The statement of
identity appears in accord with Sec. Sec. 201.61 and 299.4 of this
chapter. The ingredient name
[[Page 93]]
``acetaminophen'' must appear highlighted (e.g., fluorescent or color
contrast) or in bold type, be in lines generally parallel to the base on
which the package rests as it is designed to be displayed, and be in one
of the following sizes, whichever is greater:
(A) At least one-quarter as large as the size of the most prominent
printed matter on the principal display panel (PDP), or
(B) At least as large as the size of the ``Drug Facts'' title, as
required in Sec. 201.66(d)(2). The presence of acetaminophen must
appear as part of the established name of the drug, as defined in Sec.
299.4 of this chapter. Combination products containing acetaminophen and
a nonanalgesic ingredient(s) (e.g., cough-cold) must include the name
``acetaminophen'' and the name(s) of the other active ingredient(s) in
the product on the PDP in accord with this paragraph. Only the name
``acetaminophen'' must appear highlighted or in bold type, and in a
prominent print size, as described in this paragraph.
(ii) Active Ingredient and Purpose Headings. The information
required under Sec. 201.66(c)(2) and (c)(3) of this chapter must be
included under these headings. The information under these headings, but
not the headings, may appear highlighted.
(iii) For products labeled for adults only. The labeling of the
product states the following warnings under the heading ``Warnings'':
(A) The liver warning states ``Liver warning [heading in bold type]:
This product contains acetaminophen. Severe liver damage may occur if
you take [bullet] more than [insert maximum number of daily dosage
units] in 24 hours, which is the maximum daily amount [optional: `for
this product'] [bullet] with other drugs containing acetaminophen
[bullet] 3 or more alcoholic drinks every day while using this
product''. This ``Liver'' warning must be the first warning under the
``Warnings'' heading. For products that contain both acetaminophen and
aspirin, this ``Liver'' warning must appear after the ``Reye's
syndrome'' and ``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A)
and (c)(5)(ii)(B) and before the ``Stomach bleeding'' warning in
paragraph (a)(2)(iii)(A) of this section. If there is an outer and
immediate container of a retail package, this warning must appear on
both the outer and immediate containers. If the immediate container is a
blister card, the warning must appear on the blister card and remain
intact and readable when drug product is removed from the blister card.
The warning does not need to be included on each blister unit.
(B) ``Do not use with any other drug containing acetaminophen
(prescription or nonprescription). If you are not sure whether a drug
contains acetaminophen, ask a doctor or pharmacist.''
(C) ``Ask a doctor before use if you have liver disease''.
(D) ``Ask a doctor or pharmacist before use if you are taking the
blood thinning drug warfarin'' except on the labeling of combination
products that contain acetaminophen and NSAID(s).
(iv) For products labeled only for children under 12 years of age.
(A) Warnings. The labeling of the product states the following
warnings under the heading ``Warnings'':
(1) The liver warning states ``Liver warning [heading in bold type]:
This product contains acetaminophen. Severe liver damage may occur if
your child takes [bullet] more than 5 doses in 24 hours, which is the
maximum daily amount [optional: `for this product'] [bullet] with other
drugs containing acetaminophen''. This ``Liver'' warning must be the
first warning under the ``Warnings'' heading. If there is an outer and
immediate container of a retail package, this warning must appear on
both the outer and immediate containers. If the immediate container is a
blister card, the warning must appear on the blister card and remain
intact and readable when drug product is removed from the blister card.
The warning is not required to be included on each blister unit.
(2) ``Do not use with any other drug containing acetaminophen
(prescription or nonprescription). If you are not sure whether a drug
contains acetaminophen, ask a doctor or pharmacist.''
(3) ``Ask a doctor before use if your child has liver disease''.
(4) ``Ask a doctor or pharmacist before use if your child is taking
the blood thinning drug warfarin'' except
[[Page 94]]
on the labeling of combination products that contain acetaminophen and
NSAID(s).
(B) Directions. The labeling of the product contains the following
information under the heading ``Directions'': ``this product does not
contain directions or complete warnings for adult use'' [in bold type].
(v) For products labeled for adults and children under 12 years of
age. The labeling of the product states all of the warnings in
paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of this
section with the following modifications:
(A) The liver warning states ``Liver warning [heading in bold type]:
This product contains acetaminophen. Severe liver damage may occur if
[bullet] adult takes more than [insert maximum number of daily dosage
units] in 24 hours, which is the maximum daily amount [optional: `for
this product'] [bullet] child takes more than 5 doses in 24 hours
[bullet] taken with other drugs containing acetaminophen [bullet] adult
has 3 or more alcoholic drinks everyday while using this product.'' If
there is an outer and immediate container of a retail package, this
warning must appear on both the outer and immediate containers. If the
immediate container is a blister card, the warning must appear on the
blister card and remain intact and readable when drug product is removed
from the blister card. The warning is not required to be included on
each blister unit.
(B) ``Ask a doctor before use if the user has liver disease.''
(C) ``Do not use with any other drug containing acetaminophen
(prescription or nonprescription). If you are not sure whether a drug
contains acetaminophen, ask a doctor or pharmacist.''
(D) ``Ask a doctor or pharmacist before use if the user is taking
the blood thinning drug warfarin'' except on the labeling of combination
products that contain acetaminophen and NSAID(s).
(2) Nonsteroidal anti-inflammatory analgesic/antipyretic active
ingredients--including, but not limited to, aspirin, carbaspirin
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium
salicylate, naproxen sodium, and sodium salicylate.
(i) Statement of identity. The statement of identity appears in
accord with Sec. Sec. 201.61 and 299.4 of this chapter. The word
``(NSAID)'' must appear highlighted (e.g., fluorescent or color
contrast) or in bold type, be in lines generally parallel to the base on
which the package rests as it is designed to be displayed, and be in one
of the following sizes, whichever is greater:
(A) At least one-quarter as large as the size of the most prominent
printed matter on the PDP, or
(B) At least as large as the size of the ``Drug Facts'' title, as
required in Sec. 201.66(d)(2). The word ``(NSAID)'' must appear as part
of the established name of the drug, as defined in Sec. 299.4 of this
chapter, or after the general pharmacological (principal intended)
action of the NSAID ingredient. Combination products containing an NSAID
and a nonanalgesic ingredient(s) (e.g., cough-cold) must include the
name of the NSAID ingredient and the word ``(NSAID)'' in accordance with
this paragraph, and the name(s) of the other active ingredient(s) in the
product on the PDP. Only the word ``(NSAID)'' needs to appear
highlighted or in bold type, and in a prominent print size, as described
in this paragraph.
(ii) Active Ingredient and Purpose Headings. The information
required under Sec. 201.66(c)(2) and (c)(3) of this chapter must be
included under these headings. The active ingredient(s) section of the
product's labeling, as defined in Sec. 201.66(c)(2), contains the term
``(NSAID*)'' after the NSAID active ingredient with an asterisk
statement at the end of the active ingredient(s) section that defines
the term ``NSAID'' and states ``* nonsteroidal anti-inflammatory drug.''
The information under these headings may appear highlighted. However,
the headings ``Active Ingredient'' and ``Purpose'' may not appear
highlighted.
(iii) For products labeled for adults only. The labeling of the
product states the following warnings under the heading ``Warnings'':
(A) The stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is
[[Page 95]]
higher if you [bullet] are age 60 or older [bullet] have had stomach
ulcers or bleeding problems [bullet] take a blood thinning
(anticoagulant) or steroid drug [bullet] take other drugs containing
prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or
others) [bullet] have 3 or more alcoholic drinks every day while using
this product [bullet] take more or for a longer time than directed''.
This ``Stomach bleeding'' warning must appear after the ``Reye's
syndrome'' and ``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A)
and (c)(5)(ii)(B). For products that contain both acetaminophen and
aspirin, the acetaminophen ``Liver'' warning in paragraph (a)(1)(iii) of
this section must appear before the ``Stomach bleeding'' warning in this
paragraph. If there is an outer and immediate container of a retail
package, this warning must appear on both the outer and immediate
containers. If the immediate container is a blister card, the warning
must appear on the blister card and remain intact and readable when drug
product is removed from the blister card. The warning is not required to
be included on each blister unit.
(B) ``Ask a doctor before use if [bullet] stomach bleeding warning
applies to you [bullet] you have a history of stomach problems, such as
heartburn [bullet] you have high blood pressure, heart disease, liver
cirrhosis, or kidney disease [bullet] you are taking a diuretic''.
(C) ``Stop use and ask a doctor if [bullet] you experience any of
the following signs of stomach bleeding:'' [add the following as second
level of statements: ``[bullet] feel faint [bullet] vomit blood [bullet]
have bloody or black stools [bullet] have stomach pain that does not get
better''].
(iv) For products labeled only for children under 12 years of age.
(A) Warnings. The labeling of the product states the following
warnings under the heading ``Warnings'':
(1) The stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is higher if your child [bullet] has
had stomach ulcers or bleeding problems [bullet] takes a blood thinning
(anticoagulant) or steroid drug [bullet] takes other drugs containing
prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or
others) [bullet] takes more or for a longer time than directed''. The
``Stomach bleeding'' warning must appear after the ``Reye's syndrome''
and ``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A) and
(c)(5)(ii)(B). If there is an outer and immediate container of a retail
package, this warning must appear on both the outer and immediate
containers. If the immediate container is a blister card, the warning
must appear on the blister card and remain intact and readable when drug
product is removed from the blister card. The warning is not required to
be included on each blister unit.
(2) ``Ask a doctor before use if [bullet] stomach bleeding warning
applies to your child [bullet] child has a history of stomach problems,
such as heartburn [bullet] child has not been drinking fluids [bullet]
child has lost a lot of fluid due to vomiting or diarrhea [bullet] child
has high blood pressure, heart disease, liver cirrhosis, or kidney
disease [bullet] child is taking a diuretic''.
(3) ``Stop use and ask a doctor if [bullet] child experiences any of
the following signs of stomach bleeding:'' [add the following as second
level of statements: [bullet] feels faint [bullet] vomits blood [bullet]
has bloody or black stools [bullet] has stomach pain that does not get
better''].
(B) Directions. The labeling of the product contains the following
information under the heading ``Directions'': ``this product does not
contain directions or complete warnings for adult use'' [in bold type].
(v) For products labeled for adults and children under 12 years of
age. The labeling of the product states all of the warnings in
paragraphs (a)(2)(iii)(A) through (a)(2)(iii)(C) of this section with
the following modifications:
(A) The Stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is higher if the user [bullet] has
had stomach ulcers or bleeding problems
[[Page 96]]
[bullet] takes a blood thinning (anticoagulant) or steroid drug [bullet]
takes other drugs containing prescription or nonprescription NSAIDs
(aspirin, ibuprofen, naproxen, or others) [bullet] takes more or for a
longer time than directed [bullet] is age 60 or older [bullet] has 3 or
more alcoholic drinks everyday while using this product''. The ``Stomach
bleeding'' warning must appear after the ``Reye's syndrome`` and
``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A) and
(c)(5)(ii)(B). If there is an outer and immediate container of a retail
package, this warning must appear on both the outer and immediate
containers. If the immediate container is a blister card, the warning
must appear on the blister card and remain intact and readable when drug
product is removed from the blister card. The warning is not required to
be included on each blister unit.
(B) The labeling states ``Ask a doctor before use if [bullet]
stomach bleeding warning applies to user [bullet] user has history of
stomach problems, such as heartburn [bullet] user has high blood
pressure, heart disease, liver cirrhosis, or kidney disease [bullet]
user takes a diuretic [bullet] user has not been drinking fluids
[bullet] user has lost a lot of fluid due to vomiting or diarrhea''.
(C) The labeling states ``Stop use and ask a doctor if [bullet] user
experiences any of the following signs of stomach bleeding:'' [add the
following as second level of statements: [bullet] feels faint [bullet]
vomits blood [bullet] has bloody or black stools [bullet] has stomach
pain that does not get better''].
(b) New warnings information statement. The labeling of any drug
product subject to this section that is initially introduced or
initially delivered for introduction into interstate commerce before or
on April 29, 2010, must bear on its PDP, as defined in Sec. 201.60, the
statement ``See new warnings information''. This statement must appear
highlighted (e.g., fluorescent or color contrast) or in bold type, be in
lines generally parallel to the base on which the package rests as it is
designed to be displayed, and be in one of the following sizes,
whichever is greater:
(1) At least one-quarter as large as the size of the most prominent
printed matter on the PDP, or
(2) At least as large as the size of the ``Drug Facts'' title, as
required in Sec. 201.66(d)(2). The new warnings information statement
must remain on the PDP of the drug product for at least 1 year from the
date the product is initially introduced into interstate commerce.
(c) Requirements to supplement approved application. Holders of
approved applications for OTC drug products that contain internal
analgesic/antipyretic active ingredients that are subject to the
requirements of paragraph (a) of this section must submit supplements
under Sec. 314.70(c) of this chapter to include the required
information in the product's labeling. Such labeling may be put into use
without advance approval of FDA provided it includes at least the exact
information included in paragraph (a) of this section.
[74 FR 19407, Apr. 29, 2009, as amended at 74 FR 31180, June 30, 2009;
74 FR 61514, Nov. 25, 2009]
Sec. 201.327 Over-the-counter sunscreen drug products; required
labeling based on effectiveness testing.
The following provisions apply to sunscreen products containing
aminobenzoic acid, avobenzone, cinoxate, dioxybenzone, ensulizole,
homosalate, meradimate, octinoxate, octisalate, octocrylene, oxybenzone,
padimate O, sulisobenzone, titanium dioxide, trolamine salicylate, or
zinc oxide, alone or in combination. The provisions do not apply to
sunscreen products marketed under approved new drug applications or
abbreviated new drug applications.
(a) Principal display panel. In addition to the statement of
identity in paragraph (b) of this section, the following labeling shall
be prominently placed on the principal display panel:
(1) Effectiveness claim--(i) For products that pass the broad
spectrum test in paragraph (j) of this section. (A) The labeling states
``Broad Spectrum SPF [insert numerical SPF value resulting from testing
under paragraph (i) of this section]''.
[[Page 97]]
(B) Prominence. The Broad Spectrum SPF statement shall appear as
continuous text with no intervening text or graphic. The entire text
shall appear in the same font style, size, and color with the same
background color.
(ii) For sunscreen products that do not pass the broad spectrum test
in paragraph (j) of this section. The labeling states ``SPF [insert
numerical SPF value resulting from testing under paragraph (i) of this
section]''. The entire text shall appear in the same font style, size,
and color with the same background color.
(2) Water resistance statements--(i) For products that provide 40
minutes of water resistance according to the test in paragraph (i)(7)(i)
of this section. The labeling states ``Water Resistant (40 minutes)''.
(ii) For products that provide 80 minutes of water resistance
according to the test in paragraph (i)(7)(ii) of this section. The
labeling states ``Water Resistant (80 minutes)''.
(b) Statement of identity. The labeling of the product contains the
established name of the drug, if any, and identifies the drug as a
``sunscreen.''
(c) Indications. The labeling of the product states, under the
heading ``Uses,'' the phrases listed in this paragraph (c), as
appropriate. Other truthful and nonmisleading statements, describing
only the uses that have been established and listed in this paragraph
(c), may also be used, as provided in Sec. 330.1(c)(2) of this chapter,
subject to the provisions of section 502 of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) relating to misbranding and the prohibition
in section 301(d) of the FD&C Act against the introduction or delivery
for introduction into interstate commerce of unapproved new drugs in
violation of section 505(a) of the FD&C Act.
(1) For all sunscreen products, the following indication statement
must be included under the heading ``Uses'': ``[Bullet] helps prevent
sunburn''. See Sec. 201.66(b)(4) of this chapter for definition of
bullet.
(2) For sunscreen products with a Broad Spectrum SPF value of 15 or
higher according to the tests in paragraphs (i) and (j) of this section,
the labeling may include the following statement in addition to the
indication in Sec. 201.327(c)(1): ``[Bullet] if used as directed with
other sun protection measures (see Directions [in bold italic font]),
decreases the risk of skin cancer and early skin aging caused by the
sun''.
(3) Any labeling or promotional materials that suggest or imply that
the use, alone, of any sunscreen reduces the risk of or prevents skin
cancer or early skin aging will cause the product to be misbranded under
section 502 of the FD&C Act (21 U.S.C. 352).
(d) Warnings. The labeling of the product contains the following
warnings under the heading ``Warnings''.
(1) For all sunscreen products. (i) The labeling states ``Do not use
[bullet] on damaged or broken skin''.
(ii) The labeling states ``When using this product [bullet] keep out
of eyes. Rinse with water to remove.''
(iii) The labeling states ``Stop use and ask a doctor if [bullet]
rash occurs''.
(2) For sunscreen products that are broad spectrum with SPF values
of at least 2 but less than 15 according to the SPF test in paragraph
(i) of this section or that do not pass the broad spectrum test in
paragraph (j) of this section. The first statement under the heading
``Warnings'' states ``Skin Cancer/Skin Aging Alert [in bold font];
Spending time in the sun increases your risk of skin cancer and early
skin aging. This product has been shown only to help prevent sunburn,
not [in bold font] skin cancer or early skin aging.''
(e) Directions. The labeling of the product contains the following
statements, as appropriate, under the heading ``Directions.'' More
detailed directions applicable to a particular product formulation may
also be included.
(1) For all sunscreen products. (i) As an option, the labeling may
state ``For sunscreen use:''.
(ii) The labeling states ``[bullet] apply [select one of the
following: `Liberally' or `generously'] [and, as an option: `And
evenly'] 15 minutes before sun exposure''.
(iii) As an option, the labeling may state ``[bullet] apply to all
skin exposed to the sun''.
[[Page 98]]
(iv) The labeling states ``[bullet] children under 6 months of age:
Ask a doctor''.
(2) For sunscreen products with a Broad Spectrum SPF value of 15 or
higher according to the tests in paragraphs (i) and (j) of this section.
The labeling states ``[bullet] Sun Protection Measures. [in bold font]
Spending time in the sun increases your risk of skin cancer and early
skin aging. To decrease this risk, regularly use a sunscreen with a
Broad Spectrum SPF value of 15 or higher and other sun protection
measures including: [Bullet] limit time in the sun, especially from 10
a.m.-2 p.m. [bullet] wear long-sleeved shirts, pants, hats, and
sunglasses''.
(3) For products that satisfy the water resistance test in paragraph
(i)(7) of this section. The labeling states ``[bullet] reapply: [Bullet]
after [select one of the following determined by water resistance test:
`40 minutes of' or `80 minutes of'] swimming or sweating [bullet]
immediately after towel drying [bullet] at least every 2 hours''.
(4) For products that do not satisfy the water resistance test in
paragraph (i)(7) of this section. The labeling states ``[bullet] reapply
at least every 2 hours [bullet] use a water resistant sunscreen if
swimming or sweating''.
(f) Other information. The labeling of the product contains the
following statement under the heading ``Other information:'' ``[bullet]
protect the product in this container from excessive heat and direct
sun''.
(g) False and misleading claims. There are claims that would be
false and/or misleading on sunscreen products. These claims include but
are not limited to the following: ``Sunblock,'' ``sweatproof,'' and
``waterproof.'' These or similar claims will cause the product to be
misbranded under section 502 of the FD&C Act (21 U.S.C. 352).
(h) Labeling of products containing a combination of sunscreen and
skin protectant active ingredients. Statements of identity, indications,
warnings, and directions for use, respectively, applicable to each
ingredient in the product may be combined to eliminate duplicative words
or phrases so that the resulting information is clear and
understandable. Labeling provisions in Sec. 347.50(e) of this chapter
shall not apply to these products.
(i) SPF test procedure--(1) UV source (solar simulator). (i)
Emission spectrum. A single port or multiport solar simulator should be
filtered so that it provides a continuous emission spectrum from 290 to
400 nanometers (nm) with a limit of 1,500 Watts per square meter (W/
m\2\) on total irradiance for all wavelengths between 250 and 1,400 nm.
(A) The solar simulator should have the following percentage of
erythema-effective radiation in each specified range of wavelengths:
Solar Simulator Emission Spectrum
------------------------------------------------------------------------
Percent erythemal
Wavelength range (nm) contribution \1\
------------------------------------------------------------------------
<290................................................. <0.1
290-300.............................................. 1.0-8.0
290-310.............................................. 49.0-65.0
290-320.............................................. 85.0-90.0
290-330.............................................. 91.5-95.5
290-340.............................................. 94.0-97.0
290-400.............................................. 99.9-100.0
------------------------------------------------------------------------
\1\ Calculation of erythema action spectrum described in Sec.
201.327(i)(1)(ii) of this section.
(B) In addition, UVA II (320-340 nm) irradiance should equal or
exceed 20 percent of the total UV (290-400 nm) irradiance. UVA I (340-
400 nm) irradiance should equal or exceed 60 percent of the total UV
irradiance.
(ii) Erythema action spectrum. (A) Calculate the erythema action
spectrum weighting factor (Vi) at each wavelength [lambda]:
(1) Vi ([lambda]) = 1.0 (250 <[lambda] <=298 nm)
(2) Vi ([lambda]) = 10\0.094\* (\298\-[lambda])
(298 <[lambda] <=328 nm)
(3) Vi ([lambda]) = 10\0.015\* (\140\-[lambda])
(328 <[lambda] <=400 nm)
(B) Calculate the erythema-effective UV dose (E) delivered by a
solar simulator as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.002
Where Vi([lambda]) = erythema action spectrum weighting
factor at each wavelength [lambda]
I([lambda]) = irradiance (Watts per square meter) at each wavelength
[lambda]
t = exposure time (seconds)
Erythema-effective dose (E) is expressed as effective Joules per square
meter (J/m\2\-eff).
[[Page 99]]
(C) The emission spectrum must be determined using a handheld
radiometer with a response weighted to match the spectrum in ISO 17166
CIE S 007/E entitled ``Erythemal reference action spectrum and standard
erythema dose,'' dated 1999 (First edition, 1999-12-15; corrected and
reprinted 2000-11-15), which is incorporated by reference in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51. You may obtain a copy from the
ISO Copyright Office, Case Postale 56, CH-1211, Geneva 20, Switzerland,
telephone +41-22-749-01-11 or fax +41-22-74-09-47. http://www.iso.org.
You may inspect a copy at the Center for Drug Evaluation and Research,
10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993, call 301-
796-2090, or at the National Archives and Records Administration (NARA).
For information on the availability of this material at NARA, call 202-
741-6030, or go to: http://www.archives.gov/federal_register/
code_of_federal_regulations/ibr_locations.html. The solar simulator
output should be measured before and after each phototest or, at a
minimum, at the beginning and end of each test day. This radiometer
should be calibrated using side-by-side comparison with the
spectroradiometer (using the weighting factors determined according to
paragraph (i)(1)(ii)(A) of this section) at the time of the annual
spectroradiometric measurement of the solar simulator as described in
paragraph (i)(1)(iv) of this section.
(iii) Operation. A solar simulator should have no significant time-
related fluctuations (within 20 percent) in radiation emissions after an
appropriate warm-up time and demonstrate good beam uniformity (within 20
percent) in the exposure plane. The delivered dose to the UV exposure
site must be within 10 percent of the expected dose.
(iv) Periodic measurement. To ensure that the solar simulator
delivers the appropriate spectrum of UV radiation, the emission spectrum
of the solar simulator should be measured at least annually with an
appropriate and accurately calibrated spectroradiometer system (results
should be traceable to the National Institute for Standards and
Technology). In addition, the solar simulator must be recalibrated if
there is any change in the lamp bulb or the optical filtering components
(i.e., filters, mirrors, lenses, collimating devices, or focusing
devices). Daily solar simulator radiation intensity should be monitored
with a broadband radiometer with a response weighted to match the
erythema action spectrum in ISO 17166 CIE S 007/E entitled ``Erythemal
reference action spectrum and standard erythema dose,'' which is
incorporated by reference in paragraph (i)(1)(ii)(C) of this section. If
a lamp must be replaced due to failure or aging during a phototest,
broadband device readings consistent with those obtained for the
original calibrated lamp will suffice until measurements can be
performed with the spectroradiometer at the earliest possible
opportunity.
(2) SPF standard--(i) Preparation. The SPF standard should be a
formulation containing 7-percent padimate O and 3-percent oxybenzone.
Composition of the Padimate O/oxybenzone SPF Standard
------------------------------------------------------------------------
Percent by
Ingredients weight
------------------------------------------------------------------------
Part A:
Lanolin.................................................. 4.50
Cocoa butter............................................. 2.00
Glyceryl monostearate.................................... 3.00
Stearic acid............................................. 2.00
Padimate O............................................... 7.00
Oxybenzone............................................... 3.00
Part B:
Purified water USP....................................... 71.60
Sorbitol solution........................................ 5.00
Triethanolamine, 99 percent.............................. 1.00
Methylparaben............................................ 0.30
Propylparaben............................................ 0.10
Part C:
Benzyl alcohol........................................... 0.50
Part D:
Purified water USP....................................... QS \1\
------------------------------------------------------------------------
\1\ Quantity sufficient to make 100 grams.
Step 1. Add the ingredients of Part A into a suitable stainless
steel kettle equipped with a propeller agitator. Mix at 77 to 82 [deg]C
until uniform.
Step 2. Add the water of Part B into a suitable stainless steel
kettle equipped with a propeller agitator and begin mixing at 77 to 82
[deg]C. Add the remaining ingredients of Part B and mix until uniform.
Step 3. Add the batch of Step 1 to the batch of Step 2 and mix at 77
to 82 [deg]C until smooth and uniform. Slowly cool the batch to 49 to 54
[deg]C.
[[Page 100]]
Step 4. Add the benzyl alcohol of Part C to the batch of Step 3 at
49 to 54 [deg]C. Mix until uniform. Continue to cool batch to 35 to 41
[deg]C.
Step 5. Add sufficient water of Part D to the batch of Step 4 at 35
to 41 [deg]C to obtain 100 grams of SPF standard. Mix until uniform.
Cool batch to 27 to 32 [deg]C.
(ii) HPLC assay. Use the following high performance liquid
chromatography (HPLC) procedure to verify the concentrations of padimate
O and oxybenzone in the SPF standard:
(A) Instrumentation. (1) Equilibrate a suitable liquid chromatograph
to the following or equivalent conditions:
------------------------------------------------------------------------
------------------------------------------------------------------------
(i) Column................................ C-18, 250 millimeters (mm)
length, 4.6 mm inner
diameter (5 microns)
(ii) Mobile Phase......................... 85:15:0.5 methanol: water:
acetic acid
(iii) Flow Rate........................... 1.5 milliliters (mL) per
minute
(iv) Temperature.......................... Ambient
(v) Detector.............................. UV spectrophotometer at 308
nanometers
(vi) Attenuation.......................... As needed
------------------------------------------------------------------------
(2) Use HPLC grade reagents for mobile phase.
(B) Preparation of the HPLC reference standard. (1) Weigh 0.50 gram
(g) of oxybenzone USP reference standard into a 250-mL volumetric flask.
Dissolve and dilute to volume with isopropanol. Mix well.
(2) Weigh 0.50 g of padimate O USP reference standard into a 250-mL
volumetric flask. Dissolve and dilute to volume with isopropanol. Mix
well.
(3) Pipet 3.0 mL of the oxybenzone solution and 7.0 mL of the
padimate O solution into a 100-mL volumetric flask. Dilute to volume
with isopropanol and mix well.
(C) HPLC system suitability. (1) Make three replicate 10-microliter
injections of the HPLC reference standard (described in paragraph
(i)(2)(ii)(B) of this section). The relative standard deviation in peak
areas should not be more than 2.0 percent for either oxybenzone or
padimate O.
(2) Calculate the resolution (R) between the oxybenzone and padimate
O peaks from one chromatogram as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.003
Where to = retention time for oxybenzone
tp = retention time for padimate O
Wo = oxybenzone peak width at baseline
Wp = padimate O peak width at baseline
If the resolution (R) is less than 3.0, adjust the mobile phase or
replace the column.
(D) SPF standard assay--(1) The SPF standard is diluted to the same
concentration as the HPLC reference standard according to the following
steps:
(i) Step 1. Weigh 1.0 g of the SPF standard (described in paragraph
(i)(2)(i) of this section) into a 50-mL volumetric flask.
(ii) Step 2. Add approximately 30 mL of isopropanol and heat with
swirling until contents are evenly dispersed.
(iii) Step 3. Cool to room temperature (15 to 30 [deg]C) and dilute
to volume with isopropanol. Mix well.
(iv) Step 4. Pipet 5.0 mL of the preparation into a 50-mL volumetric
flask and dilute to volume with isopropanol. Mix well.
(2)(i) Inject 10-microliter of diluted SPF standard from paragraph
(i)(2)(D)(1) of this section and calculate the amount of oxybenzone and
padimate O as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.004
[[Page 101]]
(ii) The percent of oxybenzone and padimate O in the SPF standard
should be between 95 and 105.
(3) Test subjects--(i) Number of subjects. A test panel should
include enough subjects to produce a minimum of 10 valid test results. A
maximum of three subjects may be rejected from this panel based on
paragraph (i)(5)(v)) of this section.
(ii) Medical history. (A) Obtain a medical history from each subject
with emphasis on the effects of sunlight on the subject's skin.
Determine that each subject is in good general health with skin type I,
II, or III as follows:
(1) Always burns easily; never tans (sensitive).
(2) Always burns easily; tans minimally (sensitive).
(3) Burns moderately; tans gradually (light brown) (normal).
(4) Burns minimally; always tans well (moderate brown) (normal).
(5) Rarely burns; tans profusely (dark brown) (insensitive).
(6) Never burns; deeply pigmented (insensitive).
(B) Skin type is based on first 30 to 45 minutes of sun exposure
after a winter season of no sun exposure. Determine that each subject is
not taking topical or systemic medication that is known to alter
responses to UV radiation. Determine that each subject has no history of
sensitivities to topical products and/or abnormal responses to sunlight,
such as a phototoxic or photoallergic response.
