[Federal Register Volume 74, Number 226 (Wednesday, November 25, 2009)]
[Rules and Regulations]
[Pages 61512-61516]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-28296]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. FDA-1977-N-0013] (formerly Docket No. 1977-N-0094L)
RIN 0910-AF36
Organ-Specific Warnings; Internal Analgesic, Antipyretic, and
Antirheumatic Drug Products for Over-the-Counter Human Use; Final
Monograph; Technical Amendment
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule; technical amendment.
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SUMMARY: The Food and Drug Administration (FDA) is amending a final
rule that appeared in the Federal Register of April 29, 2009 (74 FR
19385) (as amended in the Federal Register of June 30, 2009 (74 FR
31177). The final rule requires important new organ-specific warnings
and related labeling for over-the-counter (OTC) internal analgesic,
antipyretic, and antirheumatic (IAAA) drug products. The new labeling
informs consumers about the risk of liver injury when using
acetaminophen and the risk of stomach bleeding when using nonsteroidal
anti-inflammatory drugs (NSAIDs). This document is intended to clarify
some provisions in the final rule which may be unclear. Specifically,
this document addresses how blister cards can be labeled to comply with
the new required labeling, clarifies the length of time that the ``See
new warnings'' flag is required to appear in the labeling, and provides
some optional wording to clarify the liver injury warning on OTC
acetaminophen products containing multiple active ingredients.
DATES: Effective Date: This final rule is effective April 29, 2010.
Compliance Date: The compliance date for all products subject to
this final rule, including products with annual sales less than
$25,000, is April 29, 2010.
FOR FURTHER INFORMATION CONTACT: Arlene Solbeck, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, rm. 5411, Silver Spring, MD 20993-0002, 301-
796-2090.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is amending the final rule that was published in the Federal
Register of
[[Page 61513]]
April 29, 2009, (the April 29, 2009, final rule) which requires
important new organ-specific warnings and related labeling for OTC IAAA
drug products. The new labeling informs consumers about the risk of
liver injury when using acetaminophen and the risk of stomach bleeding
when using NSAIDs. After the April 29, 2009, final rule was published,
we received feedback from manufacturers stating that some of the
requirements in the final rule are unclear (Refs. 1 and 2). We are
amending the final rule to address these issues raised by the
submissions (see section II of this document). One issue involves the
liver injury and stomach bleeding warnings that must appear on
immediate container labeling. Another issue concerns the posting of a
``See new warnings'' flag on the principal display panel (PDP) of the
retail packaging. The third issue concerns the wording of the first
bulleted statement in the liver injury warning.
Publication of this document constitutes final action on the change
under the Administrative Procedures Act (5 U.S.C. 553). This technical
amendment merely clarifies the intent of the final rule with respect to
the three minor issues raised in the submissions. FDA therefore, for
good cause shown, has determined that notice and public comment are
unnecessary under 5 U.S.C. 553(b)(3)(B).
II. April 29, 2009, Final Rule Requirements Being Addressed in This
Document
A. Immediate Container Labeling
In the final rule, we require that the new liver injury and stomach
bleeding warnings appear on the outer and the immediate container of
the retail packaging, where applicable (Sec. 201.326(a)(1)(iii)(A),
(a)(1)(iv)(A)(1), (a)(1)(v)(A), (a)(2)(iii)(A), (a)(2)(iv)(A)(1), and
(a)(2)(v)(A) (21 CFR 201.326(a)(1)(iii)(A), (a)(1)(iv)(A)(1),
(a)(1)(v)(A), (a)(2)(iii)(A), (a)(2)(iv)(A)(1), and (a)(2)(v)(A)). We
received feedback from manufacturers seeking clarification of these
final rule requirements for blister card packaging (Ref. 1). We did not
intend for the final rule to require liver injury or stomach bleeding
warnings to appear on each blister unit on a blister card. Rather, we
believe it is acceptable that the appropriate warning appear on the
blister card in one place, as long as the warning stays intact and
readable when drug product is removed from the blister card. Therefore,
in this document, we are stating explicitly that the liver injury and
stomach bleeding warnings are not required to appear on each blister
unit of a blister card, as long as the appropriate warning appears on
the blister card and remains intact and readable when drug is removed
from the blister card. These modifications appear in Sec.
201.326(a)(1)(iii)(A), (a)(1)(iv)(A)(1), (a)(1)(v)(A), (a)(2)(iii)(A),
(a)(2)(iv)(A)(1), and (a)(2)(v)(A) in the regulatory text of this
document.
