[Federal Register: December 26, 2006 (Volume 71, Number 247)]
[Proposed Rules]
[Page 77314-77352]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26de06-12]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201 and 343
[Docket No. 1977N-0094L]
RIN 0910-AF36
Internal Analgesic, Antipyretic, and Antirheumatic Drug Products
for Over-the-Counter Human Use; Proposed Amendment of the Tentative
Final Monograph; Required Warnings and Other Labeling
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
its over-the-counter (OTC) labeling regulations and the tentative final
monograph (TFM) for OTC internal analgesic, antipyretic, and
antirheumatic (IAAA) drug products to include new warnings and other
labeling requirements advising consumers about potential risks and when
to consult a doctor. FDA is also proposing to remove the alcohol
warning in its regulations and add new warnings and other labeling for
all OTC IAAA drug products. The new labeling would be required for all
OTC drug products containing an IAAA active ingredient whether marketed
under an OTC drug monograph or an approved new drug application (NDA).
FDA is issuing this proposal as part of its ongoing review of OTC drug
products after considering the advice of its Nonprescription Drugs
Advisory Committee (NDAC) and other available information. FDA is
proposing these labeling changes because it has tentatively concluded
they are necessary for these ingredients to be considered generally
recognized as safe and effective and not misbranded for OTC use. FDA
will address information about the cardiovascular risks of nonsteroidal
anti-inflammatory drugs (NSAIDs) that was discussed at a February 16-
18, 2005, FDA advisory committee meeting, and the ``Allergy alert''
warning for NSAID products, in a future issue of the Federal Register.
DATES: Submit written or electronic comments, including comments on
FDA's economic impact determination, by May 25, 2007. The specified
comment period is longer than is normally provided for proposed rules.
Because of the complexity of the proposed rule, FDA is providing an
additional 60 days (beyond the normal comment period) for comments to
be submitted and does not plan to extend the comment period beyond this
date. Please see section XV of this document for the proposed effective
and compliance dates of any final rule that may publish based on this
proposal.
ADDRESSES: You may submit comments, identified by Docket No. 1977N-
0094L and Regulatory Information Number (RIN) 0910-AF36 by any of the
following methods:
Electronic Submissions
Submit electronic comments in the following ways:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://www.fda.gov/dockets/ecomments.
Follow instructions for submitting comments on the agency Web site.
Written Submissions
Submit written submissions in the following ways:
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
To ensure more timely processing of comments, FDA is no longer
accepting comments submitted to the agency by e-mail. FDA encourages
you to continue to submit electronic comments by using the Federal
eRulemaking Portal or the agency Web site, as described in the
Electronic Submissions portion of this paragraph.
Instructions: All submissions received must include the agency name
and Docket No. and RIN for this rulemaking. All comments received may
be posted without change to http://www.fda.gov/ohrms/dockets/default.htm
, including any personal information provided. For
additional information on submitting comments, see the ``Comments''
heading of the SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number(s), found in brackets in the heading of
this document, into the ``Search'' box and follow the prompts and/or go
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Marina Chang, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Silver Spring, MD, 20993-0002, 301-796-2090.
[[Page 77315]]
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Background
A. Development of OTC IAAA Drug Product Warnings
B. Completion of the OTC IAAA Drug Products Final Monograph (FM)
III. NDAC Meeting
A. Data and Information Reviewed
B. Acetaminophen
C. Aspirin and Other NSAIDs
IV. Additional Data and Information FDA Reviewed
A. Pre-existing Liver Disease as a Risk Factor for Acetaminophen
Hepatotoxicity
B. Updated Literature about Acetaminophen Toxicity
C. Aspirin and Other NSAIDs
V. FDA's Tentative Conclusions
A. Acetaminophen
B. Aspirin and Other NSAIDs
VI. FDA's Proposal
A. Alcohol Warning
B. Acetaminophen
C. Aspirin and other NSAIDs
D. Requirements to Supplement Approved Applications
E. Regulatory Action
F. Conforming Changes to the OTC IAAA TFM
VII. Additional Issues for Consideration
A. Safe and Effective Daily Acetaminophen Dose
B. Daily Dose Recommendations for Alcohol Abusers
C. Combinations With Methionine or Acetylcysteine
D. Package Size and Configuration Limitations
E. Label Warning for Individuals With Human Immunodeficiency Virus
(HIV)
F. Drug Interactions Between Acetaminophen and Warfarin
VIII. Legal Authority
A. Statement About Warnings
B. Marketing Conditions
IX. Voluntary Implementation
X. Analysis of Impacts
A. Need for the Rule
B. Impact of the Rule
C. Impact on Affected Sectors
D. Alternatives
E. Benefits
XI. Paperwork Reduction Act of 1995
XII. Environmental Impact
XIII. Federalism
XIV. Request for Comments
XV. Proposed Effective and Compliance Dates
XVI. References
I. Introduction
FDA is proposing to: (1) Amend the TFM for OTC IAAA drug products,
(2) remove the alcohol warning, and (3) add new warnings and other
labeling for all OTC IAAA drug products. The proposed warnings and
other labeling requirements will advise consumers of potential risks
and when to consult a doctor. More specifically, FDA is proposing the
following changes to the labeling:
Requiring a new liver warning for products that contain
acetaminophen.
Requiring a new stomach bleeding warning for products that
contain an NSAID (e.g., aspirin or ibuprofen).
Removing the alcohol warning currently required for all
OTC IAAA drug products in Sec. 201.322 (21 CFR 201.322) and
incorporating an alcohol warning in the new liver warning for
acetaminophen and the new stomach bleeding warning for NSAIDs.
Requiring that the ingredient acetaminophen be prominently
identified on the product's principal display panel (PDP) of the
immediate container and the outer carton, if applicable.
Requiring that the name of the NSAID ingredient followed
by the term ``NSAID'' be prominently identified on the product's PDP of
the immediate container and the outer carton, if applicable.
This new labeling would be required for all OTC drug products
containing an IAAA active ingredient, whether marketed under an OTC
drug monograph or an approved NDA. FDA bases this proposal on its
reviews of the medical literature, data provided to FDA, and
recommendations made by NDAC. FDA has tentatively concluded that new
labeling for OTC IAAA drug products is necessary for the safe and
effective use of these products by consumers.
II. Background
FDA believes that acetaminophen and NSAIDs, when labeled
appropriately and used as directed, are safe and effective OTC drug
products that benefit tens of millions of consumers every year. FDA
believes that these products should continue to be accessible to
consumers in the OTC setting.
Internal analgesics have long been very effective OTC drug
products for the intermittent treatment of minor aches and pains and
fever.
At their recommended OTC doses, these products are only
rarely associated with serious adverse events relative to the number of
consumers who use these products.
A. Development of OTC IAAA Drug Product Warnings
The development of a monograph for OTC IAAA drug products began in
1977 with publication of an expert panel report and continued in 1988
with publication of the TFM. The development of labeling for OTC IAAA
drug products is recorded in the following documents.
1. Warnings for Aspirin and Acetaminophen
In the Federal Register of July 8, 1977 (42 FR 35346), FDA
published the report of the Advisory Review Panel on OTC Internal
Analgesic, Antipyretic, and Antirheumatic Drug Products (the IAAA
Panel) for OTC IAAA active ingredients: Acetaminophen, aspirin,
carbaspirin calcium, choline salicylate, magnesium salicylate, and
sodium salicylate. The recommendations included labeling and warnings
for:
Aspirin: ``Caution: Do not take this product if you have
stomach distress, ulcers or bleeding problems except under the advice
and supervision of a physician'' (42 FR 35346 at 35387), and
Acetaminophen: ``Do not exceed recommended dosage because
severe liver damage may occur'' (42 FR 35346 at 35415).
In the Federal Register of November 16, 1988 (53 FR 46204), FDA
published a tentative monograph with the following warnings for:
Aspirin: ``Do not take this product if you have stomach
problems (such as heartburn, upset stomach, or stomach pain) that
persist or recur, or if you have ulcers or bleeding problems, unless
directed by a doctor'' (53 FR 46204 at 46256), and
Acetaminophen: ``Prompt medical attention is critical for
adults as well as for children even if you do not notice any signs or
symptoms.'' This warning follows the general overdose warnings in 21
CFR 330.1(g) (53 FR 46204 at 46213).
2. Warnings in the Professional Labeling for Aspirin
In the Federal Register of October 23, 1998 (63 FR 56802), FDA
published labeling for health professionals (not available in OTC drug
product labeling) that provided for cardiovascular and rheumatologic
indications. The labeling listed adverse reactions reported in the
literature, e.g., hypotension (low blood pressure); tachycardia (rapid
heart rate); dizziness; headache; dyspepsia (indigestion); bleeding,
ulceration, and perforation of the gastrointestinal (GI) tract; nausea;
and vomiting. FDA determined that consumers were not able to determine
when they needed to take aspirin to prevent cardiovascular events, such
as stroke, myocardial infarction (damage to the heart muscle), or other
conditions. FDA did not
[[Page 77316]]
consider it possible to provide adequate directions and warnings to
enable the layperson to make a reasonable self-diagnosis of these
cardiovascular and rheumatologic conditions.
3. Alcohol Warnings for Acetaminophen and NSAIDs
In the Federal Register of October 23, 1998 (63 FR 56789), FDA
published a final regulation stating that any OTC drug product, labeled
for adult use, containing acetaminophen, aspirin, carbaspirin calcium,
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate,
naproxen sodium, and sodium salicylate must bear an alcohol warning
statement in its labeling. Section 201.322 requires the following
statements:
For products containing acetaminophen:
Alcohol Warning: If you consume 3 or more alcoholic drinks every
day, ask your doctor whether you should take acetaminophen or other
pain relievers/fever reducers. Acetaminophen may cause liver damage.
For products containing aspirin, carbaspirin calcium,
choline salicylate, ibuprofen, ketoprofen, magnesium salicylate,
naproxen sodium, and sodium salicylate:
Alcohol Warning: If you consume 3 or more alcoholic drinks every
day, ask your doctor whether you should take (name of active
ingredient) or other pain relievers/fever reducers. (Name of active
ingredient) may cause stomach bleeding.
For products containing acetaminophen with other IAAA
active ingredients:
Alcohol Warning: If you consume 3 or more alcoholic drinks every
day, ask your doctor whether you should take (insert acetaminophen and
one other IAAA active ingredient--including, but not limited to
aspirin, carbaspirin calcium, choline salicylate, magnesium salicylate,
or sodium salicylate) or other pain relievers/fever reducers.
Acetaminophen and (insert name of one other IAAA active ingredient--
including, but not limited to aspirin, carbaspirin calcium, choline
salicylate, magnesium salicylate, or sodium salicylate) may cause liver
damage and stomach bleeding.
4. Proposed Amendment to Include Ibuprofen as a Generally Recognized
Safe and Effective OTC IAAA Active Ingredient
In the Federal Register of August 21, 2002 (67 FR 54139), FDA
proposed to include ibuprofen in the monograph for OTC IAAA drug
products with additional warnings:
Ask a doctor before use if you have:
Problems or serious side effects from taking pain
relievers or fever reducers
Stomach problems that last or come back, such as
heartburn, upset stomach, or pain
Ulcers
Bleeding problems
High blood pressure, heart or kidney disease, are taking a
diuretic, or are over 65 years of age.
FDA received several comments (Refs. 1 and 2) about the proposed
warning for kidney disease and reopened the administrative record on
June 4, 2003 (68 FR 33429), to allow for additional public comment. FDA
continues to propose a warning about kidney disease for ibuprofen and
other NSAIDs in this document. In a future issue of the Federal
Register, we will publish our final decision about this warning and the
proposed inclusion of ibuprofen in the monograph.
B. Completion of the OTC IAAA Drug Products FM
In the process of completing the FM for OTC IAAA drug products, FDA
reviewed a variety of data regarding the safety of acetaminophen,
aspirin, and other NSAIDs. FDA continued to receive serious adverse
event reports associated with the use of these products during this
review. These serious adverse events included unintentional
acetaminophen hepatotoxicity and NSAID-related GI bleeding and renal
toxicity. Although the occurrence of these events is rare, relative to
the extensive use of the products, as described in the text that
follows, FDA believes that labeling changes are necessary for the safe
and effective use of these products and to reduce the associated
morbidity.
1. Unintentional Acetaminophen Hepatotoxicity
Acetaminophen is widely available in numerous single ingredient and
combination OTC drug products, and in many prescription drug products,
as a pain reliever and/or fever reducer. OTC acetaminophen drug
products, as currently labeled and used, have been reported to be
associated with unintentional overdose that may lead to serious
hepatotoxicity (Ref. 3). The IAAA Panel discussed overdose-related
hepatotoxicity (42 FR 35346 at 35413 to 35414), and FDA addressed it in
the IAAA TFM (53 FR 46204 at 46213 to 46218). (See section II.A.1 of
this document.)
2. Aspirin and Other NSAIDs--GI Bleeding and Renal Toxicity
Aspirin and other NSAIDs are available OTC for the treatment of
minor aches and pain, for the treatment of headaches, and for fever
reduction. Per aspirin's professional labeling (not part of the OTC
drug product labeling), aspirin may be used to reduce the risk of
serious cardiovascular events when taken on a daily basis under the
direction of a physician. Aspirin is also effective in treating a
variety of rheumatologic diseases under the direction of a physician.
The professional labeling also includes information about the potential
risk of GI bleeding and renal toxicity associated with aspirin.
OTC nonaspirin salicylates include the NSAIDs ibuprofen, naproxen
sodium, and ketoprofen. The product labels for these products are not
required to contain warnings about GI bleeding and renal toxicity.
These ingredients are, however, also available by prescription at
strengths higher than in OTC products and the prescription product
labeling contains warnings about these risks.
III. NDAC Meeting
At a September 19 and 20, 2002, meeting, NDAC considered products
currently marketed with OTC IAAA ingredients, including acetaminophen,
aspirin, carbaspirin calcium, choline salicylate, ibuprofen,
ketoprofen, magnesium salicylate, naproxen sodium, and sodium
salicylate. FDA expressed its belief that these products should remain
available OTC given their overall effectiveness and safety, the benefit
to consumers of having a pain reliever and fever reducer available OTC,
and the use of these products by tens of millions of people weekly. FDA
suggested that certain interventions could decrease the frequency and
morbidity of these serious adverse events. NDAC members were asked to
consider which additional interventions were necessary to reduce the
occurrence of serious adverse events. The presentations made at the
meeting, and NDAC's findings, are summarized in this document. More
information about the September 2002 NDAC meeting is available on the
Internet and in the Division of Dockets Management (see ADDRESSES).
A. Data and Information Reviewed
FDA provided NDAC with the following data and information (Ref. 3):
Applicable sections of rulemakings for OTC IAAA active
ingredients.
[[Page 77317]]
Proposed and final rules for the alcohol warning for OTC
IAAA drug products.
Final rule for professional labeling of OTC drug products
containing aspirin.
Amendment to propose inclusion of ibuprofen in the
monograph for OTC IAAA drug products.
For acetaminophen, FDA reviews of data, poisoning data in
Toxic Exposure Surveillance System (TESS), exposure data from poison
control centers, overdose reference articles, and an abstract
describing trends in acute liver failure in the United States.
For aspirin/NSAIDs, FDA reviews of data and articles from
the medical literature.
NDAC also considered submissions and presentations from industry
and individuals during the open public sessions (Refs. 4 and 5).
B. Acetaminophen
On the first day of the meeting (September 19, 2002), NDAC
considered safety issues related to the use of acetaminophen,
unintentional overdose, and the potential for hepatotoxicity from both
OTC and prescription acetaminophen products.
1. Points for Discussion
FDA asked NDAC to discuss possible factors that might contribute to
unintentional overdose (Ref. 3) and provided the following points for
consideration:
Acetaminophen is available to consumers in many OTC and
prescription drug products (i.e., single ingredient and combinations
with various other active ingredients).
Consumers fail to identify acetaminophen as an ingredient
in their OTC and prescription drug products.
Consumers are unaware of the risks of exceeding the
recommended dose of acetaminophen with a single product, or of
simultaneously using multiple products containing acetaminophen.
FDA asked NDAC what additional measures could be taken to better
ensure that prescribers and other people are aware of the potential
risks associated with exceeding the recommended dose of prescription or
OTC drug products containing acetaminophen and with using multiple
products containing acetaminophen. FDA suggested the following possible
measures for OTC drug products:
Consumer education
Changes in labeling that identify and highlight the risks
Packaging that may enhance appropriate use
Consumer inserts.
For prescription products, FDA suggested:
Unit of use packaging with labeling on each blister pack
Physician and pharmacist education
Publication of information in professional journals
Consumer education
FDA publications to identify and highlight the danger and
risk
Providing patient information leaflets and stickers when
dispensing the prescription.
FDA also asked NDAC if there are identifiable factors that might
make some individuals more susceptible to hepatic toxicity (e.g.,
underlying liver disease, malnutrition, drug interactions, and alcohol
users). If subpopulations at increased risk of acetaminophen-induced
hepatotoxicity could be identified, FDA asked NDAC what reasonable
measures could be taken to decrease their risk. FDA suggested some
possible measures:
Adjustment of the maximum total daily dose or dosing
interval
Changes in labeling that identify the population and
highlight the risks
Additional research on specific subpopulations
Consumer and physician education.
FDA asked NDAC whether additional studies are needed to evaluate
these issues. FDA suggested a number of subjects for potential
research:
Evaluation of the effectiveness of educational programs
Evaluation of revised labeling
Surveillance of serious acetaminophen hepatotoxicity cases
Enhanced collection of information when medication errors
occur
Better understanding of consumer use of these products.
2. Presentations and Submissions to NDAC
As a lead-in to the liver toxicity discussion, Dr. William Lee, of
the University of Texas Southwestern Medical Center at Dallas,
presented the results of acute liver failure (ALF) studies in the
United States (Ref. 6). He estimated that between 1,000 and 2,000 ALF
cases occur in the United States each year and are associated with high
mortality. Dr. Lee conducted a retrospective analysis of 177 cases of
ALF reported in the literature between 1986 and 1998. Of these, 20
percent were attributed to acetaminophen toxicity. To study ALF
prospectively, Dr. Lee also formed a study group of 25 treatment
centers in 1998. Details of the group's initial 308 cases are presented
in table 1. Approximately 40 percent of the cases were due to
acetaminophen toxicity, which was increased when compared to the rate
of acetaminophen toxicity in the cohort from Dr. Lee's retrospective
analysis.
Table 1.-- Study Group Series of ALF Cases (N = 308)
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ALF Etiology
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Case Report Data All Other
Acetaminophen Induced Drug (Not Acetaminphen) Indeterminate Causes P value
(n=120) Induced (n=40) Cause (n=53) (n=95)
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Sex (% Female) 79 73 60 72 NS*
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Age (years) 36 41 38 43 0.02
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Jaundice (days) 1 12 12 4 < 0.001
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Coma (%) 50 43 47 47 NS
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Alanine aminotransferase (ALT) (International Units/ 4310 574 947 1060 < 0.001
Liter (IU/L))**
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Bilirubin 4.3 20.2 24.5 12.6 < 0.001
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[[Page 77318]]
Transplant (%) 6 53 51 36 < 0.001
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Spontaneous survival (%) 68 25 17 33 < 0.001
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Overall survival (%) 73 70 64 61 NS
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* Not significant ** ALT (normal range 0-35 IU/L)
Of the 120 acetaminophen toxicity cases identified in Dr. Lee's
series, 12 were omitted due to concomitant patient issues that would
have confounded the analysis. The remaining 108 cases were analyzed and
showed that alcohol use was reported in 57 percent of the cases and
alcohol abuse was reported in 19 percent of the cases. Individuals in
38 percent of the cases were taking both narcotic-acetaminophen
prescription products and OTC acetaminophen products at the same time,
some for as long as 2 to 3 months. In 70 percent of the cases, patients
ingested more than 4 grams (g) of acetaminophen per day (recommended
maximum daily dose), and 32 percent of the cases reported ingestion of
more than 10 g per day.
A comparison was conducted among the 108 cases of toxicity due to
accidental (ingestion of drugs for pain relief, without suicidal
intent) and suicidal (ingestion with admitted suicidal attempt)
ingestion. The type of ingestion could not be determined in 5 cases,
resulting in a comparison of 103 cases (table 2). More than half of the
acetaminophen toxicity cases (57 percent) were accidental.
Table 2.--Suicidal vs. Accidental Acetaminophen ALF Cases
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Accidental (n=59) Suicidal (n=44) p-value
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Age 39 33 0.011
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Acetaminophen total (g) 20 29 NS
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Antidepressant 36% 34% NS
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Alcohol (non-abuse use) 55% 61% NS
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Double use* 24% 5% 0.02
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Narcotic/acetaminophen 54% 14% 0.001
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ALT (IU/L) 3,616 5,929 < 0.001
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Creatine 2.5 1.3 0.008
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Survival 71% 75% NS
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* Use of more than one acetaminophen containing product.
The incidence of use of antidepressants and alcohol was nearly
identical in the accidental and suicidal groups. The accidental cases
included a larger percentage of subjects who double-dosed or used a
narcotic/acetaminophen combination product. Survival rates were also
similar. Lee concluded that acetaminophen toxicity accounted for about
a third of all deaths from ALF in this case series and appears to be a
growing problem in the United States.
FDA staff presented a safety analysis of hepatotoxicity associated
with acetaminophen (Ref. 7). The cases were reported as ``intentional
overdose'' and ``unintentional overdose.'' The reported doses were
rarely within the recommended range. Four national databases were used
to estimate the occurrence of these events:
1. National Hospital Ambulatory Care Survey: Emergency Department
(ED) Component--a probability survey sampling of visits made to
emergency departments and short stay hospitals in the United States.
2. National Electronic Injury Surveillance System--collects
information on consumer product-related injuries treated in emergency
departments of 66 selected hospitals.
3. National Hospital Discharge Survey--a probability survey
sampling of patient discharge records from non-Federal, short stay
hospitals in the United States.
4. Multiple Cause of Death Files--a data file that contains
information from death certificates.
Acetaminophen overdose (unintentional and intentional) was
associated with an annual average of over 56,000 emergency department
visits (1993 to 1999) and more than 26,000 hospitalizations (1990 to
1999). Between 1996 and 1998, an annual average of 458 deaths was
attributed, at least in part, to acetaminophen overdose. Unintentional
acetaminophen overdose was associated with an annual average of over
13,000 emergency department visits (1993 to 1999), 2,189
hospitalizations (1990 to 1999), and 100 deaths (1996 to 1998). Each
event in these tallies is independent from the others. No information
about associated
[[Page 77319]]
hepatotoxicity was available for these cases. FDA reviewed the age
distribution for acetaminophen overdoses. Medication use varies by age
and different OTC drug products containing acetaminophen are available
for different age groups. The age distribution of unintentional
overdose cases varies among reporting databases and is shown in table
3. While emergency department visits are most prevalent among young
people, this age group accounts for the lowest percentage of cases of
mortality.
