Guidance for Industry:
Warnings and Precautions, Contraindications, and Boxed Warning
Sections of Labeling for Human Prescription Drug and Biological
Products —
Content and Format
(PDF
format of this document)
DRAFT GUIDANCE
This guidance document is being
distributed for comment purposes only.
Comments and suggestions regarding this draft
document should be submitted within 90 days of publication in the
Federal Register of the notice announcing the availability
of the draft guidance. Submit comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions regarding this draft document
contact (CDER) Janet Norden at 301-796-2270, or (CBER) Toni
Stifano at 301-827-6190.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
Labeling
Guidance for Industry
Warnings and Precautions, Contraindications, and Boxed Warning
Sections of Labeling for Human Prescription Drug and Biological
Products —
Content and Format
Additional copies are available
from:
Office of Training and
Communications
Division of Drug Information, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet)
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training
and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800
(Internet)
http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
January 2006
Labeling
Guidance for Industry
Warnings and Precautions,
Contraindications, and Boxed Warning Sections of Labeling for
Human
Prescription Drug and Biological Products — Content and Format
This
draft guidance, when finalized, will represent the Food and Drug
Administration's (FDA's) current thinking on this topic. It does
not create or confer any rights for or on any person and does not
operate to bind FDA or the public. An alternative approach may be
used if such approach satisfies the requirements of the applicable
statutes and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing this
guidance. If you cannot identify the appropriate FDA staff, call
the appropriate number listed on the title page of this guidance.
This
guidance is intended to assist applicants and reviewers in drafting
the WARNINGS AND PRECAUTIONS, CONTRAINDICATIONS, and BOXED WARNING
sections of labeling, as described in the final rule amending the
requirements for the content and format of labeling for human
prescription drug and biological products (21 CFR 201.56 and
201.57).
The recommendations in this guidance are intended to help ensure
that the labeling is clear, useful, informative, and to the extent
possible, consistent in content and format.
This
guidance provides recommendations on the following:
·
How to decide which
adverse reactions are significant enough to warrant inclusion in the
WARNINGS AND PRECAUTIONS section; what information to include when
describing those adverse reactions; and how to organize the section
·
What situations warrant a
contraindication; what information to provide in those situations
when the use of the product is contraindicated; and how to organize
the CONTRAINDICATIONS section
·
When to include a boxed
warning; and what information to include in the BOXED WARNING
section
FDA's guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency's current thinking on a topic
and should be viewed only as recommendations, unless specific
regulatory or statutory requirements are cited. The use of the word
should in Agency guidances means that something is suggested
or recommended, but not required.
This section includes clinically
significant adverse reactions observed in association with the use
of a drug for which there is reasonable evidence of a causal
association between the drug and the adverse reaction (a causal
relationship need not have been established):
IF
·
The adverse
reaction is serious (see glossary for definition of serious adverse
reaction).
OR
·
The adverse
reaction does not meet the definition of a serious adverse reaction,
but is still considered clinically significant (otherwise
clinically significant). Adverse reactions that are considered
otherwise clinically significant could include:
— Adverse reactions that
require discontinuation, dosage or regimen adjustment, or addition
of another drug
— Adverse reactions that
could be prevented or managed with appropriate patient selection or
avoidance of concomitant therapy
— Adverse reactions that
significantly affect patient compliance
OR
·
The product
interferes with a laboratory test.
There are circumstances in which
an adverse reaction can be expected to occur with a drug, despite
its not having been observed with that drug, based on observations
from other members of the drug class or animal studies. An expected
adverse reaction may not be observed, for example, in clinical
trials for newer drugs in a class where the trials are designed to
exclude populations that were determined to be vulnerable to the
adverse reaction with earlier members of the drug class.
The WARNINGS AND PRECAUTIONS
section includes adverse reactions that are expected to occur with a
drug, but have yet to be observed if:
·
The reaction is
serious or otherwise clinically significant as discussed
above
AND EITHER
·
Based on what is
known about the pharmacology, chemistry, or class of the drug, it
appears likely that the adverse reaction will occur with the drug.