(iii) Physical examination. Conduct a physical examination to
determine the presence of sunburn, suntan, scars, active dermal lesions,
and uneven skin tones on the areas of the back to be tested. A suitable
source of low power UVA, such as a Woods lamp, is helpful in this
process. If any of these conditions are present, the subject is not
qualified to participate in the study. The presence of nevi, blemishes,
or moles will be acceptable if, in the physician's judgment, they will
neither compromise the study nor jeopardize a subject's safety. Subjects
with dysplastic nevi should not be enrolled. Excess hair on the back is
acceptable if the hair is clipped. Shaving is unacceptable because it
may remove a significant portion of the stratum corneum and temporarily
alter the skin's response to UV radiation.
(iv) Informed consent. Obtain legally effective written informed
consent from all test subjects.
(4) Sunscreen application. (i) Test site. Test sites are locations
on each subject's back, between the beltline and the shoulder blades
(scapulae) and lateral to the midline, where skin responses to UV
radiation are determined. Responses on unprotected skin (no test
material applied) and protected skin (sunscreen test product(s) or SPF
standard applied) are determined at separate unprotected and protected
test sites, respectively. Test sites should be randomly located in a
blinded manner. Each test site should be a minimum of 30 square
centimeters and outlined with indelible ink.
(ii) Test subsite. Test subsites are the locations to which UV
radiation is administered within a test site. At least five test
subsites should receive UV doses within each test site. Test subsites
should be at least 0.5 square centimeters (cm\2\) in area and should be
separated from each other by at least 0.8 cm. Each test subsite should
be outlined with indelible ink.
(iii) Applying test materials. Apply the sunscreen test product and
the SPF standard at 2 milligrams per square centimeter (mg/cm\2\) to
their respective test sites. Use a finger cot compatible with the
sunscreen to spread the product as evenly as possible.
(iv) Waiting period. Wait at least 15 minutes after applying a
sunscreen product before exposing the test sites to UV radiation as
described in paragraph (i)(5)) of this section. For water resistant
sunscreen products, proceed with the water resistance testing procedure
described in paragraph (i)(7) of this section after waiting at least 15
minutes.
(5) UV exposure--(i) Definition of minimal erythema dose (MED). The
minimal erythema dose (MED) is the smallest UV dose that produces
perceptible redness of the skin (erythema) with clearly defined borders
at 16 to 24 hours after UV exposure. The MED for unprotected skin
(MEDu) is determined on a test site that does not have
sunscreen applied. The MED for protected skin (MEDp) is
determined on a test site
[[Page 102]]
that has sunscreen applied. An MEDp is determined for the SPF
standard (ssMEDp). An MEDp is determined for the
sunscreen test product (tpMEDp).
(ii) UV exposure for initial MEDu. For each test subject,
administer a series of UV radiation doses expressed as J/m\2\-eff (as
determined according to paragraph (a)(2) of this section) to the test
subsites within an unprotected test site using an accurately calibrated
solar simulator. Select doses that are a geometric series represented by
1.25\n\ (i.e., each dose is 25 percent greater than the previous dose).
(iii) UV exposure for final MEDu, ssMEDp, and
tpMEDp. For each subject, determine the final
MEDu, ssMEDp, and tpMEDp by
administering a series of five UV doses to the appropriate test sites.
The middle dose (X) in each of these dose series (i.e., the third dose)
should equal the initial MEDu times the expected SPF. Note
that the expected SPF equals 1 and 16.3 for the final MEDu
and ssMEDp, respectively. The remaining UV doses in the
series depend upon the expected SPF value of the sunscreen test
product(s).
For products with an expected SPF less than 8, administer UV doses
that increase by 25 percent with each successive dose (i.e., 0.64X,
0.80X, 1.00X, 1.25X, and 1.56X). For products with an expected SPF from
8 to 15, administer UV doses that increase by 20 percent with each
successive dose (i.e., 0.69X, 0.83X, 1.00X, 1.20X, and 1.44X). For
products with an expected SPF higher than 15, administer UV doses that
increase by 15 percent with each successive dose (i.e., 0.76X, 0.87X,
1.00X, 1.15X, and 1.32X).
(iv) Evaluation of test subsites. In order that the person who
evaluates the test subsites is not biased, he/she should not be the same
person who applied the sunscreen drug product to the test site or
administered the UV doses. After UV doses are administered, all
immediate responses should be recorded. These may include an immediate
darkening or tanning, typically grayish or purplish in color, which
fades in 30 to 60 minutes; an immediate reddening at the subsite, due to
heating of the skin, which fades rapidly; and an immediate generalized
heat response, spreading beyond the subsite, which fades in 30 to 60
minutes. After the immediate responses are noted, each subject should
shield the exposed area from further UV radiation until the MED is
determined. Determine the MED 16 to 24 hours after UV exposure. Because
erythema is evaluated 16 to 24 hours after UV exposure, the final
MEDu, ssMEDp, and tpMEDp are typically
determined the day following determination of the initial
MEDu. Evaluate the erythema responses of each test subsite
using either tungsten or warm white fluorescent lighting that provides
at least 450 lux of illumination at the test site. For the evaluation,
the test subject should be in the same position as when the test site
was irradiated.
(v) Invalid test data. Reject test data for a test subject if
erythema is not present on either the unprotected or protected test
sites; or erythema is present at all subsites; or the responses are
inconsistent with the series of UV doses administered; or the subject
was noncompliant (e.g., the subject withdraws from the test due to
illness or work conflicts or does not shield the exposed testing sites
from further UV radiation until the MED is determined).
(6) Determination of SPF. (i) Calculate an SPF value for each test
subject (SPFi) as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.005
(ii) Calculate the mean
[GRAPHIC] [TIFF OMITTED] TR17JN11.009
and the standard deviation (s) from the SPFi values.
Calculate the standard error (SE), which equals s/[radic]n (where n
equals the number of subjects who provided valid test results). Obtain
the t value from Student's t distribution table corresponding to the
upper 5-percent point with n--1 degrees of freedom. Determine the
labeled SPF value, which equals the largest whole number less than
[GRAPHIC] [TIFF OMITTED] TR17JN11.012
In order for the SPF determination of a test product to be considered
valid, the SPF value of the SPF standard
[[Page 103]]
should fall within the standard deviation range of the expected SPF
(i.e., 16.3 3.43).
(7) Determination of water resistance. The following procedure
should be performed in an indoor fresh water pool, whirlpool, and/or hot
tub maintained at 23 to 32 [deg]C. Fresh water is clean drinking water
that meets the standards in 40 CFR part 141. The pool and air
temperature and the relative humidity should be recorded.
(i) Water resistance (40 minutes). The labeled SPF should be
determined after 40 minutes of water immersion using the following
procedure:
(A) Step 1: Apply the sunscreen as described in paragraph (d) of
this section.
(B) Step 2: Perform moderate activity in water for 20 minutes.
(C) Step 3: Rest out of water for 15 minutes. Do not towel test
site(s).
(D) Step 4: Perform moderate activity in water for 20 minutes.
(E) Step 5: Allow test sites to dry completely without toweling.
(F) Step 6: Apply the SPF standard as described in paragraph (d) of
this section.
Step 1. Expose test sites to UV doses as described in paragraph (e)
of this section.
(ii) Water resistance (80 minutes). The labeled SPF should be
determined after 80 minutes of water immersion using the following
procedure:
(A) Step 1: Apply the sunscreen as described in paragraph (d) of
this section.
(B) Step 2: Perform moderate activity in water for 20 minutes.
(C) Step 3: Rest out of water for 15 minutes. Do not towel test
site(s).
(D) Step 4: Perform moderate activity in water for 20 minutes.
(E) Step 5: Rest out of water for 15 minutes. Do not towel test
site(s).
(F) Step 6: Perform moderate activity in water for 20 minutes.
(G) Step 7: Rest out of water for 15 minutes. Do not towel test
site(s).
(H) Step 8: Perform moderate activity in water for 20 minutes.
(I) Step 9: Allow test sites to dry completely without toweling.
(J) Step 10: Apply the SPF standard as described in paragraph (d) of
this section.
(K) Step 11: Expose test sites to UV doses as described in paragraph
(e) of this section.
(j) Broad spectrum test procedure--(1) UV Spectrometry. (i) Plate.
Use optical-grade polymethylmethacrylate (PMMA) plates suitable for UV
transmittance measurements. The plate should be roughened on one side to
a three dimensional surface topography measure (Sa) between 2 and 7
micrometers and must have a rectangular application area of at least 16
square centimeters (with no side shorter than 4 cm).
(ii) Sample holder. The sample holder should hold the PMMA plate in
a horizontal position to avoid flowing of the sunscreen drug product
from one edge of the PMMA plate to the other. It should be mounted as
close as possible to the input optics of the spectrometer to maximize
capture of forward scattered radiation. The sample holder should be a
thin, flat plate with a suitable aperture through which UV radiation can
pass. The PMMA plate should be placed on the upper surface of the sample
holder with the roughened side facing up.
(iii) Light source. The light source should produce a continuous
spectral distribution of UV radiation from 290 to 400 nanometers.
(iv) Input optics. Unless the spectrometer is equipped with an
integrating sphere, an ultraviolet radiation diffuser should be placed
between the sample and the input optics of the spectrometer. The
diffuser will be constructed from any UV radiation transparent material
(e.g., Teflon [supreg] or quartz). The diffuser ensures that the
radiation received by the spectrometer is not collimated. The
spectrometer input slits should be set to provide a bandwidth that is
less than or equal to 1 nanometer.
(v) Dynamic range of the spectrometer. The dynamic range of the
spectrometer should be sufficient to measure transmittance accurately
through a highly absorbing sunscreen product at all terrestrial solar UV
wavelengths (290 to 400 nm).
(2) Sunscreen product application to PMMA plate. The accuracy of the
test depends upon the application of a precisely controlled amount of
sunscreen
[[Page 104]]
product with a uniform distribution over the PMMA plate. The product is
applied at 0.75 mg per square centimeter to the roughened side of the
PMMA plate. The sunscreen product should be applied in a series of small
dots over the entire PMMA plate and then spread evenly using a gloved
finger. Spreading should be done with a very light spreading action for
approximately 30 seconds followed by spreading with greater pressure for
approximately 30 seconds. The plate should then be allowed to
equilibrate for 15 minutes in the dark before the pre-irradiation
described in paragraph (c) of this section.
(3) Sunscreen product pre-irradiation. To account for lack of
photostability, apply the sunscreen product to the PMMA plate as
described in paragraph (b) of this section and then irradiate with a
solar simulator described in section 352.70(b) of this chapter. The
irradiation dose should be 4 MEDs which is equivalent to an erythemal
effective dose of 800 J/m\2\ (i.e., 800 J/m\2\-eff).
(4) Calculation of mean transmittance values. After pre-irradiation
described in paragraph (c) of this section, mean transmittance values
should be determined for each wavelength [lambda] over the full UV
spectrum (290 to 400 nanometers). The transmittance values should be
measured at 1 nanometer intervals. Measurements of spectral irradiance
transmitted for each wavelength [lambda] through control PMMA plates
coated with 15 microliters of glycerin (no sunscreen product) should be
obtained from at least 5 different locations on the PMMA plate
[C1([lambda]), C2([lambda]), C3([lambda]), C4([lambda]), and
C5([lambda])]. In addition, a minimum of 5 measurements of spectral
irradiance transmitted for each wavelength [lambda] through the PMMA
plate covered with the sunscreen product will be similarly obtained
after pre-irradiation of the sunscreen product [P1([lambda]),
P2([lambda]), P3([lambda]), P4([lambda]), and P5([lambda])].
The mean transmittance for each wavelength,
[GRAPHIC] [TIFF OMITTED] TR17JN11.010
is the ratio of the mean of the C([lambda]) values to the mean of the
P([lambda]) values, as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.006
Where n =5
(5) Calculation of mean absorbance values. (i) Mean transmittance
values,
[GRAPHIC] [TIFF OMITTED] TR17JN11.010
are converted into mean absorbance values,
[GRAPHIC] [TIFF OMITTED] TR17JN11.011
at each wavelength by taking the negative logarithm of the mean
transmittance value as follows:
[GRAPHIC] [TIFF OMITTED] TR17JN11.008
(ii) The calculation yields 111 monochromatic absorbance values in 1
nanometer increments from 290 to 400 nanometers.
(6) Number of plates. For each sunscreen product, mean absorbance
values should be determined from at least three individual PMMA plates.
Because paragraph (d) of this section requires at least 5 measurements
per plate, there should be a total of at least 15 measurements.
(7) Calculation of the critical wavelength. The critical wavelength
is identified as the wavelength at which the integral of the spectral
absorbance curve reaches 90 percent of the integral over the UV spectrum
from 290 to 400 nm. The following equation defines the critical
wavelength:
[GRAPHIC] [TIFF OMITTED] TR17JN11.007
Where [lambda]c = critical wavelength
A([lambda]) = mean absorbance at each wavelength
d[lambda] = wavelength interval between measurements
A mean critical wavelength of 370 nm or greater is classified as broad
spectrum protection.
[76 FR 35660, June 17, 2011, as amended at 76 FR 38975, July 5, 2011]
[[Page 105]]
Sec. 201.328 Labeling of medical gas containers.
(a) Portable cryogenic medical gas containers. For the purposes of
this section a ``portable cryogenic medical gas container'' is one that
is capable of being transported and is intended to be attached to a
medical gas supply system within a hospital, health care entity, nursing
home, other facility, or home health care setting, or is a base unit
used to fill small cryogenic gas containers for use by individual
patients. The term does not include cryogenic containers that are not
designed to be connected to a medical gas supply system, e.g., tank
trucks, trailers, rail cars, or small cryogenic gas containers for use
by individual patients (including portable liquid oxygen units as
defined at Sec. 868.5655 of this chapter).
(1) Each portable cryogenic medical gas container must be
conspicuously marked with a 360[deg] wraparound label identifying its
contents. Such label must meet the requirements of Sec. 211.94(e)(2) of
this chapter and the following additional requirements.
(i) If the container holds a single gas, the name of the gas held in
the container must be printed on the label in one of the following ways:
(A) Using lettering that appears in the color designated for the gas
in paragraph (c) of this section and that is printed against a white
background, or
(B) Using lettering that appears in white against a background that
is painted in the color for the gas designated in paragraph (c) of this
section.
(ii) The lettering for the name of the gas on the label must be at
least 2 inches high.
(iii) The name of the gas must be printed continuously around the
label and be capable of being read around the entire container.
(iv) The label must be on the sidewall of the container, as close to
the top of the container as possible but below the top weld seam.
(v) A portable cryogenic medical gas container may only be colored
in the color or colors designated in paragraph (c) of this section if
the gas or gases held within the container correspond to that color or
those colors.
(2) A label on the container (either the 360[deg] wraparound label
required in paragraph (a)(1) of this section or a separate label) must
include, in conspicuous lettering, the phrase ``For Medical Use'',
``Medical Gas,'' or some similar phrase that indicates the gas is for
medical use.
(b) High-pressure medical gas cylinders. Each high-pressure medical
gas cylinder must be colored on the shoulder portion of the cylinder in
the color or colors designated in paragraph (c) of this section. The
color or colors must be visible when viewed from the top of cylinder.
(c) Medical gas colors. The colors required to identify medical
gases under paragraph (a) and (b) of this section are:
------------------------------------------------------------------------
Medical gas Color
------------------------------------------------------------------------
Medical Air............................... Yellow.
Carbon Dioxide............................ Gray.
Helium.................................... Brown.
Nitrogen.................................. Black.
Nitrous Oxide............................. Blue.
Oxygen.................................... Green.
Mixture or Blend.......................... Colors corresponding to each
component gas.
------------------------------------------------------------------------
[81 FR 81696, Nov. 18, 2016]
Sec. 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.
[[Page 106]]
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.
III. Examples of Sec. 201.66 Standard Labeling and Modified Labeling
Formats
[[Page 107]]
A. Section 201.66 Standard Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.007
B. Section 201.66 Modified Labeling Format
[GRAPHIC] [TIFF OMITTED] TR17MR99.008
PART 202_PRESCRIPTION DRUG ADVERTISING--Table of Contents
Authority: 21 U.S.C. 321, 331, 352, 355, 360b, 371.
Sec. 202.1 Prescription-drug advertisements.
(a)(1) The ingredient information required by section 502(n) of the
Federal Food, Drug, and Cosmetic Act shall appear together, without any
intervening
[[Page 108]]
written, printed, or graphic matter, except the proprietary names of
ingredients, which may be included with the listing of established
names.
(2) The order of listing of ingredients in the advertisement shall
be the same as the order of listing of ingredients on the label of the
product, and the information presented in the advertisement concerning
the quantity of each such ingredient shall be the same as the
corresponding information on the label of the product.
(3) The advertisement shall not employ a fanciful proprietary name
for the drug or any ingredient in such a manner as to imply that the
drug or ingredient has some unique effectiveness or composition, when,
in fact, the drug or ingredient is a common substance, the limitations
of which are readily recognized when the drug or ingredient is listed by
its established name.
(4) The advertisement shall not feature inert or inactive
ingredients in a manner that creates an impression of value greater than
their true functional role in the formulation.
(5) The advertisement shall not designate a drug or ingredient by a
proprietary name that, because of similarity in spelling or
pronunciation, may be confused with the proprietary name or the
established name of a different drug or ingredient.
(b)(1) If an advertisement for a prescription drug bears a
proprietary name or designation for the drug or any ingredient thereof,
the established name, if such there be, corresponding to such
proprietary name or designation shall accompany such proprietary name or
designation each time it is featured in the advertisement for the drug;
but, except as provided below in this subparagraph, the established name
need not be used with the proprietary name or designation in the running
text of the advertisement. On any page of an advertisement in which the
proprietary name or designation is not featured but is used in the
running text, the established name shall be used at least once in the
running text in association with such proprietary name or designation
and in the same type size used in the running text: Provided, however,
That if the proprietary name or designation is used in the running text
in larger size type, the established name shall be used at least once in
association with, and in type at least half as large as the type used
for, the most prominent presentation of the proprietary name or
designation in such running text. If any advertisement includes a column
with running text containing detailed information as to composition,
prescribing, side effects, or contraindications and the proprietary name
or designation is used in such column but is not featured above or below
the column, the established name shall be used at least once in such
column of running text in association with such proprietary name or
designation and in the same type size used in such column of running
text: Provided, however, That if the proprietary name or designation is
used in such column of running text in larger size type, the established
name shall be used at least once in association with, and in type at
least half as large as the type used for, the most prominent
presentation of the proprietary name or designation in such column of
running text. Where the established name is required to accompany or to
be used in association with the proprietary name or designation, the
established name shall be placed in direct conjunction with the
proprietary name or designation, and the relationship between the
proprietary name or designation and the established name shall be made
clear by use of a phrase such as ``brand of'' preceding the established
name, by brackets surrounding the established name, or by other suitable
means.
(2) The established name shall be printed in letters that are at
least half as large as the letters comprising the proprietary name or
designation with which it is joined, and the established name shall have
a prominence commensurate with the prominence with which such
proprietary name or designation appears, taking into account all
pertinent factors, including typography, layout, contrast, and other
printing features.
(c) In the case of a prescription drug containing two or more active
ingredients, if the advertisement bears a proprietary name or
designation for such mixture and there is no established
[[Page 109]]
name corresponding to such proprietary name or designation, the
quantitative ingredient information required in the advertisement by
section 502(n) of the act shall be placed in direct conjunction with the
most prominent display of the proprietary name or designation. The
prominence of the quantitative ingredient information shall bear a
reasonable relationship to the prominence of the proprietary name.
(d)(1) If the advertisement employs one proprietary name or
designation to refer to a combination of active ingredients present in
more than one preparation (the individual preparations differing from
each other as to quantities of active ingredients and/or the form of the
finished preparation) and there is no established name corresponding to
such proprietary name or designation, a listing showing the established
names of the active ingredients shall be placed in direct conjunction
with the most prominent display of such proprietary name or designation.
The prominence of this listing of active ingredients shall bear a
reasonable relationship to the prominence of the proprietary name and
the relationship between such proprietary name or designation, and the
listing of active ingredients shall be made clear by use of such phrase
as ``brand of'', preceding the listing of active ingredients.
(2) The advertisement shall prominently display the name of at least
one specific dosage form and shall have the quantitative ingredient
information required by section 502(n) of the act in direct conjunction
with such display. If other dosage forms are listed in the
advertisement, the quantitative ingredient information for such dosage
forms shall appear in direct conjunction and in equal prominence with
the most prominent listing of the names of such dosage forms.
(e) True statement of information in brief summary relating to side
effects, contraindications, and effectiveness:
(1) When required. All advertisements for any prescription drug
(``prescription drug'' as used in this section means drugs defined in
section 503(b)(1) of the act and Sec. 201.105, applicable to drugs for
use by man and veterinary drugs, respectively), except advertisements
described in paragraph (e)(2) of this section, shall present a true
statement of information in brief summary relating to side effects,
contraindications (when used in this section ``side effects,
contraindications'' include side effects, warnings, precautions, and
contraindications and include any such information under such headings
as cautions, special considerations, important notes, etc.) and
effectiveness. Advertisements broadcast through media such as radio,
television, or telephone communications systems shall include
information relating to the major side effects and contraindications of
the advertised drugs in the audio or audio and visual parts of the
presentation and unless adequate provision is made for dissemination of
the approved or permitted package labeling in connection with the
broadcast presentation shall contain a brief summary of all necessary
information related to side effects and contraindications.
(2) Exempt advertisements. The following advertisements are exempt
from the requirements of paragraph (e)(1) of this section under the
conditions specified:
(i) Reminder advertisements. Reminder advertisements are those which
call attention to the name of the drug product but do not include
indications or dosage recommendations for use of the drug product. These
reminder advertisements shall contain only the proprietary name of the
drug product, if any; the established name of the drug product, if any;
the established name of each active ingredient in the drug product; and,
optionally, information relating to quantitative ingredient statements,
dosage form, quantity of package contents, price, the name and address
of the manufacturer, packer, or distributor or other written, printed,
or graphic matter containing no representation or suggestion relating to
the advertised drug product. If the Commissioner finds that there is
evidence of significant incidence of fatalities or serious injury
associated with the use of a particular prescription drug, he may
withdraw this exemption by so notifying the manufacturer, packer, or
distributor of the drug by letter. Reminder advertisements, other than
those solely intended to convey
[[Page 110]]
price information including, but not limited to, those subject to the
requirements of Sec. 200.200 of this chapter, are not permitted for a
prescription drug product whose labeling contains a boxed warning
relating to a serious hazard associated with the use of the drug
product. Reminder advertisements which are intended to provide consumers
with information concerning the price charged for a prescription for a
drug product are exempt from the requirements of this section if they
meet all of the conditions contained in Sec. 200.200 of this chapter.
Reminder advertisements, other than those subject to the requirements of
Sec. 200.200 of this chapter, are not permitted for a drug for which an
announcement has been published pursuant to a review on the labeling
claims for the drug by the National Academy of Sciences/National
Research Council (NAS/NRC), Drug Efficacy Study Group, and for which no
claim has been evaluated as higher than ``possibly effective.'' If the
Commissioner finds the circumstances are such that a reminder
advertisement may be misleading to prescribers of drugs subject to NAS/
NRC evaluation, such advertisements will not be allowed and the
manufacturer, packer, or distributor will be notified either in the
publication of the conclusions on the effectiveness of the drug or by
letter.
(ii) Advertisements of bulk-sale drugs. Advertisements of bulk-sale
drugs that promote sale of the drug in bulk packages in accordance with
the practice of the trade solely to be processed, manufactured, labeled,
or repackaged in substantial quantities and that contain no claims for
the therapeutic safety or effectiveness of the drug.
(iii) Advertisements of prescription-compounding drugs.
Advertisements of prescription-compounding drugs that promote sale of a
drug for use as a prescription chemical or other compound for use by
registered pharmacists in compounding prescriptions if the drug
otherwise complies with the conditions for the labeling exemption
contained in Sec. 201.120 and the advertisement contains no claims for
the therapeutic safety or effectiveness of the drug.
(3) Scope of information to be included; applicability to the entire
advertisement. (i) The requirement of a true statement of information
relating to side effects, contraindications, and effectiveness applies
to the entire advertisement. Untrue or misleading information in any
part of the advertisement will not be corrected by the inclusion in
another distinct part of the advertisement of a brief statement
containing true information relating to side effects, contraindications,
and effectiveness of the drug. If any part or theme of the advertisement
would make the advertisement false or misleading by reason of the
omission of appropriate qualification or pertinent information, that
part or theme shall include the appropriate qualification or pertinent
information, which may be concise if it is supplemented by a prominent
reference on each page to the presence and location elsewhere in the
advertisement of a more complete discussion of such qualification or
information.
(ii) The information relating to effectiveness is not required to
include information relating to all purposes for which the drug is
intended but may optionally be limited to a true statement of the
effectiveness of the drug for the selected purpose(s) for which the drug
is recommended or suggested in the advertisement. The information
relating to effectiveness shall include specific indications for use of
the drug for purposes claimed in the advertisement; for example, when an
advertisement contains a broad claim that a drug is an antibacterial
agent, the advertisement shall name a type or types of infections and
microorganisms for which the drug is effective clinically as
specifically as required, approved, or permitted in the drug package
labeling.
(iii) The information relating to side effects and contraindications
shall disclose each specific side effect and contraindication (which
include side effects, warnings, precautions, and contraindications and
include any such information under such headings as cautions, special
considerations, important notes, etc.; see paragraph (e)(1) of this
section) contained in required, approved, or permitted labeling for the
advertised drug dosage form(s): Provided, however,
(a) The side effects and contraindications disclosed may be limited
to those
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pertinent to the indications for which the drug is recommended or
suggested in the advertisement to the extent that such limited
disclosure has previously been approved or permitted in drug labeling
conforming to the provisions of Sec. Sec. 201.100 or 201.105; and
(b) The use of a single term for a group of side effects and
contraindications (for example, ``blood dyscrasias'' for disclosure of
``leukopenia,'' ``agranulocytosis,'' and ``neutropenia'') is permitted
only to the extent that the use of such a single term in place of
disclosure of each specific side effect and contraindication has been
previously approved or permitted in drug labeling conforming to the
provisions of Sec. Sec. 201.100 or 201.105.
(4) Substance of information to be included in brief summary. (i)(a)
An advertisement for a prescription drug covered by a new-drug
application approved pursuant to section 505 of the act after October
10, 1962, or a prescription drug covered by a new animal drug
application approved pursuant to section 512 of the act after August 1,
1969, or any approved supplement thereto, or for a prescription drug
listed in the index pursuant to section 572 of the act, or any granted
modification thereto, shall not recommend or suggest any use that is not
in the labeling accepted in such approved new-drug application or
supplement, new animal drug application or supplement, or new animal
drug index listing or modification. The advertisement shall present
information from labeling required, approved, permitted, or granted in a
new-drug or new animal drug application or new animal drug index listing
relating to each specific side effect and contraindication in such
labeling that relates to the uses of the advertised drug dosage form(s)
or shall otherwise conform to the provisions of paragraph (e)(3)(iii) of
this section.
(b) If a prescription drug was covered by a new-drug application or
a supplement thereto that became effective prior to October 10, 1962, an
advertisement may recommend or suggest:
(1) Uses contained in the labeling accepted in such new-drug
application and any effective, approved, or permitted supplement
thereto.
(2) Additional uses contained in labeling in commercial use on
October 9, 1962, to the extent that such uses did not cause the drug to
be an unapproved ``new drug'' as ``new drug'' was defined in section
201(p) of the act as then in force, and to the extent that such uses
would be permitted were the drug subject to paragraph (e)(4)(iii) of
this section.
(3) Additional uses contained in labeling in current commercial use
to the extent that such uses do not cause the drug to be an unapproved
``new drug'' as defined in section 201(p) of the act as amended or a
``new animal drug'' as defined in section 201(v) of the act as amended.
The advertisement shall present information from labeling required,
approved, or permitted in a new-drug application relating to each
specific side effect and contraindication in such labeling that relates
to the uses of the advertised drug dosage form(s) or shall otherwise
conform to the provisions of paragraph (e)(3)(iii) of this section.
(ii) In the case of an advertisement for a prescription drug other
than a drug the labeling of which causes it to be an unapproved ``new
drug'' and other than drugs covered by paragraph (e)(4)(i) of this
section, an advertisement may recommend and suggest the drug only for
those uses contained in the labeling thereof:
(a) For which the drug is generally recognized as safe and effective
among experts qualified by scientific training and experience to
evaluate the safety and effectiveness of such drugs; or
(b) For which there exists substantial evidence of safety and
effectiveness, consisting of adequate and well-controlled
investigations, including clinical investigations (as used in this
section ``clinical investigations,'' ``clinical experience,'' and
``clinical significance'' mean in the case of drugs intended for
administration to man, investigations, experience, or significance in
humans, and in the case of drugs intended for administration to other
animals, investigations, experience, or significance in the specie or
species for which the drug is advertised), by experts qualified by
scientific training and experience to evaluate the
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safety and effectiveness of the drug involved, on the basis of which it
can fairly and responsibly be concluded by such experts that the drug is
safe and effective for such uses; or
(c) For which there exists substantial clinical experience (as used
in this section this means substantial clinical experience adequately
documented in medical literature or by other data (to be supplied to the
Food and Drug Administration, if requested)), on the basis of which it
can fairly and responsibly be concluded by qualified experts that the
drug is safe and effective for such uses; or
(d) For which safety is supported under any of the preceding clauses
in paragraphs (e)(4)(iii) (a), (b), and (c) of this section and
effectiveness is supported under any other of such clauses.
The advertisement shall present information relating to each specific
side effect and contraindication that is required, approved, or
permitted in the package labeling by Sec. Sec. 201.100 or 201.105 of
this chapter of the drug dosage form(s) or shall otherwise conform to
the provisions of paragraph (e)(3)(iii) of this section.