Table 3.--Age Distribution of Unintentional Cases
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Age (years)
--------------------------------------------------------------------------------
<17 17--64 >65
----------------------------------------------------------------------------------------------------------------
Emergency department visit 74% 25% < 1%
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Hospitalization 23% 70% 7%
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Mortality 1% 75% 23%
----------------------------------------------------------------------------------------------------------------
Chronic liver disease has been postulated to be one of the factors
that increases the risk of hepatotoxicity from acetaminophen. Using the
multiple cause of death database, the presence of chronic liver disease
among cases of unintentional and intentional overdose with mortality
outcomes was examined (table 4).
Table 4.--Percent of Liver Disease Reported Among Fatal Acetaminophen Overdose Cases, Mortality Data, 1996-1998
----------------------------------------------------------------------------------------------------------------
Liver Disease Reported Unintentional (N=235) Intentional (N=1,010)
----------------------------------------------------------------------------------------------------------------
Chronic alcoholic 13% 1%
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Other chronic liver disease 48% 8%
----------------------------------------------------------------------------------------------------------------
These findings suggest that chronic liver disease, in the presence
or absence of alcohol, may be a risk factor for developing or
increasing severity of hepatotoxicity among people with unintentional
overdose. However, this analysis has limitations. If the presence of
alcohol or alcohol use was not mentioned on the death certificate,
alcohol related liver disease may be misclassified as other chronic
liver disease. In addition, suicide cases may be misclassified as
unintentional overdose to protect privacy.
FDA also presented an analysis of cases of hepatotoxicity
associated with acetaminophen from the published literature. A MEDLINE
search identified all U.S. case series containing at least 10 cases
that had been published in the previous 10 years (Ref. 7). Eight case
series were identified, four of which were derived exclusively from
review of hospital medical charts. In two series, cases were obtained
from hospitals, published cases, the FDA adverse event reporting
system, and poison control center databases. One case series was from a
registry of cases reported by hepatologists and other practitioners.
One case series was obtained exclusively from a consortium of liver
transplant centers. The number of cases per series ranged from 47 to
73. Two case series were largely pediatric, and the remaining six case
series consisted of largely adult populations. Six of the case series
reported gender, and in all six there was a preponderance of females.
Intentionality was reported in five of the series. Table 5 shows the
acetaminophen dose reported among in the unintentional overdose groups.
Table 5.--Hepatotoxicity Series: Unintentional Toxicity Cases
----------------------------------------------------------------------------------------------------------------
No. of Cases With Typical
Case Series Reported Daily Doses (g/day) No. of Cases in Series Daily Dose of < =4g/day
----------------------------------------------------------------------------------------------------------------
Johnston 1.3-20 53 9
----------------------------------------------------------------------------------------------------------------
Schiodt 2-30 21 3
----------------------------------------------------------------------------------------------------------------
Zimmerman ``<4''-``>15''* 67 27
----------------------------------------------------------------------------------------------------------------
Whitcomb 3.5-25 21 None
----------------------------------------------------------------------------------------------------------------
Broughan 15.9 (mean) 8 None
----------------------------------------------------------------------------------------------------------------
* Dose was reported categorically.
Nine people in the Johnston case series and three people in the
Schiodt case series ingested 4 g/day or less of acetaminophen. In the
Zimmerman case series, 27 people used acetaminophen at the recommended
dose, while 13 people used between 4.1 and 6 g/day. In the Whitcomb
case series, 3 people used acetaminophen at, or slightly above, the
recommended dose (i.e., 3.5 to 5 g/day in one case and 4 to 6 g/day in
two cases). In the Broughan case study, none of the people took
acetaminophen at the recommended dose.
[[Page 77320]]
Table 6 compares the number of deaths and serious outcomes for the
unintentional and intentional groups. Intentionality could only be
compared in the adult case series. Serious outcomes were defined as
hepatic coma, acute liver failure, and liver transplant.
Table 6.--Comparison of Unintentional and Intentional Toxicity Groups: Cases of Death or Serious Outcome
----------------------------------------------------------------------------------------------------------------
Case Series Unintentional Intentional
----------------------------------------------------------------------------------------------------------------
Johnston 17/53 NA*
----------------------------------------------------------------------------------------------------------------
Schiodt 11/21 4/50
----------------------------------------------------------------------------------------------------------------
Zimmerman 13/67 NA*
----------------------------------------------------------------------------------------------------------------
Whitcomb 5/21 NR**
----------------------------------------------------------------------------------------------------------------
Broughan 2/8 0/40
----------------------------------------------------------------------------------------------------------------
*NA: Not applicable; **NR: Not reported
FDA also presented case data from the TESS of the American
Association of Poison Control Centers (AAPCC). At that time, AAPCC had
a repository of over 27 million human poison exposures reported by over
60 participating centers. These centers covered over 90 percent of the
U.S. population. Examination of AAPCC's annual reports from 1995 to
1999 of cases listing acetaminophen as the primary (first) agent showed
acetaminophen to be the leading cause of poisonings. In 1999,
acetaminophen-related calls represented 10 percent of all calls to
AAPCC. There was a decrease in calls between 1995 (111,175) and 1999
(108,102). In 1999, nearly 50 percent of the poison victims associated
with the calls received treatment in health care facilities. Two
percent of these victims were reported to have developed major effects
resulting from the poisoning, i.e., the signs or symptoms occurring as
a result of acetaminophen exposure were life-threatening or resulted in
significant residual disability. Fifty percent of the calls involved
children and adolescents (19 years of age or under). Of the
acetaminophen related calls regarding children under 6 years of age
(approximately 40,000 calls), 22 percent occurred in children who
ingested adult formulations of acetaminophen.
In 1995, there were at least 76 acetaminophen-related fatalities.
By 1999, the number of acetaminophen-related fatalities increased to
141. Of these, 92 (65 percent) were a result of suicidal intent, 43 (30
percent) were unintentional, and the dosing intent for 6 (4 percent)
was undetermined. Among the 43 unintentional fatalities, 28 (65
percent) took one OTC drug product containing only acetaminophen; 4 (9
percent) took one prescription product containing acetaminophen, and 11
(26 percent) took more than one acetaminophen product simultaneously.
These AAPCC data may underreport the actual number of acetaminophen
toxicity cases, because serious cases that go directly to emergency
departments, and chronic users of acetaminophen, are unlikely to
generate poison control center contacts.
FDA staff reviewed spontaneous reports of hepatoxicity in FDA's
adverse event reporting system (AERS). U.S. cases were identified that
had been received by FDA between January 1998 and July 2001 and in
which one or more acetaminophen containing products had been ingested.
Of 633 reports, 43 were duplicates. Another 283 were excluded for
various reasons, primarily to exclude cases in which there was apparent
suicidal intent. A total of 307 cases were included in FDA's analysis
(25 pediatric and 282 adult cases).
Pediatric cases (of children age 1 day to 8 years) consisted
primarily of males (approximately 70 percent), although gender was not
reported in each case. Fifteen of the 25 pediatric cases involved
severe, life-threatening liver injury. Of the 25 children, 10 died, 21
were hospitalized, and 2 required only treatment in an emergency
department. The dose was estimated, based upon reported daily doses and
weight, in 10 cases to be 106 to 375 milligrams/kilogram (mg/kg) per
day. The recommended pediatric dose is 75 mg/kg/day (Ref. 7). Twenty-
two of the children (88 percent) took only 1 product containing
acetaminophen and 3 children (12 percent) took 2 or more products
containing acetaminophen. Sixteen of the cases (53 percent) reported
ingestion of a single ingredient acetaminophen product (APAP), 12 cases
(40 percent) reported ingestion of an ``unspecified APAP product'' and
the remainder of the cases reported ingestion of combination products.
Of the single ingredient products, concentrated drops containing
acetaminophen 100 mg/milliliter (mL) were reportedly ingested in seven
cases.
In 20 of the pediatric cases, 1 or more medication errors were
reported. In three cases, the wrong product was used, i.e., the
concentrated drops instead of the children's acetaminophen liquid
formulation. In four cases, incorrect measuring devices were used,
i.e., teaspoonfuls instead of dropperfuls. Five cases reported
instances of misinterpretation of labeled dosing guidelines or
misinterpretation of instructions provided by a health care provider.
Sixty percent of the 282 adult cases (15 to 85 years old) were
female and 229 required hospitalization. A total of 169 adults
experienced severe, life-threatening liver injury; 124 of these
patients died and 7 required a liver transplant. One hundred ninety-
nine (71 percent) adults reported using an acetaminophen product for a
therapeutic indication, primarily analgesia. In 74 (26 percent) cases,
the indication for use was unknown, and in 9 (3 percent) cases, abuse
of a narcotic-acetaminophen prescription product was reported. One
hundred thirty-eight (38 percent) cases listed an unspecified
acetaminophen product (unknown whether single ingredient or combination
product and whether OTC or prescription), 122 (33 percent) cases
involved the use of a narcotic-acetaminophen prescription product, and
76 (21 percent) cases reported use of an OTC single ingredient
acetaminophen product. Approximately 25 percent of all adult cases
reported use of more than one acetaminophen product. When more than one
acetaminophen product was reported, a narcotic-acetaminophen
prescription product in combination with an OTC product containing
acetaminophen was used more often than any other
[[Page 77321]]
combination of acetaminophen products. These cases also used higher
doses than people who took only one acetaminophen-containing product.
Dosing amounts were reported in 132 of the 282 adult cases. The
mean and median daily dose were 6.5 and 5 g, respectively, but ranged
from 650 mg to 30 g/day. Where the dosage strength was known, 500 mg
acetaminophen was reported most often. If a dose range was reported in
the case, the mid-point was used in the analysis. If the strength was
unknown, a 500-mg strength was assumed. Dosing in the 65 adults with
severe liver injury from this group showed a mean and median daily dose
of 7.1 and 6.23 g, respectively. Twenty-three of the 65 cases with
severe liver injury reported doses of less than 4 g/day. People who
used more than one acetaminophen product reported taking higher doses
than people who took a single product. Qualitative dosing information
was provided for an additional 43 (15 percent) cases with terms such as
``excessive doses'' or ``recommended doses.'' Two out of three of these
cases suggest that greater than recommended doses were used.
Alcohol use was reported in 116 of the adult cases and the content
of the reports was highly variable. Alcohol use in these cases was
defined by FDA as alcoholism or alcohol abuse in 64 cases; regular,
daily, or moderate use in 23 cases; occasional use in 10 cases;
previous use in 6 cases; and 13 cases did not provide a description.
Eighty-six (74 percent) of the 116 alcohol users developed severe liver
injury. For those cases with acetaminophen dose information, the mean
dose associated with toxicity was lower for alcohol users compared to
nonalcohol users (table 7).
Table 7.--Acetaminophen Dose and Alcohol Use
----------------------------------------------------------------------------------------------------------------
Category of Liver Disease (Developed Post-
Acetaminophen) Alcohol Users (Mean Dose) Non-Users (Mean Dose)
----------------------------------------------------------------------------------------------------------------
All (N=132) 5.6 g (N=53) 6.9 g (N=79)
----------------------------------------------------------------------------------------------------------------
Severe only (N=65) 6.0 g (N=38) 8.6 g (N=27)
----------------------------------------------------------------------------------------------------------------
A history of prior liver disease, or possible underlying liver
disease, was reported in 70 cases. In at least 20 of these cases, the
pre-existing liver disease was reportedly due to alcohol. Twenty-three
people reported a history of, or possible, viral hepatitis. Among the
70 cases with pre-existing liver disease, 49 percent (70 percent)
developed severe liver injury. Table 8 shows the dose that was
associated with liver injury for cases with and without pre-existing
liver disease. The first row includes all cases (all degrees of acute
liver injury) that reported dosing information. The second row shows a
dose comparison in people who experienced severe liver injury after
acetaminophen exposure.
Table 8.--Acetaminophen Dose and Liver Disease
----------------------------------------------------------------------------------------------------------------
Category of Liver Injury Associated With Cases With Pre-existing Liver Cases With No Pre-existing Liver
Acetaminophen Dosing Disease (Mean Dose) Disease (Mean Dose)
----------------------------------------------------------------------------------------------------------------
All (N=132) 5.4 g (N=36) 6.8 g (N=96)
----------------------------------------------------------------------------------------------------------------
Severe only (N=65) 5.7 g (N=23) 7.8 g (N=42)
----------------------------------------------------------------------------------------------------------------
Some additional factors may have contributed to the development of
hepatotoxicity in these adults. Use of other medications that may have
contributed to hepatotoxicity was reported in 93 cases, including 63
cases that involved products that are labeled with warnings about
potential hepatotoxicity. A small number of reports also mentioned the
existence of concomitant malnutrition or decreased oral intake.
FDA noted that there are limitations to interpreting the AERS data.
Dosing information may be unreliable. Acetaminophen products are
generally taken on an as-needed basis, so the actual dose ingested can
be difficult to ascertain. There is no certainty that all of the adult
cases included in this analysis were unintentional. Stigma may be
associated with reporting suicide, so cases may be reported as
unintentional when they were intentional overdoses. In addition,
spontaneous reporting systems cannot provide certainty that
acetaminophen was the cause of any of the reported adverse event.
Furthermore, incidence rates cannot be determined, because the
numerator or denominator descriptors for the entire population are not
available. Overall, spontaneous reports may be subject to significant
underreporting.
The AERS cases strongly suggest that particular circumstances were
likely to have led to hepatotoxicity. Some examples of those
circumstances follow:
Errors related to product confusion were mostly observed
in pediatric cases. These errors primarily involved confusion over
varying product formulations and strengths and use of inappropriate
measuring devices.
Many adults were taking more than the recommended dose of
acetaminophen and, in some cases, use of multiple products likely
contributed to hepatotoxicity.
Risk factors, such as alcohol use or pre-existing liver
disease, were identified and may have increased the risk for
hepatotoxicity.
FDA presented NDAC with several questions that remained unaddressed
by FDA's review:
Do users lack knowledge of the potential for and symptoms
of hepatotoxicity when using a product containing acetaminophen?
Does malnutrition or fasting affect severity of
hepatoxicity?
What is the contribution of concomitant hepatotoxic
medication?
What additional factors place a small number of
individuals at risk for severe hepatotoxicity at various dose levels
(i.e., under, at, or above the recommended dose)?
It is clear that unintentional acetaminophen doses are associated
with a large number of emergency department and hospital admissions and
are related to an estimated 100 deaths each year. Using a number of
data sources, analyses have shown that circumstances leading to
[[Page 77322]]
acetaminophen hepatotoxicity are multifactorial. FDA asked the
committee to consider the contribution of each of the following in
producing unintentional overdose toxicity:
Product--the ingredient is present in multiple
prescription and OTC drug products and in multiple oral formulation
strengths
Knowledge--since a number of cases have occurred from
multiple product use and overuse, there is likely a lack of knowledge
about safe use of acetaminophen
Risk factors--multiple data sources identify alcohol and
underlying liver disease as risk factors that may increase the
potential for hepatotoxicity.
Several drug manufacturers and other interested parties provided
additional comment (Ref. 4):
One major manufacturer of acetaminophen OTC drug products
provided the following comments:
1. The precise incidence of harmful, unintentional overuse cannot
be accurately determined from the current databases. Forty-eight
million American adults use products containing acetaminophen in any
single week; thus, harm is rare and is caused by inadvertent overdose.
2. There are limitations to the AERS data set for assessing hepatic
events. Patients consistently underestimate the dose taken, and suicide
attempts are often not recorded in patients who are found unconscious
or intoxicated. The AERS reports found to be definitely associated with
acetaminophen involved substantial overdose in individuals with self-
abusive behaviors (e.g., alcohol abuse, bulimia). Causality cannot be
ascertained using retrospective data, especially case reports, because
the dose history is often inaccurate.
3. Formulations most commonly reported were OTC single-ingredient
and prescription combination acetaminophen products. OTC acetaminophen
combination products were rarely reported.
4. Serious hepatotoxicity occurs following substantial overdose (a
single dose of approximately 15 g or use of approximately 12 g for
multiple days).
5. FDA focused on unintentional misuse. The manufacturer noted they
had implemented labeling changes to minimize the inadvertent overuse of
analgesics. The manufacturer recommended an organ specific overdose
warning.
One manufacturer of ibuprofen OTC drug products provided
the following comments:
1. In overdose situations, in any given year, the number of deaths
for acetaminophen reported by the AAPCC is approximately 20 times that
for ibuprofen.
2 . Unintentional overdose of acetaminophen can put consumers in a
life-threatening situation due to the delayed onset of clinical
symptoms of toxicity.
3. Advertising portrays acetaminophen as a totally safe ingredient.
This portrayal may exacerbate use and contribute to the silent danger
resulting from overdose.
One individual presented a review of acetaminophen
overdose admissions at the University of Pennsylvania hospital over a
4-year period. Fifty-four reports of acetaminophen overdose were found
in the hospital's database. Of the 47 cases reviewed to date, 23 (50
percent) were reported to be unintentional overdoses. In 13 of these 23
cases, the reviewer was able to document that an attending physician or
a psychiatry consultant concluded that there had been no suicidal
intent.
1. The median and average doses were between 6 and 8 g/day. These
values are above the recommended maximum daily dose (4 g/day), but
below the 10 to 15 g dosage usually considered to be toxic. There were
three cases of intentional overdose and three cases of unintentional
overdose involving prescription acetaminophen products. OTC products
were associated with 20 intentional and 21 unintentional overdoses.
More patients in the unintentional overdose group used single
ingredient acetaminophen (i.e., not a combination product). The primary
reason reported for exceeding the maximum dose was to treat unrelieved
pain. Many patients stated that they knew they were exceeding the
recommended dose and did so because they thought it was a safe drug.
Thirty percent of the patients used the drug over a period of greater
than 7 days.
2. The unintentional overdose group experienced greater morbidity
and mortality than the intentional overdose group. The peak
acetaminophen levels in the intentional overdose group were much lower
compared to the unintentional overdose group (27.8 versus 115.1 mg/L).
The unintentional overdose group had much higher peak levels of Alanine
aminotransferase (ALT) (5,193 versus 3,065 units/L), Aspartate
aminotransferase (AST) (6,819 versus 2,742 units/L), International
Normalized Ratio (INR) (4 versus 2.5), and total bilirubin (5.87 versus
1.87 mg/dL). Patient outcomes were generally worse in the unintentional
overdose group, in which more patients failed to have resolution of the
liver problems from the overdose (31 versus 4 percent). More patients
were evaluated for transplants (11 versus 9), received transplants (2
versus 0), and died (3 versus 0) as a result of unintentional
overdoses.
3. Compared to the intentional overdose group, the unintentional
overdose group was more likely to have one or more of the following
risk factors for acetaminophen toxicity: (1) Hepatic disease, (2) acute
or chronic alcohol use, (3) drug abuse, or (4) concomitant disease.
Ninety-six percent of cases in the unintentional overdose group had one
or more of these risk factors, as compared to 70 percent in the
intentional group. Acute and chronic alcohol use was present in 87
percent of unintentional overdose cases, as compared to 61 percent of
the intentional overdose cases. Thus, the existence of risk factors may
have an impact on toxicity in unintentional ingestions.
One individual described the untimely death of her son who
initially used a prescription product. When the prescription was
finished, he purchased an OTC acetaminophen product and developed flu
like symptoms. Another OTC acetaminophen product was subsequently used
to treat the flu symptoms, resulting in hepatotoxicity. He was
hospitalized and ultimately died.
A professional pharmaceutical association encouraged
consumers to carefully read product labeling. The association also
recommended: (1) Clear labeling on all prescription and OTC drug
products containing acetaminophen with special statements (e.g.,
``contains acetaminophen'' on the product's PDP), and (2) pharmacists
placing auxiliary labels on the vial of prescription drug products
containing acetaminophen to identify this ingredient.
A consumer public health organization described a consumer
survey showing that many consumers do not recognize the potential for
harm from: (1) Taking more than the recommended dose, (2) taking more
than one product containing acetaminophen, or (3) inappropriately
combining OTC and prescription drug products containing acetaminophen.
A member of a national health foundation expressed concern
that present marketing practices make it very difficult to find the
standard 325-mg acetaminophen dosage unit. As a result, many consumers
believe that the 500-mg product is the only one available. This failure
to more broadly market the lower dose may contribute to increased
adverse events. The individual
[[Page 77323]]
advocated educational efforts to help minimize this problem.
A spokesperson for a national consumer organization
described marketing limitations that are employed in the United Kingdom
and intended to limit the potential for overdose. In September 1998, a
restriction was placed on the number of tablets in acetaminophen
packages for sale without a prescription. If sold in a supermarket, the
maximum is 16 tablets per package. If sold in a pharmacy, the maximum
is 32 tablets per package. There is also an overall restriction that a
maximum of 100 tablets can be purchased at one time. The representative
stated that early evaluations of this program have shown decreases in
(1) total and severe acetaminophen overdoses and (2) overdoses related
to liver transplant and death.
Several drug manufacturers and others submitted additional
information for the committee to review (Ref. 5):
One major manufacturer of acetaminophen OTC drug products
provided the following comments (Ref. 5, Tab A):
1. AERS serves as a signal generating system for rare, unexpected
adverse events in marketed products. It cannot be used to determine
event rates, dose ingested, or patient dosing intent.
2. FDA's review of the AERS data set was intended to exclude
obvious suicide, usually associated with very large drug ingestion.
Thus, the reported dosage (which could only be estimated in 48 percent
of the reports in the data set) is skewed significantly toward labeled
directions for use, so cases may falsely appear to be consistent with
inadvertent misuse.
3. The selective data in FDA's AERS review cannot be used to
determine an acetaminophen toxicity threshold associated with any
patient condition (i.e., concomitant drug, alcohol history, or pre-
existing concomitant disease).
4. The quality of the 281 adult reports in AERS was evaluated by
the manufacturer. The manufacturer concluded that 168 reports (24
percent) contained insufficient information to estimate the dose taken
and 212 reports (88 percent) contained no liver pathology information.
AST and ALT levels were not reported in 108 cases (38 percent). Only 61
reports (25 percent) had information about viral hepatitis testing and,
of these, 29 reports were positive for hepatitis A, B, or C.
5. There are flaws in the derivation of FDA's theory that alcohol
use, underlying/history of liver disease, and potentially the use of
hepatotoxic concomitant medications, may increase susceptibility to
acetaminophen-associated hepatotoxicity at unexpectedly low doses of
acetaminophen. The manufacturer provided arguments that the existence
of any of these factors in a case report may each inherently interfere,
for various reasons, with establishing the correct assessment of a
hepatotoxic dose of acetaminophen.