OR
·
Animal data raise
substantial concern about the potential for occurrence of the
adverse reaction in humans (e.g., animal data demonstrating that a
drug has teratogenic effects).
In these cases, the labeling
should acknowledge that the adverse reaction has not been observed,
but may be expected to occur.
The following factors should
also be considered in determining whether to include an adverse
reaction in the WARNINGS AND PRECAUTIONS section of labeling:
·
Indication
The relative seriousness of the
disease or condition for which a drug is indicated will influence
whether an adverse reaction would be considered clinically
significant and thus appropriate for inclusion in the WARNINGS AND
PRECAUTIONS section. For example, for a drug intended to treat a
minor, self-limiting condition (e.g., allergic rhinitis, cosmetic
conditions, transient insomnia), a nonserious adverse reaction
(e.g., nausea, pruritis, alopecia) may be considered clinically
significant and, therefore, appropriate for inclusion in the
section. For a drug intended to treat a serious or life-threatening
condition (e.g., cancer), the same adverse reaction may be
considered much less clinically significant and not appropriate for
inclusion in the section.
·
Incidence
Typically, the nature of an
adverse reaction and a drug’s indication are the most influential
factors in determining whether an adverse reaction should be
included in the WARNINGS AND PRECAUTIONS section. In some cases,
however, the absolute risk or rate of an adverse reaction can be an
important factor when deciding whether to include the reaction in
this section (e.g., when the risk or rate is high).
·
Ability to Manage
or Prevent an Adverse Reaction
The ability to manage or prevent
an adverse reaction through patient monitoring, proper dose
selection or titration, or avoidance of concomitant therapy can also
be an important factor in deciding whether to discuss an adverse
reaction in the WARNINGS AND PRECAUTIONS section.
FDA may require a specific
warning relating to an unapproved use if the drug is commonly
prescribed for a disease or condition and such usage is associated
with a clinically significant risk or hazard (§ 201.57(c)(6)(i)).
Clinically significant adverse reactions that appear to be linked
primarily to an unapproved use of a drug (e.g., use for a disease,
condition, or population not included in the INDICATIONS AND USE
section, use of an unapproved dose or regimen) should be identified
and discussed in the WARNINGS AND PRECAUTIONS section. The
discussion should include a statement indicating that safety and
effectiveness have not been established in that setting and that the
use is not approved by FDA.
The WARNINGS AND PRECAUTIONS
section should include a discussion of any known or predicted drug
interactions with serious or otherwise clinically significant
outcomes, with a cross-reference to any additional information in
the DRUG INTERACTIONS or CLINICAL PHARMACOLOGY sections.
The WARNINGS AND PRECAUTIONS
section must identify any laboratory tests helpful in following the
patient’s response or in identifying possible adverse reactions
(§ 201.57(c)(6)(iii)), and, if appropriate, information about the
frequency of testing and expected ranges of normal and abnormal
values.
The WARNINGS AND PRECAUTIONS
section should contain the following information for each adverse
reaction, if such information is known:
·
A description of
the adverse reaction and outcome (e.g., time to resolution,
significant sequelae)
·
An estimate of
risk or adverse reaction rate
·
A discussion of
known risk factors for the adverse reaction (e.g., age, gender,
race, comorbid conditions, dose, duration of use, coadministered
drugs)
·
A discussion of
steps to take to reduce the risk of, decrease the likelihood of,
shorten the duration of, or minimize the severity of an adverse
reaction. These steps could include, for example, necessary
evaluation prior to use, titration and other kinds of dose
adjustment, monitoring during dose adjustment or prolonged use,
avoidance of other drugs or substances, or special care during
comorbid events (e.g., dehydration, infection)
·
A discussion of
how to treat, or otherwise manage, an adverse reaction that has
occurred
Although the following issues
would typically be discussed elsewhere in labeling, they can also be
mentioned in the WARNINGS AND PRECAUTIONS section when such
information would help prescribers understand the clinical
significance of an adverse reaction:
·
A discussion of
the mechanism of the adverse reaction
·
The source of
information about the adverse reaction (e.g., it may be informative
to know whether the information is from clinical trials or
postmarketing reports, or whether an adverse reaction was seen only
in foreign experience with the drug)
The information and advice
provided in this section should be reasonably qualified, where
appropriate, to convey whatever uncertainties may exist about
judgments and conclusions made (e.g., concerning causality
assessments, estimated adverse reaction rates, and value of proposed
monitoring).
