Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use — Small Entity Compliance Guide

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Organ-Specific Warnings: Internal
Analgesic, Antipyretic, and
Antirheumatic Drug Products for
Over-the-Counter Human Use —
Small Entity Compliance Guide
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2010
OTC

Guidance for Industry
Organ-Specific Warnings: Internal
Analgesic, Antipyretic, and
Antirheumatic Drug Products for
Over-the-Counter Human Use —Small
Entity Compliance Guide
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
July 2010
OTC

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	SUMMARY OF THE REGULATION AND THIS GUIDANCE................................ 1
III. 	QUESTIONS AND ANSWERS....................................................................................... 4

Contains Nonbinding Recommendations
Guidance for Industry1
Organ-Specific Warnings; Internal Analgesic, Antipyretic,
and Antirheumatic Drug Products for Over-the-Counter
Human Use — Small Entity Compliance Guide
This guidance represents 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.
You can use an alternative approach if the 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.
I. 	INTRODUCTION
This guidance is intended to help small businesses understand and comply with FDA’s organ-
specific labeling regulation for over-the-counter (OTC) internal analgesic, antipyretic, and
antirheumatic (IAAA) drug products. The regulation requires IAAA manufacturers to label their
products with specific warnings and related information to alert consumers about potential liver
injury and stomach bleeding associated with IAAA drug products. Manufacturers must be in
compliance with the final rule beginning on April 29, 2010. The Food and Drug Administration
(FDA) has prepared this guidance in accordance with section 212 of the Small Business
Regulatory Fairness Act (Public Law 104-121).
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.
II. 	SUMMARY OF THE REGULATION AND THIS GUIDANCE
In the Federal Register of December 26, 2006 (71 FR 77314), the FDA published a proposed
rule on the requirements for compliance with FDA’s organ-specific labeling regulation for OTC
IAAA drug products. In the Federal Register of April 29, 2009 (74 FR 19385), the FDA
1 This small business compliance guide was developed by the Office of Nonprescription Products in the Center for
Drug Evaluation and Research, FDA.
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published the final rule (2009 final rule), codified at 21 CFR 201.326.2 On November 25, 2009,
FDA published technical amendments to clarify several points in response to industry feedback.
The 2009 final rule changed the labeling requirements for OTC IAAA drug products by adding
new warnings about liver injury for those using acetaminophen, and stomach bleeding for those
using nonsteroidal anti-inflammatory drugs (NSAIDs). The rule also makes related changes to
the principal display panel (PDP), ingredient listings, and other labeling information to highlight
the presence of acetaminophen or NSAIDs and draw attention to the organ-specific warnings.
Table 1 summarizes the requirements in the final rule. The specific language to be used in
required warnings is shown in Table 2. 	You also will need to refer directly to the final rule for
additional formatting instructions, such as type sizes, that are not described in this guidance.
2 The regulation published in the Code of Federal Regulations (CFR) will reflect both the final rule and the technical
amendments. This regulation replaces the alcohol warning that was previously in 21 CFR 201.322; the alcohol
warning is now in 21 CFR 203.326(a)(1)(iii)(A).
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Table 1: Summary of Labeling Requirements
Acetaminophen 	• 	Requirements apply to any OTC IAAA product
Products 	containing acetaminophen, either alone or in
(21 CFR 201.326(a)(1)) 	combination with other active ingredients.
• 	“Acetaminophen” must be included in the statement
of identity on the principal display panel (PDP).
• 	A “see new warning information” flag must appear
on the PDP of all products that were first marketed
on or before April 29, 2010, and must continue to be
used for 1 year after the flag is first added to the
PDP.
• 	The “Warnings” section of Drug Facts labeling must
include a “liver warning,” and related warnings
against using more than one acetaminophen product
at the same time, and “ask a doctor” warnings for
persons who have liver disease or are taking
warfarin.
• 	If a retail product has both an outer and inner
package/container, the “liver warning” must appear
on both.
• 	Different warning language is used for products
labeled only for adults, only for children under 12
years old, or for adults and children under 12 years
old.
• 	Specific language to be used in required warnings is
shown in Table 2 of this guidance.
• 	Required labeling also must follow the instructions
on format and placement detailed in the regulations
(e.g., bolding/highlighting, type size, order of
warnings).
NSAID products 	• 	Applies to any OTC IAAA product containing any
(21 CFR 201.326(a)(2)) 	NSAID active ingredient, either alone or in combination
with other active ingredients.