An expert panel sponsored by a manufacturer of
acetaminophen products reviewed all 281 adult reports in AERS and
assigned a probability category relating the reported hepatic adverse
events to acetaminophen exposure. In 3 reports the adverse event and
exposure were considered ``definitely'' related, in 74 reports they
were ``probably'' related, 47 reports they were ``possibly'' related,
in 53 reports they were unlikely to be related, and in 27 reports they
were definitely not related. Data were considered insufficient in 73
reports, 3 reports were not able to be evaluated and there was no
consensus regarding the evaluation of 1 report.
Based on an assessment of several databases, a sponsor calculated
that the worst case scenario of deaths from acetaminophen overdose is
estimated to be 213 deaths per year (Ref. 5, Tab A).
One manufacturer submitted an analysis of data from TESS
(Ref. 5, Tab B). The manufacturer made the following conclusions from
these data:
1. The majority of hepatotoxicity cases (65 percent of cases in the
year 2000) involved use of one acetaminophen-containing analgesic
product.
2. Acetaminophen-containing cough/cold medications were not a
significant contributor to the total number of reports of acetaminophen
associated hepatotoxicity (2 percent of cases in the year 2000).
3. Only 1 percent of the reported cases of hepatotoxicity in 2000
involved use of an OTC acetaminophen-containing cough/cold product
concomitantly with other acetaminophen-containing product(s).
One physician stated that 3 to 4 g of acetaminophen per
day is the upper range of a safe dose (Ref. 5 Tab C). For an individual
who is a regular user of alcohol, in a prolonged fasting or in a rapid
weight loss program, the upper limit of a safe dose is unknown, but
unlikely to not exceed 2 g of acetaminophen. No data were provided to
support these observations.
Several organizations urged that labeling be improved to
provide clear directions about the appropriate doses for use and
frequency of administration, especially for combination products (Ref.
5 Tab D). Consumers need to know the type of medication and the dose of
OTC analgesic in every combination product to ensure safe and effective
use.
3. NDAC Deliberations and Recommendations Concerning Acetaminophen
NDAC unanimously agreed that the evidence of risk associated with
unintentional overdose of acetaminophen warrants FDA labeling changes,
without awaiting the outcome of further studies. NDAC noted the
following four major areas of concern:
1. Unintentional use of multiple acetaminophen containing products
2. Exceeding the recommended dose without recognizing the
consequences
3. Improper dosing of infants
4. The unknown consequences of use in special populations, such as
alcohol abusers.
NDAC recommended that the minimum requirements for change should
include, for all products containing acetaminophen (including those
available by prescription), the addition of distinctive labeling
(highlighted or bold type) on the front panel or PDP to state that the
products contain acetaminophen. FDA noted that the nonproprietary name
of prescription drugs must appear in labeling in letters at least half
the size of the brand name (see 21 CFR 201.10(g)(2)). NDAC recommended
that a similar provision also be applied to OTC drug products
containing acetaminophen, such as a standard to ensure prominence of
important information. NDAC stated that consumers need to be informed
that combining products containing acetaminophen can result in
exceeding the recommended dose.
NDAC commented that there are insufficient data in the OTC setting
on risk management, understanding consumer behavior, and the
effectiveness of warnings on labels. This lack of data makes it
difficult to determine which factors contribute to liver injury.
Although these factors are not clearly understood, NDAC concluded that
labeling revisions are needed to help minimize any risks.
Separate liver toxicity and alcohol warnings. NDAC
recommended a liver toxicity statement, separate from the alcohol
warning, be added to the label so that the potential for liver toxicity
would not appear to be applicable only to consumers who drink alcohol.
NDAC noted that alcohol is not the only risk factor for hepatotoxicity.
It was also felt to be important to warn consumers of the consequences
of taking multiple products containing acetaminophen and that toxicity
can be related to the total
[[Page 77324]]
dose of acetaminophen taken during a given period of time. NDAC felt it
would be more prudent to describe these risks in a separate warning to
more fully inform consumers who do not abuse alcohol.
NDAC did not propose exact language. It was believed that it was
important that the message not refer to ``overdose,'' but rather to a
statement such as ``do not take more'' or ``do not exceed the
recommended dose.'' NDAC believed that the term ``overdose'' would not
be understood to be pertinent to consumers whose intent was to use the
product safely. One NDAC member stated the term ``exceed'' is not part
of consumers' common vocabulary and proposed that it would be more
useful to inform consumers of a specific allowable total dose (e.g.,
not to take more than a specified number of tablets in a given period).
NDAC re-examined the currently required alcohol warning for
acetaminophen, which states: ``Alcohol Warning: If you consume 3 or
more alcoholic drinks every day, ask your doctor whether you should
take acetaminophen or other pain relievers/fever reducers.
Acetaminophen may cause liver damage.'' NDAC inquired why ``three
drinks'' were used in the alcohol warning. FDA responded that the
number is from recommendations of the American Heart Association as to
what constitutes excessive alcohol use. FDA stated that it recognized
this may seem arbitrary and asked NDAC to provide further
recommendations. NDAC questioned whether doctors are well-informed with
proper information about the relationship between alcohol and
acetaminophen use and whether educational efforts should also include
educational efforts directed at health care professionals and
consumers. NDAC was concerned about the lack of available data on which
to base such advice, noting that there is a lack of information about
how to determine the amount of alcohol that may be harmful to any
individual. NDAC noted that reducing the risk of drug adverse events is
the goal, but believed that more data are essential for them to make
specific recommendations.
FDA asked NDAC to comment on whether the current maximum allowable
daily dose of acetaminophen should be used by individuals consuming
three or more drinks per day. One NDAC member agreed that was prudent
to lower the dose, however, the majority of NDAC members believed that
more information is needed before dose reductions could be implemented
for this population. NDAC stated that, intuitively, a lower dose would
decrease potential toxicity, but noted that there is a lack of
information to support such labeling.
One NDAC member mentioned that although some evidence appeared to
show an association of increased acetaminophen toxicity for patients
with pre-existing liver disease, this finding is contrary to
hepatologists' experience with acetaminophen. Generally, acetaminophen
is considered safe for use in patients with liver disease, including
people awaiting liver transplantation. Most hepatologists recommend
acetaminophen for such patients, but at reduced doses, such as 2 g
maximum in a 24-hour period. NDAC urged more studies, not only of risk
factors, but of a plan to reduce risk.
Consumer and healthcare provider education. NDAC concluded
that FDA and manufacturers have a joint responsibility to reduce the
occurrence of unintentional overdoses from acetaminophen. NDAC
considered it essential that consumer and professional educational
programs heighten awareness of the risk, particularly to certain
populations. NDAC believed consumers are unfamiliar with the term
``acetaminophen'' and are more likely to know the brand names. NDAC
stated that an effort should be made to create a broader educational
campaign to inform consumers that acetaminophen is an analgesic,
because most people are familiar with aspirin and not with
acetaminophen. NDAC also suggested that the packaging, display, format,
and wording recommendations in OTC drug product labeling should also be
extended to all product advertisements, both in print and media,
because advertising is an educational tool for many consumers.
NDAC stated that many physicians and pharmacists may not be aware
of the risks of unintentional overdose. NDAC added that, along with
consumer education, professional programs are important, because
prescription products containing acetaminophen are widely used.
Education of pharmacists would be needed to support the use of
additional labeling information (stick-on labels, etc.) attached to
prescription containers. NDAC stated that auxiliary labeling is
critical to conveying information that the prescription product
contains acetaminophen.
Pediatric dosage. NDAC also expressed concern about the
lack of standardized pediatric dosage information, especially for
infants under 2 years of age. FDA stated that a separate rulemaking on
this issue was in progress and will be addressed in a future Federal
Register publication.
C. Aspirin and Other NSAIDs
On the second day of the meeting (September 20, 2002), NDAC
considered safety issues related to the use of aspirin and other OTC
NSAIDs. The primary areas for discussion included the potential for GI
bleeding and renal toxicity from using these drugs. The prescription
labeling for NSAIDs and the professional labeling for aspirin have
warnings for GI bleeding and possible renal toxicity. Aside from the
alcohol warning required on all OTC NSAID drug products, current OTC
labeling does not have warnings about damage to specific organs.
1. Points for Discussion
FDA asked NDAC to consider the relative risks for GI bleeding and
renal toxicity associated with OTC doses of NSAIDs, including aspirin,
and to consider the following issues:
How should the relative risk of GI bleeding or renal
toxicity be described to consumers who use the maximum recommended
daily OTC dose?
Are there subpopulations of consumers who are at a greater
risk for developing GI bleeding or renal toxicity with OTC doses?
If additional warnings are recommended, should such
warnings inform consumers about the risk, provide information on the
at-risk populations, or provide expanded information to all consumers
about symptoms of toxicity?
Should the warnings that are currently in professional
labeling for aspirin be conveyed to consumers as part of the OTC
labeling?
If yes, which warnings should be conveyed and how should
they appear in OTC drug product labeling?
Are any additional studies needed to evaluate
subpopulations at risk for serious adverse events, labeling revisions,
and any other issues?
Should the labeling and packaging of these products more
prominently state that the product contains aspirin or the specific
NSAID?
2. Presentations and Submissions to NDAC
GI bleeding
FDA staff described cases of GI bleeding (spontaneous reports from
AERS received by FDA between 1998 and 2001) in individuals who used OTC
NSAIDS (including aspirin) as an analgesic and/or antipyretic (Ref. 8).
The review was limited to cases that mentioned ``OTC'' in the narrative
of the report. Any cases that appeared to involve prescription NSAID
products were excluded. A total of 279 cases of
[[Page 77325]]
GI bleeding were included: 82 for aspirin and 197 for nonaspirin NSAIDs
(i.e., ibuprofen, ketoprofen, and naproxen). The mean age was 59 years
(ranging from 1 to 99 years). There were 138 (49.5 percent) males, 119
(42.7 percent) females, and 22 cases (7.9 percent) in which gender was
not reported.
Cases that specified the location in the GI tract of the bleed
included: Stomach (63 cases), duodenum (35 cases), unspecified upper GI
site (15 cases), esophagus (13 cases), and rectum/colon/small intestine
(9 cases). For nonaspirin NSAIDs, the median time to onset was 7 days.
Time to onset was defined as the time between each person's first use
of the drug and the time that bleeding occurred. For aspirin, time to
onset was about 30 days. For both aspirin and nonaspirin NSAIDs, there
was a wide range in time to onset. FDA reviewed the cases for common
risk factors for GI bleeding that are recognized in the medical
literature, including previous GI bleed or history of an ulcer, social
history (alcohol or tobacco use), concomitant use of other drugs
(NSAIDs, aspirin, anticoagulants, corticosteroids), use of doses higher
than recommended, and advanced age (65 years and older). The results
included 195 (70 percent) cases with at least one risk factor, 112 (40
percent) cases with more than one risk factor, and 81 (29 percent)
cases with no risk factors apparent in the report. The most commonly
reported risk factors were:
Concomitant use of another NSAID or aspirin (50 percent)
Advanced age (40 percent)
History of a previous GI bleed (18 percent)
Using NSAID doses above the recommended OTC dose (14
percent)
Alcohol or tobacco use (5 percent).
In the aspirin cases, only one person was reported to have exceeded
the OTC recommended dose. Of the 279 aspirin and nonaspirin cases, 212
people (76 percent) were hospitalized. Most recovered; however, 13 (4.7
percent) people died.
FDA indicated that these reports suggest that serious GI bleeding
events can occur with NSAID and aspirin use at OTC dosage strengths,
within the duration of use described in the OTC labeling.
Dr. Byron Cryer, of the University of Texas Southwestern Medical
School, provided an overview of the GI risks from NSAID use (Ref. 9).
His review was not limited to OTC dosing of NSAIDs and extended to all
NSAIDs. He made the following points:
Despite the overall decrease in prevalence of
uncomplicated ulceration, the incidence of complicated ulcerations
(specifically, bleeding ulcers) has increased in the past few years.
This is likely due to increased NSAID exposure, possibly from OTC use.
Gastric ulceration (15 percent prevalence) associated with NSAIDs (at
recommended doses) is much more common than duodenal ulceration (5
percent prevalence). Clinically relevant ulceration (i.e., ulcers that
present with bleeding), has a prevalence of approximately 2 percent.
A history of prior bleeding, anticoagulant use,
corticosteroid use, and increasing age are factors that increase the
risk of bleeding associated with NSAIDs (Refs. 10 through 13).
The prevalence of upper GI bleeding from aspirin use is
different than for nonaspirin NSAID use. A study evaluated the
prevalence of aspirin and nonaspirin NSAID use in 421 patients
evaluated for upper GI bleeding (Ref. 14). Patients were asked at the
time of hospital admission whether they were using prescription or OTC
products and whether they were using nonaspirin NSAIDs or aspirin. The
results show that 42 percent of GI bleeding was associated with aspirin
use. Fourteen percent of patients admitted to the hospital were using
prescription NSAIDs and 9 percent were using OTC NSAIDs.
A recent study suggests that up to 80 percent of people
with GI bleeding are taking an NSAID, primarily low dose aspirin (Ref.
15). The relative risk (RR) (i.e., the probability of an event in the
active group divided by the probability of the event in the control
group) was 2.4 for a low/medium NSAID dose and 4.9 for a high dose.
Another study compared the use of OTC aspirin, ibuprofen,
naproxen, and acetaminophen between two case groups, one group who
experienced GI bleeding events and a control group of cases who did not
experience GI bleeding (Ref 16). The patients in the GI bleeding group
were more likely to be taking aspirin or OTC NSAIDs prior to the GI
bleeding event than were patients in the control group. The extent of
use of acetaminophen was comparable between the two groups. This study
included people with chronic disease and chronic analgesic exposure,
providing information about a subgroup of patients that may be
different from relatively healthy individuals exposed to OTC analgesics
for acute, short-term, or intermittent use.
The risk of combining low dose aspirin with nonaspirin
NSAIDs was examined in a large national cohort study in Denmark (Ref.
17) in which 27,000 people were given 100 to 150 mg aspirin every day.
The study showed that there is an increased risk of upper GI bleeding
in patients who combine low dose aspirin and other NSAIDs compared to
the incidence of GI bleeding events in the general population (RR 5.6;
95% confidence interval (CI) 4.4--7.0). The risk of GI bleeding among
patients taking more than one NSAID was approximately double the risk
among patients taking aspirin alone.
In an American College of Gastroenterology Bleeding
Registry (Ref. 18), cases of GI bleeding were assessed for use of
aspirin or OTC NSAIDs and concomitant use of alcohol. These cases were
compared to data from a control cohort of cases with no GI bleeding.
The results suggest an increased risk of bleeding when alcohol is used
while taking an OTC NSAID (odds ratio 4.47; 95 percent CI 2.73 -7.32)
compared to the use of either alcohol or OTC NSAIDs alone (odds ratio
for alcohol alone 2.07; 95 percent CI 1.48--2.88/ odds ratio for NSAID
alone 2.76; 95 percent CI 2.03--3.74). Dr. Cryer noted that the results
of the study were confounded because 12 percent of the subjects in the
registry had gastric or esophageal varices (enlarged veins). He
suggested that there may be an increased risk particularly to patients
with an extensive history of alcohol use who are exposed to OTC NSAIDs.
Another report (Ref. 19) evaluated subjects who regularly
or occasionally used aspirin or ibuprofen and compared the RR of GI
bleeding between those who never used alcohol and those who used
alcohol. The results suggest a modest increase in RR of upper GI
bleeding in alcohol users; however, the statistical analyses did not
provide a strong distinction between alcohol users and non-users.
Dr. Marie Griffin of Vanderbilt University discussed additional
information obtained from large population studies regarding GI
complications associated with the use of NSAIDs (Ref. 20). She made the
following points:
The risk of ulcer disease was shown to increase 10-fold in
older people and this risk is increased further by use of NSAIDs (Ref.
21). This ulcer hospitalization study found the absolute risks to
increase from approximately 4 hospitalizations per 1,000 person-years
in older non-users of NSAIDs to approximately 16 hospitalizations per
1,000 person-years in older users of NSAIDs. In general, consumers
taking NSAIDs for a year at moderate doses have about a 1 to 2 percent
chance of being hospitalized with a complication.
[[Page 77326]]
The risk of hospitalization for peptic ulcer disease
(PUD), and risk of GI complications, increases with increasing NSAID
doses (Refs. 20, 22, and 23).
Data obtained from the Tennessee Medicaid database
indicate that the greatest absolute risk for hospitalization for PUD
occurs in the first 30 days of NSAID use among patients older than 65
years of age (Ref. 23). For older patients, there were 26.3
hospitalizations for PUD per 1,000 NSAID users per year within 30 days
of starting NSAID therapy, 20.9 hospitalizations between 31 and 180
days of use, and 16.2 hospitalizations for use longer than 180 days. In
contrast, there were 4.2 hospitalizations per 1,000 NSAID non-users per
year. Overall, people of all ages have a 1 to 2 percent chance of being
hospitalized with a complication when using NSAIDs for over a year at
moderate doses.
Surveys in the 1980s showed that approximately 1 to 3
percent of people 65 and older take a prescription corticosteroid drug.
The concomitant use of an OTC NSAID with a corticosteroid increases the
risk of ulcer complication 13- to 15-fold over NSAID non-users. The
ulcer hospitalization rate in people using both drugs was about 5 to 6
per 100 people per year.
In the 1980s, 1 to 2 percent of the elderly population
were co-prescribed warfarin (an anticoagulant drug) and NSAIDs. The
risk of GI bleeding increased by 12 fold in patients who used both
therapies compared to NSAID non-users. The risk of hospitalization for
GI bleeding is approximately 3 per 100 per year in patients who use
warfarin and NSAIDs.
Several drug manufacturers and others provided additional comments
(Ref. 4):
One drug manufacturer of ibuprofen OTC drug products
stated that the OTC ibuprofen daily regimen is 1,200 mg/day versus
2,400 to 3,200 mg a day for prescription use. Unlike acetaminophen, the
OTC directions clearly state to take one 200-mg tablet and, only if
necessary, a second tablet may be taken. OTC use of NSAIDs is limited
to a maximum of 10 days, whereas prescription use is chronic.
One drug manufacturer stated that each analgesic
ingredient requires appropriate labeling for its pattern of use and
that it is inappropriate to label OTC products with risks associated
with chronic, long-term prescription dosing. The prescription and OTC
uses of NSAIDs are distinct and these two dose levels have different
risk-benefit profiles. The OTC use is short-term for pain relief and
fever reduction, with a low risk. Results of prevention studies of
secondary and acute myocardial infarction have shown that for people
whose 10-year risk of having a subsequent cardiovascular event is
between 20 and 50 percent, the cardiovascular benefit of aspirin far
outweighs the risks. The relative and absolute risks of aspirin are
low.
One consumer advocacy organization stated that GI bleeding
caused by NSAIDs (reference to prescription or OTC products was not
specified) is now recognized as the most common serious adverse drug
reaction in the United States and accounts for as many as 16,000 deaths
a year. The organization requested that: (1) Product labeling contain a
clear organ-specific warning about GI bleeding, (2) packaging include
consumer education on GI bleeding, such as a leaflet inside the
packaging listing specific symptoms and factors associated with
increased risk, and (3) a separate warning, about increased risk of GI
bleeding associated with alcohol use, be added and directed at
consumers who drink some alcohol.
Several drug manufacturers submitted additional information (Ref.
5):
One manufacturer stated that the safety profile for OTC
ibuprofen, generated over 18 years of OTC use by millions of consumers,
indicates that the current labeling has been effective in informing
consumers of the appropriate use of the drug (Ref. 5, Tab E). The
manufacturer stated that FDA has received an average of 18 reports per
year of GI perforations, ulcers, or hemorrhage associated with OTC use.
One manufacturer stated that no antidote is available for
aspirin or ibuprofen overdose (Ref. 5 Tab F). Acute overdose and
chronic aspirin toxicity are associated with significant morbidity (as
high as 25 percent). If acetaminophen was restricted, aspirin and other
NSAID use would increase. Available data suggest that more people would
die from aspirin and other NSAID-related GI bleeding. The net public
health impact of changing labeling for OTC IAAA drug products should be
taken into consideration in the formulation of any regulatory policy.
One manufacturer stated that the risk patterns associated
with use of acetaminophen and aspirin are distinct from one another and
support different product labeling for the various ingredients in OTC
IAAA drug products (Ref. 5, Tab G). There are no data to support the
view that a balanced warning for acetaminophen will cause a significant
number of patients to switch to another OTC analgesic. Available data
indicate that both the absolute number, and the rate (per billion
tablets sold), of fatalities associated with acetaminophen overdose in
the United States significantly exceeds the corresponding figures for
aspirin overdose.
One manufacturer stated that the occurrence of GI adverse
events with naproxen/naproxen sodium at single low dose (220 mg), at
multiple doses (up to 880 mg), and as needed OTC doses, are comparable
to the occurrence associated with use of placebo (Ref. 5, Tab H).
Nausea, dyspepsia, and vomiting are the most common GI adverse events.
Renal effects
FDA staff presented information about the potential for OTC NSAIDs
to cause nephrotoxicity (Ref. 24) and made the following points:
NSAID-induced nephrotoxicity at prescription doses is
characterized by fluid and electrolyte disturbances leading to sodium
retention, edema (accumulation of watery fluid in cells and tissues),
and hyperkalemia (high concentration of potassium in the blood). These
drugs can also cause blood pressure to increase. The majority of
healthy people who are exposed to therapeutic doses of NSAIDs for a
limited time tolerate these drugs without untoward renal effects. Some
subsets of the population are more susceptible to potentially life-
threatening nephrotoxicity (e.g., acute renal failure and serious fluid
and electrolyte disorders), including people who have volume depletion,
underlying kidney disease, congestive heart failure, or liver
dysfunction with ascites (accumulation of fluid in the peritoneal
cavity of the abdomen), and the elderly. The use of NSAIDs in the last
trimester of pregnancy has been associated with significant neonatal
nephrotoxicity.
Ideally, an assessment of the nephrotoxic risk associated
with OTC NSAIDs should rely on data derived from prospective,
randomized, placebo-controlled and adequately powered studies in
healthy, as well as at-risk, populations. However, such data are not
available. In 1995, the National Kidney Foundation (NKF) convened a
group of investigators and clinicians to consider and develop
recommendations on the issue of analgesic-related kidney disease. The
database used to make their recommendations was comprised of 556
articles published in the medical literature on aspirin, acetaminophen,
aspirin-acetaminophen combinations, and NSAID-related nephrotoxicity.
The NKF recommended ``[t]here should be an explicit label warning
people taking over-the-counter NSAIDs of the potential renal risks of
consuming the drugs.''
