Proposed Rule2024-04840
Labeling Requirements for Approved or Conditionally Approved New Animal Drugs
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Published
March 12, 2024
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA) is proposing to revise the requirements for the content and format of labeling for approved or conditionally approved new animal drugs to provide for a more comprehensive set of requirements in one location in the Code of the Federal Register (CFR). As part of this revision, certain current requirements would be updated and moved, and certain obsolete requirements would be removed. The proposed requirements would apply to the labeling of prescription and over-the-counter (OTC) new animal drugs, as well as new animal drugs for use in animal feeds.
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[Federal Register Volume 89, Number 49 (Tuesday, March 12, 2024)]
[Proposed Rules]
[Pages 18262-18337]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2024-04840]
[[Page 18261]]
Vol. 89
Tuesday,
No. 49
March 12, 2024
Part V
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Parts 201, 500, 501, et al.
Labeling Requirements for Approved or Conditionally Approved New Animal
Drugs; Proposed Rule
Federal Register / Vol. 89 , No. 49 / Tuesday, March 12, 2024 /
Proposed Rules
[[Page 18262]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201, 500, 501, 510, 514, and 516
[Docket No. FDA-2023-N-5160]
RIN 0910-AI43
Labeling Requirements for Approved or Conditionally Approved New
Animal Drugs
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to revise
the requirements for the content and format of labeling for approved or
conditionally approved new animal drugs to provide for a more
comprehensive set of requirements in one location in the Code of the
Federal Register (CFR). As part of this revision, certain current
requirements would be updated and moved, and certain obsolete
requirements would be removed. The proposed requirements would apply to
the labeling of prescription and over-the-counter (OTC) new animal
drugs, as well as new animal drugs for use in animal feeds.
DATES: Either electronic or written comments on the proposed rule must
be submitted by June 10, 2024. Submit written comments (including
recommendations) on information collection issues under the Paperwork
Reduction Act of 1995 by April 11, 2024.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of June 10, 2024. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2023-N-5160 for ``Labeling Requirements for Approved or
Conditionally Approved New Animal Drugs.'' Received comments, those
filed in a timely manner (see ADDRESSES), will be placed in the docket
and, except for those submitted as ``Confidential Submissions,''
publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents, the
plain language summary of the proposed rule of not more than 100 words
are required by the ``Providing Accountability Through Transparency
Act,'' or the electronic and written/paper comments received, go to
<a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in
brackets in the heading of this document, into the ``Search'' box and
follow the prompts and/or go to the Dockets Management Staff, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852.
Submit comments on information collection issues under the
Paperwork Reduction Act of 1995 to the Office of Management and Budget
(OMB) <a href="https://www.reginfo.gov/public/do/PRAMain">https://www.reginfo.gov/public/do/PRAMain</a>. Find this particular
information collection by selecting ``Currently under Review--Open for
Public Comments'' or by using the search function. The title of this
proposed collection is ``Labeling Requirements for Approved or
Conditionally Approved New Animal Drugs.''
FOR FURTHER INFORMATION CONTACT:
With regard to the proposed rule: Suzanne Sechen, Center for
Veterinary Medicine, Food and Drug Administration, 7500 Standish Pl.,
Rockville, MD 20855, 240-402-0814, <a href="/cdn-cgi/l/email-protection#fcaf89869d929299d2af999f949992bc9a989dd294948fd29b938a"><span class="__cf_email__" data-cfemail="a7f4d2ddc6c9c9c289f4c2c4cfc2c9e7c1c3c689cfcfd489c0c8d1">[email protected]</span></a>.
With regard to the information collection: Amber Sanford, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-8867,
<a href="/cdn-cgi/l/email-protection#5c0c0e1d0f283d3a3a1c3a383d7234342f723b332a"><span class="__cf_email__" data-cfemail="acfcfeedffd8cdcacaeccac8cd82c4c4df82cbc3da">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose and Coverage of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
[[Page 18263]]
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. Introduction
B. Need for the Regulation
C. FDA's Current Regulatory Framework
D. History of the Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
A. Scope (Proposed Sec. 201.401)
B. Definitions (Proposed Sec. 201.403)
C. General Requirements (Proposed Sec. 201.404)
D. Content and Format for Prescription (Rx) New Animal Drug
Labeling--Overview (Proposed Sec. 201.405)
E. Content and Format for Over-The-Counter (OTC) New Animal Drug
Labeling--Overview (Proposed Sec. 201.407)
F. Content and Format of Labeling for New Animal Drugs for Use
in Animal Feeds--Overview (Proposed Sec. 201.409)
G. Exemptions From Labeling Requirements for Approved or
Conditionally Approved New Animal Drugs (Proposed Sec. 201.411)
H. Labeling Requirements for Certain Approved or Conditionally
Approved New Animal Drugs (Proposed Sec. 201.413)
I. Proposed Conforming Amendments
VI. Proposed Effective/Compliance Dates
VII. Preliminary Economic Analysis of Impacts
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References
I. Executive Summary
A. Purpose and Coverage of the Proposed Rule
FDA proposes to revise the existing regulations regarding the
content and format of labeling for approved or conditionally approved
new animal drugs. These proposed regulations would apply to the
labeling of prescription and OTC new animal drugs, as well as new
animal drugs for use in animal feeds. Certain existing regulations
regarding the labeling of new animal drugs would be updated and moved
from their current location and incorporated into the proposed
regulations, including a new subpart H in part 201 (21 CFR part 201).
FDA also proposes to amend or remove certain current regulations to
ensure consistency with the proposed regulations.
Proposed subpart H would not apply to heritable intentional genomic
alterations in animals. Proposed subpart H would also not apply to
labeling of indexed legally marketed unapproved new animal drugs for
minor species. In addition, proposed subpart H would not apply to
promotional labeling or advertising.
B. Summary of the Major Provisions of the Proposed Rule
The proposed rule would revise the existing requirements for the
content and format of labeling for approved or conditionally approved
new animal drugs. If finalized, sponsors of these new animal drugs
would need to comply with these proposed regulations on a staggered
schedule, over the course of 6 years, according to a schedule based on
application number, with approved NADAs with higher application numbers
having the earliest compliance date because they are more recently
approved and therefore likely to need the fewest labeling revisions.
If finalized, this rule would enable FDA to provide sponsors with
predictable requirements for the content and format of labeling for new
animal drugs and codify FDA's longstanding practices with respect to
the review of labeling submitted as part of a new animal drug
application (NADA), certain abbreviated new animal drug applications
(ANADAs) that reference a new animal drug for which the NADA has been
withdrawn, or a new animal drug application for conditional approval
(CNADA).
Currently a comprehensive set of regulations establishing labeling
requirements for the content and format of labeling for new animal
drugs does not exist in the CFR. These proposed regulations would
provide sponsors with predictable requirements for the content and
format of labeling for new animal drugs. Also, these proposed
regulations would help sponsors more efficiently prepare labeling for
new animal drugs to be submitted as part of an NADA, CNADA, or certain
ANADAs by providing clear and consistent requirements for the
information that would need to be included on each component of
labeling for a new animal drug, as well as the format in which the
information is to be presented.
FDA is proposing specific requirements for content and format of
the labeling for approved or conditionally approved prescription and
OTC new animal drugs, as well as approved or conditionally approved new
animal drugs for use in animal feeds.
The proposed regulations would provide the following:
<bullet> The content and format of labeling components applicable
to approved or conditionally approved new animal drugs.
<bullet> Definitions of labeling terms for approved or
conditionally approved new animal drugs.
<bullet> A schedule for sponsors of approved or conditionally
approved and marketed new animal drugs to comply with these proposed
regulations within a maximum of 6 years from the effective date of any
final rule.
<bullet> Provisions for foreign language translation of the
labeling for approved or conditionally approved new animal drugs.
<bullet> A process for sponsors of new animal drugs to request
exemptions from the proposed labeling requirements.
<bullet> Consolidation of the labeling requirements for the content
and format of labeling for approved or conditionally approved new
animal drugs into one section of the regulations. At present, existing
requirements are dispersed throughout the regulations.
C. Legal Authority
FDA's revisions to the content and format requirements for animal
drug labeling are authorized by various provisions of the Federal Food,
Drug, and Cosmetic Act (FD&C Act). The premarket approval provisions of
the FD&C Act authorize FDA to require that new animal drug labeling
provide adequate information to permit safe and effective use of the
drug.
The FD&C Act requires certain information be included on a drug's
label and provides for certain exemptions from these requirements.
Also, the FD&C Act authorizes FDA to establish additional exemptions by
regulation.
The FD&C Act requires that new animal drug applications include
specimens of the labeling proposed to be used for the drug. A new
animal drug will be deemed unsafe if its labeling fails to conform to
the approved labeling in the applicable approved new animal drug
application, conditionally approved new animal drug application, or new
animal drug index listing. Unsafe drugs are deemed adulterated under
the provisions of the FD&C Act. The FD&C Act prohibits the marketing of
drugs that are adulterated or misbranded as well as their adulteration
or misbranding while in interstate commerce.
In addition to the other statutory provisions described above, the
FD&C Act gives the FDA general rulemaking authority to issue
regulations for the efficient enforcement of the FD&C Act.
D. Costs and Benefits
If this proposed rule is finalized, industry and FDA would incur
cost savings from a reduction in the quantity and time burden of new
animal drug labeling amendments and informal communications related to
new animal drug labeling. There may be additional
[[Page 18264]]
benefits to users of approved or conditionally approved new animal
drugs from greater predictability and ease of reading new animal drug
labeling in the form of time saved searching for content, as well as
benefits to animal or human health, which we are unable to quantify.
We expect that new animal drug sponsors would incur one-time costs
to read and understand the rule, revise standard operating procedures
(SOPs) related to labeling, and train employees on the revised SOPs.
New animal drug sponsors would also bear costs to update labeling and
prepare supplemental labeling applications to conform to the proposed
requirements. FDA would incur costs to review these supplemental
applications.
FDA estimates that the annualized benefits over 10 years would
range from $0.143 million to $0.243 million at a 2 percent discount
rate, with a primary estimate of $0.193 million. The annualized costs
would range from $2.16 million to $2.77 million at a 2 percent discount
rate, with a primary estimate of $2.45 million.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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ADAA......................... Animal Drug Availability Act.
ANADA........................ Abbreviated New Animal Drug Application
CFR.......................... Code of Federal Regulations.
CNADA........................ Conditionally Approved New Animal Drug
Application.
FD&C Act..................... Federal Food, Drug, and Cosmetic Act.
FDA.......................... Food and Drug Administration.
FR........................... Federal Register.
HHS.......................... Health and Human Services.
INAD......................... Investigational New Animal Drug.
MUMS......................... Minor Use Minor Species.
NADA......................... New Animal Drug Application.
NDC.......................... National Drug Code.
NEPA......................... National Environmental Policy Act.
OMB.......................... Office of Management and Budget.
OTC.......................... Over-the-counter.
PCBs......................... Polychlorinated biphenyls.
PRA.......................... Paperwork Reduction Act of 1995.
RLNAD........................ Reference-Listed New Animal Drug.
Rx........................... Prescription.
U.S.......................... United States.
U.S.C........................ United States Code.
VFD.......................... Veterinary Feed Directive.
VMF.......................... Veterinary Master File.
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III. Background
A. Introduction
In accordance with the definition in section 201(k) of the FD&C Act
(21 U.S.C. 321(k)) the ``label'' is a display of written, printed, or
graphic matter upon the immediate container of any article. Under
section 201(m) of the FD&C Act, the term ``labeling'' means ``all
labels and other written, printed, or graphic matter (1) upon any
article or any of its containers or wrappers, or (2) accompanying such
article.'' Labeling, therefore, includes the label of any article,
including new animal drugs.
Under existing regulations, proposed labeling must be included as
part of an application filed with FDA for approval of a new animal
drug, in accordance with section 512(b)(1)(F) of the FD&C Act (21
U.S.C. 360b(b)(1)(F)). Labeling for nonprescription, known as over-the-
counter (OTC), new animal drugs should include adequate directions for
use by the layperson under all conditions of use for which the new
animal drug is intended, recommended, or suggested in any of the
labeling or advertising sponsored by the applicant (see Sec.
514.1(b)(3)(ii) (21 CFR 514.1(b)(3)(ii)). Labeling for prescription new
animal drugs should bear adequate information for use under which
veterinarians can use the new animal drug safely and for the purposes
for which it is intended, including those purposes for which it is to
be advertised or represented, in accordance with Sec. 201.105 (21 CFR
201.105) (see Sec. 514.1(b)(3)(iii)). All labeling for prescription or
OTC new animal drugs must provide any necessary use restrictions
prominently and conspicuously displayed (see Sec. 514.1(b)(3)(iv)).
Labeling for new animal drugs intended for use in the manufacture
of medicated feeds must include: (1) specimens of labeling to be used
for such new animal drug with adequate directions for the manufacture
and use of finished feeds for all conditions for which the new animal
drug is intended, recommended, or suggested in any of the labeling,
including advertising, sponsored by the applicant; and (2)
representative labeling proposed to be used for Type B and Type C
medicated feeds containing the new animal drug (see Sec.
514.1(b)(3)(v)). Sponsors of new animal drug applications commit to
providing labeling for the new animal drug that prescribes, recommends,
or suggests its use only under the conditions stated in the labeling
included as part of the application (see Sec. 514.1(b)(11)). All
representations of labeling in the application apply to the new animal
drug produced until changes are made in conformity with Sec. 514.8 (21
CFR 514.8) (see Sec. 514.1(b)(11)).
Sponsors of new animal drug applications may submit draft labeling
for FDA's preliminary consideration of an application (see Sec.
514.1(b)(3)(vi)). For example, sponsors sometimes include draft
labeling content pertinent to key components of an application that are
submitted for preliminary FDA review (e.g., manufacturing components
and composition, evidence to establish safety and effectiveness, and
environmental assessment).
Under section 502(a)(1) of the FD&C Act (21 U.S.C. 352(a)(1)), a
drug shall be deemed to be misbranded if its labeling is false or
misleading in any particular. A new animal drug for which an approval
or conditional approval is in effect will be considered unsafe if its
labeling fails to conform to the approved or conditionally approved
application (section 512(a)(1)(A) and (B) of the FD&C Act).
[[Page 18265]]
B. Need for the Regulation
Based on FDA's experience in reviewing labeling for approved or
conditionally approved prescription new animal drugs and informal
feedback from sponsors of such new animal drugs in the past 60 years,
it has become clear that sponsors would benefit from having more
detailed requirements on the content, format, and order of information
on labeling so that they can efficiently prepare adequate labeling for
approved or conditionally approved prescription new animal drugs to be
submitted as part of an NADA, CNADA, or certain ANADAs that reference a
new animal drug for which the NADA has been withdrawn.
For example, existing Sec. 201.105(c) provides requirements for
labeling ``on or within the package'' from which prescription animal
drugs are dispensed, and paragraph (d) of that section provides
requirements for all labeling for prescription new animal drugs.
Labeling for prescription new animal drugs typically consists of
multiple components, such as the label, one or more package inserts,
secondary container labeling, multiple unit carton labeling, shipping
labeling, and/or display carton labeling. However, neither paragraph
(c) nor (d) of Sec. 201.105 provides direction on the format or order
of information with respect to specific labeling components.
Furthermore, it is not clear whether the information required by
paragraph (d) of Sec. 201.105 needs to be presented on all components
of labeling for prescription new animal drugs, or if not, what critical
information needs to be provided on specific labeling components,
particularly smaller components of limited size.
Whereas existing Sec. 201.105 provides at least some requirements
for the content of labeling for prescription new animal drugs, there
are currently no regulations that provide requirements for the general
content and format of labeling for OTC new animal drugs and new animal
drugs administered in animal feeds.
The lack of direction regarding format and content for each
component of labeling has resulted in confusion for sponsors as they
prepare labeling for FDA's review and sometimes results in poor quality
labeling submissions. Poor quality labeling submissions increase the
time needed by sponsors to revise and resubmit adequate labeling, and
they increase time needed by FDA to review and approve labeling, and
consequently, the application.
New animal drug labeling that presents information in an
inconsistent manner can contribute to medication errors by making it
difficult for veterinarians and animal owners to readily locate and
understand critical directions and safety information. Information in
the labeling for approved or conditionally approved new animal drugs
presented in a consistent manner communicates information that is
important to the safe use of a new animal drug in the medication use
process (i.e., from prescription, to procurement, preparation, and
dispensing and administration of the medication to the animal).
Other regulations specifically pertaining to the labeling of
certain new animal drugs include Sec. 500.25 (21 CFR 500.25),
``Anthelmintic drugs for use in animals,'' Sec. 500.55 (21 CFR
500.55), ``Exemption from certain drug-labeling requirements,'' Sec.
510.105 (21 CFR 510.105), ``Labeling of drugs for use in milk-producing
animals,'' Sec. 510.106 (21 CFR 510.106), ``Labeling of antibiotic and
antibiotic-containing drugs intended for use in milk-producing
animals,'' and Sec. 510.410 (21 CFR 510.410), ``Corticosteroids for
oral, injectable, and ophthalmic use in animals; warnings and labeling
requirements.''
The proposed rule would locate the labeling requirements for
``Anthelmintic drugs for use in animals,'' currently in Sec. 500.25,
with other labeling requirements for new animal drugs.
The proposed rule would remove the exemption in Sec. 500.55,
``Exemption from certain drug-labeling requirements,'' because we
believe that full disclosure labeling is needed for all prescription
new animal drugs to ensure veterinarians are able to use these products
safely and effectively.
In addition, the proposed rule would remove the labeling
requirements in Sec. 510.105, ``Labeling of drugs for use in milk-
producing animals,'' and Sec. 510.106, ``Labeling of antibiotic and
antibiotic-containing drugs intended for use in milk-producing
animals.'' The labeling requirements in these regulations do not
provide adequate flexibility for targeted and informative statements
with respect to human food safety warnings, including milk discard
times, withdrawal periods, and residue warning statements for the
labeling of new animal drugs intended for use in milk-producing
animals.
Section 510.410, ``Corticosteroids for oral, injectable, and
ophthalmic use in animals; warnings and labeling requirements,''
contains background information and warning and labeling requirements
for this category of new animal drugs. We propose a conforming
amendment to remove Sec. 510.410 and to move portions of that section
to be located with the other labeling requirements for new animal
drugs.
C. FDA's Current Regulatory Framework
Current Sec. 201.105 provides conditions that must be met for
exempting prescription animal drugs from section 502(f)(1) of the FD&C
Act, which requires the labeling to bear adequate directions for use.
Section 201.105(b) requires the following information to appear on the
label for prescription animal drugs for such products to be exempt from
section 502(f)(1) of the FD&C Act:
<bullet> a standard statement restricting use to or on the order of
a licensed veterinarian,
<bullet> dosage,
<bullet> route of administration if it is not oral,
<bullet> quantity or proportion of each active ingredient as well
as information required, in accordance with section 502(e) of the FD&C
Act,
<bullet> names of inactive ingredients if the drug is for other
than oral use (with some exemptions), and
<bullet> an identifying lot or control number.
For containers too small or otherwise unable to fit a label with
enough space to display all the required information, Sec. 201.105(b)
allows eliminating some information from these labels and placing it on
other approved labeling.
