[Code of Federal Regulations]
[Title 21, Volume 4, Parts 200 to 299]
[Revised as of April 1, 1997]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR201.57]
[Page 19-28]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES
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 drugs.
Each section heading listed in Sec. 201.56(d), if not omitted under
Sec. 201.56(d)(3), shall contain the following information in the
following order:
(a) Description. (1) Under this section heading, the labeling shall
contain:
(i) The proprietary name and the established name, if any, as
defined in section 502(e)(2) of the act, of the drug;
(ii) The type of dosage form and the route of administration to
which the labeling applies;
(iii) The same qualitative and/or quantitative ingredient
information as required under Sec. 201.100(b) for labels;
(iv) If the product is sterile, a statement of that fact;
(v) The pharmacological or therapeutic class of the drug;
(vi) The chemical name and structural formula of the drug;
(vii) If the product is radioactive, a statement of the important
nuclear physical characteristics, such as the principal radiation
emission data, external radiation, and physical decay characteristics.
(2) If appropriate, other important chemical or physical
information, such as physical constants, or pH, shall be stated.
(b) Clinical Pharmacology. (1) Under this section heading, the
labeling shall contain a concise factual summary of the clinical
pharmacology and actions of the drug in humans. The summary may include
information based on in vitro and/or animal data if the information is
essential to a description of the biochemical and/or physiological mode
of action of the drug or is otherwise pertinent to human therapeutics.
Pharmacokinetic information that is important to safe and effective use
of the drug is required, if known, e.g., degree and rate of absorption,
pathways of biotransformation, percentage of dose as unchanged drug and
metabolites, rate or half-time of elimination, concentration in body
fluids associated with therapeutic and/or toxic effects, degree of
binding to plasma proteins, degree of uptake by a particular organ or in
the fetus, and passage across the blood brain barrier. Inclusion of
pharmacokinetic information is restricted to that which relates to
clinical use of the drug. If the pharmacological mode of action of the
drug is unknown or if important metabolic or pharmacokinetic data in
humans are
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unavailable, the labeling shall contain a statement about the lack of
information.
(2) Data that demonstrate activity or effectiveness in in vitro or
animal tests and that have not been shown by adequate and well-
controlled clinical studies to be pertinent to clinical use may be
included under this section of the labeling only under the following
circumstances:
(i) In vitro data for anti-infective drugs may be included if the
data are immediately preceded by the statement ``The following in vitro
data are available but their clinical significance is unknown.''
(ii) For other classes of drugs, in vitro and animal data that have
not been shown by adequate and well-controlled clinical studies, as
defined in Sec. 314.126(b) of this chapter, to be pertinent to clinical
use may be used only if a waiver is granted under Sec. 201.58 or
Sec. 314.126(b) of this chapter.
(c) Indications and Usage. (1) Under this section heading, the
labeling shall state that:
(i) The drug is indicated in the treatment, prevention, or diagnosis
of a recognized disease or condition, e.g., penicillin is indicated for
the treatment of pneumonia due to susceptible pneumococci; and/or
(ii) The drug is indicated for the treatment, prevention, or
diagnosis of an important manifestation of a disease or condition, e.g.,
chlorothiazide is indicated for the treatment of edema in patients with
congestive heart failure; and/or
(iii) The drug is indicated for the relief of symptoms associated
with a disease or syndrome, e.g., chlorpheniramine is indicated for the
symptomatic relief of nasal congestion in patients with vasomotor
rhinitis; and/or
(iv) The drug, if used for a particular indication only in
conjuction with a primary mode of therapy, e.g., diet, surgery, or some
other drug, is an adjunct to the mode of therapy.
(2) All indications shall 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(b) of this chapter.
(3) This section of the labeling shall also contain the following
additional information:
(i) If evidence is available to support the safety and effectiveness
of the drug only in selected subgroups of the larger population with a
disease, syndrome, or symptom under consideration, e.g., patients with
mild disease or patients in a special age group, the labeling shall
describe the available evidence and state the limitations of usefulness
of the drug. The labeling shall also identify specific tests needed for
selection or monitoring of the patients who need the drug, e.g., microbe
susceptibility tests. Information on the approximate kind, degree, and
duration of improvement to be anticipated shall be stated if available
and shall be based on substantial evidence derived from adequate and
well-controlled studies as defined in Sec. 314.126(b) of this chapter
unless the requirement is waived under Sec. 201.58 or Sec. 314.126(b) of
this chapter. If the information is relevant to the recommended
intervals between doses, the usual duration of treatment, or any
modification of dosage, it shall be stated in the ``Dosage and
Administration'' section of the labeling and referenced in this section.
