Organ-Specific Warnings; Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Final Monograph; Corrections, 31177-31180 [E9-15403]
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Federal Register / Vol. 74, No. 124 / Tuesday, June 30, 2009 / Rules and Regulations
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
VI. Analysis of Impacts with the
following text:
Food and Drug Administration
VI. Analysis of Impacts
We have examined the impacts of the final
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 final 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. 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 $130 million, using the most
current (2007) Implicit Price Deflator for the
Gross Domestic Product. We do not expect
this final rule to result in any 1-year
expenditure that would meet or exceed this
amount.
We conclude that this final rule is
consistent with the principles set out in
Executive Order 12866 and in these two
statutes. As discussed in this section, we
have determined that this final rule will not
have a significant economic impact on a
substantial number of small entities, but we
lack sufficient information on the
distribution of the burden to certify that it is
not significant.
The impact on industry, in terms of costs
of compliance, are presented in section VI.B
of this document and summarized in table 2
of this document. The societal costs and
benefits of this final rule are summarized in
table 3 of section VI.B of this document.
21 CFR Part 201
[Docket No. FDA–1977–N–0013] (formerly
Docket No. 1977N–0094L)
RIN 0910–AF36
Organ-Specific Warnings; Internal
Analgesic, Antipyretic, and
Antirheumatic Drug Products for Overthe-Counter Human Use; Final
Monograph; Corrections
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule, corrections.
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SUMMARY: The Food and Drug
Administration (FDA) is correcting a
final rule that appeared in the Federal
Register of April 29, 2009. The
document requires important new
organ-specific warnings and related
labeling for over-the-counter (OTC)
internal analgesic, antipyretic, and
antirheumatic 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 antiinflammatory drugs (NSAIDs). The
document was published with an
incorrect Analysis of Impacts section
and omitted a reference from the
reference section of the final rule. The
document was also published with an
error in the codified text regarding the
introductory sentence to the stomach
bleeding warning for NSAIDs. This
document replaces the incorrect
Analysis of Impacts section with the
correct Analysis of Impacts section,
adds a reference to the reference section
of the final rule, and corrects the
codified text.
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, Silver Spring,
MD 20993, 301–796–2090.
SUPPLEMENTARY INFORMATION: In FR Doc.
E9–9684, published on April 29, 2009
(74 FR 19385), make the following
corrections:
1. Beginning on page 19401 and
ending on page 19406, replace section
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A. Need for the Rule
In 2002, an FDA Advisory Committee
recommended changes to the labeling of OTC
acetaminophen and NSAID drug products to
better inform consumers about the active
ingredients and possible side effects caused
by improper use. Current labels provide
inadequate information about the risk of
improper use. Although we consider
acetaminophen to be safe and effective when
labeled and used correctly, using too much
can lead to liver injury and death. Similarly,
the use of NSAIDs can lead to stomach
bleeding and kidney damage. The number of
cases of injury reported is a very low
percentage of the total use of OTC
acetaminophen and NSAID drug products.
For many people, the risks are quite low
because they use these products only
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31177
occasionally. The risks may be greater for
people who use these products more
frequently and/or do not follow the labeling
information on the package. The risk of
injury may be increased for certain
populations and under certain conditions of
use.
There are multiple reasons for
unintentional acetaminophen overdoses.
First, acetaminophen is an active ingredient
in a wide variety of both OTC and
prescription drug products. For prescription
products, the immediate container may not
state that the product contains
acetaminophen or state the maximum daily
dose limit. Consumers may often fail to
recognize the presence and amount of
acetaminophen ingredients in OTC and
prescription drug products. This lack of
knowledge can result in a person using two
different products containing acetaminophen
simultaneously. Moreover, many consumers
are unaware that exceeding the
recommended dosage for acetaminophen can
lead to unintentional overdosing and cause
potential harm. Based on the evidence
discussed in this document, we find that
there is sufficient incidence of liver injury
associated with acetaminophen to warrant
new labeling, and that without the new
labeling, acetaminophen products would no
longer be considered generally recognized as
safe and effective and not misbranded for
OTC use.
Results of several large-scale clinical
studies performed in the United States and
in other countries have established that the
use of NSAIDs is an important risk factor for
serious stomach adverse events, especially
bleeding. The risk is higher for certain
populations. Based on the evidence
discussed in this document, we further find
that NSAIDs increase the risk for stomach
adverse events and that, without a new
stomach bleeding warning in the labeling for
NSAIDs, the products would no longer be
considered generally recognized as safe and
effective and not misbranded for OTC use.
The purpose of this final rule is to amend
our OTC drug labeling regulations to include
new warnings and other labeling
requirements to advise consumers of
potential risks and when to consult a doctor
(see table 1 in section II.B.2 of this
document). We are also removing the alcohol
warning in § 201.322 and incorporating new
alcohol-related warnings and other labeling
for all OTC acetaminophen and NSAID drug
products. We are requiring certain warning
information targeted to age-specific
populations. In addition, we are requiring
that the presence of acetaminophen or any
NSAID would appear prominently on a
product’s principal display panel (PDP).
Without this final rule, the labeling of these
products will not provide sufficient warnings
of risks to consumers.