[[Page 77327]]
FDA staff identified all cases in the AERS database
reporting acute renal failure, chronic renal failure, and renal failure
in association with the use of OTC doses of NSAIDs. The time period
reviewed was from the OTC approval date for ibuprofen (1984), naproxen
sodium (1994), and ketoprofen (1995) through August 10, 1999. FDA's
review included cases that specified that either OTC dosages and/or an
OTC NSAID product had a role in the adverse reaction. People with pre-
existing conditions were not included. Table 9 shows the number of
cases of renal failure reported, including 94 cases for ibuprofen, 26
cases for naproxen sodium, and 1 case for ketoprofen. Fifty-six people
who used ibuprofen required hospitalization; nine needed dialysis; and
nine died. Renal failure occurred within less than 7 days of exposure
to the drug. Fourteen ibuprofen cases were within the pediatric age
group. For naproxen sodium, 25 people were hospitalized, 4 required
dialysis, and 3 died. The single ketoprofen case was hospitalized.
Table 9.--FDA AERS Cases of Renal Failure at OTC Doses of NSAIDs
----------------------------------------------------------------------------------------------------------------
Ibuprofen Naproxen Sodium Ketoprofen
----------------------------------------------------------------------------------------------------------------
Reporting Period 15 years 5 years 4 years
----------------------------------------------------------------------------------------------------------------
Renal Failure Cases-- 94 26 1
Total
----------------------------------------------------------------------------------------------------------------
Renal Failure Cases-- 80 26 1
Adult
----------------------------------------------------------------------------------------------------------------
Renal Failure Cases-- 14 0 0
Pediatric
----------------------------------------------------------------------------------------------------------------
Next, Dr. Griffin discussed renal complications from the use of
NSAIDs obtained from large population studies (Ref. 20). A study of
patients 65 years of age and older in the Tennessee Medicaid database
(Ref. 23) included the following information:
Eighteen percent of the patients presenting with acute
renal failure used NSAIDs at either prescription or OTC doses. A RR for
acute renal failure in NSAID users was calculated to be 1.58 compared
to NSAID non-users.
The RR for acute renal failure with ibuprofen was dose
related. The RR of acute renal failure associated with use of daily
doses of less than 1,200 mg was approximately 1 compared to use of no
ibuprofen. Daily doses of 1,200 to 2,400 mg (above the OTC range of
1,200 mg per day or less) increased the RR of renal failure to 1.89.
The greatest risk for renal failure was within the first
30 days of therapy with an NSAID. The RR was 2.83.
Several drug manufacturers and others provided additional comments
(Ref. 4). One drug manufacturer stated that the incidence of renal
failure and other serious renal events are rare with use of either
prescription or OTC ibuprofen. One drug manufacturer claimed that there
was an average of approximately five reports of renal failure per year
from FDA's safety surveillance data. The manufacturers also suggested
that serious renal events are almost always reversible, even in the
elderly or chronically ill. It was stated that serious renal events
following NSAID therapy almost always occur in patients with pre-
existing renal dysfunction, congestive heart failure, or compromised
hepatic function.
Several drug manufacturers submitted additional information
suggesting that (Ref. 5):
The number of renal side effects that have been reported
with OTC ibuprofen are minimal (less than two cases of renal failure
per year), confirming that the drug is well-tolerated.
The renal safety profile of naproxen/naproxen sodium is
consistent with other currently marketed NSAIDs with which it has been
compared. Even at prescription doses, reports of adverse events
involving the kidney have been rare.
3. NDAC Deliberations and Recommendations Concerning Aspirin and Other
NSAIDs
GI bleeding. NDAC members agreed that NSAIDs increase the
risk for GI adverse events. The risk appears to be related to dose.
Aspirin, even at lower doses, has some GI risks. However, the benefits
from use far exceed any risks. NDAC stated that low dose aspirin should
be available OTC for the elderly for cardiovascular prophylaxis as
described in the professional labeling. NDAC believed that the absolute
risk of GI bleeding from use of low dose aspirin is probably comparable
to the risk from using aspirin at analgesic doses. Therefore, NDAC
recommended that the information on risk provided in OTC aspirin
labeling to consumers need not be categorized by dose.
NDAC agreed that the data support a separate and distinct stomach
bleeding warning and suggested that the heading ``stomach bleeding
warning'' be used. NDAC recommended that this heading be in bold type
and that the warning be included as one of the first warnings in
labeling along with the Reye's syndrome warning. One NDAC member
suggested the heading ``bleeding alert'' because aspirin and the other
NSAIDs can cause more than stomach bleeding, and it is very important
to stop using an OTC IAAA active ingredient when signs of bleeding are
present (e.g., vomiting blood or bloody or black stools). Most NDAC
members felt that stomach bleeding was the major safety problem and
should be the focus of the warning statement.
NDAC found that low dose aspirin, combined with another NSAID, will
increase the risk for GI bleeding two to four times more than use of an
NSAID alone. From the data reviewed, enteric-coated or buffered aspirin
preparations do not change the risk associated with use of multiple
NSAID products. NDAC recommended that the labeling for aspirin and
other NSAIDs include a stomach bleeding warning advising consumers of
the risks of taking more than directed or using more than one NSAID. In
addition, NDAC concluded that the warning should advise consumers that
the risk is greater for individuals who are over 65 years of age, have
a history of ulcers, stomach, or bleeding problems, or are taking
steroids or anticoagulants (blood thinners).
A majority of NDAC members believed that there were insufficient
data and a lack of a scientific rationale to support a warning about
using alcohol while taking NSAIDs. Recognizing that the data are mixed
and not conclusive, the members believed that a majority of the trials
reviewed failed to show a direct and convincing association with
alcohol. NDAC urged FDA to remove the existing alcohol warning from
labeling and encouraged
[[Page 77328]]
FDA to examine future cases of GI bleeding in individuals who consume
alcohol and are alcohol abusers to explore the impact of concomitant
use of NSAIDs.
Renal effects. NDAC considered particular groups at risk
for short-term adverse renal consequences from NSAID use. While NDAC
agreed that small increases in blood pressure of limited duration
(e.g., several days) in normotensive or hypertensive individuals is not
a significant risk, the labeling for NSAIDs should warn about the
potential association of long-term use and renal failure in individuals
who have high blood pressure, heart or kidney disease, use diuretics,
or are over 65 years of age. NDAC agreed with the OTC labeling proposed
for ibuprofen in the Federal Register of August 21, 2002, including the
warning to ask a doctor before use in the presence of high blood
pressure, heart or kidney disease, if also using a diuretic, or if over
65 years of age.
Labeling. NDAC members agreed that labeling continues to be a major
factor in promoting the safe and effective use of OTC NSAID products.
NDAC expressed concern that consumers do not read labels adequately and
are often unaware of the names of the medicines that they are taking.
This lack of awareness is especially problematic for people who are
also taking prescription medicines concomitantly with OTC drug
products. NDAC expressed concern about the ability to communicate
meaningful information in the confines of a small package label,
especially to the elderly. NDAC suggested that patient information be
included in a package insert to provide expanded information beyond
what could be presented clearly on a small label.
NDAC strongly recommend that the term ``NSAID'' be used throughout
OTC product labeling. The term NSAID is becoming more widely recognized
and is often found in drug information leaflets. NDAC suggested that
meaning of the NSAID acronym could be spelled out somewhere on the
label. Additionally, NDAC recommended that this term should be included
on the front panel or PDP, advising consumers that the product contains
an NSAID, especially if the product is a combination containing an
NSAID. Finally, NDAC members agreed that there is a need for additional
label comprehension studies to identify ways to improve communication
with consumers.
IV. FDA's Review of Additional Data and Information
A. Pre-existing Liver Disease as a Risk Factor for Acetaminophen
Hepatotoxicity
Following publication of the OTC IAAA TFM in 1988, FDA received
comments urging adoption of a warning to advise consumers with pre-
existing liver disease against using acetaminophen, unless directed by
a doctor. The comments cited reports in the medical literature
concerning toxicity in persons with liver disease. Other comments
asserted that there is no evidence to warrant a warning. At that time,
FDA believed the evidence was insufficient to propose a warning. NDAC
briefly discussed this issue in September 2002, but concluded that
there were not sufficient data to make specific recommendations.
FDA has reconsidered its previous position on this issue and now
believes that the current evidence supports a warning. At the NDAC
meeting, FDA reported information derived from mortality data of
acetaminophen overdose (intentional and unintentional). Among patients
with chronic alcoholic or other chronic liver disease, death associated
with unintentional acetaminophen overdose was reported far more
frequently than in association with intentional overdose (see table 4
of this document). In the series of 282 AERS cases of hepatoxicity
associated with acetaminophen use presented at the meeting, 70 cases
were reported as having underlying liver disease.
Metabolic activation and deactivation are involved in acetaminophen
elimination (Ref. 25). At a therapeutic dose, the majority (greater
than 90 percent) of acetaminophen combines with glucuronic acid (the
major metabolic pathway for adults) and sulfuric acid (the major
metabolic pathway for children). There is also a second, minor
metabolic pathway in which a small portion of acetaminophen undergoes
cytochrome P450 phase I metabolism to the toxic acetaminophen
metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). This toxic metabolite
is normally inactivated through combination with hepatic glutathione
(GSH). Any factors that can change GSH availability (by decreasing
synthesis and/or increasing utilization or interfering with the
conjugation enzyme) could potentially influence the hepatotoxicity of
acetaminophen. Any factors that disturb the balance between these two
metabolic pathways may affect the amount of acetaminophen metabolized
by each pathway. After the NDAC meeting, FDA conducted a literature
review (1966 to January 2003) and determined that the following factors
may place patients with pre-existing liver disease at a greater risk
for acetaminophen toxicity (Ref. 26).
Depletion of hepatic GSH has been found in both alcoholic
and nonalcoholic liver diseases, suggesting that the diseased liver may
have less capacity to inactivate the toxic metabolite of acetaminophen.
(Refs. 27 through 34)
The hepatic cytochrome P450 enzyme, P450-2E1, metabolizes
acetaminophen to the toxic metabolite that causes hepatotoxicity.
Expression of hepatic P450-2E1 tends to increase in stable chronic
liver diseases.
Studies have shown that the clearance of acetaminophen
from the body is impaired in people with chronic liver disease (Refs.
35, 36, and 37). The disease status of the liver alters drug metabolism
and drug metabolites made by each metabolic pathway (Refs. 38 and 39).
In chronic liver disease, hepatic glucuronide and sulfate
conjugation are decreased (Refs. 40 through 43).
Significant impairment of total hepatic P450 expression is
found only in people with severe liver disease (hepatitis with liver
failure and decompensated cirrhosis) (Ref. 38). Recent studies indicate
that different types (viral, chemical, or immunological factors) and/or
states (acute, chronic, or severe) of liver disease selectively
influence expression of different P450 isozymes.
Chronic alcohol use significantly induces hepatic P450-2E1
and increases this enzyme's ability to metabolize acetaminophen to
NAPQI (Ref. 44). In other types of human liver disease, changes in
expression and activity of P450-2E1, as well as other P450 isozymes
(1A2 and 3A4) involved in acetaminophen metabolism, are variable (Refs.
38, 45, 46, and 47). Both human and animal studies show that hepatic
P450-2E1 expression is significantly increased in a nonalcoholic fatty
liver (Refs. 48 and 49).
Few clinical trials directly assess the hepatotoxicity of
acetaminophen in people with nonalcoholic liver disease. One double-
blind, placebo controlled, crossover study was conducted in 20 people
with stable chronic liver disease (including Laennec's cirrhosis,
alcoholic liver cirrhosis, primary biliary cirrhosis, or chronic
hepatitis) (Ref. 50). The subjects received 1 g of acetaminophen or
placebo every 4 hours (a total of 4 g/day) for 13 days. The author
stated that there were no significant changes in laboratory tests or
clinical status in the
[[Page 77329]]
acetaminophen and placebo treatments. The author concluded that
underlying liver disease does not increase patient sensitivity to the
hepatotoxic effects of acetaminophen at a therapeutic dose. Because of
the small sample size and crossover study design, FDA believes this
study is inadequate to make any conclusions regarding the risk for
acetaminophen hepatotoxicity in patients with chronic liver disease.
In summary, the single prospective clinical study found by FDA in
the literature that evaluated the susceptibility of the diseased liver
to acetaminophen toxicity was not definitive. Analyses of an
acetaminophen overdose database and a review of the AERS case reports
suggest, however, that people with a history of liver disease may have
increased susceptibility to acetaminophen-induced hepatotoxicity. In
addition, the depletion of hepatic GSH has been found in both alcoholic
and nonalcoholic liver diseases, suggesting that the diseased liver may
have less capacity to inactivate the toxic metabolite of acetaminophen.
Expression of hepatic P450-2E1, a major enzyme for metabolic activation
of acetaminophen, tends to be increased in stable chronic liver
diseases, particularly in nonalcoholic fatty liver disease. FDA
believes that these data collectively establish that it is necessary to
alert patients with chronic liver disease that they may be at risk for
developing acetaminophen hepatotoxicity, as an important factor in the
safe and effective use of acetaminophen products.
B. Updated Literature About Acetaminophen Hepatoxicity
The Acute Liver Study Group recently published an update of the
prospective data in patients diagnosed with ALF at 22 tertiary care
centers. Over a 6-year period from January 1, 1998, to December 31,
2003, 662 patients fulfilled standard criteria for ALF. Of these cases,
275 were attributed to acetaminophen hepatotoxicity. The criteria for
attribution to acetaminophen included one or more of the following: (1)
A history of potentially toxic acetaminophen ingestion (> 4 g/day)
within 7 days of presentation; (2) detection of any level of
acetaminophen in the serum; or (3) a serum alanine aminotransferase
(ALT) > 1,000 IU/L with a history of acetaminophen ingestion,
irrespective of acetaminophen level (Ref. 51).
Of the 275 cases attributed to acetaminophen, the following
observations were made:
48% were designated as unintentional injury, 44% were
designated as an intentional injury and 8% could not be classified to
either group;
147 (53%) used an OTC product, including 6 of 147 who used
more than one OTC product at the same time and 41 of 147 who also used
a prescription combination product;
120 (44%) reported use of a narcotic/acetaminophen
combination;
55% had a history of alcohol use and 35% had a history of
alcohol abuse;
108 (39%) also used a antidepressant;
65% survived without transplant; and
22% used more than one acetaminophen product.
The authors also compared characteristics between those classified
as unintentional versus intentional liver injury. Females predominate
in both groups. The clinical outcomes are similar for both groups.
Narcotic/acetaminophen use was more prevalent in the unintentional
injury group (63% vs. 18%). The unintentional injury group had a
greater percentage with stage 3-4 hepatic coma score at admission and
at peak during the hospitalization. FDA believes that these data
support the previous NDAC conclusion that acetaminophen hepatotoxicity
is an important public health consideration and that additional
labeling is necessary for it to continue to be generally recognized as
safe and effective.
C. Aspirin and Other NSAIDs
1. GI Bleeding
Following the NDAC meeting, FDA reviewed additional data and
information related to the use of OTC NSAIDs and GI bleeding.
One individual asserted in a citizen petition that
incomplete information about aspirin reaches consumers and increases
the danger that aspirin will be misused with serious consequences (Ref.
52). The citizen petition suggested that additional labeling for
aspirin should be implemented without delay to state: ``CAUTION: This
product can cause severe hemorrhaging and should not be taken for more
than five days except under the supervision of a physician. When used
for fever, if symptoms persist more than three days, consult a
physician.''
NSAIDs are being used by an estimated 17 million Americans
on a daily basis (Ref. 53). The estimated rate of serious adverse
events is about 1 percent for clinically significant GI bleeding in the
first 3 months of use (Ref. 54). NSAID use is so widespread that NSAID-
induced gastropathy has been identified by some as one of the most
prevalent, serious drug toxicities in the United States (Ref. 55).
NSAID-associated serious GI complications are estimated to result in
over 200,000 hospitalizations per year in the United States. Although
these adverse event rates are for prescription and OTC NSAID
formulations combined, there is a significant prevalence of OTC NSAID
use among people presenting to hospitals with upper GI bleeding (Ref.
56). The rate of consumption of OTC NSAIDs by consumers is estimated to
be as much as seven times that of prescribed NSAIDs (Ref. 54).
The American College of Gastroenterology guideline for
treatment and prevention of NSAID-induced ulcers indicates an increased
risk of NSAID-associated GI complications for people greater than 60
years of age (Ref. 56). A United Kingdom (UK) population-based,
retrospective case-control study evaluated the risk of various NSAIDs
(Ref. 10). The study reported a RR of 3.7 for upper GI bleeding (UGIB)
and GI perforation in people under 60 years old exposed to NSAIDs, 13.2
in people 60 years and older exposed to NSAIDs, and 2.8 in people 60
years and older not exposed to NSAIDs.
FDA analyzed a series of studies that used the Medicaid
population in Tennessee (Refs. 12, 13, 56, 57, and 58). These case-
controlled retrospective studies were based on hospitalizations for GI
bleeds. The study population totaled 103,954 individuals, about 15
percent of Tennessee's elderly population, with 209,066 person-years of
followup. There were 1,371 hospitalizations for PUD. These studies
found increased risk of GI bleeds in people who were:
Over 65 years old (RR of 4.7),
Taking an increased NSAID dose (RR of 2.8 for the lowest
dose vs. RR of 8 for the highest dose category), or
Taking concomitant corticosteroid (RR of 4.4) or anti-
coagulant (RR 12.7) drug products.
In addition, the risk of GI bleeds among people taking NSAIDs was
greatest within the first 30 days of use (RR of 7.2).
A multicenter, case-control study of 550 people with UGIB
admitted to a hospital with bloody stools or vomiting blood and 1,202
controls identified from census lists, compared risks of major GI
bleeding for plain, coated, and buffered formulations of low-dose
aspirin (Ref. 59). Each of these types of low-dose aspirin formulations
(less than 325 mg
[[Page 77330]]
per day) had about a 2.5 to 3 times increased risk of major UGIB.
A double-blind, randomized, placebo-controlled, ulcer
prevention study in 8,843 people with rheumatoid arthritis identified
several risk factors for upper GI complications from NSAID use: (1) Age
75 years or older (odds ratio 2.48), (2) prior peptic ulcer (odds ratio
2.29), (3) prior GI bleeding (odds ratio 2.56), and (4) history of
cardiovascular disease (odds ratio 1.84) (Ref. 60).
A case control study of 1,122 subjects admitted
consecutively for UGIB to four hospitals in Spain and 2,231 controls
from the same geographic area, showed that a prior history of UGIB is a
risk factor (odds ratio 3.7) for UGIB in people who used NSAIDs (Ref.
61).
In summary, results of several large-scale clinical studies,
conducted in the United States and worldwide, have established that use
of OTC NSAIDs is an important risk factor for serious GI adverse
events, especially bleeding. The risk is higher for people age 60 or
older, who have a history of stomach ulcers or bleeding problems, or
who use corticosteroids or anticoagulants.
2. Renal Effects
NSAIDs decrease renal prostaglandin production, which may result in
acute reduction in renal blood flow and glomerular filtration, leading
to fluid retention, edema, and elevation of serum creatinine (Ref. 62).
Marked reduction in renal blood flow may result in renal failure.
NSAID use may also result in higher than normal levels of potassium
in the bloodstream. This occurs most commonly in people with diabetes
mellitus or mild to moderate renal insufficiency as well as in people
taking beta-blocker, angiotensin-converting enzyme inhibitor, or
potassium-sparing diuretic drugs.
By inhibiting the production of vasodilatory prostaglandins, NSAIDs
may decrease renal blood flow and the rate of glomerular filtration in
subjects with congestive heart failure, liver failure with ascites,
chronic renal disease, or those who are hypovolemic (abnormal volume
decrease of circulating fluid (plasma) in the body) (Refs. 63, 64, and
65).
a. Pediatric population. The medical literature includes sporadic
reports of acute renal failure in pediatric subjects taking ibuprofen
within the OTC dose range, including the following cases:
One article describes three cases in children 5-, 6.5-,
and 7.5-years-old in which ibuprofen treatment led to varying degrees
of renal failure (Ref. 66). Two subjects with dehydration and pre-
existing renal problems were prescribed ibuprofen for the treatment of
fever due to acute illness. Both had a recovery of renal function on
withdrawal of the drug. The third child (a 7.5-year-old girl) developed
progressive chronic renal failure. She had underlying hyper Ig-E
syndrome and was treated with a single dose of ibuprofen 5 mg /kg for
fever due to severe pulmonary infection. Her illness was also
complicated by moderate dehydration. Her renal biopsy showed evidence
of kidney damage consistent with loss of blood circulation.
Ibuprofen-induced acute renal failure was reported in a 9-
month-old girl (Ref. 67). A family practitioner treated the infant for
diarrhea, vomiting, and fever. She was given oral rehydration therapy
and acetaminophen and was sent home. Symptoms persisted for 48 hours
and the acetaminophen was changed to ibuprofen 50 mg (5 mg/kg/dose)
three times a day. Seven doses of ibuprofen were given over a 40-hour
period, but the child's clinical state deteriorated. She was admitted
to an emergency facility 18 hours after the last dose with a creatinine
concentration of 2.1 mg/deciliter (dL). For the first 12 hours after
admission, the infant's kidneys failed to secrete urine in spite of
receiving adequate hydration and an intravenous diuretic (furosemide).
The creatinine concentration increased to 2.4 mg/dL. Renal function
slowly recovered; 4 days after admission her creatinine was 0.9 mg/dL
and 3 weeks later was 0.5 mg/dL. Clinical diagnosis was kidney damage
secondary to ibuprofen use in a dehydrated child.
Primack, et al. reported acute renal failure with use of
ibuprofen in an 11-year-old boy (Ref. 68). The child was diagnosed with
possible sinusitis and given an antibiotic; on the third day symptoms
worsened with associated headaches, fatigue and anorexia, and his serum
creatinine was 0.7 mg/dL. The antibiotic was continued and ibuprofen
200 mg was added, alternating with acetaminophen every 4 hours for
fever. He received a total of 24 200-mg ibuprofen tablets during the 12
days prior to hospitalization. The fever persisted with improvement in
the other symptoms. The child became progressively weaker and began
vomiting. Approximately 2 weeks after his illness began, the child was
admitted with a serum creatinine of 7.6 milliequivalent/L. After 3 days
of symptomatic treatment, his serum creatinine was 4.1 mg/dL and 1 week
later his serum creatinine was 2.2 mg/dL. Findings of renal biopsy on
the third hospital day were consistent with acute interstitial
nephritis, which the authors attributed to beta-lactam antibiotic use.
These case reports demonstrate the variety of situations in which
ibuprofen-associated renal toxicity can occur. In many of the cases,
the children were already at risk for renal adverse effects because of
underlying disease states, concomitant medications, or dehydration.