Labeling for prescription new animal drugs must bear adequate
information for use, including indications, effects, dosages, routes,
methods, and frequency and duration of administration; any relevant
warnings, hazards, contraindications, side effects, and precautions
under which veterinarians can use the drug safely and for the intended
purposes; and ingredient information as required for the label (see
Sec. 201.105(c) through (e)). All prescription animal drug labeling,
except for labels and cartons, must bear the issuance dates of the
latest revisions of such labeling (see Sec. 201.105(e)). Applicants
may submit a written request to the Commissioner of Food and Drugs for
an exemption from inclusion of adequate information for use required in
Sec. 201.105(c)(1) from the dispensing package of prescription new
animal drugs for which directions, hazards, warnings, and use
information are commonly known to licensed veterinarians (see Sec.
201.105(c)(2)).
A prescription drug intended for both human and veterinary use must
comply with paragraphs (e) and (f) of Sec. 201.105, in addition to
Sec. 201.100, which provides
[[Page 18266]]
requirements for prescription drugs for human use (see Sec.
201.105(f)).
D. History of the Rulemaking
In 1955, FDA issued regulations at Sec. 1.106(c) establishing
requirements primarily for the label of prescription animal drugs (20
FR 9525 at 9533, December 20, 1955). The initial requirements were
expanded in 1960 to cover the labeling of such drugs more fully (25 FR
12592, December 9, 1960). As part of FDA's reorganization of its
regulations, in 1975 Sec. 1.106(c) was redesignated as Sec. 201.105
(40 FR 13494 at 13496, March 27, 1975). Most provisions in current
Sec. 201.105 are similar to the 1960 version of Sec. 1.106(c).
IV. Legal Authority
FDA's revisions to the content and format requirements for animal
drug labeling are authorized by various provisions of the FD&C Act,
including sections 201, 301, 501, 502, 503, 504, 512, 571, and 701 (21
U.S.C. 321, 331, 351, 352, 353, 354, 360b, 360ccc, and 371). Section
201 contains definitions relevant to the proposed content and format
requirements, including for the terms ``label'' and ``labeling''.
Pursuant to section 201(k) of the FD&C Act, the term ``label'' means
``a display of written, printed, or graphic matter upon the immediate
container of any article.'' That provision requires that any words,
statements, or other information appearing on the label also appear on
the outside container or wrapper of the retail package, or be easily
legible through the outside container or wrapper. Section 201(m) of the
FD&C Act defines ``labeling'' to mean ``all labels and other written,
printed, or graphic matter (1) upon any article or any of its
containers or wrappers, or (2) accompanying such article.''
Section 301 of the FD&C Act prohibits the marketing of drugs that
are adulterated or misbranded as well as their adulteration or
misbranding while in interstate commerce. Section 501(a)(5) of the FD&C
Act deems a new animal drug to be adulterated if it is unsafe within
the meaning of section 512 of the FD&C Act. Under section 512 of the
FD&C Act, a new animal drug will be deemed unsafe if its labeling fails
to conform to the applicable approved application under section 512 of
the FD&C Act, conditionally approved application under section 571 of
the FD&C Act, or index listing under section 572 of the FD&C Act (21
U.S.C. 360ccc-1).
Section 502 of the FD&C Act specifies conditions that cause a drug
to be misbranded. Under section 502(a) of the FD&C Act, a drug is
deemed to be misbranded if its labeling is false or misleading ``in any
particular.'' Section 201(n) of the FD&C Act deems a product's labeling
misleading if it fails to reveal facts regarding the consequences that
may result from using the article under the conditions of use
prescribed in the labeling or under such conditions of use as are
customary or usual. Under section 502(b) of the FD&C Act, a drug in
package form is deemed to be misbranded unless its label bears the name
and place of business of the manufacturer, packer, or distributor, and
it contains an accurate statement of the quantity of the contents in
terms of weight, measure, or numerical count. Section 502(c) of the
FD&C Act, deems a drug misbranded if any word, statement, or other
information required by law or regulation to be included on the label
or labeling does not appear with such prominence and conspicuousness,
and in such terms, that it is likely to be read and understood by
ordinary individuals under customary conditions of purchase and use.
Section 502(e) of the FD&C Act specifies requirements for including
the established name of the drug and for listing the active and
inactive ingredients on the drug's label. It also provides for certain
exemptions from the requirement to list active and inactive ingredients
and authorizes the Secretary to establish additional exemptions from
some of the requirements in section 502(e) by promulgating regulations
where compliance would be impracticable.
Section 502(f) of the FD&C Act deems a drug to be misbranded if its
labeling lacks adequate directions for use and adequate warnings
against use in those pathological conditions where its use may be
dangerous to health, as well as adequate warnings against unsafe dosage
or methods or duration of administration or application, in such manner
and form, as are necessary for the protection of users.
Section 502(j) of the FD&C Act deems a drug to be misbranded if it
is dangerous to health when used in the dosage or manner, or with the
frequency or duration, prescribed, recommended, or suggested in its
labeling.
Under section 502(w)(1) of the FD&C Act, a new animal drug that has
been conditionally approved is deemed to be misbranded if its labeling
fails to conform with the approved application or fails to include the
labeling information required under section 571(f) of the FD&C Act.
Section 571(f) requires the label and labeling of a new animal drug
with a conditional approval to contain the statement ``conditionally
approved by FDA pending a full demonstration of effectiveness under
application number,'' in addition to other information as required by
the Secretary. Effective September 30, 2023, section 502(w)(3) requires
the labeling of new animal drugs that have received approval under
section 512 of the FD&C Act to include the application number in the
format ``Approved by FDA under (A)NADA # xxx-xxx.''
Section 503(f) of the FD&C Act provides certain labeling
requirements specific to prescription animal drugs, including a
required cautionary statement. Section 503(f)(2) exempts prescription
animal drugs from having to comply with some of the requirements in
section 502 of the FD&C Act, including the requirement for there to be
adequate directions for use (section 502(f)), provided certain
dispensing and labeling requirements specified in section 503(f) are
met.
Section 504 of the FD&C Act authorizes the Secretary to issue
regulations specific to veterinary feed directive (VFD) drugs for use
in or on animal feed, including regulations prescribing a cautionary
statement and other information to be included on the labeling of VFD
drugs and animal feed containing such drugs. Under section 504(b), VFD
drugs and feed containing such drugs will be deemed to be misbranded if
their labeling fails to include such required information.
In addition, the premarket approval provisions of the FD&C Act
authorize FDA to require that animal drug labeling provide adequate
information to permit safe and effective use of the drug. Under section
512 of the FD&C Act, FDA will approve a NADA only if the drug is shown
to be both safe and effective under the conditions of use set forth in
the drug's labeling. Under section 571 of the FD&C Act, FDA will
conditionally approve a new animal drug application (CNADA) only if the
drug is shown to be safe, and there is a reasonable expectation of
effectiveness for use, under the conditions of use set forth in the
drug's labeling. Section 512(b)(1)(F) of the FD&C Act requires that the
application for approval of a new animal drug include specimens of the
labeling proposed to be used for the drug. A new animal drug that has
been approved or conditionally approved by FDA will be deemed to be
unsafe (and therefore adulterated under section 501(a)(5) of the FD&C
Act) if its labeling does not conform to its approved application.
In addition to the other statutory provisions described above,
section 701(a) of the FD&C Act gives the Secretary general rulemaking
authority
[[Page 18267]]
to issue regulations for the efficient enforcement of the FD&C Act.
FDA has previously issued implementing regulations governing the
format and content of labeling for animal drugs. This proposed rule,
when finalized, would revise the content and format of labeling
requirements applicable to approved and conditionally approved new
animal drugs and would consolidate these requirements in subpart H of
part 201.
V. Description of the Proposed Rule
FDA proposes to add subpart H to part 201 (hereafter called
proposed subpart H) to revise the existing requirements for the content
and format of labeling for approved or conditionally approved new
animal drugs. Proposed subpart H would be titled ``Labeling
Requirements for Approved or Conditionally Approved New Animal Drugs''
and would apply to new animal drugs that are approved under section 512
of the FD&C Act or conditionally approved under section 571 of the FD&C
Act. These regulations would not apply to legally marketed unapproved
new animal drugs for minor species that are indexed in accordance with
section 572 of the FD&C Act. These regulations would not apply to the
labeling of heritable intentional genomic alterations in animals, or to
promotional labeling or advertising.
Sponsors of approved or conditionally approved and marketed new
animal drugs would need to comply with these requirements per the
schedule in proposed Sec. 201.404(a)(4), (b), (c), or (d). Consistent
with current practice, we expect that sponsors of new animal drugs that
are the subject of an ANADA approved or submitted pursuant to section
512(n) of the FD&C Act (i.e., a generic new animal drug) will submit a
supplemental application to their ANADA to conform the labeling of
their generic new animal drugs with the revised labeling of the
reference-listed new animal drug (RLNAD). Therefore, in the preliminary
regulatory impact analysis we examine the costs and benefits of these
requirements for ANADAs that reference an NADA that has not been
withdrawn. However, for generic new animal drugs that are the subject
of an ANADA that reference a new animal drug for which the NADA has
been voluntarily withdrawn for reasons other than safety or
effectiveness, or that reference a new animal drug for which the NADA
that has been withdrawn on the basis of one or more of the grounds
included under section 512(e) of FD&C Act and for which the ANADA's
approval was not affected by the withdrawal, labeling for such ANADAs
would need to comply with proposed subpart H per the proposed schedule
described in proposed Sec. 201.404(a)(4)(iii).
The proposed requirements are based on FDA's experience in
reviewing labeling submitted for the approval or conditional approval
of new animal drugs and its experience in implementing existing
regulations for labeling of new animal drugs, as well as input received
from new animal drug sponsors, end users of animal drugs, information
collected from post approval surveillance, and other stakeholders. We
intend for these proposed regulations to provide consistent formatting
of new animal drug labeling by identifying the specific labeling
components that would be required and permitted for each new animal
drug, the information needed for each component, and the order in which
information would appear on labeling. Consistent and standardized
content and format of new animal drug labeling may make it easier for
end users (veterinarians, animal owners, or persons treating the
animals) to access, read, and use the information to make informed
decisions quickly, while promoting safe use of the drug. Such labeling
may contribute to reducing medication errors.
Providing clear and consistent requirements in these proposed
regulations should help to reduce the amount of time needed by sponsors
of new animal drugs to prepare high quality proposed labeling for their
new animal drugs. The submission of higher quality proposed labeling by
sponsors of new animal drugs may reduce the amount of time needed by
FDA to review and approve labeling, and consequently, the new animal
drug application.
We include the following eight sections in proposed subpart H:
<bullet> Sec. 201.401 Scope.
<bullet> Sec. 201.403 Definitions.
<bullet> Sec. 201.404 General requirements.
<bullet> Sec. 201.405 Content and format for prescription new
animal drug labeling.
<bullet> Sec. 201.407 Content and format for OTC new animal drug
labeling.
<bullet> Sec. 201.409 Content and format of labeling for new
animal drugs for use in animal feeds.
<bullet> Sec. 201.411 Exemptions from labeling requirements for
approved or conditionally approved new animal drugs.
<bullet> Sec. 201.413 Labeling requirements for certain approved
or conditionally approved new animal drugs.
A. Scope (Proposed Sec. 201.401)
The proposed rule would revise the existing requirements for the
content and format of labeling for prescription (Rx) new animal drugs,
OTC new animal drugs other than those for use in animal feeds in
accordance with part 558 (21 CFR part 558), and new animal drugs for
use in animal feeds that are subject to part 558, including VFD drugs,
that are subject of the specific applications identified in proposed
Sec. 201.401(a)(1) through (4).
Subpart H would apply to the labeling of new animal drugs that are
the subject of an NADA approved or submitted pursuant to section 512 of
the FD&C Act (see proposed Sec. 201.401(a)(1)), new animal drugs that
are the subject of a CNADA conditionally approved or submitted pursuant
to section 571 of the FD&C Act (see proposed Sec. 201.401(a)(2)), and
new animal drugs that are the subject of an ANADA approved or submitted
pursuant to section 512(n) of the FD&C Act (i.e., a generic new animal
drug) that reference a new animal drug for which the NADA has been
voluntarily withdrawn for reasons other than safety or effectiveness,
or that reference a new animal drug for which the NADA has been
withdrawn on the basis of one or more of the grounds included under
section 512(e) of the FD&C Act and for which the generic new animal
drug's approval was not affected by the withdrawal (see proposed Sec.
201.401(a)(3)).
For some proprietary Type B or Type C medicated feeds, the
formulation and labeling are approved and maintained in an NADA or
CNADA file. In other situations, the underlying data and labeling for
the proprietary Type B or Type C medicated feed to support the approved
uses are maintained in a Veterinary Master File (VMF). The latter would
include, as an example, situations in which a proprietary Type B or
Type C medicated feed is manufactured via modification to an approved
formulation published in the CFR or where a feed manufacturer creates
its own proprietary formulation. The labeling of these proprietary
medicated feeds is maintained in a VMF and would be required to comply
with proposed subpart H (see proposed Sec. 201.401(a)(4)).
The proposed requirements would apply to the applications described
in proposed Sec. 201.401(a)(1) through (4) for new animal drugs that
are approved before the effective date of any final rule based on this
proposed rule, pending on the effective date of any final rule based on
this proposed rule, or submitted on
[[Page 18268]]
or after the effective date of any final rule based on this proposed
rule (see proposed Sec. 201.401(c)). The schedule for compliance is
provided in proposed Sec. 201.404(a)(4).
The proposed requirements would deem any approved or conditionally
approved new animal drug subject to this subpart that does not fully
comply with the applicable requirements in accordance with the schedule
proposed in Sec. 201.404(a)(4) to be misbranded under section 502 of
the FD&C Act and, if that drug is a VFD drug, also under section 504(b)
of the FD&C Act (see proposed Sec. 201.401(c)).
The proposed requirements would not apply to the labeling of
legally marketed unapproved new animal drugs for minor species that are
indexed in accordance with section 572 of the FD&C Act (see proposed
Sec. 201.401(d)(1)) or to the labeling of heritable intentional
genomic alterations in animals (see proposed Sec. 201.401(d)(2)).
The proposed requirements would not apply to promotional labeling
or advertising (see proposed Sec. 201.401(d)(3)). Promotional labeling
for new animal drugs is generally any labeling other than labeling
required in an application for a new animal drug (see Sec.
514.1(b)(3)). Materials that may be considered promotional labeling or
advertising include, for example, brochures, booklets, mailing pieces,
or reminder labeling. These materials are described in more detail for
prescription human drugs and prescription new animal drugs in existing
21 CFR 202.1.
B. Definitions (Proposed Sec. 201.403)
Proposed Sec. 201.403 would establish definitions for terms used
in proposed subpart H.
The proposed definitions for the following terms would be the same
as those already in the FD&C Act or elsewhere in the regulations:
<bullet> ``active ingredient''
<bullet> ``adverse drug experience''
<bullet> ``ANADA''
<bullet> ``drug product''
<bullet> ``established name''
<bullet> ``extralabel use''
<bullet> ``free-choice medicated feed''
<bullet> ``inactive ingredient''
<bullet> ``label''
<bullet> ``labeling''
<bullet> ``lot number''
<bullet> ``control number''
<bullet> ``batch number''
<bullet> ``NADA''
<bullet> ``new animal drug''
<bullet> ``sponsor''
<bullet> ``strength''
<bullet> ``Type A medicated article''
<bullet> ``Type B medicated feed''
<bullet> ``Type C medicated feed''
<bullet> ``veterinary feed directive (VFD)''
<bullet> ``VFD drug''
We would base the definition of ``full prescribing information''
for prescription new animal drugs on the requirements for full
prescribing information for prescription human drugs and biologics
established in Sec. 201.57(c) (21 CFR 201.57(c)).
For OTC new animal drugs, we would create a similar term, called
``full product information.'' We would define ``full product
information'' as all information necessary for the safe and effective
use of an OTC new animal drug.
We would base the definitions of other terms on the requirements
established in Sec. 201.57(c) for full prescribing information of
prescription human drugs and biologics. These terms include ``adverse
reaction,'' ``boxed warning,'' and ``contraindication.'' The proposed
definition of ``precaution'' would be based on the requirements for the
``Other special care precautions'' labeling section described in Sec.
201.57(c)(6)(ii). The proposed definition of ``warning'' would be based
on general requirements for the ``Warnings and Precautions'' section
described in Sec. 201.57(c)(6)(i).
We would define ``active moiety'' as the molecule or ion, excluding
those appended portions of the molecule that cause the drug to be an
ester, salt (including a salt with hydrogen or coordination bonds), or
other noncovalent derivative (such as a complex, chelate, or clathrate)
of the molecule, responsible for the physiological or pharmacological
action of the drug substance.
We would define ``field study'' as a type of adequate and well-
controlled study designed to assess the effectiveness and/or safety of
a new animal drug in the target animal under conditions that closely
approximate the actual conditions of use.
The term ``indication'' would mean ``the use for which the new
animal drug is approved or conditionally approved.''
We would define ``milk discard time'' as the interval between the
time of the last administration of a new animal drug and the time when
the milk can be safely consumed.
We would define ``residue warning statement'' as a statement that
warns against the use of the new animal drug in animals for which the
withdrawal period and/or milk discard time has not been determined,
and/or provides other information to prevent illegal drug residues in
food products from animals treated with the new animal drug.
The term ``target animal'' would mean the species, or collection of
species, of animals, and if applicable, the specific subset(s) of
animals (e.g., life stage, production class, age, gender) for which the
new animal drug is approved or conditionally approved. Particularly for
food-producing animals, new animal drugs may be approved for use only
during a specific life stage (e.g., growing, pregnant, lactating),
production class (e.g., growing beef steers and heifers fed in
confinement for slaughter, broiler chickens, finishing pigs), age, or
gender of the animal.
We would define ``environmental warning'' as a warning that
identifies any potential hazard to the human environment associated
with the use of the new animal drug. We would define ``user safety
warning'' as a warning that identifies any serious adverse reaction or
potential hazard to human health associated with human exposure during
use of a new animal drug via contact, inhalation, ingestion, injection,
or by other means.
The term ``withdrawal period'' would mean the interval between the
time of the last administration of a new animal drug and the time when
the animal can be safely slaughtered for food.
The proposed regulations would provide definitions for terms
associated with key labeling components for new animal drugs, including
``immediate container,'' ``package insert,'' ``secondary container,''
``small label,'' ``shipping labeling,'' ``representative Type B
medicated feed labeling,'' and ``representative Type C medicated feed
labeling.''
C. General Requirements (Proposed Sec. 201.404)
The proposed rule would require the labeling for approved or
conditionally approved new animal drugs to conform to an application
approved under section 512 of the FD&C Act or conditionally approved
under section 571 of the FD&C Act (see proposed Sec. 201.404(a)(1)).
The proposed rule would require the labeling to be informative and
accurate and neither promotional in tone nor false or misleading in any
particular and would require the labeling to be updated if new
information becomes available to cause the labeling to become
inaccurate, false, or misleading, in accordance with Sec. 514.8 of
this chapter (see proposed Sec. 201.404(a)(2) and (3)).
The proposed rule would require labeling conforming to this subpart
to be submitted to FDA per the earliest applicable compliance date
provided in the schedule, unless Sec. 201.404(b), (c), or (d) was
applicable (see proposed Sec. 201.404(a)(4)). See also section VI for
[[Page 18269]]
discussion of Proposed Effective/Compliance Dates.
