[Code of Federal Regulations]
[Title 21, Volume 4]
[Revised as of April 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR201.57]
[Page 23-38]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES (CONTINUED)
PART 201 LABELING--Table of Contents
Subpart B Labeling Requirements for Prescription Drugs and/or Insulin
Sec. 201.57 Specific requirements on content and format of labeling for
human prescription drug and biological products described in Sec.
201.56(b)(1).
The requirements in this section apply only to prescription drug
products described in Sec. 201.56(b)(1) and must be implemented
according to the schedule specified in Sec. 201.56(c), except for the
requirement in paragraph (c)(18) of this section to reprint any FDA-
approved patient labeling at the end of prescription drug labeling or
accompany the prescription drug labeling, which must be implemented no
later than June 30, 2007.
(a) Highlights of prescribing information. The following information
must appear in all prescription drug labeling:
(1) Highlights limitation statement. The verbatim statement ``These
highlights do not include all the information
[[Page 24]]
needed to use (insert name of drug product) safely and effectively. See
full prescribing information for (insert name of drug product).''
(2) Drug names, dosage form, route of administration, and controlled
substance symbol. The proprietary name and the established name of the
drug, if any, as defined in section 502(e)(3) of the Federal Food, Drug,
and Cosmetic Act (the act) or, for biological products, the proper name
(as defined in Sec. 600.3 of this chapter) including any appropriate
descriptors. This information must be followed by the drug's dosage form
and route of administration. For controlled substances, the controlled
substance symbol designating the schedule in which the controlled
substance is listed must be included as required by Sec. 1302.04 of
this chapter.
(3) Initial U.S. approval. The verbatim statement ``Initial U.S.
Approval'' followed by the four-digit year in which FDA initially
approved a new molecular entity, new biological product, or new
combination of active ingredients. The statement must be placed on the
line immediately beneath the established name or, for biological
products, proper name of the product.
(4) Boxed warning. A concise summary of any boxed warning required
by paragraph (c)(1) of this section, not to exceed a length of 20 lines.
The summary must be preceded by a heading, in upper-case letters,
containing the word ``WARNING'' and other words that are appropriate to
identify the subject of the warning. The heading and the summary must be
contained within a box and bolded. The following verbatim statement must
be placed immediately following the heading of the boxed warning: ``See
full prescribing information for complete boxed warning.''
(5) Recent major changes. A list of the section(s) of the full
prescribing information, limited to the labeling sections described in
paragraphs (c)(1), (c)(2), (c)(3), (c)(5), and (c)(6) of this section,
that contain(s) substantive labeling changes that have been approved by
FDA or authorized under Sec. 314.70(c)(6) or (d)(2), or Sec.
601.12(f)(1) through (f)(3) of this chapter. The heading(s) and, if
appropriate, the subheading(s) of the labeling section(s) affected by
the change must be listed together with each section's identifying
number and the date (month/year) on which the change was incorporated in
labeling. These labeling sections must be listed in the order in which
they appear in the full prescribing information. A changed section must
be listed under this heading in Highlights for at least 1 year after the
date of the labeling change and must be removed at the first printing
subsequent to the 1 year period.
(6) Indications and usage. A concise statement of each of the
product's indications, as required under paragraph (c)(2) of this
section, with any appropriate subheadings. Major limitations of use
(e.g., lack of effect in particular subsets of the population, or second
line therapy status) must be briefly noted. If the product is a member
of an established pharmacologic class, the concise statement under this
heading in Highlights must identify the class in the following manner:
``(Drug) is a (name of class) indicated for (indication(s)).''
(7) Dosage and administration. A concise summary of the information
required under paragraph (c)(3) of this section, with any appropriate
subheadings, including the recommended dosage regimen, starting dose,
dose range, critical differences among population subsets, monitoring
recommendations, and other clinically significant clinical pharmacologic
information.
(8) Dosage forms and strengths. A concise summary of the information
required under paragraph (c)(4) of this section, with any appropriate
subheadings (e.g., tablets, capsules, injectable, suspension), including
the strength or potency of the dosage form in metric system (e.g., 10-
milligram tablets) and whether the product is scored.
(9) Contraindications. A concise statement of each of the product's
contraindications, as required under paragraph (c)(5) of this section,
with any appropriate subheadings.
(10) Warnings and precautions. A concise summary of the most
clinically significant information required under paragraph (c)(6) of
this section, with any appropriate subheadings, including information
that would affect decisions
[[Page 25]]
about whether to prescribe a drug, recommendations for patient
monitoring that are critical to safe use of the drug, and measures that
can be taken to prevent or mitigate harm.
(11) Adverse reactions. (i) A list of the most frequently occurring
adverse reactions, as described in paragraph (c)(7) of this section,
along with the criteria used to determine inclusion (e.g., incidence
rate). Adverse reactions important for other reasons (e.g., because they
are serious or frequently lead to discontinuation or dosage adjustment)
must not be repeated under this heading in Highlights if they are
included elsewhere in Highlights (e.g., Warnings and Precautions,
Contraindications).
(ii) For drug products other than vaccines, the verbatim statement
``To report SUSPECTED ADVERSE REACTIONS, contact (insert name of
manufacturer) at (insert manufacturer's phone number) or FDA at (insert
current FDA phone number and Web address for voluntary reporting of
adverse reactions).''
(iii) For vaccines, the verbatim statement ``To report SUSPECTED
ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert
manufacturer's phone number) or VAERS at (insert the current VAERS phone
number and Web address for voluntary reporting of adverse reactions).''
(iv) For manufacturers with a Web site for voluntary reporting of
adverse reactions, the Web address of the direct link to the site.
(12) Drug interactions. A concise summary of the information
required under paragraph (c)(8) of this section, with any appropriate
subheadings.
(13) Use in specific populations. A concise summary of the
information required under paragraph (c)(9) of this section, with any
appropriate subheadings.
(14) Patient counseling information statement. The verbatim
statement ``See 17 for Patient Counseling Information'' or, if the
product has FDA-approved patient labeling, the verbatim statement ``See
17 for Patient Counseling Information and (insert either FDA-approved
patient labeling or Medication Guide).''