(ii) If safety considerations are such that the drug should be
reserved for certain situations, e.g., cases refractory to other drugs,
this information shall be stated in this section.
(iii) If there are specific conditions that should be met before the
drug is used on a long-term basis, e.g., demonstration of responsiveness
to the drug in a short-term trial, the labeling shall identify the
conditions; or, if the indications for long-term use are different from
those for short-term use, the labeling shall identify the specific
indications for each use.
(iv) If there is a common belief that the drug may be effective for
a certain use or if there is a common use of the drug for a condition,
but the preponderance of evidence related to the use or condition shows
that the drug is ineffective, the Food and Drug Administration may
require that the labeling state that there is a lack of evidence
[[Page 21]]
that the drug is effective for that use or condition.
(v) Any statements comparing the safety or effectiveness, either
greater or less, of the drug with other agents for the same indication
shall be supported by adequate and well-controlled studies as defined in
Sec. 314.126(b) of this chapter unless this requirement is waived under
Sec. 201.58 or Sec. 314.126(b) of this chapter.
(d) Contraindications. Under this section heading, the labeling
shall describe those situations in which the drug should not be used
because the risk of use clearly outweighs any possible benefit. These
situations include administration of the drug to patients known to have
a hypersensitivity to it; use of the drug in patients who, because of
their particular age, sex, concomitant therapy, disease state, or other
condition, have a substantial risk of being harmed by it; or continued
use of the drug in the face of an unacceptably hazardous adverse
reaction. Known hazards and not theoretical possibilities shall be
listed, e.g., if hypersensitivity to the drug has not been demonstrated,
it should not be listed as a contraindication. If no contraindications
are known, this section of the labeling shall state ``None known.''
(e) Warnings. Under this section heading, the labeling shall
describe serious adverse reactions and potential safety hazards,
limitations in use imposed by them, and steps that should be taken if
they occur. The labeling shall be revised to include a warning as soon
as there is reasonable evidence of an association of a serious hazard
with a drug; a causal relationship need not have been proved. A specific
warning relating to a use not provided for under the ``Indications and
Usage'' section of the labeling may be required by the Food and Drug
Administration if the drug is commonly prescribed for a disease or
condition, and there is lack of substantial evidence of effectivenes for
that disease or condition, and such usage is associated with serious
risk or hazard. Special problems, particularly those that may lead to
death or serious injury, may be required by the Food and Drug
Administration to be placed in a prominently displayed box. The boxed
warning ordinarily shall be based on clinical data, but serious animal
toxicity may also be the basis of a boxed warning in the absence of
clinical data. If a boxed warning is required, its location will be
specified by the Food and Drug Administration. The frequency of these
serious adverse reactions and, if known, the approximate mortality and
morbidity rates for patients sustaining the reaction, which are
important to safe and effective use of the drug, shall be expressed as
provided under the ``Adverse Reactions'' section of the labeling.
(f) Precautions. Under this section heading, the labeling shall
contain the following subsections as appropriate for the drug:
(1) General. This subsection of the labeling shall contain
information regarding any special care to be exercised by the
practitioner for safe and effective use of the drug, e.g., precautions
not required under any other specific section or subsection of the
labeling.
(2) Information for patients. This subsection of the labeling shall
contain information to be given to patients for safe and effective use
of the drug, e.g., precautions concerning driving or the concomitant use
of other substances that may have harmful additive effects. Any printed
patient information required under this chapter to be distributed to the
patient shall be referenced under the ``Precautions'' section of the
labeling and the full text of such patient information shall be
reprinted at the end of the labeling.
(3) Laboratory tests. This subsection of the labeling shall identify
any laboratory tests that may be helpful in following the patient's
response or in identifying possible adverse reactions. If appropriate,
information shall be provided on such factors as the range of normal and
abnormal values expected in the particular situation and the recommended
frequency with which tests should be done before, during, and after
therapy.