Labeling included in NADAs, CNADAs, or supplements to NADAs or
CNADAs subject to Sec. 514.8(c)(2) that are submitted to FDA for
approval more than 180 days after the effective date of any final rule
based on this proposed rule would be required to conform to the
regulations as part of the application (see proposed Sec.
201.404(a)(4)(i)).
The proposed rule would require sponsors with NADAs, CNADAs, or
supplements to NADAs or CNADAs subject to Sec. 514.8(c)(2) that are
pending with FDA on the effective date of any final rule based on this
proposed rule, or submitted within 180 days after the effective date of
any final rule based on this proposed rule, to submit conforming
labeling as part of the application or supplemental application, or
alternatively, as a supplement to the approved application or
supplemental application within 180 days after the approval date of the
application or supplemental application, as determined by FDA (see
proposed Sec. 201.404(a)(4)(ii)).
The proposed rule would establish a timeline for submission of
supplements with conforming labeling for marketed new animal drugs
originally approved before the effective date of any final rule based
on this proposed rule, based on NADA number (see proposed Sec.
201.404(a)(4)(iii) through (vii)).
For an ANADA that references a new animal drug for which the NADA
has been voluntarily withdrawn for reasons other than safety or
effectiveness, or that references a new animal drug for which the NADA
has been withdrawn on the basis of one or more grounds included under
section 512(e) of the FD&C Act and the ANADA's approval was not
affected by the withdrawal, the labeling for such an ANADA would be
required to be submitted between the [effective date of a final rule
plus 1 year] and the [effective date of a final rule plus 2 years] (see
proposed Sec. 201.404(a)(4)(iii)). For an ANADA that references a new
animal drug for which the NADA has not been withdrawn, consistent with
current practice, we expect that the sponsor of such a generic new
animal drug will submit a supplemental application to the ANADA to
conform the labeling of the generic new animal drug with the revised
labeling of the RLNAD once the labeling of the RLNAD has been revised
in accordance with the schedule in proposed Sec. 201.404.
Sponsors of proprietary Type B or Type C medicated feeds for which
the underlying data and labeling are maintained in a VMF would be
required to submit conforming labeling to the VMF within 180 days after
all conforming labeling has been approved for the NADA or CNADA that is
the approved or conditionally approved source of the new animal drug
used to manufacture the proprietary medicated feed (see proposed Sec.
201.404(b)).
The labeling for new animal drugs conditionally approved before the
effective date of a final rule would not be required to comply with
proposed subpart H until an application for full approval is submitted
unless a supplement subject to Sec. 514.8(c)(2) is submitted to the
CNADA after the effective date of a final rule (see proposed Sec.
201.404(c)). The conditional approval is valid for 1 year and can be
renewed annually for up to a total of 5 years by the sponsor showing
active progress towards demonstrating substantial evidence of
effectiveness. The conditional approval will be terminated if
substantial evidence of effectiveness is not demonstrated (section
571(d) of the FD&C Act).
The proposed rule would also establish an alternative schedule for
submitting conforming labeling for combination new animal drugs
intended for use in animal feed or drinking water and approved, on or
before the effective date of a final rule, in accordance with section
512(d)(4) of the FD&C Act, i.e., per the Animal Drug Availability Act
(ADAA) of 1996. Section 512(d)(4) was amended as part of the Minor Use
Minor Species (MUMS) Act of 2004 to clarify that only products approved
under section 512(b)(1) of the FD&C Act can be used in ADAA
combinations. Thus, ADAA combination new animal drugs exclude
conditionally approved drugs subject to section 571 of the FD&C Act.
These ADAA combination new animal drugs generally provide for more than
one approved new animal drug (as a Type A medicated article) to be
mixed into medicated feed or drinking water. These ADAA combination new
animal drug approvals result in new representative (``Blue Bird'')
labeling for medicated feeds containing the combination (see proposed
Sec. 201.409).
Representative labeling for medicated feed containing the approved
combination of new animal drugs includes information from the approved
labeling for the individual drugs. Thus, it would be appropriate that
the labeling for individual drugs included in the combination be
updated to conform to any final regulations before representative
labeling for the feeds containing the combination approval is updated.
However, the ADAA combination approval would occur after the individual
drugs are approved; therefore, the NADA number for the combination
approval would be higher than the NADA numbers for the individual new
animal drugs. Thus, according to the schedule proposed in Sec.
201.404(a)(4), the conforming labeling for a combination approval would
likely need to be submitted before the conforming labeling for the
individual drugs in the combination. To address this problem, the
proposed rule would require the conforming labeling for the combination
new animal drug to be submitted within 180 days of the approval of all
conforming labeling for the individual new animal drugs used in the
combination (see proposed Sec. 201.404(d)).
The range of NADA numbers provided as ``breakpoints'' in the
proposed schedule for the submission of conforming labeling are
intended to provide for a relatively uniform number of labeling
supplements during each 1-year interval. The schedule would require
more recently approved new animal drugs to conform to the requirements
first because they are more likely to be consistent with the new
requirements than the labeling of older new animal drugs. Sponsors of
older new animal drug applications would have a longer amount of time
to comply with the new requirements. Table 1 provides these NADA ranges
in the first column. Table 1 provides in the second column the number
of currently approved and marketed NADAs within the ranges of NADAs
calculated by FDA as of September 2023 and adjusts for ADAA combination
new animal drugs that would need to conform after all individual new
animal drugs in the combination have conformed (see proposed Sec.
201.404(d)). The first row of the second column of table 1 includes
ANADAs that reference a new animal drug for which the NADA has been
voluntarily withdrawn for reasons other than safety or effectiveness,
or that reference a new animal drug for which the NADA has been
withdrawn on the basis of one or more of the grounds included under
section 512(e) of FD&C Act and for which the ANADA's approval was not
affected by the withdrawal. Table 1 also provides in the third column
the number of currently approved and marketed ANADAs with a RLNAD that
has not been withdrawn, as calculated by FDA as of September 2023;
these ANADAs are included in the row that corresponds to the NADA
number for the RLNAD.
[[Page 18270]]
Table 1--Number of Affected Applications as of September 2023 \1\
----------------------------------------------------------------------------------------------------------------
ANADA with a
NADA Nos. NADA RLNAD \2\ Total
----------------------------------------------------------------------------------------------------------------
N-141-300 +; certain ANADAs..................................... \3\ 104 9 113
N-141-000 to N-141-299.......................................... 101 86 187
N-115-000 to N-140-999.......................................... 105 87 192
N-045-000 to N-114-999.......................................... 116 68 184
N-000-001 to N-044-999.......................................... 86 66 152
-----------------------------------------------
Total....................................................... 512 316 828
----------------------------------------------------------------------------------------------------------------
\1\ These numbers will be updated in a final rule.
\2\ These are ANADAs with a RLNAD that has not been withdrawn, and they are in the row that corresponds to the
NADA number for the RLNAD.
\3\ This number includes six ANADAs that reference a withdrawn NADA.
The proposed rule would provide direction for situations in which
it may not be clear how a requirement in subpart H applies to a
particular new animal drug, or whether it applies. FDA approves and
conditionally approves new animal drugs for many species of animals.
For some new animal drugs, certain sections or subsections of labeling
required by proposed subpart H would not be applicable. For example,
new animal drugs approved or conditionally approved for use in non-
food-producing animals (e.g., cats, dogs) would not require the
labeling subsection entitled either ``Withdrawal Periods and Residue
Warnings'' or ``Withdrawal Periods''. As another example, certain new
animal drugs may not have contraindications. We would make the final
determination in these situations as to the applicability of
requirements in subpart H to specific new animal drugs (see proposed
Sec. 201.404(e)).
In addition, some sections in subpart H propose different options
to meet the labeling requirements. For example, proposed Sec.
201.405(b) would provide various options for presenting the
``Indications for Use'' section on the label for a prescription new
animal drug, depending on size of the label. In those situations where
the most appropriate option is not clear, we would make the final
determination (see proposed Sec. 201.404(e)). Ordinarily, such
determinations would be made during the review of the new animal drug
and its labeling.
When sponsors would submit labeling for purposes of conforming to
the requirements of proposed subpart H according to the schedule in
proposed Sec. 201.404(a)(4), the proposed rule would require all
labeling components for an approved or conditionally approved new
animal drug to be provided in one submission. FDA would refuse to file
labeling submissions intended to conform to this subpart that are
incomplete. This would ensure that the content and format is consistent
across all the labeling components for a particular new animal drug.
Also, this would enable FDA to review and compare all labeling
components at the same time to ensure that they conform to the proposed
regulations when finalized (see proposed Sec. 201.404(f)).
The proposed rule would establish general requirements for the
format of labeling of approved or conditionally approved new animal
drugs in proposed Sec. 201.404(g). The format and content of labeling
for prescription new animal drugs, OTC new animal drugs, or new animal
drugs for use in animal feeds would be required to comply with the
general requirements in proposed Sec. 201.404(g), as applicable, in
addition to format and content specific requirements for each type of
new animal drug (see proposed Sec. Sec. 201.405, 201.407, or 201.409,
respectively).
The proposed rule would establish requirements for the placement,
size, and prominence of the established name relative to the
proprietary name for approved or conditionally approved prescription
new animal drugs in proposed Sec. 201.404(g)(1). These requirements
are in accordance with Sec. 201.10(g)(1) and (2) (21 CFR 210.10(g)(1)
and (2)) and section 502(e)(1)(B) of the FD&C Act.
The proposed rule would establish requirements for the placement,
size, and prominence of the established name relative to the
proprietary name of approved or conditionally approved OTC new animal
drugs and labeling for approved or conditionally approved new animal
drugs for use in animal feeds, excluding representative Type B and Type
C medicated feed labeling (see proposed Sec. 201.404(g)(2)).
The proposed rule would provide the requirements for the placement,
size, and prominence of the established name on representative Type B
and Type C medicated feed labeling for approved or conditionally
approved new animal drugs for use in animal feeds (see proposed Sec.
201.404(g)(3)).
The proposed rule would require labeling text to be easy to read
and with letters that do not touch. For certain text on labeling for
new animal drugs, we believe that black text on a white background and
use of a single type style is the easiest to read. Accordingly, the
proposed rule would require that the running text, section headings,
and subsection headings of package inserts must be in black type and on
a white background and use a single type style because package inserts
provide full prescribing information for prescription new animal drugs
and full product information for OTC new animal drugs. Black text on a
white background also would be required for representative labeling for
Type B and C medicated feeds. For all other labeling components for new
animal drugs, other color combinations would be allowed, provided that
there is sufficient contrast between text and the background colors to
ensure readability. See proposed Sec. 201.404(g)(4) and (5).
The proposed rule would establish requirements for presentation of
graphics and designs on labeling for approved or conditionally approved
new animal drugs (see proposed Sec. 201.404(g)(6)). Representative
labeling for Type B and C medicated feeds would not be permitted to
have logos, graphics, or designs other than illustrations or tables
that FDA determines are necessary for proper use of the medicated feed.
This proposed format is consistent with the purpose of representative
labeling for Type B and C medicated feeds for use as template labeling
and is also consistent with the format of representative labeling for
Type B and C medicated feeds currently used in the medicated feeds
industry. The proposed rule would require the presentation of graphics
and designs on other labeling components for approved or conditionally
approved new animal drugs to comply with Sec. 201.15(b)(1) (21
[[Page 18271]]
CFR 201.15(b)(1)) and proposed Sec. 201.404(a)(2) (see proposed Sec.
201.404(g)(6)). If graphics are incorporated into the background of
these labeling components, for any text appearing over the graphics
there would need to be sufficient contrast between the text and the
graphics colors to ensure readability of the text. The use of
compressed arrows on labeling would be limited to the subsection
entitled either ``Withdrawal Periods and Residue Warnings'' or
``Withdrawal Periods,'' in accordance with the requirements in proposed
Sec. 201.404(g)(8) (see proposed Sec. 201.404(g)(6)).
The proposed rule would establish minimum letter height or type
size requirements that would vary for each labeling component and
ensure appropriate space on each component while maintaining
readability of text (see proposed Sec. 201.404(g)(7)).
Section headings and subsection headings would be required to be in
bold type that prominently distinguishes them from other approved
labeling information. Section headings would be required to be left
justified or centered, whereas subsection headings would be required to
be left justified. An exception would be the subsection of labeling
entitled either ``Withdrawal Periods and Residue Warnings'' or
``Withdrawal Periods,'' in which the subsection heading, and the
contents of the subsection, would be required to be centered within
compressed arrows (see proposed Sec. 201.404(g)(8)).
The proposed rule would require that, if the National Drug Code is
included on labeling of new animal drugs, then it must appear in
accordance with 21 CFR 207.33 (see proposed Sec. 201.404(h)).
The proposed rule would require all words, statements, and other
information on the labeling for approved or conditionally approved new
animal drugs to appear in English. In addition, the proposed rule would
also establish requirements for additional foreign language
translations of new animal drug labeling (see proposed Sec.
201.404(i)).
For approved or conditionally approved prescription new animal
drugs, the proposed rule would require that if any section or wording
of a labeling component is translated into a foreign language, the
entire full prescribing information would also be required to be
translated into the foreign language. In certain situations, FDA may
also require additional wording on other labeling components for the
prescription new animal drug to be translated into the foreign
language. These requirements would ensure that all information
necessary for the safe and effective use of the prescription new animal
drug would be provided in the foreign language (see proposed Sec.
201.404(i)(1)).
For approved or conditionally approved OTC new animal drugs, the
proposed rule would require that if any section or wording of a
labeling component is translated into a foreign language, the entire
full product information would also be required to be translated into
the foreign language. In certain situations, FDA may also require
additional wording on other labeling components for the OTC new animal
drug to be translated into the foreign language. These requirements
would ensure that all information necessary for the safe and effective
use of the OTC new animal drug would be provided in the foreign
language (see proposed Sec. 201.404(i)(2)).
For approved or conditionally approved new animal drugs for use in
animal feeds, the proposed rule would require that if the labeling
contains any representation in a foreign language, all labeling must
also appear in the foreign language (see proposed Sec. 201.404(i)(3)).
For all situations where labeling for new animal drugs is
translated into a foreign language, the translated wording would be
required to comply with the format and content requirements for
prescription, OTC, or new animal drugs for use in animal feeds in
proposed Sec. 201.405(a), Sec. 201.407(a), or Sec. 201.409,
respectively.
FDA may limit the number of languages into which labeling
information is translated to ensure clarity of information and the safe
and effective use of the new animal drug. This proposed limitation
would avoid multipage labeling in multiple languages. We intend for
this limitation to reduce medication errors and reduce the time needed
to locate information on labeling (see proposed Sec. 201.404(i)(4)).
The proposed rule would allow the predominant language to be
substituted for English on the labeling for new animal drugs
distributed solely in the Commonwealth of Puerto Rico or in a Territory
where the predominant language is other than English. We may determine
that such new animal drugs may be altogether exempt from the
requirements in proposed Sec. 201.404(i) (see proposed Sec.
201.404(j)).
D. Content and Format for Prescription (Rx) New Animal Drug Labeling--
Overview (Proposed Sec. 201.405)
The proposed rule provides content and format requirements for all
components of labeling for approved or conditionally approved
prescription (Rx) new animal drugs. Proposed Sec. 201.405 would not
apply to approved or conditionally approved new animal drugs intended
for use in or on animal feed under the professional supervision of a
licensed veterinarian because, in accordance with section 504(a) of the
FD&C Act, such drugs are approved or conditionally approved as VFD
drugs. Proposed Sec. 201.409 would establish the content and format
requirements for all components of labeling for approved or
conditionally approved new animal drugs intended for use in animal
feeds that are subject to part 558, including VFD drugs.
The proposed rule would require that labeling sections or
subsections that do not apply be omitted from the labeling for approved
or conditionally approved Rx new animal drugs (see proposed Sec.
201.405). For example, Rx new animal drugs approved or conditionally
approved for use in non-food-producing animals (e.g., cats, dogs) would
not require the labeling subsection entitled either ``Withdrawal
Periods and Residue Warnings'' or ``Withdrawal Periods''.
FDA determines the final content of each applicable section of
labeling during the review of each new animal drug as part of the
approval process.
Full prescribing information for Rx new animal drugs would include
all information necessary for safe and effective use of the Rx new
animal drug. Thus, all approved or conditionally approved Rx new animal
drugs would be required to provide a labeling component that includes
full prescribing information. The proposed rule would identify the
information that would be required to be included on the labeling
component that would provide full prescribing information for Rx new
animal drugs. If a package insert is provided with an Rx new animal
drug, the proposed rule would require the package insert to include
full prescribing information. If only partial information is provided
on a package insert, the user may mistakenly assume the package insert
includes complete information on the safe and effective use of the drug
when in fact it does not. If no package insert is provided with an Rx
new animal drug, the secondary container labeling would be required to
include full prescribing information (see proposed Sec. 201.405(a)).
The label is the labeling component that appears on the immediate
container, which is the container in contact with the drug. The
proposed rule would establish content and format requirements for the
label for an approved or conditionally approved Rx new animal drug (see
proposed Sec. 201.405(b)) and for a small label for an
[[Page 18272]]
approved or conditionally approved Rx new animal drug that FDA
determines lacks sufficient space to comply with proposed Sec.
201.405(b) (see proposed Sec. 201.405(c)).
For purposes of proposed subpart H, the proposed rule would define
a package insert for an approved or conditionally approved Rx new
animal drug as a labeling component that contains full prescribing
information and is included with the immediate container or secondary
container or is attached to the label (see proposed Sec. 201.403).
Where the package insert is attached to the label, which is sometimes
referred to as, for example, ``extended labeling,'' ``onserts,'' or
``outserts,'' for purposes of proposed subpart H, the package insert
providing full prescribing information and attached to the label would
need to comply with proposed Sec. 201.405(a). The label would need to
comply with proposed Sec. 201.405(b) or (c), as applicable.
FDA considers the secondary container for a new animal drug to be
the packaging that surrounds the immediate container. The proposed rule
would establish content and format requirements for secondary container
labeling for an approved or conditionally approved Rx new animal drug
(see proposed Sec. 201.405(d)). If a package insert is provided with
an Rx new animal drug, then the secondary container labeling would be
required to comply with proposed Sec. 201.405(d), and the package
insert would be required to provide full prescribing information to
comply with proposed Sec. 201.405(a). If no package insert is provided
with an Rx new animal drug, the proposed rule would require full
prescribing information to appear on the secondary container labeling
(see proposed Sec. 201.405(a)).
In accordance with the definition of ``label'' in section 201(k) of
the FD&C Act, information on the label must also appear on an outside
container or wrapper of the retail package, if it exists, or be easily
legible through the outside container or wrapper. For purposes of these
proposed regulations, FDA considers the secondary container to be an
``outside container or wrapper of the retail package'' for new animal
drugs. Therefore, if a secondary container exists, the proposed rule
would require the secondary container labeling to include all
information that would be on the label in accordance with proposed
Sec. 201.405(b) or (c), unless the information on the label is easily
legible through the secondary container (see proposed Sec. 201.405(a)
and (d)).