B. Impact of the Rule
We contracted Eastern Research Group,
Inc. (ERG) to assess the costs and benefits of
the proposed rule on which this final rule is
based. The full ERG report (Ref. 56),
including details on methods, assumptions,
cost calculations, and findings, is on file in
the Division of Dockets Management (71 FR
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77314 at 77341). The most significant change
from the proposal is the requirement that
warning statements appear on both the outer
container and on the immediate container.
We, therefore, contracted with ERG to
perform an updated store survey and analysis
to assess the costs of the changes in this final
rule. ERG’s 2008 ‘‘Addendum to the Cost
Benefit Analysis: Final Internal Analgesic,
Antipyretic, and Antirheumatic Drug
Products Rulemaking’’ (Ref. 57) is also on file
with the Division of Dockets Management.
Most of ERG’s methods, assumptions and
analysis used for the proposed rule remain
unchanged for this final rule. The following
is a summary of ERG’s findings.
1. Cost of Compliance
Manufacturers and marketers of OTC
acetaminophen and NSAID drug products
would incur one-time costs to revise affected
product labeling to comply with this rule. We
estimated costs for a major labeling revision
using a pharmaceutical labeling revision cost
model. We used an implementation period of
12 months. The labeling model is described
in detail in Appendix A of the ERG report
cited in the 2006 proposed rule.
To develop the original model, we and
ERG interviewed pharmaceutical
representatives from regulatory, legal,
manufacturing controls, and labeling
departments to collect information on
labeling change cost components, type of
personnel affected, and costs. The model
incorporates data on average industry costs
by company size, including, where
applicable, modifications to packaging
configurations. Industry consultants also
provided information on model inputs
related to the OTC acetaminophen and
NSAID drug product industry, the labeling
revision process, the costs of modifying
labeling, and the frequency of packaging
reconfiguration changes.
The baseline for this final rule is full
compliance with the format and content
requirements for OTC drug product labeling
in 21 CFR 201.66 established in a 1999 final
rule (64 FR 13254, March 17, 1999). In the
1999 final rule, we accounted for the total
incremental costs to comply with the format
and content requirements, including using a
6 point font size and related costs for
increased package size and longer labeling
where applicable. We note that, although
some forms of packaging (for small
quantities) have been granted extensions on
compliance dates, many packaging
alternatives now exist that can accommodate
the format and content requirements.
Manufacturers routinely redesign labels at
varying intervals and have standardized
procedures in place for complying with our
requirements. Based on consultant input,
manufacturers of OTC acetaminophen and
NSAID drug products typically redesign onehalf of their labels every 2 years, the
remainder every 3 years. The costs of labeling
change depend on the type of labeling (e.g.,
carton and container label) and whether there
is sufficient labeling space to accommodate
the proposed changes.
There are an estimated 22,500 OTC
acetaminophen and NSAID drug product
stock keeping units (SKUs), split evenly
among branded and private labels, according
to an industry consultant.9 We assume that
branded SKUs are distributed as follows by
firm size: 50 percent small, 17 percent
medium, and 33 percent large. Based on
ERG’s store survey, roughly 98 percent of
OTC acetaminophen and NSAID drug
products were packaged in containers within
cartons and 2 percent in containers without
outer cartons. About 5 percent of the 98
percent of products packaged in cartons
contained blister packs. For the final rule,
ERG revised the distribution of SKUs among
OTC acetaminophen and NSAID drug
products as follows: Acetaminophen, 32
percent; NSAIDs except ibuprofen, 32
percent; ibuprofen, 34 percent; and
combinations of acetaminophen and NSAIDs,
2 percent.10
To assess the increase in label space and
package size requirements, ERG purchased a
variety of OTC IAAA packaging
arrangements. ERG then determined the
current baseline warning language and
evaluated spacing constraints on packaging.
Consistent with findings discussed in the
proposed rule, ERG concluded that all
current packaging except blister packs can
accommodate the required changes in this
final rule without altering label sizes,
package sizes, or adding nonstandard labels.
For blister packages, all outer cartons were
judged to have adequate label space
available. With respect to the immediate
container, blister packs for OTC
acetaminophen were judged able to
accommodate warning statements, but the
OTC NSAID blister packs could not.
Therefore, ERG estimated that for OTC
NSAIDs, both the inner blister pack container
and the outer carton would need to be
expanded. This assumption allows for the
same number of unit doses per card and a
larger carton to accommodate the larger
cards.
Table 2 of this document presents the
estimated total one-time and recurring
annual costs of compliance with this final
rule in 2002 dollars. The total estimated firstyear one-time costs to revise labeling are
$62.7 million. Recurring costs are $1.5
million per year. The increases in cost from
the proposed rule are driven by the increased
percentage of OTC ibuprofen SKUs, the
doubling of packaging changes needed due to
the final regulation, and the need to change
package sizes for OTC NSAID blister packs.
TABLE 2.—ESTIMATED TOTAL ONE-TIME AND RECURRING ANNUAL COSTS OF COMPLIANCE WITH THIS RULE (IN 2002
DOLLARS)
Product Type
Company Type
Acetaminophen
NSAIDs Except
Ibuprofen
Ibuprofen
Combinations of
Acetaminophen and
NSAIDs
Total
Total one-time costs (expressed as millions of dollars)
Small brand
$2.2
$4.2
$4.0
$0.2
$10.7
Medium brand
$2.2
$3.1
$2.9
$0.2
$8.4
Large brand
$6.1
$8.5
$8.0
$0.5
$23.0
Private label
$4.5
$8.0
$7.5
$0.5
$20.5
$15.0
$23.8
$22.4
$1.4
$62.7
Total
Total recurring costs (expressed as millions of dollars)
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Small brand
$0.000
9 Estimates of affected SKUs are 18,000 by FDA
and 20,000 to 25,000 by industry consultant. This
number of SKUs includes products marketed by
manufacturers, repackers, relabelers, and
distributors.