(4)(i) Drug interactions. This subsection of the labeling shall
contain
[[Page 22]]
specific practical guidance for the physician on preventing clinically
significant drug/drug and drug/food interactions that may occur in vivo
in patients taking the drug. Specific drugs or classes of drugs with
which the drug to which the labeling applies may interact in vivo shall
be identified, and the mechanism(s) of the interaction shall be briefly
described. Information in this subsection of the labeling shall be
limited to that pertaining to clinical use of the drug in patients. Drug
interactions supported only by animal or in vitro experiments may not
ordinarily be included, but animal or in vitro data may be used if shown
to be clinically relevant. Drug incompatibilities, i.e., drug
interactions that may occur when drugs are mixed in vitro, as in a
solution for intravenous administration, shall be discussed under the
``Dosage and Administration'' section of the labeling rather than under
this subsection of the labeling.
(ii) Drug/laboratory test interactions. This subsection of the
labeling shall contain practical guidance on known interference of the
drug with laboratory tests.
(5) Carcinogenesis, mutagenesis, impairment of fertility. This
subsection of the labeling shall state whether long-term studies in
animals have been performed to evaluate carcinogenic potential and, if
so, the species and results. If reproduction studies or other data in
animals reveal a problem or potential problem concerning mutagenesis or
impairment of fertility in either males or females, the information
shall be described. Any precautionary statement on these topics shall
include practical, relevant advice to the physician on the significance
of these animal findings. If there is evidence from human data that the
drug may be carcinogenic or mutagenic or that it impairs fertility, this
information shall be included under the ``Warnings'' section of the
labeling. Also, under ``Precautions,'' the labeling shall state: ``See
`Warnings' section for information on carcinogenesis, mutagenesis, and
impairment of fertility.''
(6) Pregnancy. This subsection of the labeling may be omitted only
if the drug is not absorbed systemically and the drug is not known to
have a potential for indirect harm to the fetus. For all other drugs,
this subsection of the labeling shall contain the following information:
(i) Teratogenic effects. Under this heading the labeling shall
identify one of the following categories that applies to the drug, and
the labeling shall bear the statement required under the category:
(a) 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 shall 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
shall also contain a description of the human studies. If animal
reproduction studies are available and they fail to demonstrate a risk
to the fetus, the labeling shall also state: ``Reproduction studies have
been performed in (kinds of animal(s)) at doses up to (x) times the
human dose and have revealed no evidence of impaired fertility or harm
to the fetus due to (name of drug).'' The labeling shall also contain a
description of available data on the effect of the drug on the later
growth, development, and functional maturation of the child.
(b) 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 shall 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
[[Page 23]]
pregnant women. Because animal reproduction studies are not always
predictive of human response, this drug should be used during pregnancy
only if clearly needed.'' If animal reproduction studies have shown an
adverse effect (other than decrease in fertility), but adequate and
well-controlled studies in pregnant women have failed to demonstrate a
risk to the fetus during the first trimester of pregnancy (and there is
no evidence of a risk in later trimesters), the labeling shall state:
``Pregnancy Category B. Reproduction studies in (kind(s) of animal(s))
have shown (describe findings) at (x) times the human dose. Studies in
pregnant women, however, have not shown that (name of drug) increases
the risk of abnormalities when administered during the first (second,
third, or all) trimester(s) of pregnancy. Despite the animal findings,
it would appear that the possibility of fetal harm is remote, if the
drug is used during pregnancy. Nevertheless, because the studies in
humans cannot rule out the possibility of harm, (name of drug) should be
used during pregnancy only if clearly needed.'' The labeling shall also
contain a description of the human studies and a description of
available data on the effect of the drug on the later growth,
development, and functional maturation of the child.
(c) 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 shall 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 shall contain a description of the animal studies. If there are
no animal reproduction studies and no adequate and well-controlled
studies in humans, the labeling shall state: ``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 shall contain a description of any available data
on the effect of the drug on the later growth, development, and
functional maturation of the child.
(d) 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 shall state: ``Pregnancy Category
D. See `Warnings' section.'' Under the ``Warnings'' section, the
labeling states: ``(Name of drug) can cause fetal harm when administered
to a pregnant woman. (Describe the human data and any pertinent animal
data.) If this drug is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the
potential hazard to the fetus.''
