Chapter 5: Pharmaceutical Labeling in the US
40 Regulatory Affairs Professionals Society (RAPS)
heading “Full Prescribing Information: Contents”
is marked with an asterisk corresponding to text
at the end of Highlights stating, “Sections or
subsections omitted from the full prescribing
information are not listed.” When a section or
subsection is omitted, the numbering outlined in
21 CFR 201.56 should be maintained.
Full Prescribing Information (Select
Sections)
Boxed Warnings
The FDA may require certain contraindications
or serious warnings to be presented in a text box
at the beginning of the FPI, especially those that
may lead to death or serious injury or if there
is a serious adverse reaction that can be pre-
vented or reduced in frequency or severity. This
boxed text provides a brief and concise sum-
mary of information critical for the prescriber
to consider and refers to details included under
Contraindications or Warnings and Precautions.
Contraindications
A drug is contraindicated in situations where the
risk of use clearly outweighs the potential benefit.
Only known hazards, and not theoretical possi-
bilities, can be the basis for a contraindication.
Contraindications can result from an observed
adverse reaction or an anticipated adverse reac-
tion, which is distinguishable from a theoretical
possibility. Anticipated adverse reactions are
supported by data.
Warnings and Precautions
Warnings and precautions include serious or
otherwise clinically significant adverse reactions
or other potential safety hazards, such as drug
interactions or known risks for the pharmaco-
logic class, steps to avoid them and actions to
take if they occur. This section also describes any
recommended monitoring and notes the poten-
tial for interference with laboratory tests.
Adverse Reactions
Another interesting feature of US format-
ting occurs with Section 6 Adverse Reactions.
An adverse reaction is an undesirable effect
reasonably associated with the use of a drug.
This section does not include all adverse events
observed, only those for which there is a basis
for a causal relationship between the drug and
the occurrence of the adverse event. This section
begins with a description of a drug’s overall
adverse reaction profile on the entire safety data-
base, followed by separate subsections:
• Clinical trial experience presents adverse
reactions identified in clinical studies.
Provide a description of the clinical trial data
source present a listing of common adverse
reactions at or above a specified rate fol-
lowed by a separate listing of less common
adverse reactions. For adverse reactions with
significant clinical implications, the listings
must be supplemented by additional detail
about the adverse reaction’s nature, fre-
quency, and severity.
• Immunogenicity information, if pertinent.
• Postmarketing experience lists adverse reac-
tions identified from domestic and foreign
spontaneous reporting. This listing must be
separate from the listing of adverse reactions
identified in the clinical trial experience.
Pregnancy and Lactation Labeling
Rule (PLLR)42,43,48
After a decade-long initiative and the issuance
of a proposed rule in 2008, the FDA published
the final Pregnancy and Lactation Labeling Rule
(PLLR) in December 2014 for prescription drug
and biologics’ pregnancy and lactation labeling
content and format. It also issued a guidance to
facilitate compliance with the new requirements.
The PLLR redefined the content and
reconfigured the format of these subsections in
PLLR Section 8, Use in Specific Populations (see
Figure 5-149).
• The rule merged the previous Pregnancy
and Labor and Delivery subsections into
Pregnancy, which should include a summary
of the risks of the drug during pregnancy,
details of any pregnancy registries, and
guidance to clinicians for decision mak-
ing and counseling. Information in this
40 Regulatory Affairs Professionals Society (RAPS)
heading “Full Prescribing Information: Contents”
is marked with an asterisk corresponding to text
at the end of Highlights stating, “Sections or
subsections omitted from the full prescribing
information are not listed.” When a section or
subsection is omitted, the numbering outlined in
21 CFR 201.56 should be maintained.
Full Prescribing Information (Select
Sections)
Boxed Warnings
The FDA may require certain contraindications
or serious warnings to be presented in a text box
at the beginning of the FPI, especially those that
may lead to death or serious injury or if there
is a serious adverse reaction that can be pre-
vented or reduced in frequency or severity. This
boxed text provides a brief and concise sum-
mary of information critical for the prescriber
to consider and refers to details included under
Contraindications or Warnings and Precautions.
Contraindications
A drug is contraindicated in situations where the
risk of use clearly outweighs the potential benefit.
Only known hazards, and not theoretical possi-
bilities, can be the basis for a contraindication.
Contraindications can result from an observed
adverse reaction or an anticipated adverse reac-
tion, which is distinguishable from a theoretical
possibility. Anticipated adverse reactions are
supported by data.
Warnings and Precautions
Warnings and precautions include serious or
otherwise clinically significant adverse reactions
or other potential safety hazards, such as drug
interactions or known risks for the pharmaco-
logic class, steps to avoid them and actions to
take if they occur. This section also describes any
recommended monitoring and notes the poten-
tial for interference with laboratory tests.
Adverse Reactions
Another interesting feature of US format-
ting occurs with Section 6 Adverse Reactions.
An adverse reaction is an undesirable effect
reasonably associated with the use of a drug.
This section does not include all adverse events
observed, only those for which there is a basis
for a causal relationship between the drug and
the occurrence of the adverse event. This section
begins with a description of a drug’s overall
adverse reaction profile on the entire safety data-
base, followed by separate subsections:
• Clinical trial experience presents adverse
reactions identified in clinical studies.
Provide a description of the clinical trial data
source present a listing of common adverse
reactions at or above a specified rate fol-
lowed by a separate listing of less common
adverse reactions. For adverse reactions with
significant clinical implications, the listings
must be supplemented by additional detail
about the adverse reaction’s nature, fre-
quency, and severity.
• Immunogenicity information, if pertinent.
• Postmarketing experience lists adverse reac-
tions identified from domestic and foreign
spontaneous reporting. This listing must be
separate from the listing of adverse reactions
identified in the clinical trial experience.
Pregnancy and Lactation Labeling
Rule (PLLR)42,43,48
After a decade-long initiative and the issuance
of a proposed rule in 2008, the FDA published
the final Pregnancy and Lactation Labeling Rule
(PLLR) in December 2014 for prescription drug
and biologics’ pregnancy and lactation labeling
content and format. It also issued a guidance to
facilitate compliance with the new requirements.
The PLLR redefined the content and
reconfigured the format of these subsections in
PLLR Section 8, Use in Specific Populations (see
Figure 5-149).
• The rule merged the previous Pregnancy
and Labor and Delivery subsections into
Pregnancy, which should include a summary
of the risks of the drug during pregnancy,
details of any pregnancy registries, and
guidance to clinicians for decision mak-
ing and counseling. Information in this