(NSAIDs include, but 	• 	The word “NSAID” must be included in the statement of
are not limited to, the 	identity on the PDP, either as part of the ingredient name
following active 	(e.g., “ibuprofen (NSAID)”, or after the intended action
ingredients: 	of the NSAID ingredient (e.g., “Pain Reliever
aspirin, carbaspirin 	(NSAID)”).
calcium, choline 	• 	A “see new warning information” flag must appear on
salicylate, ibuprofen, 	the PDP of all products that were first marketed on or
ketoprofen, magnesium 	before April 29, 2010, and must continue to be used for
salicylate, naproxen 	1 year after the flag is first added to the PDP.
sodium, and sodium 	• 	The “Ingredients” section of the label must contain the
salicylate.) 	term “NSAID*” after the NSAID ingredient, with an
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asterisk statement at the end of the ingredient list that
states “*nonsteroidal anti-inflammatory drug.”
• 	The “Warnings” section of Drug Facts labeling must
include a “stomach bleeding warning” and related “ask a
doctor” warnings.
• 	If a retail product has both an outer and inner
package/container, the “stomach bleeding warning” must
appear on both.
• 	Different warning language is used for products labeled
only for adults, only for children under 12 years old, or
for adults and children under 12 years old.
• 	For products labeled only for children under 12 years
old, the “Directions” section of the label must state “this
product does not contain directions or complete
warnings for adult use.”
• 	Specific language to be used in required warnings is
shown in Table 2 of this guidance.
• 	Required labeling also must follow the instructions on
format and placement detailed in the regulations (e.g.,
bolding/highlighting, type size, order of warnings).
III. 	QUESTIONS AND ANSWERS
Question: 	Is the product I manufacture subject to this rule?
Answer: 	This rule applies to all OTC IAAA drug products that contain acetaminophen or
any NSAID, either as a single active ingredient or in combination with any other
active ingredients. This rule applies to OTC IAAA drug products marketed under
an OTC monograph or an approved new drug application (NDA) or abbreviated
new drug application (ANDA). This rule does not apply to topical drug products
that contain acetaminophen or NSAIDs.
Question: 	How do I know if an active ingredient in my product is an NSAID?
Answer: 	NSAIDs are analgesic/antipyretic ingredients used to relieve pain, fever, and/or
inflammation. They include, but are not limited to, aspirin, carbaspirin calcium,
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen sodium,
and sodium salicylate. If you are uncertain whether an ingredient is an NSAID,
ask the FDA Contact shown below.
Question: 	I manufacture an OTC IAAA product with annual sales of less than $25,000. Is
my drug product subject to this rule?
Answer: 	Yes. Small businesses are not exempt from this rule.
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Question: 	When must I be in compliance with this rule? Can I still distribute inventory
that was labeled, but not shipped, before the new requirements became
effective?
Answer: 	This rule (including the November 25, 2009, technical amendments) became
effective on April 29, 2010. After that time, all products that you introduce or deliver
for introduction into interstate commerce must be labeled in compliance with this
rule.
Question: 	What will happen if I fail to comply with this rule by April 29, 2010?
Answer: 	Beginning April 29, 2010, your drug product will be misbranded under section
502(f)(2) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 352(f)(2)), and
subject to regulatory action.
Question: 	Does the regulation specify the exact language I must use for warnings and other
required label statements?
Answer: 	Table 2 shows the exact language that must be used for the required warning
statements. The rule also specifies exact language for some other required
statements (e.g., statement of identity, ingredient lists, directions); these are
indicated by quotation marks in Table 1.
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Table 2: Required Wording for Warnings
Acetaminophen 	NSAIDs
Products
Labeled for
Adults Only
“Liver warning: This product
contains acetaminophen.
Severe liver damage may occur
if you take ● more than [insert
maximum number of daily
dosage units] in 24 hours,
which is the maximum daily
amount [optional: ‘for this
product’] ● with other drugs
containing acetaminophen ● 3
or more alcoholic drinks every
day while using this product.”
“Do not use with any other
drug containing acetaminophen
(prescription or non-
prescription). If you are not
sure whether a drug contains
acetaminophen, ask a doctor or
pharmacist.”
“Ask a doctor before use if you
have liver disease.”
“Ask a doctor or pharmacist
before use if you are taking the
blood thinning drug warfarin.”