Children with underlying illnesses or those dehydrated are at greatest
risk for this injury. FDA currently requires all OTC pediatric products
containing ibuprofen marketed under new drug applications to include
warnings for children ages 2 to 11 years to ask a doctor before use if
the child has ``not been drinking fluids'' or has ``lost a lot of fluid
due to continued vomiting or diarrhea.''
b. Alcohol use. Binge drinking of alcohol reduces the production of
antidiuretic hormone causing increased urine production. Two cases of
reversible acute deterioration in renal function following binge
drinking of beer with use of NSAIDs have been reported in adults (Ref.
69):
The authors reported a case of a 22-year old male admitted
to the hospital with low back pain and worsening renal function. Four
days prior to admission, he had consumed an unknown amount of beer; 2
days later as the pain intensified he had taken six doses of 400-mg
ibuprofen with no relief. Upon admission, his serum creatinine was 3.1
mg/dL. Biopsy of the kidney was consistent with the diagnosis of acute
kidney failure. The subject's serum creatinine increased to a peak of
6.5 mg/dL on the fourth day and decreased to 1.4 mg/dL 6 days later.
In a second case, a 20-year old male was admitted because
of flank and back pain of 24 hours' duration. Four days before
admission, the subject drank 8 to 10 bottles of beer (355 mL per
bottle). On the evening of admission, he had taken 6 to 8 tablets of
325-mg aspirin for pain relief. The laboratory data showed a 2.0 mg/dL
serum creatinine level. Following intravenous fluid administration, the
subject urinated frequently for over 16 hours. Followup serum
creatinine 1 week later was 1.2 mg/dL. The authors concluded that
dehydration is a frequent consequence of heavy alcohol ingestion due to
water diuresis. The volume contraction may be further aggravated by
nausea and vomiting.
In the proposed rule to amend the TFM for OTC IAAA drug products to
include ibuprofen, FDA included the results of the agency's evaluation
of the adverse renal effects of OTC doses of ibuprofen (67 FR 54139 at
54144). Based on its evaluation of the data, FDA
[[Page 77331]]
concluded that OTC doses of ibuprofen can exert a variety of adverse
renal effects, particularly in those who are dependent on adequate
prostaglandin levels to maintain renal hemodynamic perfusion (i.e.,
congestive heart failure, liver failure with ascites, etc.). It was
further noted that although the sporadic nature of idiosyncratic drug-
induced ibuprofen nephrotoxicity makes it impossible to predict which
group of individuals is at risk for developing this event, this is not
the case with individuals who experience prostaglandin-dependent
hemodynamic changes. The latter, if recognized, is reversible upon
discontinuation of the drug (67 FR 54139 at 54145).
V. FDA's Tentative Conclusions
FDA has carefully considered NDAC's recommendations and other
available data and information and determined that labeling revisions
are necessary for OTC IAAA drug products to advise consumers of
potential health risks and to recommend, under certain circumstances,
that they consult a doctor for advice about taking products containing
OTC IAAA active ingredients.
FDA continues to believe that acetaminophen and NSAIDs, when
labeled appropriately and used as directed, are generally recognized as
safe and effective OTC IAAA drugs for consumer self-use. However, the
available evidence clearly indicates that both drugs can cause serious
side effects. When taken in excess amounts, acetaminophen can cause
liver injury. NSAIDs have the potential to cause GI bleeding and renal
(kidney) injury even at OTC dosing levels.
When compared to the extensive use of OTC acetaminophen and NSAID
drug products, the incidence of injury appears relatively low. However,
based on the available evidence and the seriousness of the risks, FDA
believes it is necessary for consumers to be made aware of the possible
serious side effects associated with using these 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, have certain risk factors, and/or do not
follow the labeling information on the package. FDA believes that
providing additional labeling information about how to correctly use
OTC drug products containing acetaminophen and NSAIDs could reduce
injuries and is necessary for the products to be considered generally
recognized as safe and effective and not misbranded.
FDA plans to act on several fronts:
Propose revised OTC labeling for these products
Continue a consumer and health provider educational
campaign
Continue to monitor AERS in various databases
Examine available data to determine whether other measures
may be needed in the future to try to decrease morbidity associated
with OTC acetaminophen and NSAIDs.
In addition to the changes to the IAAA TFM proposed in this
document, FDA encourages manufacturers of these products to undertake
education initiatives regarding safe use of OTC products containing
acetaminophen and NSAIDs. FDA plans to increase its monitoring of AERS
in various databases to see how this new proposed labeling, if
implemented, is working to reduce injuries resulting from OTC
acetaminophen and NSAID drug products and to determine whether further
measures need to be proposed.
A. Acetaminophen
1. Hepatotoxicity
FDA tentatively concludes that additional new labeling is needed
for OTC drug products that contain acetaminophen. Data from Lee (Ref.
6), a case series from the University of Pennsylvania Hospital (Ref.
4), and the FDA AERS database show that unintentional overuse of
acetaminophen is associated with severe hepatic injury. One
manufacturer provided calculations of a ``worst case'' scenario for
acetaminophen hepatic failure deaths using estimates by Lee (Ref. 70)
and calculated 213 deaths per year. FDA does not know the exact number
of cases of liver failure or deaths related to unintentional
acetaminophen overdose. FDA thinks that improved labeling may help
prevent events that are catastrophic to the unintentional victims and
their family members. FDA has determined that adding a liver warning is
necessary for safe and effective use of the drug and to reduce the
number of unintentional overdoses. Thus, FDA is proposing a ``liver
warning'' stating use factors that could lead to liver injury.
FDA notes that NDAC recommended both an alcohol warning and a liver
toxicity statement separate from the alcohol warning for OTC drug
products containing acetaminophen. FDA has combined this information
because it is interrelated and a shorter warning saves label space on
products that already contain extensive labeling information. FDA
believes that two, separate warnings may be less likely to be read and
understood by consumers.
FDA also tentatively concludes that a new warning is needed to
advise consumers who have liver disease to consult a doctor before
using OTC drug products that contain acetaminophen. FDA notes that many
of the case reports in the databases involved people who had pre-
existing liver disease (the rate of the number of cases in the
databases exceeds the rate of underlying liver disease in the general
population). This observation may also be due to a difference in the
use of acetaminophen by people with chronic liver disease or that they
are at greater risk to develop liver failure in general. As described
in section IV.A of this document, people with chronic liver disease can
have changes in the liver enzymes responsible for the metabolism of
acetaminophen. It is not clear whether these changes increase the risk
in these individuals. It was noted at NDAC that some physicians who
treat patients with chronic liver disease recommend lower total daily
doses. FDA believes this additional warning will alert patients with
chronic liver disease to ask their doctor before using acetaminophen.
FDA recognizes there is limited information supporting the need for
different dose recommendations in people with liver disease. FDA seeks
comment on the information this warning should provide and encourages
healthcare providers and researchers who treat patients with chronic
liver disease to provide information on how much they recommend as an
appropriate dose and the basis for their recommendation.
2. Other Labeling
FDA also tentatively concludes that the name ``acetaminophen'' on
the PDP should be enhanced to allow consumers to better identify
acetaminophen containing products among the many products currently
available on the OTC market. First, FDA is proposing that the name be
highlighted (e.g., in fluorescent or color contrast to other
information on the PDP) or in bold type so that the name is prominent
and stands out from other text. Second, FDA is proposing that the name
have a size that is prominent compared to other printed matter on the
PDP. FDA's regulation for the statement of identity for OTC drug
products in Sec. 201.61(c) (21 CFR 201.61(c)) states that ``the
statement of identity shall be presented in bold face type on the PDP,
shall be in a size reasonably related to the most prominent printed
matter on such panel ***.'' FDA is proposing that manufacturers
determine the prominence of the name ``acetaminophen'' on the PDP by
[[Page 77332]]
selecting, from the two options that follow, the print size option that
is greater:
The name ``acetaminophen'' is at least one-quarter as
large as the size of the most prominent printed matter on the PDP; or
The name ``acetaminophen'' is at least as large as the
size of the ``Drug Facts'' title, as required in Sec. 201.66(d)(2) (21
CFR 201.66(d)(2)).
Finally, FDA notes that NDAC expressed concern about the lack of
standardized pediatric dosage information, especially for infants under
2 years of age. FDA intends to address this issue in another Federal
Register publication.
B. Aspirin and Other NSAIDs
1. GI Bleeding
FDA tentatively concludes that epidemiological data indicate a
dose-related risk for GI bleeding with NSAIDs. The data demonstrate a
slight increase in risk for GI bleeding at OTC daily doses. Because
many people use OTC NSAIDs intermittently, the risk for bleeding for
the average person is quite low. People who use NSAIDs for several days
may be at greater risk but it is still low compared to chronic NSAID
users. People who have certain identifiable risk factors (e.g., stomach
ulcers or bleeding problems, taking certain other drugs or alcohol
concurrently) are at greater risk of GI bleeding when they take a
product containing an NSAID. FDA believes that additional warnings
alerting these people about these potential risks and some of the
symptoms associated with GI bleeding could reduce morbidity from using
these OTC NSAID drug products.
Based on the NDAC's recommendations and the agency's review of the
literature, FDA has determined that additional new warning labeling is
needed to continue to consider OTC NSAID products generally recognized
as safe and effective. Such warnings should advise people not to take
more than one product containing NSAIDs (aspirin, ibuprofen, naproxen,
or others) and not to take more drug or take the drug for a longer time
than recommended in product labeling. NDAC also acknowledged that
people age 65 and older are at increased risk for GI bleed.
FDA subsequently reviewed the results of several large-scale
clinical studies, conducted in the United States and worldwide, and has
established that use of NSAIDs is an important risk factor for serious
GI adverse events, especially bleeding. These studies show that the
risk is higher for people age 60 or older, who have had stomach ulcers
or bleeding problems, or who use corticosteroids or anticoagulants
(Refs. 10 and 55). Based on these studies, FDA believes that people 60
years of age and older are at increased risk and is proposing to
include this age group in the warning.
In September 1993, NDAC concluded that the use of aspirin,
ibuprofen, and naproxen sodium increases the risk of UGIB in people who
are heavy alcohol users or abusers. At the September 2002 meeting,
during discussion of the relative risks for GI bleeding associated with
the use of OTC NSAIDs, some NDAC members questioned whether the
incidence of GI bleeding is increased by the concurrent use of NSAIDs
and alcohol. NDAC members were divided almost equally. Some members
thought that there was no clear evidence that alcohol potentiates the
risk of bleeding in NSAID or aspirin users. They proposed removal of
the existing alcohol warning. Other NDAC members suggested that the
alcohol warning should remain in effect, but be separated from the GI
bleeding warning.
Subsequently, FDA considered NDAC's recommendations and evaluated
the alcohol warning for OTC drug products containing an NSAID. FDA did
a new literature search, selecting new articles describing the
relationship between alcohol use and the risk of GI bleeding in OTC
IAAA users. After reviewing these articles (Ref. 71), FDA finds that
these studies, despite some flaws in their design and methodology,
suggest that combining NSAIDs with alcohol increases the risks of a GI
bleed. FDA has determined that it is necessary to retain a warning
regarding use of OTC NSAID drug products with alcohol. FDA tentatively
concludes that a warning about this risk should be incorporated in a
``Stomach bleeding warning'', in place of the current alcohol warning.
Although NDAC recommended that a GI bleeding warning be distinct from a
warning against alcohol ingestion with NSAIDs, FDA is proposing to
combine these two warnings to conserve labeling space and avoid
redundancy.
2. Renal Effects
FDA tentatively concludes that people who get acute renal
insufficiency from using NSAIDs generally have a pre-existing condition
that will predispose them to this insufficiency. There is a
pharmacological basis for this to occur. Normal renal blood flow
depends on prostaglandin metabolism. NSAIDs inhibit renal prostaglandin
production. In predisposed people, suppression of prostaglandin
production may result in acute reduction in renal blood flow and
glomerular filtration, leading to renal insufficiency. These cases are
often reversible. Although the epidemiological data are limited and the
number of reported cases are rare relative to their use, FDA believes
it is important to alert consumers about underlying conditions that may
increase their risk if they take an NSAID without first asking a doctor
because of potential serious side effects.
NDAC agreed with the OTC labeling proposed for ibuprofen in the
Federal Register of August 21, 2002, including the warning to ask a
doctor before use in the presence of high blood pressure, heart or
kidney disease, concomitant use of a diuretic, or if they are over 65
years of age. Based upon a further review of the literature that
indicates that the risk is higher for people age 60 or older, FDA is
proposing to lower the age from 65 years of age to 60 years of age.
Children's NSAID products marketed under an NDA already have
warnings regarding dehydration and fluid loss. FDA tentatively
concludes that similar language is needed for children's NSAIDs
products marketed under the OTC drug monograph. There are, however, few
case reports suggesting a problem in adults. FDA is seeking comment on
the need for similar language for adults. Although there are few
reported cases in adults, it is anticipated that prostaglandin has
similar effects on renal physiology.
3. Other Labeling
FDA agrees with NDAC that the term ``NSAID'' should be prominently
displayed in OTC drug product labeling so consumers are aware of the
presence of the ingredient in the product. The term should also be
defined in the labeling as ``nonsteroidal anti-inflammatory drug.'' FDA
tentatively concludes that the presence of an ``NSAID'' ingredient in
an OTC drug product should be prominently stated on the PDP and in the
Drug Facts labeling.
In section V.A.2 of this document, FDA discusses its proposed
requirements for the name ``acetaminophen'' to be prominently presented
on the PDP. FDA considers the same degree of prominence necessary to
identify the presence of an ``NSAID'' ingredient in an OTC IAAA drug
product. Accordingly, FDA is proposing that the name of the NSAID
ingredient and the word ``(NSAID)'' be 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
[[Page 77333]]
displayed, and be in one 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). In the Drug
Facts labeling, FDA is proposing that the active ingredient(s) section,
as defined in Sec. 201.66(c)(2), be required to contain the term
``(NSAID)'' after the NSAID active ingredient with an asterisk
statement at the end of the active ingredient(s) section that defines
the term ``NSAID'' as a `` * nonsteroidal anti-inflammatory drug.''
In addition, FDA has conducted a detailed review of available data
regarding the potential risks of serious cardiovascular events in
patients receiving COX-2 selective and non-selective NSAIDs. FDA also
held a joint meeting of its Arthritis and Drug Safety and Risk
Management on February 16-18, 2005, to consider these issues. FDA is
currently considering whether additional labeling changes related to
these risks are warranted, and will address this in a future issue of
the Federal Register.
VI. FDA's Proposal
Based on the available evidence, FDA is proposing to amend its
regulations and the OTC IAAA TFM to make a number of changes. FDA is
proposing new labeling for OTC IAAA drug products (proposed Sec.
201.325). This labeling includes a number of important new warnings. To
alert consumers to these new warnings, FDA is proposing to require that
the statement ``See new warnings information'' appear on the PDP of all
OTC IAAA drug products for a limited time after the effective date of a
final rule based on this proposal (proposed Sec. 201.325(b)).
The labeling statements in this proposed rule are in the OTC Drug
Facts labeling format (see Sec. 201.66), which is being implemented
for all OTC drug products. For ease of reading, the following
descriptions of the proposed labeling statements do not include the
bracketed formatting instructions included in the codified portion of
this document.
A. Alcohol Warning
FDA is proposing to remove Sec. 201.322 of the regulations
entitled ``Over-the-counter drug products containing internal
analgesic/antipyretic active ingredients required alcohol warning.''
B. Acetaminophen
1. For All Acetaminophen Products
Proposed Sec. 201.325(a)(1)(i) includes the following provisions:
The presence of acetaminophen in the product must be
prominently stated on the PDP. The word ``acetaminophen'' 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 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 presence of acetaminophen must appear as part of the
established name of the drug, as defined in Sec. 299.4 (21 CFR 299.4).
Combination products containing acetaminophen and a non-
analgesic ingredient(s) (e.g., cough-cold) must include the name
``acetaminophen'' and the names of the other active ingredients in the
product on the PDP. Only the name ``acetaminophen'' must appear
highlighted (e.g., fluorescent or color contrast) or in bold type, and
be in one 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).
2. For Acetaminophen Products Labeled for Adults Only
Under proposed Sec. 201.325(a)(1)(iii), the labeling would be
required to include the following statement:
Liver warning: This product contains acetaminophen. Severe liver
damage may occur if you take
more than (insert maximum number of daily dosage units) in
24 hours
with other drugs containing acetaminophen
3 or more alcoholic drinks every day while using this
product.
This ``Liver warning'' would be the first warning under the
``Warnings'' heading. For products that contain both acetaminophen and
aspirin, the ``Liver warning'' would 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 NSAID ``Stomach bleeding warning'' in
proposed Sec. 201.325(a)(2)(iii)(A).
The labeling would also be required to include the statements ``Do
not use with any other drug containing acetaminophen (prescription or
nonprescription). Ask a doctor or pharmacist before using with other
drugs if you are not sure'' and ``Ask a doctor before use if you have
liver disease.''
3. For Acetaminophen Products Labeled Only for Children Under 12 Years
of Age
Under proposed Sec. 201.325(a)(1)(iv), the labeling would be
required to include the following statement:
Liver warning: This product contains acetaminophen. Severe liver
damage may occur if the child takes
more than 5 doses in 24 hours
with other drugs containing acetaminophen.
This ``Liver warning'' must be the first warning under the
``Warnings'' heading.
The labeling would also be required to include the statements ``Do
not use with any other drug containing acetaminophen (prescription or
nonprescription). Ask a doctor or pharmacist before using with other
drugs if you are not sure'' and ``Ask a doctor before use if the child
has liver disease.''
FDA is aware that products labeled for children only are sometimes
used by adults who cannot take solid oral dosage forms or who are
taking a product marketed in children's strengths. Accordingly, FDA is
proposing to include the statement ``this product does not contain
directions or warnings for adult use'' in bold type in the labeling of
these products under the heading ``Directions''.
4. For Acetaminophen Products Labeled for Adults and Children Under 12
Years of Age
Under proposed Sec. 201.325(a)(1)(v), the labeling would be
required to include all of the warnings for adults with the following
modifications:
Liver warning: This product contains acetaminophen. Severe liver
damage may occur if
adult takes more than [insert maximum number of daily
dosage units] in 24 hours
child takes more than 5 doses in 24 hours
taken with other drugs containing acetaminophen.
adult has 3 or more alcoholic drinks every day while using
this product.
This ``Liver warning'' must be the first warning under the
``Warnings'' heading. FDA is proposing to use the term ``the user''
instead of ``you or the child'' for warnings applying to both children
and adults. The ``ask a doctor'' statement is modified to read: ``Ask a
doctor before use if the user has liver disease.''
C. Aspirin and Other NSAIDs
The NSAID category includes, but is not limited to, aspirin,
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen,
magnesium salicylate,
[[Page 77334]]
naproxen sodium, and sodium salicylate. In the Federal Register of
August 21, 2002 (67 FR 54139 at 54159), FDA proposed a number of
warnings for products containing ibuprofen if added to the OTC IAAA
drug products monograph. FDA is adding information and further revising
portions of some of those warnings in this document and proposing these
warnings be applicable to all OTC NSAIDs.
1. For All Products Containing NSAIDs
Proposed Sec. 201.325(a)(2)(i) includes the following provisions:
The presence of an NSAID ingredient in the product must be
prominently stated on the PDP. The name of the NSAID ingredient and the
word ``(NSAID)'' 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 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).
For single ingredient products, the word ``(NSAID)'' must
appear as part of the established name of the drug, as defined in Sec.
299.4 of this chapter, or as part of the statement of identity of the
drug, as defined in Sec. 201.61 of this chapter. For example, either
of the following would be acceptable:
Ibuprofen Tablets (NSAID)
Pain reliever/ fever reducer
or
Ibuprofen Tablets
Pain reliever/ fever reducer (NSAID)
Combination products containing an NSAID and a non-
analgesic ingredient(s) (e.g., cough-cold) must include the name of the
NSAID ingredient and the names of the other active ingredients in the
product on the PDP. The word ``(NSAID)'' must appear after either the
name of the NSAID ingredient or the general pharmacological (principal
intended) action of the NSAID ingredient (see previous examples). Only
the name of the NSAID ingredient and the word ``(NSAID)'' must appear
highlighted (e.g., fluorescent or color contrast) or in bold type, and
be in one 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).
2. For NSAID Products Labeled for Adults Only
Warnings for NSAIDS are proposed in Sec. 201.325(a)(2)(iii). Some
of the proposed warning statements are discussed here.
Stomach bleeding warning: This product contains a nonsteroidal
anti-inflammatory drug (NSAID), which may cause stomach bleeding. The
chance is higher if you:
are age 60 or older
have had stomach ulcers or bleeding problems
take a blood thinning (anticoagulant) or steroid drug
take other drugs containing an NSAID (aspirin, ibuprofen,
naproxen, or others)
have 3 or more alcoholic drinks every day while using this
product
take more or for a longer time than directed.
This ``Stomach bleeding warning'' would 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'' would appear before the
NSAID ``Stomach bleeding warning.''
The labeling would be required to include the following statement:
Ask a doctor before use if you have
stomach problems that last or come back, such as
heartburn,
upset stomach, or stomach pain
ulcers
bleeding problems
high blood pressure
heart or kidney disease
taken a diuretic
reached age 60 or older.
The labeling would be required to include the statement:
Ask a doctor or pharmacist before use if you are
taking any other drug containing an NSAID (prescription or
nonprescription)
taking a blood thinning (anticoagulant) or steroid drug
The labeling would be required to include the statement:
Stop use and ask a doctor if
you feel faint, vomit blood, or have bloody or black
stools. These are signs of stomach bleeding.
stomach pain or upset gets worse or lasts
3. For NSAID Products Labeled Only for Children Under 12 Years of Age
Under proposed Sec. 201.325(a)(2)(iv), the labeling would be
required to include the following statement:
Stomach bleeding warning: This product contains a nonsteroidal
anti-inflammatory drug (NSAID), which may cause stomach bleeding. The
chance is higher if the child:
has had stomach ulcers or bleeding problems
takes a blood thinning (anticoagulant) or steroid drug
takes other drugs containing an NSAID (aspirin, ibuprofen,
naproxen, or others)
takes more or for a longer time than directed.
The ``Stomach bleeding warning'' would appear after the ``Reye's
syndrome'' and ``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A)
and (c)(5)(ii)(B).
The labeling would be required to include the following statement:
Ask a doctor before use if the child has
stomach problems that last or come back, such as
heartburn, upset stomach, or stomach pain
ulcers
bleeding problems
not been drinking fluids
lost a lot of fluid due to vomiting or diarrhea
high blood pressure
heart or kidney disease
taken a diuretic.