Shipping labeling is associated with the outermost carton
containing a new animal drug, which is intended for shipping, but not
displaying the product. The proposed rule would establish content and
format requirements for the shipping labeling of approved or
conditionally approved Rx new animal drugs, including a requirement
that such shipping labeling identify the new animal drug, the
manufacturer, and drug storage and handling information. However,
approved or conditionally approved Rx new animal drugs that are
controlled substances would not include information that identifies the
drug, in accordance with Sec. 1301.74(e) (21 CFR 1301.74(e)), to guard
against storage or in-transit losses (see proposed Sec. 201.405(e)).
Depending on how a sponsor intends to sell or display an approved
or conditionally approved Rx new animal drug, there may be other
containers such as display cartons and multiple unit (multi-unit)
cartons that contain immediate containers or secondary containers.
These containers may be packaged in shipping cartons. The proposed rule
would establish content and format requirements for the labeling of
these other containers for Rx new animal drugs (see proposed Sec.
201.405(f)).
Labeling sections and subsections for Rx new animal drugs would not
be numbered. Headings of sections and subsections that would be
required to appear verbatim on labeling are identified in the proposed
regulations in quotations. Similarly, certain other labeling text would
be required to appear verbatim on labeling; this text is also
identified in the proposed regulations in quotations.
The proposed rule would require the labeling of approved or
conditionally approved Rx new animal drugs to comply with other
applicable requirements in proposed subpart H (see proposed Sec.
201.405).
1. Labeling Providing Full Prescribing Information (Proposed Sec.
201.405(a))
FDA uses the term ``full prescribing information'' to identify all
information necessary for the safe and effective use of approved or
conditionally approved Rx new animal drugs. The proposed rule would
establish content and format requirements for the component of labeling
that provides full prescribing information for approved or
conditionally approved Rx new animal drugs (see proposed Sec.
201.405(a)).
If a package insert is provided with an approved or conditionally
approved Rx new animal drug, the proposed rule would require the
package insert to include full prescribing information (see proposed
Sec. 201.405(a)). If a package insert is provided with an approved or
conditionally approved Rx new animal drug, any secondary container
labeling would be required to comply with proposed Sec. 201.405(d).
If a package insert is not provided with an approved or
conditionally approved Rx new animal drug, then secondary container
labeling would be required, and the secondary container labeling would
be required to provide full prescribing information (see proposed Sec.
201.405(a)). If full prescribing information is provided on the
secondary container labeling, in accordance with section 201(k) of the
FD&C Act, proposed Sec. 201.405(a) would allow the secondary container
labeling to exclude any portions of full prescribing information that
would be required to appear on the label if such information is easily
legible through the secondary container (see proposed in Sec.
201.405(d)).
The proposed rule would require the following information to be
presented in full prescribing information for approved or conditionally
approved Rx animal drugs and in the following order:
a. Drug product identification. The proposed rule would require
this section of full prescribing information to include the proprietary
name of the finished drug product and the established name of the drug
product. If not included as part of the established name of the drug
product, the route(s) of administration and dosage form of the finished
drug product would be required to be included in this section as well
(see proposed Sec. 201.405(a)(1)(i) through (iv)).
The established name and strength or concentration of each active
ingredient would also be required. The strength or concentration of
each active ingredient would be allowed to be excluded from full
prescribing information provided on a package insert if the package
insert applies to multiple strengths or concentrations for the same Rx
new animal drug (see proposed Sec. 201.405(a)(1)(v)).
If FDA determines that identifying the pharmacological class of an
Rx new animal drug on labeling would be helpful in facilitating its
safe and effective use by the prescribing veterinarian, the proposed
rule would require that the pharmacological class be included in this
section of full prescribing information (see proposed Sec.
201.405(a)(1)(vi)).
For Rx new animal drugs that are controlled substances, symbols
provided in part 1302 (21 CFR part
[[Page 18273]]
1302) to identify the controlled substance schedule would also appear
in this section of full prescribing information. See proposed Sec.
201.405(a)(1)(vii).
Prescription statement. The proposed rule would require this
section of full prescribing information to include the prescription
statement, ``Caution: Federal law restricts this drug to use by or on
the order of a licensed veterinarian.'' Prescription new animal drugs
are limited to use under the professional supervision of a licensed
veterinarian (section 503(f)(1)(A) of the FD&C Act). The prescription
statement would indicate that the Rx new animal drug is restricted to
use by or under the order of a licensed veterinarian. Including the
prescription statement on full prescribing information would be
consistent with its inclusion on the label for Rx new animal drugs,
which is required by section 503(f)(4) of the FD&C Act. The requirement
for including the prescription statement as part of full prescribing
information is proposed under the authority granted to FDA under
sections 502(a), 201(n), and 701(a) of the FD&C Act. See proposed Sec.
201.405(a)(2).
c. Conditional approval statement. For conditionally approved Rx
new animal drugs, the proposed rule would require this section of full
prescribing information to include, in accordance with section
571(f)(1)(A) of the FD&C Act, the statement indicating conditional
approval by FDA and the application number: ``conditionally approved by
FDA pending a full demonstration of effectiveness under application
number [insert number]''. This statement would be required to be
prominent and conspicuous (see proposed Sec. 201.405(a)(3)).
d. Boxed warnings. For Rx new animal drugs requiring boxed
warnings, the proposed rule would require this section of full
prescribing information to include the boxed warnings. Boxed warnings
convey the most significant risks associated with the use of a Rx new
animal drug. If applicable to the product, they would appear at this
prominent location. An upper case ``WARNING'' heading would be included
in the box, and the box, heading, and contents would be bolded. The
boxed warning would be brief, with reference to more detailed
information in other sections of full prescribing information if
applicable (see proposed Sec. 201.405(a)(4)).
e. Extralabel use prohibition statement. For approved new animal
drugs prohibited from extralabel use, in accordance with Sec. 530.41
(21 CFR 530.41), the proposed rule would require this section of full
prescribing information to include an extralabel use prohibition
statement that begins with the phrase: ``Federal law prohibits the
extralabel use of this drug . . .'' and concludes with a description of
the prohibition as described in Sec. 530.41 (see proposed Sec.
201.405(a)(5)). For example, ``Federal law prohibits the extralabel use
of this drug in lactating dairy cows.''
Certain new animal drugs are prohibited from extralabel use in some
or all animals, in accordance with Sec. 530.41. This information is
critical for inclusion on labeling. If a user fails to comply with an
extralabel use prohibition statement, there could be serious safety
consequences for the target animal, or in the case of a food-producing
animal, also for humans consuming food derived from the target animal.
f. ``Description.'' The proposed rule would require this section of
full prescribing information to have the heading ``Description,''
followed by a description of the new animal drug. The description would
include the proprietary name of the finished drug product and
established name of the drug product, and the route(s) of
administration and dosage form if not included as part of the
established name. The description would also include identifying
characteristics of the dosage form, such as color, shape, coating,
scoring, and imprinting. All approved and available strengths or
concentrations of the new animal drug to which full prescribing
information applies would need to be identified in this section of full
prescribing information. If the drug product was sterile, this fact
would also be identified in this section of full prescribing
information (see proposed Sec. 201.405(a)(6)).
The established name of each inactive ingredient would be required
to be included in the ``Description'' section of full prescribing
information. The proposed rule would require all inactive ingredients
to be listed in decreasing order of predominance, by weight or
concentration (see proposed Sec. 201.405(a)(6)(viii)). FDA believes
that listing inactive ingredients in decreasing order of predominance
based on either weight or concentration would provide the most
clinically useful information to users.
In accordance with section 502(e)(1)(A)(iii) of the FD&C Act, the
proposed rule would not require the listing of inactive ingredients on
full prescribing information under circumstances that would result in
disclosure of trade secret information. Therefore, where sponsors
believe the listing of inactive ingredients on product labeling would
result in disclosure of trade secret information, they would be able to
request exemption from this labeling requirement under proposed Sec.
201.411. If an exemption from the listing of inactive ingredients to
avoid divulgence of trade secret information is granted under Sec.
201.411, this section of full prescribing information would be required
to state: ``Certain inactive ingredients are not listed to avoid
disclosing trade secret information.'' (see proposed Sec.
201.405(a)(6)(viii)(A)).
Section 502(e)(1)(B) of the FD&C Act allows an exemption from
listing inactive ingredients on the label of Rx drugs if doing so would
be impracticable. The current regulations at Sec. 201.105(b)(5) for Rx
animal drugs state that names of flavorings, perfumes, certain color
additives, and ``trace amounts of harmless substances added solely for
individual product identification'' may be exempt from listing on the
labels for products other than for oral use. The regulations at Sec.
201.105 predate the requirements in section 502(e)(1)(B) of the FD&C
Act and are outdated. The proposed rule would replace the requirements
for labels for approved or conditionally approved Rx new animal drugs
currently provided in Sec. 201.105(b) with the requirements in
proposed Sec. 201.405(b) and (c) (see discussion in section V.D.2. and
3). Thus, the labels for approved or conditionally approved Rx new
animal drugs would no longer qualify for the exemptions currently
identified in Sec. 201.105(b)(5).
If under proposed Sec. 201.411 FDA grants an exemption from
listing inactive ingredients because their listing would be
impracticable, this section of full prescribing information would need
to state the following: ``Certain inactive ingredients are not listed
because their listing would be impracticable.'' (see proposed Sec.
201.405(a)(6)(viii)(B)).
g. ``Indications for Use.'' This section of full prescribing
information would be required to have the heading ``Indications for
Use,'' followed by the approved or conditionally approved indication(s)
and target animal(s) in the following format: ``For [indication(s)] in
[target animal(s)]'' (see proposed Sec. 201.405(a)(7)(i)).
Consistent with regulations for the labeling of Rx human products
in Sec. 201.57(c)(2)(i)(A), if a Rx new animal drug is approved or
conditionally approved for use only under specific conditions, e.g., in
conjunction with a primary mode of therapy, special diet, surgery,
behavioral modification, or some other drug, the proposed rule
[[Page 18274]]
would require that this information be specified in the ``Indications
for Use'' section of full prescribing information (see proposed Sec.
201.405(a)(7)(ii)).
If, in approving or conditionally approving an application, FDA
requires, for safety and/or effectiveness reasons, a statement(s) on
labeling identifying animals for which the Rx new animal drug has not
been approved or conditionally approved, the proposed rule would
require that statement(s) to appear in the ``Indications for Use''
section of full prescribing information (see proposed Sec.
201.405(a)(7)(iii)). We currently require the statement(s) proposed in
Sec. 201.405(a)(7)(iii) to appear on labeling of some approved new
animal drugs, particularly new animal drugs for use in food-producing
animals, to clarify the target animal for which the drug is approved.
The statements are typically required if we determine that unapproved
use of a drug in animals similar to the target animal(s) is reasonably
foreseeable and we believe that inclusion of such a statement on the
labeling of the new animal drug could increase the safe and effective
use of the drug. For example, feedlot beef cattle are not intended to
provide milk for human consumption. Therefore, we will not likely
require an evaluation of the human food safety of a new animal drug in
lactating dairy cows if the new animal drug is only to be approved for
use in feedlot cattle. However, we will often require a statement on
labeling that the drug is not for use in lactating dairy cows intended
to produce milk for human consumption to avoid use of the drug in this
unapproved and unevaluated manner.
The statement(s) proposed in Sec. 201.405(a)(7)(iii) is not
intended to prohibit extralabel use of approved new animal drugs
allowed under specific circumstances, in accordance with section
512(a)(4) of the FD&C Act and part 530 (21 CFR part 530), but would
help to clarify that some specific uses are extralabel and have not
been evaluated for safety and effectiveness by FDA. Currently, there is
no uniform place on the labeling for new animal drugs for such
statements to appear. If we require such statements on labeling to
ensure safe and effective use of a new animal drug, the proposed rule
would require the statements to be placed within the ``Indications for
Use'' section of full prescribing information. Inclusion of such
statements in the ``Indications for Use'' section would not necessarily
preclude also including similar statements in other sections or
subsections of full prescribing information if warranted. For example,
it may be appropriate to include a similar statement as a residue
warning statement in the ``Withdrawal Periods and Residue Warnings''
subsection to expand upon human food safety risks of the extralabel use
of the new animal drug in animals other than the target animal.
h. ``Dosage and Administration.'' The proposed rule would require
this section of full prescribing information to have the heading
``Dosage and Administration,'' followed by the dosage and
administration information for the new animal drug for each indication
and target animal (see proposed Sec. 201.405(a)(8)).
Sometimes FDA requires additional labeling for Rx new animal drugs
that provides important information for the animal owner or person
treating the animal. If such additional labeling is required, the
proposed ``Dosage and Administration'' section of full prescribing
information would advise the veterinarian to provide the additional
labeling to the animal owner or person treating the animal (see
proposed Sec. 201.405(a)(8)(i)).
The remainder of this section of full prescribing information would
be required to include information necessary for treatment of the
animal with the Rx new animal drug in accordance with FDA approval or
conditional approval, including: route(s) of administration and
specific site(s) of administration, if applicable; dose or dose range;
intervals between doses, if applicable; and duration of treatment. For
some injectable products, FDA may require a statement of the maximum
volume per injection site to facilitate the drug's safe and effective
use, and the proposed rule would require this information to be
included in this section of full prescribing information. Also, certain
animal populations may require modifications to the dosage and
administration for safe and effective use. These modifications would be
required to appear in this section of full prescribing information.
Other required dosage and administration information would also be
included in this section of full prescribing information. See proposed
Sec. 201.405(a)(8).
i. ``Contraindications.'' For Rx new animal drugs with
contraindications, the proposed rule would require this section of full
prescribing information to have the heading ``Contraindications,''
followed by the contraindications (see proposed Sec. 201.405(a)(9)).
As defined in proposed Sec. 201.403, a contraindication would include
any situation in which the new animal drug should not be used because
the risk of use clearly outweighs any possible benefit to the animal
and includes only known hazards.
j. ``Warnings and Precautions.'' The proposed rule would require
this section of full prescribing information for all approved or
conditionally approved Rx new animal drugs, and it would have the
heading ``Warnings and Precautions'' (see proposed Sec.
201.405(a)(10)). As defined in proposed Sec. 201.403, warnings would
describe any serious adverse reactions or potential hazards associated
with the use of the new animal drug. In addition, precautions would be
defined as any special care to be exercised for safe and effective use
of the new animal drug, which may include recommended screening,
monitoring, or diagnostic tests. Multiple subsections, if applicable,
would be included in the ``Warnings and Precautions'' section of full
prescribing information as described below and in the following order,
and the warnings and precautions would be provided in the applicable
subsection:
i. ``Withdrawal Periods and Residue Warnings'' or ``Withdrawal
Periods.'' All Rx new animal drugs approved or conditionally approved
for use in food-producing animals would be required to have as the
first subsection of the ``Warnings and Precautions'' section of full
prescribing information a subsection entitled either ``Withdrawal
Periods and Residue Warnings'' or ``Withdrawal Periods'' (see proposed
Sec. 201.405(a)(10)(i)). This subsection would provide all human food
safety warnings, including milk discard times, withdrawal periods, and
residue warning statements, as applicable to the new animal drug.
As defined in proposed Sec. 201.403, a withdrawal period is the
interval between the time of the last administration of a new animal
drug and the time when the animal can be safely slaughtered for food.
Withdrawal periods apply to all food-producing animals. As defined in
proposed Sec. 201.403, a milk discard time is the interval between the
time of the last administration of a new animal drug and the time when
the milk can be safely consumed. Milk discard times apply to female
animals that produce milk for human consumption. A new animal drug
approved for use in female animals that produce milk for human
consumption may have both a milk discard time and a withdrawal period.
As defined in proposed Sec. 201.403, a residue warning statement
warns against the use of the new animal drug in animals for which the
withdrawal period and/or milk discard time has not been determined,
and/or provides other
[[Page 18275]]
information to prevent illegal drug residues in food products from
animals treated with the new animal drug.
If there are any residue warning statements for the new animal
drug, the proposed rule would require this subsection of full
prescribing information to have the title ``Withdrawal Periods and
Residue Warnings.'' If there are no residue warning statements
associated with the new animal drug, this subsection of full
prescribing information would be required to have the title
``Withdrawal Periods'' (see proposed Sec. 201.405(a)(10)(i)(A)).
If the new animal drug is approved or conditionally approved for
use in food-producing animals excluding female animals that produce
milk for human consumption, the proposed rule would require this
subsection of full prescribing information to include the withdrawal
period(s) followed by any residue warning statements (see proposed
Sec. 201.405(a)(10)(i)(B)).
If the new animal drug is approved or conditionally approved for
use in food-producing animals excluding female animals that produce
milk for human consumption and there is no withdrawal period, the
proposed rule would require this subsection of full prescribing
information to state, ``No withdrawal period is required when used
according to labeling.'' This statement would be followed by any
residue warnings statements (see proposed Sec. 201.405(a)(10)(i)(C)).
If the new animal drug is approved or conditionally approved for
use in female animals that produce milk for human consumption, the
proposed rule would require this subsection of full prescribing
information to include the milk discard time(s), followed by the
withdrawal period(s), followed by any residue warning statements (see
proposed Sec. 201.405(a)(10)(i)(D)).
If the new animal drug is approved or conditionally approved for
use in female animals that produce milk for human consumption, and
there is a milk discard time(s) but no withdrawal period, the proposed
rule would require this subsection of full prescribing information to
include the milk discard time(s), followed by the statement, ``No
withdrawal period is required when used according to labeling.'' This
statement would be followed by any residue statements (see proposed
Sec. 201.405(a)(10)(i)(E)).
If the new animal drug is approved or conditionally approved for
use in female animals that produce milk for human consumption and there
is no milk discard time but there is a withdrawal period(s), the
proposed rule would require this subsection of full prescribing
information to include the withdrawal period(s), followed by the
statement, ``No milk discard time is required when used according to
labeling.'' This statement would be followed by any residue warnings
statements (see proposed Sec. 201.405(a)(10)(i)(F)).
If the new animal drug is approved or conditionally approved for
use in female animals that produce milk for human consumption and there
is no milk discard time and no withdrawal period, the proposed rule
would require this subsection of full prescribing information to state,
``No milk discard time and no withdrawal period is required when used
according to labeling.'' This statement would be followed by any
residue warnings statements (see proposed Sec. 201.405(a)(10)(i)(G)).
Currently, new animal drugs approved for use in food-producing
animals that have no milk discard time and/or withdrawal period may or
may not indicate this information on labeling. If this information is
not provided on labeling, potentially it could be confusing to the user
of the new animal drug as to whether or not there is a milk discard
time or withdrawal period for the new animal drug. Requiring this
subsection of full prescribing information for all new animal drugs
approved or conditionally approved for use in food-producing animals,
and requiring a statement, if appropriate, to indicate that there is no
milk discard time or withdrawal period when the new animal drug is used
according to labeling, will better ensure the safe use of animal drugs
in food-producing animals.
To further highlight for users this critical subsection of full
prescribing information, the title of this subsection and all
information in this subsection would be required to be centered and
placed entirely within compressed arrows, in accordance with proposed
Sec. 201.404(g)(8). The compressed arrows would be black for package
inserts, or a color that clearly contrasts from background colors for
other approved labeling (see proposed Sec. 201.405(a)(10)(i)(A)).