We also received feedback that certain immediate containers, such
as stick packs and sachets, also present space limitations for labeling
and that we should not require the liver injury and stomach bleeding
warnings to appear on these immediate container packages (Ref 1). We do
not agree that these types of immediate containers should be exempt
from the requirements in the final rule. Although these packages have
limited labeling space, we believe that there is adequate space to
accommodate the required warnings on these types of packages. We are
also concerned that consumers may routinely remove these packages from
the outer carton and, therefore, fail to see the liver injury and
stomach bleeding warnings if they are only printed on the carton. For
these reasons, we are not exempting these types of immediate containers
from the final rule requirements.
B. ``See New Warnings'' Flag
In the April 29, 2009, final rule, we require a ``See new
warnings'' flag on the PDP of all OTC drug products containing
acetaminophen or NSAIDs to advise consumers of the new required
warnings. In the final rule, we state that ``we will require that the
`See New Warnings' flag appear on the PDP for one year after the final
rule is published, rather than for the 6 or 9 months suggested by the
submission'' (74 FR 19385 at 19388). We explained that ``we continue to
believe that educating consumers about the risks associated with OTC
IAAA drug products is very important and more likely to be successful
if the flag remains on products for 1 year'' (74 FR 19385 at 19388
through 19389). In Sec. 201.326(b) (21 CFR 201.326(b)), the final rule
states: ``The labeling of any drug product subject to this section that
is initially introduced or initially delivered for introduction into
interstate commerce before the effective date and within 12 months
after the effective date of the final rule must bear on its PDP, as
defined in Sec. 201.60, the statement `See new warnings
information.'''
We intended this provision to require that the ``See new warnings''
statement appear on the PDPs of all OTC drug products containing
acetaminophen or NSAIDs that are introduced into interstate commerce by
the effective date of the final rule (i.e., by April 29, 2010). We did
not intend to require the ``See new warnings'' statement for those
products that are introduced into interstate commerce after the final
rule effective date. We also intended the provision to require that the
statement remain on the label for at least 1 year from the time the
product is introduced into interstate commerce. We did not intend to
require that the statement remain on the label for any longer than the
1-year period from the time of introduction into interstate commerce.
For example, if the ``See new warnings'' flag is included on the PDP of
a product introduced into interstate commerce 6 months after
publication of the final rule (i.e., October 29, 2009), then the flag
must remain on the PDP for a full year (i.e., until October 29, 2010).
To make this requirement clear, we are modifying Sec. 201.326(b) in
the regulatory text of this document.
C. Liver Injury Warning for OTC Acetaminophen Products Containing
Multiple Active Ingredients
In the April 29, 2009, final rule, we require a liver injury
warning for all OTC drug products containing acetaminophen. The
introductory sentence and first bulleted statement of this warning
state: ``This product contains acetaminophen. Severe liver damage may
occur if you take [bullet] more than the [insert maximum number of
daily dosage units] in 24 hours, which is the maximum daily amount * *
*''. Our intention was that the warning would prevent consumers from
taking more than 4 grams (g) of an OTC acetaminophen product daily, the
proposed maximum safe daily dose for OTC acetaminophen. After the final
rule was published, we received feedback from manufacturers of OTC
acetaminophen products who were concerned that consumers may be
confused about the warning on OTC acetaminophen containing multiple
active ingredients (e.g., cold-cold/analgesic combination products)
(Refs. 1 and 2). For some combination products, the maximum number of
daily dosage units may be limited by an active ingredient other than
acetaminophen in the products. In such cases, the maximum number of
daily dosage units result in a maximum daily dose of acetaminophen
which is significantly below 4 g. To clarify that the maximum number of
daily dosage units may not be the maximal daily dose of acetaminophen,
we are allowing the optional statement ``for this product'' at the end
of the first bulleted statement: ``more than [insert maximum number of
daily dosage units] in 24 hours, which
[[Page 61514]]
is the maximum daily amount'' [optional: ``for this product'']. We
agree with manufacturers that this revision will clarify the warning
for OTC acetaminophen products containing multiple active ingredients.
III. Request for Enforcement Discretion
We received feedback requesting that we exercise enforcement
discretion for manufacturers of OTC combination acetaminophen products
so that they could revise the first bulleted statement of the liver
injury warning to clarify that the maximum number of daily dosage units
may not be the maximal daily dose of acetaminophen for those products
(Ref. 2). As discussed in section II.C of this document, we are
allowing the optional statement ``for this product'' at the end of the
first bulleted statement: ``more than [insert maximum number of daily
dosage units] in 24 hours, which is the maximum daily amount.'' The
request asked us to exercise enforcement discretion until we revise
this bulleted statement in the final rule. Because we are amending this
bulleted statement in this document, the request that we exercise
enforcement discretion is no longer applicable.