The labeling would be required to include the statement:
Ask a doctor or pharmacist before use if the child is
taking any other drug containing an NSAID (prescription or
nonprescription)
taking a blood thinning (anticoagulant) or steroid drug
The labeling would also be required to include the statement:
Stop use and ask a doctor if
the child feels faint, vomits blood, or has bloody or
black stools. These
are signs of stomach bleeding.
stomach pain or upset gets worse or lasts
FDA is aware that products labeled only for children are sometimes
used by adults who cannot take solid oral dosage forms or who are
taking a product marketed in children's strengths. Accordingly, FDA is
proposing to include the statement ``this product does not contain
directions or warnings for adult use'' in bold type in the labeling of
these products under the heading ``Directions''.
4. For NSAID Products Labeled for Adults and Children Under 12 Years of
Age
Under proposed Sec. 201.325(a)(2)(v), the labeling would be
required to include all of the warnings for adults with the following
modifications:
Stomach bleeding warning: This product contains a nonsteroidal
anti-
[[Page 77335]]
inflammatory drug (NSAID), which may cause stomach bleeding. The chance
is higher if the user:
has had stomach ulcers or bleeding problems
takes a blood thinning (anticoagulant) or steroid drug
takes other drugs containing an NSAID (aspirin, ibuprofen,
naproxen, or others)
takes more or for a longer time than directed
is age 60 or older
has 3 or more alcoholic drinks everyday while using this
product.
The ``Stomach bleeding warning'' would appear after the ``Reye's
syndrome'' and ``Allergy alert'' warnings in Sec. 201.66(c)(5)(ii)(A)
and (c)(5)(ii)(B).
FDA is proposing to use the term ``the user'' instead of ``you or
the child'' for warnings applying to both children and adults in the
above and following modified statements.
The labeling would be required to include the following statement:
Ask a doctor before use if the user has
stomach problems that last or come back, such as
heartburn, upset stomach, or stomach pain
ulcers
bleeding problems
high blood pressure
heart or kidney disease
taken a diuretic
not been drinking fluids
lost a lot of fluid due to vomiting or diarrhea
reached age 60 or older
The labeling would be required to include the statement:
Ask a doctor or pharmacist before use if the user is
taking any other drug containing an NSAID (prescription or
nonprescription)
taking a blood thinning (anticoagulant) or steroid drug
The labeling would also be required to include the statement:
Stop use and ask a doctor if
the user feels faint, vomits blood, or has bloody or black
stools. These are signs of stomach bleeding.
stomach pain or upset gets worse or lasts.
5. Active Ingredients
Under proposed Sec. 201.325(a)(2)(v), the active ingredient(s)
section of the product's labeling, as defined in Sec. 201.66(c)(2),
would be required to contain the term ``(NSAID)*'' after the NSAID
active ingredient with an asterisk statement at the end of the active
ingredient(s) section that defines the term ``NSAID'' as a ``*
nonsteroidal anti-inflammatory drug.''
D. Requirements to Supplement Approved Applications
Holders of approved applications for OTC IAAA drug products who
voluntarily implement the proposed labeling changes in proposed Sec.
201.325(a) would be required to submit supplements under Sec.
314.70(c) (21 CFR 314.70(c)), but could implement the proposed labeling
without advance approval from FDA, provided the labeling includes the
information in proposed Sec. 201.325(a). See section IX of this
document on voluntary implementation.
E. Regulatory Action
Proposed Sec. 201.325(c) sets out the implementation dates for the
proposed labeling changes after publication of any final rule based on
this proposal. See section VIII.B of this document on marketing
conditions.
F. Conforming Changes to the OTC IAAA TFM
This proposed rule includes changes to the OTC IAAA TFM in proposed
Sec. 343.50. Proposed Sec. 343.50(c)(1)(i), (c)(1)(iii),
(c)(1)(iv)(A), (c)(1)(v)(A), (c)(1)(v)(B), (c)(1)(v)(C), (c)(1)(ix)(A),
(c)(1)(ix)(B), (c)(1)(ix)(C), (c)(1)(ix)(E), (c)(2)(i), (c)(2)(iii),
(c)(2)(iv)(A), (c)(2)(v)(A), (c)(2)(v)(B) and (c)(2)(v)(C) (as proposed
in 53 FR 46204 and 67 FR 54139) would be amended and new paragraphs
(b)(4)(i)(c) and (c)(3)(i) through (c)(3)(v)(C) would be added to
either include references to proposed Sec. 201.325 and/or additional
language to conform to that section.
VII. Additional Issues for Consideration
A. Safe and Effective Daily Acetaminophen Dose
In 1960, FDA first approved (under the NDA process) a 325-mg
immediate-release acetaminophen tablet formulation for OTC marketing in
the United States. The recommended dose was one to two tablets every 4
to 6 hours, with a maximum daily dose of 3,900 mg in a 24-hour period
(Ref. 3).
In 1973, FDA approved (under the NDA process) a 500-mg immediate-
release acetaminophen capsule formulation for OTC marketing in the
United States. The sponsor's rationale for this product was that the
higher strength would have greater analgesic efficacy. Four double-
blind, placebo-controlled, post partum pain studies evaluated the
effectiveness of a single dose of two 500-mg capsules (1,000 mg) to a
single dose of two 325-mg tablets (650 mg) in 338 subjects. Two of the
studies demonstrated that a single 1,000-mg dose was significantly more
effective than a single 650-mg dose. One of the other studies failed to
demonstrate a dose response between the two doses, and the last study
failed to show separation of the active treatments from placebo. The
overall safety profile for the 1,000-mg dose was similar to the 650-mg
dose, with the exception of a higher incidence of dizziness. In 1975,
FDA approved a 500-mg immediate-release tablet. Data from two crossover
bioequivalence studies comparing two 500-mg capsules to two 500-mg
tablets demonstrated the bioequivalence of the two formulations (Ref.
3).
The IAAA Panel further evaluated acetaminophen and recommended in
its 1977 report (42 FR 35346) that acetaminophen be generally
recognized as safe and effective. The IAAA Panel's evaluation of
effectiveness was based on data from a number of controlled and
uncontrolled studies of the effectiveness of a variety of acetaminophen
doses, i.e., 300, 325, 330, 500, 600, 1,000, and 1,200 mg (42 FR 35346
at 35412). However, the IAAA Panel's evaluation did not include an
assessment of the relative effectiveness of each of the dosage
strengths. The Panel determined the maximum daily safe dosage to be not
greater than 4 g in a 24-hour period. Upon publication of that
document, FDA permitted OTC marketing without an NDA provided the
product was consistent with the IAAA Panel's recommended labeling.
FDA's 1988 TFM for OTC IAAA drug products proposed to include
acetaminophen as a monograph ingredient (53 FR 46204 at 46255). FDA
revised the IAAA Panel's recommended dosing regimens but maintained the
maximum limit of 4 g in a 24-hour period.
To determine the maximum daily safe dosage (4 g of acetaminophen in
a 24-hour period), the Panel reviewed numerous references that describe
cases of serious liver damage associated with excessive use of
acetaminophen (42 FR 35346 at 35413). Most of these cases were
associated with single dose oral ingestions of greater than 15 g of
acetaminophen. Based on this information, the Panel concluded that a
single dose less than 15 g is not usually associated with serious liver
injury. The Panel also noted that 15 g is 23 times the usual
recommended dose of 650 mg and approximately 4 times the maximum
recommended daily dose of 4 g. In estimating the safety margin, the
Panel decided the comparison with the single dose (650 mg) was probably
more appropriate than the comparison with the daily therapeutic dose (4
g). The current information on unintentional overdose suggests that the
margin of
[[Page 77336]]
safety may be less than originally determined. The data on liver
failure presented by Dr. Lee at the September 2002 NDAC meeting and the
adverse event reports in the FDA AERS data suggest daily doses less
than 10 g, ingested on consecutive days, presents a risk for liver
injury in some individuals.
FDA invites comment on whether there are subpopulations of
individuals who are more susceptible to developing liver injury when
taking acetaminophen. The dosing information included in the AERS cases
of hepatotoxicity reported for acetaminophen suggest that the median
daily dose is in the 5- to 6-g range. FDA recognizes, however, that
dosing information in the AERS reports is sometimes inaccurate and is
difficult to validate. The information in the AERS cases of
hepatotoxicity is adequate to raise concerns that there may be
subpopulations at risk for developing hepatotoxicity with doses lower
than the currently labeled maximum daily dose of 4 g. If such
subpopulations can be identified, the maximum daily dose of 4 g may no
longer be considered safe for those individuals and should be lowered.
If the at risk subpopulations cannot be identified, or addressed
through appropriate labeling, and cases of liver injury continue to be
reported, FDA may reconsider whether the labeled maximum daily dose is
still generally recognized as safe and effective for use in the general
population.
B. Daily Dose Recommendation for Alcohol Abusers
Following publication of the IAAA TFM in 1988, FDA received a
comment recommending that the maximum daily dose of acetaminophen be
reduced from 4 to 2 g per day for alcohol abusers. The comment did not
provide any data to support a reduced maximum daily dose. In June 1993,
NDAC considered: (1) Identifying a population at risk in terms of
alcohol consumption, e.g., people who rarely drink, social drinkers, or
alcohol abusers, (2) whether the data are sufficient to support a
reduced maximum daily dose for alcohol abusers, and (3) if yes, what
the reduced maximum daily dose should be. NDAC found the data
insufficient and was unable to recommend a reduced maximum daily
acetaminophen dose for alcohol abusers.
At the September 19, 2002, NDAC meeting, FDA described cases of
hepatotoxicity involving the use of prescription combination (narcotic/
acetaminophen) products (Refs. 6 and 7). Many of these cases involved
people with a history of alcohol abuse. NDAC was unable to recommend a
reduced maximum daily acetaminophen dose for alcohol abusers, because
of a lack of specific data.
One drug manufacturer issued a ``Dear Doctor'' letter to inform
health professionals about the September 2002 NDAC meeting (Ref. 72).
The letter stated: ``The NDAC proceedings may generate media interest
and, as a result, people may contact you with questions about OTC pain
relievers such as acetaminophen.'' The letter summarized the existing
data that support the safety of acetaminophen, including the statement:
``Prospective data indicate that chronic alcoholics can take
recommended doses of acetaminophen up to 4,000 mg/day without risk of
liver injury.'' The letter cited two references from the medical
literature to support the statement (Refs. 73 and 74). The letter
continued: ``Acetaminophen can be used safely, at recommended doses, by
the occasional moderate consumer of alcohol.''
FDA has reviewed the two references (studies of hepatotoxicity of
the therapeutic dose of acetaminophen in people with alcohol abuse,
conducted by the same investigators). One (Ref. 73) is a full study
report of 201 people (102 on acetaminophen and 99 on placebo). The
other (Ref. 75) was an abstract describing a pilot trial with 60 people
(30 each on acetaminophen and placebo). A full report of this study is
not available (Ref. 75).
Both studies were randomized, double-blind, placebo-controlled
clinical trials conducted in an alcohol detoxification center to
evaluate the hepatotoxicity of maximum therapeutic dosing of
acetaminophen in long-term alcoholic subjects. In both studies, the
subjects were treated with the maximum therapeutic dose of
acetaminophen (1g four times a day) for 2 days, followed by a 2-day
observation. The results showed that acetaminophen treatment did not
significantly increase serum ALT, Aspartate Aminotransferase (AST), and
International Normalized Ratio (INR), as compared to the placebo
control. The authors concluded that there was no evidence that the
daily maximum therapeutic dose of acetaminophen caused liver injury in
alcoholics. However, FDA finds the data insufficient to support this
conclusion.
Neither study included an assessment of the quantity, frequency,
and duration of alcohol use by the subjects. Alcoholic detoxification
history and information on alcohol-related disorders, including more
specific hepatic evaluations (such as hepatic CYP2E1 p450 enzyme
levels, glutathione levels, or biopsy), were not reported. That
information would have enabled a better evaluation of chronic alcohol
use and underlying alcohol-induced liver abnormalities. Subjects with
AST and ALT higher than 120 IU/L were excluded from the study, so no
evaluation of subjects with underlying liver damage evidenced by slight
elevations of liver function tests could be assessed. Such subjects may
respond differently than those with more substantial hepatic
impairment. Other investigators have similarly criticized the studies
(Refs. 76 and 77). Assessing the change in liver function tests after
drug administration may not adequately support a conclusion that the
drug is without risk of liver injury in this population. If
subpopulations of chronic alcoholics are sensitive to lower doses of
acetaminophen, this type of study would be inadequate to make any
assessment of risk.
FDA also finds that a 2-day treatment period may be too short to
deplete the lowered hepatic gluthianone capacity in alcoholic people.
The 2-day regimen cannot be extrapolated into the recommended 10-day
dosing regimen in OTC drug product labeling. One individual agreed,
stating that the investigators gave no rationale for dosing
acetaminophen for only 2 consecutive days while the drug is approved
for 4 g/day for 10 consecutive days and commonly used for prolonged
periods of time (Ref. 78). Further, the individual stated that the lack
of elevation in liver enzyme values after only 2 days of acetaminophen
lends little support to the authors' conclusion regarding its safety in
alcoholic people. FDA's detailed assessment of these studies is on file
in the Division of Dockets Management (Ref. 79).
FDA concludes that these studies do not provide reliable evidence
that people with chronic alcohol use can safely take 4 g/day of
acetaminophen, particularly for up to 10 days in accordance with OTC
drug product labeling. Based on the data presented by Dr. Lee on liver
failure, the experience in the University of Pennsylvania Hospital
series, and data from the AERS database, FDA believes that alcohol
users are a significant percentage of persons who develop severe liver
injury. Acetaminophen products already have an alcohol warning to alert
consumers of the risk for developing hepatotoxicity. It is important to
determine whether the labeling should include a lower daily dose for
chronic alcohol users. At this time, FDA is seeking both comments and
data to support a specific dosage for acetaminophen as safe and
effective in people who consume alcohol.
[[Page 77337]]
C. Combinations With Methionine or Acetylcysteine
FDA is currently evaluating different safety measures to reduce the
relative risks for hepatotoxicity associated with the use of
acetaminophen. Theoretically, one method might be to administer
acetaminophen and N-acetylcysteine (NAC) together. NAC is a chemical
produced by the body that enhances the production of the enzyme
glutathione. A small portion of acetaminophen undergoes cytochrome
P450-mediated N-hydroxylation to form N-acetyl-p-benzoquinoneimine
(NAPQI, a toxic metabolite of acetaminophen). Liver toxicity from
acetaminophen overdose depends in part on production of NAPQ to levels
that exceed the ability of the normal hepatic detoxification pathway to
eliminate NAPQ. Glutathione is produced predominantly in the liver and
is an important detoxifier of NAPQ. In the event of acetaminophen
overdose in people with enhanced activity of CYP 2E1 (alcoholics, or
people using anticonvulsants), glutathione liver stores are depleted.
One substrate for glutathione synthesis is cysteine. NAC protects
against liver damage in early acetaminophen poisoning by production of
cysteine, a glutathione precursor. The administration of precursors of
cysteine, such as NAC or methionine, may prevent depletion of
glutathione and, thus, liver injury (Refs. 80 and 81).
Scientific data supports the efficacy of treating acute
acetaminophen overdose with early administration of NAC (Refs. 82
through 85). To determine whether there is any usage data of
acetaminophen with NAC or methionine for the purposes of prevention of
liver toxicity, FDA examined the literature from 1975 to December 2002.
FDA did not find any articles that specifically addressed whether
either combination (when used at the therapeutic dose level) would
prevent liver toxicity.
The UK is the only country where a combination product containing
acetaminophen and methionine is available. The marketed product
contains 500 mg acetaminophen and 100 mg methionine. One published
study summarized the issues related to combining acetaminophen and
methionine (Ref. 85). The authors acknowledge that there are no data
available on the relative efficacy or the prophylactic antidotal dose
of methionine for protecting the liver after acetaminophen overdose in
humans.
At this time, FDA finds insufficient evidence that combinations of
acetaminophen with NAC or methionine would prevent or reduce
acetaminophen-induced liver toxicity. FDA seeks comments and data on
this issue.
D. Package Size and Configuration Limitations
At the September 19, 2002, NDAC meeting, a representative from a
national consumer organization reported that the UK implemented package
size restrictions on acetaminophen. He noted that an early assessment
of the effect of the package size restrictions in the UK shows
decreases in total and severe acetaminophen overdoses, as well as
decreases in acetaminophen related toxicity leading to liver transplant
or death. The representative did not provide any data to support his
comments. FDA seeks comments on package size and package configuration
limitations as a mechanism to increase safe use of acetaminophen
products by reducing overdose. Comments should address the possible
impact of such measures on unintentional and intentional overdose.
E. Label Warning for Individuals With Human Immunodeficiency Virus
(HIV)
A citizen petition (Refs. 86 and 87) requested that FDA consider
the need for a warning about the increased risk of liver injury from
the use of acetaminophen by individuals infected with HIV. The request
is based on the following reasoning:
Glutathione (GSH) deficiency is frequent in HIV-infected
individuals.
Acetaminophen depletes GSH (essential for the
detoxification of acetaminophen's toxic metabolite) and is potentially
more toxic to GSH-deficient individuals.
GSH deficiency is associated with impaired survival in
persons with HIV disease, and acetaminophen may further reduce survival
by depleting GSH.
In support of this request, the petitioner (Ref. 86) provided
published studies of: (1) GSH and cysteine levels in plasma, peripheral
blood monocytes and lymphocytes, and in the pleural fluid of HIV-
positive individuals, and (2) the effects of GSH replacement in model
systems and HIV-infected individuals. A subsequent submission (Ref. 87)
provided a search of the worldwide literature that included studies of:
(1) Nonhepatic GSH levels in numerous disease states, (2) the effects
of treatment with NAC or other GSH-replenishing drugs in diseases and
conditions in which GSH is decreased, (3) the causes of GSH deficiency
in persons with HIV disease, (4) an association between GSH deficiency
and impaired survival in persons with HIV disease, and (5) the effect
of NAC replacement therapy on clinical outcomes in persons with HIV
disease.
A comment (Ref. 88) disagreed with the petitioner's assertions for
the following reasons:
The available data do not demonstrate that acetaminophen
reduces total body or circulating GSH when taken as recommended.
There currently are no studies that demonstrate that
acetaminophen has any impact on the survival of HIV patients.
The depletion of hepatic GSH that occurs after
acetaminophen overdose is not related to plasma GSH levels.
The source of plasma GSH in humans is not clearly defined.
FDA finds that although data from in vitro and in vivo studies
(Refs. 89 through 96) have documented low levels of GSH and its
precursors in HIV infection, the effect of this deficiency on survival
has not been clearly established. Data from in vitro studies (Refs. 97
through 100) have demonstrated improvement in healthy and HIV-infected
T-cell functioning post exposure to NAC. However, these findings have
not been correlated with survival from in vivo studies. While some
studies of the effects of NAC administration in HIV-infected
individuals (Refs. 89, 90, and 101 through 104) have demonstrated an
increase in GSH, the majority of studies were not designed to assess
survival.
Herzenberg, et al. (Ref. 102) discussed results from several
studies in HIV-infected patients that evaluated the relationship
between GSH levels and survival, the administration of NAC in patients
with low GSH levels in whole blood and in CD4 T cells, and the effect
of NAC on survival in patients with low GSH levels in CD4 T cells. The
presentation of data in the report made it difficult to understand the
study design details. Other problems based on the information presented
included: Survival data was not collected in a significant proportion
of the population (17 percent), baseline characteristics of the
individuals in all of the trials were not presented, the use of
antiviral treatments and other medications before and during the
studies was not provided, and NAC administration after 8 weeks was not
randomized. In their conclusions, the authors recommend that excessive
exposure to acetaminophen be avoided in HIV-infected individuals. The
report references acetaminophen overdose leading to GSH deficiency as a
basis to support their recommendation. However, it does not provide
sufficient
[[Page 77338]]
information suggesting that intermittent or short-term use presents a
problem in HIV patients. FDA concludes that this report does not
provide a sufficient basis to restrict that use of acetaminophen in
patients infected with HIV.
Further, a search of FDA's AERS database for hepatic adverse events
in HIV-infected individuals who took acetaminophen failed to identify
any case reports which fit the search parameters, i.e., acetaminophen,
HIV infection, and hepatotoxicity. Thus, there is no clinical evidence
of toxicity or decrease survival that can be attributed to the
recommended use of acetaminophen in HIV-infected individuals since GSH
levels were never validated to predict survival.
Given these facts, FDA does not consider the current data a
sufficient basis for a warning. However, the issues raised by the
petition highlight the need for additional information or research to
clarify whether acetaminophen poses additional risk for certain
population subgroups (e.g., conditions in which GSH is reduced).
Therefore, FDA invites the submission of data and comments on this
issue.
F. Drug Interactions Between Acetaminophen and Warfarin
The labeling for a currently marketed warfarin-containing
prescription drug product lists acetaminophen as a drug that can
increase warfarin's anticoagulant effect (Ref. 105). A reciprocal
warning is not currently included on the consumer labeling for any OTC
drug products that contain acetaminophen. To evaluate the need for a
consumer warning regarding co-administration of warfarin-containing
drugs with acetaminophen, FDA considered postmarketing adverse event
case reports in our AERS database, studies published in the worldwide
literature (Refs. 106 through 125), and three consultative reviews
(Ref. 126, 127, and 128).
In the consultative reviews, FDA epidemiologists identified a
cumulative total of 20 (3 probable and 17 possible) postmarketing
adverse event case reports of prolongation of laboratory tests that
monitor the ability of the blood to clot. These tests are the INR or
Prothrombin Time (PT). These reports occur in individuals treated
chronically with warfarin who concomitantly took acetaminophen and had
minor or severe bleeding events. Of note, the only background
characteristics that were identifiable in these case reports were that
the individuals involved were generally elderly, had been on stable
anticoagulant therapy for a prolonged period of time (several months to
years), and used acetaminophen ``regularly'' instead of
``intermittently'' for approximately 3 to 14 days prior to the
discovery of their abnormally prolonged INR or PT. The dosages of
acetaminophen reportedly ingested by these individuals ranged from 1.2
to 4.5g/day. FDA's epidemiologists attribute the small number of
postmarketing case reports collected to underreporting. We believe that
the actual number of cases is much higher, based on the numbers of
people who are treated with anticoagulant therapy.
FDA's epidemiologists also conducted two literature searches on
this topic. In the first (Ref. 126), FDA reviewed 11 published articles
describing three double-blind, placebo-controlled, randomized studies
that demonstrated a prolongation of warfarin's anticoagulant effect
when acetaminophen was used concomitantly in a chronic manner (Refs.