[Note: this statement does not
apply to combination products
that contain acetaminophen and
NSAIDs, which are already
required to include a warning
about blood thinning
drugs under the stomach
bleeding warning
for NSAIDs. ]
“Stomach bleeding warning:
This product contains an NSAID,
which may cause severe stomach
bleeding. The chance is higher if
you ● are age 60 or older ● have
had stomach ulcers or bleeding
problems ● take a blood thinning
(anticoagulant) or steroid drug
● 	take other drugs containing
prescription or nonprescription
NSAIDs (aspirin, ibuprofen,
naproxen, or others) ● have 3 or
more alcoholic drinks every day
while using this product ● take
more or for a longer time than
directed.”
“Ask a doctor before use if
● stomach bleeding warning
applies to you ● you have a
history of stomach problems, such
as heartburn ● you have high
blood pressure, heart disease, liver
cirrhosis, or kidney disease ● you
are taking a diuretic.”
“Stop use and ask a doctor if you
experience any of the following
signs of stomach bleeding: 	● feel
faint 	● vomit blood 	● 	have
bloody or black stools 	● 	have
stomach pain that does not get
better.”
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Acetaminophen 	NSAIDs
Products labeled
only for children
under 12 years of
age
“Liver warning: This product
contains acetaminophen.
Severe liver damage may occur
if your child takes ● more than
5 doses in 24 hours, which is
the maximum daily amount
● with other drugs containing
acetaminophen.”
“Do not use with any other
drug containing acetaminophen
(prescription or non-
prescription). If you are not
sure whether a drug contains
acetaminophen, ask a doctor or
pharmacist.”
“Ask a doctor before use if
your child has liver disease.”
“Ask a doctor or pharmacist
before use if your child is
taking the blood thinning drug
warfarin.” [Note: this
statement does not apply to
combination products that
contain acetaminophen and
NSAIDs, which
are already required to include
a warning about blood thinning
drugs under the stomach
bleeding warning for NSAIDs.]
“Stomach bleeding warning:
This product contains an NSAID,
which may cause severe stomach
bleeding. The chance is higher if
your child 	● 	has had stomach
ulcers or bleeding problems
● 	takes a blood thinning
(anticoagulant) or steroid drug
● 	takes other drugs containing
prescription or nonprescription
NSAIDs (aspirin, ibuprofen,
naproxen, or others) 	● takes
more or for a longer time
than directed.”
“Ask a doctor before use if
● stomach bleeding warning
applies to your child 	● 	child has
a history of stomach problems,
such as heartburn 	● child has not
been drinking fluids 	● 	child has
lost a lot of fluid due to vomiting
or diarrhea 	● child has high
blood pressure, heart disease, liver
cirrhosis, or kidney disease
● child is taking a diuretic.”
“Stop use and ask a doctor if
child experiences any of the
following signs of stomach
bleeding: ● feels faint 	● vomits
blood ● 	has bloody or black
stools ● 	has stomach pain that
does not get better.”
Products Labeled 	“Liver warning: This 	‘Stomach bleeding warning:
for Adults and 	product contains 	This product contains an
Children Under 	acetaminophen. Severe liver 	NSAID, which may cause
12 Years of Age 	damage may occur if ● adult
takes more than [insert
maximum number of daily
dosage units] in 24 hours,
which is the maximum daily
amount ● child takes more
than 5 doses in 24 hours
severe stomach bleeding. The
chance is higher if the user
● 	has had stomach ulcers or
bleeding problems 	● 	takes a
blood thinning (anticoagulant)
or steroid drug ● 	takes other
drugs containing prescription
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Acetaminophen 	NSAIDs
● taken with other drugs
containing acetaminophen ●
adult has 3 or more alcoholic
drinks everyday while using
this product.”
“Do not use with any other drug
containing acetaminophen
(prescription or non-
prescription). If you are not
sure whether a drug contains
acetaminophen, ask a doctor or
pharmacist.”
“Ask a doctor before use if the
user has liver disease.”
“Ask a doctor or pharmacist
before use if the user is taking
the blood thinning drug
warfarin.” [Note: 	this
statement does not apply to
combination products that
contain acetaminophen and
NSAIDs, which are already
required to include a warning
about blood thinning
drugs under the stomach
bleeding warning for NSAIDs.]
or nonprescription NSAIDs
(aspirin, ibuprofen, naproxen, or
others) 	● 	takes more or for a
longer time than directed 	● 	is
age 60 or older 	● has 3 or more
alcoholic drinks everyday while
using this product.”