IV. Analysis of Impacts
We have examined the impacts of this rule under Executive Order
12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and the
Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). We believe that this
rule is not a significant regulatory action under the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Our April 29, 2009, final rule requires important
new organ-specific warnings (i.e., liver injury and stomach bleeding
warnings) and related labeling for OTC drug products containing
acetaminophen and NSAIDs to advise consumers of potential risks and
when to consult a doctor (74 FR 19385). We are amending the final rule
in this document to clarify some of the labeling requirements specified
in the final rule. Three amendments are being made. One amendment
specifies that manufacturers of OTC acetaminophen and NSAID drug
products are not required to put the liver injury or stomach bleeding
warning on each blister unit of a blister card as long as the
appropriate warning appears on the blister card and remains intact and
readable when drug is removed from the blister card (Sec.
201.326(a)(1)(iii)(A), (a)(1)(iv)(A)(1), (a)(1)(v)(A), (a)(2)(iii)(A),
(a)(2)(iv)(A)(1), and (a)(2)(v)(A)). The second amendment specifies
that the ``See new warnings'' flag (Sec. 201.326(b)) must remain on
the label for at least 1 year from the time the manufacturer puts the
statement on the PDP. The third amendment clarifies the liver injury
warning on OTC acetaminophen products containing multiple active
ingredients. We examined the impacts of the amended labeling
requirements described in this document when we developed the April 29,
2009, final rule. We determined that the final rule would not have a
significant impact on a substantial number of small entities. Because
this amendment does not add any new requirements that were not
considered in developing the final rule, we do not believe this rule
will have a significant economic impact on a substantial number of
small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $133 million, using the most current (2008) Implicit
Price Deflator for the Gross Domestic Product. We do not expect the
final rule as amended to result in any 1-year expenditure that would
meet or exceed this amount.
V. Paperwork Reduction Act of 1995
We conclude that the labeling requirements in this document are not
subject to review by the Office of Management and Budget because they
do not constitute a ``collection of information'' under the Paperwork
Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the labeling
statements are a ``public disclosure of information originally supplied
by the Federal government to the recipient for the purpose of
disclosure to the public'' (5 CFR 1320.3(c)(2)).
VI. Environmental Impact
We have determined under 21 CFR 25.31(a) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VII. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. Section 4(a) of the Executive order
requires agencies to ``construe * * * a Federal statute to preempt
State law only where the statute contains an express preemption
provision or there is some other clear evidence that the Congress
intended preemption of State law, or where the exercise of State
authority conflicts with the exercise of Federal authority under the
Federal statute.'' The sole statutory provision giving preemptive
effect to the final rule is section 751 of the Federal Food, Drug, and
Cosmetic Act (21 U.S.C. 379r).
We believe that we have complied with all of the applicable
requirements under the Executive order and have determined that the
preemptive effects of this rule are consistent with Executive Order
13132.
VIII. References
The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852 and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
1. FDA-1977-N-0013-0039.
2. FDA-1977-N-0013-0040.
List of Subjects in 21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
201, (as added in the Federal Registers of April 29, 2009, and amended
June 30, 2009), is amended as follows:
PART 201--LABELING
0
1. The authority citation for 21 CFR part 201 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360,
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
0
2. Section 201.326, (as added at 74 FR 19385, April 29, 2009, and
amended at 74 FR 31177, June 30, 2009) is further amended by revising
paragraphs (a)(1)(iii)(A), (a)(1)(iv)(A)(1), (a)(1)(v)(A),
(a)(2)(iii)(A), (a)(2)(iv)(A)(1), (a)(2)(v)(A), and (b) to read as
follows:
[[Page 61515]]
Sec. 201.326 Over-the-counter drug products containing internal
analgesic/antipyretic active ingredients; required warnings and other
labeling.
(a) * * *
(1) * * *
(iii) * * *
(A) The liver warning states ``Liver warning [heading in bold
type]: This product contains acetaminophen. Severe liver damage may
occur if you take [bullet] more than [insert maximum number of daily
dosage units] in 24 hours, which is the maximum daily amount [optional:
`for this product'] [bullet] with other drugs containing acetaminophen
[bullet] 3 or more alcoholic drinks every day while using this
product''. This ``Liver'' warning must be the first warning under the
``Warnings'' heading. For products that contain both acetaminophen and
aspirin, this ``Liver'' warning must appear after the ``Reye's
syndrome'' and ``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A)
and (c)(5)(ii)(B) and before the ``Stomach bleeding'' warning in
paragraph (a)(2)(iii)(A) of this section. If there is an outer and
immediate container of a retail package, this warning must appear on
both the outer and immediate containers. If the immediate container is
a blister card, the warning must appear on the blister card and remain
intact and readable when drug product is removed from the blister card.
The warning does not need to be included on each blister unit.