(5) ``True statement'' of information. An advertisement does not
satisfy the requirement that it present a ``true statement'' of
information in brief summary relating to side effects,
contraindications, and effectiveness if:
(i) It is false or misleading with respect to side effects,
contraindications, or effectiveness; or
(ii) It fails to present a fair balance between information relating
to side effects and contraindications and information relating to
effectiveness of the drug in that the information relating to
effectiveness is presented in greater scope, depth, or detail than is
required by section 502(n) of the act and this information is not fairly
balanced by a presentation of a summary of true information relating to
side effects and contraindications of the drug; Provided, however, That
no advertisement shall be considered to be in violation of this section
if the presentation of true information relating to side effects and
contraindications is comparable in depth and detail with the claims for
effectiveness or safety.
(iii) It fails to reveal facts material in the light of its
representations or material with respect to consequences that may result
from the use of the drug as recommended or suggested in the
advertisement.
(6) Advertisements that are false, lacking in fair balance, or
otherwise misleading. An advertisement for a prescription drug is false,
lacking in fair balance, or otherwise misleading, or otherwise violative
of section 502(n) of the act, among other reasons, if it:
(i) Contains a representation or suggestion, not approved or
permitted for use in the labeling, that a drug is better, more
effective, useful in a broader range of conditions or patients (as used
in this section patients means humans and in the case of veterinary
drugs, other animals), safer, has fewer, or less incidence of, or less
serious side effects or contraindications than has been demonstrated by
substantial evidence or substantial clinical experience (as described in
paragraphs (e)(4)(ii) (b) and (c) of this section) whether or not such
representations are made by comparison with other drugs or treatments,
and whether or not such a representation or suggestion is made directly
or through use of published or unpublished literature, quotations, or
other references.
(ii) Contains a drug comparison that represents or suggests that a
drug is safer or more effective than another drug in some particular
when it has not been demonstrated to be safer or more effective in such
particular by substantial evidence or substantial clinical experience.
(iii) Contains favorable information or opinions about a drug
previously regarded as valid but which have been rendered invalid by
contrary and more credible recent information, or contains literature
references or quotations that are significantly more favorable to the
drug than has been demonstrated by substantial evidence or substantial
clinical experience.
(iv) Contains a representation or suggestion that a drug is safer
than it has been demonstrated to be by substantial evidence or
substantial clinical experience, by selective presentation of
information from published articles or other references that report no
side effects or
[[Page 113]]
minimal side effects with the drug or otherwise selects information from
any source in a way that makes a drug appear to be safer than has been
demonstrated.
(v) Presents information from a study in a way that implies that the
study represents larger or more general experience with the drug than it
actually does.
(vi) Contains references to literature or studies that misrepresent
the effectiveness of a drug by failure to disclose that claimed results
may be due to concomitant therapy, or by failure to disclose the
credible information available concerning the extent to which claimed
results may be due to placebo effect (information concerning placebo
effect is not required unless the advertisement promotes the drug for
use by man).
(vii) Contains favorable data or conclusions from nonclinical
studies of a drug, such as in laboratory animals or in vitro, in a way
that suggests they have clinical significance when in fact no such
clinical significance has been demonstrated.
(viii) Uses a statement by a recognized authority that is apparently
favorable about a drug but fails to refer to concurrent or more recent
unfavorable data or statements from the same authority on the same
subject or subjects.
(ix) Uses a quote or paraphrase out of context to convey a false or
misleading idea.
(x) Uses literature, quotations, or references that purport to
support an advertising claim but in fact do not support the claim or
have relevance to the claim.
(xi) Uses literature, quotations, or references for the purpose of
recommending or suggesting conditions of drug use that are not approved
or permitted in the drug package labeling.
(xii) Offers a combination of drugs for the treatment of patients
suffering from a condition amenable to treatment by any of the
components rather than limiting the indications for use to patients for
whom concomitant therapy as provided by the fixed combination drug is
indicated, unless such condition is included in the uses permitted under
paragraph (e)(4) of this section.
(xiii) Uses a study on normal individuals without disclosing that
the subjects were normal, unless the drug is intended for use on normal
individuals.
(xiv) Uses ``statistics'' on numbers of patients, or counts of
favorable results or side effects, derived from pooling data from
various insignificant or dissimilar studies in a way that suggests
either that such ``statistics'' are valid if they are not or that they
are derived from large or significant studies supporting favorable
conclusions when such is not the case.
(xv) Uses erroneously a statistical finding of ``no significant
difference'' to claim clinical equivalence or to deny or conceal the
potential existence of a real clinical difference.
(xvi) Uses statements or representations that a drug differs from or
does not contain a named drug or category of drugs, or that it has a
greater potency per unit of weight, in a way that suggests falsely or
misleadingly or without substantial evidence or substantial clinical
experience that the advertised drug is safer or more effective than such
other drug or drugs.
(xvii) Uses data favorable to a drug derived from patients treated
with dosages different from those recommended in approved or permitted
labeling if the drug advertised is subject to section 505 of the act,
or, in the case of other drugs, if the dosages employed were different
from those recommended in the labeling and generally recognized as safe
and effective. This provision is not intended to prevent citation of
reports of studies that include some patients treated with dosages
different from those authorized, if the results in such patients are not
used.
(xviii) Uses headline, subheadline, or pictorial or other graphic
matter in a way that is misleading.
(xix) Represents or suggests that drug dosages properly recommended
for use in the treatment of certain classes of patients or disease
conditions are safe and effective for the treatment of other classes of
patients or disease conditions when such is not the case.
(xx) Presents required information relating to side effects or
contraindications by means of a general term for a group in place of
disclosing each specific side effect and contraindication
[[Page 114]]
(for example employs the term blood dyscrasias instead of
``leukopenia,'' ``agranulocytosis,'' ``neutropenia,'' etc.) unless the
use of such general term conforms to the provisions of paragraph
(e)(3)(iii) of this section.
Provided, however, That any provision of this paragraph shall be waived
with respect to a specified advertisement as set forth in a written
communication from the Food and Drug Administration on a petition for
such a waiver from a person who would be adversely affected by the
enforcement of such provision on the basis of a showing that the
advertisement is not false, lacking in fair balance, or otherwise
misleading, or otherwise violative of section 502(n) of the act. A
petition for such a waiver shall set forth clearly and concisely the
petitioner's interest in the advertisement, the specific provision of
this paragraph from which a waiver is sought, a complete copy of the
advertisement, and a showing that the advertisement is not false,
lacking in fair balance, or otherwise misleading, or otherwise violative
of section 502(n) of the act.
(7) Advertisements that may be false, lacking in fair balance, or
otherwise misleading. An advertisement may be false, lacking in fair
balance, or otherwise misleading or otherwise violative of section
502(n) of the act if it:
(i) Contains favorable information or conclusions from a study that
is inadequate in design, scope, or conduct to furnish significant
support for such information or conclusions.
(ii) Uses the concept of ``statistical significance'' to support a
claim that has not been demonstrated to have clinical significance or
validity, or fails to reveal the range of variations around the quoted
average results.
(iii) Uses statistical analyses and techniques on a retrospective
basis to discover and cite findings not soundly supported by the study,
or to suggest scientific validity and rigor for data from studies the
design or protocol of which are not amenable to formal statistical
evaluations.
(iv) Uses tables or graphs to distort or misrepresent the
relationships, trends, differences, or changes among the variables or
products studied; for example, by failing to label abscissa and ordinate
so that the graph creates a misleading impression.
(v) Uses reports or statements represented to be statistical
analyses, interpretations, or evaluations that are inconsistent with or
violate the established principles of statistical theory, methodology,
applied practice, and inference, or that are derived from clinical
studies the design, data, or conduct of which substantially invalidate
the application of statistical analyses, interpretations, or
evaluations.
(vi) Contains claims concerning the mechanism or site of drug action
that are not generally regarded as established by scientific evidence by
experts qualified by scientific training and experience without
disclosing that the claims are not established and the limitations of
the supporting evidence.
(vii) Fails to provide sufficient emphasis for the information
relating to side effects and contraindications, when such information is
contained in a distinct part of an advertisement, because of repetition
or other emphasis in that part of the advertisement of claims for
effectiveness or safety of the drug.
(viii) Fails to present information relating to side effects and
contraindications with a prominence and readability reasonably
comparable with the presentation of information relating to
effectiveness of the drug, taking into account all implementing factors
such as typography, layout, contrast, headlines, paragraphing, white
space, and any other techniques apt to achieve emphasis.
(ix) Fails to provide adequate emphasis (for example, by the use of
color scheme, borders, headlines, or copy that extends across the
gutter) for the fact that two facing pages are part of the same
advertisement when one page contains information relating to side
effects and contraindications.
(x) In an advertisement promoting use of the drug in a selected
class of patients (for example, geriatric patients or depressed
patients), fails to present with adequate emphasis the significant side
effects and contraindications or the significant dosage considerations,
when dosage recommendations are included in an advertisement, especially
[[Page 115]]
applicable to that selected class of patients.
(xi) Fails to present on a page facing another page (or on another
full page) of an advertisement on more than one page, information
relating to side effects and contraindications when such information is
in a distinct part of the advertisement.
(xii) Fails to include on each page or spread of an advertisement
the information relating to side effects and contraindications or a
prominent reference to its presence and location when it is presented as
a distinct part of an advertisement.
(xiii) Contains information from published or unpublished reports or
opinions falsely or misleadingly represented or suggested to be
authentic or authoritative.
(f)-(i) [Reserved]
(j)(1) No advertisement concerning a particular prescription drug
may be disseminated without prior approval by the Food and Drug
Administration if:
(i) The sponsor or the Food and Drug Administration has received
information that has not been widely publicized in medical literature
that the use of the drug may cause fatalities or serious damage;
(ii) The Commissioner (or in his absence the officer acting as
Commissioner), after evaluating the reliability of such information, has
notified the sponsor that the information must be a part of the
advertisements for the drug; and
(iii) The sponsor has failed within a reasonable time as specified
in such notification to present to the Food and Drug Administration a
program, adequate in light of the nature of the information, for
assuring that such information will be publicized promptly and
adequately to the medical profession in subsequent advertisements.
If the Commissioner finds that the program presented is not being
followed, he will notify the sponsor that prior approval of all
advertisements for the particular drug will be required. Nothing in this
paragraph is to be construed as limiting the Commissioner's or the
Secretary's rights, as authorized by law, to issue publicity, to suspend
any new-drug application, to decertify any antibiotic, or to recommend
any regulatory action.
(2) Within a reasonable time after information concerning the
possibility that a drug may cause fatalities or serious damage has been
widely publicized in medical literature, the Food and Drug
Administration shall notify the sponsor of the drug by mail that prior
approval of advertisements for the drug is no longer necessary.
(3) Dissemination of an advertisement not in compliance with this
paragraph shall be deemed to be an act that causes the drug to be
misbranded under section 502(n) of the act.
(4) Any advertisement may be submitted to the Food and Drug
Administration prior to publication for comment. If the advertiser is
notified that the submitted advertisement is not in violation and, at
some subsequent time, the Food and Drug Administration changes its
opinion, the advertiser will be so notified and will be given a
reasonable time for correction before any regulatory action is taken
under this section. Notification to the advertiser that a proposed
advertisement is or is not considered to be in violation shall be in
written form.
(5) The sponsor shall have an opportunity for a regulatory hearing
before the Food and Drug Administration pursuant to part 16 of this
chapter with respect to any determination that prior approval is
required for advertisements concerning a particular prescription drug,
or that a particular advertisement is not approvable.
(k) An advertisement issued or caused to be issued by the
manufacturer, packer, or distributor of the drug promoted by the
advertisement and which is not in compliance with section 502(n) of the
act and the applicable regulations thereunder shall cause stocks of such
drug in possession of the person responsible for issuing or causing the
issuance of the advertisement, and stocks of the drug distributed by
such person and still in the channels of commerce, to be misbranded
under section 502(n) of the act.
(l)(1) Advertisements subject to section 502(n) of the act include
advertisements in published journals, magazines, other periodicals, and
newspapers, and advertisements broadcast
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through media such as radio, television, and telephone communication
systems.
(2) Brochures, booklets, mailing pieces, detailing pieces, file
cards, bulletins, calendars, price lists, catalogs, house organs,
letters, motion picture films, film strips, lantern slides, sound
recordings, exhibits, literature, and reprints and similar pieces of
printed, audio, or visual matter descriptive of a drug and references
published (for example, the ``Physicians Desk Reference'') for use by
medical practitioners, pharmacists, or nurses, containing drug
information supplied by the manufacturer, packer, or distributor of the
drug and which are disseminated by or on behalf of its manufacturer,
packer, or distributor are hereby determined to be labeling as defined
in section 201(m) of the act.
[40 FR 14016, Mar. 27, 1975, as amended at 40 FR 58799, Dec. 18, 1975;
41 FR 48266, Nov. 2, 1976; 42 FR 15674, Mar. 22, 1977; 60 FR 38480, July
27, 1995; 72 FR 69119, Dec. 6, 2007]
Effective Date Note: At 44 FR 37467, June 26, 1979, Sec.
202.1(e)(6) (ii) and (vii) were revised. At 44 FR 74817, Dec. 18, 1979,
paragraphs (e)(6) (ii) and (vii) were stayed indefinitely. At 64 FR 400,
Jan. 5, 1999, these paragraphs were amended. For the convenience of the
user, paragraphs (e)(6) (ii) and (vii), published at 44 FR 37467, are
set forth below:
Sec. 202.1 Prescription-drug advertisements.
* * * * *
(e) * * *
(6) * * *
(ii) Represents or suggests that a prescription drug is safer or
more effective than another drug in some particular when the difference
has not been demonstrated by substantial evidence. An advertisement for
a prescription drug may not, either directly or by implication, e.g., by
use of comparative test data or reference to published reports,
represent that the drug is safer or more effective than another drug,
nor may an advertisement contain a quantitative statement of safety or
effectiveness (a) unless the representation has been approved as part of
the labeling in a new drug application or biologic license, or (b) if
the drug is not a new drug or biologic, unless the representation of
safety or effectiveness is supported by substantial evidence derived
from adequate and well-controlled studies as defined in Sec.
314.111(a)(5)(ii) of this chapter, or unless the requirement for
adequate and well-controlled studies is waived as provided in Sec.
314.111(a)(5)(ii) of this chapter.
* * * * *
(vii) Suggests, on the basis of favorable data or conclusions from
nonclinical studies of a prescription drug, such as studies in
laboratory animals or in vitro, that the studies have clinical
significance, if clinical significance has not been demonstrated. Data
that demonstrate activity or effectiveness for a prescription drug in
animal or in vitro tests and have not been shown by adequate and well-
controlled clinical studies to pertain to clinical use may be used in
advertising except that (a), in the case of anti-infective drugs, in
vitro data may be included in the advertisement, if data are immediately
preceded by the statement ``The following in vitro data are available
but their clinical significance is unknown'' and (b), in the case of
other drug classes, in vitro and animal data that have not been shown to
pertain to clinical use by adequate and well-controlled clinical studies
as defined in Sec. 314.111(a)(5)(ii) of this chapter may not be used
unless the requirement for adequate and well-controlled studies is
waived as provided in Sec. 314.111(a)(5)(ii) of this chapter.
* * * * *
PART 203_PRESCRIPTION DRUG MARKETING--Table of Contents
Subpart A_General Provisions
Sec.
203.1 Scope.
203.2 Purpose.
203.3 Definitions.
Subpart B_Reimportation
203.10 Restrictions on reimportation.
203.11 Applications for reimportation to provide emergency medical care.
203.12 An appeal from an adverse decision by the district office.
Subpart C_Sales Restrictions
203.20 Sales restrictions.
203.22 Exclusions.
203.23 Returns.
Subpart D_Samples
203.30 Sample distribution by mail or common carrier.
203.31 Sample distribution by means other than mail or common carrier
(direct delivery by a representative or detailer).
203.32 Drug sample storage and handling requirements.
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203.33 Drug sample forms.
203.34 Policies and procedures; administrative systems.
203.35 Standing requests.
203.36 Fulfillment houses, shipping and mailing services, comarketing
agreements, and third-party recordkeeping.
203.37 Investigation and notification requirements.
203.38 Sample lot or control numbers; labeling of sample units.
203.39 Donation of drug samples to charitable institutions.
Subpart E_Wholesale Distribution
203.50 Requirements for wholesale distribution of prescription drugs.
Subpart F_Request and Receipt Forms, Reports, and Records
203.60 Request and receipt forms, reports, and records.
Subpart G_Rewards
203.70 Application for a reward.
Authority: 21 U.S.C. 331, 333, 351, 352, 353, 360, 371, 374, 381.
Source: 64 FR 67756, Dec. 3, 1999, unless otherwise noted.
Subpart A_General Provisions
Sec. 203.1 Scope.
This part sets forth procedures and requirements pertaining to the
reimportation and wholesale distribution of prescription drugs,
including both bulk drug substances and finished dosage forms; the sale,
purchase, or trade of (or the offer to sell, purchase, or trade)
prescription drugs, including bulk drug substances, that were purchased
by hospitals or health care entities, or donated to charitable
organizations; and the distribution of prescription drug samples. Blood
and blood components intended for transfusion are excluded from the
restrictions in and the requirements of the Prescription Drug Marketing
Act of 1987 and the Prescription Drug Amendments of 1992.
Sec. 203.2 Purpose.
The purpose of this part is to implement the Prescription Drug
Marketing Act of 1987 and the Prescription Drug Amendments of 1992,
except for those sections relating to State licensing of wholesale
distributors (see part 205 of this chapter), to protect the public
health, and to protect the public against drug diversion by establishing
procedures, requirements, and minimum standards for the distribution of
prescription drugs and prescription drug samples.
Sec. 203.3 Definitions.
(a) The act means the Federal Food, Drug, and Cosmetic Act, as
amended (21 U.S.C. 301 et seq.).
(b) Authorized distributor of record means a distributor with whom a
manufacturer has established an ongoing relationship to distribute such
manufacturer's products.
(c) Blood means whole blood collected from a single donor and
processed either for transfusion or further manufacturing.
(d) Blood component means that part of a single-donor unit of blood
separated by physical or mechanical means.
(e) Bulk drug substance means any substance that is represented for
use in a drug and that, when used in the manufacturing, processing, or
packaging of a drug, becomes an active ingredient or a finished dosage
form of the drug, but the term does not include intermediates used in
the synthesis of such substances.
(f) Charitable institution or charitable organization means a
nonprofit hospital, health care entity, organization, institution,
foundation, association, or corporation that has been granted an
exemption under section 501(c)(3) of the Internal Revenue Code of 1954,
as amended.
(g) Common control means the power to direct or cause the direction
of the management and policies of a person or an organization, whether
by ownership of stock, voting rights, by contract, or otherwise.
(h) Distribute means to sell, offer to sell, deliver, or offer to
deliver a drug to a recipient, except that the term ``distribute'' does
not include:
(1) Delivering or offering to deliver a drug by a common carrier in
the usual course of business as a common carrier; or
(2) Providing of a drug sample to a patient by:
[[Page 118]]
(i) A practitioner licensed to prescribe such drug;
(ii) A health care professional acting at the direction and under
the supervision of such a practitioner; or
(iii) The pharmacy of a hospital or of another health care entity
that is acting at the direction of such a practitioner and that received
such sample in accordance with the act and regulations.
(i) Drug sample means a unit of a prescription drug that is not
intended to be sold and is intended to promote the sale of the drug.
(j) Drug coupon means a form that may be redeemed, at no cost or at
reduced cost, for a drug that is prescribed in accordance with section
503(b) of the act.
(k) Electronic record means any combination of text, graphics, data,
audio, pictorial, or other information representation in digital form
that is created, modified, maintained, archived, retrieved, or
distributed by a computer system.
(l) Electronic signature means any computer data compilation of any
symbol or series of symbols executed, adopted, or authorized by an
individual to be the legally binding equivalent of the individual's
handwritten signature.
(m) Emergency medical reasons include, but are not limited to,
transfers of a prescription drug between health care entities or from a
health care entity to a retail pharmacy to alleviate a temporary
shortage of a prescription drug arising from delays in or interruption
of regular distribution schedules; sales to nearby emergency medical
services, i.e., ambulance companies and fire fighting organizations in
the same State or same marketing or service area, or nearby licensed
practitioners, of drugs for use in the treatment of acutely ill or
injured persons; provision of minimal emergency supplies of drugs to
nearby nursing homes for use in emergencies or during hours of the day
when necessary drugs cannot be obtained; and transfers of prescription
drugs by a retail pharmacy to another retail pharmacy to alleviate a
temporary shortage; but do not include regular and systematic sales to
licensed practitioners of prescription drugs that will be used for
routine office procedures.
(n) FDA means the U.S. Food and Drug Administration.
(o) Group purchasing organization means any entity established,
maintained, and operated for the purchase of prescription drugs for
distribution exclusively to its members with such membership consisting
solely of hospitals and health care entities bound by written contract
with the entity.
(p) Handwritten signature means the scripted name or legal mark of
an individual handwritten by that individual and executed or adopted
with the present intention to authenticate a writing in a permanent
form. The act of signing with a writing or marking instrument such as a
pen or stylus is preserved. The scripted name or legal mark, while
conventionally applied to paper, may also be applied to other devices
that capture the name or mark.
(q) Health care entity means any person that provides diagnostic,
medical, surgical, or dental treatment, or chronic or rehabilitative
care, but does not include any retail pharmacy or any wholesale
distributor. Except as provided in Sec. 203.22(h) and (i), a person
cannot simultaneously be a ``health care entity'' and a retail pharmacy
or wholesale distributor.
(r) Licensed practitioner means any person licensed or authorized by
State law to prescribe drugs.
(s) Manufacturer means any person who is a manufacturer as defined
by Sec. 201.1 of this chapter.
(t) Nonprofit affiliate means any not-for-profit organization that
is either associated with or a subsidiary of a charitable organization
as defined in section 501(c)(3) of the Internal Revenue Code of 1954.
(u) Ongoing relationship means an association that exists when a
manufacturer and a distributor enter into a written agreement under
which the distributor is authorized to distribute the manufacturer's
products for a period of time or for a number of shipments. If the
distributor is not authorized to distribute a manufacturer's entire
product line, the agreement must identify the specific drug products
that the distributor is authorized to distribute.
[[Page 119]]
(v) PDA means the Prescription Drug Amendments of 1992.
(w) PDMA means the Prescription Drug Marketing Act of 1987.
(x) Person includes any individual, partnership, corporation, or
association.
(y) Prescription drug means any drug (including any biological
product, except for blood and blood components intended for transfusion
or biological products that are also medical devices) required by
Federal law (including Federal regulation) to be dispensed only by a
prescription, including finished dosage forms and bulk drug substances
subject to section 503(b) of the act.
(z) Representative means an employee or agent of a drug manufacturer
or distributor who promotes the sale of prescription drugs to licensed
practitioners and who may solicit or receive written requests for the
delivery of drug samples. A detailer is a representative.
(aa) Sample unit means a packet, card, blister pack, bottle,
container, or other single package comprised of one or more dosage units
of a prescription drug sample, intended by the manufacturer or
distributor to be provided by a licensed practitioner to a patient in an
unbroken or unopened condition.
(bb) Unauthorized distributor means a distributor who does not have
an ongoing relationship with a manufacturer to sell or distribute its
products.
(cc) Wholesale distribution means distribution of prescription drugs
to persons other than a consumer or patient, but does not include:
(1) Intracompany sales;
(2) The purchase or other acquisition by a hospital or other health
care entity that is a member of a group purchasing organization of a
drug for its own use from the group purchasing organization or from
other hospitals or health care entities that are members of such
organizations;
(3) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug by a charitable organization to a nonprofit
affiliate of the organization to the extent otherwise permitted by law;
(4) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug among hospitals or other health care entities
that are under common control;
(5) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug for emergency medical reasons;
(6) The sale, purchase, or trade of a drug, an offer to sell,
purchase, or trade a drug, or the dispensing of a drug under a
prescription executed in accordance with section 503(b) of the act;
(7) The distribution of drug samples by manufacturers' and
authorized distributors' representatives;
(8) The sale, purchase, or trade of blood or blood components
intended for transfusion;
(9) Drug returns, when conducted by a hospital, health care entity,
or charitable institution in accordance with Sec. 203.23; or
(10) The sale of minimal quantities of drugs by retail pharmacies to
licensed practitioners for office use.
(dd) Wholesale distributor means any person engaged in wholesale
distribution of prescription drugs, including, but not limited to,
manufacturers; repackers; own-label distributors; private-label
distributors; jobbers; brokers; warehouses, including manufacturers' and
distributors' warehouses, chain drug warehouses, and wholesale drug
warehouses; independent wholesale drug traders; and retail pharmacies
that conduct wholesale distributions.
[64 FR 67756, Dec. 3, 1999, as amended at 73 FR 59500, Oct. 9, 2008]
Subpart B_Reimportation
Sec. 203.10 Restrictions on reimportation.
No prescription drug or drug composed wholly or partly of insulin
that was manufactured in a State and exported from the United States may
be reimported by anyone other than its manufacturer, except that FDA may
grant permission to a person other than the manufacturer to reimport a
prescription drug or insulin-containing drug if it determines that such
reimportation is required for emergency medical care.
[[Page 120]]
Sec. 203.11 Applications for reimportation to provide emergency medical care.
(a) Applications for reimportation for emergency medical care shall
be submitted to the director of the FDA District Office in the district
where reimportation is sought (addresses found in part 5, subpart M of
this chapter).
(b) Applications for reimportation to provide emergency medical care
shall be reviewed and approved or disapproved by each district office.
[64 FR 67756, Dec. 3, 1999, as amended at 69 FR 17292, Apr. 2, 2004]
Sec. 203.12 An appeal from an adverse decision by the district office.
An appeal from an adverse decision by the district office involving
insulin-containing drugs or human prescription drugs or biological
products regulated by the Center for Drug Evaluation and Research may be
made to the Office of Compliance, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver
Spring, MD 20993-0002. An appeal from an adverse decision by the
district office involving human prescription biological products
regulated by the Center for Biologics Evaluation and Research may be
made to the Food and Drug Administration, Center for Biologics
Evaluation and Research, Document Control Center, 10903 New Hampshire
Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002.
[80 FR 18090, Apr. 3, 2015]
Subpart C_Sales Restrictions
Sec. 203.20 Sales restrictions.
Except as provided in Sec. 203.22 or Sec. 203.23, no person may
sell, purchase, or trade, or offer to sell, purchase, or trade any
prescription drug that was:
(a) Purchased by a public or private hospital or other health care
entity; or
(b) Donated or supplied at a reduced price to a charitable
organization.
Sec. 203.22 Exclusions.
Section 203.20 does not apply to:
(a) The purchase or other acquisition of a drug for its own use by a
hospital or other health care entity that is a member of a group
purchasing organization from the group purchasing organization or from
other hospitals or health care entities that are members of the
organization.
(b) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug by a charitable organization to a nonprofit
affiliate of the organization to the extent otherwise permitted by law.
(c) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug among hospitals or other health care entities
that are under common control.
(d) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug for emergency medical reasons.
(e) The sale, purchase, or trade of a drug, an offer to sell,
purchase, or trade a drug, or the dispensing of a drug under a valid
prescription.
(f) The sale, purchase, or trade of a drug or the offer to sell,
purchase, or trade a drug by hospitals or health care entities owned or
operated by Federal, State, or local governmental units to other
hospitals or health care entities owned or operated by Federal, State,
or local governmental units.
(g) The sale, purchase, or trade of, or the offer to sell, purchase,
or trade blood or blood components intended for transfusion.
(h) The sale, purchase, or trade of, or the offer to sell, purchase,
or trade, by a registered blood establishment that qualifies as a health
care entity any:
(1) Drug indicated for a bleeding or clotting disorder, or anemia;
(2) Blood collection container approved under section 505 of the
act; or
(3) Drug that is a blood derivative (or a recombinant or synthetic
form of a blood derivative); as long as all of the health care services
that the establishment provides are related to its activities as a
registered blood establishment or the health care services consist of
collecting, processing, storing, or administering human hematopoietic
stem/progenitor cells or performing diagnostic testing of specimens
provided that these specimens are tested together with specimens
undergoing routine donor testing. Blood establishments relying on the
exclusion in this
[[Page 121]]
paragraph must satisfy all other requirements of the act and this part
applicable to a wholesale distributor or retail pharmacy.
(i) The sale, purchase, or trade of, or the offer to sell, purchase,
or trade, by a comprehensive hemophilia diagnostic treatment center that
is receiving a grant under section 501(a)(2) of the Social Security Act
and that qualifies as a health care entity, any drug indicated for a
bleeding or clotting disorder, or anemia, or any drug that is a blood
derivative (or a recombinant or synthetic form of a blood derivative).
Comprehensive hemophilia diagnostic treatment centers relying on the
exclusion in this paragraph must satisfy all other requirements of the
act and this part applicable to a wholesale distributor or retail
pharmacy.
[64 FR 67756, Dec. 3, 1999, as amended at 73 FR 59500, Oct. 9, 2008]
Sec. 203.23 Returns.
The return of a prescription drug purchased by a hospital or health
care entity or acquired at a reduced price by or donated to a charitable
institution is exempt from the prohibitions in Sec. 203.20, provided
that:
(a) The hospital, health care entity, or charitable institution
documents the return by filling out a credit memo specifying:
(1) The name and address of the hospital, health care entity, or
charitable institution;
(2) The name and address of the manufacturer or wholesale
distributor from which it was acquired;
(3) The product name and lot or control number;
(4) The quantity returned; and
(5) The date of the return.
(b) The hospital, health care entity, or charitable institution
forwards a copy of each credit memo to the manufacturer and retains a
copy of each credit memo for its records;
(c) Any drugs returned to a manufacturer or wholesale distributor
are kept under proper conditions for storage, handling, and shipping,
and written documentation showing that proper conditions were maintained
is provided to the manufacturer or wholesale distributor to which the
drugs are returned.
Subpart D_Samples
Sec. 203.30 Sample distribution by mail or common carrier.