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$0.089
10 ERG
$0.050
conducted a sensitivity analysis using the
same distribution of products at proposal and found
that costs would have been about 3 percent lower.
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$0.005
$0.145
The former distribution was: Acetaminophen, 45
percent; NSAIDs except ibuprofen, 38 percent;
ibuprofen, 15 percent; and combinations of
acetaminophen and NSAIDs, 2 percent.
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TABLE 2.—ESTIMATED TOTAL ONE-TIME AND RECURRING ANNUAL COSTS OF COMPLIANCE WITH THIS RULE (IN 2002
DOLLARS)—Continued
Product Type
Company Type
Acetaminophen
NSAIDs Except
Ibuprofen
Ibuprofen
Combinations of
Acetaminophen and
NSAIDs
Total
Medium brand
$0.000
$0.065
$0.037
$0.004
$0.106
Large brand
$0.000
$0.467
$0.264
$0.026
$0.756
Private label
$0.000
$0.290
$0.164
$0.016
$0.470
Total
$0.000
$0.911
$0.515
$0.050
$1.476
2. Alternatives
We considered and rejected the following
alternatives: (1) Not adding the new
information to OTC acetaminophen and
NSAID drug product labeling and (2) a longer
implementation period. We do not consider
either of these approaches acceptable because
they do not ensure that consumers will have
the most current labeling information needed
for the safe and effective use of these
products. We consider this final rule the least
burdensome alternative that meets the public
health objectives of this rule.
3. Benefits
Our final rule requirements are intended to
enhance consumer awareness and knowledge
of the active ingredient in OTC
acetaminophen and NSAID drug products.
These new warnings include:
• New label warnings
• Age-specific information
• Advising consumers of potential risks
and when to consult a doctor
• Prominent display of active ingredients
on the PDP
The revised alcohol statements are intended
to provide clearer warnings to high-risk
individuals about product use. The overall
intent of these requirements is to reduce the
liver injury and stomach bleeding episodes
that occur due to unintentional overdosing
with these drugs. The requirements are also
intended to reduce the incidence of adverse
health outcomes among high-risk
subpopulations consuming proper doses of
OTC acetaminophen and NSAID drug
products (e.g., people with liver disease or
people prone to stomach bleeding).
Our estimate of the potential benefits of
this final rule remains unchanged from the
estimate discussed in the proposed rule. We
estimated benefits assuming a reduction of
from 1 percent to 3 percent in unintentional
overdosing with OTC acetaminophen and
NSAID drug products. Reducing the number
of unintentional overdoses with OTC
acetaminophen and NSAID drug products
would reduce the number of emergency room
visits, hospitalizations, and deaths
attributable to these unintentional overdoses.
The monetary value of these avoided adverse
events, in 2007 dollars, is shown in table 3
of this document.
4. Benefit-Cost Comparison
Table 3 of this document summarizes the
present value over 10 years of the compliance
costs and the benefits of a 1 percent and 3
percent reduction in deaths and
hospitalizations using discount rates of 7 and
3 percent. We converted ERG’s present value
comparison of costs and benefits to 2007
dollars using the Gross Domestic Product
index of 1.0948 relative to 2001. The low end
of the benefits range uses an estimate of $5
million as the value of a statistical life and
includes savings from reduced
hospitalizations. The high end of the benefits
range uses an updated value of $7 million per
statistical life and does not include savings
from reduced hospitalizations. The costs of
this final rule exceed the benefits using the
most conservative assumption of benefits.
The benefits exceed the costs of this rule at
the mid to upper end of the benefits range.
Comparing the present value of costs and
benefits over 10 years, in 2007 dollars, costs
would exceed benefits if this rule reduced
deaths and hospitalizations by 2 percent or
more.
TABLE 3.—PRESENT VALUE AND ANNUALIZED PRESENT VALUE OF COMPLIANCE COSTS AND POTENTIAL BENEFITS OVER
10 YEARS (IN 2007 DOLLARS)
Present Value (millions of dollars)
Discount Rate
Costs1
Annualized Present Value Over 10 Years (millions
of dollars)
Benefits2
Benefits2
Costs
7 percent
$77.8
$45.1 - $172.8
$11.1
$6.4 - $24.6
3 percent
$79.8
$53.8 - $202.0
$9.4
$6.3 - $23.7
1 The
present value of compliance costs over 10 years in 2001 dollars equals $71.0 million at 7 percent and $72.9 million at 3 percent.
2 Assumes that this final rule would reduce adverse events by 1 to 3 percent.
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5. Break-Even Analysis
We note that we lack the data needed to
confidently predict a percent reduction in
serious cases related to unintentional
overdosing. Because of the uncertainty in
these estimates, we estimated an annual
average number of adverse events that would
need to be avoided over a 10 year period to
reach a break-even point (i.e., the present
value of the cost of compliance divided by
the present value of the monetary value of
avoiding an adverse event each year for 10
years). The following calculations are based
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on 2001 dollars, which will not affect the
estimated break-even values to be calculated.