Currently, the compressed arrows are used voluntarily, although not
consistently, on the labeling for many new animal drugs approved for
use in food-producing animals. Currently other statements not
associated with human food safety may also appear within the compressed
arrows. The proposed rule would limit the use of compressed arrows to
the subsection entitled either ``Withdrawal Periods and Residue
Warnings'' or ``Withdrawal Periods'' (see proposed Sec.
201.404(g)(6)), which would only contain human food safety information.
ii ``User Safety Warnings.'' The proposed rule would require this
subsection of the ``Warnings and Precautions'' section of full
prescribing information to have the heading ``User Safety Warnings,''
followed by the user safety warnings. As defined in proposed Sec.
201.403, a user safety warning would be a warning that identifies
serious adverse reactions or potential hazards to human health
associated with human exposure during use of a new animal drug via
contact, inhalation, ingestion, injection, or by other means. This
information would be required to prevent or decrease the risk of harm
to humans.
The first statements that would be included in this subsection of
full prescribing information are: ``Not for use in humans. Keep out of
reach of children.'' The subsection would next list all additional user
safety warnings listed in decreasing order of severity or frequency.
The final information that would be included in this subsection of full
prescribing information would be a sentence explaining how to obtain
Safety Data Sheet(s) for the drug. Chemical manufacturers,
distributors, and/or importers are required pursuant to 29 CFR
1910.1200(g) to provide Safety Data Sheets for each hazardous chemical
to downstream users to communicate information on these hazards. Safety
Data Sheets include information such as the properties of each
chemical; their physical, health, and environmental health hazards;
protective measures; and safety precautions for handling, storing, and
transporting the chemical. The sentence in this subsection of full
prescribing information would be required to be formatted as follows:
``To obtain a Safety Data Sheet(s), contact [insert name of
manufacturer] at [insert manufacturer's telephone number] or [insert
manufacturer's website].'' See proposed Sec. 201.405(a)(10)(ii).
iii. ``Animal Safety Warnings and Precautions.'' For Rx new animal
drugs with target animal safety warnings and precautions, the proposed
rule would require this subsection of the ``Warnings and Precautions''
section of full prescribing information to have the heading ``Animal
Safety Warnings and Precautions,'' followed by the target animal safety
warnings and precautions (see proposed Sec. 201.405(a)(10)(iii)).
Target animal safety warnings identify any serious adverse reactions or
potential hazards to the target animal(s) associated with the use of
the new animal drug. Precautions for Rx new
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animal drugs often include recommendations for specific screening,
monitoring, diagnostic tests, or special care that should be taken by
the prescribing veterinarian for safe and effective use of the new
animal drug (see definition in proposed Sec. 201.403). The heading of
the subsection would include the term ``animal safety warnings'', i.e.,
``Animal Safety Warnings and Precautions,'' because we believe the term
``animal safety warnings'' is more familiar to users of Rx new animal
drugs than ``target animal safety warnings.''
Precautions are sometimes difficult to distinguish from target
animal safety warnings. Currently, target animal safety warnings and
precautions are sometimes presented separately on the labeling for Rx
new animal drugs. However, because the two sets of information are
often closely related, it is advantageous to combine them into one
subsection of full prescribing information.
Warnings and precautions are combined in the ``Highlights'' and
``Full Prescribing Information'' for human Rx drugs and biologics (see
Sec. Sec. 201.56 and 57). Similarly, combining target animal safety
warnings and precautions in the ``Animal Safety Warnings and
Precautions'' subsection of full prescribing information would be less
burdensome for sponsors of Rx new animal drugs because sponsors would
not be required to distinguish one from the other.
iv. ``Environmental Warnings.'' For approved or conditionally
approved new animal drugs that have environmental warnings, the
proposed rule would require this subsection of the ``Warnings and
Precautions'' section of full prescribing information to have the
heading ``Environmental Warnings,'' followed by the environmental
warnings (see proposed Sec. 201.405(a)(10)(iv)). FDA's regulations at
21 CFR part 25 implementing the National Environmental Policy Act
(NEPA), 42 U.S.C. 4321 et seq., address the environmental impact
considerations required for products regulated by FDA, including new
animal drugs. Under NEPA, the responsible Agency official examines the
environmental risks of the proposed action and the alternative courses
of action, selects a course of action, and ensures that any necessary
mitigating measures are implemented as a condition for approving the
selected course of action (see 21 CFR 25.40(e)). In some instances,
sponsors may choose to include environmental warnings on the labeling
for their new animal drugs as a means to mitigate or reduce the
potential for environmental impacts to occur from the use or disposal
of the drug (see 21 CFR 25.45). These warnings would generally include
information to prevent or decrease the risk of any environmental
effects. The proposed rule would require any environmental warnings
applicable to the new animal drug that are included in an approved or
conditionally approved application be provided in this subsection of
full prescribing information (see proposed Sec. 201.405(a)(10)(iv)).
v. ``Other Warnings.'' For new animal drugs having warnings not
more appropriately placed in other ``Warnings and Precautions''
subsections, the proposed rule would require the last subsection of the
``Warnings and Precautions'' section of full prescribing information to
have the heading ``Other Warnings,'' followed by those warnings (see
proposed Sec. 201.405(a)(10)(v)).
k. ``Adverse Reactions.'' For Rx new animal drugs that we determine
have adverse reactions, this section of full prescribing information
would be required to have the heading ``Adverse Reactions,'' followed
by the adverse reactions (see proposed Sec. 201.405(a)(11)). Adverse
reactions would be defined in proposed Sec. 201.403 as undesirable
effects, reasonably associated with the use of the drug product, that
may occur as part of the pharmacological action of the drug or that may
be unpredictable in occurrence. The proposed rule would require this
section of full prescribing information to include adverse reactions
that occur with use of the Rx new animal drug and with use of drugs in
the same pharmacologically active and chemically related classes, if
applicable. Furthermore, we may require additional information as
necessary for the prescribing veterinarian to interpret the adverse
reactions, such as the total number of animals exposed to the drug and
the extent and nature of exposure.
The proposed rule would also require that adverse reactions be
presented within the following categories, as applicable, in decreasing
order of severity or frequency: preapproval experience, foreign market
experience known prior to U.S. approval for drugs also commercially
marketed outside of the United States, and post-approval experience
(see proposed Sec. 201.405(a)(11)). For previously approved Rx new
animal drugs for which the labeling would be updated in accordance with
the schedule provided in this rule, if the preapproval experience and/
or foreign market experience categories were not included on full
prescribing information when the drug was approved, we may allow one or
both of these subsections to be excluded from the ``Adverse Reactions''
section of full prescribing information if we determine that including
such information is not necessary to ensure the safe and effective use
of the drug. Post-approval experience would typically be added to
labeling of the drug after it has been approved in the United States
and if additional adverse drug experiences (as defined by Sec. 514.3)
associated with the use of the drug have been identified.
l. ``Contact Information.'' The proposed rule would require this
section of full prescribing information to have the heading ``Contact
Information,'' followed by the sponsor's contact information for
veterinarians or consumers to facilitate requesting additional
information or to report suspected adverse drug experiences. FDA's
contact information for voluntary reporting of adverse drug experiences
for animal drugs would also be required. Requiring contact information
on new animal drug labeling increases the likelihood that a user will
report adverse drug events to the sponsor and/or to the Center for
Veterinary Medicine (CVM). Increasing the likelihood of receiving
adverse drug event reports would allow new animal drug sponsors and CVM
to better monitor and detect emerging safety issues with approved or
conditionally approved new animal drugs on the market. Any increase in
adverse drug event reporting and monitoring resulting from this
proposed requirement would benefit both animal and human health.
The sponsor's contact information would be the name of the
manufacturer, packer, or distributor, whichever is identified in the
``Name and place of business'' section of full prescribing information
per proposed Sec. 201.405(a)(22). If more than one business is
identified in the ``Name and place of business'' section of full
prescribing information, the drug sponsor would select the most
appropriate of these businesses to use in the ``Contact Information''
section to provide additional information about the Rx new animal drug
and to contact regarding suspected adverse drug experiences.
The statements in this section of full prescribing information
would be required to be structured as follows: ``Contact [insert name
of business] at [insert business telephone number] or [insert business
web address]. To report suspected adverse drug experiences, contact
[insert name of business] at [insert business telephone number]. For
additional information about reporting adverse drug experiences for
animal drugs, contact FDA at [insert current
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FDA telephone number for voluntary reporting of adverse drug
experiences] or [insert current FDA web address for voluntary reporting
of adverse drug experiences].'' See proposed Sec. 201.405(a)(12).
Sponsors can search FDA's website or contact FDA by telephone to find
the current FDA telephone number and web address for voluntary
reporting of adverse drug experiences for animal drugs.
m. ``Information for Animal Owner.'' For Rx new animal drugs
required to have additional information to be communicated by the
prescribing veterinarian to the animal owner or person treating the
animal to ensure safe and effective use of the Rx new animal drug, the
proposed rule would require this section of full prescribing
information to have the heading ``Information for Animal Owner,''
followed by the specific information.
For some new animal drugs, FDA may determine it is necessary for
sponsors to provide the animal owner or person treating the animal with
additional labeling, such as a ``client information sheet,'' to ensure
the safe and effective use of the Rx new animal drug. If we determine
that such additional labeling is necessary, a printed copy of the
additional labeling would be required to be attached to or accompany
the package insert or secondary container labeling if no package insert
is provided. See proposed Sec. 201.405(a)(13).
n. ``Clinical Pharmacology.'' For Rx new animal drugs required to
include clinical pharmacology information on labeling, the proposed
rule would require this section of full prescribing information to have
the heading ``Clinical Pharmacology,'' followed by the clinical
pharmacology information for the Rx new animal drug in the target
animal(s). The required information would be relevant for understanding
the relationship between dose, systemic drug exposure, safety, and
clinical effectiveness. This information may help the prescribing
veterinarian to predict how the Rx new animal drug would perform in the
different animal patient populations likely to be encountered under
clinical use conditions. This section of full prescribing information
would be required to include the following three separate subsections,
as applicable to the Rx new animal drug: ``Mechanism of action,''
``Pharmacodynamics,'' and ``Pharmacokinetics'' (see proposed Sec.
201.405(a)(14)).
o. ``Microbiology.'' For antimicrobial Rx new animal drugs, the
proposed rule would require this section of full prescribing
information to have the heading ``Microbiology,'' followed by a
description of microbiologic data associated with the studies used to
support the effectiveness of the drug against the indicated pathogens.
The microbiology data would be required to be restricted to organisms
named in the approved or conditionally approved indications.
If in vitro data for antimicrobial new animal drugs are included in
this section of full prescribing information and the data have not been
correlated to clinical effectiveness, then such in vitro data would be
required to be immediately preceded by the following statement: ``The
following in vitro data are available, but their clinical significance
is unknown.'' See proposed Sec. 201.405(a)(15).
p. ``Target Animal Safety.'' The proposed rule would require this
section of full prescribing information to have the heading ``Target
Animal Safety,'' followed by a summary of the basis for the conclusion
that the new animal drug is safe in the target animal(s) when used as
approved or conditionally approved (see proposed Sec. 201.405(a)(16)).
q. ``Effectiveness.'' The proposed rule would require this section
of full prescribing information to have the heading ``Effectiveness,''
followed by a summary of the basis for the conclusion that the new
animal drug is effective in the target animal(s) when used as approved.
For conditionally approved drugs, the ``Effectiveness'' section of full
prescribing information would be required to include a summary of the
basis for the reasonable expectation of effectiveness (see proposed
Sec. 201.405(a)(17)).
r. ``Net Contents.'' The proposed rule would require this section
of full prescribing information, when presented on the secondary
container labeling, to have the heading ``Net Contents,'' followed by
the contents of the secondary container. The proposed rule would
exclude a ``Net Contents'' section from package inserts (see proposed
Sec. 201.405(a)(18)).
s. ``How Supplied.'' The proposed rule would require this section
of full prescribing information to have the heading ``How Supplied,''
followed by information on available drug strengths, concentrations,
and container sizes to which the labeling applies. The information in
this section would be required to be revised if new strengths,
concentrations, or container sizes are added (see proposed Sec.
201.405(a)(19)).
t. ``Storage, Handling, and Disposal.'' The proposed rule would
require this section of full prescribing information to have the
heading ``Storage, Handling, and Disposal'' (see proposed Sec.
201.405(a)(20)). Drug storage information would be included in this
section and may include, for example, required temperature, humidity,
and/or light exposure conditions to maintain the potency of the Rx new
animal drug until its established expiration date. Also, any handling
and drug disposal information that we determine to be necessary for
safe and effective use of the Rx new animal drug would be included in
this section. Handling information may include, for example,
recommendations to reseal reusable bottles promptly after opening and
conditions necessary to maintain potency of reconstituted new animal
drugs. Drug disposal information may include, for example, instructions
on disposal of unused portions of new animal drugs remaining after
treatment, as well as used needles and/or syringes.
u. NADA/ANADA approval statement. In accordance with section
502(w)(3) of the FD&C Act, by no later than September 30, 2023,
approved new animal drugs must include the following statement on
labeling: ``Approved by FDA under NADA # xxx-xxx''. By no later than
September 30, 2023, approved generic Rx new animal drugs must include
the following statement on labeling: ``Approved by FDA under ANADA #
xxx-xxx''. For approved Rx new animal drugs, the proposed rule would
require this section of full prescribing information to include the
``NADA approval statement,'' indicating the product's NADA number and
that it was approved by FDA. For approved generic Rx new animal drugs
that would be covered by these regulations (i.e., those that reference
an NADA that has been withdrawn for reasons other than safety or
effectiveness or under section 512(e) of the FD&C Act and the ANADA's
approval was not affected by the withdrawal), the proposed rule would
require this section of full prescribing information to include the
``ANADA approval statement.'' The proposed rule would establish format
requirements for the approval statement and would require that the
approval statement not be so prominent as to obscure other required
information. The approval statement could not be incorporated into a
seal, stamp, logo, or graphic. See proposed Sec. 201.405(a)(21).
v. Name and place of business. The proposed rule would require this
section of full prescribing information to identify the name and place
of business of the manufacturer, packer, or distributor (see proposed
Sec. 201.405(a)(22)).
w. ``Lot Number and Expiration Date.'' The proposed rule would
require
[[Page 18278]]
this section of full prescribing information when provided on the
secondary container labeling. Package inserts are excluded from this
requirement because they might apply to multiple lots of secondary or
immediate containers of the Rx new animal drug. When full prescribing
information is provided on the secondary container labeling, this
section would be required to have the heading ``Lot Number and
Expiration Date,'' followed by the identifying lot or control number of
the Rx new animal drug within the secondary container (see proposed
Sec. 201.405(a)(23)). Should a problem be reported to FDA, a lot or
control number would help us more easily to identify and trace back a
specific lot of a product. The proposed rule would also require this
section to include the expiration date of the Rx new animal drug within
the secondary container, in accordance with Sec. 201.17 (21 CFR
201.17). An expiration date better ensures that the new animal drug
would not be used after it expires.
Alternatively, the proposed rule would allow for this section of
full prescribing information to refer to the location on the secondary
container labeling or secondary container where the lot or control
number and expiration date are printed (see proposed Sec.
201.405(a)(23)). As an example, if the lot number and expiration date
are printed on the bottom flap of a secondary container, then the
secondary container labeling may state in this section, ``See carton
bottom flap for lot number and expiration date.'' However, in
accordance with Sec. 201.17, the proposed rule would allow an
expiration date to be excluded from the secondary container labeling or
secondary container if the expiration date provided on the label or
immediate container is easily legible through the secondary container.
x. ``Revision Date.'' The proposed rule would require this section
of full prescribing information to have the heading ``Revision Date,''
followed by the date of the most recent revision of the component of
labeling that provides full prescribing information, listing the month
followed by the year (see proposed Sec. 201.405(a)(24)). This
information is important to ensure that the most current approved
version of the labeling is being used.
2. Prescription New Animal Drug Label (Rx Label) (Proposed Sec.
201.405(b))
The proposed rule would establish content and format requirements
for the information presented on the label for approved or
conditionally approved Rx new animal drugs (Rx label) (see proposed
Sec. 201.405(b)). As defined in proposed Sec. 201.403, ``label'' has
the same meaning as given in section 201(k) of the FD&C Act, which
defines the term ``label'' to mean a display of written, printed, or
graphic matter upon the immediate container of any article. As defined
in proposed Sec. 201.403, the immediate container means the container
in contact with the new animal drug, and it excludes package liners.
Proposed Sec. 201.405(b) would apply to Rx labels that are of
adequate size to contain the proposed required information per that
paragraph, whereas proposed Sec. 201.405(c) would apply to small
labels for Rx new animal drugs that are not of adequate size to contain
all the proposed required information in proposed Sec. 201.405(b).
Prescription new animal drugs labels to which Sec. 201.405(b)
would apply may consist of a single panel, a front panel and one side
or back panel, or a front panel and multiple side and/or back panels,
and the proposed rule would provide for such label designs (see Sec.
201.405(b)). For Rx labels with a front panel and one side or back
panel, the proposed rule would require certain information for the
front panel (see proposed Sec. 201.405(b)(1)), and the side or back
panel (see proposed Sec. 201.405(b)(2)). For Rx labels consisting of a
single panel, the proposed rule would require the information
identified in proposed Sec. 201.405(b)(1) followed by the information
identified in proposed Sec. 201.405(b)(2), in order, on the single
panel. For Rx labels with a front panel and multiple side and/or back
panels, the information identified in proposed Sec. 201.405(b)(1)
followed by the information identified in proposed Sec. 201.405(b)(2)
would be required in order, starting on the front panel, continuing on
the panel immediately to the right of the front panel, and continuing
to fill the panels to the right until all of the information in
proposed Sec. 201.405(b)(1) and (b)(2) was presented. In all
instances, the information proposed in Sec. 201.405(b)(2)(iii) and
(iv), i.e., ``Active Ingredient'' or ``Active Ingredients'' and
``Inactive Ingredients,'' would need to appear on the same panel.
a. Front panel. The proposed rule would require the following
information to be presented on the front panel of the Rx label for an
approved or conditionally approved Rx new animal drug and in the
following order. Unless otherwise indicated, this information would be
the same as that required by proposed Sec. 201.405(a) for full
prescribing information.
i. Drug product identification. The proposed rule would require
this section of the Rx label to include drug product identification
information (see proposed Sec. 201.405(b)(1)(i)). This information may
help the user quickly and correctly identify the product and
distinguish it from other, similar products. The information included
in this section of the Rx label would include the same information as
that in the drug product identification section of full prescribing
information, as described in proposed Sec. 201.405(a)(1), in addition
to a statement that the drug product is sterile, if applicable. Full
prescribing information would require a drug product identification
section and a ``Description'' section. Full prescribing information for
sterile Rx new animal drugs would be required to identify in the
``Description'' section that the drug is sterile. However, due to space
limitations, no ``Description'' section is proposed for the Rx label.