(a) Requirements for drug sample distribution by mail or common
carrier. A manufacturer or authorized distributor of record may
distribute a drug sample to a practitioner licensed to prescribe the
drug that is to be sampled or, at the written request of a licensed
practitioner, to the pharmacy of a hospital or other health care entity,
by mail or common carrier, provided that:
(1) The licensed practitioner executes and submits a written request
to the manufacturer or authorized distributor of record, as set forth in
paragraph (b) of this section, before the delivery of the drug sample;
(2) The manufacturer or authorized distributor of record verifies
with the appropriate State authority that the practitioner requesting
the drug sample is licensed or authorized under State law to prescribe
the drug product;
(3) The recipient executes a written receipt, as set forth in
paragraph (c) of this section, when the drug sample is delivered; and
(4) The receipt is returned to the manufacturer or distributor from
which the drug sample was received.
(b) Contents of the written request form for delivery of samples by
mail or common carrier. (1) A written request for a drug sample to be
delivered by mail or common carrier to a licensed practitioner is
required to contain the following:
(i) The name, address, professional title, and signature of the
practitioner making the request;
(ii) The practitioner's State license or authorization number or,
where a scheduled drug product is requested, the practitioner's Drug
Enforcement Administration number.
(iii) The proprietary or established name and the strength of the
drug sample requested;
(iv) The quantity requested;
(v) The name of the manufacturer and the authorized distributor of
record, if the drug sample is requested from an authorized distributor
of record; and
(vi) The date of the request.
[[Page 122]]
(2) A written request for a drug sample to be delivered by mail or
common carrier to the pharmacy of a hospital or other health care entity
is required to contain, in addition to all of the information in
paragraph (b)(l) of this section, the name and address of the pharmacy
of the hospital or other health care entity to which the drug sample is
to be delivered.
(c) Contents of the receipt to be completed upon delivery of a drug
sample. The receipt is to be on a form designated by the manufacturer or
distributor, and is required to contain the following:
(1) If the drug sample is delivered to the licensed practitioner who
requested it, the receipt is required to contain the name, address,
professional title, and signature of the practitioner or the
practitioner's designee who acknowledges delivery of the drug sample;
the proprietary or established name and strength of the drug sample and
the quantity of the drug sample delivered; and the date of the delivery.
(2) If the drug sample is delivered to the pharmacy of a hospital or
other health care entity at the request of a licensed practitioner, the
receipt is required to contain the name and address of the requesting
licensed practitioner; the name and address of the hospital or health
care entity pharmacy designated to receive the drug sample; the name,
address, professional title, and signature of the person acknowledging
delivery of the drug sample; the proprietary or established name and
strength of the drug sample; the quantity of the drug sample delivered;
and the date of the delivery.
Sec. 203.31 Sample distribution by means other than mail or
common carrier (direct delivery by a representative or detailer).
(a) Requirements for drug sample distribution by means other than
mail or common carrier. A manufacturer or authorized distributor of
record may distribute by means other than mail or common carrier, by a
representative or detailer, a drug sample to a practitioner licensed to
prescribe the drug to be sampled or, at the written request of such a
licensed practitioner, to the pharmacy of a hospital or other health
care entity, provided that:
(1) The manufacturer or authorized distributor of record receives
from the licensed practitioner a written request signed by the licensed
practitioner before the delivery of the drug sample;
(2) The manufacturer or authorized distributor of record verifies
with the appropriate State authority that the practitioner requesting
the drug sample is licensed or authorized under State law to prescribe
the drug product;
(3) A receipt is signed by the recipient, as set forth in paragraph
(c) of this section, when the drug sample is delivered;
(4) The receipt is returned to the manufacturer or distributor; and
(5) The requirements of paragraphs (d) through (e) of this section
are met.
(b) Contents of the written request forms for delivery of samples by
a representative. (1) A written request for delivery of a drug sample by
a representative to a licensed practitioner is required to contain the
following:
(i) The name, address, professional title, and signature of the
practitioner making the request;
(ii) The practitioner's State license or authorization number, or,
where a scheduled drug product is requested, the practitioner's Drug
Enforcement Administration number;
(iii) The proprietary or established name and the strength of the
drug sample requested;
(iv) The quantity requested;
(v) The name of the manufacturer and the authorized distributor of
record, if the drug sample is requested from an authorized distributor
of record; and
(vi) The date of the request.
(2) A written request for delivery of a drug sample by a
representative to the pharmacy of a hospital or other health care entity
is required to contain, in addition to all of the information in
paragraph (b) of this section, the name and address of the pharmacy of
the hospital or other health care entity to which the drug sample is to
be delivered.
(c) Contents of the receipt to be completed upon delivery of a drug
sample.
[[Page 123]]
The receipt is to be on a form designated by the manufacturer or
distributor, and is required to contain the following:
(1) If the drug sample is received at the address of the licensed
practitioner who requested it, the receipt is required to contain the
name, address, professional title, and signature of the practitioner or
the practitioner's designee who acknowledges delivery of the drug
sample; the proprietary or established name and strength of the drug
sample; the quantity of the drug sample delivered; and the date of the
delivery.
(2) If the drug sample is received by the pharmacy of a hospital or
other health care entity at the request of a licensed practitioner, the
receipt is required to contain the name and address of the requesting
licensed practitioner; the name and address of the hospital or health
care entity pharmacy designated to receive the drug sample; the name,
address, professional title, and signature of the person acknowledging
delivery of the drug sample; the proprietary or established name and
strength of the drug sample; the quantity of the drug sample delivered;
and the date of the delivery.
(d) Inventory and reconciliation of drug samples of manufacturers'
and distributors' representatives. Each drug manufacturer or authorized
distributor of record that distributes drug samples by means of
representatives shall conduct, at least annually, a complete and
accurate physical inventory of all drug samples. All drug samples in the
possession or control of each manufacturer's and distributor's
representatives are required to be inventoried and the results of the
inventory are required to be recorded in an inventory record, as
specified in paragraph (d)(1) of this section. In addition,
manufacturers and distributors shall reconcile the results of the
physical inventory with the most recently completed prior physical
inventory and create a report documenting the reconciliation process, as
specified in paragraph (d)(2) of this section.
(1) The inventory record is required to identify all drug samples in
a representative's stock by the proprietary or established name, dosage
strength, and number of units.
(2) The reconciliation report is required to include:
(i) The inventory record for the most recently completed prior
inventory;
(ii) A record of each drug sample shipment received since the most
recently completed prior inventory, including the sender and date of the
shipment, and the proprietary or established name, dosage strength, and
number of sample units received;
(iii) A record of drug sample distributions since the most recently
completed inventory showing the name and address of each recipient of
each sample unit shipped, the date of the shipment, and the proprietary
or established name, dosage strength, and number of sample units
shipped. For the purposes of this paragraph and paragraph (d)(2)(v) of
this section, ``distributions'' includes distributions to health care
practitioners or designated hospital or health care entity pharmacies,
transfers or exchanges with other firm representatives, returns to the
manufacturer or authorized distributor, destruction of drug samples by a
sales representative, and other types of drug sample dispositions. The
specific type of distribution must be specified in the record;
(iv) A record of drug sample thefts or significant losses reported
by the representative since the most recently completed prior inventory,
including the approximate date of the occurrence and the proprietary or
established name, dosage strength, and number of sample units stolen or
lost; and
(v) A record summarizing the information required by paragraphs
(d)(2)(ii) through (d)(2)(iv) of this section. The record must show, for
each type of sample unit (i.e., sample units having the same established
or proprietary name and dosage strength), the total number of sample
units received, distributed, lost, or stolen since the most recently
completed prior inventory. For example, a typical entry in this record
may read ``50 units risperidone (1 mg) returned to manufacturer'' or
simply ``Risperidone (1 mg)/50/returned to manufacturer.''
(3) Each drug manufacturer or authorized distributor of record shall
[[Page 124]]
take appropriate internal control measures to guard against error and
possible fraud in the conduct of the physical inventory and
reconciliation, and in the preparation of the inventory record and
reconciliation report.
(4) A manufacturer or authorized distributor of record shall
carefully evaluate any apparent discrepancy or significant loss revealed
through the inventory and reconciliation process and shall fully
investigate any such discrepancy or significant loss that cannot be
justified.
(e) Lists of manufacturers' and distributors' representatives. Each
drug manufacturer or authorized distributor of record who distributes
drug samples by means of representatives shall maintain a list of the
names and addresses of its representatives who distribute drug samples
and of the sites where drug samples are stored.
Sec. 203.32 Drug sample storage and handling requirements.
(a) Storage and handling conditions. Manufacturers, authorized
distributors of record, and their representatives shall store and handle
all drug samples under conditions that will maintain their stability,
integrity, and effectiveness and ensure that the drug samples are free
of contamination, deterioration, and adulteration.
(b) Compliance with compendial and labeling requirements.
Manufacturers, authorized distributors of record, and their
representatives can generally comply with this section by following the
compendial and labeling requirements for storage and handling of a
particular prescription drug in handling samples of that drug.
Sec. 203.33 Drug sample forms.
A sample request or receipt form may be delivered by mail, common
carrier, or private courier or may be transmitted photographically or
electronically (i.e., by telephoto, wirephoto, radiophoto, facsimile
transmission (FAX), xerography, or electronic data transfer) or by any
other system, provided that the method for transmission meets the
security requirements set forth in Sec. 203.60(c).
Sec. 203.34 Policies and procedures; administrative systems.
Each manufacturer or authorized distributor of record that
distributes drug samples shall establish, maintain, and adhere to
written policies and procedures describing its administrative systems
for the following:
(a) Distributing drug samples by mail or common carrier, including
methodology for reconciliation of requests and receipts;
(b) Distributing drug samples by means other than mail or common
carrier including the methodology for:
(1) Reconciling requests and receipts, identifying patterns of
nonresponse, and the manufacturer's or distributor's response when such
patterns are found;
(2) Conducting the annual physical inventory and preparation of the
reconciliation report;
(3) Implementing a sample distribution security and audit system,
including conducting random and for-cause audits of sales
representatives by personnel independent of the sales force; and
(4) Storage of drug samples by representatives;
(c) Identifying any significant loss of drug samples and notifying
FDA of the loss; and
(d) Monitoring any loss or theft of drug samples.
Sec. 203.35 Standing requests.
Manufacturers or authorized distributors of record shall not
distribute drug samples on the basis of open-ended or standing requests,
but shall require separate written requests for each drug sample or
group of samples. An arrangement by which a licensed practitioner
requests in writing that a specified number of drug samples be delivered
over a period of not more than 6 months, with the actual delivery dates
for parts of the order to be set by subsequent oral communication or
electronic transmission, is not considered to be a standing request.
Sec. 203.36 Fulfillment houses, shipping and mailing services,
comarketing agreements, and third-party recordkeeping.
(a) Responsibility for creating and maintaining forms, reports, and
records.
[[Page 125]]
Any manufacturer or authorized distributor of record that uses a
fulfillment house, shipping or mailing service, or other third party, or
engages in a comarketing agreement with another manufacturer or
distributor to distribute drug samples or to meet any of the
requirements of PDMA, PDA, or this part, remains responsible for
creating and maintaining all requests, receipts, forms, reports, and
records required under PDMA, PDA, and this part.
(b) Responsibility for producing requested forms, reports, or
records. A manufacturer or authorized distributor of record that
contracts with a third party to maintain some or all of its records
shall produce requested forms, reports, records, or other required
documents within 2 business days of a request by an authorized
representative of FDA or another Federal, State, or local regulatory or
law enforcement official.
Sec. 203.37 Investigation and notification requirements.
(a) Investigation of falsification of drug sample records. A
manufacturer or authorized distributor of record that has reason to
believe that any person has falsified drug sample requests, receipts, or
records, or is diverting drug samples, shall:
(1) Notify FDA, by telephone or in writing, within 5 working days;
(2) Immediately initiate an investigation; and
(3) Provide FDA with a complete written report, including the reason
for and the results of the investigation, not later than 30 days after
the date of the initial notification in paragraph (a)(1) of this
section.
(b) Significant loss or known theft of drug samples. A manufacturer
or authorized distributor of record that distributes drug samples or a
charitable institution that receives donated drug samples from a
licensed practitioner shall:
(1) Notify FDA, by telephone or in writing, within 5 working days of
becoming aware of a significant loss or known theft;
(2) Immediately initiate an investigation into the significant loss
or known theft; and
(3) Provide FDA with a complete written report, including the reason
for and the results of the investigation, not later than 30 days after
the date of the initial notification in paragraph (b)(1) of this
section.
(c) Conviction of a representative. (1) A manufacturer or authorized
distributor of record that distributes drug samples shall notify FDA, by
telephone or in writing, within 30 days of becoming aware of the
conviction of one or more of its representatives for a violation of
section 503(c)(1) of the act or any State law involving the sale,
purchase, or trade of a drug sample or the offer to sell, purchase, or
trade a drug sample.
(2) A manufacturer or authorized distributor of record shall provide
FDA with a complete written report not later than 30 days after the date
of the initial notification.
(d) Selection of individual responsible for drug sample information.
A manufacturer or authorized distributor of record that distributes drug
samples shall inform FDA in writing within 30 days of selecting the
individual responsible for responding to a request for information about
drug samples of that individual's name, business address, and telephone
number.
(e) Whom to notify at FDA. Notifications and reports concerning
human prescription drugs or biological products regulated by the Center
for Drug Evaluation and Research shall be made to the Division of
Compliance Risk Management and Surveillance, Office of Compliance,
Center for Drug Evaluation and Research, Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993-0002. Notifications
and reports concerning human prescription biological products regulated
by the Center for Biologics Evaluation and Research shall be made to the
Food and Drug Administration, Center for Biologics Evaluation and
Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71,
Rm. G112, Silver Spring, MD 20993-0002.
[64 FR 67756, Dec. 3, 1999, as amended at 69 FR 48775, Aug. 11, 2004; 70
FR 14981, Mar. 24, 2005; 74 FR 13112, Mar. 26, 2009; 80 FR 18090, Apr.
3, 2015]
[[Page 126]]
Sec. 203.38 Sample lot or control numbers; labeling of sample units.
(a) Lot or control number required on drug sample labeling and
sample unit label. The manufacturer or authorized distributor of record
of a drug sample shall include on the label of the sample unit and on
the outside container or packaging of the sample unit, if any, an
identifying lot or control number that will permit the tracking of the
distribution of each drug sample unit.
(b) Records containing lot or control numbers required for all drug
samples distributed. A manufacturer or authorized distributor of record
shall maintain for all samples distributed records of drug sample
distribution containing lot or control numbers that are sufficient to
permit the tracking of sample units to the point of the licensed
practitioner.
(c) Labels of sample units. Each sample unit shall bear a label that
clearly denotes its status as a drug sample, e.g., ``sample,'' ``not for
sale,'' ``professional courtesy package.''
(1) A drug that is labeled as a drug sample is deemed to be a drug
sample within the meaning of the act.
(2) A drug product dosage unit that bears an imprint identifying the
dosage form as a drug sample is deemed to be a drug sample within the
meaning of the act.
(3) Notwithstanding paragraphs (c)(1) and (c)(2) of this section,
any article that is a drug sample as defined in section 503(c)(1) of the
act and Sec. 203.3(i) that fails to bear the label required in this
paragraph (c) is a drug sample.
Sec. 203.39 Donation of drug samples to charitable institutions.
A charitable institution may receive a drug sample donated by a
licensed practitioner or another charitable institution for dispensing
to a patient of the charitable institution, or donate a drug sample to
another charitable institution for dispensing to its patients, provided
that the following requirements are met:
(a) A drug sample donated by a licensed practitioner or donating
charitable institution shall be received by a charitable institution in
its original, unopened packaging with its labeling intact.
(b) Delivery of a donated drug sample to a recipient charitable
institution shall be completed by mail or common carrier, collection by
an authorized agent or employee of the recipient charitable institution,
or personal delivery by a licensed practitioner or an agent or employee
of the donating charitable institution. Donated drug samples shall be
placed by the donor in a sealed carton for delivery to or collection by
the recipient charitable institution.
(c) A donated drug sample shall not be dispensed to a patient or be
distributed to another charitable institution until it has been examined
by a licensed practitioner or registered pharmacist at the recipient
charitable institution to confirm that the donation record accurately
describes the drug sample delivered and that no drug sample is
adulterated or misbranded for any reason, including, but not limited to,
the following:
(1) The drug sample is out of date;
(2) The labeling has become mutilated, obscured, or detached from
the drug sample packaging;
(3) The drug sample shows evidence of having been stored or shipped
under conditions that might adversely affect its stability, integrity,
or effectiveness;
(4) The drug sample is for a prescription drug product that has been
recalled or is no longer marketed; or
(5) The drug sample is otherwise possibly contaminated,
deteriorated, or adulterated.
(d) The recipient charitable institution shall dispose of any drug
sample found to be unsuitable by destroying it or by returning it to the
manufacturer. The charitable institution shall maintain complete records
of the disposition of all destroyed or returned drug samples.
(e) The recipient charitable institution shall prepare at the time
of collection or delivery of a drug sample a complete and accurate
donation record, a copy of which shall be retained by the recipient
charitable institution for at least 3 years, containing the following
information:
(1) The name, address, and telephone number of the licensed
practitioner (or donating charitable institution);
[[Page 127]]
(2) The manufacturer, brand name, quantity, and lot or control
number of the drug sample donated; and
(3) The date of the donation.
(f) Each recipient charitable institution shall maintain complete
and accurate records of donation, receipt, inspection, inventory,
dispensing, redistribution, destruction, and returns sufficient for
complete accountability and auditing of drug sample stocks.
(g) Each recipient charitable institution shall conduct, at least
annually, an inventory of prescription drug sample stocks and shall
prepare a report reconciling the results of each inventory with the most
recent prior inventory. Drug sample inventory discrepancies and
reconciliation problems shall be investigated by the charitable
institution and reported to FDA.
(h) A recipient charitable institution shall store drug samples
under conditions that will maintain the sample's stability, integrity,
and effectiveness, and will ensure that the drug samples will be free of
contamination, deterioration, and adulteration.
(i) A charitable institution shall notify FDA within 5 working days
of becoming aware of a significant loss or known theft of prescription
drug samples.
Subpart E_Wholesale Distribution
Sec. 203.50 Requirements for wholesale distribution of
prescription drugs.
(a) Identifying statement for sales by unauthorized distributors.
Before the completion of any wholesale distribution by a wholesale
distributor of a prescription drug for which the seller is not an
authorized distributor of record to another wholesale distributor or
retail pharmacy, the seller shall provide to the purchaser a statement
identifying each prior sale, purchase, or trade of such drug. This
identifying statement shall include:
(1) The proprietary and established name of the drug;
(2) Dosage;
(3) Container size;
(4) Number of containers;
(5) The drug's lot or control number(s);
(6) The business name and address of all parties to each prior
transaction involving the drug, starting with the manufacturer; and
(7) The date of each previous transaction.
(b) The drug origin statement is subject to the record retention
requirements of Sec. 203.60 and must be retained by all wholesale
distributors involved in the distribution of the drug product, whether
authorized or unauthorized, for 3 years.
(c) Identifying statement not required when additional manufacturing
processes are completed. A manufacturer that subjects a drug to any
additional manufacturing processes to produce a different drug is not
required to provide to a purchaser a statement identifying the previous
sales of the component drug or drugs.
(d) List of authorized distributors of record. Each manufacturer
shall maintain at the corporate offices a current written list of all
authorized distributors of record.
(1) Each manufacturer's list of authorized distributors of record
shall specify whether each distributor listed thereon is authorized to
distribute the manufacturer's full product line or only particular,
specified products.
(2) Each manufacturer shall update its list of authorized
distributors of record on a continuing basis.
(3) Each manufacturer shall make its list of authorized distributors
of record available on request to the public for inspection or copying.
A manufacturer may impose reasonable copying charges for such requests
from members of the public.
Subpart F_Request and Receipt Forms, Reports, and Records
Sec. 203.60 Request and receipt forms, reports, and records.
(a) Use of electronic records, electronic signatures, and
handwritten signatures executed to electronic records. (1) Provided the
requirements of part 11 of this chapter are met, electronic records,
electronic signatures, and handwritten signatures executed to electronic
records may be used as an alternative to paper records and handwritten
signatures executed on paper
[[Page 128]]
to meet any of the record and signature requirements of PDMA, PDA, or
this part.
(2) Combinations of paper records and electronic records, electronic
records and handwritten signatures executed on paper, or paper records
and electronic signatures or handwritten signatures executed to
electronic records, may be used to meet any of the record and signature
requirements of PDMA, PDA, or this part, provided that:
(i) The requirements of part 11 of this chapter are met for the
electronic records, electronic signatures, or handwritten signatures
executed to electronic records; and
(ii) A reasonably secure link between the paper-based and electronic
components exists such that the combined records and signatures are
trustworthy and reliable, and to ensure that the signer cannot readily
repudiate the signed records as not genuine.
(3) For the purposes of this paragraph (a), the phrase ``record and
signature requirements of PDMA, PDA, or this part'' includes drug sample
request and receipt forms, reports, records, and other documents, and
their associated signatures required by PDMA, PDA, and this part.
(b) Maintenance of request and receipt forms, reports, records, and
other documents created on paper. Request and receipt forms, reports,
records, and other documents created on paper may be maintained on paper
or by photographic imaging (i.e., photocopies or microfiche), provided
that the security and authentication requirements described in paragraph
(c) of this section are followed. Where a required document is created
on paper and electronically scanned into a computer, the resulting
record is an electronic record that must meet the requirements of part
11 of this chapter.
(c) Security and authentication requirements for request and receipt
forms, reports, records, and other documents created on paper. A request
or receipt form, report, record, or other document, and any signature
appearing thereon, that is created on paper and that is maintained by
photographic imaging, or transmitted electronically (i.e., by facsimile)
shall be maintained or transmitted in a form that provides reasonable
assurance of being:
(1) Resistant to tampering, revision, modification, fraud,
unauthorized use, or alteration;
(2) Preserved in accessible and retrievable fashion; and
(3) Available to permit copying for purposes of review, analysis,
verification, authentication, and reproduction by the person who
executed the form or created the record, by the manufacturer or
distributor, and by authorized personnel of FDA and other regulatory and
law enforcement agencies.
(d) Retention of request and receipt forms, reports, lists, records,
and other documents. Any person required to create or maintain reports,
lists, or other records under PDMA, PDA, or this part, including records
relating to the distribution of drug samples, shall retain them for at
least 3 years after the date of their creation.
(e) Availability of request and receipt forms, reports, lists, and
records. Any person required to create or maintain request and receipt
forms, reports, lists, or other records under PDMA, PDA, or this part
shall make them available, upon request, in a form that permits copying
or other means of duplication, to FDA or other Federal, State, or local
regulatory and law enforcement officials for review and reproduction.
The records shall be made available within 2 business days of a request.
Subpart G_Rewards
Sec. 203.70 Application for a reward.
(a) Reward for providing information leading to the institution of a
criminal proceeding against, and conviction of, a person for the sale,
purchase, or trade of a drug sample. A person who provides information
leading to the institution of a criminal proceeding against, and
conviction of, a person for the sale, purchase, or trade of a drug
sample, or the offer to sell, purchase, or trade a drug sample, in
violation of section 503(c)(1) of the act, is entitled to one-half the
criminal fine imposed and collected for such violation, but not more
than $125,000.
[[Page 129]]
(b) Procedure for making application for a reward for providing
information leading to the institution of a criminal proceeding against,
and conviction of, a person for the sale, purchase, or trade of a drug
sample. A person who provides information leading to the institution of
a criminal proceeding against, and conviction of, a person for the sale,
purchase, or trade of a drug sample, or the offer to sell, purchase, or
trade a drug sample, in violation of section 503(c)(1) of the act, may
apply for a reward by making written application to:
(1) Director, Office of Compliance, Center for Drug Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver
Spring, MD 20993-0002; or
(2) Food and Drug Administration, Center for Biologics Evaluation
and Research, Office of Compliance and Biologics Quality (ATTN:
Director), Document Control Center, 10903 New Hampshire Ave., Bldg. 71,
Rm. G112, Silver Spring, MD 20993-0002, as appropriate.
[64 FR 67756, Dec. 3, 1999, as amended at 69 FR 48775, Aug. 11, 2004; 74
FR 13112, Mar. 26, 2009; 80 FR 18091, Apr. 3, 2013]
PART 205_GUIDELINES FOR STATE LICENSING OF WHOLESALE PRESCRIPTION
DRUG DISTRIBUTORS--Table of Contents
Sec.
205.1 Scope.
205.2 Purpose.
205.3 Definitions.
205.4 Wholesale drug distributor licensing requirement.
205.5 Minimum required information for licensure.
205.6 Minimum qualifications.
205.7 Personnel.
205.8 Violations and penalties.
205.50 Minimum requirements for the storage and handling of prescription
drugs and for the establishment and maintenance of
prescription drug distribution records.
Authority: 21 U.S.C. 351, 352, 353, 371, 374.
Source: 55 FR 38023, Sept. 14, 1990, unless otherwise noted.
Sec. 205.1 Scope.
This part applies to any person, partnership, corporation, or
business firm in a State engaging in the wholesale distribution of human
prescription drugs in interstate commerce.
Sec. 205.2 Purpose.
The purpose of this part is to implement the Prescription Drug
Marketing Act of 1987 by providing minimum standards, terms, and
conditions for the licensing by State licensing authorities of persons
who engage in wholesale distributions in interstate commerce of
prescription drugs.
Sec. 205.3 Definitions.
(a) Blood means whole blood collected from a single donor and
processed either for transfusion or further manufacturing.
(b) Blood component means that part of blood separated by physical
or mechanical means.
(c) Drug sample means a unit of a prescription drug that is not
intended to be sold and is intended to promote the sale of the drug.
(d) Manufacturer means anyone who is engaged in manufacturing,
preparing, propagating, compounding, processing, packaging, repackaging,
or labeling of a prescription drug.
(e) Prescription drug means any human drug required by Federal law
or regulation to be dispensed only by a prescription, including finished
dosage forms and active ingredients subject to section 503(b) of the
Federal Food, Drug, and Cosmetic Act.
(f) Wholesale distribution and wholesale distribution means
distribution of prescription drugs to persons other than a consumer or
patient, but does not include:
(1) Intracompany sales;
(2) The purchase or other acquisition by a hospital or other health
care entity that is a member of a group purchasing organization of a
drug for its own use from the group purchasing organization or from
other hospitals or health care entities that are members of such
organizations;
(3) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug by a charitable organization described in
section 501(c)(3) of the Internal Revenue Code of 1954 to a nonprofit
affiliate of the organization to the extent otherwise permitted by law;
[[Page 130]]
(4) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug among hospitals or other health care entities
that are under common control; for purposes of this section, common
control means the power to direct or cause the direction of the
management and policies of a person or an organization, whether by
ownership of stock, voting rights, by contract, or otherwise;
(5) The sale, purchase, or trade of a drug or an offer to sell,
purchase, or trade a drug for emergency medical reasons; for purposes of
this section, emergency medical reasons includes transfers of
prescription drugs by a retail pharmacy to another retail pharmacy to
alleviate a temporary shortage;
(6) The sale, purchase, or trade of a drug, an offer to sell,
purchase, or trade a drug, or the dispensing of a drug pursuant to a
prescription;
(7) The distribution of drug samples by manufacturers'
representatives or distributors' representatives; or
(8) The sale, purchase, or trade of blood and blood components
intended for transfusion.
(9) Drug returns, when conducted by a hospital, health care entity,
or charitable institution in accordance with Sec. 203.23 of this
chapter; or
(10) The sale of minimal quantities of drugs by retail pharmacies to
licensed practitioners for office use.
(g) Wholesale distributor means any one engaged in wholesale
distribution of prescription drugs, including, but not limited to,
manufacturers; repackers; own-label distributors; private-label
distributors; jobbers; brokers; warehouses, including manufacturers' and
distributors' warehouses, chain drug warehouses, and wholesale drug
warehouses; independent wholesale drug traders; and retail pharmacies
that conduct wholesale distributions.
(h) Health care entity means any person that provides diagnostic,
medical, surgical, or dental treatment, or chronic or rehabilitative
care, but does not include any retail pharmacy or any wholesale
distributor. Except as provided in Sec. 203.22(h) and (i) of this
chapter, a person cannot simultaneously be a ``health care entity'' and
a retail pharmacy or wholesale distributor.
[55 FR 38023, Sept. 14, 1990, as amended at 64 FR 67762, Dec. 3, 1999,
73 FR 59501, Oct. 9, 2008]
Sec. 205.4 Wholesale drug distributor licensing requirement.
Every wholesale distributor in a State who engages in wholesale
distributions of prescription drugs in interstate commerce must be
licensed by the State licensing authority in accordance with this part
before engaging in wholesale distributions of prescription drugs in
interstate commerce.
Sec. 205.5 Minimum required information for licensure.
(a) The State licensing authority shall require the following
minimum information from each wholesale drug distributor as part of the
license described in Sec. 205.4 and as part of any renewal of such
license:
(1) The name, full business address, and telephone number of the
licensee;
(2) All trade or business names used by the licensee;
(3) Addresses, telephone numbers, and the names of contact persons
for all facilities used by the licensee for the storage, handling, and
distribution of prescription drugs;
(4) The type of ownership or operation (i.e., partnership,
corporation, or sole proprietorship); and
(5) The name(s) of the owner and/or operator of the licensee,
including:
(i) If a person, the name of the person;
(ii) If a partnership, the name of each partner, and the name of the
partnership;
(iii) If a corporation, the name and title of each corporate officer
and director, the corporate names, and the name of the State of
incorporation; and
(iv) If a sole proprietorship, the full name of the sole proprietor
and the name of the business entity.
(b) The State licensing authority may provide for a single license
for a business entity operating more than one facility within that
State, or for a parent entity with divisions, subsidiaries, and/or
affiliate companies within
[[Page 131]]
that State when operations are conducted at more than one location and
there exists joint ownership and control among all the entities.
(c) Changes in any information in paragraph (a) of this section
shall be submitted to the State licensing authority as required by such
authority.