* * * * *
(iv) * * *
(A) * * *
(1) The liver warning states ``Liver warning [heading in bold
type]: This product contains acetaminophen. Severe liver damage may
occur if your child takes [bullet] more than 5 doses in 24 hours, which
is the maximum daily amount [optional: `for this product'] [bullet]
with other drugs containing acetaminophen''. This ``Liver'' warning
must be the first warning under the ``Warnings'' heading. If there is
an outer and immediate container of a retail package, this warning must
appear on both the outer and immediate containers. If the immediate
container is a blister card, the warning must appear on the blister
card and remain intact and readable when drug product is removed from
the blister card. The warning is not required to be included on each
blister unit.
* * * * *
(v) * * *
(A) The liver warning states ``Liver warning [heading in bold
type]: This product contains acetaminophen. Severe liver damage may
occur if [bullet] adult takes more than [insert maximum number of daily
dosage units] in 24 hours, which is the maximum daily amount [optional:
`for this product'] [bullet] child takes more than 5 doses in 24 hours
[bullet] taken with other drugs containing acetaminophen [bullet] adult
has 3 or more alcoholic drinks everyday while using this product.'' If
there is an outer and immediate container of a retail package, this
warning must appear on both the outer and immediate containers. If the
immediate container is a blister card, the warning must appear on the
blister card and remain intact and readable when drug product is
removed from the blister card. The warning is not required to be
included on each blister unit.
* * * * *
(2) * * *
* * * * *
(iii) * * *
(A) The stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is higher if you [bullet] are age
60 or older [bullet] have had stomach ulcers or bleeding problems
[bullet] take a blood thinning (anticoagulant) or steroid drug [bullet]
take other drugs containing prescription or nonprescription NSAIDs
(aspirin, ibuprofen, naproxen, or others) [bullet] have 3 or more
alcoholic drinks every day while using this product [bullet] take more
or for a longer time than directed''. This ``Stomach bleeding'' warning
must appear after the ``Reye's syndrome'' and ``Allergy alert''
warnings in Sec. 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For products
that contain both acetaminophen and aspirin, the acetaminophen
``Liver'' warning in paragraph (a)(1)(iii) of this section must appear
before the ``Stomach bleeding'' warning in this paragraph. If there is
an outer and immediate container of a retail package, this warning must
appear on both the outer and immediate containers. If the immediate
container is a blister card, the warning must appear on the blister
card and remain intact and readable when drug product is removed from
the blister card. The warning is not required to be included on each
blister unit.
* * * * *
(iv) * * *
(A) * * *
(1) The stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is higher if your child [bullet]
has had stomach ulcers or bleeding problems [bullet] takes a blood
thinning (anticoagulant) or steroid drug [bullet] takes other drugs
containing prescription or nonprescription NSAIDs (aspirin, ibuprofen,
naproxen, or others) [bullet] takes more or for a longer time than
directed''. The ``Stomach bleeding'' warning must appear after the
``Reye's syndrome'' and ``Allergy alert'' warnings in Sec.
201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an outer and
immediate container of a retail package, this warning must appear on
both the outer and immediate containers. If the immediate container is
a blister card, the warning must appear on the blister card and remain
intact and readable when drug product is removed from the blister card.
The warning is not required to be included on each blister unit.
* * * * *
(v) * * *
(A) The Stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains an NSAID, which may cause
severe stomach bleeding. The chance is higher if the user [bullet] has
had stomach ulcers or bleeding problems [bullet] takes a blood thinning
(anticoagulant) or steroid drug [bullet] takes other drugs containing
prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen,
or others) [bullet] takes more or for a longer time than directed
[bullet] is age 60 or older [bullet] has 3 or more alcoholic drinks
everyday while using this product''. The ``Stomach bleeding'' warning
must appear after the ``Reye's syndrome`` and ``Allergy alert''
warnings in Sec. 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). If there is an
outer and immediate container of a retail package, this warning must
appear on both the outer and immediate containers. If the immediate
container is a blister card, the warning must appear on the blister
card and remain intact and readable when drug product is removed from
the blister card. The warning is not required to be included on each
blister unit.
* * * * *
(b) New warnings information statement. The labeling of any drug
product subject to this section that is initially introduced or
initially delivered for introduction into interstate commerce before or
on April 29, 2010, must bear on its PDP, as defined in Sec. 201.60,
the statement ``See new warnings information''. This statement must
appear highlighted (e.g., fluorescent or color contrast) or in bold
type, be in lines generally parallel to the base on which the package
rests as it is designed to be displayed, and be in one
[[Page 61516]]
of the following sizes, whichever is greater:
(1) At least one-quarter as large as the size of the most prominent
printed matter on the PDP, or
(2) At least as large as the size of the ``Drug Facts'' title, as
required in Sec. 201.66(d)(2). The new warnings information statement
must remain on the PDP of the drug product for at least 1 year from the
date the product is initially introduced into interstate commerce.
* * * * *
Dated: November 17, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-28296 Filed 11-24-09; 8:45 am]
BILLING CODE 4160-01-S