For benefits to equal costs, this final rule
would need to prevent about 2 deaths each
year over 10 years [1.9 deaths ($71.0 million/
$37.6 million at a 7 percent discount rate)
and 1.7 deaths ($72.9 million/$43.9 million
at a 3 percent discount rate)]. This estimate
of deaths avoided is based on a value of $5
million per statistical life. Alternatively, if no
deaths are avoided, the final rule would need
to prevent about 1,058 hospitalizations each
year over the 10-year period at the 7 percent
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discount rate ($71.0 million/$67,156), and
928 hospitalizations a year at the 3 percent
discount rate ($72.9 million/$78,513). This
estimate of hospitalizations avoided is based
on the lowest monetized value of a poisoning
episode requiring hospitalization: $8,936 per
episode over 10 years at a 7 percent discount
rate.
Although we lack evidence to predict with
certainty a specific level of reduction in
adverse events, if we assume only a 2 percent
reduction in the illnesses and deaths
analyzed, the benefits of this final rule
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outweigh the costs. We find that this final
rule will enhance public health and promote
the safer use of OTC acetaminophen and
NSAID drug products.
6. Final Regulatory Flexibility Analysis
This economic analysis, together with
other relevant sections of this document,
serves as our final regulatory flexibility
analysis, as required under the Regulatory
Flexibility Act. For our preliminary
regulatory flexibility analysis, we calculated
the average annualized compliance costs for
firms in each size category and determined
that the average annualized compliance costs
totaled less than 1 percent of average receipts
for all firm sizes. In 2007 dollars, the
estimated annualized present value cost per
SKU is $492 (i.e., $11.1 million divided by
22,500 SKUs) using a 7 percent discount rate
over 10 years, and $416 per SKU ($9.4
million divided by 22,500 SKUs) using a 3
percent discount rate over 10 years. For
private label SKUs only, the annualized
present value cost per SKU is $321 ($3.6
million divided by 11,250 SKUs) using a 7
percent discount rate over 10 years, or $271
per private label SKU ($3.0 divided by 11,250
SKUs) using a 3 percent discount rate over
10 years. Similar to the proposed rule, the
average annualized compliance costs of the
final rule remain under 1 percent of average
receipts for all firm sizes. Therefore, we
tentatively conclude that this final rule will
not have a significant economic impact on a
substantial number of small entities.
2. On page 19407, in the second
column, add the following reference:
57. Eastern Research Group, Inc.,
‘‘Addendum to the Cost Benefit Analysis:
Final Internal Analgesic, Antipyretic and
Antirheumatic Drug Products Rulemaking,’’
Final Report, July 30, 2008.
§ 201.326
[Corrected]
3. On page 19408, in the third column,
correct the first sentence in
§ 201.326(a)(2)(iii)(A) to read as follows:
‘‘Stomach bleeding warning [heading in
bold type]: This product contains an
NSAID, which may cause severe
stomach bleeding.’’
■ 4. On page 19409, in the first column,
correct the first sentence in
§ 201.326(a)(2)(iv)(A)(1) to read as
follows: ‘‘Stomach bleeding warning
[heading in bold type]: This product
contains an NSAID, which may cause
severe stomach bleeding.’’
■ 5. On page 19409, in the second
column, correct the first sentence in
§ 201.326(a)(2)(v)(A) to read as follows:
‘‘Stomach bleeding warning [heading in
bold type]: This product contains an
NSAID, which may cause severe
stomach bleeding.’’
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■
Dated: June 23, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and
Planning.
[FR Doc. E9–15403 Filed 6–29–09; 8:45 am]
BILLING CODE 4160–01–S
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DEPARTMENT OF HOMELAND
SECURITY
Coast Guard
33 CFR Part 117
[USCG–2008–1216]
RIN 1625–AA09
Drawbridge Operation Regulations;
Potomac River, Between MD and VA
Coast Guard, DHS.
Final rule.
AGENCY:
ACTION:
SUMMARY: The Coast Guard is changing
the drawbridge operation regulations of
the new Woodrow Wilson Memorial (I–
95) Bridge, mile 103.8, across the
Potomac River between Alexandria, VA
and Oxon Hill, MD. This rule is being
made in an effort to minimize the
potential for major regional vehicular
traffic impacts and consequences during
bridge openings of the draw span while
still providing for reasonable needs of
marine traffic.
DATES: This rule is effective July 30,
2009.
Comments and related
materials received from the public, as
well as documents mentioned in this
preamble as being available in the
docket, are part of docket USCG–2008–
1216 and are available online at
https://www.regulations.gov. This
material is also available for inspection
or copying at two locations: The Docket
Management Facility (M–30), U.S.
Department of Transportation, West
Building Ground Floor, Room W12–140,
1200 New Jersey Avenue, SE.,
Washington, DC 20590, between 9 a.m.
and 5 p.m., Monday through Friday,
except Federal holidays, and the
Commander (dpb), Fifth Coast Guard
District, Federal Building, 1st Floor, 431
Crawford Street, Portsmouth, VA
23704–5004 between 8 a.m. and 4 p.m.,
Monday through Friday, except Federal
holidays.
FOR FURTHER INFORMATION CONTACT: If
you have questions on this rule, call
Waverly W. Gregory, Jr., Bridge
Administrator, Fifth Coast Guard
District, at 757–398–6222. If you have
questions on viewing or submitting
material to the docket, call Renee V.