(Approved by the Office of Management and Budget under control number
0910-0251)
Sec. 205.6 Minimum qualifications.
(a) The State licensing authority shall consider, at a minimum, the
following factors in reviewing the qualifications of persons who engage
in wholesale distribution of prescription drugs within the State:
(1) Any convictions of the applicant under any Federal, State, or
local laws relating to drug samples, wholesale or retail drug
distribution, or distribution of controlled substances;
(2) Any felony convictions of the applicant under Federal, State, or
local laws;
(3) The applicant's past experience in the manufacture or
distribution of prescription drugs, including controlled substances;
(4) The furnishing by the applicant of false or fraudulent material
in any application made in connection with drug manufacturing or
distribution;
(5) Suspension or revocation by Federal, State, or local government
of any license currently or previously held by the applicant for the
manufacture or distribution of any drugs, including controlled
substances;
(6) Compliance with licensing requirements under previously granted
licenses, if any;
(7) Compliance with requirements to maintain and/or make available
to the State licensing authority or to Federal, State, or local law
enforcement officials those records required under this section; and
(8) Any other factors or qualifications the State licensing
authority considers relevant to and consistent with the public health
and safety.
(b) The State licensing authority shall have the right to deny a
license to an applicant if it determines that the granting of such a
license would not be in the public interest.
Sec. 205.7 Personnel.
The State licensing authority shall require that personnel employed
in wholesale distribution have appropriate education and/or experience
to assume responsibility for positions related to compliance with State
licensing requirements.
Sec. 205.8 Violations and penalties.
(a) State licensing laws shall provide for the suspension or
revocation of licenses upon conviction of violations of Federal, State,
or local drug laws or regulations, and may provide for fines,
imprisonment, or civil penalties.
(b) State licensing laws shall provide for suspension or revocation
of licenses, where appropriate, for violations of its provisions.
Sec. 205.50 Minimum requirements for the storage and handling
of prescription drugs and for the establishment and maintenance
of prescription drug distribution records.
The State licensing law shall include the following minimum
requirements for the storage and handling of prescription drugs, and for
the establishment and maintenance of prescription drug distribution
records by wholesale drug distributors and their officers, agents,
representatives, and employees:
(a) Facilities. All facilities at which prescription drugs are
stored, warehoused, handled, held, offered, marketed, or displayed
shall:
(1) Be of suitable size and construction to facilitate cleaning,
maintenance, and proper operations;
(2) Have storage areas designed to provide adequate lighting,
ventilation, temperature, sanitation, humidity, space, equipment, and
security conditions;
(3) Have a quarantine area for storage of prescription drugs that
are outdated, damaged, deteriorated, misbranded, or adulterated, or that
are in immediate or sealed, secondary containers that have been opened;
(4) Be maintained in a clean and orderly condition; and
(5) Be free from infestation by insects, rodents, birds, or vermin
of any kind.
[[Page 132]]
(b) Security. (1) All facilities used for wholesale drug
distribution shall be secure from unauthorized entry.
(i) Access from outside the premises shall be kept to a minimum and
be well-controlled.
(ii) The outside perimeter of the premises shall be well-lighted.
(iii) Entry into areas where prescription drugs are held shall be
limited to authorized personnel.
(2) All facilities shall be equipped with an alarm system to detect
entry after hours.
(3) All facilities shall be equipped with a security system that
will provide suitable protection against theft and diversion. When
appropriate, the security system shall provide protection against theft
or diversion that is facilitated or hidden by tampering with computers
or electronic records.
(c) Storage. All prescription drugs shall be stored at appropriate
temperatures and under appropriate conditions in accordance with
requirements, if any, in the labeling of such drugs, or with
requirements in the current edition of an official compendium, such as
the United States Pharmacopeia/National Formulary (USP/NF).
(1) If no storage requirements are established for a prescription
drug, the drug may be held at ``controlled'' room temperature, as
defined in an official compendium, to help ensure that its identity,
strength, quality, and purity are not adversely affected.
(2) Appropriate manual, electromechanical, or electronic temperature
and humidity recording equipment, devices, and/or logs shall be utilized
to document proper storage of prescription drugs.
(3) The recordkeeping requirements in paragraph (f) of this section
shall be followed for all stored drugs.
(d) Examination of materials. (1) Upon receipt, each outside
shipping container shall be visually examined for identity and to
prevent the acceptance of contaminated prescription drugs or
prescription drugs that are otherwise unfit for distribution. This
examination shall be adequate to reveal container damage that would
suggest possible contamination or other damage to the contents.
(2) Each outgoing shipment shall be carefully inspected for identity
of the prescription drug products and to ensure that there is no
delivery of prescription drugs that have been damaged in storage or held
under improper conditions.
(3) The recordkeeping requirements in paragraph (f) of this section
shall be followed for all incoming and outgoing prescription drugs.
(e) Returned, damaged, and outdated prescription drugs. (1)
Prescription drugs that are outdated, damaged, deteriorated, misbranded,
or adulterated shall be quarantined and physically separated from other
prescription drugs until they are destroyed or returned to their
supplier.
(2) Any prescription drugs whose immediate or sealed outer or sealed
secondary containers have been opened or used shall be identified as
such, and shall be quarantined and physically separated from other
prescription drugs until they are either destroyed or returned to the
supplier.
(3) If the conditions under which a prescription drug has been
returned cast doubt on the drug's safety, identity, strength, quality,
or purity, then the drug shall be destroyed, or returned to the
supplier, unless examination, testing, or other investigation proves
that the drug meets appropriate standards of safety, identity, strength,
quality, and purity. In determining whether the conditions under which a
drug has been returned cast doubt on the drug's safety, identity,
strength, quality, or purity, the wholesale drug distributor shall
consider, among other things, the conditions under which the drug has
been held, stored, or shipped before or during its return and the
condition of the drug and its container, carton, or labeling, as a
result of storage or shipping.
(4) The recordkeeping requirements in paragraph (f) of this section
shall be followed for all outdated, damaged, deteriorated, misbranded,
or adulterated prescription drugs.
(f) Recordkeeping. (1) Wholesale drug distributors shall establish
and maintain inventories and records of all transactions regarding the
receipt and
[[Page 133]]
distribution or other disposition of prescription drugs. These records
shall include the following information:
(i) The source of the drugs, including the name and principal
address of the seller or transferor, and the address of the location
from which the drugs were shipped;
(ii) The identity and quantity of the drugs received and distributed
or disposed of; and
(iii) The dates of receipt and distribution or other disposition of
the drugs.
(2) Inventories and records shall be made available for inspection
and photocopying by authorized Federal, State, or local law enforcement
agency officials for a period of 3 years after the date of their
creation.
(3) Records described in this section that are kept at the
inspection site or that can be immediately retrieved by computer or
other electronic means shall be readily available for authorized
inspection during the retention period. Records kept at a central
location apart from the inspection site and not electronically
retrievable shall be made available for inspection within 2 working days
of a request by an authorized official of a Federal, State, or local law
enforcement agency.
(g) Written policies and procedures. Wholesale drug distributors
shall establish, maintain, and adhere to written policies and
procedures, which shall be followed for the receipt, security, storage,
inventory, and distribution of prescription drugs, including policies
and procedures for identifying, recording, and reporting losses or
thefts, and for correcting all errors and inaccuracies in inventories.
Wholesale drug distributors shall include in their written policies and
procedures the following:
(1) A procedure whereby the oldest approved stock of a prescription
drug product is distributed first. The procedure may permit deviation
from this requirement, if such deviation is temporary and appropriate.
(2) A procedure to be followed for handling recalls and withdrawals
of prescription drugs. Such procedure shall be adequate to deal with
recalls and withdrawals due to:
(i) Any action initiated at the request of the Food and Drug
Administration or other Federal, State, or local law enforcement or
other government agency, including the State licensing agency;
(ii) Any voluntary action by the manufacturer to remove defective or
potentially defective drugs from the market; or
(iii) Any action undertaken to promote public health and safety by
replacing of existing merchandise with an improved product or new
package design.
(3) A procedure to ensure that wholesale drug distributors prepare
for, protect against, and handle any crisis that affects security or
operation of any facility in the event of strike, fire, flood, or other
natural disaster, or other situations of local, State, or national
emergency.
(4) A procedure to ensure that any outdated prescription drugs shall
be segregated from other drugs and either returned to the manufacturer
or destroyed. This procedure shall provide for written documentation of
the disposition of outdated prescription drugs. This documentation shall
be maintained for 2 years after disposition of the outdated drugs.
(h) Responsible persons. Wholesale drug distributors shall establish
and maintain lists of officers, directors, managers, and other persons
in charge of wholesale drug distribution, storage, and handling,
including a description of their duties and a summary of their
qualifications.
(i) Compliance with Federal, State, and local law. Wholesale drug
distributors shall operate in compliance with applicable Federal, State,
and local laws and regulations.
(1) Wholesale drug distributors shall permit the State licensing
authority and authorized Federal, State, and local law enforcement
officials to enter and inspect their premises and delivery vehicles, and
to audit their records and written operating procedures, at reasonable
times and in a reasonable manner, to the extent authorized by law.
(2) Wholesale drug distributors that deal in controlled substances
shall register with the appropriate State controlled substance authority
and with the Drug Enforcement Administration
[[Page 134]]
(DEA), and shall comply with all applicable State, local, and DEA
regulations.
(j) Salvaging and reprocessing. Wholesale drug distributors shall be
subject to the provisions of any applicable Federal, State, or local
laws or regulations that relate to prescription drug product salvaging
or reprocessing, including parts 207, 210, and 211 of this chapter.
(Approved by the Office of Management and Budget under control number
0910-0251)
[55 FR 38023, Sept. 14, 1990, as amended at 64 FR 67763, Dec. 3, 1999]
PART 206_IMPRINTING OF SOLID ORAL DOSAGE FORM DRUG PRODUCTS FOR
HUMAN USE--Table of Contents
Sec.
206.1 Scope.
206.3 Definitions.
206.7 Exemptions.
206.10 Code imprint required.
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 371; 42 U.S.C. 262.
Source: 58 FR 47958, Sept. 13, 1993, unless otherwise noted.
Sec. 206.1 Scope.
This part applies to all solid oral dosage form human drug products,
including prescription drug products, over-the-counter drug products,
biological drug products, and homeopathic drug products, unless
otherwise exempted under Sec. 206.7.
Sec. 206.3 Definitions.
The following definitions apply to this part:
The act means the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
301 et seq.).
Debossed means imprinted with a mark below the dosage form surface.
Drug product means a finished dosage form, e.g., a tablet or capsule
that contains a drug substance, generally, but not necessarily, in
association with one or more other ingredients.
Embossed means imprinted with a mark raised above the dosage form
surface.
Engraved means imprinted with a code that is cut into the dosage
form surface after it has been completed.
Imprinted means marked with an identification code by means of
embossing, debossing, engraving, or printing with ink.
Manufacturer means the manufacturer as described in Sec. Sec. 201.1
and 600.3(t) of this chapter.
Solid oral dosage form means capsules, tablets, or similar drug
products intended for oral use.
Sec. 206.7 Exemptions.
(a) The following classes of drug products are exempt from
requirements of this part:
(1) Drug products intended for use in a clinical investigation under
section 505(i) of the act, but not including drugs distributed under a
treatment IND under part 312 of this chapter or distributed as part of a
nonconcurrently controlled study. Placebos intended for use in a
clinical investigation are exempt from the requirements of this part if
they are designed to copy the active drug products used in that
investigation.
(2) Drugs, other than reference listed drugs, intended for use in
bioequivalence studies.
(3) Drugs that are extemporaneously compounded by a licensed
pharmacist, upon receipt of a valid prescription for an individual
patient from a practitioner licensed by law to prescribe or administer
drugs, to be used solely by the patient for whom they are prescribed.
(4) Radiopharmaceutical drug products.
(b) Exemption of drugs because of size or unique physical
characteristics:
(1) For a drug subject to premarket approval, FDA may provide an
exemption from the requirements of Sec. 206.10 upon a showing that the
product's size, shape, texture, or other physical characteristics make
imprinting technologically infeasible or impossible.
(i) Exemption requests for products with approved applications shall
be made in writing to the appropriate review division in the Center for
Drug Evaluation and Research (CDER), Food and Drug Administration, 5901-
B Ammendale Rd., Beltsville, MD 20705-1266 or the Food and Drug
Administration, Center for Biologics Evaluation
[[Page 135]]
and Research, Document Control Center, 10903 New Hampshire Ave., Bldg.
71, Rm. G112, Silver Spring, MD 20993-0002. If FDA denies the request,
the holder of the approved application will have 1 year after the date
of an agency denial to imprint the drug product.
(ii) Exemption requests for products that have not yet received
approval shall be made in writing to the appropriate review division in
CDER or CBER.
(2) Any product not subject to premarket approval is exempt from the
requirement of Sec. 206.10 if, based on the product's size, shape,
texture, or other physical characteristics, the manufacturer or
distributor of the product is prepared to demonstrate that imprinting
the dosage form is technologically infeasible or impossible.
(c) For drugs that are administered solely in controlled health care
settings and not provided to patients for self-administration, sponsors
may submit requests for exemptions from the requirements of this rule.
Controlled settings include physicians' offices and other health care
facilities. Exemption requests should be submitted in writing to the
appropriate review division in CDER or CBER.
[58 FR 47958, Sept. 13, 1993, as amended at 70 FR 14981, Mar. 24, 2005;
74 FR 13112, Mar. 26, 2009; 80 FR 18091, Apr. 3, 2015]
Sec. 206.10 Code imprint required.
(a) Unless exempted under Sec. 206.7, no drug product in solid oral
dosage form may be introduced or delivered for introduction into
interstate commerce unless it is clearly marked or imprinted with a code
imprint that, in conjunction with the product's size, shape, and color,
permits the unique identification of the drug product and the
manufacturer or distributor of the product. Identification of the drug
product requires identification of its active ingredients and its dosage
strength. Inclusion of a letter or number in the imprint, while not
required, is encouraged as a more effective means of identification than
a symbol or logo by itself. Homeopathic drug products are required only
to bear an imprint that identifies the manufacturer and their
homeopathic nature.
(b) A holder of an approved application who has, under Sec. 314.70
(b) of this chapter, supplemented its application to provide for a new
imprint is not required to bring its product into compliance with this
section during the pendency of the agency's review. Once the review is
complete, the drug product is subject to the requirements of the rule.
(c) A solid oral dosage form drug product that does not meet the
requirement for imprinting in paragraph (a) of this section and is not
exempt from the requirement may be considered adulterated and misbranded
and may be an unapproved new drug.
(d) For purposes of this section, code imprint means any single
letter or number or any combination of letters and numbers, including,
e.g., words, company name, and National Drug Code, or a mark, symbol,
logo, or monogram, or a combination of letters, numbers, and marks or
symbols, assigned by a drug firm to a specific drug product.
[58 FR 47958, Sept. 13, 1993, as amended at 60 FR 19846, Apr. 21, 1995;
69 FR 18763, Apr. 8, 2004]
PART 207_REQUIREMENTS FOR FOREIGN AND DOMESTIC ESTABLISHMENT
REGISTRATION AND LISTING FOR HUMAN DRUGS, INCLUDING DRUGS THAT ARE
REGULATED UNDER A BIOLOGICS LICENSE APPLICATION, AND ANIMAL DRUGS,
AND THE NATIONAL DRUG CODE--Table of Contents
Subpart A_General
Sec.
207.1 What definitions and interpretations of terms apply to this part?
207.3 Bulk drug substance.
207.5 What is the purpose of this part?
207.9 Who does this part cover?
207.13 Who is exempt from the registration and listing requirements?
Subpart B_Registration
207.17 Who must register?
207.21 When must initial registration information be provided?
207.25 What information is required for registration?
207.29 What are the requirements for reviewing and updating registration
information?
[[Page 136]]
Subpart C_National Drug Code
207.33 What is the National Drug Code (NDC), how is it assigned, and
what are its requirements?
207.35 What changes require a new NDC?
207.37 What restrictions pertain to the use of the NDC?
Subpart D_Listing
207.41 Who must list drugs and what drugs must they list?
207.45 When, after initial registration of an establishment, must drug
listing information be submitted?
207.49 What listing information must a registrant submit for a drug that
it manufactures?
207.53 What listing information must a registrant submit for a drug that
it repacks or relabels?
207.54 What listing information must a registrant submit for a drug that
it salvages?
207.55 What additional drug listing information may FDA require?
207.57 What information must registrants submit when updating listing
information and when?
Subpart E_Electronic Format for Registration and Listing
207.61 How is registration and listing information provided to FDA?
207.65 How can a waiver of the electronic submission requirement be
obtained?
Subpart F_Miscellaneous
207.69 What are the requirements for an official contact and a United
States agent?
207.77 What legal status is conferred by registration and listing?
207.81 What registration and listing information will FDA make available
for public disclosure?
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360b, 371, 374,
381, 393; 42 U.S.C. 262, 264, 271.
Source: 81 FR 60212, Aug. 31, 2016, unless otherwise noted.
Subpart A_General
Sec. 207.1 What definitions and interpretations of terms apply
to this part?
The definitions and interpretations of terms in sections 201 and 510
of the Federal Food, Drug, and Cosmetic Act apply to the terms used in
this part, if not otherwise defined in this section. The following
definitions apply to this part:
Active pharmaceutical ingredient means any substance that is
intended for incorporation into a finished drug product and 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. Active pharmaceutical
ingredient does not include intermediates used in the synthesis of the
substance.
Bulk drug substance, as referenced in sections 503A(b)(1)(A) and
503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, means the same
as ``active pharmaceutical ingredient'' as defined in this section.
Commercial distribution means any distribution of a human drug,
except for investigational use under part 312 of this chapter, and any
distribution of an animal drug or an animal feed bearing or containing
an animal drug, except for investigational use under part 511 of this
chapter. The term does not include internal or interplant transfer
between registered establishments under common ownership and control,
including a parent, subsidiary, or affiliate company. For foreign
establishments that manufacture, repack, relabel, or salvage, or for
foreign private label distributors, the term ``commercial distribution''
has the same meaning except the term does not include distribution of
any drug that is neither imported nor offered for import into the United
States.
Content of labeling means:
(1) For human prescription drugs that are subject to section 505 of
the Federal Food, Drug, and Cosmetic Act or section 351 of the Public
Health Service Act: The content of the prescription drug labeling (as
specified in Sec. Sec. 201.56, 201.57, and 201.80 of this chapter),
including all text, tables, and figures.
(2) For human prescription drugs that are not subject to section 505
of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public
Health Service Act: The labeling equivalent to the content of the
prescription drug labeling (as specified in Sec. Sec. 201.56, 201.57,
and 201.80 of this chapter), including all text, tables, and figures.
[[Page 137]]
(3) For human over-the-counter (OTC) drugs: All text, tables, and
figures including the drug facts labeling required by Sec. 201.66 of
this chapter.
(4) For animal drugs (including, but not limited to, drugs that are
subject to section 512 of the Federal Food, Drug, and Cosmetic Act): The
content of the labeling that accompanies the drug that is necessary to
enable safe and proper administration of the drug (e.g., the labeling
applicable to veterinary drugs specified in part 201 of this chapter),
including all text, tables, and figures.
Domestic for purposes of registration and listing under this part,
when used to modify the term ``registrant,'' ``manufacturer,''
``repacker,'' ``relabeler,'' ``salvager,'' ``private label
distributor,'' or ``establishment,'' refers to a registrant,
manufacturer, repacker, relabeler, salvager, private label distributor,
or establishment within any State or Territory of the United States, the
District of Columbia, or the Commonwealth of Puerto Rico.
Drug, for the purposes of registration and listing under this part,
has the meaning given in section 201(g)(1) of the Federal Food, Drug,
and Cosmetic Act.
Establishment means a place of business under one management at one
general physical location. The term includes, among others, independent
laboratories that engage in control activities for a registered drug
establishment (e.g., consulting laboratories), manufacturers of
medicated feeds and of vitamin products that are drugs in accordance
with section 201(g) of the Federal Food, Drug, and Cosmetic Act, human
blood donor centers, and animal facilities used for the production or
control testing of licensed biologicals, and establishments engaged in
salvaging.
Establishment registration number means the number assigned to the
establishment, as identified by FDA, after the establishment
registration required in this part.
Finished drug product means a finished dosage form (e.g., tablet,
capsule, or solution) that contains at least one active pharmaceutical
ingredient, generally, but not necessarily, in association with other
ingredients in finished package form suitable for distribution to
pharmacies, hospitals, or other sellers or dispensers of the drug
product to patients or consumers.
Foreign for the purposes of registration and listing under this
part:
(1) When used to modify the term ``manufacturer,'' ``repacker,''
``relabeler,'' or ``salvager,'' refers to a manufacturer, repacker,
relabeler, or salvager, who is located in a foreign country and who
manufactures, repacks, relabels, or salvages a drug, or an animal feed
bearing or containing a new animal drug, that is imported or offered for
import into the United States.
(2) When used to modify the term ``establishment'' refers to an
establishment that is located in a foreign country and is engaged in the
manufacture, repackaging, relabeling, or salvaging of any drug, or any
animal feed bearing or containing a new animal drug, that is imported or
offered for import into the United States.
Importer means, for purposes of this part, a person in the United
States that is an owner, consignee, or recipient, at the time of entry,
of a foreign establishment's drug, or an animal feed bearing or
containing a new animal drug, that is imported into the United States.
Manufacture means each step in the manufacture, preparation,
propagation, compounding, or processing of a drug or an animal feed
bearing or containing a new animal drug. Manufacture includes the making
by chemical, physical, biological, or other procedures or manipulations
of a drug, or an animal feed bearing or containing a new animal drug,
including control procedures applied to the final product or to any part
of the process. Manufacture includes manipulation, sampling, testing, or
control procedures applied to the final product or to any part of the
process, including, for example, analytical testing of drugs for another
registered establishment's drug. For purposes of this part, and in order
to clarify the responsibilities of the entities engaged in different
operations, the term manufacture is defined and used separately from the
terms relabel, repackage, and salvage, although the
[[Page 138]]
term ``manufacture, preparation, propagation, compounding, or
processing,'' as used in section 510 of the Federal Food, Drug, and
Cosmetic Act, includes relabeling, repackaging, and salvaging
activities.
Manufacturer means a person who owns or operates an establishment
that manufactures a drug or an animal feed bearing or containing a new
animal drug. This term includes, but is not limited to, control
laboratories, contract laboratories, contract manufacturers, contract
packers, contract labelers, and other entities that manufacture a drug,
or an animal feed bearing or containing a new animal drug, as defined in
this paragraph. For purposes of this part, and in order to clarify the
responsibilities of the entities engaged in different operations, the
term manufacturer is defined and used separately from the terms
relabeler, repacker, and salvager, although the term ``manufacture,
preparation, propagation, compounding, or processing,'' as used in
section 510 of the Federal Food, Drug, and Cosmetic Act, includes the
activities of relabelers, repackers, and salvagers. Repackers,
relabelers, and salvagers are subject to the provisions of this part
that are applicable to repackers, relabelers, and salvagers, but are not
subject to the provisions of this part that are applicable to
manufacturers. When not modified by ``domestic'' or ``foreign,'' the
term includes both domestic manufacturers and foreign manufacturers.
Material change means any change in any drug listing information, as
required under Sec. Sec. 207.49, 207.53, 207.54, 207.55, or 207.57
except changes in format of labeling, labeling changes of an editorial
nature, or inclusion of a bar code or initial inclusion of an NDC on the
label.
Outsourcing facility means a compounder that has elected to register
with FDA under section 503B of the Federal Food, Drug, and Cosmetic Act
and that meets all of the conditions of section 503B.
Person who imports or offers for import means, for purposes of this
part, the owner or exporter of a drug who consigns and ships a drug from
a foreign country to the United States. This includes persons who send a
drug to the United States by international mail or other private
delivery service, but it does not include carriers who merely transport
the drug.
Private label distribution means commercial distribution of a drug
under the label or trade name of a person who did not manufacture,
repack, relabel, or salvage that drug.
Private label distributor means, with respect to a particular drug,
a person who did not manufacture, repack, relabel, or salvage the drug
but under whose label or trade name the drug is commercially
distributed.
Registrant means any person that owns or operates an establishment
that manufactures, repacks, relabels, or salvages a drug, and is not
otherwise exempt from establishment registration requirements under
section 510 of the Federal Food, Drug, and Cosmetic Act or this part.
Relabel means to change the existing label or labels on a drug or
drug package, or change or alter the existing labeling for a drug or
drug package, without repacking the drug or drug package. This term does
not include the addition or modification of information affixed solely
for purposes of delivery to a customer, customer identification, and/or
inventory management.
Relabeler means a person who owns or operates an establishment that
relabels a drug. When not modified by ``domestic'' or ``foreign,'' the
term includes both domestic relabelers and foreign relabelers.
Repack or repackage means the act of taking a finished drug product
or unfinished drug from the container in which it was placed in
commercial distribution and placing it into a different container
without manipulating, changing, or affecting the composition or
formulation of the drug.
Repacker means a person who owns or operates an establishment that
repacks a drug or drug package. When not modified by ``domestic'' or
``foreign,'' the term includes both domestic repackers and foreign
repackers.
Representative sampling of advertisements means typical advertising
material (including the promotional material described in Sec.
202.1(l)(1) of this
[[Page 139]]
chapter, but excluding labeling as determined in Sec. 202.1(l)(2) of
this chapter), that gives a balanced picture of the promotional claims
used for the drug.
Representative sampling of any other labeling means typical labeling
material (including the labeling material described in Sec. 202.1(l)(2)
of this chapter, but excluding labels and package inserts) that gives a
balanced picture of the promotional claims used for the drug.
Salvage means the act of segregating out those finished drug
products that may have been subjected to improper storage conditions
(such as extremes in temperature, humidity, smoke, fumes, pressure, age,
or radiation) for the purpose of returning the products to the
marketplace and includes applying manufacturing controls such as those
required by current good manufacturing practice in parts 210 and 211 of
this chapter.
Salvager means a person who owns or operates an establishment that
engages in salvaging. When not modified by ``domestic'' or ``foreign,''
the term includes both domestic and foreign salvagers.
Unfinished drug means an active pharmaceutical ingredient either
alone or together with one or more other ingredients but does not
include finished drug products.
[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]
Sec. 207.3 Bulk drug substance.
Bulk drug substance, as referenced in sections 503A(b)(1)(A) and
503B(a)(2) of the Federal Food, Drug, and Cosmetic Act, previously
defined in Sec. 207.3(a)(4), means the same as ``active pharmaceutical
ingredient'' as defined in Sec. 207.1.
[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]
Sec. 207.5 What is the purpose of this part?
Establishment registration information helps FDA identify who is
manufacturing, repacking, relabeling, and salvaging drugs and where
those operations are performed. Drug listing information gives FDA a
current inventory of drugs manufactured, repacked, relabeled, or
salvaged for commercial distribution. Both types of information
facilitate implementation and enforcement of the Federal Food, Drug, and
Cosmetic Act and are used for many important public health purposes.
Sec. 207.9 Who does this part cover?
(a) Except as provided in paragraph (b) of this section, this part
applies to:
(1) Domestic manufacturers, domestic repackers, domestic relabelers
and domestic salvagers, not exempt under section 510(g) of the Federal
Food, Drug, and Cosmetic Act or Sec. 207.13, regardless of whether
their drugs enter interstate commerce;
(2) Foreign manufacturers, foreign repackers, foreign relabelers and
foreign salvagers, not exempt under section 510(g) of the Federal Food,
Drug, and Cosmetic Act or Sec. 207.13;
(3) Private label distributors, because they must have labeler
codes;
(4) Establishments engaged in the manufacture, repacking,
relabeling, or salvaging of human drugs regulated under a biologics
license application (BLA). These establishments are subject to the
requirements of this part unless they are required to register and list
such drugs as human blood or blood products under part 607 of this
chapter and do not engage in activities that would otherwise require
them to register and list under this part.
(5) Establishments engaged in the manufacture (as defined in Sec.
1271.3(e) of this chapter) of human cells, tissues, and cellular and
tissue-based products (HCT/Ps) (as defined in Sec. 1271.3(d) of this
chapter) that, under Sec. 1271.20 of this chapter, are also drugs
regulated under section 351 of the Public Health Service Act or section
505 of the Federal Food, Drug, and Cosmetic Act. These establishments
must register and list those HCT/Ps following the procedures described
in this part.
(b) This part does not apply to owners and operators of
establishments that collect or process human whole blood and blood
products unless the establishment also manufactures, repacks, or
relabels other drugs. For purposes of this paragraph (b), human whole
blood and blood products do not include plasma derivatives such as
albumin, Immune Globulin, Factor VIII
[[Page 140]]
and Factor IX, and recombinant versions of plasma derivatives or animal
derived plasma derivatives, or bulk product substances such as
fractionation intermediates or pastes. Establishments that collect or
process human whole blood and blood products as well as establishments
involved in testing of human whole blood and blood products must
register and list under part 607 of this chapter. Manufacturers of
licensed devices and manufacturers of licensed biological products used
in a licensed device must register and list under part 607 of this
chapter.
(c) This part does not apply to establishments that solely
manufacture, prepare, propagate, compound, assemble, or process medical
devices. Registration and listing regulations for such establishments
are codified in part 807 of this chapter.
Sec. 207.13 Who is exempt from the registration and listing
requirements?
Except as provided in Sec. 207.13(l), the following classes of
persons are exempt from registration and drug listing in accordance with
section 510(g) of the Federal Food, Drug, and Cosmetic Act or because
FDA has determined, under section 510(g)(5) of the Federal Food, Drug,
and Cosmetic Act, that their registration is not necessary for the
protection of the public health. This exemption is limited to
establishment registration and drug listing requirements and does not
relieve a person from other statutory or regulatory obligations.