(e) 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 shall
state: ``Pregnancy Category X. See `Contraindications' section.'' Under
``Contraindications,'' the labeling shall state: ``(Name of drug) may
(can) cause fetal harm when administered to a pregnant woman. (Describe
the human data and any pertinant animal data.) (Name of drug) is
contraindicated in
[[Page 24]]
women who are or may become pregnant. If this drug is used during
pregnancy, or if the patient becomes pregnant while taking this drug,
the patient should be apprised of the potential hazard to the fetus.''
(ii) Nonteratogenic effects. Under this heading the labeling shall
contain other information on the drug's effects on reproduction and the
drug's use during pregnancy that is not required specifically by one of
the pregnancy categories, if the information is relevant to the safe and
effective use of the drug. Information required under this heading shall
include nonteratogenic effects in the fetus or newborn infant (for
example, withdrawal symptoms or hypoglycemia) that may occur because of
a pregnant woman's chronic use of the drug for a preexisting condition
or disease.
(7) Labor and delivery. If the drug has a recognized use during
labor or delivery (vaginal or abdominal delivery), whether or not the
use is stated in the indications section of the labeling, this
subsection of the labeling shall describe the available information
about the effect of the drug on the mother and the fetus, on the
duration of labor or delivery, on the possibility that forceps delivery
or other intervention or resuscitation of the newborn will be necessary,
and the effect of the drug on the later growth, development, and
functional maturation of the child. If any information required under
this subsection is unknown, this subsection of the labeling shall state
that the information is unknown.
(8) Nursing mothers. (i) If a drug is absorbed systemically, this
subsection of the labeling shall contain, if known, information about
excretion of the drug in human milk and effects on the nursing infant.
Pertinent adverse effects observed in animal offspring shall be
described.
(ii) If a drug is absorbed systemically and is known to be excreted
in human milk, this subsection of the labeling shall contain one of the
following statements, as appropriate. If the drug is associated with
serious adverse reactions or if the drug has a known tumorigenic
potential, the labeling shall state: ``Because of the potential for
serious adverse reactions in nursing infants from (name of drug) (or,
``Because of the potential for tumorigenicity shown for (name of drug)
in (animal or human) studies), a decision should be made whether to
discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.'' If the drug is not associated
with serious adverse reactions and does not have a known tumorigenic
potential, the labeling shall state: ``Caution should be exercised when
(name of drug) is administered to a nursing woman.''
(iii) If a drug is absorbed systemically and information on
excretion in human milk is unknown, this subsection of the labeling
shall contain one of the following statements, as appropriate. If the
drug is associated with serious adverse reactions or has a known
tumorigenic potential, the labeling shall state: ``It is not known
whether this drug is excreted in human milk. Because many drugs are
excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from (name of drug) (or, ``Because of the
potential for tumorigenicity shown for (name of drug) in (animal or
human) studies), a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance
of the drug to the mother.'' If the drug is not associated with serious
adverse reactions and does not have a known tumorigenic potential, the
labeling shall state: ``It is not known whether this drug is excreted in
human milk. Because many drugs are excreted in human milk, caution
should be exercised when (name of drug) is administered to a nursing
woman.''
(9) Pediatric use.
(i) Pediatric population(s)/pediatric patient(s): For the purposes
of paragraphs (f)(9)(ii) through (f)(9)(viii) of this setion, the terms
pediatric population(s) and pediatric patient(s) are defined as the
pediatric age group, from birth to 16 years, including age groups often
called neonates, infants, children, and adolescents.
(ii) If there is a specific pediatric indication (i.e., an
indication different from those approved for adults) that is
[[Page 25]]
supported by adequate and well-controlled studies in the pediatric
population, it shall be described under the ``Indications and Usage''
section of the labeling, and appropriate pediatric dosage information
shall be given under the ``Dosage and Administration'' section of the
labeling. The ``Pediatric use'' subsection shall cite any limitations on
the pediatric indication, need for specific monitoring, specific hazards
associated with use of the drug in any subsets of the pediatric
population (e.g., neonates), differences between pediatric and adult
responses to the drug, and other information related to the safe and
effective pediatric use of the drug. Data summarized in this subsection
of the labeling should be discussed in more detail, if appropriate,
under the ``Clinical Pharmacology'' or ``Clinical Studies'' section. As
appropriate, this information shall also be contained in the
``Contraindications,'' ``Warnings,'' and elsewhere in the
``Precautions'' sections.