Instead, the drug product identification section of the Rx label for
sterile Rx new animal drugs would be required to state that the drug
product is sterile. See proposed Sec. 201.405(b)(1)(i).
ii. Prescription statement. The proposed rule would require this
section of the Rx label to include the prescription statement (see
proposed Sec. 201.405(b)(1)(ii)). In accordance with section 503(f)(4)
of the FD&C Act, all Rx new animal drugs must state on the label:
``Caution: Federal law restricts this drug to use by or on the order of
a licensed veterinarian.''
iii. Conditional approval statement. For conditionally approved new
animal drugs, the proposed rule would require this section of the Rx
label to include a conditional approval statement, as described in
proposed Sec. 201.405(a)(3) for full prescribing information (see
proposed Sec. 201.405(b)(1)(iii)).
iv. Boxed warnings. For approved or conditionally approved Rx new
animal drugs requiring boxed warnings, the proposed rule would require
this section of the Rx label to include the boxed warnings, as
described in proposed Sec. 201.405(a)(4) for full prescribing
information (see proposed Sec. 201.405(b)(1)(iv)).
v. ``Indications for Use.'' The proposed rule would require this
section of the Rx label to have the heading ``Indications for Use,''
followed by the ``Indications for Use'' section, as described in
proposed Sec. 201.405(a)(7) for full prescribing information. If we
determine that there is insufficient space on the Rx label for the
complete ``Indications for Use'' section as described in proposed Sec.
201.405(a)(7), then the proposed rule would require
[[Page 18279]]
the sponsor to include in this section of the Rx label the statement
required in proposed Sec. 201.405(a)(7)(i), i.e., ``For
[indication(s)] in [target animal(s)]''. If there is insufficient space
on the Rx label for the statement in proposed Sec. 201.405(a)(7)(i),
then an abbreviated version of the statement would be required: ``For
[abbreviated indication(s)] in [target animal(s)]''. In either
situation where there is insufficient space on the Rx label for the
complete ``Indications for Use'' section as specified in proposed Sec.
201.405(a)(7), the required statement would be followed by one of the
following statements: ``See package insert for complete `Indications
for Use' '' if full prescribing information is provided on a package
insert; or ``See package labeling for complete `Indications for Use' ''
if full prescribing information is provided on the secondary container
labeling. See proposed Sec. 201.405(b)(1)(v).
The complete ``Indications for Use'' section as described in
proposed Sec. 201.405(a)(7) may exceed the available space on the Rx
label if, for example, it includes specific conditions of use (proposed
Sec. 201.405(a)(7)(ii)) or animals for which the new animal drug is
not approved or conditionally approved (proposed Sec.
201.405(a)(7)(iii)), and/or the indication(s) is lengthy and/or
complex. For example, a new animal drug approved to treat and control
multiple species of roundworms, lungworms, lice, and mites in beef
cattle would ordinarily identify all of those species in the
``Indications for Use'' section of the label. However, if space is
insufficient on the Rx label to provide the identity of all of the
species of the roundworms, lungworms, lice, and mites for which the
drug is effective, an acceptable ``abbreviated'' version of the
``Indications for Use'' section on the Rx label for this product might
include, for example, ``For treatment and control of certain species of
roundworms, lungworms, lice, and mites in beef cattle. See package
insert for complete `Indications for Use'.''
vi. Extralabel use prohibition statement. For approved Rx new
animal drugs prohibited from extralabel use, in accordance with Sec.
530.41, the proposed rule would require this section of the Rx label to
include the extralabel use prohibition statement, as described in
proposed Sec. 201.405(a)(5) for full prescribing information (see
proposed Sec. 201.405(b)(1)(vi)).
vii. ``Withdrawal Periods and Residue Warnings'' or ``Withdrawal
Periods.'' For new animal drugs approved or conditionally approved for
use in food-producing animals, the proposed rule would require this
section of the Rx label to have the heading ``Withdrawal Periods and
Residue Warnings'' or ``Withdrawal Periods,'' followed by all human
food safety warnings, including milk discard times, withdrawal periods,
and residue warning statements, as described in proposed Sec.
201.405(a)(10)(i) for full prescribing information. If there is
insufficient space on the front panel of Rx labels with only a front
panel and one side or back panel, the proposed rule would require this
section to be provided on the side or back panel of the Rx label
immediately following the full prescribing information statement
specified in proposed Sec. 201.405(b)(2)(i). See proposed Sec.
201.405(b)(1)(vii).
viii. ``Net Contents.'' The proposed rule would require this
section of the Rx label to have the heading ``Net Contents,'' followed
by the contents of the immediate container, in accordance with Sec.
201.51 (see proposed Sec. 201.405(b)(1)(viii)).
ix. NADA/ANADA approval statement. For approved new animal drugs or
approved generic new animal drugs, the proposed rule would require this
section of the Rx label to include the NADA or ANADA approval
statement, as described in proposed Sec. 201.405(a)(21) for full
prescribing information (see proposed Sec. 201.405(b)(1)(ix)).
b. Side or back panel. The proposed rule would require the
following information to be presented on the side or back panel of the
Rx label for an approved or conditionally approved Rx new animal drug
in the following order (see proposed Sec. 201.405(b)(2)). Unless
otherwise indicated, this information would be the same as that
required by proposed Sec. 201.405(a) for full prescribing information.
i. Full prescribing information statement. The proposed rule would
require this section of the Rx label to include one of two statements
(see proposed Sec. 201.405(b)(2)(i)). If full prescribing information
is provided on the package insert, the following statement would be
used: ``Before using this drug, read package insert for full
prescribing information.'' If full prescribing information is provided
on the secondary container labeling, the following statement would be
used: ``Before using this drug, read package labeling for full
prescribing information.'' Because full prescribing information would
not be provided on the Rx label, the purpose of the statements would be
to remind the veterinarian to read full prescribing information before
using the Rx new animal drug.
ii. ``Dosage and Administration.'' The proposed rule would require
this section of the Rx label to have the heading ``Dosage and
Administration,'' followed by the ``Dosage and Administration''
section, as described in proposed Sec. 201.405(a)(8) for full
prescribing information. If there is insufficient space on the Rx label
for the complete requirements as specified in proposed Sec.
201.405(a)(8), or if it is necessary for additional information
provided in full prescribing information that is not provided on the Rx
label to be read before administering the drug (e.g., complete warnings
and precautions, contraindications, and/or target animal safety), then
FDA may exclude this section from the Rx label (see proposed Sec.
201.405(b)(2)(ii)). For example, with respect to the latter situation,
if careful observation of the animal after dosing is advised to watch
for adverse reactions, this information typically would be described in
the ``Animal Safety Warnings and Precautions'' subsection, which would
not be required on the Rx label but would be required on full
prescribing information. Excluding the ``Dosage and Administration''
section from the Rx label in this situation helps to ensure that the
veterinarian would read full prescribing information, which would
include the ``Dosage and Administration'' section as well as the
``Animal Safety Warnings and Precautions'' subsection, before treating
the animal. Users would also be reminded to read full prescribing
information before using the drug via the full prescribing information
statement that would be required in the previous section of the Rx
label by proposed Sec. 201.405(b)(2)(i).
iii. ``Active Ingredient'' or ``Active Ingredients.'' The proposed
rule would require this section of the Rx label to have the heading
``Active Ingredient'' or ``Active Ingredients,'' followed by the
established name and strength or concentration of each active
ingredient. If the Rx new animal drug contains one active ingredient,
the proposed rule would require this section of the Rx label to be
entitled ``Active Ingredient.'' If the Rx new animal drug contains more
than one active ingredient, the proposed rule would require this
section of the Rx label to be entitled ``Active Ingredients.'' The
requirement to provide established name and strength or concentration
of each active ingredient on the Rx label would be consistent with the
requirement for the established name and quantity or proportion of each
active ingredient on the label of prescription drugs, in
[[Page 18280]]
accordance with section 502(e)(1)(A)(ii), (B), and (g) of the FD&C Act
(see proposed Sec. 201.405(b)(2)(iii)). This information is currently
required to be on the label for Rx animal drugs, in accordance with
Sec. 201.105(b)(4). Proposed Sec. 201.405(b) and (c) would establish
the content and format requirements for the label for approved or
conditionally approved Rx new animal drugs and would replace the
requirements for the label of approved or conditionally approved Rx new
animal drugs currently provided in Sec. 201.105(b). Furthermore, Sec.
201.105 would be amended to refer to proposed Sec. 201.405 for the
content and format requirements for labeling components for approved or
conditionally approved Rx new animal drugs.
iv. ``Inactive Ingredients.'' The proposed rule would require this
section of the Rx label to have the heading ``Inactive Ingredients,''
followed by the established name of each inactive ingredient, as
described in proposed Sec. 201.405(a)(6)(viii) for full prescribing
information (see proposed Sec. 201.405(b)(2)(iv)).
v. ``Storage, Handling, and Disposal.'' The proposed rule would
require this section of the Rx label to have the heading ``Storage,
Handling, and Disposal,'' followed by drug storage, handling, and
disposal information, as described in proposed Sec. 201.405(a)(20) for
full prescribing information (see proposed Sec. 201.405(b)(2)(v)).
vi. Name and place of business. The proposed rule would require
this section of the Rx label to identify the name and place of business
of the manufacturer, packer, or distributor, as required in section
502(b) of the FD&C Act (see proposed Sec. 201.405(b)(2)(vi)).
vii. ``Lot Number and Expiration Date'' or ``Lot Number.'' The
proposed rule would require this section of the Rx label to have the
heading ``Lot Number and Expiration Date'' or ``Lot Number,'' followed
by the identifying lot or control number of the Rx new animal drug
within the immediate container (see proposed Sec. 201.405(b)(2)(vii)).
A lot or control number would allow us to more easily identify and
trace back a specific lot of a product should a problem be reported to
FDA. We would also require this section of the Rx label to include the
expiration date of the Rx new animal drug within the immediate
container, in accordance with Sec. 201.17.
An expiration date on the Rx label better ensures that the new
animal drug would not be used after it expires. Alternatively, the
proposed rule would allow for this section to refer to the location on
the Rx label or immediate container where the lot or control number and
expiration date are printed (see proposed Sec. 201.405(b)(2)(vii)). As
an example, if the lot number and expiration date are printed at the
top of the immediate container, then the Rx label may state in this
section, ``See top of container for lot number and expiration date.''
If the immediate container provides a single dose of the Rx new animal
drug and is packaged individually in a secondary container that
provides an expiration date on the secondary container labeling or
secondary container, the proposed rule would not require an expiration
date on the Rx label or immediate container, in accordance with Sec.
201.17. Under such provision, this section of the Rx label would be
required to be entitled ``Lot Number.''
viii. ``Revision Date.'' The proposed rule would require the last
section of the Rx label to have the heading ``Revision Date,'' followed
by the date of the most recent revision of the Rx label, listing the
month followed by the year (see proposed Sec. 201.405(b)(2)(viii)).
3. Prescription New Animal Drug Small Label (Rx Small Label) (Proposed
Sec. 201.405(c))
The proposed rule would establish content and format requirements
for the small label for Rx new animal drugs (Rx small label) (see
proposed Sec. 201.405(c)). Some immediate containers, such as blister
packs, pre-filled syringes, and small vials, are so small that only a
minimal amount of information can be included on their label. The
proposed rule would establish requirements for Rx small labels for
approved or conditionally approved Rx new animal drugs (see proposed
Sec. 201.405(c)). We recognize that the size of the label is dependent
upon the size of the immediate container. If an immediate container
lacks sufficient space to contain a label that accommodates all of the
information required by proposed Sec. 201.405(b), the requirements of
proposed Sec. 201.405(c) would instead apply. We would ordinarily make
this determination during the review of the new animal drug and its
labeling, taking into consideration the readability and legibility of
the information.
The proposed rule would require the following information to be
presented on the Rx small label for an approved or conditionally
approved Rx new animal drug and in the following order (see proposed
Sec. 201.405(c)).
a. Proprietary name of the finished drug product. The proposed rule
would require this section of the Rx small label to include the
proprietary name of the finished drug product (see proposed Sec.
201.405(c)(1)). This requirement already exists for small labels for
drugs in general in Sec. 201.10(i)(1), but is repeated in these
proposed regulations to include all requirements for labeling of
approved or conditionally approved new animal drugs in proposed subpart
H.
b. Established name of the drug product. The proposed rule would
require this section of the Rx small label to include the established
name of the drug product (see proposed Sec. 201.405(c)(2)). This
requirement already exists for small labels for drugs in general in
Sec. 201.10(i)(1), but is repeated in these proposed regulations to
include all requirements for labeling of approved or conditionally
approved new animal drugs in proposed subpart H.
c. Active ingredient(s). The proposed rule would require this
section of the Rx small label to include the established name and
strength or concentration of each active ingredient, which is
consistent with the requirement for the established name and quantity
or proportion of each active ingredient on the label of prescription
drugs, in accordance with section 502(e)(1)(A)(ii), (B), and (g) of the
FD&C Act (see proposed Sec. 201.405(c)(3)). This information is
currently required to be on the label for Rx animal drugs, in
accordance with Sec. 201.105(b)(4).
Proposed Sec. 201.405(b) and (c) would establish the content and
format requirements for the label for approved or conditionally
approved Rx new animal drugs and would replace the requirements for the
label of approved or conditionally approved Rx new animal drugs
currently provided in Sec. 201.105(b). Furthermore, Sec. 201.105
would be amended to cross-reference proposed Sec. 201.405 for the
content and format requirements for labeling components for approved or
conditionally approved Rx new animal drugs (see discussion in section
V.I.).
d. Controlled substance symbol. For Rx new animal drugs that are
controlled substances, the proposed rule would require this section of
the Rx small label to include the controlled substance schedule symbol
in accordance with part 1302 designating the schedule for the drug
substance (see proposed Sec. 201.405(c)(4)).
e. Prescription statement. The proposed rule would require this
section of the Rx small label to state: ``Rx Animal Use'' (see proposed
Sec. 201.405(c)(5)). In accordance with section 503(f)(4) of the FD&C
Act, the label for all Rx new animal drugs must include the following
statement: ``Caution: Federal law restricts this drug to use by or on
the order of a licensed
[[Page 18281]]
veterinarian.'' However, since 1960 (25 FR 12592) Sec. 201.105(b)(6)
exempts ``containers too small or otherwise unable to accommodate a
label with sufficient space'' to include the full prescription
statement provided that the full statement may be placed on the outer
container only. We are proposing the ``Rx Animal Use'' statement for a
Rx small label for Rx new animal drugs. This statement would
appropriately identify the Rx status of the new animal drug and would
require minimal space.
f. ``For [target animal(s)] only.'' The proposed rule would require
this section of the Rx small label to include a brief listing of the
approved target animal(s) as follows: ``For [target animal(s)] only''
(see proposed Sec. 201.405(c)(6)). The brief listing of the approved
target animal(s) would be used in place of full ``Indications for Use''
information because Rx small labels lack sufficient space. This listing
would not require as much space on the Rx small label.
g. Full prescribing information statement. The proposed rule would
require this section of the Rx small label to include one of two
statements. If full prescribing information is provided on the package
insert, the following statement would be used: ``Read package insert
for full prescribing information.'' If full prescribing information is
provided on the secondary container labeling, the following statement
would be used: ``Read package labeling for full prescribing
information.'' See proposed Sec. 201.405(c)(7). Because full
prescribing information would not be provided on the Rx small label,
the purpose of the statements would be to remind the veterinarian to
read full prescribing information before using the Rx new animal drug.
h. ``Net Contents.'' The proposed rule would require this section
of the Rx small label to have the heading ``Net Contents,'' followed by
the contents of the immediate container, in accordance with Sec.
201.51 (see proposed Sec. 201.405(c)(8)).
i. Name and place of business. The proposed rule would require this
section of the Rx small label to identify the name and place of
business of the manufacturer, packer, or distributor, as required in
section 502(b) of the FD&C Act (see proposed Sec. 201.405(c)(9)).
j. ``Lot, Exp. and Storage'' or ``Lot and Storage.'' The proposed
rule would require this section of the Rx small label to have the
heading ``Lot, Exp. and Storage'' or ``Lot and Storage,'' followed by
the identifying lot or control number of the Rx new animal drug within
the immediate container (see proposed Sec. 201.405(c)(10)). Should a
problem be reported to FDA, a lot or control number would allow us more
easily to identify and trace back a specific lot of a product. We would
also require this section of the Rx small label to include the
expiration date of the Rx new animal drug within the immediate
container, in accordance with Sec. 201.17. An expiration date on the
Rx small label better ensures that the new animal drug would not be
used after it expires.
The proposed rule would also require this section of the Rx small
label to include drug storage information for the new animal drug (see
proposed Sec. 201.405(c)(10)). Storage information is necessary to
maintain potency of the drug before its expiration date. Requiring this
information on the Rx small label is needed for safe and effective use
of new animal drugs. If the immediate container provides a single dose
of the Rx new animal drug and is packaged individually in a secondary
container that provides an expiration date on the secondary container
labeling or secondary container, the proposed rule would not require an
expiration date on the Rx small label or immediate container, in
accordance with Sec. 201.17. Under such provision, this section of the
Rx small label would be required to be entitled ``Lot and Storage.''
k. ``Revision Date.'' The proposed rule would require this section
of the Rx small label to have the heading ``Revision Date,'' followed
by the date of the most recent revision of the Rx small label, listing
the month followed by the year (see proposed Sec. 201.405(c)(11)).
4. Labeling for Secondary Containers for Rx New Animal Drugs That
Include a Package Insert (Rx Secondary Container Labeling) (Proposed
Sec. 201.405(d))
The proposed rule would establish content and format requirements
for the information on the labeling for secondary containers of
approved or conditionally approved Rx new animal drugs that include a
package insert (Rx secondary container labeling) (see proposed Sec.
201.405(d)). In this situation, the package insert would be required to
include full prescribing information, as described in proposed Sec.
201.405(a).
In accordance with section 201(k) of the FD&C Act, the Rx secondary
container labeling could exclude any information described in proposed
Sec. 201.405(d) that would be required to appear on the Rx label or Rx
small label (see proposed Sec. 201.405(b) or (c), respectively) if
such information on the Rx label or Rx small label was easily legible
through the secondary container.
The Rx secondary container labeling to which proposed Sec.
201.405(d) would apply may consist of a front panel and one side or
back panel, or a front panel and multiple side and/or back panels.
Proposed Sec. 201.405(d) would provide for such Rx secondary container
labeling designs. For Rx secondary container labeling with a front
panel and one side or back panel, proposed Sec. 201.405(d)(1) would
provide required information for the front panel, and proposed Sec.
201.405(d)(2) would provide required information for the side or back
panel. For Rx secondary container labeling with a front panel and
multiple side and/or back panels, the information identified in
proposed Sec. 201.405(d)(1) followed by the information identified in
proposed Sec. 201.405(d)(2) would be required in order, starting on
the front panel, continuing on the panel immediately to the right of
the front panel, and continuing to fill the panels to the right until
all of the information in proposed Sec. 201.405(d)(1) and (d)(2) was
presented. In all instances, the information proposed in Sec.
201.405(d)(2)(v) and (vi), i.e., ``Active Ingredient'' or ``Active
Ingredients'' and ``Inactive Ingredients,'' would need to appear on the
same panel.
a. Front panel. The proposed rule would require the following
information to be presented on the front panel of the Rx secondary
container labeling and in the following order (see proposed Sec.