(a)(1) Pharmacies that:
(i) Operate in conformance with all applicable local laws regulating
the practice of pharmacy and medicine, including all applicable local
laws regulating the dispensing of prescription drugs;
(ii) Regularly engage in dispensing prescription drugs upon a valid
prescription by practitioners licensed by law to administer these drugs
to patients under their professional care; and
(iii) Do not manufacture, repack, relabel, or salvage drugs other
than in the regular course of their business of dispensing or selling
drugs at retail.
(2) The exemption in this paragraph (a) is limited to pharmacies
located in any State as defined in section 201(a)(1) of the Federal
Food, Drug, and Cosmetic Act.
(b)(1) Hospitals, clinics, other health care entities, and public
health agencies that:
(i) Operate establishments in conformance with all applicable local
laws regulating the practice of pharmacy and medicine, including all
applicable local laws regulating the dispensing of prescription drugs;
(ii) Regularly engage in dispensing prescription drugs, other than
human whole blood or blood products, upon a valid order or prescription
by practitioners licensed by law to administer these drugs to patients
under their professional care; and
(iii) Do not manufacture, repack, relabel, or salvage drugs other
than in the regular course of their practice of pharmacy, including
dispensing.
(2) The exemption in this paragraph (b) is limited to hospitals,
clinics, other health care entities, and public health agencies located
in any State as defined in section 201(a)(1) of the Federal Food, Drug,
and Cosmetic Act.
(c) Individuals or establishments under contract, agreement, or
other arrangement with a registered establishment and engaged solely in
recovering cells or tissues and sending the recovered cells or tissues
to the registered establishment to become components of a biological
product are exempt from registration and listing under this part unless
FDA determines that drug establishment registration and listing is
necessary for the protection of the public health.
(d) Practitioners who are licensed by law to prescribe or administer
drugs and who manufacture, repack, relabel, or salvage drugs solely for
use in their professional practice.
(e) Manufacturers, repackers, relabelers, or salvagers who
manufacture, repack, relabel, or salvage drugs solely for use in
research, teaching, or chemical analysis and not for sale.
(f) Manufacturers, repackers, and relabelers of harmless inactive
ingredients such as excipients, colorings,
[[Page 141]]
flavorings, emulsifiers, lubricants, preservatives, or solvents that
become components of drugs.
(g) Manufacturers, repackers, relabelers, or salvagers of Type B or
Type C medicated feeds, except for persons who manufacture, repack,
relabel, or salvage Type B or Type C medicated feeds starting from
Category II, Type A medicated articles for which a medicated feed mill
license approved under part 515 of this chapter is required. This
exemption also does not apply to persons that would otherwise be
required to register (such as manufacturers, repackers, relabelers, or
salvagers of certain free-choice feeds, as defined in Sec. 510.455 of
this chapter, or certain liquid feeds, as defined in Sec. 558.5 of this
chapter, where the specifications and/or formulas are not published and
a medicated feed mill license is required). All manufacturers,
repackers, relabelers, or salvagers of Type B or Type C medicated feeds
are exempt from listing.
(h) Any manufacturer, repacker, relabeler, or salvager of a virus,
serum, toxin, or analogous product intended for the treatment of
domestic animals who holds an unsuspended and unrevoked license issued
by the Secretary of Agriculture under the animal virus-serum-toxin law
of March 4, 1913 (37 Stat. 832 (21 U.S.C. 151 et seq.)), provided that
this exemption from registration applies only to the manufacturer,
repacker, relabeler, or salvager of that animal virus, serum, toxin, or
analogous product.
(i) Carriers, in their receipt, carriage, holding, or delivery of
drugs in the usual course of business as carriers.
(j) Foreign establishments whose drugs are imported or offered for
import into the United States must comply with the establishment
registration and listing requirements of this part unless exempt under
this section or unless:
(1) Their drugs enter a foreign trade zone and are re-exported
without having entered U.S. commerce, or
(2) Their drugs are imported in conformance with section 801(d)(3)
of the Federal Food, Drug, and Cosmetic Act.
(k) Entities that are registered with FDA as outsourcing facilities
and that compound drugs in conformance with section 503B of the Federal
Food, Drug, and Cosmetic Act.
(l) The exemptions provided in paragraphs (a) through (k) of this
section do not apply to such persons if they:
(1) Manufacture (as defined in Sec. 207.1), repack, relabel, or
salvage compounded positron emission tomography drugs as defined in
section 201(ii) of the Federal Food, Drug, and Cosmetic Act;
(2) Manufacture (as defined in Sec. 600.3(u) of this chapter) a
human biological product subject to licensing under section 351 of the
Public Health Service Act; or
(3) Engage in activities that would otherwise require them to
register under this part.
[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]
Subpart B_Registration
Sec. 207.17 Who must register?
(a) Unless exempt under section 510(g) of the Federal Food, Drug,
and Cosmetic Act or this part, all manufacturers, repackers, relabelers,
and salvagers must register each domestic establishment that
manufactures, repacks, relabels, or salvages a drug, or an animal feed
bearing or containing a new animal drug, and each foreign establishment
that manufactures, repacks, relabels, or salvages a drug, or an animal
feed bearing or containing a new animal drug, that is imported or
offered for import into the United States. When operations are conducted
at more than one establishment and common ownership and control among
all the establishments exists, the parent, subsidiary, or affiliate
company may submit registration information for all establishments.
(b) Private label distributors who do not also manufacture, repack,
relabel, or salvage drugs are not required to register under this part.
FDA will accept registration or listing information submitted by a
private label distributor only if it is acting as an authorized agent
for and submitting information that pertains to an establishment that
manufactures, repacks, relabels, or salvages drugs.
[[Page 142]]
Sec. 207.21 When must initial registration information be provided?
(a) Registrants must register each domestic establishment no later
than 5 calendar days after beginning to manufacture, repack, relabel, or
salvage a drug or an animal feed bearing or containing a new animal drug
at such establishment.
(b) Registrants must register each foreign establishment before a
drug or an animal feed bearing or containing a new animal drug
manufactured, repacked, relabeled, or salvaged at the establishment is
imported or offered for import into the United States.
Sec. 207.25 What information is required for registration?
Registrants must provide the following information:
(a) Name of the owner or operator of each establishment; if a
partnership, the name of each partner; if a corporation, the name of
each corporate officer and director, and the place of incorporation;
(b) Each establishment's name, physical address, and telephone
number(s);
(c) All name(s) of the establishment, including names under which
the establishment conducts business or names by which the establishment
is known;
(d) Registration number of each establishment, if previously
assigned by FDA;
(e) A Unique Facility Identifier in accordance with the system
specified under section 510 of the Federal Food, Drug, and Cosmetic Act.
(f) All types of operations performed at each establishment;
(g) Name, mailing address, telephone number, and email address of
the official contact for the establishment, as provided in Sec.
207.69(a); and
(h) Additionally, with respect to foreign establishments subject to
registration, the name, mailing address, telephone number, and email
address must be provided for:
(1) The United States agent, as provided in Sec. 207.69(b);
(2) Each importer in the United States of drugs manufactured,
repacked, relabeled, or salvaged at the establishment that is known to
the establishment; and
(3) Each person who imports or offers for import such drug to the
United States.
Sec. 207.29 What are the requirements for reviewing and updating
registration information?
(a) Expedited updates. Registrants must update their registration
information no later than 30 calendar days after:
(1) Closing or selling an establishment;
(2) Changing an establishment's name or physical address; or
(3) Changing the name, mailing address, telephone number, or email
address of the official contact or the United States agent. A
registrant, official contact, or United States agent may notify FDA
about a change of information for the designated official contact or
United States agent, but only a registrant is permitted to designate a
new official contact or United States agent.
(b) Annual review and update of registration information.
Registrants must review and update all registration information required
under Sec. 207.25 for each establishment.
(1) The first review and update must occur during the period
beginning on October 1 and ending December 31 of the year of initial
registration, if the initial registration occurs prior to October 1.
Subsequent reviews and updates must occur annually, during the period
beginning on October 1 and ending December 31 of each calendar year.
(2) The updates must reflect all changes that have occurred since
the last annual review and update.
(3) If no changes have occurred since the last registration,
registrants must certify that no changes have occurred.
Subpart C_National Drug Code
Sec. 207.33 What is the National Drug Code (NDC), how is it
assigned, and what are its requirements?
(a) What is the NDC for a drug and what products must have unique
NDCs? The NDC for a drug is a numeric code. Each finished drug product
or unfinished drug subject to the listing requirements of this part must
have a
[[Page 143]]
unique NDC to identify its labeler, product, and package size and type.
(b) What is the format of an NDC? (1) Except as described in
paragraph (b)(4) of this section, the NDC must consist of 10 or 11
digits, divided into three segments as follows:
(i) The first segment of the NDC is the labeler code and consists of
4, 5, or 6 digits. The labeler code is assigned by FDA.
(ii) The second segment of the NDC is the product code and consists
of 3 or 4 digits, as specified in paragraphs (b)(2) and (3) of this
section.
(iii) The third segment of the NDC is the package code and consists
of 1 or 2 digits as specified in paragraphs (b)(2) and (3) of this
section. The package code identifies the package size and type of the
drug and differentiates between different quantitative and qualitative
attributes of the product packaging.
(2) The following combinations of labeler code, product code and
package code character lengths are permissible:
(i) If a labeler code is either 5 or 6 digits in length, it may be
combined with:
(A) A product code consisting of 4 digits and a package code
consisting of 1 digit for a total NDC length of 10 or 11 digits (5-4-1
or 6-4-1), or
(B) A product code consisting of 3 digits and a package code
consisting of 2 digits for a total NDC length of 10 or 11 digits (5-3-2
or 6-3-2).
(ii) If a labeler code is 4 digits in length, it may be combined
only with a product code consisting of 4 digits and a package code
consisting of 2 digits for a total NDC length of 10 digits (4-4-2).
(3) A registrant or private label distributor with a given labeler
code must use only one Product-Package Code configuration (e.g., a 3-
digit product code combined with a 2-digit package code or a 4-digit
product code combined with a 1-digit package code). This single
configuration must be used in all NDCs that include the given labeler
code that are reserved in accordance with Sec. 207.33(d)(3) or listed
in accordance with Sec. 207.49 or Sec. 207.53.
(4) An alternatively formatted NDC that is approved for use by the
relevant Center Director may be used for the following HCT/Ps if they
are minimally manipulated: Hematopoietic stem/progenitor cells derived
from peripheral and cord blood, and lymphocytes collected from
peripheral blood.
(c) Who must obtain an NDC labeler code and how is the code assigned
and updated? (1) Each person who engages in manufacturing, repacking,
relabeling, or private label distribution of a drug subject to listing
under this part must apply for an NDC labeler code, by providing the
following information:
(i) The name, physical address, email address, and other contact
information FDA may request, of the person for whom the NDC labeler code
is requested;
(ii) The type(s) of activities (e.g., manufacture or repacking) in
which the person requesting the NDC labeler code engages with respect to
human drugs; and
(iii) The type(s) of drug(s) (human, animal, or both, and
prescription, nonprescription, or both) to which the NDC labeler code
will be applied.
(2) Each person who is assigned an NDC labeler code must update the
information submitted under paragraph (c)(1)of this section within 30
calendar days after any change to that information.
(d) How is an NDC proposed for assignment by FDA, when is an NDC
assigned by FDA, and how can a proposed NDC be reserved? (1) An NDC is
proposed for assignment by FDA when it is submitted for the first time
with listing information in accordance with Sec. 207.49 or Sec.
207.53, as applicable.
(i) Each manufacturer, repacker, or relabeler must propose for
assignment by FDA an NDC that includes its own labeler code for each
package size and type of drug that it manufactures, repacks, or relabels
for commercial distribution.
(ii) In addition, if a drug is distributed under the trade name or
label of a private label distributor, the manufacturer, repacker, or
relabeler must also propose for assignment by FDA an NDC that includes
the labeler code of the private label distributor under whose trade name
or label the drug is distributed, for each package size and type so
distributed.
[[Page 144]]
(2) If a proposed NDC conforms to the requirements of this section
and is not reserved for a different drug or was not previously assigned
to a different drug, FDA will assign the NDC to a drug when it receives
listing information required for that drug under Sec. 207.49 or Sec.
207.53.
(3) A manufacturer, repacker, relabeler, or private label
distributor may voluntarily reserve a proposed NDC for a drug, before
the drug is listed, by submitting the following information:
(i) A proposed NDC that conforms to the requirements of this
section;
(ii) The established name of the active ingredient(s) and the
strength of each active ingredient in the drug; and
(iii) In the case of a finished drug product, the dosage form, and
route of administration.
(4) If the required information is submitted and the proposed NDC is
properly formatted and not already assigned or reserved, FDA will
reserve the proposed NDC for a period of 2 years from the date of
submission. If the drug for which the proposed NDC is reserved is not
listed in accordance with Sec. 207.49 or Sec. 207.53 during such 2-
year period, the reservation of the proposed NDC will lapse. FDA may
also cancel the reservation of a proposed NDC at any time on the request
of the person whose labeler code is included in the proposed NDC.
(e) How must the information be submitted to us? The information
described in paragraphs (c) and (d) of this section must be submitted
electronically unless FDA grants a waiver under Sec. 207.65.
Sec. 207.35 What changes require a new NDC?
(a) Once an NDC has been assigned by FDA, the registrant must
propose a new and unique NDC for a drug when there is a change, after
the drug is initially marketed, to any of the information identified in
paragraphs (b) and (c) of this section. A new NDC must be proposed to
FDA for assignment through an updated listing in accordance with Sec.
207.57.
(b) The proposed new NDC must include a new product code when there
is a change to any of the following information:
(1) The drug's established name or proprietary name, if any;
(2) Any active pharmaceutical ingredient or the strength of any
active pharmaceutical ingredient;
(3) The dosage form;
(4) A change in the drug's status, between prescription and
nonprescription, or for animal drugs, between prescription,
nonprescription, or veterinary feed directive (VFD) status;
(5) A change in the drug's intended use between human and animal; or
(6) The drug's distinguishing characteristics such as size, shape,
color, code imprint, flavor, and scoring (if any).
(c) When there is a change only to the package size or type,
including the immediate unit-of-use container, if any, the proposed new
NDC must include only a new package code and retain the existing product
code unless all available package codes have already been combined with
the existing product code in NDCs assigned by FDA.
Sec. 207.37 What restrictions pertain to the use of the NDC?
(a) A product may be deemed to be misbranded if an NDC is used:
(1) To represent a different drug than the drug for which the NDC
has been assigned, as described in Sec. 207.33;
(2) To denote or imply FDA approval of a drug; or
(3) On products that are not subject to parts 207, 607 of this
chapter, or 1271 of this chapter, such as dietary supplements and
medical devices.
(b) If marketing is resumed for a discontinued drug, and no changes
have been made to the drug that would require a new NDC under Sec.
207.35, the drug must have the same NDC that was assigned to it as
described in Sec. 207.33, before marketing was discontinued.
Subpart D_Listing
Sec. 207.41 Who must list drugs and what drugs must they list?
(a) Each registrant must list each drug that it manufactures,
repacks, relabels, or salvages for commercial distribution. Each
domestic registrant must list each such drug regardless of whether the
drug enters interstate
[[Page 145]]
commerce. When operations are conducted at more than one establishment,
and common ownership and control exists among all the establishments,
the parent, subsidiary, or affiliate company may submit listing
information for any drug manufactured, repacked, relabeled, or salvaged
at any such establishment. A drug manufactured, repacked, or relabeled
for private label distribution must be listed in accordance with
paragraph (c) of this section.
(b) Registrants must provide listing information for each drug in
accordance with the listing requirements described in Sec. Sec. 207.49,
207.53, and 207.54 that correspond to the activity or activities they
engage in for that drug.
(c)(1) For both animal and human drugs, each registrant must list
each drug it manufactures, repacks, or relabels for commercial
distribution under the trade name or label of a private label
distributor using an NDC that includes such private label distributor's
labeler code.
(2) Additionally, in the case of human drugs, each registrant must
list each human drug it manufactures, repacks, or relabels using an NDC
that includes the registrant's own labeler code, regardless of whether
the drug is commercially distributed under the registrant's own label or
trade name or under the label or trade name of a private label
distributor.
Sec. 207.45 When, after initial registration of an establishment,
must drug listing information be submitted?
For each drug being manufactured, repacked, relabeled, or salvaged
for commercial distribution at an establishment at the time of initial
registration, drug listing information must be submitted no later than 3
calendar days after the initial registration of the establishment.
Sec. 207.49 What listing information must a registrant submit
for a drug it manufactures?
(a) Each registrant must provide the following listing information
for each drug it manufactures for commercial distribution.
(1) The appropriate NDC(s), as described in Sec. 207.33, that
include all package code variations. In the case of human drugs, the
appropriate NDC(s) submitted under this paragraph include the
registrant's labeler code. In the case of animal drugs, the appropriate
NDC(s) submitted under this paragraph include the registrant's labeler
code, except that when the drug is manufactured for commercial
distribution under the trade name or label of a private label
distributor, the appropriate NDC(s) for animal drugs include the private
label distributor's labeler code;
(2) Package type and volume information corresponding to the package
code segment of the NDC;
(3) The listed drug's established name and proprietary name, if any;
(4) The name and quantity of each active pharmaceutical ingredient
in the listed drug;
(5) The name of each inactive ingredient in the listed drug, along
with any assertions of confidentiality associated with individual
inactive ingredients;
(6) The dosage form;
(7) The drug's approved U.S. application number, if any;
(8) The drug type (e.g., as applicable, finished vs. unfinished,
human vs. animal, prescription vs. nonprescription);
(9) In the case of an unfinished drug, the number assigned to the
Drug Master File or Veterinary Master File, if any, that describes the
manufacture of the drug;
(10) For each drug that is subject to the imprinting requirements of
part 206 of this chapter including products that are exempted under
Sec. 206.7(b), the drug's size, shape, color, scoring, and code imprint
(if any);
(11) The route or routes of administration of the drug;
(12) For each drug bearing an NDC:
(i) The name and Unique Facility Identifier of the establishment
where the registrant who lists the drug manufactures it and the type of
operation performed on the drug at that establishment, and
(ii) The name and Unique Facility Identifier of every other
establishment where manufacturing is performed for the drug and the type
of operation performed at each such establishment. This includes all
establishments involved in the production of each unfinished drug
received by the registrant
[[Page 146]]
for use in the production of the drug being listed. The names, Unique
Facility Identifiers, and type of operations for establishments involved
in production of each unfinished drug received by the registrant for use
in the production of the drug being listed may be provided by including
the properly assigned and listed NDC for such unfinished drug.
(13) The schedule of the drug under section 202 of the Controlled
Substances Act, if applicable;
(14) Advertisements:
(i) A representative sampling of advertisements for a human
prescription drug that is not subject to section 505 of the Federal
Food, Drug, and Cosmetic Act or section 351 of the Public Health Service
Act;
(ii) If FDA requests it, for good cause, a copy of all
advertisements for a human prescription drug that is not subject to
section 505 of the Federal Food, Drug, and Cosmetic Act or section 351
of the Public Health Service Act, including those advertisements
described in Sec. 202.1(l)(1) of this chapter. Such advertisements must
be submitted within 30 calendar days after FDA's request.
(15) For drugs bearing the NDC(s) reported under paragraph (a)(1) of
this section, except those drugs manufactured exclusively for private
label distribution and not distributed under the registrant's own name
and label, provide the following labeling, as applicable:
(i) Human prescription drugs. All current labeling except that only
one representative container or carton label need be submitted where
differences exist only in the quantity of contents statement or the bar
code. This labeling submission must include the content of labeling, as
defined in Sec. 207.1.
(ii) Human nonprescription drugs. (A) For each human nonprescription
drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health Service Act, all current labeling,
except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement or the bar code. This labeling submission must include the
content of labeling, as defined in Sec. 207.1.
(B) For each human nonprescription drug not subject to section 505
of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public
Health Service Act, the current label (except that only one
representative container or carton label need be submitted where
differences exist only in the quantity of contents statement or the bar
code), the package insert (if any), and a representative sampling of any
other labeling. This labeling submission must include the content of
labeling as defined in section Sec. 207.1.
(iii) Animal drugs. (A) For each animal drug that is subject to
section 512 of the Federal Food, Drug, and Cosmetic Act, which includes,
but is not limited to, new animal drugs that have been approved,
conditionally approved, or indexed under sections 512, 571, or 572 of
the Federal Food, Drug, and Cosmetic Act, a copy of all current labeling
(except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement), including the content of labeling as defined in Sec. 207.1;
(B) For all other animal drugs, a copy of the current label (except
that only one representative container or carton label need be submitted
where differences exist only in the quantity of contents statement), the
package insert, the content of labeling as defined in Sec. 207.1, and a
representative sampling of any other labeling;
(iv) All other listed drugs. For all other listed drugs, including
unfinished drugs, the label (if any), except that only one
representative label need be submitted where differences exist only in
the quantity of contents statement.
(16) Listing submissions described in Sec. 207.41(c)(2) for human
drugs manufactured for private label distribution must include all
information specified in Sec. 207.49(a)(2) through (14) and:
(i) The appropriate NDC(s) (as described in Sec. 207.33) that
include the private label distributor's labeler code and all package
code variations;
(ii) The name, mailing address, telephone number, and email address
of the private label distributor; and
[[Page 147]]
(iii) For drugs bearing the NDC(s) reported under paragraph
(a)(16)(i) of this section, labeling as described in paragraph (a)(15)
of this section that accompanies the private label distributor's
product.
(b) Additionally, each registrant is requested, but not required, to
provide the following information for each human drug it manufactures
for commercial distribution:
(1) The drug's over-the-counter monograph reference, if any; and
(2) The date on which the drug was or will be introduced into
commercial distribution.
[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]
Sec. 207.53 What listing information must a registrant submit for
a drug that it repacks or relabels?
Each registrant must provide the following listing information for
each drug it repacks or relabels:
(a) NDC. The appropriate NDC(s), as described in Sec. 207.33, that
include the registrant's labeler code and all package code variations;
(b) Source NDC. The NDC assigned to each finished drug received by
the registrant for repacking or relabeling, with the exception of
medical gases. Each such NDC must be associated with the corresponding
NDC(s) for repacked or relabeled drugs, reported under paragraph (a) of
this section.
(c) Name and Unique Facility Identifier. For each drug identified by
an NDC reported under paragraph (a) of this section, the name and Unique
Facility Identifier of every establishment where repacking or relabeling
is performed for the drug and the type of operation (repacking vs.
relabeling) performed at each such establishment.
(d) Labeling. For each drug identified by an NDC reported under
paragraph (a) of this section, except those human drugs repacked or
relabeled exclusively for private label distribution and not distributed
under the registrant's own name and label, provide the following:
(1) Human prescription drugs. All current labeling for the repacked
or relabeled drug except that only one representative container or
carton label need be submitted where differences exist only in the
quantity of contents statement or the bar code. This labeling submission
must include the content of labeling, as defined in section Sec. 207.1.
(2) Human nonprescription drugs. (i) For each human nonprescription
drug subject to section 505 of the Federal Food, Drug, and Cosmetic Act
or section 351 of the Public Health Service Act, all current labeling,
except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement or the bar code. This labeling submission must include the
content of labeling, as defined in Sec. 207.1.
(ii) For each human nonprescription drug not subject to section 505
of the Federal Food, Drug, and Cosmetic Act or section 351 of the Public
Health Service Act, the current label (except that only one
representative container or carton label need be submitted where
differences exist only in the quantity of contents statement or the bar
code), the package insert (if any), and a representative sampling of any
other labeling. This labeling submission must include the content of
labeling as defined in Sec. 207.1.
(3) Animal drugs. (i) For each animal drug that is subject to
section 512 of the Federal Food, Drug, and Cosmetic Act, which includes
but is not limited to, new animal drugs that have been approved,
conditionally approved, or indexed under sections 512, 571, or 572 of
the Federal Food, Drug, and Cosmetic Act, a copy of all current labeling
(except that only one representative container or carton label need be
submitted where differences exist only in the quantity of contents
statement), including the content of labeling as defined in Sec. 207.1;
(ii) For all other animal drugs, a copy of the current label (except
that only one representative container or carton label need be submitted
where differences exist only in the quantity of contents statement), the
package insert, the content of labeling as defined in Sec. 207.1, and a
representative sampling of any other labeling;
(4) All other. For all other listed drugs, including unfinished
drugs, the label (if any), except that only one representative label
need be submitted
[[Page 148]]
where differences exist only in the quantity of contents statement.
(e) Advertisements. (1) A representative sampling of advertisements
for a human prescription drug that is not subject to section 505 of the
Federal Food, Drug, and Cosmetic Act or section 351 of the Public Health
Service Act;
(2) If we request it for good cause, a copy of all advertisements
for a particular drug described in paragraph (e)(1) of this section,
including advertisements described in Sec. 202.1(l)(1) of this chapter.
Such advertisements must be submitted within 30 calendar days after our
request.
(f) Private label distributor products. A listing submission for a
human drug distributed by a private label distributor described in Sec.
207.41(c)(2) must include information specified in Sec. 207.53(b)
through (e) as applicable and:
(1) The appropriate NDC(s) (as described in Sec. 207.33) that
include the private label distributor's labeler code and all package
code variations;
(2) The name, mailing address, telephone number, and email address
of the private label distributor; and
(3) For drugs bearing the NDC(s) reported under paragraph (f)(1) of
this section, labeling as described in paragraphs (d)(1) through (4) of
this section, as applicable, that accompanies the private label
distributor's product.
[81 FR 60212, Aug. 31, 2016, as amended at 86 FR 17061, Apr. 1, 2021]
Sec. 207.54 What listing information must a registrant submit for
a drug that it salvages?
A registrant who also relabels or repacks a drug that it salvages
must list the drug it relabels or repacks in accordance with Sec.
207.53 rather than in accordance with this section. A registrant who
performs only salvaging with respect to a drug must provide the
following listing information for that drug.
(a) The NDC assigned to the drug immediately before the drug is
received by the registrant for salvaging;
(b) The lot number and expiration date of the salvaged drug product;
and
(c) The name and Unique Facility Identifier for each establishment
where the registrant salvages the drug.
Sec. 207.55 What additional drug listing information may FDA require?
For a particular listed drug, upon our request, the registrant must
briefly state the basis for its belief that the drug is not subject to
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or
section 351 of the Public Health Service Act.
Sec. 207.57 What information must registrants submit when updating
listing information and when?
Registrants must review and update listing information at a minimum,
as follows:
(a) Registrants must provide listing information at the time of
annual establishment registration for any drug manufactured, repacked,
relabeled, or salvaged by them for commercial distribution that has not
been listed previously.
(b) Registrants must review and update their drug listing
information each June and December. When doing so, registrants must:
(1)(i) Provide listing information, in accordance with Sec. Sec.
207.49, 207.53, and 207.54, for any drug manufactured, repacked,
relabeled, or salvaged by them for commercial distribution that has not
been previously listed;
(ii) Submit the date that they discontinued the manufacture,
repacking, relabeling or salvaging for commercial distribution of a
listed drug and provide the expiration date of the last lot
manufactured, repacked, relabeled, or salvaged;
(iii) Submit the date that they resumed the manufacture, repacking,
or relabeling for commercial distribution of a drug previously
discontinued, and provide any required listing information not
previously submitted; and
(iv) Submit any material changes in any information previously
submitted pursuant to Sec. Sec. 207.49, 207.53, 207.54, or other
relevant sections of this part; or
(2) For each listed drug, certify that no changes subject to
reporting under paragraph (b)(1)(iv) of this section have occurred if no
such changes have occurred since the last review and update. If a drug
is discontinued and FDA has received the information required
[[Page 149]]
under paragraph (b)(1)(ii) of this section, no further certifications
are necessary for the discontinued drug. After initial electronic
listing, registrants may satisfy the listing update requirement with
respect to unchanged listing information by making a single ``no
changes'' certification during the annual registration update under
Sec. 207.29(b) applicable to all of the registrant's listed drugs for
which no changes have been made since the previous annual registration
update.
(c) Registrants are encouraged to submit listing information for
every drug subject to listing under this part prior to commercial
distribution and are encouraged to update listing information at the
time of any change affecting information previously submitted.
Subpart E_Electronic Format for Registration and Listing
Sec. 207.61 How is registration and listing information provided
to FDA?
(a) Electronic format. (1) Except as provided in Sec. 207.65, all
information submitted under this part must be transmitted to FDA in
electronic format by using our electronic drug registration and listing
system, in a form that we can process, review, and archive. We may
periodically issue guidance on how to provide registration and listing
information in electronic format (specifying for example method of
transmission, media, file formats, preparation, and organization of
files).
(2) Information provided in electronic format must comply with part
11 of this chapter, except as follows:
(i) Advertisements and labeling, including the content of labeling,
required under this part are exempt from the requirements in Sec.
11.10(a), (c) through (h), and (k) of this chapter and the corresponding
requirements in Sec. 11.30 of this chapter.
(ii) All other information submitted under this part is exempt from
the requirements in Sec. 11.10(b), (c), and (e) of this chapter and the
corresponding requirements in Sec. 11.30 of this chapter.
(b) English language. Drug establishment registration and drug
listing information must be provided in the English language. The
content of labeling must be provided at a minimum in the English
language. Where Sec. 201.15(c) of this chapter permits product labeling
solely in a foreign language, the content of labeling must be submitted
in that language along with an accurate English translation.
Sec. 207.65 How can a waiver of the electronic submission requirement
be obtained?
(a) All information submitted under this part must be transmitted to
FDA electronically in accordance with Sec. 207.61(a) unless FDA has
granted a request for waiver of this requirement prior to the date on
which submission of such information is due. Submission of a request for
waiver does not excuse timely compliance with the registration and
listing requirements. FDA will grant a waiver request if FDA determines
that the use of electronic means for submission of registration and
listing information is not reasonable for the registrant making the
waiver request.
(b) Waiver requests under this section must be submitted in writing
and must include the specific reasons why electronic submission is not
reasonable for the registrant and a U.S. telephone number and mailing
address where FDA can contact the registrant. All waiver requests must
be sent to: SPL Coordinator, U.S. Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 32, Silver Spring, MD 20993.