(iii) If there are specific statements on pediatric use of the drug
for an indication also approved for adults that are based on adequate
and well-controlled studies in the pediatric population, they shall be
summarized in the ``Pediatric use'' subsection of the labeling and
discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' and ``Clinical Studies'' sections. Appropriate pediatric
dosage shall be given under the ``Dosage and Administration'' section of
the labeling. The ``Pediatric use'' subsection of the labeling shall
also cite any limitations on the pediatric use statement, need for
specific monitoring, specific hazards associated with use of the drug in
any subsets of the pediatric population (e.g., neonates), differences
between pediatric and adult responses to the drug, and other information
related to the safe and effective pediatric use of the drug. As
appropriate, this information shall also be contained in the
``Contraindications,'' ``Warnings,'' and elsewhere in the
``Precautions'' sections.
(iv) FDA may approve a drug for pediatric use based on adequate and
well-controlled studies in adults, with other information supporting
pediatric use. In such cases, the agency will have concluded that the
course of the disease and the effects of the drug, both beneficial and
adverse, are sufficiently similar in the pediatric and adult populations
to permit extrapolation from the adult efficacy data to pediatric
patients. The additional information supporting pediatric use must
ordinarily include data on the pharmacokinetics of the drug in the
pediatric population for determination of appropriate dosage. Other
information, such as data from pharmacodynamic studies of the drug in
the pediatric population, data from other studies supporting the safety
or effectiveness of the drug in pediatric patients, pertinent
premarketing or postmarketing studies or experience, may be necessary to
show that the drug can be used safely and effectively in pediatric
patients. When a drug is approved for pediatric use based on adequate
and well-controlled studies in adults with other information supporting
pediatric use, the ``Pediatric use'' subsection of the labeling shall
contain either the following statement, or a reasonable alternative:
``The safety and effectiveness of (drug name) have been established in
the age groups -- to -- (note any limitations, e.g., no data for
pediatric patients under 2, or only applicable to certain indications
approved in adults). Use of (drug name) in these age groups is supported
by evidence from adequate and well-controlled studies of (drug name) in
adults with additional data (insert wording that accurately describes
the data submitted to support a finding of substantial evidence of
effectiveness in the pediatric population).'' Data summarized in the
preceding prescribed statement in this subsection of the labeling shall
be discussed in more detail, if appropriate, under the ``Clinical
Pharmacology'' or the ``Clinical Studies'' section. For example,
pediatric pharmacokinetic or pharmacodynamic studies and dose-response
information should be described in the ``Clinical Pharmacology''
section. Pediatric dosing instructions shall be included in the ``Dosage
and Administration'' section of the labeling. Any differences between
pediatric and adult responses, need for specific monitoring, dosing
adjustments, and any other information related to safe and effective use
of the drug in pediatric patients shall be cited
[[Page 26]]
briefly in the ``Pediatric use'' subsection and, as appropriate, in the
``Contraindications,'' ``Warnings,'' ``Precautions,'' and ``Dosage and
Administration'' sections.
(v) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for a particular pediatric population, the ``Pediatric use''
subsection of the labeling shall contain an appropriate statement such
as ``Safety and effectiveness in pediatric patients below the age of (--
) have not been established.'' If use of the drug in this pediatric
population is associated with a specific hazard, the hazard shall be
described in this subsection of the labeling, or, if appropriate, the
hazard shall be stated in the ``Contraindications'' or ``Warnings''
section of the labeling and this subsection shall refer to it.
(vi) If the requirements for a finding of substantial evidence to
support a pediatric indication or a pediatric use statement have not
been met for any pediatric population, this subsection of the labeling
shall contain the following statement: ``Safety and effectiveness in
pediatric patients have not been established.'' If use of the drug in
premature or neonatal infants, or other pediatric subgroups, is
associated with a specific hazard, the hazard shall be described in this
subsection of the labeling, or, if appropriate, the hazard shall be
stated in the ``Contraindications'' or ``Warnings'' section of the
labeling and this subsection shall refer to it.