Wright, Program Manager, Docket
Operations, telephone 202–366–9826.
SUPPLEMENTARY INFORMATION:
ADDRESSES:
Regulatory Information
On February 9, 2009, we published a
notice of proposed rulemaking (NPRM)
entitled, ‘‘Drawbridge Operation
Regulations; Potomac River, Between
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MD and VA’’ (74 FR 6359). We received
no comments on the published NPRM.
No public meeting was requested, and
none was held.
Background and Purpose
On July 2, 2008, we published a
temporary regulation entitled
‘‘Drawbridge Operation Regulations;
Potomac River, Between MD and VA,’’
in the Federal Register (73 FR 37806).
While construction continued, the
temporary rule allowed the drawbridge
to remain closed-to-navigation each day
from 10 a.m. to 2 p.m. until and
including March 1, 2009.
The MD State Highway
Administration and the VA Department
of Transportation, co-owners of the
drawbridge, requested to permanently
maintain the Woodrow Wilson Bridge in
the closed-to-navigation position each
day from 10 a.m. to 2 p.m. This request
was made in an effort to minimize the
potential for major regional vehicular
traffic impacts and consequences during
bridge openings.
In reaching our decision to implement
this request, we balanced the large
volume of vehicular traffic moving
across the bridge against the lack of
large commercial vessel traffic seeking
to use the bridge during this period. The
Woodrow Wilson Bridge is part of the
Capital Beltway Interstate Highway
System. It is a critical component of that
system for both local and regional traffic
moving into, around, and through the
Washington, DC metro area. Bridge
openings cause significant traffic delays.
From a river-user standpoint, the
coordinators for the construction of the
new Woodrow Wilson Bridge Project
have received no requests from boaters
or mariners to open the bridge during
the 10 a.m. to 2 p.m. timeframe since
the first temporary deviation was issued
in late June 2006. In fact, no requests
have been received for an opening of the
new bridge at all since July 3, 2006.
Finally, the coordinators have received
no complaints on the 10 a.m. to 2 p.m.
restriction. This rule will affect only
vessels with mast heights of 75 feet or
greater. Furthermore, all operators of
affected vessels with mast heights
greater than 75 feet will be able to
request an opening of the drawbridge in
the ‘‘off-peak’’ vehicle traffic hours
(evening and overnight) in accordance
with 33 CFR 117.255(a). As discussed in
the Notice of Proposed Rulemaking,
currently, 33 CFR 117.255(a)(2)(i) states
(paraphrasing) that the drawbridge need
not open for the passage of a
commercial vessel, Monday through
Friday, 5 a.m. to 10 a.m. and 2 p.m. to
8 p.m. This final rule connects the two
time periods by extending the operating
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]]>Agencies
[Federal Register Volume 74, Number 124 (Tuesday, June 30, 2009)]
[Rules and Regulations]
[Pages 31177-31180]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E9-15403]
[[Page 31177]]
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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. 1977N-0094L)
RIN 0910-AF36
Organ-Specific Warnings; Internal Analgesic, Antipyretic, and
Antirheumatic Drug Products for Over-the-Counter Human Use; Final
Monograph; Corrections
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule, corrections.
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SUMMARY: The Food and Drug Administration (FDA) is correcting a final
rule that appeared in the Federal Register of April 29, 2009. The
document requires important new organ-specific warnings and related
labeling for over-the-counter (OTC) internal analgesic, antipyretic,
and antirheumatic 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). The document was published with an incorrect Analysis of
Impacts section and omitted a reference from the reference section of
the final rule. The document was also published with an error in the
codified text regarding the introductory sentence to the stomach
bleeding warning for NSAIDs. This document replaces the incorrect
Analysis of Impacts section with the correct Analysis of Impacts
section, adds a reference to the reference section of the final rule,
and corrects the codified text.
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, Silver Spring, MD 20993, 301-796-2090.
SUPPLEMENTARY INFORMATION: In FR Doc. E9-9684, published on April 29,
2009 (74 FR 19385), make the following corrections:
1. Beginning on page 19401 and ending on page 19406, replace
section VI. Analysis of Impacts with the following text:
VI. Analysis of Impacts
We have examined the impacts of the final 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 final 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. 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 $130
million, using the most current (2007) Implicit Price Deflator for
the Gross Domestic Product. We do not expect this final rule to
result in any 1-year expenditure that would meet or exceed this
amount.
We conclude that this final rule is consistent with the
principles set out in Executive Order 12866 and in these two
statutes. As discussed in this section, we have determined that this
final rule will not have a significant economic impact on a
substantial number of small entities, but we lack sufficient
information on the distribution of the burden to certify that it is
not significant.
The impact on industry, in terms of costs of compliance, are
presented in section VI.B of this document and summarized in table 2
of this document. The societal costs and benefits of this final rule
are summarized in table 3 of section VI.B of this document.
A. Need for the Rule
In 2002, an FDA Advisory Committee recommended changes to the
labeling of OTC acetaminophen and NSAID drug products to better
inform consumers about the active ingredients and possible side
effects caused by improper use. Current labels provide inadequate
information about the risk of improper use. Although we consider
acetaminophen to be safe and effective when labeled and used
correctly, using too much can lead to liver injury and death.