(c) If FDA grants the waiver request, FDA may limit its duration and
will specify terms of the waiver and provide information on how to
submit establishment registration, drug listings, other information, and
updates, as applicable.
Subpart F_Miscellaneous
Sec. 207.69 What are the requirements for an official contact
and a United States agent?
(a) Official contact. Registrants subject to the registration
requirements of this part must designate an official contact for each
establishment. The official contact is responsible for:
(1) Ensuring the accuracy of registration and listing information;
and
[[Page 150]]
(2) Reviewing, disseminating, routing, and responding to all
communications from FDA including emergency communications.
(b) United States agent. Registrants of foreign establishments
subject to this part must designate a single United States agent. The
United States agent must reside or maintain a place of business in the
United States and may not be a mailbox, answering machine or service, or
other place where a person acting as the United States agent is not
physically present. The United States agent is responsible for:
(1) Reviewing, disseminating, routing, and responding to all
communications from FDA including emergency communications;
(2) Responding to questions concerning those drugs that are imported
or offered for import to the United States;
(3) Assisting FDA in scheduling inspections; and
(4) If FDA is unable to contact a foreign registrant directly or
expeditiously, FDA may provide the information and/or documents to the
United States agent. FDA's providing information and/or documents to the
United States agent is equivalent to providing the same information and/
or documents to the foreign registrant.
Sec. 207.77 What legal status is conferred by registration and listing?
(a) Registration of an establishment or listing of a drug does not
denote approval of the establishment, the drug, or other drugs of the
establishment, nor does it mean that a product may be legally marketed.
Any representation that creates an impression of official approval or
that a drug is approved or is legally marketable because of registration
or listing is misleading and constitutes misbranding.
(b) FDA's acceptance of registration and listing information,
inclusion of a drug in our database of drugs, or assignment of an NDC
does not denote approval of the establishment or the drug or any other
drugs of the establishment, nor does it mean that the drug may be
legally marketed. Any representation that creates the impression that a
drug is approved or is legally marketable because it appears in our
database of drugs, has been assigned or displays an NDC, or the
establishment has been assigned an establishment registration number or
Unique Facility Identifier is misleading and constitutes misbranding.
Failure to comply with Sec. 207.37 may also constitute misbranding.
(c) Neither registration nor listing constitutes a determination by
FDA that a product is a drug as defined by section 201(g)(1) of the
Federal Food, Drug, and Cosmetic Act. Registration or listing may,
however, be evidence that a facility intends to or does manufacture,
repack, relabel, distribute, or salvage drugs or that a product is
intended to be a drug.
Sec. 207.81 What registration and listing information will FDA
make available for public disclosure?
(a) Except as provided in paragraphs (b) and (c) of this section,
the following information will be available for public disclosure, upon
request or at FDA's discretion:
(1) All establishment registration information, and
(2) After a drug is marketed, information obtained under Sec.
207.33, Sec. 207.49, Sec. 207.53, Sec. 207.54, or Sec. 207.57.
(b) Unless such information is publicly available or FDA finds that
confidentiality would be inconsistent with protection of the public
health, FDA will not make publicly available:
(1) Any information submitted under Sec. 207.55 as the basis upon
which it has been determined that a particular drug is not subject to
section 505 or 512 of the Federal Food, Drug, and Cosmetic Act or
section 351 of the Public Health Service Act,
(2) The names of any inactive ingredients submitted under Sec.
207.49(a)(4) for which the registrant makes a valid assertion of
confidentiality under Sec. 20.61 of this chapter or other provision of
law, or
(3) Drug listing information obtained under Sec. 207.33(d)(3),
Sec. 207.49(a)(9) and (12), Sec. 207.53(b) and (c), or Sec. 207.54(a)
or (c).
(c) FDA may determine, in limited circumstances and on a case-by-
case basis, that it would be consistent with the protection of the
public health and
[[Page 151]]
the Freedom of Information Act to exempt from public disclosure specific
information identified in paragraph (a) of this section.
PART 208_MEDICATION GUIDES FOR PRESCRIPTION DRUG PRODUCTS-
-Table of Contents
Subpart A_General Provisions
Sec.
208.1 Scope and purpose.
208.3 Definitions.
Subpart B_General Requirements for a Medication Guide
208.20 Content and format of a Medication Guide.
208.24 Distributing and dispensing a Medication Guide.
208.26 Exemptions and deferrals.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 360,
371, 374; 42 U.S.C. 262.
Source: 63 FR 66396, Dec. 1, 1998, unless otherwise noted.
Subpart A_General Provisions
Sec. 208.1 Scope and purpose.
(a) This part sets forth requirements for patient labeling for human
prescription drug products, including biological products, that the Food
and Drug Administration (FDA) determines pose a serious and significant
public health concern requiring distribution of FDA-approved patient
information. It applies primarily to human prescription drug products
used on an outpatient basis without direct supervision by a health
professional. This part shall apply to new prescriptions and refill
prescriptions.
(b) The purpose of patient labeling for human prescription drug
products required under this part is to provide information when the FDA
determines in writing that it is necessary to patients' safe and
effective use of drug products.
(c) Patient labeling will be required if the FDA determines that one
or more of the following circumstances exists:
(1) The drug product is one for which patient labeling could help
prevent serious adverse effects.
(2) The drug product is one that has serious risk(s) (relative to
benefits) of which patients should be made aware because information
concerning the risk(s) could affect patients' decision to use, or to
continue to use, the product.
(3) The drug product is important to health and patient adherence to
directions for use is crucial to the drug's effectiveness.
Sec. 208.3 Definitions.
For the purposes of this part, the following definitions shall
apply:
(a) Authorized dispenser means an individual licensed, registered,
or otherwise permitted by the jurisdiction in which the individual
practices to provide drug products on prescription in the course of
professional practice.
(b) Dispense to patients means the act of delivering a prescription
drug product to a patient or an agent of the patient either:
(1) By a licensed practitioner or an agent of a licensed
practitioner, either directly or indirectly, for self-administration by
the patient, or the patient's agent, or outside the licensed
practitioner's direct supervision; or
(2) By an authorized dispenser or an agent of an authorized
dispenser under a lawful prescription of a licensed practitioner.
(c) Distribute means the act of delivering, other than by
dispensing, a drug product to any person.
(d) Distributor means a person who distributes a drug product.
(e) Drug product means a finished dosage form, e.g., tablet,
capsule, or solution, that contains an active drug ingredient,
generally, but not necessarily, in association with inactive
ingredients. For purposes of this part, drug product also means
biological product within the meaning of section 351(a) of the Public
Health Service Act.
(f) Licensed practitioner means an individual licensed, registered,
or otherwise permitted by the jurisdiction in which the individual
practices to prescribe drug products in the course of professional
practice.
(g) Manufacturer means for a drug product that is not also a
biological product, both the manufacturer as described in Sec. 201.1
and the applicant as
[[Page 152]]
described in Sec. 314.3(b) of this chapter, and for a drug product that
is also a biological product, the manufacturer as described in Sec.
600.3(t) of this chapter.
(h) Medication Guide means FDA-approved patient labeling conforming
to the specifications set forth in this part and other applicable
regulations.
(i) Packer means a person who packages a drug product.
(j) Patient means any individual with respect to whom a drug product
is intended to be, or has been, used.
(k) Serious risk or serious adverse effect means an adverse drug
experience, or the risk of such an experience, as that term is defined
in Sec. Sec. 310.305, 312.32, 314.80, and 600.80 of this chapter.
Subpart B_General Requirements for a Medication Guide
Sec. 208.20 Content and format of a Medication Guide.
(a) A Medication Guide shall meet all of the following conditions:
(1) The Medication Guide shall be written in English, in
nontechnical, understandable language, and shall not be promotional in
tone or content.
(2) The Medication Guide shall be scientifically accurate and shall
be based on, and shall not conflict with, the approved professional
labeling for the drug product under Sec. 201.57 of this chapter, but
the language of the Medication Guide need not be identical to the
sections of approved labeling to which it corresponds.
(3) The Medication Guide shall be specific and comprehensive.
(4) The letter height or type size shall be no smaller than 10
points (1 point = 0.0138 inches) for all sections of the Medication
Guide, except the manufacturer's name and address and the revision date.
(5) The Medication Guide shall be legible and clearly presented.
Where appropriate, the Medication Guide shall also use boxes, bold or
underlined print, or other highlighting techniques to emphasize specific
portions of the text.
(6) The words ``Medication Guide'' shall appear prominently at the
top of the first page of a Medication Guide. The verbatim statement
``This Medication Guide has been approved by the U.S. Food and Drug
Administration'' shall appear at the bottom of a Medication Guide.
(7) The brand and established or proper name of the drug product
shall appear immediately below the words ``Medication Guide.'' The
established or proper name shall be no less than one-half the height of
the brand name.
(b) A Medication Guide shall contain those of the following headings
relevant to the drug product and to the need for the Medication Guide in
the specified order. Each heading shall contain the specific information
as follows:
(1) The brand name (e.g., the trademark or proprietary name), if
any, and established or proper name. Those products not having an
established or proper name shall be designated by their active
ingredients. The Medication Guide shall include the phonetic spelling of
either the brand name or the established name, whichever is used
throughout the Medication Guide.
(2) The heading, ``What is the most important information I should
know about (name of drug)?'' followed by a statement describing the
particular serious and significant public health concern that has
created the need for the Medication Guide. The statement should describe
specifically what the patient should do or consider because of that
concern, such as, weighing particular risks against the benefits of the
drug, avoiding particular behaviors (e.g., activities, drugs), observing
certain events (e.g., symptoms, signs) that could prevent or mitigate a
serious adverse effect, or engaging in particular behaviors (e.g.,
adhering to the dosing regimen).
(3) The heading, ``What is (name of drug)?'' followed by a section
that identifies a drug product's indications for use. The Medication
Guide may not identify an indication unless the indication is identified
in the indications and usage section of the professional labeling for
the product required under Sec. 201.57 of this chapter. In appropriate
circumstances, this section may also explain the nature of the disease
or condition the drug product is intended to treat, as well as the
benefit(s) of treating the condition.
[[Page 153]]
(4) The heading, ``Who should not take (name of drug)?'' followed by
information on circumstances under which the drug product should not be
used for its labeled indication (its contraindications). The Medication
Guide shall contain directions regarding what to do if any of the
contraindications apply to a patient, such as contacting the licensed
practitioner or discontinuing use of the drug product.
(5) The heading, ``How should I take (name of drug)?'' followed by
information on the proper use of the drug product, such as:
(i) A statement stressing the importance of adhering to the dosing
instructions, if this is particularly important;
(ii) A statement describing any special instructions on how to
administer the drug product, if they are important to the drug's safety
or effectiveness;
(iii) A statement of what patients should do in case of overdose of
the drug product; and
(iv) A statement of what patients should do if they miss taking a
scheduled dose(s) of the drug product, where there are data to support
the advice, and where the wrong behavior could cause harm or lack of
effect.
(6) The heading ``What should I avoid while taking (name of drug)?''
followed by a statement or statements of specific, important precautions
patients should take to ensure proper use of the drug, including:
(i) A statement that identifies activities (such as driving or
sunbathing), and drugs, foods, or other substances (such as tobacco or
alcohol) that patients should avoid when using the medication;
(ii) A statement of the risks to mothers and fetuses from the use of
the drug during pregnancy, if specific, important risks are known;
(iii) A statement of the risks of the drug product to nursing
infants, if specific, important risks are known;
(iv) A statement about pediatric risks, if the drug product has
specific hazards associated with its use in pediatric patients;
(v) A statement about geriatric risks, if the drug product has
specific hazards associated with its use in geriatric patients; and
(vi) A statement of special precautions, if any, that apply to the
safe and effective use of the drug product in other identifiable patient
populations.
(7) The heading, ``What are the possible or reasonably likely side
effects of (name of drug)?'' followed by:
(i) A statement of the adverse reactions reasonably likely to be
caused by the drug product that are serious or occur frequently.
(ii) A statement of the risk, if there is one, of patients'
developing dependence on the drug product.
(iii) For drug products approved under section 505 of the act, the
following verbatim statement: ``Call your doctor for medical advice
about side effects. You may report side effects to FDA at 1-800-FDA-
1088.''
(8) General information about the safe and effective use of
prescription drug products, including:
(i) The verbatim statement that ``Medicines are sometimes prescribed
for purposes other than those listed in a Medication Guide'' followed by
a statement that patients should ask health professionals about any
concerns, and a reference to the availability of professional labeling;
(ii) A statement that the drug product should not be used for a
condition other than that for which it is prescribed, or given to other
persons;
(iii) The name and place of business of the manufacturer, packer, or
distributor of a drug product that is not also a biological product, or
the name and place of business of the manufacturer or distributor of a
drug product that is also a biological product, and in any case the name
and place of business of the dispenser of the product may also be
included; and
(iv) The date, identified as such, of the most recent revision of
the Medication Guide placed immediately after the last section.
(9) Additional headings and subheadings may be interspersed
throughout the Medication Guide, if appropriate.
[63 FR 66396, Dec. 1, 1998, as amended at 73 FR 404, Jan. 3, 2008]
[[Page 154]]
Sec. 208.24 Distributing and dispensing a Medication Guide.
(a) The manufacturer of a drug product for which a Medication Guide
is required under this part shall obtain FDA approval of the Medication
Guide before the Medication Guide may be distributed.
(b) Each manufacturer who ships a container of drug product for
which a Medication Guide is required under this part is responsible for
ensuring that Medication Guides are available for distribution to
patients by either:
(1) Providing Medication Guides in sufficient numbers to
distributors, packers, or authorized dispensers to permit the authorized
dispenser to provide a Medication Guide to each patient receiving a
prescription for the drug product; or
(2) Providing the means to produce Medication Guides in sufficient
numbers to distributors, packers, or authorized dispensers to permit the
authorized dispenser to provide a Medication Guide to each patient
receiving a prescription for the drug product.
(c) Each distributor or packer that receives Medication Guides, or
the means to produce Medication Guides, from a manufacturer under
paragraph (b) of this section shall provide those Medication Guides, or
the means to produce Medication Guides, to each authorized dispenser to
whom it ships a container of drug product.
(d) The label of each container or package, where the container
label is too small, of drug product for which a Medication Guide is
required under this part shall instruct the authorized dispenser to
provide a Medication Guide to each patient to whom the drug product is
dispensed, and shall state how the Medication Guide is provided. These
statements shall appear on the label in a prominent and conspicuous
manner.
(e) Each authorized dispenser of a prescription drug product for
which a Medication Guide is required under this part shall, when the
product is dispensed to a patient (or to a patient's agent), provide a
Medication Guide directly to each patient (or to the patient's agent)
unless an exemption applies under Sec. 208.26.
(f) An authorized dispenser or wholesaler is not subject to section
510 of the Federal Food, Drug, and Cosmetic Act, which requires the
registration of producers of drugs and the listing of drugs in
commercial distribution, solely because of an act performed by the
authorized dispenser or wholesaler under this part.
Sec. 208.26 Exemptions and deferrals.
(a) FDA on its own initiative, or in response to a written request
from an applicant, may exempt or defer any Medication Guide content or
format requirement, except those requirements in Sec. 208.20 (a)(2) and
(a)(6), on the basis that the requirement is inapplicable, unnecessary,
or contrary to patients' best interests. Requests from applicants should
be submitted to the director of the FDA division responsible for
reviewing the marketing application for the drug product, or for a
biological product, to the application division in the office with
product responsibility.
(b) If the licensed practitioner who prescribes a drug product
subject to this part determines that it is not in a particular patient's
best interest to receive a Medication Guide because of significant
concerns about the effect of a Medication Guide, the licensed
practitioner may direct that the Medication Guide not be provided to the
particular patient. However, the authorized dispenser of a prescription
drug product subject to this part shall provide a Medication Guide to
any patient who requests information when the drug product is dispensed
regardless of any such direction by the licensed practitioner.
PART 209_REQUIREMENT FOR AUTHORIZED DISPENSERS AND PHARMACIES TO
DISTRIBUTE A SIDE EFFECTS STATEMENT--Table of Contents
Subpart A_General Provisions
Sec.
209.1 Scope and purpose.
209.2 Definitions.
Subpart B_Requirements
209.10 Content and format of the side effects statement.
[[Page 155]]
209.11 Dispensing and distributing the side effects statement.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 371; 42
U.S.C. 241.
Source: 73 FR 404, Jan. 3, 2008, unless otherwise noted.
Subpart A_General Provisions
Sec. 209.1 Scope and purpose.
(a) This part sets forth requirements for human prescription drug
products approved under section 505 of the Federal Food, Drug, and
Cosmetic Act and dispensed by authorized dispensers and pharmacies to
consumers. This part requires distribution of a side effects statement
and applies to new and refill prescriptions. This part is not intended
to apply to authorized dispensers dispensing or administering
prescription drug products to inpatients in a hospital or health care
facility under an order of a licensed practitioner, or as part of
supervised home health care.
(b) The purpose of providing the side effects statement is to enable
consumers to report side effects of prescription drug products to FDA.
Sec. 209.2 Definitions.
For the purposes of this part, the following definitions apply:
Act means the Federal Food, Drug, and Cosmetic Act (sections 201-907
(21 U.S.C. 301-397)).
Authorized dispenser means an individual licensed, registered, or
otherwise permitted by the jurisdiction in which the individual
practices to provide drug products on prescription in the course of
professional practice.
Consumer medication information means written information
voluntarily provided to consumers by dispensing pharmacists as part of
patient medication counseling activities.
Medication Guide means FDA-approved patient labeling conforming to
the specifications set forth in part 208 of this chapter and other
applicable regulations.
Pharmacy includes, but is not limited to, a retail, mail order,
Internet, hospital, university, or clinic pharmacy, or a public health
agency, regularly and lawfully engaged in dispensing prescription drugs.
Side effects statement means the following verbatim statement:
``Call your doctor for medical advice about side effects. You may report
side effects to FDA at 1-800-FDA-1088.''
Subpart B_Requirements
Sec. 209.10 Content and format of the side effects statement.
(a) Content. The side effects statement provided with each
prescription drug product approved under section 505 of the act must
read: ``Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088.''
(b) Format. The side effects statement must be in a single, clear,
easy-to-read type style. The letter height or type size used for the
side effects statement in accordance with paragraphs (b)(1) and (b)(2)
of Sec. 209.11 must be no smaller than 6 points (1 point = 0.0138
inch). The letter height or type size for the side effects statement
under paragraphs (b)(3), (b)(4), and (b)(5) of Sec. 209.11 must be no
smaller than 10 points.
Sec. 209.11 Dispensing and distributing the side effects statement.
(a) Each authorized dispenser or pharmacy must distribute the side
effects statement with each prescription drug product approved under
section 505 of the act and dispensed. The side effects statement must be
distributed with new and refill prescriptions.
(b) An authorized dispenser or pharmacy must choose one or more of
the following options to distribute the side effects statement:
(1) Distribute the side effects statement on a sticker attached to
the unit package, vial, or container of the drug product;
(2) Distribute the side effects statement on a preprinted pharmacy
prescription vial cap;
(3) Distribute the side effects statement on a separate sheet of
paper;
(4) Distribute the side effects statement in consumer medication
information; or
(5) Distribute the appropriate FDA-approved Medication Guide that
contains the side effects statement.
[[Page 156]]
PART 210_CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING,
PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL-
-Table of Contents
Sec.
210.1 Status of current good manufacturing practice regulations.
210.2 Applicability of current good manufacturing practice regulations.
210.3 Definitions.
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C.
216, 262, 263a, 264.
Source: 43 FR 45076, Sept. 29, 1978, unless otherwise noted.
Sec. 210.1 Status of current good manufacturing practice regulations.
(a) The regulations set forth in this part and in parts 211, 225,
and 226 of this chapter contain the minimum current good manufacturing
practice for methods to be used in, and the facilities or controls to be
used for, the manufacture, processing, packing, or holding of a drug to
assure that such drug meets the requirements of the act as to safety,
and has the identity and strength and meets the quality and purity
characteristics that it purports or is represented to possess.
(b) The failure to comply with any regulation set forth in this part
and in parts 211, 225, and 226 of this chapter in the manufacture,
processing, packing, or holding of a drug shall render such drug to be
adulterated under section 501(a)(2)(B) of the act and such drug, as well
as the person who is responsible for the failure to comply, shall be
subject to regulatory action.
(c) Owners and operators of establishments engaged in the recovery,
donor screening, testing (including donor testing), processing, storage,
labeling, packaging, or distribution of human cells, tissues, and
cellular and tissue-based products (HCT/Ps), as defined in Sec.
1271.3(d) of this chapter, that are drugs (subject to review under an
application submitted under section 505 of the act or under a biological
product license application under section 351 of the Public Health
Service Act), are subject to the donor-eligibility and applicable
current good tissue practice procedures set forth in part 1271 subparts
C and D of this chapter, in addition to the regulations in this part and
in parts 211, 225, and 226 of this chapter. Failure to comply with any
applicable regulation set forth in this part, in parts 211, 225, and 226
of this chapter, in part 1271 subpart C of this chapter, or in part 1271
subpart D of this chapter with respect to the manufacture, processing,
packing or holding of a drug, renders an HCT/P adulterated under section
501(a)(2)(B) of the act. Such HCT/P, as well as the person who is
responsible for the failure to comply, is subject to regulatory action.
[43 FR 45076, Sept. 29, 1978, as amended at 69 FR 29828, May 25, 2004;
74 FR 65431, Dec. 10, 2009]
Sec. 210.2 Applicability of current good manufacturing practice
regulations.
(a) The regulations in this part and in parts 211, 225, and 226 of
this chapter as they may pertain to a drug; in parts 600 through 680 of
this chapter as they may pertain to a biological product for human use;
and in part 1271 of this chapter as they are applicable to a human cell,
tissue, or cellular or tissue-based product (HCT/P) that is a drug
(subject to review under an application submitted under section 505 of
the act or under a biological product license application under section
351 of the Public Health Service Act); shall be considered to
supplement, not supersede, each other, unless the regulations explicitly
provide otherwise. In the event of a conflict between applicable
regulations in this part and in other parts of this chapter, the
regulation specifically applicable to the drug product in question shall
supersede the more general.
(b) If a person engages in only some operations subject to the
regulations in this part, in parts 211, 225, and 226 of this chapter, in
parts 600 through 680 of this chapter, and in part 1271 of this chapter,
and not in others, that person need only comply with those regulations
applicable to the operations in which he or she is engaged.
(c) An investigational drug for use in a phase 1 study, as described
in Sec. 312.21(a) of this chapter, is subject to the statutory
requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such
drug is exempt from compliance with the regulations in part 211 of this
[[Page 157]]
chapter. However, this exemption does not apply to an investigational
drug for use in a phase 1 study once the investigational drug has been
made available for use by or for the sponsor in a phase 2 or phase 3
study, as described in Sec. 312.21(b) and (c) of this chapter, or the
drug has been lawfully marketed. If the investigational drug has been
made available in a phase 2 or phase 3 study or the drug has been
lawfully marketed, the drug for use in the phase 1 study must comply
with part 211.
[69 FR 29828, May 25, 2004, as amended at 73 FR 40462, July 15, 2008; 74
FR 65431, Dec. 10, 2009]
Sec. 210.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the act shall be applicable to such terms when used in this part and in
parts 211, 225, and 226 of this chapter.
(b) The following definitions of terms apply to this part and to
parts 211, 225, and 226 of this chapter.
(1) Act means the Federal Food, Drug, and Cosmetic Act, as amended
(21 U.S.C. 301 et seq.).
(2) Batch means a specific quantity of a drug or other material that
is intended to have uniform character and quality, within specified
limits, and is produced according to a single manufacturing order during
the same cycle of manufacture.
(3) Component means any ingredient intended for use in the
manufacture of a drug product, including those that may not appear in
such drug product.
(4) Drug product means a finished dosage form, for example, tablet,
capsule, solution, etc., that contains an active drug ingredient
generally, but not necessarily, in association with inactive
ingredients. The term also includes a finished dosage form that does not
contain an active ingredient but is intended to be used as a placebo.
(5) Fiber means any particulate contaminant with a length at least
three times greater than its width.
(6) Nonfiber releasing filter means any filter, which after
appropriate pretreatment such as washing or flushing, will not release
fibers into the component or drug product that is being filtered.
(7) 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 man or other
animals. 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.
(8) Inactive ingredient means any component other than an active
ingredient.
(9) In-process material means any material fabricated, compounded,
blended, or derived by chemical reaction that is produced for, and used
in, the preparation of the drug product.
(10) Lot means a batch, or a specific identified portion of a batch,
having uniform character and quality within specified limits; or, in the
case of a drug product produced by continuous process, it is a specific
identified amount produced in a unit of time or quantity in a manner
that assures its having uniform character and quality within specified
limits.
(11) Lot number, control number, or batch number means any
distinctive combination of letters, numbers, or symbols, or any
combination of them, from which the complete history of the manufacture,
processing, packing, holding, and distribution of a batch or lot of drug
product or other material can be determined.
(12) Manufacture, processing, packing, or holding of a drug product
includes packaging and labeling operations, testing, and quality control
of drug products.
(13) The term medicated feed means any Type B or Type C medicated
feed as defined in Sec. 558.3 of this chapter. The feed contains one or
more drugs as defined in section 201(g) of the act. The manufacture of
medicated feeds is subject to the requirements of part 225 of this
chapter.
(14) The term medicated premix means a Type A medicated article as
defined in Sec. 558.3 of this chapter. The article contains one or more
drugs as defined
[[Page 158]]
in section 201(g) of the act. The manufacture of medicated premixes is
subject to the requirements of part 226 of this chapter.
(15) Quality control unit means any person or organizational element
designated by the firm to be responsible for the duties relating to
quality control.
(16) Strength means:
(i) The concentration of the drug substance (for example, weight/
weight, weight/volume, or unit dose/volume basis), and/or
(ii) The potency, that is, the therapeutic activity of the drug
product as indicated by appropriate laboratory tests or by adequately
developed and controlled clinical data (expressed, for example, in terms
of units by reference to a standard).
(17) Theoretical yield means the quantity that would be produced at
any appropriate phase of manufacture, processing, or packing of a
particular drug product, based upon the quantity of components to be
used, in the absence of any loss or error in actual production.
(18) Actual yield means the quantity that is actually produced at
any appropriate phase of manufacture, processing, or packing of a
particular drug product.
(19) Percentage of theoretical yield means the ratio of the actual
yield (at any appropriate phase of manufacture, processing, or packing
of a particular drug product) to the theoretical yield (at the same
phase), stated as a percentage.
(20) Acceptance criteria means the product specifications and
acceptance/rejection criteria, such as acceptable quality level and
unacceptable quality level, with an associated sampling plan, that are
necessary for making a decision to accept or reject a lot or batch (or
any other convenient subgroups of manufactured units).
(21) Representative sample means a sample that consists of a number
of units that are drawn based on rational criteria such as random
sampling and intended to assure that the sample accurately portrays the
material being sampled.
(22) Gang-printed labeling means labeling derived from a sheet of
material on which more than one item of labeling is printed.
[43 FR 45076, Sept. 29, 1978, as amended at 51 FR 7389, Mar. 3, 1986; 58
FR 41353, Aug. 3, 1993; 73 FR 51931, Sept. 8, 2008; 74 FR 65431, Dec.
10, 2009]
PART 211_CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED
PHARMACEUTICALS--Table of Contents
Subpart A_General Provisions
Sec.
211.1 Scope.
211.3 Definitions.
Subpart B_Organization and Personnel
211.22 Responsibilities of quality control unit.
211.25 Personnel qualifications.
211.28 Personnel responsibilities.
211.34 Consultants.
Subpart C_Buildings and Facilities
211.42 Design and construction features.
211.44 Lighting.
211.46 Ventilation, air filtration, air heating and cooling.
211.48 Plumbing.
211.50 Sewage and refuse.
211.52 Washing and toilet facilities.
211.56 Sanitation.
211.58 Maintenance.
Subpart D_Equipment
211.63 Equipment design, size, and location.
211.65 Equipment construction.
211.67 Equipment cleaning and maintenance.
211.68 Automatic, mechanical, and electronic equipment.
211.72 Filters.
Subpart E_Control of Components and Drug Product Containers and Closures
211.80 General requirements.
211.82 Receipt and storage of untested components, drug product
containers, and closures.
211.84 Testing and approval or rejection of components, drug product
containers, and closures.
211.86 Use of approved components, drug product containers, and
closures.
211.87 Retesting of approved components, drug product containers, and
closures.
211.89 Rejected components, drug product containers, and closures.
211.94 Drug product containers and closures.
[[Page 159]]
Subpart F_Production and Process Controls
211.100 Written procedures; deviations.
211.101 Charge-in of components.
211.103 Calculation of yield.
211.105 Equipment identification.
211.110 Sampling and testing of in-process materials and drug products.
211.111 Time limitations on production.
211.113 Control of microbiological contamination.
211.115 Reprocessing.
Subpart G_Packaging and Labeling Control
211.122 Materials examination and usage criteria.
211.125 Labeling issuance.
211.130 Packaging and labeling operations.
211.132 Tamper-evident packaging requirements for over-the-counter (OTC)
human drug products.
211.134 Drug product inspection.
211.137 Expiration dating.
Subpart H_Holding and Distribution
211.142 Warehousing procedures.
211.150 Distribution procedures.
Subpart I_Laboratory Controls
211.160 General requirements.
211.165 Testing and release for distribution.
211.166 Stability testing.
211.167 Special testing requirements.
211.170 Reserve samples.
211.173 Laboratory animals.
211.176 Penicillin contamination.
Subpart J_Records and Reports
211.180 General requirements.
211.182 Equipment cleaning and use log.
211.184 Component, drug product container, closure, and labeling
records.
211.186 Master production and control records.
211.188 Batch production and control records.
211.192 Production record review.
211.194 Laboratory records.
211.196 Distribution records.
211.198 Complaint files.
Subpart K_Returned and Salvaged Drug Products
211.204 Returned drug products.
211.208 Drug product salvaging.
Authority: 21 U.S.C. 321, 351, 352, 355, 360b, 371, 374; 42 U.S.C.