(15) Revision date. The date of the most recent revision of the
labeling, identified as such, placed at the end of Highlights.
(b) Full prescribing information: Contents. Contents must contain a
list of each heading and subheading required in the full prescribing
information under Sec. 201.56(d)(1), if not omitted under Sec.
201.56(d)(4), preceded by the identifying number required under Sec.
201.56(d)(1). Contents must also contain any additional subheading(s)
included in the full prescribing information preceded by the identifying
number assigned in accordance with Sec. 201.56(d)(2).
(c) Full prescribing information. The full prescribing information
must contain the information in the order required under paragraphs
(c)(1) through (c)(18) of this section, together with the headings,
subheadings, and identifying numbers required under Sec. 201.56(d)(1),
unless omitted under Sec. 201.56(d)(4). If additional subheadings are
used within a labeling section, they must be preceded by the identifying
number assigned in accordance with Sec. 201.56(d)(2).
(1) Boxed warning. Certain contraindications or serious warnings,
particularly those that may lead to death or serious injury, may be
required by the FDA to be presented in a box. The boxed warning
ordinarily must be based on clinical data, but serious animal toxicity
may also be the basis of a boxed warning in the absence of clinical
data. The box must contain, in uppercase letters, a heading inside the
box that includes the word ``WARNING'' and conveys the general focus of
the information in the box. The box must briefly explain the risk and
refer to more detailed information in the ``Contraindications'' or
``Warnings and Precautions'' section, accompanied by the identifying
number for the section or subsection containing the detailed
information.
(2) 1 Indications and usage. This section must state that the drug
is indicated for the treatment, prevention, mitigation, cure, or
diagnosis of a recognized disease or condition, or of a manifestation of
a recognized disease or condition, or for the relief of symptoms
associated with a recognized disease or condition.
[[Page 26]]
(i) This section must include the following information when the
conditions listed are applicable:
(A) If the drug is used for an indication only in conjunction with a
primary mode of therapy (e.g., diet, surgery, behavior changes, or some
other drug), a statement that the drug is indicated as an adjunct to
that mode of therapy.
(B) If evidence is available to support the safety and effectiveness
of the drug or biological product only in selected subgroups of the
larger population (e.g., patients with mild disease or patients in a
special age group), or if the indication is approved based on a
surrogate endpoint under Sec. 314.510 or Sec. 601.41 of this chapter,
a succinct description of the limitations of usefulness of the drug and
any uncertainty about anticipated clinical benefits, with reference to
the ``Clinical Studies'' section for a discussion of the available
evidence.
(C) If specific tests are necessary for selection or monitoring of
the patients who need the drug (e.g., microbe susceptibility tests), the
identity of such tests.
(D) If information on limitations of use or uncertainty about
anticipated clinical benefits is relevant to the recommended intervals
between doses, to the appropriate duration of treatment when such
treatment should be limited, or to any modification of dosage, a concise
description of the information with reference to the more detailed
information in the ``Dosage and Administration'' section.
(E) If safety considerations are such that the drug should be
reserved for specific situations (e.g., cases refractory to other
drugs), a statement of the information.
(F) If there are specific conditions that should be met before the
drug is used on a long term basis (e.g., demonstration of responsiveness
to the drug in a short term trial in a given patient), a statement of
the conditions; or, if the indications for long term use are different
from those for short term use, a statement of the specific indications
for each use.
(ii) If there is a common belief that the drug may be effective for
a certain use or if there is a common use of the drug for a condition,
but the preponderance of evidence related to the use or condition shows
that the drug is ineffective or that the therapeutic benefits of the
product do not generally outweigh its risks, FDA may require that this
section state that there is a lack of evidence that the drug is
effective or safe for that use or condition.
(iii) Any statements comparing the safety or effectiveness of the
drug with other agents for the same indication must, except for
biological products, be supported by substantial evidence derived from
adequate and well-controlled studies as defined in Sec. 314.126(b) of
this chapter unless this requirement is waived under Sec. 201.58 or
Sec. 314.126(c) of this chapter. For biological products, such
statements must be supported by substantial evidence.
(iv) For drug products other than biological products, all
indications listed in this section must be supported by substantial
evidence of effectiveness based on adequate and well-controlled studies
as defined in Sec. 314.126(b) of this chapter unless the requirement is
waived under Sec. 201.58 or Sec. 314.126(c) of this chapter.
Indications or uses must not be implied or suggested in other sections
of the labeling if not included in this section.
(v) For biological products, all indications listed in this section
must be supported by substantial evidence of effectiveness. Indications
or uses must not be implied or suggested in other sections of the
labeling if not included in this section.
(3) 2 Dosage and administration. (i) This section must state the
recommended dose and, as appropriate:
(A) The dosage range,
(B) An upper limit beyond which safety and effectiveness have not
been established, or beyond which increasing the dose does not result in
increasing effectiveness,
(C) Dosages for each indication and subpopulation,
(D) The intervals recommended between doses,
(E) The optimal method of titrating dosage,
(F) The usual duration of treatment when treatment duration should
be limited,
[[Page 27]]
(G) Dosing recommendations based on clinical pharmacologic data
(e.g., clinically significant food effects),
(H) Modification of dosage needed because of drug interactions or in
special patient populations (e.g., in children, in geriatric age groups,
in groups defined by genetic characteristics, or in patients with renal
or hepatic disease),
(I) Important considerations concerning compliance with the dosage
regimen,
(J) Efficacious or toxic concentration ranges and therapeutic
concentration windows of the drug or its metabolites, if established and
clinically significant. Information on therapeutic drug concentration
monitoring (TDM) must also be included in this section when TDM is
necessary.
(ii) Dosing regimens must not be implied or suggested in other
sections of the labeling if not included in this section.
(iii) Radiation dosimetry information must be stated for both the
patient receiving a radioactive drug and the person administering it.
(iv) This section must also contain specific direction on dilution,
preparation (including the strength of the final dosage solution, when
prepared according to instructions, in terms of milligrams of active
ingredient per milliliter of reconstituted solution, unless another
measure of the strength is more appropriate), and administration of the
dosage form, if needed (e.g., the rate of administration of parenteral
drug in milligrams per minute; storage conditions for stability of the
reconstituted drug, when important; essential information on drug
incompatibilities if the drug is mixed in vitro with other drugs or
diluents; and the following verbatim statement for parenterals:
``Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and
container permit.'')