FDA recommends that each adverse
reaction, syndrome, or constellation of reactions (e.g., thrombotic
events, hemorrhagic events) included in the WARNINGS AND PRECAUTIONS
section have its own subheading. There would ordinarily be no
reason to further subcategorize adverse reactions (e.g., separating
observed and expected adverse reactions by placing them under
different subheadings).
The order in which adverse
reactions are presented should reflect the relative public health
significance of the adverse reactions. Factors to consider include
the relative seriousness of the adverse reaction, the ability to
prevent or mitigate the adverse reaction, the likelihood of
occurrence, and the size of the population that is potentially
affected. In general, the relative seriousness of the adverse
reaction and the ability to prevent or mitigate it weigh more
heavily than the likelihood of occurrence or the size of the
affected population.
Bolded text, or other emphasis,
can be used to highlight particular adverse reactions or parts of
the discussion of particular adverse reactions (e.g., steps to be
taken to avoid a problem, subpopulations at particular risk).
Emphasis should be used sparingly so that its impact is not
diminished. When information is to be emphasized, also consider
whether that information should be in a boxed warning (see section
IV on BOXED WARNING section).
Information discussed in the
WARNINGS AND PRECAUTIONS section often is discussed or mentioned in
other sections of the labeling (e.g., ADVERSE REACTIONS, DOSAGE AND
ADMINISTRATION, DRUG INTERACTIONS). Information appearing in other
locations should be appropriately cross-referenced.
A drug should be contraindicated
only in those clinical situations for which the risk from use
clearly outweighs any possible therapeutic benefit. Only known
hazards, and not theoretical possibilities, must be listed. If
there are no known contraindications for a drug, this section must
state “None.”
For observed adverse reactions,
the following would ordinarily be reason to contraindicate a drug:
·
The risk of the
adverse reaction in the clinical situation to which the
contraindication will apply, based on both likelihood and severity
of the adverse reaction, outweighs any potential benefit to the
patient.
AND
·
The causal
relationship between exposure to the drug and the adverse reaction
is well established.
Adverse reactions that are
expected to occur when a drug is used in a specific clinical
situation can be the basis for a contraindication.
The following would ordinarily be reason to contraindicate a drug on
the basis of an expected adverse reaction.
The risk of the adverse
reaction in the clinical situation to which the contraindication
will apply, based on both likelihood and severity of the adverse
reaction, outweighs any potential benefit to the patient
AND EITHER
·
Based on what is
known about the pharmacology, chemistry, or class of the drug, it
appears highly likely that the adverse reaction will occur with the
drug.
OR
·
Animal data raise
substantial concern about the potential for occurrence of the
adverse reaction in humans (e.g., animal data demonstrating that a
drug has teratogenic effects).
The labeling should acknowledge
that the adverse reaction has not yet been observed, but is expected
to occur.
A contraindication usually
involves one or more of the following clinical situations:
·
Comorbid condition or
coexistent physiological state (e.g., existing hepatic disease,
renal disease, congenital long QT syndrome, hypokalemia, pregnancy
or childbearing potential, CYP 2D6 poor metabolizer)
·
Demographic risk factor
(e.g., age, sex, race, genetic vulnerability)
·
The risks of the drug are
such that the drug should never be used in a selected subset of the
larger population with a disease
·
Coadministered drug where
the combination is dangerous (e.g., MAO inhibitor and
sympathomimetic drug, a drug known to prolong the QT interval and a
drug known to interfere with the metabolism of that drug)
Contraindications based on drug
interactions with serious outcomes should be described in the
CONTRAINDICATIONS section and cross-referenced to more detailed
information in the DRUG INTERACTIONS or CLINICAL PHARMACOLOGY
sections.