216, 262, 263a, 264.
Source: 43 FR 45077, Sept. 29, 1978, unless otherwise noted.
Subpart A_General Provisions
Sec. 211.1 Scope.
(a) The regulations in this part contain the minimum current good
manufacturing practice for preparation of drug products (excluding
positron emission tomography drugs) for administration to humans or
animals.
(b) The current good manufacturing practice regulations in this
chapter as they pertain to drug products; in parts 600 through 680 of
this chapter, as they pertain to drugs that are also biological products
for human use; and in part 1271 of this chapter, as they are applicable
to drugs that are also human cells, tissues, and cellular and tissue-
based products (HCT/Ps) and that are drugs (subject to review under an
application submitted under section 505 of the act or under a biological
product license application under section 351 of the Public Health
Service Act); supplement and do not supersede the regulations in this
part unless the regulations explicitly provide otherwise. In the event
of a conflict between applicable regulations in this part and in other
parts of this chapter, or in parts 600 through 680 of this chapter, or
in part 1271 of this chapter, the regulation specifically applicable to
the drug product in question shall supersede the more general.
(c) Pending consideration of a proposed exemption, published in the
Federal Register of September 29, 1978, the requirements in this part
shall not be enforced for OTC drug products if the products and all
their ingredients are ordinarily marketed and consumed as human foods,
and which products may also fall within the legal definition of drugs by
virtue of their intended use. Therefore, until further notice,
regulations under parts 110 and 117 of this chapter, and where
applicable, parts 113 through 129 of this chapter, shall be applied in
determining whether these OTC drug products that are also foods are
manufactured, processed, packed, or held under current good
manufacturing practice.
[43 FR 45077, Sept. 29, 1978, as amended at 62 FR 66522, Dec. 19, 1997;
69 FR 29828, May 25, 2004; 74 FR 65431, Dec. 10, 2009; 80 FR 56168,
Sept. 17, 2015]
[[Page 160]]
Sec. 211.3 Definitions.
The definitions set forth in Sec. 210.3 of this chapter apply in
this part.
Subpart B_Organization and Personnel
Sec. 211.22 Responsibilities of quality control unit.
(a) There shall be a quality control unit that shall have the
responsibility and authority to approve or reject all components, drug
product containers, closures, in-process materials, packaging material,
labeling, and drug products, and the authority to review production
records to assure that no errors have occurred or, if errors have
occurred, that they have been fully investigated. The quality control
unit shall be responsible for approving or rejecting drug products
manufactured, processed, packed, or held under contract by another
company.
(b) Adequate laboratory facilities for the testing and approval (or
rejection) of components, drug product containers, closures, packaging
materials, in-process materials, and drug products shall be available to
the quality control unit.
(c) The quality control unit shall have the responsibility for
approving or rejecting all procedures or specifications impacting on the
identity, strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality
control unit shall be in writing; such written procedures shall be
followed.
Sec. 211.25 Personnel qualifications.
(a) Each person engaged in the manufacture, processing, packing, or
holding of a drug product shall have education, training, and
experience, or any combination thereof, to enable that person to perform
the assigned functions. Training shall be in the particular operations
that the employee performs and in current good manufacturing practice
(including the current good manufacturing practice regulations in this
chapter and written procedures required by these regulations) as they
relate to the employee's functions. Training in current good
manufacturing practice shall be conducted by qualified individuals on a
continuing basis and with sufficient frequency to assure that employees
remain familiar with CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture,
processing, packing, or holding of a drug product shall have the
education, training, and experience, or any combination thereof, to
perform assigned functions in such a manner as to provide assurance that
the drug product has the safety, identity, strength, quality, and purity
that it purports or is represented to possess.
(c) There shall be an adequate number of qualified personnel to
perform and supervise the manufacture, processing, packing, or holding
of each drug product.
Sec. 211.28 Personnel responsibilities.
(a) Personnel engaged in the manufacture, processing, packing, or
holding of a drug product shall wear clean clothing appropriate for the
duties they perform. Protective apparel, such as head, face, hand, and
arm coverings, shall be worn as necessary to protect drug products from
contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter
those areas of the buildings and facilities designated as limited-access
areas.
(d) Any person shown at any time (either by medical examination or
supervisory observation) to have an apparent illness or open lesions
that may adversely affect the safety or quality of drug products shall
be excluded from direct contact with components, drug product
containers, closures, in-process materials, and drug products until the
condition is corrected or determined by competent medical personnel not
to jeopardize the safety or quality of drug products. All personnel
shall be instructed to report to supervisory personnel any health
conditions that may have an adverse effect on drug products.
Sec. 211.34 Consultants.
Consultants advising on the manufacture, processing, packing, or
holding
[[Page 161]]
of drug products shall have sufficient education, training, and
experience, or any combination thereof, to advise on the subject for
which they are retained. Records shall be maintained stating the name,
address, and qualifications of any consultants and the type of service
they provide.
Subpart C_Buildings and Facilities
Sec. 211.42 Design and construction features.
(a) Any building or buildings used in the manufacture, processing,
packing, or holding of a drug product shall be of suitable size,
construction and location to facilitate cleaning, maintenance, and
proper operations.
(b) Any such building shall have adequate space for the orderly
placement of equipment and materials to prevent mixups between different
components, drug product containers, closures, labeling, in-process
materials, or drug products, and to prevent contamination. The flow of
components, drug product containers, closures, labeling, in-process
materials, and drug products through the building or buildings shall be
designed to prevent contamination.
(c) Operations shall be performed within specifically defined areas
of adequate size. There shall be separate or defined areas or such other
control systems for the firm's operations as are necessary to prevent
contamination or mixups during the course of the following procedures:
(1) Receipt, identification, storage, and withholding from use of
components, drug product containers, closures, and labeling, pending the
appropriate sampling, testing, or examination by the quality control
unit before release for manufacturing or packaging;
(2) Holding rejected components, drug product containers, closures,
and labeling before disposition;
(3) Storage of released components, drug product containers,
closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug products;
(8) Storage of drug products after release;
(9) Control and laboratory operations;
(10) Aseptic processing, which includes as appropriate:
(i) Floors, walls, and ceilings of smooth, hard surfaces that are
easily cleanable;
(ii) Temperature and humidity controls;
(iii) An air supply filtered through high-efficiency particulate air
filters under positive pressure, regardless of whether flow is laminar
or nonlaminar;
(iv) A system for monitoring environmental conditions;
(v) A system for cleaning and disinfecting the room and equipment to
produce aseptic conditions;
(vi) A system for maintaining any equipment used to control the
aseptic conditions.
(d) Operations relating to the manufacture, processing, and packing
of penicillin shall be performed in facilities separate from those used
for other drug products for human use.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995]
Sec. 211.44 Lighting.
Adequate lighting shall be provided in all areas.
Sec. 211.46 Ventilation, air filtration, air heating and cooling.
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure, micro-
organisms, dust, humidity, and temperature shall be provided when
appropriate for the manufacture, processing, packing, or holding of a
drug product.
(c) Air filtration systems, including prefilters and particulate
matter air filters, shall be used when appropriate on air supplies to
production areas. If air is recirculated to production areas, measures
shall be taken to control recirculation of dust from production. In
areas where air contamination occurs during production, there shall be
adequate exhaust systems or other systems adequate to control
contaminants.
[[Page 162]]
(d) Air-handling systems for the manufacture, processing, and
packing of penicillin shall be completely separate from those for other
drug products for human use.
Sec. 211.48 Plumbing.
(a) Potable water shall be supplied under continuous positive
pressure in a plumbing system free of defects that could contribute
contamination to any drug product. Potable water shall meet the
standards prescribed in the Environmental Protection Agency's Primary
Drinking Water Regulations set forth in 40 CFR part 141. Water not
meeting such standards shall not be permitted in the potable water
system.
(b) Drains shall be of adequate size and, where connected directly
to a sewer, shall be provided with an air break or other mechanical
device to prevent back-siphonage.
[43 FR 45077, Sept. 29, 1978, as amended at 48 FR 11426, Mar. 18, 1983]
Sec. 211.50 Sewage and refuse.
Sewage, trash, and other refuse in and from the building and
immediate premises shall be disposed of in a safe and sanitary manner.
Sec. 211.52 Washing and toilet facilities.
Adequate washing facilities shall be provided, including hot and
cold water, soap or detergent, air driers or single-service towels, and
clean toilet facilities easily accesible to working areas.
Sec. 211.56 Sanitation.
(a) Any building used in the manufacture, processing, packing, or
holding of a drug product shall be maintained in a clean and sanitary
condition, Any such building shall be free of infestation by rodents,
birds, insects, and other vermin (other than laboratory animals). Trash
and organic waste matter shall be held and disposed of in a timely and
sanitary manner.
(b) There shall be written procedures assigning responsibility for
sanitation and describing in sufficient detail the cleaning schedules,
methods, equipment, and materials to be used in cleaning the buildings
and facilities; such written procedures shall be followed.
(c) There shall be written procedures for use of suitable
rodenticides, insecticides, fungicides, fumigating agents, and cleaning
and sanitizing agents. Such written procedures shall be designed to
prevent the contamination of equipment, components, drug product
containers, closures, packaging, labeling materials, or drug products
and shall be followed. Rodenticides, insecticides, and fungicides shall
not be used unless registered and used in accordance with the Federal
Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 135).
(d) Sanitation procedures shall apply to work performed by
contractors or temporary employees as well as work performed by full-
time employees during the ordinary course of operations.
Sec. 211.58 Maintenance.
Any building used in the manufacture, processing, packing, or
holding of a drug product shall be maintained in a good state of repair.
Subpart D_Equipment
Sec. 211.63 Equipment design, size, and location.
Equipment used in the manufacture, processing, packing, or holding
of a drug product shall be of appropriate design, adequate size, and
suitably located to facilitate operations for its intended use and for
its cleaning and maintenance.
Sec. 211.65 Equipment construction.
(a) Equipment shall be constructed so that surfaces that contact
components, in-process materials, or drug products shall not be
reactive, additive, or absorptive so as to alter the safety, identity,
strength, quality, or purity of the drug product beyond the official or
other established requirements.
(b) Any substances required for operation, such as lubricants or
coolants, shall not come into contact with components, drug product
containers, closures, in-process materials, or drug products so as to
alter the safety, identity, strength, quality, or purity of the drug
product beyond the official or other established requirements.
[[Page 163]]
Sec. 211.67 Equipment cleaning and maintenance.
(a) Equipment and utensils shall be cleaned, maintained, and, as
appropriate for the nature of the drug, sanitized and/or sterilized at
appropriate intervals to prevent malfunctions or contamination that
would alter the safety, identity, strength, quality, or purity of the
drug product beyond the official or other established requirements.
(b) Written procedures shall be established and followed for
cleaning and maintenance of equipment, including utensils, used in the
manufacture, processing, packing, or holding of a drug product. These
procedures shall include, but are not necessarily limited to, the
following:
(1) Assignment of responsibility for cleaning and maintaining
equipment;
(2) Maintenance and cleaning schedules, including, where
appropriate, sanitizing schedules;
(3) A description in sufficient detail of the methods, equipment,
and materials used in cleaning and maintenance operations, and the
methods of disassembling and reassembling equipment as necessary to
assure proper cleaning and maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipment from contamination prior to use;
(6) Inspection of equipment for cleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and
inspection as specified in Sec. Sec. 211.180 and 211.182.
[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51931, Sept. 8, 2008]
Sec. 211.68 Automatic, mechanical, and electronic equipment.
(a) Automatic, mechanical, or electronic equipment or other types of
equipment, including computers, or related systems that will perform a
function satisfactorily, may be used in the manufacture, processing,
packing, and holding of a drug product. If such equipment is so used, it
shall be routinely calibrated, inspected, or checked according to a
written program designed to assure proper performance. Written records
of those calibration checks and inspections shall be maintained.
(b) Appropriate controls shall be exercised over computer or related
systems to assure that changes in master production and control records
or other records are instituted only by authorized personnel. Input to
and output from the computer or related system of formulas or other
records or data shall be checked for accuracy. The degree and frequency
of input/output verification shall be based on the complexity and
reliability of the computer or related system. A backup file of data
entered into the computer or related system shall be maintained except
where certain data, such as calculations performed in connection with
laboratory analysis, are eliminated by computerization or other
automated processes. In such instances a written record of the program
shall be maintained along with appropriate validation data. Hard copy or
alternative systems, such as duplicates, tapes, or microfilm, designed
to assure that backup data are exact and complete and that it is secure
from alteration, inadvertent erasures, or loss shall be maintained.
(c) Such automated equipment used for performance of operations
addressed by Sec. Sec. 211.101(c) or (d), 211.103, 211.182, or
211.188(b)(11) can satisfy the requirements included in those sections
relating to the performance of an operation by one person and checking
by another person if such equipment is used in conformity with this
section, and one person checks that the equipment properly performed the
operation.
[43 FR 45077, Sept. 29, 1978, as amended at 60 FR 4091, Jan. 20, 1995;
73 FR 51932, Sept. 8, 2008]
Sec. 211.72 Filters.
Filters for liquid filtration used in the manufacture, processing,
or packing of injectable drug products intended for human use shall not
release fibers into such products. Fiber-releasing filters may be used
when it is not possible to manufacture such products without the use of
these filters. If use of a fiber-releasing filter is necessary, an
additional nonfiber-releasing filter having a maximum nominal pore size
[[Page 164]]
rating of 0.2 micron (0.45 micron if the manufacturing conditions so
dictate) shall subsequently be used to reduce the content of particles
in the injectable drug product. The use of an asbestos-containing filter
is prohibited.
[73 FR 51932, Sept. 8, 2008]
Subpart E_Control of Components and Drug Product Containers and Closures
Sec. 211.80 General requirements.
(a) There shall be written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
testing, and approval or rejection of components and drug product
containers and closures; such written procedures shall be followed.
(b) Components and drug product containers and closures shall at all
times be handled and stored in a manner to prevent contamination.
(c) Bagged or boxed components of drug product containers, or
closures shall be stored off the floor and suitably spaced to permit
cleaning and inspection.
(d) Each container or grouping of containers for components or drug
product containers, or closures shall be identified with a distinctive
code for each lot in each shipment received. This code shall be used in
recording the disposition of each lot. Each lot shall be appropriately
identified as to its status (i.e., quarantined, approved, or rejected).
Sec. 211.82 Receipt and storage of untested components, drug
product containers, and closures.
(a) Upon receipt and before acceptance, each container or grouping
of containers of components, drug product containers, and closures shall
be examined visually for appropriate labeling as to contents, container
damage or broken seals, and contamination.
(b) Components, drug product containers, and closures shall be
stored under quarantine until they have been tested or examined,
whichever is appropriate, and released. Storage within the area shall
conform to the requirements of Sec. 211.80.
[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]
Sec. 211.84 Testing and approval or rejection of components,
drug product containers, and closures.
(a) Each lot of components, drug product containers, and closures
shall be withheld from use until the lot has been sampled, tested, or
examined, as appropriate, and released for use by the quality control
unit.
(b) Representative samples of each shipment of each lot shall be
collected for testing or examination. The number of containers to be
sampled, and the amount of material to be taken from each container,
shall be based upon appropriate criteria such as statistical criteria
for component variability, confidence levels, and degree of precision
desired, the past quality history of the supplier, and the quantity
needed for analysis and reserve where required by Sec. 211.170.
(c) Samples shall be collected in accordance with the following
procedures:
(1) The containers of components selected shall be cleaned when
necessary in a manner to prevent introduction of contaminants into the
component.
(2) The containers shall be opened, sampled, and resealed in a
manner designed to prevent contamination of their contents and
contamination of other components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used
when necessary.
(4) If it is necessary to sample a component from the top, middle,
and bottom of its container, such sample subdivisions shall not be
composited for testing.
(5) Sample containers shall be identified so that the following
information can be determined: name of the material sampled, the lot
number, the container from which the sample was taken, the date on which
the sample was taken, and the name of the person who collected the
sample.
(6) Containers from which samples have been taken shall be marked to
[[Page 165]]
show that samples have been removed from them.
(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of
each component of a drug product. Specific identity tests, if they
exist, shall be used.
(2) Each component shall be tested for conformity with all
appropriate written specifications for purity, strength, and quality. In
lieu of such testing by the manufacturer, a report of analysis may be
accepted from the supplier of a component, provided that at least one
specific identity test is conducted on such component by the
manufacturer, and provided that the manufacturer establishes the
reliability of the supplier's analyses through appropriate validation of
the supplier's test results at appropriate intervals.
(3) Containers and closures shall be tested for conformity with all
appropriate written specifications. In lieu of such testing by the
manufacturer, a certificate of testing may be accepted from the
supplier, provided that at least a visual identification is conducted on
such containers/closures by the manufacturer and provided that the
manufacturer establishes the reliability of the supplier's test results
through appropriate validation of the supplier's test results at
appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that
is liable to contamination with filth, insect infestation, or other
extraneous adulterant shall be examined against established
specifications for such contamination.
(6) Each lot of a component, drug product container, or closure with
potential for microbiological contamination that is objectionable in
view of its intended use shall be subjected to microbiological tests
before use.
(e) Any lot of components, drug product containers, or closures that
meets the appropriate written specifications of identity, strength,
quality, and purity and related tests under paragraph (d) of this
section may be approved and released for use. Any lot of such material
that does not meet such specifications shall be rejected.
[43 FR 45077, Sept. 29, 1978, as amended at 63 FR 14356, Mar. 25, 1998;
73 FR 51932, Sept. 8, 2008]
Sec. 211.86 Use of approved components, drug product containers,
and closures.
Components, drug product containers, and closures approved for use
shall be rotated so that the oldest approved stock is used first.
Deviation from this requirement is permitted if such deviation is
temporary and appropriate.
Sec. 211.87 Retesting of approved components, drug product
containers, and closures.
Components, drug product containers, and closures shall be retested
or reexamined, as appropriate, for identity, strength, quality, and
purity and approved or rejected by the quality control unit in
accordance with Sec. 211.84 as necessary, e.g., after storage for long
periods or after exposure to air, heat or other conditions that might
adversely affect the component, drug product container, or closure.
Sec. 211.89 Rejected components, drug product containers, and closures.
Rejected components, drug product containers, and closures shall be
identified and controlled under a quarantine system designed to prevent
their use in manufacturing or processing operations for which they are
unsuitable.
Sec. 211.94 Drug product containers and closures.
(a) Drug product containers and closures shall not be reactive,
additive, or absorptive so as to alter the safety, identity, strength,
quality, or purity of the drug beyond the official or established
requirements.
(b) Container closure systems shall provide adequate protection
against foreseeable external factors in storage and use that can cause
deterioration or contamination of the drug product.
[[Page 166]]
(c) Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to remove
pyrogenic properties to assure that they are suitable for their intended
use. Such depyrogenation processes shall be validated.
(d) Standards or specifications, methods of testing, and, where
indicated, methods of cleaning, sterilizing, and processing to remove
pyrogenic properties shall be written and followed for drug product
containers and closures.
(e) Medical gas containers and closures must meet the following
requirements--(1) Gas-specific use outlet connections. Portable
cryogenic medical gas containers that are not manufactured with
permanent gas use outlet connections (e.g., those that have been silver-
brazed) must have gas-specific use outlet connections that are attached
to the valve body so that they cannot be readily removed or replaced
(without making the valve inoperable and preventing the containers' use)
except by the manufacturer. For the purposes of this paragraph, the term
``manufacturer'' includes any individual or firm that fills high-
pressure medical gas cylinders or cryogenic medical gas containers. For
the purposes of this section, a ``portable cryogenic medical gas
container'' is one that is capable of being transported and is intended
to be attached to a medical gas supply system within a hospital, health
care entity, nursing home, other facility, or home health care setting,
or is a base unit used to fill small cryogenic gas containers for use by
individual patients. The term does not include cryogenic containers that
are not designed to be connected to a medical gas supply system, e.g.,
tank trucks, trailers, rail cars, or small cryogenic gas containers for
use by individual patients (including portable liquid oxygen units as
defined at Sec. 868.5655 of this chapter).
(2) Label and coloring requirements. The labeling specified at Sec.
201.328(a) of this chapter must be affixed to the container in a manner
that does not interfere with other labeling and such that it is not
susceptible to becoming worn or inadvertently detached during normal
use. Each such label as well as materials used for coloring medical gas
containers must be reasonably resistant to fading, durable when exposed
to atmospheric conditions, and not readily soluble in water.
[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008;
81 FR 81697, Nov. 18, 2016]
Subpart F_Production and Process Controls
Sec. 211.100 Written procedures; deviations.
(a) There shall be written procedures for production and process
control designed to assure that the drug products have the identity,
strength, quality, and purity they purport or are represented to
possess. Such procedures shall include all requirements in this subpart.
These written procedures, including any changes, shall be drafted,
reviewed, and approved by the appropriate organizational units and
reviewed and approved by the quality control unit.
(b) Written production and process control procedures shall be
followed in the execution of the various production and process control
functions and shall be documented at the time of performance. Any
deviation from the written procedures shall be recorded and justified.
Sec. 211.101 Charge-in of components.
Written production and control procedures shall include the
following, which are designed to assure that the drug products produced
have the identity, strength, quality, and purity they purport or are
represented to possess:
(a) The batch shall be formulated with the intent to provide not
less than 100 percent of the labeled or established amount of active
ingredient.
(b) Components for drug product manufacturing shall be weighed,
measured, or subdivided as appropriate. If a component is removed from
the original container to another, the new container shall be identified
with the following information:
(1) Component name or item code;
(2) Receiving or control number;
(3) Weight or measure in new container;
[[Page 167]]
(4) Batch for which component was dispensed, including its product
name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components
shall be adequately supervised. Each container of component dispensed to
manufacturing shall be examined by a second person to assure that:
(1) The component was released by the quality control unit;
(2) The weight or measure is correct as stated in the batch
production records;
(3) The containers are properly identified. If the weighing,
measuring, or subdividing operations are performed by automated
equipment under Sec. 211.68, only one person is needed to assure
paragraphs (c)(1), (c)(2), and (c)(3) of this section.
(d) Each component shall either be added to the batch by one person
and verified by a second person or, if the components are added by
automated equipment under Sec. 211.68, only verified by one person.
[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]
Sec. 211.103 Calculation of yield.
Actual yields and percentages of theoretical yield shall be
determined at the conclusion of each appropriate phase of manufacturing,
processing, packaging, or holding of the drug product. Such calculations
shall either be performed by one person and independently verified by a
second person, or, if the yield is calculated by automated equipment
under Sec. 211.68, be independently verified by one person.
[73 FR 51932, Sept. 8, 2008]
Sec. 211.105 Equipment identification.
(a) All compounding and storage containers, processing lines, and
major equipment used during the production of a batch of a drug product
shall be properly identified at all times to indicate their contents
and, when necessary, the phase of processing of the batch.
(b) Major equipment shall be identified by a distinctive
identification number or code that shall be recorded in the batch
production record to show the specific equipment used in the manufacture
of each batch of a drug product. In cases where only one of a particular
type of equipment exists in a manufacturing facility, the name of the
equipment may be used in lieu of a distinctive identification number or
code.
Sec. 211.110 Sampling and testing of in-process materials and
drug products.
(a) To assure batch uniformity and integrity of drug products,
written procedures shall be established and followed that describe the
in-process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch. Such control
procedures shall be established to monitor the output and to validate
the performance of those manufacturing processes that may be responsible
for causing variability in the characteristics of in-process material
and the drug product. Such control procedures shall include, but are not
limited to, the following, where appropriate:
(1) Tablet or capsule weight variation;
(2) Disintegration time;
(3) Adequacy of mixing to assure uniformity and homogeneity;
(4) Dissolution time and rate;
(5) Clarity, completeness, or pH of solutions.
(6) Bioburden testing.
(b) Valid in-process specifications for such characteristics shall
be consistent with drug product final specifications and shall be
derived from previous acceptable process average and process variability
estimates where possible and determined by the application of suitable
statistical procedures where appropriate. Examination and testing of
samples shall assure that the drug product and in-process material
conform to specifications.
(c) In-process materials shall be tested for identity, strength,
quality, and purity as appropriate, and approved or rejected by the
quality control unit, during the production process, e.g., at
commencement or completion of significant phases or after storage for
long periods.
(d) Rejected in-process materials shall be identified and controlled
under
[[Page 168]]
a quarantine system designed to prevent their use in manufacturing or
processing operations for which they are unsuitable.
[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]
Sec. 211.111 Time limitations on production.
When appropriate, time limits for the completion of each phase of
production shall be established to assure the quality of the drug
product. Deviation from established time limits may be acceptable if
such deviation does not compromise the quality of the drug product. Such
deviation shall be justified and documented.
Sec. 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent
objectionable microorganisms in drug products not required to be
sterile, shall be established and followed.
(b) Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting to be sterile,
shall be established and followed. Such procedures shall include
validation of all aseptic and sterilization processes.
[43 FR 45077, Sept. 29, 1978, as amended at 73 FR 51932, Sept. 8, 2008]
Sec. 211.115 Reprocessing.
(a) Written procedures shall be established and followed prescribing
a system for reprocessing batches that do not conform to standards or
specifications and the steps to be taken to insure that the reprocessed
batches will conform with all established standards, specifications, and
characteristics.
(b) Reprocessing shall not be performed without the review and
approval of the quality control unit.
Subpart G_Packaging and Labeling Control
Sec. 211.122 Materials examination and usage criteria.
(a) There shall be written procedures describing in sufficient
detail the receipt, identification, storage, handling, sampling,
examination, and/or testing of labeling and packaging materials; such
written procedures shall be followed. Labeling and packaging materials
shall be representatively sampled, and examined or tested upon receipt
and before use in packaging or labeling of a drug product.
(b) Any labeling or packaging materials meeting appropriate written
specifications may be approved and released for use. Any labeling or
packaging materials that do not meet such specifications shall be
rejected to prevent their use in operations for which they are
unsuitable.
(c) Records shall be maintained for each shipment received of each
different labeling and packaging material indicating receipt,
examination or testing, and whether accepted or rejected.
(d) Labels and other labeling materials for each different drug
product, strength, dosage form, or quantity of contents shall be stored
separately with suitable identification. Access to the storage area
shall be limited to authorized personnel.
(e) Obsolete and outdated labels, labeling, and other packaging
materials shall be destroyed.
(f) Use of gang-printed labeling for different drug products, or
different strengths or net contents of the same drug product, is
prohibited unless the labeling from gang-printed sheets is adequately
differentiated by size, shape, or color.
(g) If cut labeling is used for immediate container labels,
individual unit cartons, or multiunit cartons containing immediate
containers that are not packaged in individual unit cartons, packaging
and labeling operations shall include one of the following special
control procedures:
(1) Dedication of labeling and packaging lines to each different
strength of each different drug product;
(2) Use of appropriate electronic or electromechanical equipment to
conduct a 100-percent examination for correct labeling during or after
completion of finishing operations; or
(3) Use of visual inspection to conduct a 100-percent examination
for correct labeling during or after completion of finishing operations
for hand-applied labeling. Such examination
[[Page 169]]
shall be performed by one person and independently verified by a second
person.
(4) Use of any automated technique, including differentiation by
labeling size and shape, that physically prevents incorrect labeling
from being processed by labeling and packaging equipment.
(h) Printing devices on, or associated with, manufacturing lines
used to imprint labeling upon the drug product unit label or case shall
be monitored to assure that all imprinting conforms to the print
specified in the batch production record.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41353, Aug. 3, 1993;
77 FR 16163, Mar. 20, 2012]
Sec. 211.125 Labeling issuance.
(a) Strict control shall be exercised over labeling issued for use
in drug product labeling operations.
(b) Labeling materials issued for a batch shall be carefully
examined for identity and conformity to the labeling specified in the
master or batch production records.
(c) Procedures shall be used to reconcile the quantities of labeling
issued, used, and returned, and shall require evaluation of
discrepancies found between the quantity of drug product finished and
the quantity of labeling issued when such discrepancies are outside
narrow preset limits based on historical operating data. Such
discrepancies shall be investigated in accordance with Sec. 211.192.
Labeling reconciliation is waived for cut or roll labeling if a 100-
percent examination for correct labeling is performed in accordance with
Sec. 211.122(g)(2). Labeling reconciliation is also waived for 360[deg]
wraparound labels on portable cryogenic medical gas containers.
(d) All excess labeling bearing lot or control numbers shall be
destroyed.
(e) Returned labeling shall be maintained and stored in a manner to
prevent mixups and provide proper identification.
(f) Procedures shall be written describing in sufficient detail the
control procedures employed for the issuance of labeling; such written
procedures shall be followed.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993;
81 FR 81697, Nov. 18, 2016]
Sec. 211.130 Packaging and labeling operations.
There shall be written procedures designed to assure that correct
labels, labeling, and packaging materials are used for drug products;
such written procedures shall be followed. These procedures shall
incorporate the following features:
(a) Prevention of mixups and cross-contamination by physical or
spatial separation from operations on other drug products.
(b) Identification and handling of filled drug product containers
that are set aside and held in unlabeled condition for future labeling
operations to preclude mislabeling of individual containers, lots, or
portions of lots. Identification need not be applied to each individual
container but shall be sufficient to determine name, strength, quantity
of contents, and lot or control number of each container.
(c) Identification of the drug product with a lot or control number
that permits determination of the history of the manufacture and control
of the batch.
(d) Examination of packaging and labeling materials for suitability
and correctness before packaging operations, and documentation of such
examination in the batch production record.
(e) Inspection of the packaging and labeling facilities immediately
before use to assure that all drug products have been removed from
previous operations. Inspection shall also be made to assure that
packaging and labeling materials not suitable for subsequent operations
have been removed. Results of inspection shall be documented in the
batch production records.
[43 FR 45077, Sept. 29, 1978, as amended at 58 FR 41354, Aug. 3, 1993]