201.405(d)(1)). Unless otherwise indicated, this information would be
the same as that required by proposed Sec. 201.405(a) for full
prescribing information.
i. Drug product identification. The proposed rule would require
this section of the Rx secondary container labeling to include drug
product identification (see proposed Sec. 201.405(d)(1)(i)). The
information would be the same as that included in the drug product
identification section for full prescribing information, as described
in proposed Sec. 201.405(a)(1), and would also identify if the drug
product is sterile. Full prescribing information would require a drug
product identification section and a ``Description'' section. Full
prescribing information for sterile Rx new animal drugs would be
required to identify in the ``Description'' section that the drug is
sterile. However, due to space limitations, no ``Description'' section
would be required on the Rx secondary container labeling. Instead, the
drug product identification section of the Rx secondary container
labeling for sterile Rx new animal drugs would be required to state
that the drug is sterile.
ii. Prescription statement. The proposed rule would require this
section of the Rx secondary container
[[Page 18282]]
labeling to include the prescription statement, as described in
proposed Sec. 201.405(a)(2) for full prescribing information (see
proposed Sec. 201.405(d)(1)(ii)).
iii. Conditional approval statement. For conditionally approved Rx
new animal drugs, the proposed rule would require this section of the
Rx secondary container labeling to include a conditional approval
statement, as described in proposed Sec. 201.405(a)(3) for full
prescribing information (see proposed Sec. 201.405(d)(1)(iii)).
iv. Boxed warnings. For approved or conditionally approved Rx new
animal drugs requiring boxed warnings, the proposed rule would require
this section of the Rx secondary container labeling to include the
boxed warnings, as described in proposed Sec. 201.405(a)(4) for full
prescribing information (see proposed Sec. 201.405(d)(1)(iv)).
v. ``Indications for Use.'' The proposed rule would require this
section of the Rx secondary container labeling to have the heading
``Indications for Use,'' followed by the ``Indications for Use''
section, as described in proposed Sec. 201.405(a)(7) for full
prescribing information (see proposed Sec. 201.405(d)(1)(v)).
vi. Extralabel prohibition statement. For approved new animal drugs
prohibited from extralabel use, in accordance with Sec. 530.41, the
proposed rule would require this section of the Rx secondary container
labeling to include the extralabel use prohibition statement, as
described in proposed Sec. 201.405(a)(5) for full prescribing
information (see proposed Sec. 201.405(d)(1)(vi)).
vii. ``Net Contents.'' The proposed rule would require this section
of the Rx secondary container labeling to have the heading ``Net
Contents,'' followed by the contents of the secondary container (see
proposed Sec. 201.405(d)(1)(vii)).
viii. NADA/ANADA approval statement. For approved new animal drugs
or approved generic new animal drugs, the proposed rule would require
this section of the Rx secondary container labeling to include the NADA
or ANADA approval statement, as described in proposed Sec.
201.405(a)(21) for full prescribing information (see proposed Sec.
201.405(d)(1)(viii)).
b. Side or back panel. The proposed rule would require the
following information to be presented on the side or back panel of the
Rx secondary container labeling and in the following order (see
proposed Sec. 201.405(d)(2)). Unless otherwise indicated, this
information would be the same as that required by proposed Sec.
201.405(a) for full prescribing information.
i. Full prescribing information statement. The proposed rule would
require this section of the Rx secondary container labeling to include
the statement: ``Before using this drug, read package insert for full
prescribing information'' (see proposed Sec. 201.405(d)(2)(i)).
Because full prescribing information would not be provided on the Rx
secondary container labeling, the purpose of the full prescribing
information statement would be to remind the veterinarian to read full
prescribing information before using the Rx new animal drug.
ii. ``Dosage and Administration.'' The proposed rule would require
this section of the Rx secondary container labeling to have the heading
``Dosage and Administration,'' followed by the ``Dosage and
Administration'' section, as described in proposed Sec. 201.405(a)(8)
for full prescribing information (see proposed Sec.
201.405(d)(2)(ii)).
iii. ``Contraindications.'' The proposed rule would require this
section of the Rx secondary container labeling to have the heading
``Contraindications,'' followed by the ``Contraindications'' section,
as described in proposed Sec. 201.405(a)(9) for full prescribing
information (see proposed Sec. 201.405(d)(2)(iii)).
iv. ``Warnings and Precautions.'' The proposed rule would require
this section of the Rx secondary container labeling to have the heading
``Warnings and Precautions,'' followed by the ``Warnings and
Precautions'' section, as described in proposed Sec. 201.405(a)(10)
for full prescribing information (see proposed Sec.
201.405(d)(2)(iv)).
v. ``Active Ingredient'' or ``Active Ingredients.'' The proposed
rule would require this section of the Rx secondary container labeling
to have the heading ``Active Ingredient'' or ``Active Ingredients,''
followed by the established name and strength or concentration of each
active ingredient, as described in proposed Sec. 201.405(b)(2)(iii)
for the Rx label (see proposed Sec. 201.405(d)(2)(v)).
vi. ``Inactive Ingredients.'' The proposed rule would require this
section of the Rx secondary container labeling to have the heading
``Inactive Ingredients,'' followed by the established name of each
inactive ingredient, as described in proposed Sec. 201.405(a)(6)(viii)
for full prescribing information (see proposed Sec.
201.405(d)(2)(vi)).
vii. ``Storage, Handling, and Disposal.'' The proposed rule would
require this section of the Rx secondary container labeling to have the
heading ``Storage, Handling, and Disposal,'' followed by drug storage,
handling, and disposal information, as described in proposed Sec.
201.405(a)(20) for full prescribing information (see proposed Sec.
201.405(d)(2)(vii)).
viii. Name and place of business. The proposed rule would require
this section of the Rx secondary container labeling to identify the
manufacturer, packer, or distributor, as described in proposed Sec.
201.405(a)(22) for full prescribing information (see proposed Sec.
201.405(d)(2)(viii)).
ix. ``Lot Number and Expiration Date.'' The proposed rule would
require this section of the Rx secondary container labeling to have the
heading ``Lot Number and Expiration Date,'' followed by the identifying
lot or control number of the Rx new animal drug within the secondary
container. The proposed rule would also require this section of the Rx
secondary container labeling to include the expiration date of the Rx
new animal drug within the secondary container, in accordance with
Sec. 201.17. Alternatively, the proposed rule would allow for this
section to refer to the location on the Rx secondary container labeling
or secondary container where the lot or control number and expiration
date are printed (see proposed Sec. 201.405(d)(2)(ix)). As an example,
if the lot number and expiration date are printed on the bottom flap of
a secondary container, then the labeling may state in this section,
``See carton bottom flap for lot number and expiration date. However,
in accordance with Sec. 201.17, the proposed rule would allow an
expiration date to be excluded from the Rx secondary container labeling
or secondary container if the expiration date provided on the Rx label,
Rx small label, or immediate container is easily legible through the
secondary container.
x. ``Revision Date.'' The proposed rule would require this section
of the Rx secondary container labeling to have the heading ``Revision
Date,'' followed by the date of the most recent revision of the Rx
secondary container labeling, listing the month followed by the year
(see proposed Sec. 201.405(d)(2)(x)).
5. Shipping Labeling for Rx New Animal Drugs (Rx Shipping Labeling)
(Proposed Sec. 201.405(e))
The proposed rule would establish content and format requirements
for the information on the shipping labeling for approved or
conditionally approved Rx new animal drugs (Rx shipping labeling). As
defined in proposed Sec. 201.403, shipping labeling is associated with
the outermost carton containing immediate containers, secondary
containers, and/or multiple
[[Page 18283]]
unit (multi-unit) cartons of a new animal drug and intended for
shipment, but not display, of the product. The proposed rule would
require the Rx shipping labeling to include, among additional
information, drug product identity, the manufacturer, packer, or
distributor, and drug storage and handling conditions (see proposed
Sec. 201.405(e)). However, the Rx shipping labeling for controlled
substances would not include information that would identify the drug,
in accordance with Sec. 1301.74(e), to guard against storage or in-
transit losses due to theft or diversion.
The proposed rule would require the following information to be
presented on the Rx shipping labeling and in the following order (see
proposed Sec. 201.405(e)). Unless otherwise indicated, this
information would be the same as that required by proposed Sec.
201.405(a) for full prescribing information.
a. Proprietary name of the finished drug product. The proposed rule
would require this section of the Rx shipping labeling to include the
proprietary name of the finished drug product (see proposed Sec.
201.405(e)(1)). This section would be excluded from the Rx shipping
labeling for a controlled substance.
b. Established name of the drug product. The proposed rule would
require this section of the Rx shipping labeling to include the
established name of the drug product (see proposed Sec.
201.405(e)(2)). This section would be excluded from the Rx shipping
labeling for a controlled substance.
c. Established name and strength or concentration of each active
ingredient. The proposed rule would require this section of the Rx
shipping labeling to provide the established name and strength or
concentration of each active ingredient. This section would be excluded
from the Rx shipping labeling for a controlled substance (see proposed
Sec. 201.405(e)(3)).
d. Conditional approval statement. For conditionally approved Rx
new animal drugs, the proposed rule would require this section of the
Rx shipping labeling to include a conditional approval statement, as
described in proposed Sec. 201.405(a)(3) for full prescribing
information (see proposed Sec. 201.405(e)(4)). This section would be
excluded from the Rx shipping labeling for a controlled substance.
e. ``Net Contents.'' The proposed rule would require this section
of the Rx shipping labeling to have the heading ``Net Contents,''
followed by the contents of the shipping carton (see proposed Sec.
201.405(e)(5)).
f. ``Storage and Handling.'' The proposed rule would require this
section of the Rx shipping labeling to have the heading ``Storage and
Handling,'' followed by drug storage information (see proposed Sec.
201.405(e)(6)). Also, any handling information required for safe and
effective use of the new animal drug would be included in this section.
Information on disposal of the new animal drug would not be required to
be included on the Rx shipping labeling.
g. NADA/ANADA approval statement. For approved new animal drugs or
approved generic new animal drugs, the proposed rule would require this
section of the Rx shipping labeling to include the NADA or ANADA
approval statement, as described in proposed Sec. 201.405(a)(21) for
full prescribing information (see proposed Sec. 201.405(e)(7)). This
section would be excluded from the Rx shipping labeling for a
controlled substance.
h. Name and place of business. The proposed rule would require this
section of the Rx shipping labeling to identify the name and place of
business of the manufacturer, packer, or distributor, as described in
proposed Sec. 201.405(a)(22) for full prescribing information (see
proposed Sec. 201.405(e)(8)).
i. ``Lot Number and Expiration Date.'' The proposed rule would
require this section of the Rx shipping labeling to have the heading
``Lot Number and Expiration Date,'' followed by the identifying lot or
control number(s) and the expiration date(s) of the Rx new animal drug
within the shipping carton (see proposed Sec. 201.405(e)(9)). The
shipping carton may contain more than one lot of the new animal drug,
and therefore, more than one lot or control number and expiration date
may be listed in this section of the Rx shipping labeling.
j. ``Revision Date.'' The proposed rule would require the last
section of the Rx shipping labeling to have the heading ``Revision
Date,'' followed by the date of the most recent revision of the Rx
shipping labeling, listing the month followed by the year (see proposed
Sec. 201.405(e)(10)).
6. Other Approved Labeling for Rx New Animal Drugs (Rx Other Approved
Labeling) (Proposed Sec. 201.405(f))
The proposed rule would establish content and format requirements
for the information presented on other approved labeling for approved
or conditionally approved Rx new animal drugs (Rx other approved
labeling) (see proposed Sec. 201.405(f)). Rx other approved labeling
includes, but is not limited to, labeling on display cartons and multi-
unit cartons (excluding shipping cartons), containing the immediate
containers or the secondary containers of the Rx new animal drug.
The proposed rule would require the following information to be
presented on the Rx other approved labeling and in the following order
(see proposed Sec. 201.405(f)). Unless otherwise indicated, this
information would be the same as required by proposed Sec. 201.405(a)
for full prescribing information.
a. Proprietary name of the finished drug product. The proposed rule
would require this section of the Rx other approved labeling to include
the proprietary name of the finished drug product (see proposed Sec.
201.405(f)(1)).
b. Established name of the drug product. The proposed rule would
require this section of the Rx other approved labeling to include the
established name of the drug product (see proposed Sec.
201.405(f)(2)).
c. Established name and strength or concentration of each active
ingredient. The proposed rule would require this section of the Rx
other approved labeling to provide the established name and strength or
concentration of each active ingredient (see proposed Sec.
201.405(f)(3)).
d. Controlled substance symbol. The proposed rule would require
this section of the Rx other approved labeling for controlled
substances to include the controlled substance schedule symbol, in
accordance with part 1302 designating the schedule for the drug
substance (see proposed Sec. 201.405(f)(4)).
e. Prescription statement. The proposed rule would require this
section of the Rx other approved labeling to include the prescription
statement, as described in proposed Sec. 201.405(a)(2) for full
prescribing information (see proposed Sec. 201.405(f)(5)).
f. Conditional approval statement. For conditionally approved new
animal drugs, the proposed rule would require this section of the Rx
other approved labeling to include a conditional approval statement, as
described in proposed Sec. 201.405(a)(3) for full prescribing
information (see proposed Sec. 201.405(f)(6)).
g. Boxed warnings. For approved or conditionally approved Rx new
animal drugs requiring boxed warnings, the proposed rule would require
this section of the Rx other approved labeling to include the boxed
warnings, as described in proposed Sec. 201.405(a)(4) for full
prescribing information (see proposed Sec. 201.405(f)(7)).
[[Page 18284]]
h. Extralabel use prohibition statement. For approved new animal
drugs prohibited from extralabel use, in accordance with Sec. 530.41,
the proposed rule would require this section of the Rx other approved
labeling to include the extralabel use prohibition statement, as
described in proposed Sec. 201.405(a)(5) for full prescribing
information (see proposed Sec. 201.405(f)(8)).
i. ``Net Contents.'' The proposed rule would require this section
of the Rx other approved labeling to have the heading ``Net Contents,''
followed by the contents of the container to which the Rx other
approved labeling applies (see proposed Sec. 201.405(f)(9)).
j. ``Storage, Handling, and Disposal.'' The proposed rule would
require this section of the Rx other approved labeling to have the
heading ``Storage, Handling, and Disposal,'' followed by drug storage,
handling, and disposal information, as described in proposed Sec.
201.405(a)(20) for full prescribing information (see proposed Sec.
201.405(f)(10)).
k. NADA/ANADA approval statement. For approved new animal drugs or
approved generic new animal drugs, the proposed rule would require this
section of the Rx other approved labeling to include the NADA or ANADA
approval statement, as described in proposed Sec. 201.405(a)(21) for
full prescribing information (see proposed Sec. 201.405(f)(11)).
l. Name and place of business. The proposed rule would require this
section of the Rx other approved labeling to identify the name and
place of business of the manufacturer, packer, or distributor, as
described in proposed Sec. 201.405(a)(22) for full prescribing
information (see proposed Sec. 201.405(f)(12)).
m. ``Lot Number and Expiration Date.'' The proposed rule would
require this section of the Rx other approved labeling to have the
heading ``Lot Number and Expiration Date,'' followed by the identifying
lot or control number of the Rx new animal drug within the container to
which the Rx other approved labeling applies. This section of the Rx
other approved labeling would also be required to include the
expiration date of the Rx new animal drug within the container to which
the Rx other approved labeling applies, in accordance with Sec.
201.17. In accordance with Sec. 201.17, the proposed rule would allow
an expiration date to be excluded from the Rx other approved labeling
if the expiration date provided on containers within or their labeling
is easily legible through the container to which the Rx other approved
labeling applies (see proposed Sec. 201.405(f)(13)).
n. ``Revision Date.'' The proposed rule would require the last
section of the Rx other approved labeling to have the heading
``Revision Date,'' followed by the date of the most recent revision of
the Rx other approved labeling, listing the month followed by the year
(see proposed Sec. 201.405(f)(14)).
E. Content and Format for Over-The-Counter (OTC) New Animal Drug
Labeling--Overview (Proposed Sec. 201.407)
The proposed rules provides content and format requirements for all
components of labeling for approved or conditionally approved OTC new
animal drugs other than those for use in animal feeds that are subject
to part 558 (see proposed Sec. 201.407). Proposed Sec. 201.409 would
establish the content and format requirements for all components of
labeling for approved or conditionally approved new animal drugs
intended for use in animal feeds that are subject to part 558. OTC new
animal drugs are new animal drugs that can be used without a
prescription from a veterinarian. They are intended for use by the
layperson, such as pet owners and livestock producers. In accordance
with section 502(f) of the FD&C Act, OTC drugs must bear adequate
directions for use on labeling. Adequate directions for use means
directions under which the layperson can use a drug safely and for the
purposes for which it is intended (see Sec. 201.5).
The proposed rule would require that labeling sections or
subsections that do not apply be omitted from the labeling for approved
or conditionally approved OTC new animal drugs (see proposed Sec.
201.407). For example, OTC new animal drugs approved or conditionally
approved for use in non-food-producing animals (e.g., cats, dogs) would
not require the labeling subsection entitled either ``Withdrawal
Periods and Residue Warnings'' or ``Withdrawal Periods''.
FDA determines the final content of each applicable section of
labeling during the review of each new animal drug as part of the
approval process.
The proposed rule would identify the information that would be
required to be included on the labeling component that would provide
full product information for OTC new animal drugs in proposed Sec.
201.407(a). Full product information for OTC new animal drugs would be
similar in concept to full prescribing information for Rx new animal
drugs in that it would include all information necessary for the safe
and effective use of the OTC new animal drug. Thus, all approved or
conditionally approved OTC new animal drugs would be required to
provide a labeling component that includes full product information. If
a package insert is provided with an OTC new animal drug, the proposed
rule would require the package insert to include full product
information. If only partial information is provided on a package
insert, the user may mistakenly assume the package insert includes
complete information on the safe and effective use of the drug when in
fact it does not. If no package insert is provided with an OTC new
animal drug, the secondary container labeling would be required to
include full product information. If no package insert or secondary
container labeling is provided with the OTC new animal drug, then full
product information would need to be provided on the label (see
proposed Sec. 201.407(a)).
The label is the labeling component that appears on the immediate
container, which is the container in contact with the drug. The
proposed rule would establish content and format requirements for the
label for an approved or conditionally approved OTC new animal drug
that does not provide full product information (see proposed Sec.
201.407(b)). The proposed rule would establish content and format
requirements for a small label for an approved or conditionally
approved OTC new animal drug that we determine lacks sufficient space
to comply with proposed Sec. 201.407(b) (see proposed Sec.
201.407(c)).
For purposes of proposed subpart H, we would define a package
insert for an approved or conditionally approved OTC new animal drug as
a labeling component that contains full product information and is
included with the immediate container or secondary container or is
attached to the label (see proposed Sec. 201.403). Where the package
insert is attached to the label, which is sometimes referred to as, for
example, ``extended labeling,'' ``onserts,'' or ``outserts,'' for
purposes of proposed subpart H, the package insert providing full
product information and attached to the label would need to comply with
proposed Sec. 201.407(a). The label would need to comply with proposed
Sec. 201.407(b) or (c), as applicable.
FDA considers the secondary container for a new animal drug to be
the packaging that surrounds the immediate container. The proposed rule
would establish content and format requirements for secondary container
labeling for an approved or conditionally approved OTC new animal drug
(see proposed Sec. 201.407(d)). If a package insert is provided with
an OTC new animal drug, then the secondary container labeling would be
[[Page 18285]]
required to comply with proposed Sec. 201.407(d) and the package
insert would be required to provide full product information to comply
with proposed Sec. 201.407(a). If no package insert is provided with
an OTC new animal drug, the proposed rule would require full product
information to appear on the secondary container labeling (see proposed
Sec. 201.407(a)).