Similarly, the use of NSAIDs can lead to stomach bleeding and kidney
damage. The number of cases of injury reported is a very low
percentage of the total use of OTC acetaminophen and NSAID drug
products. For many people, the risks are quite low because they use
these products only occasionally. The risks may be greater for
people who use these products more frequently and/or do not follow
the labeling information on the package. The risk of injury may be
increased for certain populations and under certain conditions of
use.
There are multiple reasons for unintentional acetaminophen
overdoses. First, acetaminophen is an active ingredient in a wide
variety of both OTC and prescription drug products. For prescription
products, the immediate container may not state that the product
contains acetaminophen or state the maximum daily dose limit.
Consumers may often fail to recognize the presence and amount of
acetaminophen ingredients in OTC and prescription drug products.
This lack of knowledge can result in a person using two different
products containing acetaminophen simultaneously. Moreover, many
consumers are unaware that exceeding the recommended dosage for
acetaminophen can lead to unintentional overdosing and cause
potential harm. Based on the evidence discussed in this document, we
find that there is sufficient incidence of liver injury associated
with acetaminophen to warrant new labeling, and that without the new
labeling, acetaminophen products would no longer be considered
generally recognized as safe and effective and not misbranded for
OTC use.
Results of several large-scale clinical studies performed in the
United States and in other countries have established that the use
of NSAIDs is an important risk factor for serious stomach adverse
events, especially bleeding. The risk is higher for certain
populations. Based on the evidence discussed in this document, we
further find that NSAIDs increase the risk for stomach adverse
events and that, without a new stomach bleeding warning in the
labeling for NSAIDs, the products would no longer be considered
generally recognized as safe and effective and not misbranded for
OTC use.
The purpose of this final rule is to amend our OTC drug labeling
regulations to include new warnings and other labeling requirements
to advise consumers of potential risks and when to consult a doctor
(see table 1 in section II.B.2 of this document). We are also
removing the alcohol warning in Sec. 201.322 and incorporating new
alcohol-related warnings and other labeling for all OTC
acetaminophen and NSAID drug products. We are requiring certain
warning information targeted to age-specific populations. In
addition, we are requiring that the presence of acetaminophen or any
NSAID would appear prominently on a product's principal display
panel (PDP). Without this final rule, the labeling of these products
will not provide sufficient warnings of risks to consumers.
B. Impact of the Rule
We contracted Eastern Research Group, Inc. (ERG) to assess the
costs and benefits of the proposed rule on which this final rule is
based. The full ERG report (Ref. 56), including details on methods,
assumptions, cost calculations, and findings, is on file in the
Division of Dockets Management (71 FR
[[Page 31178]]
77314 at 77341). The most significant change from the proposal is
the requirement that warning statements appear on both the outer
container and on the immediate container. We, therefore, contracted
with ERG to perform an updated store survey and analysis to assess
the costs of the changes in this final rule. ERG's 2008 ``Addendum
to the Cost Benefit Analysis: Final Internal Analgesic, Antipyretic,
and Antirheumatic Drug Products Rulemaking'' (Ref. 57) is also on
file with the Division of Dockets Management. Most of ERG's methods,
assumptions and analysis used for the proposed rule remain unchanged
for this final rule. The following is a summary of ERG's findings.
1. Cost of Compliance
Manufacturers and marketers of OTC acetaminophen and NSAID drug
products would incur one-time costs to revise affected product
labeling to comply with this rule. We estimated costs for a major
labeling revision using a pharmaceutical labeling revision cost
model. We used an implementation period of 12 months. The labeling
model is described in detail in Appendix A of the ERG report cited
in the 2006 proposed rule.
To develop the original model, we and ERG interviewed
pharmaceutical representatives from regulatory, legal, manufacturing
controls, and labeling departments to collect information on
labeling change cost components, type of personnel affected, and
costs. The model incorporates data on average industry costs by
company size, including, where applicable, modifications to
packaging configurations. Industry consultants also provided
information on model inputs related to the OTC acetaminophen and
NSAID drug product industry, the labeling revision process, the
costs of modifying labeling, and the frequency of packaging
reconfiguration changes.
The baseline for this final rule is full compliance with the
format and content requirements for OTC drug product labeling in 21
CFR 201.66 established in a 1999 final rule (64 FR 13254, March 17,
1999). In the 1999 final rule, we accounted for the total
incremental costs to comply with the format and content
requirements, including using a 6 point font size and related costs
for increased package size and longer labeling where applicable. We
note that, although some forms of packaging (for small quantities)
have been granted extensions on compliance dates, many packaging
alternatives now exist that can accommodate the format and content
requirements.
Manufacturers routinely redesign labels at varying intervals and
have standardized procedures in place for complying with our
requirements. Based on consultant input, manufacturers of OTC
acetaminophen and NSAID drug products typically redesign one-half of
their labels every 2 years, the remainder every 3 years. The costs
of labeling change depend on the type of labeling (e.g., carton and
container label) and whether there is sufficient labeling space to
accommodate the proposed changes.
There are an estimated 22,500 OTC acetaminophen and NSAID drug
product stock keeping units (SKUs), split evenly among branded and
private labels, according to an industry consultant.\9\ We assume
that branded SKUs are distributed as follows by firm size: 50
percent small, 17 percent medium, and 33 percent large. Based on
ERG's store survey, roughly 98 percent of OTC acetaminophen and
NSAID drug products were packaged in containers within cartons and 2
percent in containers without outer cartons. About 5 percent of the
98 percent of products packaged in cartons contained blister packs.