“Ask a doctor before use if
● 	stomach bleeding warning
applies to user 	● 	user has
history of stomach problems,
such as heartburn 	● 	user has
high blood pressure, heart
disease, liver cirrhosis, or kidney
disease
● user takes a diuretic 	● 	user
has not been drinking fluids
● user has lost a lot of fluid due
to vomiting or diarrhea.”
“Stop use and ask a doctor if user
experiences any of the following
signs of stomach bleeding:
● 	feels faint 	● 	vomits blood
● 	has bloody or black stools
● 	has stomach pain that does not
get better.”
Question: 	Are the required warnings different for children and adults?
Answer: 	Yes. Different language is used for products labeled for adults only, products
labeled only for children under 12 years of age, and products labeled for both
adults and children under 12 years old. Please refer to Table 2 above for details.
Question: 	Does the regulation also contain instructions about the format and/or
appearance of warnings and other required labeling?
Answer: 	Yes. You must refer to the regulation for specific instructions about the
appearance, format, and placement of the required labeling (e.g.,
bolding/highlighting, type size and prominence, order of acetaminophen and/or
NSAID warnings, and other applicable warnings). Your labeling also must
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comply with other applicable labeling requirements under the OTC monograph
for IAAA drugs as well as the general labeling regulations for all OTC drugs in
21 CFR part 201, subpart C, including the “Drug Facts” labeling requirements in
21 CFR 201.66.
Question: 	The retail package of my product has both an outer carton and an immediate
container. Are the liver injury and stomach bleeding warnings required on
the outer carton and the immediate container?
Answer: 	Yes, these warnings must appear on both the outer container (e.g., carton) and the
immediate (inner) container of a retail package. If the immediate container is a
blister card, the warnings must appear on the blister card and remain intact and
readable when the drug product is removed from the blister card. The warnings
do not need to be included on each blister unit.
Question: 	The retail package of my product consists of multi-dose blister cards inside a
carton. What must I do to comply with the requirements to put the liver or
stomach bleeding warning on the “immediate container”?
Answer: 	Each blister card is considered a separate immediate container. In this case, the
appropriate warning must appear on each blister card and remain intact and
readable when individual doses of the product are removed from the blister card.
This point was clarified in the technical amendments published on November 25,
2009.
Question: 	Apart from blister cards, are there any exceptions or special provisions for
other kinds of immediate containers that have limited space for labeling,
such as stick packs and sachets?
Answer: 	No. FDA believes that these types of immediate containers can accommodate the
required warnings. We also are concerned that consumers may routinely remove
these packages from the outer carton and fail to see the liver injury and stomach
bleeding warnings if they are only printed on the carton.
Question: 	What products are required to have the “see new warning information” flag
on the PDP? How long must the flag remain on the PDP?
Answer: 	The “see new warning information” must appear on the PDP of all OTC
acetaminophen- or NSAID-containing IAAA products first marketed on or before
April 29, 2010, and remain on the product for at least 1 year after the product is
initially introduced into interstate commerce. Products newly introduced after
that date do not require the flag, but must have all other organ-specific labeling
required by this rule.
Question: 	Do I need preapproval from FDA for labeling changes required by this rule?
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Answer: 	For products marketed under the IAAA monograph, you do not need preapproval of
labeling changes. For products marketed under NDAs and ANDAs, you will need to
submit a CBE 0 (change to be effective immediately) labeling supplement.
Question: 	Do I need to list my revised labeling with FDA?
Answer: 	Yes. This change in labeling should be submitted to FDA through the drug listing
process. Any updates must be submitted every June and December (section 510(j)(2)
of the Federal Food, Drug, and Cosmetic Act; 21 CFR 207.21(b)). However,
registrants (and, if applicable, private label distributors) are encouraged to submit
updates through the registration and listing system more frequently as changes occur.
Information on this process can be found at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegi
strationandListing/ucm078801.htm.
Question: 	Does this rule apply to topical IAAA products?
Answer: 	No, only internal (oral) OTC IAAA products are affected by this rule.
Question: 	If I have questions about whether the drug product I manufacture is subject
to this rule, how to comply with the rule, or any related issues, whom should
I contact at FDA?
Answer: 	You should contact Arlene Solbeck, Center for Drug Evaluation and Research, Food
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, MS 5411, Silver
Spring, MD 20993, 301–796–2090.
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