110, 112, and 113). Two additional published double-blind, crossover
studies showed that people on a stable warfarin dose who were acutely
dosed with acetaminophen did not experience any changes in their
anticoagulant status (Refs. 111 and 117). A prospective, case-control
study looked at a cohort of people from an anticoagulant clinic, each
of whom were noted to have an INR greater than 6 on a routine followup
clinic visit. The study found that after controlling for other risk
factors associated with prolongation of anticoagulant status (i.e.,
medication use, recent diet, illness, alcohol consumption, and actual
warfarin use), the use of acetaminophen was an independent dose-
dependent risk factor for having an INR over 6 (P-value for trend
< 0.001). Other independent variables associated with the development of
a prolonged INR were identified and included: Advanced malignancy (odds
ratio [OR], 16.4; 95 percent confidence interval [CI], 2.4 to 111.0),
recent diarrheal illness (OR, 3.5; 95 percent CI, 1.4 to 8.6),
decreased oral intake (OR, 3.6; 95 percent CI, 1.3 to 9.7), ingesting a
higher dose of warfarin than prescribed (OR, 8.1; 95 percent CI, 2.2 to
30.0), and taking new medications known to interact with warfarin (OR,
8.5; 95 percent CI, 2.9 to 24.7) (Ref. 113). The validity of this
study's findings was subsequently questioned when it was publicly
criticized in the literature for its flawed methodological design, such
as the overlapping of risk factors in the population studied (i.e.,
fever and the use of acetaminophen), and the lack of reported adverse
events (Refs. 115, 116, and 118). Additionally, the mechanism by which
a possible acetaminophen-warfarin interaction occurs has yet to be
clearly identified (Refs. 119 and 120).
The second updated literature review (Ref. 127) noted two
additional case controlled studies generated from patient cohorts
followed in anticoagulation clinics that were published in the European
literature (Refs. 123 and 124). Both of these studies failed to
document the existence of a possible drug-drug interaction in stable
anticoagulated people treated with the warfarin analogues phenprocoumon
or acenocoumarol and using acetaminophen concomitantly.
The data generated from the literature searches are conflicting.
Although many of the studies controlled for other variables known to
potentate warfarin's anticoagulant effect, it is not known if they all
also controlled for life style factors such as diet, the use of
vitamins and herbal medications, physical activity, concurrent illness,
or liver status. Extrapolating the clinical findings generated from the
study by Fattinger, et al. may not be applicable to real life
situations, since this trial was conducted in people where background
life style factors such as diet and physical activity did not come into
play due to the controlled study environment (Ref. 124). The study by
van den Bemt, et al. may have also failed to demonstrate the existence
of an adverse drug-drug interaction associated with the concomitant use
of acetaminophen with either of the warfarin analogues phenprocoumon or
acenocoumarol, because these drugs may be metabolized differently than
warfarin (Ref. 123). FDA believes that the current available data do
not demonstrate sufficient evidence to warrant a consumer warning for
warfarin-acetaminophen interaction. However, we are seeking comments or
data on whether additional labeling about this drug-drug interaction is
warranted at this time.
VIII. Legal Authority
A. Statement About Warnings
Mandating warnings in an OTC drug monograph does not require a
finding that any or all of the OTC drug products covered by the
monograph actually caused an adverse event, and FDA does not so find.
Nor does FDA's requirement of warnings repudiate the prior OTC drug
monographs and monograph rulemakings under which the affected drug
products have been lawfully marketed. Rather, as a consumer protection
agency, FDA has determined that warnings are necessary to ensure that
these OTC drug products continue to be safe and effective for their
labeled indications under ordinary conditions
[[Page 77339]]
of use as those terms are defined in the Federal Food, Drug, and
Cosmetic Act (the act). This judgment balances the benefits of these
drug products against their potential risks (see 21 CFR 330.10(a)).
FDA's decision to act in this instance need not meet the standard
of proof required to prevail in a private tort action (Glastetter v.
Novartis Pharmaceuticals Corp., 252 F. 3d 986, 991 (8th Cir. 2001)). To
mandate warnings, or take similar regulatory action, FDA need not show,
nor do we allege, actual causation. For an expanded discussion of case
law supporting FDA's authority to require such warnings, see the final
rule on ``Labeling of Diphenhydramine-Containing Drug Products for
Over-the Counter Human Use'' (67 FR 72555, December 6, 2002).
B. Marketing Conditions
This proposal applies to all OTC internal analgesic/antipyretic
drug products that contain an ingredient included in proposed Sec.
201.325(a). Upon issuance of a final rule, any new labeling will apply
to any product that is initially introduced or initially delivered for
introduction into interstate commerce. Such products would be
misbranded under section 502 of the act (21 U.S.C. 352) and would be
subject to regulatory action unless:
Products marketed without an NDA include the required
labeling within 12 months after any final rule that is issued based on
this proposal.
Products marketed with an NDA include the required
labeling within 12 months after any final rule that is issued based on
this proposal. The labeling may be put into use without advance FDA
approval provided it includes the information described in the final
rule. Manufacturers should submit a supplement under Sec. 314.70(c).
If companies voluntarily implement the labeling in this proposal
before a final rule issues, FDA intends to provide those companies 18
months to implement the labeling in the final rule.
IX. Voluntary Implementation
The labeling proposed in this document represents a change from the
current labeling required for OTC IAAA drug products. Although FDA
considers these proposed labeling changes to be very important, holders
of approved NDAs for OTC IAAA drug products will not be required to
implement the proposed labeling at this time. However, holders of
approved NDAs for these drug products may implement the proposed
labeling without advance FDA approval provided the labeling includes
the information in proposed Sec. 201.325. A supplement must be
submitted under Sec. 314.70(c) to provide for the implementation of
such labeling. The supplement and its mailing cover should be clearly
marked: ``Special Supplement--Changes Being Effected.''
FDA considers the proposed labeling in this document to be
important to the safe use of OTC IAAA drug products and strongly
encourages manufacturers of these products to voluntarily implement the
proposed labeling changes before FDA issues a final rule. However,
voluntary compliance with the proposed labeling in this document is
subject to the possibility that FDA may revise the wording of some of
the proposed statements or changes, or not require the statement or
change, as a result of comments filed in response to this proposal.
Because FDA wishes to encourage the voluntary use of the proposed
labeling statements and changes, FDA advises that manufacturers will be
given 18 months after publication of a final rule to use up any
labeling implemented in conformance with this proposal (see section XV
of this document).
X. Analysis of Impacts
FDA has examined the impacts of this proposed 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). Under the Regulatory
Flexibility Act, if a rule may have a significant economic impact on a
substantial number of small entities, an agency must analyze regulatory
options that would minimize any significant impact of the 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 million or more (adjusted annually for
inflation) in any one year.''
FDA tentatively concludes that this proposed rule is consistent
with the principles set out in Executive Order 12866 and in these two
statutes. This proposed rule is not a significant regulatory action as
defined by the Executive Order and so is not subject to review under
the Executive Order. As discussed in this section, FDA has tentatively
determined that this proposed rule will not have a significant economic
impact on a substantial number of small entities. Because the rule does
not impose any mandates on state, local or tribal governments, or the
private sector that will result in an expenditure in any one year of
$100 million or more, FDA is not required to perform a cost-benefit
analysis according to the Unfunded Mandates Reform Act. The current
threshold after adjustment for inflation is about $110 million.
FDA estimates that manufacturers and marketers of OTC IAAA drug
products would incur one-time compliance costs of $32 million in the
first year to revise labeling to conform to the proposed rule. The
benefits of this proposed rule are based on estimated annual reductions
from 1 to 3 percent in serious illnesses and related hospital and
emergency room costs and in deaths related to unintentional overdosing.
If 1 to 3 percent of these adverse events are avoided, the monetized
benefits would be $6 million to $17 million per year, respectively. The
present value of the monetized benefits over a 10-year period is $41
million to $126 million assuming a 7-percent discount rate,\1\ and $49
million to $147 million at a 3-percent discount rate. If we assume only
a 1 percent reduction in the illnesses and fatalities analyzed, the
benefits of this proposed rule outweigh the costs. We summarize the
impacts in Table 10 of this document.
---------------------------------------------------------------------------
\1\Per the Office of Management and Budget (OMB) Circular A4,
revised in 2003.
---------------------------------------------------------------------------
FDA notes that we lack the data needed to confidently predict a
percent reduction in serious cases related to unintentional overdosing.
Because of the uncertainty in these estimates, we estimated an annual
average number of adverse events that would need to be avoided over a
10-year period to reach a breakeven point. Social benefits would equal
the costs of compliance if the proposed rule prevented about 1 fatality
each year (0.9 and 0.7 fatalities over 10 years at a 7-percent and a 3-
percent discount rate, respectively). Alternatively, if no fatalities
are avoided, the proposed rule would need
[[Page 77340]]
to prevent about 475 hospitalizations per year over the 10-year period
at a 7-percent discount rate. At a 3-percent discount rate, an average
reduction of 410 hospitalizations per year is needed.
Table 10.--Summary of Impacts
----------------------------------------------------------------------------------------------------------------
Benefits: ($ Million)
----------------------------------------------------------------------------------------------------------------
Monetized 1 and 3-percent reduction in illnesses and $5--$17
mortality, per year
Present value over 10 years at 7 percent $41--$126
Present value over 10 years at 3 percent $49--$147
----------------------------------------------------------------------------------------------------------------
Costs: ($ Million)
One-time label revision, first year $32
----------------------------------------------------------------------------------------------------------------
A. Need for the Rule
In September 2002, FDA's NDAC recommended changes to the labeling
of OTC IAAA drug products to better inform consumers about the active
ingredients and possible side effects caused by improper use. Although
FDA considers acetaminophen to be safe and effective when labeled and
used correctly, taking too much can lead to liver damage and death.
Similarly, the use of NSAIDs can lead to GI bleeding and renal
toxicity. 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 prescription 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 taking 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, FDA finds that there is sufficient
incidence of liver damage 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 GI adverse events,
especially bleeding. The risk is higher for certain populations. Based
on the evidence discussed in this document, FDA further finds that
NSAIDs increase the risk for GI adverse events and that without a new
stomach bleeding warning in the labeling for aspirin and other NSAIDs
the products would no longer be considered generally recognized as safe
and effective and not misbranded for OTC use.
The purpose of this proposed rule is to amend FDA's OTC drug
labeling regulations and the TFM for OTC IAAA drug products to include
new warnings and other labeling requirements to advise consumers of
potential risks and when to consult a doctor. FDA is also proposing to
remove the alcohol warning in Sec. 201.322 and incorporate new
alcohol-related warnings and other labeling for all OTC IAAA drug
products. FDA is proposing certain warning information targeted to age
specific populations. In addition, FDA is proposing that the presence
of acetaminophen or any NSAID would appear prominently on the products'
PDP. Table 11 presents an overview of the proposed changes by type of
product.
Table 11.--Overview of the Proposed Label Changes by Product Type
----------------------------------------------------------------------------------------------------------------
Type of Product Proposed Change
----------------------------------------------------------------------------------------------------------------
Acetaminophen Add a new warning to include information on serious liver
injury. Include the name acetaminophen [highlighted or in bold
type, and in a prominent print size] on the PDP.
----------------------------------------------------------------------------------------------------------------
NSAIDs (e.g., aspirin or ibuprofen) Add a new warning to include information on stomach bleeding.
Include the name of the NSAID ingredient [highlighted or in
bold type] on the PDP. Include the word ``(NSAID)''
[highlighted or in bold type, and in a prominent print size]
on the PDP either as part of the established name of the drug
or after the general pharmacological (principal intended)
action of the NSAID ingredient.
----------------------------------------------------------------------------------------------------------------
Combination products containing acetaminophen Include the name acetaminophen or the name of the NSAID
or an NSAID and a nonanalgesic ingredient ingredient [highlighted or in bold type, and in a prominent
print size] and the names of the other active ingredients on
the PDP. Products containing an NSAID ingredient must include
the word ``(NSAID)'' as stated under NSAIDS.
----------------------------------------------------------------------------------------------------------------
[[Page 77341]]
All IAAA drug products Remove the current alcohol warning in Sec. 201.322, and
incorporate new alcohol-related warnings format. For a
specific period of time, add to the PDP the statement ``See
new warnings information''. We are proposing that this
statement appear highlighted in the same way that the name
``acetaminophen'' or the presence of an NSAID appear on the
PDP. The statement would appear highlighted (e.g., fluorescent
or color contrast) or in bold type; and be in one 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).
----------------------------------------------------------------------------------------------------------------
B. Impact of the Rule
FDA contracted with Eastern Research Group, Inc. (ERG) to assess
the costs and benefits of this proposed rule. The following is a
summary of ERG's analysis; the full report, including details on
assumptions, cost calculations, and findings, is on file in the
Division of Dockets Management (Ref. 129).
Manufacturers and marketers of OTC IAAA drug products would incur
one-time costs to revise affected product labeling to comply with the
proposed labeling changes. We assumed an implementation period of 12
months for one-time costs for a major labeling revision. We estimated
one-time costs for a major labeling revision using a pharmaceutical
labeling revision cost model. This labeling model is described in
detail in Appendix A of the ERG report (Ref. 129).
To develop the original model, FDA 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 IAAA industry, the labeling revision process, the costs of
modifying labeling, and the frequency of packaging reconfiguration
changes.
The baseline for this proposed action is full compliance with the
format and content requirements for OTC drug product labeling in 21 CFR
201.66. In the final rule that established these requirements on March
17, 1999 (64 FR 13254), FDA accounted for the total incremental costs
to comply with requirements, including 6.0 font size and related costs
for increased package size and longer labeling where applicable. FDA
notes that although some forms of packaging (for small quantities) have
been granted extensions on compliance dates, many packaging
alternatives now exist to assure compliance.
Manufacturers routinely change labels at varying intervals and have
standardized procedures in place for complying with FDA requirements.
The analysis assumes that one-half of the manufacturers of OTC IAAA
drug products typically redesign their label every 2 years, the
remainder every 3 years, based on consultant input. For this analysis,
ERG assumed that manufacturers whose label redesign cycle is less than
the implementation period will not incur any regulatory costs. For
example, if a company routinely revises its product labeling annually
and is given at least that long to incorporate the required changes,
ERG judged that the regulatory revision can be made at essentially no
cost.
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 IAAA drug product stockkeeping units (SKUs), split evenly
among branded and private labels, according to an industry
consultant.\2\ FDA assumes branded SKUs are distributed by firm size:
50 percent small, 17 percent medium, and 33 percent large. Based on
consultant input, we assumed the distribution of SKUs among OTC IAAA
drug products as follows: Acetaminophen, 45 percent; NSAIDS (except
ibuprofen), 38 percent; ibuprofen, 15 percent; and combinations of
IAAAs (i.e., contain acetaminophen and aspirin), 2 percent. Cost
estimates are for small, medium, and large branded companies, private
label companies, and by affected product group. The ERG report presents
model assumptions and methods for calculating costs.
---------------------------------------------------------------------------
\2\Estimates of affected SKUs are 18,000 (CDER) and from 20,000
to 25,000 (per industry consultant). This number of SKUs includes
products marketed by manufacturers, repackers, relabelers, and
distributors.
---------------------------------------------------------------------------
ERG visited five stores--two major chain drug stores and three
convenience stores--to collect information on the distribution of types
of OTC IAAA drug product packaging. Roughly 80 percent of OTC IAAA drug
products were packaged in cartons and 20 percent in containers. To
assess the increase in label space requirements, ERG purchased 45
affected products, with an emphasis on smaller packages.
1. Label Area Changes
ERG collected and recorded descriptive packaging information on the
sampled products and measured existing font size, labeling area and
labeling text on packages, and the area needed for replacement text.
ERG then calculated the percentage increase in square millimeters
(mm\2\) needed to accommodate the proposed labeling changes. In all
cases, ERG determined that the requirement to add active ingredient
names on the PDP, while requiring major redesign in some cases, did not
impose a change in the size of the PDP or the addition of non-standard
labeling (such as adding a fifth carton panel or peelback label). ERG
estimates that the increase in existing label area needed to
accommodate the additional proposed label warnings and text ranges from
8 percent (acetaminophen) to 32 percent (ibuprofen).
2. Package size or type changes
ERG measured the available panels and white space on the 45
packages sampled. If the available white space was greater than the
estimated increase in space necessary to accommodate the new label
warnings, ERG determined the product would not require an increase in
carton or container size. Based on this review, ERG assumed that all
current packaging can accommodate the required changes in this proposal
without altering label sizes, package sizes, or adding non-standard
labels. Therefore, ERG did not assign costs for adjustments to
packaging. Although
[[Page 77342]]
finding only a few small foil packs that did not comply with the OTC
Drug Facts labeling requirements, ERG noted that alternative types of
packaging are now available to replace the older packages.
Table 12 presents the estimated total and annualized costs of
compliance with the OTC IAAA drug product proposed rule. The total
estimated one-time costs to revise labeling are $32.6 million. The
estimated annualized cost over the relevant relabeling period is $15.2
million at a 7-percent discount rate. The estimated average annualized
cost per SKU is $677 ($15.2 million/22,500 SKUs).
Table 12.--Estimated Total and Annualized Costs of Compliance ($ Million)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Product Type
----------------------------------------------------------------------------------------------------------
Total
-------
NSAID (except Combinations of Total
Company Type Acetaminophen Ibuprofen) Ibuprofen IAAAs One-
time
Costs
--------------------------------------------------------------------------------------------------------------------------------------------------- -------
Small Brand 2.2 1.8 0.7 0.1 4.9
-----------------------------------------------------------------------------------------------------------------------------------------------------
Medium Brand 2.1 1.8 0.7 0.09 4.7
-----------------------------------------------------------------------------------------------------------------------------------------------------
Large Brand 6.0 5.1 2.0 0.3 13.3
-----------------------------------------------------------------------------------------------------------------------------------------------------
Private Label 4.4 3.7 1.5 0.2 9.7
-----------------------------------------------------------------------------------------------------------------------------------------------------
Total 14.7 12.4 4.9 0.7 32.6
-----------------------------------------------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------------------------------------------
Total Annualized Costs (at 7-percent discount rate)
----------------------------------------------------------------------------------------------------------------------------------------------------
Small Brand 1.0
-----------------------------------------------------------------------------------------------------------------------------------------------------
Medium Brand 1.0
-----------------------------------------------------------------------------------------------------------------------------------------------------
Large Brand 2.8
-----------------------------------------------------------------------------------------------------------------------------------------------------
Private Label 2.0
-----------------------------------------------------------------------------------------------------------------------------------------------------
Total 6.9
--------------------------------------------------------------------------------------------------------------------------------------------------------
C. Impact on Affected Sectors
Manufacturers of OTC drug products are classified in North American
Industry Classification System (NAICS) 325412, pharmaceutical
preparation manufacturing. This classification code includes all
manufacturers of prescription and OTC pharmaceutical preparations, but
does not include relabelers, repackers, and distributors. The Small
Business Administration (SBA) defines a small business in this industry
classification code as one with fewer than 750 employees. In NAICS
325412, over 90 percent are considered small entities. The affected
industry is a subset of the OTC pharmaceutical industry. This proposed
rule affects an estimated 258 manufacturers (of which 200 are small) of
OTC IAAA drug products.
Manufacturers often package private label products, although some
chains package their own brands. SBA considers the following to be
small: (1) Any pharmacy or drug store with annual sales under $6
million, and (2) supermarkets and other grocery stores and warehouses
and superstores with sales under $23 million. Generally, only the
largest supermarket and drug store chains (263 firms) or superstores (9
firms) would have their own private label. ERG included only those
largest retail chains with annual sales of $100 million or more as
having their own private labels. Thus, FDA believes that there are no
small entities in these retail sectors that are affected. Marketers of
private label OTC drug products are classified as follows:
NAICS 446110, Pharmacies and drug stores
NAICS 445110, Supermarkets and other grocery stores
NAICS 452910, Warehouse clubs and superstores.
Packaging and labeling services that contract with pharmaceutical
manufacturing firms may also be affected, but we assume manufacturers
bear the costs of any labeling changes. Both the manufacturing and
marketing sectors will most likely share costs, but the extent is not
known. Therefore, this impact analysis first assumes that manufacturers
absorb all of the labeling costs. We then assume that all private
labeling costs are absorbed by chain stores and calculate impacts.
To assess the impact on entities in the pharmaceutical-
manufacturing sector (NAICS 325412), ERG adjusted SBA data on firm size
and revenues to estimate average receipts per firm for the affected
sector. ERG applied modeling assumptions to estimate the number of
large and small affected firms. ERG further assumed the distribution of
all 22,500 affected SKUs is one-third for large firms (producing either
branded or private label products) and two-thirds for small firms. To
estimate the share of total compliance costs for each size category,
ERG distributed the SKUs attributed to small businesses in the same
proportion as employment. The distribution of SKUs determines the
distribution of compliance costs by employment size category. Table 13
summarizes the estimated impacts for pharmaceutical manufacturers, the
total cost per firm based on $677 per SKU, and the compliance costs as
a percent of revenues.
[[Page 77343]]
Table 13.--Estimated Impacts on Pharmaceutical Preparation Manufacturing Firms by Size (NAICS 325412)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Average Receipts Assumed No. of Total Firm Cost Compliance Cost
Employment Size per Firm ($mil) SKUs SKUs per Firm ($000)\1\ as % of Receipts
--------------------------------------------------------------------------------------------------------------------------------------------------------
< 20 1.7 841 9 6.0 0.340%
--------------------------------------------------------------------------------------------------------------------------------------------------------
20-99 12.2 2,591 65 43.8 0.361%
--------------------------------------------------------------------------------------------------------------------------------------------------------
100-499 61.9 5,506 148 100.2 0.162%
--------------------------------------------------------------------------------------------------------------------------------------------------------
500-749 366.8 6,062 225 151.9 0.041%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total Small 29.1 15,000 75 50.8 0.175%
--------------------------------------------------------------------------------------------------------------------------------------------------------
>750 947.8 7,500 130 88.1 0.009%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total 109.6 22,500 87 59.1 0.054%
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Number of SKUs x $677 per SKU.
Source: SBA, 1999 and ERG estimates.
Total estimated compliance costs per firm ranged from $6,000 for
firms with fewer than 20 employees to $152,000 for firms with 500 to
749 employees. The compliance cost as a percent of receipts is less
than 1 percent for all firms; 0.18 percent for all small firms and 0.01
for large firms. This estimate of impacts is somewhat understated
because the census data used to derive estimates includes both OTC and
prescription drug manufacturers. However, no alternative revenue and
employment size information for affected product lines is available. We
tentatively conclude that this estimate of the impacts of the proposed
rule does not constitute a significant economic impact on a substantial
number of small entities.
In a similar analysis, we assume chain stores absorb costs for all
11,250 private label SKUs. Compliance costs as a percent of receipts
are less than 0.001 percent for all of the affected sectors:
Pharmacies, drug stores, superstores, supermarkets, and other grocery
stores. No small entities are affected.