(4) 3 Dosage forms and strengths. This section must contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible, including:
(i) The strength or potency of the dosage form in metric system
(e.g., 10 milligram tablets), and, if the apothecary system is used, a
statement of the strength in parentheses after the metric designation;
and
(ii) A description of the identifying characteristics of the dosage
forms, including shape, color, coating, scoring, and imprinting, when
applicable. The National Drug Code number(s) for the drug product must
not be included in this section.
(5) 4 Contraindications. This section must describe any situations
in which the drug should not be used because the risk of use (e.g.,
certain potentially fatal adverse reactions) clearly outweighs any
possible therapeutic benefit. Those situations include use of the drug
in patients who, because of their particular age, sex, concomitant
therapy, disease state, or other condition, have a substantial risk of
being harmed by the drug and for whom no potential benefit makes the
risk acceptable. Known hazards and not theoretical possibilities must be
listed (e.g., if severe hypersensitivity to the drug has not been
demonstrated, it should not be listed as a contraindication). If no
contraindications are known, this section must state ``None.''
(6) 5 Warnings and precautions. (i) General. This section must
describe clinically significant adverse reactions (including any that
are potentially fatal, are serious even if infrequent, or can be
prevented or mitigated through appropriate use of the drug), other
potential safety hazards (including those that are expected for the
pharmacological class or those resulting from drug/drug interactions),
limitations in use imposed by them (e.g., avoiding certain concomitant
therapy), and steps that should be taken if they occur (e.g., dosage
modification). The frequency of all clinically significant adverse
reactions and the approximate mortality and morbidity rates for patients
experiencing the reaction, if known and necessary for the safe and
effective use of the drug, must be expressed as provided under paragraph
(c)(7) of this section. In accordance with Sec. Sec. 314.70 and 601.12
of this chapter, the labeling must be revised to include a warning about
a clinically significant hazard as soon as there is reasonable evidence
of a causal association with a
[[Page 28]]
drug; a causal relationship need not have been definitely established. A
specific warning relating to a use not provided for under the
``Indications and Usage'' section may be required by FDA in accordance
with sections 201(n) and 502(a) of the act if the drug is commonly
prescribed for a disease or condition and such usage is associated with
a clinically significant risk or hazard.
(ii) Other special care precautions. This section must contain
information regarding any special care to be exercised by the
practitioner for safe and effective use of the drug (e.g., precautions
not required under any other specific section or subsection).
(iii) Monitoring: Laboratory tests. This section must identify any
laboratory tests helpful in following the patient's response or in
identifying possible adverse reactions. If appropriate, information must
be provided on such factors as the range of normal and abnormal values
expected in the particular situation and the recommended frequency with
which tests should be performed before, during, and after therapy.
(iv) Interference with laboratory tests. This section must briefly
note information on any known interference by the product with
laboratory tests and reference the section where the detailed
information is presented (e.g., ``Drug Interactions'' section).
(7) 6 Adverse reactions. This section must describe the overall
adverse reaction profile of the drug based on the entire safety
database. For purposes of prescription drug labeling, an adverse
reaction is an undesirable effect, reasonably associated with use of a
drug, that may occur as part of the pharmacological action of the drug
or may be unpredictable in its occurrence. This definition does not
include all adverse events observed during use of a drug, only those
adverse events for which there is some basis to believe there is a
causal relationship between the drug and the occurrence of the adverse
event.
(i) Listing of adverse reactions. This section must list the adverse
reactions that occur with the drug and with drugs in the same
pharmacologically active and chemically related class, if applicable.
The list or lists must be preceded by the information necessary to
interpret the adverse reactions (e.g., for clinical trials, total number
exposed, extent and nature of exposure).
(ii) Categorization of adverse reactions. Within a listing, adverse
reactions must be categorized by body system, by severity of the
reaction, or in order of decreasing frequency, or by a combination of
these, as appropriate. Within a category, adverse reactions must be
listed in decreasing order of frequency. If frequency information cannot
be reliably determined, adverse reactions must be listed in decreasing
order of severity.
(A) Clinical trials experience. This section must list the adverse
reactions identified in clinical trials that occurred at or above a
specified rate appropriate to the safety database. The rate of
occurrence of an adverse reaction for the drug and comparators (e.g.,
placebo) must be presented, unless such data cannot be determined or
presentation of comparator rates would be misleading. If adverse
reactions that occurred below the specified rate are included, they must
be included in a separate listing. If comparative rates of occurrence
cannot be reliably determined (e.g., adverse reactions were observed
only in the uncontrolled trial portion of the overall safety database),
adverse reactions must be grouped within specified frequency ranges as
appropriate to the safety database for the drug (e.g., adverse reactions
occurring at a rate of less than 1/100, adverse reactions occurring at a
rate of less than 1/500) or descriptively identified, if frequency
ranges cannot be determined. For adverse reactions with significant
clinical implications, the listings must be supplemented with additional
detail about the nature, frequency, and severity of the adverse reaction
and the relationship of the adverse reaction to drug dose and
demographic characteristics, if data are available and important.
(B) Postmarketing experience. This section of the labeling must list
the adverse reactions, as defined in paragraph (c)(7) of this section,
that are identified from domestic and foreign spontaneous reports. This
listing must be separate
[[Page 29]]
from the listing of adverse reactions identified in clinical trials.
(iii) Comparisons of adverse reactions between drugs. For drug
products other than biological products, any claim comparing the drug to
which the labeling applies with other drugs in terms of frequency,
severity, or character of adverse reactions must be based on adequate
and well-controlled studies as defined in Sec. 314.126(b) of this
chapter unless this requirement is waived under Sec. 201.58 or Sec.
314.126(c) of this chapter. For biological products, any such claim must
be based on substantial evidence.