For each listed
contraindication, provide the following information:
·
Brief description
of the contraindicated situation or scenario, including any
pertinent demographic or identifiable predisposing characteristics
·
Description of
anticipated consequences of the contraindicated use
FDA recommends that each
contraindication be identified by its own subheading.
The order in which
contraindications are presented should reflect the relative public
health significance of the listed contraindications. Factors to
consider include the likelihood of occurrence and the size of the
population that is potentially affected.
Bolded text,
or other emphasis, can be used to highlight particular
contraindicated situations or parts of the discussions of these
situations. Emphasis should be used sparingly so that its impact is
not diminished. When information is to be emphasized, also consider
whether that information should be in a boxed warning (see BOXED
WARNING below).
A boxed warning is ordinarily
used to highlight for prescribers one of the following situations:
·
There is an
adverse reaction so serious in proportion to the potential benefit
from the drug (e.g., a fatal, life-threatening or permanently
disabling adverse reaction) that it is essential that it be
considered in assessing the risks and benefits of using a drug
OR
·
There is a serious
adverse reaction that can be prevented or reduced in frequency or
severity by appropriate use of the drug (e.g., patient selection,
careful monitoring, avoiding certain concomitant therapy, addition
of another drug or managing patients in a specific manner, avoiding
use in a specific clinical situation)
OR
·
FDA approved the
drug with restrictions to assure safe use because FDA concluded that
the drug can be safely used only if distribution or use is
restricted (e.g., under 21 CFR part 314, subpart H, § 314.520
“Approval with restrictions to assure safe use”).
A boxed warning can also be used
in other situations to highlight warning information that is
especially important to the prescriber. Information included in the
WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS sections should
therefore be evaluated to determine whether it should also be placed
in a boxed warning.
Boxed warnings are more likely
to be based on observed adverse reactions, but there are instances
when a boxed warning based on an expected adverse reaction would be
appropriate. For example, a contraindication during pregnancy based
on evidence in humans that drugs in a pharmacologic class pose a
serious risk of developmental toxicity during that time would
usually be in a boxed warning for all drugs in that class, even
those in which the adverse reaction has not been seen.
A boxed warning can also be
considered for a drug that has important risk/benefit information
that is unique among drugs in a drug class (e.g., to note that a
drug is the only one in its class to have a particular risk that
makes it inappropriate for use as a first line therapy).
A boxed warning provides a
brief, concise summary of the information that is critical for a
prescriber to be aware of, including any restriction on distribution
or use. If there is a more detailed discussion of the concern in
either the CONTRAINDICATIONS or WARNINGS AND PRECAUTIONS section, or
any other labeling section that contains pertinent information
(e.g., DOSAGE AND ADMINISTRATION), a cross-reference to that section
must be provided (§ 201.57(c)(1)).
FDA recommends the information
in the boxed warning be presented in a bulleted format (or some
alternative format, such as subheadings) that helps to make the
information visually accessible.
Adverse Reaction (21 CFR 201.57(c)(7)):
For purposes of prescription drug labeling and this guidance, an
adverse reaction is an undesirable effect, reasonably associated
with the 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 for which there is some
basis to believe there is a causal relationship between the drug and
the occurrence of the adverse event.
Adverse reactions may include signs and
symptoms, changes in laboratory parameters, and changes in other
measures of critical body function, such as vital signs and
electrocardiogram (ECG).
Adverse Event (or adverse experience):
For the purposes of this guidance, an adverse event refers to
any untoward medical event associated with the use of a drug in
humans, whether or not considered drug-related.
Serious Adverse Reaction: For purposes
of this guidance, the term serious adverse reaction refers to
any reaction occurring at any dose that results in any of the
following outcomes: Death, a life-threatening adverse experience,
inpatient hospitalization or prolongation of existing
hospitalization, a persistent or significant disability or
incapacity, or a congenital anomaly or birth defect. Important
medical events that may not result in death, be life-threatening, or
require hospitalization may be considered serious adverse drug
reactions when, based upon appropriate medical judgment, they may
jeopardize the patient or subject and may require medical or
surgical intervention to prevent one of the outcomes listed in this
definition.
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Date created: January 18, 2006 |