(vii) If the sponsor believes that none of the statements described
in paragraphs (f)(9)(ii) through (f)(9)(vi) of this section is
appropriate or relevant to the labeling of a particular drug, the
sponsor shall provide reasons for omission of the statements and may
propose alternative statement(s). FDA may permit use of an alternative
statement if FDA determines that no statement described in those
paragraphs is appropriate or relevant to the drug's labeling and that
the alternative statement is accurate and appropriate.
(viii) If the drug product contains one or more inactive ingredients
that present an increased risk of toxic effects to neonates or other
pediatric subgroups, a special note of this risk shall be made,
generally in the ``Contraindications,'' ``Warnings,'' or ``Precautions''
section.
(g) Adverse Reactions. An adverse reaction is an undesirable effect,
reasonably associated with the use of the drug, that may occur as part
of the pharmacological action of the drug or may be unpredictable in its
occurrence.
(1) This section of the labeling shall list the adverse reactions
that occur with the drug and with drugs in the same pharmacologically
active and chemically related class, if applicable.
(2) In this listing, adverse reactions may be categorized by organ
system, by severity of the reaction, by frequency, or by toxicological
mechanism, or by a combination of these, as appropriate. If frequency
information from adequate clinical studies is available, the categories
and the adverse reactions within each category shall be listed in
decreasing order of frequency. An adverse reaction that is significantly
more severe than the other reactions listed in a category, however,
shall be listed before those reactions, regardless of its frequency. If
frequency information from adequate clinical studies is not available,
the categories and adverse reactions within each category shall be
listed in decreasing order of severity. The approximate frequency of
each adverse reaction shall be expressed in rough estimates or orders of
magnitude essentially as follows: ``The most frequent adverse
reaction(s) to (name of drug) is (are) (list reactions). This (these)
occur(s) in about (e.g., one-third of patients; one in 30 patients; less
than one-tenth of patients). Less frequent adverse reactions are (list
reactions), which occur in approximately (e.g., one in 100 patients).
Other adverse reactions, which occur rarely, in approximately (e.g., one
in 1,000 patients), are (list reactions).'' Percent figures may not
ordinarily be used unless they are documented by adequate and well-
controlled studies as defined in Sec. 314.126(b) of this chapter, they
are shown to reflect general experience, and they do not falsely imply a
greater degree of accuracy than actually exists.
(3) The ``Warnings'' section of the labeling or, if appropriate, the
``Contraindications'' section of the labeling
[[Page 27]]
shall identify any potentially fatal adverse reaction.
(4) Any claim comparing the drug to which the labeling applies with
other drugs in terms of frequency, severity, or character of adverse
reactions shall be based on adequate and well-controlled studies as
defined in Sec. 314.126(b) of this chapter unless this requirement is
waived under Sec. 201.58 or Sec. 314.126(b) of this chapter.
(h) Drug Abuse and Dependence. Under this section heading, the
labeling shall contain the following subsections, as appropriate for the
drug:
(1) Controlled Substance. If the drug is controlled by the Drug
Enforcement Administration, the schedule in which it is controlled shall
be stated.
(2) Abuse. This subsection of the labeling shall be based primarily
on human data and human experience, but pertinent animal data may also
be used. This subsection shall state the types of abuse that can occur
with the drug and the adverse reactions pertinent to them. Particularly
susceptible patient populations shall be identified.
(3) Dependence. This subsection of the labeling shall describe
characteristic effects resulting from both psychological and physical
dependence that occur with the drug and shall identify the quantity of
the drug over a period of time that may lead to tolerance or dependence,
or both. Details shall be provided on the adverse effects of chronic
abuse and the effects of abrupt withdrawal. Procedures necessary to
diagnose the dependent state shall be provided, and the principles of
treating the effects of abrupt withdrawal shall be described.
(i) Overdosage. Under this section heading, the labeling shall
describe the signs, symptoms, and laboratory findings of acute
overdosage and the general principles of treatment. This section shall
be based on human data, when available. If human data are unavailable,
appropriate animal and in vitro data may be used. Specific information
shall be provided about the following:
(1) Signs, symptoms, and laboratory findings associated with an
overdosage of the drug.
(2) Complications that can occur with the drug (for example, organ
toxicity or delayed acidosis).
(3) Oral LD<INF>50</INF> of the drug in animals; concentrations of
the drug in biologic fluids associated with toxicity and/or death;
physiologic variables influencing excretion of the drug, such as urine
pH; and factors that influence the dose response relationship of the
drug, such as tolerance. The pharmacokinetic data given in the
``Clinical Pharmacology'' section also may be referenced here, if
applicable to overdoses.