(8) 7 Drug interactions. (i) This section must contain a description
of clinically significant interactions, either observed or predicted,
with other prescription or over-the-counter drugs, classes of drugs, or
foods (e.g., dietary supplements, grapefruit juice), and specific
practical instructions for preventing or managing them. The mechanism(s)
of the interaction, if known, must be briefly described. Interactions
that are described in the ``Contraindications'' or ``Warnings and
Precautions'' sections must be discussed in more detail under this
section. Details of drug interaction pharmacokinetic studies that are
included in the ``Clinical Pharmacology'' section that are pertinent to
clinical use of the drug must not be repeated in this section.
(ii) This section must also contain practical guidance on known
interference of the drug with laboratory tests.
(9) 8 Use in specific populations. This section must contain the
following subsections:
(i) 8.1 Pregnancy. This subsection may be omitted only if the drug
is not absorbed systemically and the drug is not known to have a
potential for indirect harm to the fetus. For all other drugs, this
subsection must contain the following information:
(A) Teratogenic effects. Under this subheading, the labeling must
identify one of the following categories that applies to the drug, and
the labeling must bear the statement required under the category:
(1) Pregnancy category A. If adequate and well-controlled studies in
pregnant women have failed to demonstrate a risk to the fetus in the
first trimester of pregnancy (and there is no evidence of a risk in
later trimesters), the labeling must state: ``Pregnancy Category A.
Studies in pregnant women have not shown that (name of drug) increases
the risk of fetal abnormalities if administered during the first
(second, third, or all) trimester(s) of pregnancy. If this drug is used
during pregnancy, the possibility of fetal harm appears remote. Because
studies cannot rule out the possibility of harm, however, (name of drug)
should be used during pregnancy only if clearly needed.'' The labeling
must also contain a description of the human studies. If animal
reproduction studies are also available and they fail to demonstrate a
risk to the fetus, the labeling must also state: ``Reproduction studies
have been performed in (kinds of animal(s)) at doses up to (x) times the
human dose and have revealed no evidence of impaired fertility or harm
to the fetus due to (name of drug).'' The labeling must also contain a
description of available data on the effect of the drug on the later
growth, development, and functional maturation of the child.
(2) Pregnancy category B. If animal reproduction studies have failed
to demonstrate a risk to the fetus and there are no adequate and well-
controlled studies in pregnant women, the labeling must state:
``Pregnancy Category B. Reproduction studies have been performed in
(kind(s) of animal(s)) at doses up to (x) times the human dose and have
revealed no evidence of impaired fertility or harm to the fetus due to
(name of drug). There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are not
always predictive of human response, this drug should be used during
pregnancy only if clearly needed.'' If animal reproduction studies have
shown an adverse effect (other than decrease in fertility), but adequate
and well-controlled studies in pregnant women have failed to demonstrate
a risk to the fetus during the first trimester of pregnancy (and there
is no evidence of a risk in later trimesters), the labeling must state:
``Pregnancy Category B. Reproduction studies in (kind(s) of animal(s))
have shown (describe findings) at (x) times the human dose. Studies in
pregnant
[[Page 30]]
women, however, have not shown that (name of drug) increases the risk of
abnormalities when administered during the first (second, third, or all)
trimester(s) of pregnancy. Despite the animal findings, it would appear
that the possibility of fetal harm is remote, if the drug is used during
pregnancy. Nevertheless, because the studies in humans cannot rule out
the possibility of harm, (name of drug) should be used during pregnancy
only if clearly needed.'' The labeling must also contain a description
of the human studies and a description of available data on the effect
of the drug on the later growth, development, and functional maturation
of the child.
(3) Pregnancy category C. If animal reproduction studies have shown
an adverse effect on the fetus, if there are no adequate and well-
controlled studies in humans, and if the benefits from the use of the
drug in pregnant women may be acceptable despite its potential risks,
the labeling must state: ``Pregnancy Category C. (Name of drug) has been
shown to be teratogenic (or to have an embryocidal effect or other
adverse effect) in (name(s) of species) when given in doses (x) times
the human dose. There are no adequate and well-controlled studies in
pregnant women. (Name of drug) should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus.'' The
labeling must contain a description of the animal studies. If there are
no animal reproduction studies and no adequate and well-controlled
studies in humans, the labeling must state: ``Pregnancy Category C.
Animal reproduction studies have not been conducted with (name of drug).
It is also not known whether (name of drug) can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity.
(Name of drug) should be given to a pregnant woman only if clearly
needed.'' The labeling must contain a description of any available data
on the effect of the drug on the later growth, development, and
functional maturation of the child.
(4) Pregnancy category D. If there is positive evidence of human
fetal risk based on adverse reaction data from investigational or
marketing experience or studies in humans, but the potential benefits
from the use of the drug in pregnant women may be acceptable despite its
potential risks (for example, if the drug is needed in a life-
threatening situation or serious disease for which safer drugs cannot be
used or are ineffective), the labeling must state: ``Pregnancy Category
D. See `Warnings and Precautions' section.'' Under the ``Warnings and
Precautions'' section, the labeling must state: ``(Name of drug) can
cause fetal harm when administered to a pregnant woman. (Describe the
human data and any pertinent animal data.) If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to a fetus.''
(5) Pregnancy category X. If studies in animals or humans have
demonstrated fetal abnormalities or if there is positive evidence of
fetal risk based on adverse reaction reports from investigational or
marketing experience, or both, and the risk of the use of the drug in a
pregnant woman clearly outweighs any possible benefit (for example,
safer drugs or other forms of therapy are available), the labeling must
state: ``Pregnancy Category X. See `Contraindications' section.'' Under
``Contraindications,'' the labeling must state: ``(Name of drug) may
(can) cause fetal harm when administered to a pregnant woman. (Describe
the human data and any pertinent animal data.) (Name of drug) is
contraindicated in women who are or may become pregnant. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking
this drug, the patient should be apprised of the potential hazard to a
fetus.''
(B) Nonteratogenic effects. Under this subheading the labeling must
contain other information on the drug's effects on reproduction and the
drug's use during pregnancy that is not required specifically by one of
the pregnancy categories, if the information is relevant to the safe and
effective use of the drug. Information required under this heading must
include nonteratogenic effects in the fetus or newborn infant (for
example, withdrawal symptoms or hypoglycemia) that may occur because of
a pregnant woman's chronic use of
[[Page 31]]
the drug for a preexisting condition or disease.