In accordance with the definition of ``label'' in section 201(k) of
the FD&C Act, information on the label must also appear on an outside
container or wrapper of the retail package, if it exists, or be easily
legible through the outside container or wrapper. For purposes of these
proposed regulations, FDA considers the secondary container to be an
``outside container or wrapper of the retail package'' for new animal
drugs. Therefore, if a secondary container exists, the proposed rule
would require the secondary container labeling to include all
information that would be on the label in accordance with proposed
Sec. 201.407(b) or (c), unless the information on the label is easily
legible through the secondary container (see proposed Sec. 201.407(a)
or (d)).
Shipping labeling is associated with the outermost carton
containing a new animal drug, which is intended for shipping, but not
displaying the product. The proposed rule would establish content and
format requirements for the shipping labeling of approved or
conditionally approved OTC new animal drugs including a requirement
that such shipping labeling identify the new animal drug, the
manufacturer, and drug storage and handling information(see proposed
Sec. 201.407(e)).
Depending on how a sponsor intends to sell or display an approved
or conditionally approved OTC new animal drug, there may be other
containers such as display cartons and multiple unit (multi-unit)
cartons that contain immediate containers or secondary containers.
These containers may be packaged in shipping cartons. The proposed rule
would establish content and format requirements for the labeling of
these other containers for OTC new animal drugs (see proposed Sec.
201.407(f)).
Labeling sections and subsections for OTC new animal drugs would
not be numbered. Headings of sections and subsections that would be
required to appear verbatim on labeling are identified in the proposed
regulations in quotations. Similarly, certain other labeling text would
be required to appear verbatim on labeling; this text is also
identified in the proposed regulations in quotations.
The proposed rule would require the labeling of approved or
conditionally approved OTC new animal drugs to comply with other
applicable requirements in proposed subpart H (see proposed Sec.
201.407).
1. Labeling Providing Full Product Information (Proposed Sec.
201.407(a))
The proposed rule uses the term ``full prescribing information'' to
identify all information necessary for the safe and effective use of
approved or conditionally approved Rx new animal drugs, and the
proposed regulations use that term for Rx new animal drugs. The concept
of a component of labeling providing all information necessary for the
safe and effective use of an approved or conditionally approved OTC new
animal drug is equally important. FDA proposes that the term used for
this information for approved or conditionally approved OTC new animal
drugs would be ``full product information'' because OTC new animal
drugs are not prescribed.
The proposed rule would establish content and format requirements
for the component of labeling that provides full product information
for approved or conditionally approved OTC new animal drugs (see
proposed Sec. 201.407(a)).
If a package insert is provided with an approved or conditionally
approved OTC new animal drug, the proposed rule would require the
package insert to include full product information (see proposed Sec.
201.407(a)). If a package insert is provided with an approved or
conditionally approved OTC new animal drug, the label would be required
to comply with proposed Sec. 201.407(b) or (c), and any secondary
container labeling would be required to comply with proposed Sec.
201.407(d).
If a package insert is not provided with an approved or
conditionally approved OTC new animal drug, but a secondary container
is provided, then the secondary container labeling would be required to
provide full product information (see proposed Sec. 201.407(a)). If
full product information is provided on the secondary container
labeling, in accordance with section 201(k) of the FD&C Act, proposed
Sec. 201.407(a) would allow the secondary container labeling to
exclude any portions of full product information that would be required
to appear on the label if such information is easily legible through
the secondary container (see proposed Sec. 201.407(a)).
If no package insert or secondary container is provided with an
approved or conditionally approved OTC new animal drug, then the label
would be required to include full product information (see proposed
Sec. 201.407(a)).
The proposed rule would require the following information to be
presented in full product information for approved or conditionally
approved OTC new animal drugs and in the following order. Unless
otherwise indicated, this information would be the same as that
required by proposed Sec. 201.405(a) for full prescribing information
for approved or conditionally approved Rx new animal drugs.
a. Drug product identification. The proposed rule would require
this section of full product information to include the proprietary
name of the finished drug product and the established name of the drug
product. If not included as part of the established name of the drug
product, the route(s) of administration and dosage form of the finished
drug product would be required to be included in this section as well
(see proposed Sec. 201.407(a)(1)(i) through (iv)).
The established name and strength or concentration of each active
ingredient would also be required. The strength or concentration of
each active ingredient would be allowed to be excluded from full
product information provided on a package insert if the package insert
applies to multiple strengths or concentrations for the same OTC new
animal drug (see proposed Sec. 201.407(a)(1)(v)).
If FDA determines that identifying the pharmacological class of an
OTC new animal drug on labeling would be helpful in facilitating its
safe and effective use, the proposed rule would require that the
pharmacological class be included in this section of full product
information (see proposed Sec. 201.407(a)(1)(vi)).
b. Conditional approval statement. For conditionally approved OTC
new animal drugs, the proposed rule would require this section of full
product information to include a conditional approval statement, as
described in proposed Sec. 201.405(a)(3) for full prescribing
information for conditionally approved Rx new animal drugs (see
proposed Sec. 201.407(a)(2)).
c. ``Uses.'' This section of full product information would be
required to have the heading ``Uses,'' followed by the approved or
conditionally approved indication(s) and target animal(s) in the
following format: ``For [indication(s)] in [target animal(s)]'' (see
proposed Sec. 201.407(a)(3)).
This section of full product information would be similar to the
``Indications for Use'' section of full prescribing information for Rx
new animal drugs, as described in proposed
[[Page 18286]]
Sec. 201.405(a)(7). For OTC new animal drugs, the heading ``Uses'' may
be better understood by the layperson and is consistent with the
requirements for labeling of OTC human drugs (see Sec. 201.66(c)(4)).
If FDA approves or conditionally approves an OTC new animal drug
for use only under specific conditions, such as in conjunction with a
specific diet, then the proposed rule would require that this
information be specified in the ``Uses'' section of full product
information (see proposed Sec. 201.407(a)(3)(ii)).
FDA may require a statement in the ``Uses'' section of full product
information describing the relative effectiveness of doses within the
approved range of doses (see proposed Sec. 201.407(a)(3)(iii)). This
requirement primarily pertains to OTC new animal drugs that affect the
structure or function of the body of an animal (section 201(g)(1)(C) of
the FD&C Act) but are not intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease (section 201(g)(1)(B)
of the FD&C Act), e.g., drugs that increase the rate of weight gain or
feed efficiency in food-producing animals. For these new animal drugs,
all doses within the range presented on the approved labeling must be
effective for their intended use(s) (see 21 CFR 514.4(b)(2)(i)). For
new animal drugs intended for use in the diagnosis, cure, mitigation,
treatment, or prevention of disease, the lowest dose of the dose range
must be effective for the intended use(s). However, the doses within
the approved range do not need to be more effective than any other
doses within the same range. For OTC new animal drugs approved for
structure or function indications, if the highest approved dose(s) is
not more effective compared to the next lower approved dose(s), the
proposed rule would be able to require a statement in the ``Uses''
section to inform the user that a higher dose(s) is not more effective
than the next lower dose(s).
For safety and/or effectiveness reasons, we may require a
statement(s) in the ``Uses'' section of full product information
identifying animals for which the OTC new animal drug has not been
approved or conditionally approved (see proposed Sec.
201.407(a)(3)(iv)).
d. Extralabel use statement. The proposed rule would require this
section of full product information to include an extralabel use
statement (see proposed Sec. 201.407(a)(4)). In accordance with part
530, extralabel use of approved new animal drugs is not permitted
except by or on the order of a licensed veterinarian and under the
conditions described in that chapter. The required statement would be:
``It is a violation of Federal law to use this drug product other than
as directed in the labeling or as directed by your veterinarian.'' It
is important for the layperson to know when it is a violation of
Federal law to use drugs in animals in an extralabel manner.
e. Extralabel use prohibition statement. For approved new animal
drugs prohibited from extralabel use, in accordance with Sec. 530.41,
the proposed rule would require this section of full product
information to include an extralabel use prohibition statement, as
described in proposed Sec. 201.405(a)(5) for full prescribing
information for Rx new animal drugs (see proposed Sec. 201.407(a)(5)).
Few OTC new animal drugs are prohibited from extralabel use under Sec.
530.41. However, for the rare situation in which an approved OTC new
animal drug is prohibited from extralabel use under Sec. 530.41, this
statement would be included in addition to the appropriate extralabel
use statement that would be required by proposed Sec. 201.407(a)(4).
f. ``Description.'' The proposed rule would require this section of
full product information to have the heading ``Description,'' followed
by a description of the new animal drug. The description would include
the proprietary name of the finished drug product and established name
of the drug product, and the route(s) of administration and dosage form
if not included as part of the established name. The description would
also include identifying characteristics of the dosage form, such as
color, shape, coating, scoring, and imprinting. All approved and
available strengths or concentrations of the new animal drug to which
full product information applies would need to be identified in this
section of full product information. If the drug product was sterile,
this fact would also be identified in this section of full product
information (see proposed Sec. 201.407(a)(6)).
When inactive ingredients are provided on the labeling, the
proposed rule would require they be listed in the ``Description''
section in decreasing order of predominance, by weight or concentration
(see proposed Sec. 201.407(a)(6)(viii)). We encourage sponsors to list
all inactive ingredients on labeling to better inform users about the
product.
g. ``Warnings.'' The proposed rule would require this section of
full product information for all approved or conditionally approved OTC
new animal drugs, and it would have the heading ``Warnings'' (see
proposed Sec. 201.407(a)(7)). This section of full product information
would be similar to the ``Warnings and Precautions'' section proposed
for full prescribing information for Rx new animal drugs, as described
in proposed Sec. 201.405(a)(10). However, ``precautions'' would be
excluded from this section of full product information and instead be
provided in the ``Additional Recommendations'' section of full product
information, as described in proposed Sec. 201.407(a)(8). A more
complete explanation of the basis for this proposal is provided in the
discussion of the ``Animal Safety Warnings'' subsection for OTC new
animal drugs in proposed Sec. 201.407(a)(7)(iii).
i. ``Withdrawal Periods and Residue Warnings'' or ``Withdrawal
Periods.'' All OTC new animal drugs approved or conditionally approved
for use in food-producing animals, would be required to have as the
first subsection of the ``Warnings'' section of full product
information a subsection with the heading ``Withdrawal Periods and
Residue Warnings'' or ``Withdrawal Periods.'' This subsection would
provide human food safety warnings, including milk discard times,
withdrawal periods, and residue warning statements, as applicable to
the new animal drug (see proposed Sec. 201.407(a)(7)(i)). This
subsection of full product information would be the same as described
in proposed Sec. 201.405(a)(10)(i) for full prescribing information
for Rx new animal drugs.
ii. ``User Safety Warnings.'' The proposed rule would require this
subsection of the ``Warnings'' section of full product information to
have the heading ``User Safety Warnings,'' followed by the user safety
warnings (see proposed Sec. 201.407(a)(7)(ii)). This subsection of
full product information would be the same as described in proposed
Sec. 201.405(a)(10)(ii) for full prescribing information for Rx new
animal drugs.
iii. ``Animal Safety Warnings.'' For OTC new animal drugs with
contraindications, target animal safety warnings that identify any
serious adverse reaction or potential hazard to the target animal(s)
associated with the use of the new animal drug, adverse reactions, or
post-approval adverse drug experiences, the proposed rule would require
this subsection of the ``Warnings'' section of full product information
to have the heading ``Animal Safety Warnings,'' followed by the
contraindications, target animal safety warnings, adverse reactions,
and post-approval adverse drug experiences
[[Page 18287]]
(see proposed Sec. 201.407(a)(7)(iii)). This proposed subsection of
full product information would differ in some ways from the ``Animal
Safety Warnings and Precautions'' subsection of full prescribing
information proposed for Rx new animal drugs, as described in proposed
Sec. 201.405(a)(10)(iii), and these differences are the basis for the
different proposed titles of these sections, i.e., ``Warnings'' for OTC
new animal drugs versus ``Warnings and Precautions'' for Rx new animal
drugs.
The definition of ``precautions'' in proposed Sec. 201.403 is
``any special care to be exercised for safe and effective use of the
new animal drug. This may include recommended screening, monitoring, or
diagnostic tests.'' Precautions related to Rx new animal drugs may
include screening, special care and monitoring, or diagnostic tests
intended to be performed by a veterinarian. Furthermore, precautions
related to Rx new animal drugs are often related to, and difficult to
distinguish from, target animal safety warnings. On the other hand, OTC
new animal drugs do not require professional veterinary expertise to
properly administer the drug, provide adequate post-treatment care, or
monitor effects after use of the drug. For OTC new animal drugs,
precautions provide additional recommendations to the layperson and are
distinguishable from target animal safety warnings. For example, this
may include information on when to administer the drug relative to
feeding, or a recommendation to have a sound mastitis monitoring
program before using the drug, etc. This advice is distinguishable from
warnings for OTC new animal drugs. Therefore, for better clarity to the
layperson, we propose that precautions for OTC new animal drugs not be
included in the ``Animal Safety Warnings'' section of full product
information and instead would be included in a separate section called
``Additional Recommendations,'' as described in proposed Sec.
201.407(a)(8).
In addition, the ``Animal Safety Warnings'' subsection of full
product information for OTC new animal drugs would differ from the
``Animal Safety Warnings and Precautions'' subsection of full
prescribing information for Rx new animal drugs in terms of
presentation of warning information. For OTC new animal drugs, all
potential risks of the drug to the target animal would be included:
contraindications, target animal safety warnings, adverse reactions,
and post-approval adverse drug experiences as determined by FDA. For Rx
new animal drugs, this information would be provided in different
sections of full prescribing information.
For OTC new animal drugs, including all potential risks to the
target animal in one subsection of full product information might be
clearer for the layperson and increase the likelihood that all of the
information would be read. Furthermore, identifying the risks to the
target animal on labeling as ``contraindications,'' ``target animal
safety warnings,'' ``adverse reactions,'' or ``post-approval adverse
drug experience'' may be confusing to a layperson because they may not
know the differences between the terms. The subsection heading ``Animal
Safety Warnings'' would be understood by the layperson as meaning risks
to the target animal. Therefore, the proposed rule would require that
all risks to the target animal for OTC new animal drugs be simply
identified as ``Animal Safety Warnings'' and placed in this subsection
of full product information. All risk information listed under ``Animal
Safety Warnings'' would be required to be listed in decreasing order of
severity to emphasize the most critical risks to the target animal (see
proposed Sec. 201.407(a)(7)(iii)).
iv. ``Environmental Warnings.'' For new animal drugs having
environmental warnings, the proposed rule would require this subsection
of the ``Warnings'' section of full product information to have the
heading ``Environmental Warnings,'' followed by the environmental
warnings (see proposed Sec. 201.407(a)(7)(iv)). This subsection of
full product information would be the same as described in proposed
Sec. 201.405(a)(10)(iv) for full prescribing information for Rx new
animal drugs.
v. ``Other Warnings.'' For OTC new animal drugs having warnings not
more appropriately placed in other ``Warnings'' subsections, the
proposed rule would require the last subsection of the ``Warnings''
section of full product information to have the heading ``Other
Warnings,'' followed by those warnings (see proposed Sec.
201.407(a)(7)(v)). This subsection of full product information would be
the same as described in proposed Sec. 201.405(a)(10)(v) for full
prescribing information for Rx new animal drugs.
h. ``Additional Recommendations.'' For OTC new animal drugs having
precautions, the proposed rule would require this section of full
product information to have the heading ``Additional Recommendations,''
followed by all precautions (see proposed Sec. 201.407(a)(8)). As
described in its proposed definition, precautions include any special
care to be exercised for safe and effective use of the new animal drug.
As discussed with respect to proposed Sec. 201.407(a)(7)(iii),
regarding ``Animal Safety Warnings,'' precautions are distinguishable
from target animal safety warnings for OTC new animal drugs. However,
because the term ``precautions'' as intended by these proposed
regulations may not be known or understood by the layperson, the title
``Additional Recommendations'' is proposed.
i. ``Other Effects You May Notice.'' For OTC new animal drugs that
have effects on the target animal(s) that are not considered
contraindications, target animal safety warnings, adverse reactions, or
post-approval adverse drug experiences, and FDA determines these
effects are required to be described on labeling, the proposed rule
would require this section of full product information to have the
heading ``Other Effects You May Notice,'' followed by a description of
the effects (see proposed Sec. 201.407(a)(9)). We consider this
information important for owners of animals, and this information is
currently provided on the labeling of some OTC new animal drugs.
For example, some OTC new animal drugs approved for increased rate
of weight gain and/or feed efficiency in feedlot beef cattle have
effects on the leanness or tenderness of the carcass of those animals.
Similarly, OTC new animal drugs that increase milk production in dairy
cows or the efficiency by which they produce milk may alter the fat
percent content of the milk. These effects, which are currently
described on the approved labeling for these products, are not
considered negative health effects on the target animal nor are they of
human food safety concern. However, these effects could be mistaken for
symptoms of an underlying health problem in the target animal, such as
poor nutritional status. For this reason, information of this type may
be considered material under section 201(n) of the FD&C Act such that
it would be required to be disclosed in the labeling for these products
on the basis that such disclosures may preclude unnecessary concern and
inappropriate medical treatment. Similarly, some topically applied OTC
new animal drugs for companion animals might permanently (but
harmlessly) alter the color of the fur at the application site. These
types of potential effects that are not safety concerns, but rather
provide important information to the layperson, would be included in
this section of full product information.
j. ``Directions.'' The proposed rule would require this section of
full
[[Page 18288]]
product information to have the heading ``Directions,'' followed by the
directions for use of the OTC new animal drug for each indication and
target animal (see proposed Sec. 201.407(a)(10)). The corresponding
section of full prescribing information for Rx new animal drugs would
be called ``Dosage and Administration,'' as described in proposed Sec.
201.405(a)(9). However, for OTC new animal drugs, the term
``Directions'' may be better understood by the layperson. In addition,
the term ``Directions'' is also used in labeling of OTC human drugs
(see Sec. 201.66(c)(6)).
The ``Directions'' section of full product information is
intentionally proposed for placement after the ``Warnings'' section.
This is in contrast to the ``Dosage and Administration'' section in
full prescribing information for Rx new animal drugs, which, except for
``Boxed Warnings,'' would be placed before ``Contraindications,''
``Warnings and Precautions,'' ``Adverse Reactions,'' and other
information about the effects of the drug. The intent in presenting
``Directions'' after the ``Warnings'' section in full product
information for OTC new animal drugs is to increase the likelihood that
the layperson will read the ``Warnings'' section before using the drug.
This placement approach is similar to that used in labeling of OTC
human drugs (see Sec. 201.66(c)(6)).
The ``Directions'' section of full product information would be
required to include information necessary for treatment of the animal
with the OTC new animal drug in accordance with FDA approval or
conditional approval, including route(s) of administration; specific
site(s) of administration, if applicable; dose or dose range, intervals
between doses, if applicable; and duration of treatment. For some
injectable products, FDA may require a statement of maximum volume per
injection site to facilitate the drug's safe and effective use, and th
[…truncated; see source link]Indexed from Federal Register on March 12, 2024.
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