(4) The amount of the drug in a single dose that is ordinarily
associated with symptoms of overdosage and the amount of the drug in a
single dose that is likely to be life-threatening.
(5) Whether the drug is dialyzable.
(6) Recommended general treatment procedures and specific measures
for support of vital functions, such as proven antidotes, induced
emesis, gastric lavage, and forced diuresis. Unqualified recommendations
for which data are lacking with the specific drug or class of drugs,
especially treatment using another drug (for example, central nervous
system stimulants, respiratory stimulants) may not be stated unless
specific data or scientific rationale exists to support safe and
effective use.
(j) Dosage and Administration. This section of the labeling shall
state the recommended usual dose, the usual dosage range, and, if
appropriate, an upper limit beyond which safety and effectiveness have
not been established; dosages shall be stated for each indication when
appropriate. This section shall also state the intervals recommended
between doses, the optimal method of titrating dosage, the usual
duration of treatment, and any modification of dosage needed in special
patient populations, e.g., in children, in geriatric age groups, or in
patients with renal or hepatic disease. Specific tables or monographs
may be included to clarify dosage schedules. Radiation dosimetry
information shall be stated for both the patient receiving a radioactive
drug and the person administering it. This section shall also contain
specific direction on dilution, preparation (including the strength of
the final
[[Page 28]]
dosage solution, when prepared according to instructions, in terms of
milligrams active ingredient per milliliter of reconstituted solution,
unless another measure of the strength is more appropriate), and
administration of the dosage form, if needed, e.g., the rate of
administration of parenteral drug in milligrams per minute; storage
conditions for stability of the drug or reconstituted drug, when
important; essential information on drug incompatibilities if the drug
is mixed in vitro with other drugs; and the following statement for
parenterals: ``Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever
solution and container permit.''
(k) How Supplied. This section of the labeling shall contain
information on the available dosage forms to which the labeling applies
and for which the manufacturer or distributor is responsible. The
information shall ordinarily include:
(1) The strength of the dosage form, e.g., 10-milligram tablets, in
metric system and, if the apothecary system is used, a statement of the
strength is placed in parentheses after the metric designation;
(2) The units in which the dosage form is ordinarily available for
prescribing by practitioners, e.g., bottles of 100;
(3) Appropriate information to facilitate identification of the
dosage forms, such as shape, color, coating, scoring, and National Drug
Code; and
(4) Special handling and storage conditions.
(l) Animal Pharmacology and/or Animal Toxicology. In most cases, the
labeling need not include this section. Significant animal data
necessary for safe and effective use of the drug in humans shall
ordinarily be included in one or more of the other sections of the
labeling, as appropriate. Commonly for a drug that has been marketed for
a long time, and in rare cases for a new drug, chronic animal toxicity
studies have not been performed or completed for a drug that is
administered over prolonged periods or is implanted in the body. The
unavailability of such data shall be stated in the appropriate section
of the labeling for the drug. If the pertinent animal data cannot be
appropriately incorporated into other sections of the labeling, this
section may be used.
(m) ``Clinical Studies'' and ``References''. These sections may
appear in labeling in the place of a detailed discussion of a subject
that is of limited interest but nonetheless important. A reference to a
specific important clinical study may be made in any section of the
format required under Secs. 201.56 and 201.57 if the study is essential
to an understandable presentation of the available information.
References may appear in sections of the labeling format, other than the
``Clinical Studies'' or ``References'' section, in rare circumstances
only. A clinical study or reference may be cited in prescription drug
labeling only under the following conditions:
(1) If the clinical study or reference is cited in the labeling in
the place of a detailed discussion of data and information concerning an
indication for use of the drug, the reference shall be based upon, or
the clinical study shall constitute, an adequate and well-controlled
clinical investigation under Sec. 314.126(b) of this chapter.
(2) If the clinical study or reference is cited in the labeling in
the place of a detailed discussion of data and information concerning a
risk or risks from the use of the drug, the risk or risks shall also be
identified or discussed in the appropriate section of the labeling for
the drug.
[44 FR 37462, June 26, 1979, as amended at 55 FR 11576, Mar. 29, 1990;
59 FR 64249, Dec. 13, 1994]