(ii) 8.2 Labor and delivery. If the drug has a recognized use during
labor or delivery (vaginal or abdominal delivery), whether or not the
use is stated in the Indications and Usage section, this subsection must
describe the available information about the effect of the drug on the
mother and the fetus, on the duration of labor or delivery, on the
possibility that forceps delivery or other intervention or resuscitation
of the newborn will be necessary, and the effect of the drug on the
later growth, development, and functional maturation of the child. If
any information required under this subsection is unknown, it must state
that the information is unknown.
(iii) 8.3 Nursing mothers. (A) If a drug is absorbed systemically,
this subsection must contain, if known, information about excretion of
the drug in human milk and effects on the nursing infant. Pertinent
adverse effects observed in animal offspring must be described.
(B) If a drug is absorbed systemically and is known to be excreted
in human milk, this subsection must contain one of the following
statements, as appropriate. If the drug is associated with serious
adverse reactions or if the drug has a known tumorigenic potential, the
labeling must state: ``Because of the potential for serious adverse
reactions in nursing infants from (name of drug) (or, ``Because of the
potential for tumorigenicity shown for (name of drug) in (animal or
human) studies), a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.'' If the drug is not associated with serious
adverse reactions and does not have a known tumorigenic potential, the
labeling must state: ``Caution should be exercised when (name of drug)
is administered to a nursing woman.''
(C) If a drug is absorbed systemically and information on excretion
in human milk is unknown, this subsection must contain one of the
following statements, as appropriate. If the drug is associated with
serious adverse reactions or has a known tumorigenic potential, the
labeling must state: ``It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk and because of
the potential for serious adverse reactions in nursing infants from
(name of drug) (or, ``Because of the potential for tumorigenicity shown
for (name of drug) in (animal or human) studies), a decision should be
made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.'' If the drug is
not associated with serious adverse reactions and does not have a known
tumorigenic potential, the labeling must state: ``It is not known
whether this drug is excreted in human milk. Because many drugs are
excreted in human milk, caution should be exercised when (name of drug)
is administered to a nursing woman.''
(iv) 8.4 Pediatric use. (A) Pediatric population(s)/pediatric
patient(s): For the purposes of paragraphs (c)(9)(iv)(B) through
(c)(9)(iv)(H) of this section, the terms pediatric population(s) and
pediatric patient(s) are defined as the pediatric age group, from birth
to 16 years, including age groups often called neonates, infants,
children, and adolescents.
(B) If there is a specific pediatric indication different from those
approved for adults that is supported by adequate and well-controlled
studies in the pediatric population, it must be described under the
``Indications and Usage'' section, and appropriate pediatric dosage
information must be given under the ``Dosage and Administration''
section. The ``Pediatric use'' subsection must cite any limitations on
the pediatric indication, need for specific monitoring, specific hazards
associated with use of the drug in any subsets of the pediatric
population (e.g., neonates), differences between pediatric and adult
responses to the drug, and other information related to the safe and
effective pediatric use of the drug. Data summarized in this subsection
should be discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' or ``Clinical Studies'' section. As appropriate, this
information must also be contained in the ``Contraindications'' and/or
``Warnings and Precautions'' section(s).
[[Page 32]]
(C) If there are specific statements on pediatric use of the drug
for an indication also approved for adults that are based on adequate
and well-controlled studies in the pediatric population, they must be
summarized in the ``Pediatric use'' subsection and discussed in more
detail, if appropriate, under the ``Clinical Pharmacology'' and
``Clinical Studies'' sections. Appropriate pediatric dosage must be
given under the ``Dosage and Administration'' section. The ``Pediatric
use'' subsection of the labeling must also cite any limitations on the
pediatric use statement, need for specific monitoring, specific hazards
associated with use of the drug in any subsets of the pediatric
population (e.g., neonates), differences between pediatric and adult
responses to the drug, and other information related to the safe and
effective pediatric use of the drug. As appropriate, this information
must also be contained in the ``Contraindications'' and/or ``Warnings
and Precautions'' section(s).
(D)(1) When a drug is approved for pediatric use based on adequate
and well-controlled studies in adults with other information supporting
pediatric use, the ``Pediatric use'' subsection of the labeling must
contain either the following statement or a reasonable alternative:
The safety and effectiveness of (drug name) have been established in
the age groups ------ to ------ (note any limitations, e.g., no data for
pediatric patients under 2, or only applicable to certain indications
approved in adults). Use of (drug name) in these age groups is supported
by evidence from adequate and well-controlled studies of (drug name) in
adults with additional data (insert wording that accurately describes
the data submitted to support a finding of substantial evidence of
effectiveness in the pediatric population).
(2) Data summarized in the preceding prescribed statement in this
subsection must be discussed in more detail, if appropriate, under the
``Clinical Pharmacology'' or the ``Clinical Studies'' section. For
example, pediatric pharmacokinetic or pharmacodynamic studies and dose
response information should be described in the ``Clinical
Pharmacology'' section. Pediatric dosing instructions must be included
in the ``Dosage and Administration'' section. Any differences between
pediatric and adult responses, need for specific monitoring, dosing
adjustments, and any other information related to safe and effective use
of the drug in pediatric patients must be cited briefly in the
``Pediatric use'' subsection and, as appropriate, in the
``Contraindications,'' ``Warnings and Precautions,'' and ``Dosage and
Administration'' sections.
(E) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for a particular pediatric population, the ``Pediatric use''
subsection must contain an appropriate statement such as ``Safety and
effectiveness in pediatric patients below the age of (----) have not
been established.'' If use of the drug in this pediatric population is
associated with a specific hazard, the hazard must be described in this
subsection, or, if appropriate, the hazard must be stated in the
``Contraindications'' or ``Warnings and Precautions'' section and this
subsection must refer to it.
(F) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for any pediatric population, this subsection must contain the
following statement: ``Safety and effectiveness in pediatric patients
have not been established.'' If use of the drug in premature or neonatal
infants, or other pediatric subgroups, is associated with a specific
hazard, the hazard must be described in this subsection, or, if
appropriate, the hazard must be stated in the ``Contraindications'' or
``Warnings and Precautions'' section and this subsection must refer to
it.
