Document ID: FDA-1977-N-0013-0041
Agency: fda
Document Type: Rule
Title: Organ-Specific Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Final Monograph; Technical Amendment
Posted Date: 2009-11-25T05:00Z

[Federal Register: November 25, 2009 (Volume 74, Number 226)]
[Rules and Regulations]               
[Page 61512-61516]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25no09-7]                         

=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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