For the final rule, ERG revised the distribution of SKUs among OTC
acetaminophen and NSAID drug products as follows: Acetaminophen, 32
percent; NSAIDs except ibuprofen, 32 percent; ibuprofen, 34 percent;
and combinations of acetaminophen and NSAIDs, 2 percent.\10\
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\9\ Estimates of affected SKUs are 18,000 by FDA and 20,000 to
25,000 by industry consultant. This number of SKUs includes products
marketed by manufacturers, repackers, relabelers, and distributors.
\10\ ERG conducted a sensitivity analysis using the same
distribution of products at proposal and found that costs would have
been about 3 percent lower. The former distribution was:
Acetaminophen, 45 percent; NSAIDs except ibuprofen, 38 percent;
ibuprofen, 15 percent; and combinations of acetaminophen and NSAIDs,
2 percent.
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To assess the increase in label space and package size
requirements, ERG purchased a variety of OTC IAAA packaging
arrangements. ERG then determined the current baseline warning
language and evaluated spacing constraints on packaging. Consistent
with findings discussed in the proposed rule, ERG concluded that all
current packaging except blister packs can accommodate the required
changes in this final rule without altering label sizes, package
sizes, or adding nonstandard labels. For blister packages, all outer
cartons were judged to have adequate label space available. With
respect to the immediate container, blister packs for OTC
acetaminophen were judged able to accommodate warning statements,
but the OTC NSAID blister packs could not. Therefore, ERG estimated
that for OTC NSAIDs, both the inner blister pack container and the
outer carton would need to be expanded. This assumption allows for
the same number of unit doses per card and a larger carton to
accommodate the larger cards.
Table 2 of this document presents the estimated total one-time
and recurring annual costs of compliance with this final rule in
2002 dollars. The total estimated first-year one-time costs to
revise labeling are $62.7 million. Recurring costs are $1.5 million
per year. The increases in cost from the proposed rule are driven by
the increased percentage of OTC ibuprofen SKUs, the doubling of
packaging changes needed due to the final regulation, and the need
to change package sizes for OTC NSAID blister packs.
Table 2.--Estimated Total One-Time and Recurring Annual Costs of Compliance With This Rule (in 2002 dollars)
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Product Type
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Company Type Combinations of
Acetaminophen Ibuprofen NSAIDs Except Acetaminophen and Total
Ibuprofen NSAIDs
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Total one-time costs (expressed as millions of dollars)
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Small brand $2.2 $4.2 $4.0 $0.2 $10.7
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Medium brand $2.2 $3.1 $2.9 $0.2 $8.4
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Large brand $6.1 $8.5 $8.0 $0.5 $23.0
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Private label $4.5 $8.0 $7.5 $0.5 $20.5
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Total $15.0 $23.8 $22.4 $1.4 $62.7
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Total recurring costs (expressed as millions of dollars)
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Small brand $0.000 $0.089 $0.050 $0.005 $0.145
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[[Page 31179]]
Medium brand $0.000 $0.065 $0.037 $0.004 $0.106
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Large brand $0.000 $0.467 $0.264 $0.026 $0.756
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Private label $0.000 $0.290 $0.164 $0.016 $0.470
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Total $0.000 $0.911 $0.515 $0.050 $1.476
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2. Alternatives
We considered and rejected the following alternatives: (1) Not
adding the new information to OTC acetaminophen and NSAID drug
product labeling and (2) a longer implementation period. We do not
consider either of these approaches acceptable because they do not
ensure that consumers will have the most current labeling
information needed for the safe and effective use of these products.
We consider this final rule the least burdensome alternative that
meets the public health objectives of this rule.
3. Benefits
Our final rule requirements are intended to enhance consumer
awareness and knowledge of the active ingredient in OTC
acetaminophen and NSAID drug products. These new warnings include:
New label warnings
Age-specific information
Advising consumers of potential risks and when to
consult a doctor
Prominent display of active ingredients on the PDP
The revised alcohol statements are intended to provide clearer
warnings to high-risk individuals about product use. The overall
intent of these requirements is to reduce the liver injury and
stomach bleeding episodes that occur due to unintentional overdosing
with these drugs. The requirements are also intended to reduce the
incidence of adverse health outcomes among high-risk subpopulations
consuming proper doses of OTC acetaminophen and NSAID drug products
(e.g., people with liver disease or people prone to stomach
bleeding).
Our estimate of the potential benefits of this final rule
remains unchanged from the estimate discussed in the proposed rule.
We estimated benefits assuming a reduction of from 1 percent to 3
percent in unintentional overdosing with OTC acetaminophen and NSAID
drug products. Reducing the number of unintentional overdoses with
OTC acetaminophen and NSAID drug products would reduce the number of
emergency room visits, hospitalizations, and deaths attributable to
these unintentional overdoses. The monetary value of these avoided
adverse events, in 2007 dollars, is shown in table 3 of this
document.
4. Benefit-Cost Comparison
Table 3 of this document summarizes the present value over 10
years of the compliance costs and the benefits of a 1 percent and 3
percent reduction in deaths and hospitalizations using discount
rates of 7 and 3 percent. We converted ERG's present value
comparison of costs and benefits to 2007 dollars using the Gross
Domestic Product index of 1.0948 relative to 2001. The low end of
the benefits range uses an estimate of $5 million as the value of a
statistical life and includes savings from reduced hospitalizations.