(G) If the sponsor believes that none of the statements described in
paragraphs (c)(9)(iv)(B) through (c)(9)(iv)(F) of this section are
appropriate or relevant to the labeling of a particular drug, the
sponsor must provide reasons for omission of the statements and may
propose alternative statement(s). FDA may permit use of an alternative
statement if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling and that
the alternative statement is accurate and appropriate.
[[Page 33]]
(H) If the drug product contains one or more inactive ingredients
that present an increased risk of toxic effects to neonates or other
pediatric subgroups, a special note of this risk must be made, generally
in the ``Contraindications'' or ``Warnings and Precautions'' section.
(v) 8.5 Geriatric use. (A) A specific geriatric indication, if any,
that is supported by adequate and well-controlled studies in the
geriatric population must be described under the ``Indications and
Usage'' section, and appropriate geriatric dosage must be stated under
the ``Dosage and Administration'' section. The ``Geriatric use''
subsection must cite any limitations on the geriatric indication, need
for specific monitoring, specific hazards associated with the geriatric
indication, and other information related to the safe and effective use
of the drug in the geriatric population. Unless otherwise noted,
information contained in the ``Geriatric use'' subsection must pertain
to use of the drug in persons 65 years of age and older. Data summarized
in this subsection must be discussed in more detail, if appropriate,
under ``Clinical Pharmacology'' or the ``Clinical Studies'' section. As
appropriate, this information must also be contained in the ``Warnings
and Precautions'' and/or ``Contraindications'' section(s).
(B) Specific statements on geriatric use of the drug for an
indication approved for adults generally, as distinguished from a
specific geriatric indication, must be contained in the ``Geriatric
use'' subsection and must reflect all information available to the
sponsor that is relevant to the appropriate use of the drug in elderly
patients. This information includes detailed results from controlled
studies that are available to the sponsor and pertinent information from
well-documented studies obtained from a literature search. Controlled
studies include those that are part of the marketing application and
other relevant studies available to the sponsor that have not been
previously submitted in the investigational new drug application, new
drug application, biologics license application, or a supplement or
amendment to one of these applications (e.g., postmarketing studies or
adverse drug reaction reports). The ``Geriatric use'' subsection must
contain the following statement(s) or reasonable alternative, as
applicable, taking into account available information:
(1) If clinical studies did not include sufficient numbers of
subjects aged 65 and over to determine whether elderly subjects respond
differently from younger subjects, and other reported clinical
experience has not identified such differences, the ``Geriatric use''
subsection must include the following statement:
Clinical studies of (name of drug) did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience
has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient
should be cautious, usually starting at the low end of the dosing range,
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
(2) If clinical studies (including studies that are part of
marketing applications and other relevant studies available to the
sponsor that have not been submitted in the sponsor's applications)
included enough elderly subjects to make it likely that differences in
safety or effectiveness between elderly and younger subjects would have
been detected, but no such differences (in safety or effectiveness) were
observed, and other reported clinical experience has not identified such
differences, the ``Geriatric use'' subsection must contain the following
statement:
Of the total number of subjects in clinical studies of (name of
drug), ---- percent were 65 and over, while ---- percent were 75 and
over. (Alternatively, the labeling may state the total number of
subjects included in the studies who were 65 and over and 75 and over.)
No overall differences in safety or effectiveness were observed between
these subjects and younger subjects, and other reported clinical
experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
(3) If evidence from clinical studies and other reported clinical
experience
[[Page 34]]
available to the sponsor indicates that use of the drug in elderly
patients is associated with differences in safety or effectiveness, or
requires specific monitoring or dosage adjustment, the ``Geriatric use''
subsection must contain a brief description of observed differences or
specific monitoring or dosage requirements and, as appropriate, must
refer to more detailed discussions in the ``Contraindications,''
``Warnings and Precautions,'' ``Dosage and Administration,'' or other
sections.
(C)(1) If specific pharmacokinetic or pharmacodynamic studies have
been carried out in the elderly, they must be described briefly in the
``Geriatric use'' subsection and in detail under the ``Clinical
Pharmacology'' section. The ``Clinical Pharmacology'' and ``Drug
Interactions'' sections ordinarily contain information on drug/disease
and drug/drug interactions that is particularly relevant to the elderly,
who are more likely to have concomitant illness and to use concomitant
drugs.
(2) If a drug is known to be substantially excreted by the kidney,
the ``Geriatric use'' subsection must include the statement:
This drug is known to be substantially excreted by the kidney, and
the risk of adverse reactions to this drug may be greater in patients
with impaired renal function. Because elderly patients are more likely
to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function.
(D) If use of the drug in the elderly appears to cause a specific
hazard, the hazard must be described in the ``Geriatric use''
subsection, or, if appropriate, the hazard must be stated in the
``Contraindications'' or ``Warnings and Precautions'' section, and the
``Geriatric use'' subsection must refer to those sections.
(E) Labeling under paragraphs (c)(9)(v)(A) through (c)(9)(v)(C) of
this section may include statements, if they are necessary for safe and
effective use of the drug, and reflect good clinical practice or past
experience in a particular situation, e.g., for a sedating drug, it
could be stated that:
Sedating drugs may cause confusion and over-sedation in the elderly;
elderly patients generally should be started on low doses of (name of
drug) and observed closely.
(F) If the sponsor believes that none of the requirements described
in paragraphs (c)(9)(v)(A) through (c)(9)(v)(E) of this section are
appropriate or relevant to the labeling of a particular drug, the
sponsor must provide reasons for omission of the statements and may
propose an alternative statement. FDA may permit omission of the
statements if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling. FDA may
permit use of an alternative statement if the agency determines that
such statement is accurate and appropriate.
(vi) Additional subsections. Additional subsections may be included,
as appropriate, if sufficient data are available concerning the use of
the drug in other specified subpopulations (e.g., renal or hepatic
impairment).
(10) 9 Drug abuse and dependence. This section must contain the
following information, as appropriate:
(i) 9.1 Controlled substance. If the drug is controlled by the Drug
Enforcement Administration, the schedule in which it is controlled must
be stated.
