[Federal Register Volume 74, Number 124 (Tuesday, June 30, 2009)]
[Rules and Regulations]
[Pages 31177-31180]
From the Federal Register Online via the Government Publishing 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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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:
    <bullet> New label warnings
    <bullet> Age-specific information
    <bullet> Advising consumers of potential risks and when to 
consult a doctor
    <bullet> 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

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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.


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