The high end of the benefits range uses an updated value of $7
million per statistical life and does not include savings from
reduced hospitalizations. The costs of this final rule exceed the
benefits using the most conservative assumption of benefits. The
benefits exceed the costs of this rule at the mid to upper end of
the benefits range. Comparing the present value of costs and
benefits over 10 years, in 2007 dollars, costs would exceed benefits
if this rule reduced deaths and hospitalizations by 2 percent or
more.
Table 3.--Present Value and Annualized Present Value of Compliance Costs and Potential Benefits Over 10 Years
(in 2007 dollars)
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Present Value (millions of dollars) Annualized Present Value Over 10 Years
-------------------------------------------- (millions of dollars)
Discount Rate -------------------------------------------
Costs\1\ Benefits\2\ Costs Benefits\2\
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7 percent $77.8 $45.1 - $172.8 $11.1 $6.4 - $24.6
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3 percent $79.8 $53.8 - $202.0 $9.4 $6.3 - $23.7
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\1\ The present value of compliance costs over 10 years in 2001 dollars equals $71.0 million at 7 percent and
$72.9 million at 3 percent.
\2\ Assumes that this final rule would reduce adverse events by 1 to 3 percent.
5. Break-Even Analysis
We note that we lack the data needed to confidently predict a
percent reduction in serious cases related to unintentional
overdosing. Because of the uncertainty in these estimates, we
estimated an annual average number of adverse events that would need
to be avoided over a 10 year period to reach a break-even point
(i.e., the present value of the cost of compliance divided by the
present value of the monetary value of avoiding an adverse event
each year for 10 years). The following calculations are based on
2001 dollars, which will not affect the estimated break-even values
to be calculated. For benefits to equal costs, this final rule would
need to prevent about 2 deaths each year over 10 years [1.9 deaths
($71.0 million/$37.6 million at a 7 percent discount rate) and 1.7
deaths ($72.9 million/$43.9 million at a 3 percent discount rate)].
This estimate of deaths avoided is based on a value of $5 million
per statistical life. Alternatively, if no deaths are avoided, the
final rule would need to prevent about 1,058 hospitalizations each
year over the 10-year period at the 7 percent discount rate ($71.0
million/$67,156), and 928 hospitalizations a year at the 3 percent
discount rate ($72.9 million/$78,513). This estimate of
hospitalizations avoided is based on the lowest monetized value of a
poisoning episode requiring hospitalization: $8,936 per episode over
10 years at a 7 percent discount rate.
Although we lack evidence to predict with certainty a specific
level of reduction in adverse events, if we assume only a 2 percent
reduction in the illnesses and deaths analyzed, the benefits of this
final rule
[[Page 31180]]
outweigh the costs. We find that this final rule will enhance public
health and promote the safer use of OTC acetaminophen and NSAID drug
products.
6. Final Regulatory Flexibility Analysis
This economic analysis, together with other relevant sections of
this document, serves as our final regulatory flexibility analysis,
as required under the Regulatory Flexibility Act. For our
preliminary regulatory flexibility analysis, we calculated the
average annualized compliance costs for firms in each size category
and determined that the average annualized compliance costs totaled
less than 1 percent of average receipts for all firm sizes. In 2007
dollars, the estimated annualized present value cost per SKU is $492
(i.e., $11.1 million divided by 22,500 SKUs) using a 7 percent
discount rate over 10 years, and $416 per SKU ($9.4 million divided
by 22,500 SKUs) using a 3 percent discount rate over 10 years. For
private label SKUs only, the annualized present value cost per SKU
is $321 ($3.6 million divided by 11,250 SKUs) using a 7 percent
discount rate over 10 years, or $271 per private label SKU ($3.0
divided by 11,250 SKUs) using a 3 percent discount rate over 10
years. Similar to the proposed rule, the average annualized
compliance costs of the final rule remain under 1 percent of average
receipts for all firm sizes. Therefore, we tentatively conclude that
this final rule will not have a significant economic impact on a
substantial number of small entities.
2. On page 19407, in the second column, add the following
reference:
57. Eastern Research Group, Inc., ``Addendum to the Cost Benefit
Analysis: Final Internal Analgesic, Antipyretic and Antirheumatic
Drug Products Rulemaking,'' Final Report, July 30, 2008.
Sec. 201.326 [Corrected]
0
3. On page 19408, in the third column, correct the first sentence in
Sec. 201.326(a)(2)(iii)(A) to read as follows: ``Stomach bleeding
warning [heading in bold type]: This product contains an NSAID, which
may cause severe stomach bleeding.''
0
4. On page 19409, in the first column, correct the first sentence in
Sec. 201.326(a)(2)(iv)(A)(1) to read as follows: ``Stomach bleeding
warning [heading in bold type]: This product contains an NSAID, which
may cause severe stomach bleeding.''
0
5. On page 19409, in the second column, correct the first sentence in
Sec. 201.326(a)(2)(v)(A) to read as follows: ``Stomach bleeding
warning [heading in bold type]: This product contains an NSAID, which
may cause severe stomach bleeding.''
Dated: June 23, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-15403 Filed 6-29-09; 8:45 am]
BILLING CODE 4160-01-S