(ii) 9.2 Abuse. This subsection must state the types of abuse that
can occur with the drug and the adverse reactions pertinent to them, and
must identify particularly susceptible patient populations. This
subsection must be based primarily on human data and human experience,
but pertinent animal data may also be used.
(iii) 9.3 Dependence. This subsection must describe characteristic
effects resulting from both psychological and physical dependence that
occur with the drug and must identify the quantity of the drug over a
period of time that may lead to tolerance or dependence, or both.
Details must be provided on the adverse effects of chronic abuse and the
effects of abrupt withdrawal. Procedures necessary to diagnose the
dependent state and the principles of treating the effects of abrupt
withdrawal must be described.
(11) 10 Overdosage. This section must be based on human data. If
human data are unavailable, appropriate animal and in vitro data may be
used. The following specific information must be provided:
[[Page 35]]
(i) Signs, symptoms, and laboratory findings associated with an
overdosage of the drug;
(ii) Complications that can occur with the drug (for example, organ
toxicity or delayed acidosis);
(iii) Concentrations of the drug in biologic fluids associated with
toxicity or death; physiologic variables influencing excretion of the
drug, such as urine pH; and factors that influence the dose response
relationship of the drug, such as tolerance. The pharmacokinetic data
given in the ``Clinical Pharmacology'' section also may be referenced
here, if applicable to overdoses;
(iv) The amount of the drug in a single dose that is ordinarily
associated with symptoms of overdosage and the amount of the drug in a
single dose that is likely to be life threatening;
(v) Whether the drug is dialyzable; and
(vi) Recommended general treatment procedures and specific measures
for support of vital functions (e.g., proven antidotes, gastric lavage,
forced diuresis, or as per Poison Control Center). Such recommendations
must be based on data available for the specific drug or experience with
pharmacologically related drugs. Unqualified recommendations for which
data are lacking for the specific drug or class of drugs must not be
stated.
(12) 11 Description. (i) This section must contain:
(A) The proprietary name and the established name, if any, as
defined in section 502(e)(2) of the act, of the drug or, for biological
products, the proper name (as defined in Sec. 600.3 of this chapter)
and any appropriate descriptors;
(B) The type of dosage form(s) and the route(s) of administration to
which the labeling applies;
(C) The same qualitative and/or quantitative ingredient information
as required under Sec. 201.100(b) for drug labels or Sec. Sec. 610.60
and 610.61 of this chapter for biological product labels;
(D) If the product is sterile, a statement of that fact;
(E) The pharmacological or therapeutic class of the drug;
(F) For drug products other than biological products, the chemical
name and structural formula of the drug; and
(G) If the product is radioactive, a statement of the important
nuclear physical characteristics, such as the principal radiation
emission data, external radiation, and physical decay characteristics.
(ii) If appropriate, other important chemical or physical
information, such as physical constants or pH, must be stated.
(13) 12 Clinical pharmacology. (i) This section must contain
information relating to the human clinical pharmacology and actions of
the drug in humans. Pharmacologic information based on in vitro data
using human biomaterials or pharmacologic animal models, or relevant
details about in vivo study designs or results (e.g., drug interaction
studies), may be included in this section if essential to understand
dosing or drug interaction information presented in other sections of
the labeling. This section must include the following subsections:
(A) 12.1 Mechanism of action. This subsection must summarize what is
known about the established mechanism(s) of the drug's action in humans
at various levels (e.g., receptor, membrane, tissue, organ, whole body).
If the mechanism of action is not known, this subsection must contain a
statement about the lack of information.
(B) 12.2 Pharmacodynamics. This subsection must include a
description of any biochemical or physiologic pharmacologic effects of
the drug or active metabolites related to the drug's clinical effect in
preventing, diagnosing, mitigating, curing, or treating disease, or
those related to adverse effects or toxicity. Exposure-response
relationships (e.g., concentration-response, dose-response) and time
course of pharmacodynamic response (including short-term clinical
response) must be included if known. If this information is unknown,
this subsection must contain a statement about the lack of information.
Detailed dosing or monitoring recommendations based on pharmacodynamic
information that appear in other sections (e.g., ``Warnings and
Precautions'' or ``Dosage and Administration'') must not be repeated in
this subsection, but the location of such recommendations must be
referenced.
[[Page 36]]
(C) 12.3 Pharmacokinetics. This subsection must describe the
clinically significant pharmacokinetics of a drug or active metabolites,
(i.e., pertinent absorption, distribution, metabolism, and excretion
parameters). Information regarding bioavailability, the effect of food,
minimum concentration (Cmin), maximum concentration
(Cmax), time to maximum concentration (Tmax), area
under the curve (AUC), pertinent half-lives (t1/2), time to
reach steady state, extent of accumulation, route(s) of elimination,
clearance (renal, hepatic, total), mechanisms of clearance (e.g.,
specific enzyme systems), drug/drug and drug/food (e.g., dietary
supplements, grapefruit juice) pharmacokinetic interactions (including
inhibition, induction, and genetic characteristics), and volume of
distribution (Vd) must be presented if clinically
significant. Information regarding nonlinearity in pharmacokinetic
parameters, changes in pharmacokinetics over time, and binding (plasma
protein, erythrocyte) parameters must also be presented if clinically
significant. This section must also include the results of
pharmacokinetic studies (e.g., of metabolism or interaction) that
establish the absence of an effect, including pertinent human studies
and in vitro data. Dosing recommendations based on clinically
significant factors that change the product's pharmacokinetics (e.g.,
age, gender, race, hepatic or renal dysfunction, concomitant therapy)
that appear in other sections (e.g., ``Warnings and Precautions,''
``Dosage and Administration'' or ``Use in Specific Populations'') must
not be repeated in this subsection, but the location of such
recommendations must be referenced.
(ii) Data that demonstrate activity or effectiveness in in vitro or
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be
included under this section only under the following circumstances:
(A) In vitro data for anti-infective drugs may be included if the
data are immediately preceded by the statement ``The following in vitro
data are available but their clinical significance is unknown.''
(B) For other classes of drugs, in vitro and animal data that have
not been shown by adequate and well-controlled studies, as defined in
Sec. 314.126(b) of this chapter, to be necessary for the safe and
effective use may be included in this section only if a waiver is
granted under Sec. 201.58 or Sec. 314.126(c) of this chapter.
(14) 13 Nonclinical toxicology. This section must contain the
following subsections as appropriate:
(i) 13.1 Carcinogenesis, mutagenesis, impairment of fertility. This
subsection must state whether long term studies in animals have been
performed to evaluate carcinogenic potential and, if so, the species and
results. If results from reproduction studies or other data in animals
raise concern about mutagenesis or impairment of fertility in either
males or females, this must be described. Any precautionary statement on
these topics must include practical, relevant advice to the prescriber
on the significance of these animal findings. Human data suggesting that
the drug may be carcinogenic or mutagenic, or suggesting that it impairs
fertility, as described in the ``Warnings and Precautions'' section,
must not be included in this subsection of the labeling.
(ii) 13.2 Animal toxicology and/or pharmacology. Significant animal
data necessary for safe and effective use of the drug in humans that is
not incorporated in other sections of labeling must be included in this
section (e.g., specifics about studies used to support approval under
Sec. 314.600 or Sec. 601.90 of this chapter, the absence of chronic
animal toxicity data for a drug that is administered over prolonged
periods or is implanted in the body).
(15) 14 Clinical studies. This section must discuss those clinical
studies that facilitate an understanding of how to use the drug safely
and effectively. Ordinarily, this section will describe the studies that
support effectiveness for the labeled indication(s), including
discussion of study design, population, endpoints, and results, but must
not include an encyclopedic listing of all, or even most, studies
performed as part of the product's clinical development program. If a
specific important clinical study is mentioned in any section of
[[Page 37]]
the labeling required under Sec. Sec. 201.56 and 201.57 because the
study is essential to an understandable presentation of the information
in that section of the labeling, any detailed discussion of the study
must appear in this section.
(i) For drug products other than biological products, any clinical
study that is discussed in prescription drug labeling that relates to an
indication for or use of the drug must be adequate and well-controlled
as described in Sec. 314.126(b) of this chapter and must not imply or
suggest indications or uses or dosing regimens not stated in the
``Indications and Usage'' or ``Dosage and Administration'' section. For
biological products, any clinical study that is discussed that relates
to an indication for or use of the biological product must constitute or
contribute to substantial evidence and must not imply or suggest
indications or uses or dosing regimens not stated in the ``Indications
and Usage'' or ``Dosage and Administration'' section.
(ii) Any discussion of a clinical study that relates to a risk from
the use of the drug must also refer to the other sections of the
labeling where the risk is identified or discussed.
(16) 15 References. When prescription drug labeling must summarize
or otherwise rely on a recommendation by an authoritative scientific
body, or on a standardized methodology, scale, or technique, because the
information is important to prescribing decisions, the labeling may
include a reference to the source of the information.
(17) 16 How supplied/storage and handling. This section must contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible. The
information must include, as appropriate:
(i) The strength or potency of the dosage form in metric system
(e.g., 10 milligram tablets) and, if the apothecary system is used, a
statement of the strength in parentheses after the metric designation;
(ii) The units in which the dosage form is ordinarily available for
prescribing by practitioners (e.g., bottles of 100);
(iii) Appropriate information to facilitate identification of the
dosage forms, such as shape, color, coating, scoring, imprinting, and
National Drug Code number; and
(iv) Special handling and storage conditions.
(18) 17 Patient counseling information. This section must contain
information necessary for patients to use the drug safely and
effectively (e.g., precautions concerning driving or the concomitant use
of other substances that may have harmful additive effects). Any FDA-
approved patient labeling must be referenced in this section and the
full text of such patient labeling must be reprinted immediately
following this section or, alternatively, accompany the prescription
drug labeling. Any FDA-approved patient labeling printed immediately
following this section or accompanying the labeling is subject to the
type size requirements in paragraph (d)(6) of this section, except for a
Medication Guide to be detached and distributed to patients in
compliance with Sec. 208.24 of this chapter. Medication Guides for
distribution to patients are subject to the type size requirements set
forth in Sec. 208.20 of this chapter.
(d) Format requirements. All labeling information required under
paragraphs (a), (b), and (c) of this section must be printed in
accordance with the following specifications:
(1) All headings and subheadings required by paragraphs (a) and (c)
of this section must be highlighted by bold type that prominently
distinguishes the headings and subheadings from other labeling
information. Reverse type is not permitted as a form of highlighting.
(2) A horizontal line must separate the information required by
paragraphs (a), (b), and (c) of this section.
(3) The headings listed in paragraphs (a)(5) through (a)(13) of this
section must be presented in the center of a horizontal line.
(4) If there are multiple subheadings listed under paragraphs (a)(4)
through (a)(13) of this section, each subheading must be preceded by a
bullet point.
(5) The labeling information required by paragraphs (a)(1) through
(a)(4), (a)(11)(ii) through (a)(11)(iv), and (a)(14) of this section
must be in bold print.
(6) The letter height or type size for all labeling information,
headings, and
[[Page 38]]
subheadings set forth in paragraphs (a), (b), and (c) of this section
must be a minimum of 8 points, except for labeling information that is
on or within the package from which the drug is to be dispensed, which
must be a minimum of 6 points.
(7) The identifying numbers required by Sec. 201.56(d) and
paragraphs (c)(1) through (c)(18) of this section must be presented in
bold print and must precede the heading or subheading by at least two
square em's (i.e., two squares of the size of the letter ``m'' in 8
point type).
(8) The information required by paragraph (a) of this section, not
including the information required under paragraph (a)(4) of this
section, must be limited in length to an amount that, if printed in 2
columns on a standard sized piece of typing paper (8 1/2 by 11 inches),
single spaced, in 8 point type with 1/2-inch margins on all sides and
between columns, would fit on one-half of the page.
(9) Sections or subsections of labeling that are identified as
containing recent major changes under paragraph (a)(5) of this section
must be highlighted in the full prescribing information by the inclusion
of a vertical line on the left edge of the new or modified text.
(10) For the information required by paragraph (b) of this section,
each section heading must be in bold print. Each subheading within a
section must be indented and not bolded.
[71 FR 3988, Jan. 24, 2006]
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