Manufacturers routinely change labels at varying intervals and have
standardized procedures in place for complying with FDA requirements.
The proposed rule would not require any new reporting and record
keeping activities and no additional professional skills are needed.
There are no other Federal rules that duplicate, overlap, or conflict
with the proposed rule; FDA is proposing to remove the existing alcohol
warning in Sec. 201.322.
D. Alternatives
FDA does not believe that there are any alternatives to the
proposed rule that would adequately provide for the safe and effective
use of OTC drug products containing IAAA active ingredients.
Nonetheless, FDA considered but rejected the following alternatives:
(1) Not adding the new information to OTC IAAA drug product labeling,
and (2) a longer implementation period. FDA does not consider either of
these approaches acceptable because they do not assure that consumers
will have the most current labeling information needed for the safe and
effective use of these products. FDA considers this proposed rule the
least burdensome alternative that meets the public health objectives of
this rule.
E. Benefits
FDA's proposed requirements are intended to enhance consumer
awareness and knowledge of the active ingredient in OTC IAAA drug
products. These new proposals 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 proposed requirements is to reduce the liver damage and GI
bleeding episodes that occur due to unintentional overdosing with these
drugs. The proposed requirements are also intended to reduce the
incidence of adverse health outcomes among high-risk subpopulations
consuming proper doses of OTC IAAA drug products (e.g., people with
liver disease or prone to GI bleeding).
To estimate the benefits of this proposed rule, we developed
baseline information on the frequency of hospitalizations, emergency
room visits, and deaths related to unintentional overdosing with OTC
IAAA drug products. We used a value of $5 million to represent the
premature loss of a statistical life in previous analyses (see 66 FR
6137, January 19, 2001). We quantified the related hospital and
emergency room costs, estimated related morbidity costs, applied a
value of $5 million to the premature loss of a statistical life, and
estimated annual savings if 1 to 3 percent of these adverse events and
deaths are avoided (Ref. 129).
We lack evidence to predict with certainty a specific level of
reduction in adverse events. Nonetheless, we believe that presenting
consumers with improved label warnings and more prominently displaying
the active ingredients on the PDP will promote safer use of OTC IAAA
drug products. Specifically, prominent display of the active
ingredients on the PDP would alert consumers to the presence of the
active ingredients in OTC IAAA drug products and help minimize the
risks of unintentional overdosing. The revised warnings are intended to
assist consumers, including higher risk individuals, to use OTC IAAA
drug products more safely and lead to at least a modest reduction in
unintentional overdosing.
Table 14 summarizes the baseline and estimates of the number of
avoidable hospitalizations and emergency room visits, the average cost
per case, and potential savings from events avoided. These data do not
include reported cases of intentional overdosing. Based on the total
monetized costs per adverse health outcome and the number of cases
estimated to be avoided each year (from 1 to 3 percent), the total
monetized benefits of illness avoided range from $0.6 million to $1.8
million per year ($592,600 to $1,777,900).
[[Page 77344]]
Table 14. --Summary of Annual Monetized Benefits of Illnesses Avoided Associated with the Proposed Rule (2001 $)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Potentially Total Annual
Willing to Pay Total Monetized Preventable Annual Number of Cases Monetized Benefits
Adverse Health Event Hospital Costs to Avoid Value of Baseline Cases Avoided Due to Proposed of Illness Avoided
Illness Illness Avoided per Year(1) Rule(2) ($000)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Minor drug toxicity or emergency $209 $301 $510 3,380 34-101 $17.2-$51.7
room visits
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acetaminophen poisoning episode $8,579 $2,000 $10,579 3,424 34-103 $362.2-$1,086.8
with hospitalization
--------------------------------------------------------------------------------------------------------------------------------------------------------
NSAID poisoning episode with $8,579 $357 $8,936 2,269 23-68 $202.8-$608.3
hospitalization
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acute renal failure with $22,251 Not Estimated $22,251 5 0.05-0.15 $1.1-$3.3
hospitalization
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acute renal failure with dialysis $22,251 Not Estimated $22,251 0.7 0.007-0.021 $0.2-$0.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
GI bleeding $14,653 $357 $15,010 61 0.6-1.8 $9.2-$27.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total monetized benefit of illness NA NA NA NA NA $592.6-$1,777.9
avoided
--------------------------------------------------------------------------------------------------------------------------------------------------------
(1) The number of potentially preventable baseline cases per year is derived from data on emergency department and hospital cases of overdosing,
poisoning, or other serious adverse outcomes associated with acetaminophen and NSAID use, adjusted to estimate only unintentional cases.
(2) Assumes this proposed rule would reduce annual adverse event cases by 1 to 3 percent.
Source: FDA Section III.B.2 of this document and ERG report (Ref. 129).
In addition to estimating the value of preventing adverse drug
events that result in emergency department or hospitalization, we
consider the annual number of deaths related to unintentional
acetaminophen overdoses. FDA estimates that from 1996 to 1998, an
annual average of 99 adult deaths were related to unintentional
acetaminophen overdoses (see section III.B.2 of this document and the
ERG report (Ref. 129)). We assume the proposed rule would reduce
fatalities by 1 to 3 percent annually. Applying a value of $5 million
for each fatality prevented, we estimate the total benefits associated
with preventing 1 to 3 fatalities to be $5 to $15 million annually
($2001).
If the proposed improved labeling and warnings reduced serious
adverse events by 1 to 3 percent each year, the total monetized value
of preventing illness and fatalities because of improved labeling and
warnings would be $5.6 million to $16.8 million per year, respectively.
These benefits are presented in 2001 dollars.
Benefit Cost Comparison. Industry would incur the one-time costs of
the proposed rule of $32.6 million in the first year. In 2001, the
costs were $32.0 million. However, the estimated savings from reduced
hospital costs and deaths avoided, from $5.6 to $16.8 million, would
accrue each year. Over a 10-year period, the $5.6 to $16.8 million per
year in benefits has a present value of $41.2 to $126.1 million at a
discount rate of 7 percent, and a present value of $49.1 to $147.4
million at a discount rate of 3 percent. Thus, the benefits of this
proposed rule, assuming a 1-percent reduction in current levels of
adverse health outcomes associated with the use of OTC IAAA drug
products, will more than offset the costs of the proposed rule. Table
15 summarizes the estimated benefits and costs of this proposed rule.
Table 15.--Summary of Impacts
------------------------------------------------------------------------
Benefits/Costs ($Million)
------------------------------------------------------------------------
Benefits:
------------------------------------------------------------------------
Monetized 1 and 3 $5.6-$16.8
percent reduction in
illnesses and
mortality, per year
Present value over 10 $41-$126
years at 7 percent
[[Page 77345]]
Present value over 10 $49-$147
years at 3 percent
------------------------------------------------------------------------
Costs:
------------------------------------------------------------------------
One-time label revision, $32.6
first year
------------------------------------------------------------------------
Break-even Analysis. FDA notes 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 breakeven
point (i.e., the cost of compliance/present value of avoiding one death
each year for 10 years). The proposed rule would need to prevent about
1 fatality each year over 10 years [0.9 fatality ($32/$37.6 million at
a 7-percent discount rate) and 0.7 fatality ($32/$43.9 million at a 3
percent discount rate)]. Alternatively, if no fatalities are avoided,
the proposed rule would need to prevent about 476 hospitalizations ($32
million/$67,000) each year over the 10-year period. This estimate uses
the present value of the lowest benefit category of poisoning episode
with hospitalizations, $8,936 per episode over 10 years at a 7-percent
discount rate. At a 3 percent discount rate, an average of 407
hospitalizations ($32 million/$79,000) would need to be avoided
annually over the period.
Although we lack evidence to predict with certainty a specific
level of reduction in adverse events, if we assume only a 1-percent
reduction in the illnesses and fatalities analyzed, the benefits of
this proposed rule outweigh the costs. FDA finds that this proposed
rule will enhance public health and promote the safer use of OTC IAAA
drug products.
This economic analysis, together with other relevant sections of
this document, serves as FDA's initial regulatory flexibility analysis,
as required under the Regulatory Flexibility Act.
FDA invites public comment regarding any significant economic
impact that this rulemaking would have on affected manufacturers of
these OTC IAAA drug products. Comments regarding the impact of this
rulemaking should be accompanied by appropriate documentation. FDA is
providing 150 days from the date of publication of this proposed rule
in the Federal Register for comments on this subject to be developed
and submitted. FDA will evaluate any comments and supporting data that
are received and will reassess the economic impact of this rulemaking
in the preamble to any final rule.
XI. Paperwork Reduction Act of 1995
FDA tentatively concludes that the labeling requirements proposed
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 proposed labeling statements are public
disclosures 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)).
XII. Environmental Impact
FDA has determined under 21 CFR 25.31(a) that this proposed 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.
XIII. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized as proposed, would have a preemptive
effect on State law. 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.'' Section 751
of the Federal Food, Drug, and Cosmetic Act (act) (21 U.S.C. 379r) is
an express preemption provision that applies to nonprescription drugs.
Section 751(a) of the act (21 U.S.C. 379r(a)) provides that:
* * no State or political subdivision of a State may establish
or continue in effect any requirement-- * * * (1) that relates to
the regulation of a drug that is not subject to the requirements of
section 503(b)(1) or 503(f)(1)(A); and (2) that is different from or
in addition to, or that is otherwise not identical with, a
requirement under this Act, the Poison Prevention Packaging Act of
1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling
Act (15 U.S.C. 1451 et seq.). * * *
Currently, this provision operates to preempt States from imposing
requirements related to the regulation of nonprescription drug
products. (See section 751(b), (c), (d), and (e) of the act for the
scope of the express preemption provision, the exemption procedures,
and the exceptions to the provision.) This proposed rule, if finalized
as proposed, would amend the labeling for over-the-counter IAAA drug
products to include new warnings and other labeling requirements
advising consumers about potential risks and when to consult a doctor.
Although any final rule would have preemptive effect, in that it would
preclude States from issuing requirements related to the labeling of
IAAA drug products that are different from or in addition to, or not
otherwise identical with a requirement in the final rule, this
preemptive effect is consistent with what Congress set forth in section
751 of the act. Section 751(a) of the act displaces both state
legislative requirements and state common law duties. We also note that
even where the express preemption provision is not applicable, implied
preemption may arise. See Geier v. American Honda Co., 529 U.S. 861
(2000).
FDA believes that the preemptive effect of the proposed rule, if
finalized as proposed, would be consistent with Executive Order 13132.
Section 4(e) of the Executive Order provides that ``when an agency
proposes to act through adjudication or rulemaking to preempt State
law, the agency shall provide all affected State and local officials
notice and an opportunity for appropriate participation in the
proceedings.'' FDA is providing an opportunity for State and local
officials to comment on this rulemaking, and will conduct outreach to
State and local governments or organizations representing them.
[[Page 77346]]
XIV. Request for Comments
In addition to requesting general comments on the proposal and the
economic analysis, we are seeking comment on the following specific
issues identified in the description of the proposed rule (presented
here for the convenience of the reader):
1. Both comment and data on whether adult NSAID products should
contain a warning regarding fluid loss or dehydration similar to
children NSAID products (see section V.B.2 of this document).
2. Appropriate approaches to reduce unintentional acetaminophen
overdose (see section VII.A of this document).
3. Whether more specific directions, such as those currently
required for OTC drug products containing ibuprofen, should be
considered for acetaminophen (see section VII.A of this document).
4. Both comment and data on whether there are specific populations
of people for whom the maximum daily dose for acetaminophen is not safe
and effective and should be lowered (see section VII.A of this
document).
5. Both comment and data on specific dosage for safe and effective
use of acetaminophen in people who consume alcohol (see section VII.B
of this document).
6. Both comment and data on whether combinations of acetaminophen
with NAC or methionine would prevent or reduce acetaminophen-induced
liver toxicity (see section VII.C of this document).
7. Both comment and data on package size or package configuration
limitations on the sale of acetaminophen (see section VII.D of this
document).
8. Both comment and data on whether acetaminophen poses additional
risk for certain population subgroups (e.g., conditions in which GSH is
reduced) (see section VII.E of this document).
9. Both comment and data on whether additional labeling is
necessary regarding acetaminophen-warfarin drug-drug interaction (see
section VII.F of this document).
10. Comment on the proposal to include a warning on acetaminophen
products for patients with liver disease to ask their doctor for
advice. Also, request information and data on the current dosing
practices of health providers who treat patients with underlying liver
disease.
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or three hard copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document and may be accompanied by a supporting
memorandum or brief. Received comments may be seen in the Division of
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
XV. Proposed Effective and Compliance Dates
Because of the importance of the proposed labeling to the safe use
of OTC IAAA drug products, FDA is proposing that any final rule that
may publish based on this proposal become effective 12 months after its
date of publication in the Federal Register. Manufacturers who
voluntarily implement the labeling included in this proposal before the
final rule is published will have 18 months after the date of
publication of the final rule in the Federal Register to be in
compliance with that final rule.
XVI. References
The following references are on display in the Division of Dockets
Management (see ADDRESSES), under Docket No. 1977N-0094L, unless
otherwise indicated, and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday. (FDA has verified the Web site
addresses, but we are not responsible for subsequent changes to the Web
sites after this document publishes in the Federal Register.)
1. Comment No. C1, Docket No. 1977N-0094I (formerly Docket No.
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2. Comment No. C2, Docket No. 1977N-0094I (formerly Docket No.
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112. Boeijinga, J. J. et al., ``Interaction Between Paracetamol
and Coumarin Anticoagulants [letter],'' Lancet, 1(8270):506, 1982.
113. Rubin, R. N., R. L. Mentzer, and A. Z. Budzynski,
``Potentiation of Anticoagulant Effect of Warfarin by Acetaminophen
(Tylenol) [abstract],'' Clinical Research, 32(3):698A, 1984.
114. Hylek, E. M. et al., ``Acetaminophen and Other Risk Factors
for Excessive Warfarin Anticoagulation,'' The Journal of the
American Medical Association, 279(9): 657-662, 1998.
115. Amato, M. G. et al., ``Acetaminophen and Risk Factors for
Excess Anticoagulation With Warfarin [letter],'' The Journal of the
American Medical Association, 280(8): 695-696, 1998.
116. Riser, J. et al., ``Acetaminophen and Risk Factors for
Excess Anticoagulation With Warfarin [letter],'' The Journal of the
American Medical Association, 26; 280(8): 696, 1998.
117. Kwan, D., W. R. Bartle, and S. E. Walker, ``The Effects of
Acetaminophen on Pharmacokinetics and Pharmacodynamics of
Warfarin,'' Journal of Clinical Pharmacology, 39:68-75, 1999.
118. Shek, K. L. A., L. N. Chan, and E. Nutescu, ``Warfarin-
Acetaminophen Drug Interaction Revisited,'' Pharmacotherapy,
19(10):1153-1158, 1999.
119. Lehmann, D. F., ``Enzymatic Shunting: Resolving the
Acetaminophen-Warfarin Controversy,'' Pharmacotherapy, 20(12):1464-
1468, 2000.
120. Whyte, I. M. et al., ``Acetaminophen Causes an Increased
International Normalized Ratio by Reducing Functional Factor VII,''
Therapeutic Drug Monitoring, 22(6):742-748, 2000.
121. Bell, W. R., ``Acetaminophen and Warfarin: Undesirable
Synergy [editorial],''
[[Page 77349]]
The Journal of the American Medical Association, 279(9): 702-703,
1998.
122. Caraco, Y., J. Sheller, and A. J. Wood, ``Pharmacogenetic
determination of the effects of codeine and prediction of drug
interactions,'' Journal of Pharmacology and Experimental
Therapeutics, 278(3):1165-1174, 1996.
123. van den Bemt, P. M. et al., ``The potential interaction
between oral anticoagulants and acetaminophen in everyday
practice,'' Pharmaceutical World Science, 24(5):201-204, 2002.
124. Fattinger, K. et al., ``No clinically relevant drug
interaction between paracetamol and phenoprocoumon based on a
pharmacoepidemiological cohort study in medical in people,''
European Journal of Clinical Pharmacology, 57(12): 863-867, 2002.
125. La Grenad, L., D. J. Graham, and P. Nourjah,
``Underreporting of hemorrhagic stroke associated with
phenylpropanolamine,'' The Journal of the American Medical
Association; 286: 3081, 2001.
126. Phelan, K., ``OPDRA Postmarketing Safety Review:
Acetaminophen and Coumadin (drug interaction affecting
anticoagulation),'' FDA review dated April 20, 2001.
127. Karwoski, C. B., ``Office of Drug Safety Postmarketing
Safety Review (DO30283) Drugs--Acetaminophen and Warfarin, Reaction:
Drug Interaction affecting Anticoagulation (update),'' FDA review
dated June 27, 2003.
128. Neuner, R., ``Potentiation of Anticoagulaton Status Due to
a Possible Adverse Drug Interaction Between Warfarin and
Acetaminophen,'' FDA review dated July 9, 2003.
129. Eastern Research Group, Inc. ``Cost Benefit Analysis of
Proposed FDA Rule on Over-the-Counter Internal Analgesic,
Antipyretic, and Antirheumatic Drug Products; Required Warnings'',
Final Report, October 6, 2004.
List of Subjects
21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 343
Labeling, Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR parts 201 and 343 (as proposed in the Federal
Register of November 16, 1988 and August 21, 2002) be amended as
follows:
PART 201--LABELING
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, 360g-360s, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
0
2. Section 201.66 is amended by revising paragraph (c)(5)(ii)(E) to
read as follows:
Sec. 201.66 Format and content requirements for over-the-counter
(OTC) drug product labeling.
* * * * *
(c) * * *
(5) * * *
(ii) * * *
(E) Liver warning set forth in Sec. 201.325(a)(1)(iii) and/or
stomach bleeding warning set forth in Sec. 201.325(a)(2)(iii). The
liver warning shall follow the subheading ``Liver warning:'' and the
stomach bleeding warning shall follow the subheading ``Stomach bleeding
warning:''
* * * * *
Sec. 201.322 [Removed]
3. Section 201.322 is removed.
4. Section 201.325 is added to subpart G to read as follows:
Sec. 201.325 Over-the-counter drug products containing internal
analgesic/antipyretic active ingredients; required warnings and other
labeling.
(a) Labeling. The labeling for all over-the-counter (OTC) drug
products containing any internal analgesic/antipyretic active
ingredients (including, but not limited to, acetaminophen, aspirin,
carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen,
magnesium salicylate, naproxen sodium, and sodium salicylate) alone or
in combination must bear the following labeling in accordance with
Sec. Sec. 201.60, 201.61, and 201.66.
(1) Acetaminophen.
(i) Principal display panel. The presence of ``acetaminophen'' in
the product must be prominently stated on the principal display panel
(PDP), as defined in Sec. 201.60.
(ii) Statement of identity. The statement of identity appears in
accord with Sec. Sec. 201.61, 299.4, and 343.50(a) of this chapter.
The ingredient name acetaminophen 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 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 presence
of acetaminophen must appear as part of the established name of the
drug, as defined in Sec. 299.4 of this chapter. Combination products
containing acetaminophen and a nonanalgesic ingredient(s) (e.g., cough-
cold) must include the name ``acetaminophen'' and the name(s) of the
other active ingredient(s) in the product on the PDP in accord with
this paragraph. Only the name ``acetaminophen'' must appear highlighted
or in bold type, and in a prominent print size, as described in this
paragraph.
(iii) For products labeled for adults only. Warnings. The labeling
of the product states the following warnings under the heading
``Warnings'':
(A) ``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 [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.
(B) ``Do not use [heading in bold type] with any other drug
containing acetaminophen (prescription or nonprescription). Ask a
doctor or pharmacist before using with other drugs if you are not
sure.''
(C) ``Ask a doctor before use if you have [heading in bold type]
liver disease''.
(iv) For products labeled only for children under 12 years of age.
(A) Warnings. The labeling of the product states the following warnings
under the heading ``Warnings'':
(1) ``Liver warning [heading in bold type]: This product contains
acetaminophen. Severe liver damage may occur if the child takes
[bullet] more than 5 doses in 24 hours [bullet] with other drugs
containing acetaminophen''. This ``Liver warning'' must be the first
warning under the ``Warnings'' heading.
(2) ``Do not use [heading in bold type] with any other drug
containing acetaminophen (prescription or nonprescription). Ask a
doctor or pharmacist before using with other drugs if you are not
sure.''
(3) ``Ask a doctor before use if the child has [heading in bold
type] liver disease''.
(B) Directions. The labeling of the product contains the following
information under the heading ``Directions'': ``this product does not
[[Page 77350]]
contain directions or warnings for adult use'' [in bold type].
(v) For products labeled for adults and children under 12 years of
age. Warnings. The labeling of the product states all of the warnings
in paragraphs (a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) of
this section with the following modifications:
(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 [ 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.''
(B) ``Ask a doctor before use if the user [heading in bold type]
has liver disease.''
(2) Nonsteroidal anti-inflammatory analgesic/antipyretic active
ingredients--including, but not limited to, aspirin, carbaspirin
calcium, choline salicylate, ibuprofen, ketoprofen, magnesium
salicylate, naproxen sodium, and sodium salicylate.
(i) Principal display panel. The presence of an ``NSAID''
ingredient in the product must be prominently stated on the principal
display panel (PDP), as defined in Sec. 201.60.
(ii) Statement of identity. The statement of identity appears in
accord with Sec. Sec. 201.61, 299.4, and 343.50(a) of this chapter.
The name of the NSAID ingredient and the word ``(NSAID)'' 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 of the following sizes,
whichever is greater: At least one-quarter as large as the size of the
most prominent printed matter on the PDP, or at least as large as the
size of the ``Drug Facts'' title, as required in Sec. 201.66(d)(2).
The word ``(NSAID)'' must appear as part of the established name of the
drug, as defined in Sec. 299.4 of this chapter, or after the general
pharmacological (principal intended) action of the NSAID ingredient.
For example, either of the following would be acceptable: Ibuprofen
Tablets (NSAID) or Pain reliever/ fever reducer (NSAID). Combination
products containing an NSAID and a nonanalgesic ingredient(s) (e.g.,
cough-cold) must include the name of the NSAID ingredient and the word
``(NSAID)'' in accord with this paragraph, and the name(s) of the other
active ingredient(s) in the product on the PDP. Only the name of the
NSAID ingredient and the word ``(NSAID)'' need to appear highlighted or
in bold type, and in a prominent print size, as described in this
paragraph.
(iii) For products labeled for adults only. Warnings. The labeling
of the product states the following warnings under the heading
``Warnings'':
(A) ``Stomach bleeding warning [heading in bold type]: This product
contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause
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 an NSAID [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 Sec.
201.325(a)(1)(iii) must appear before the ``Stomach bleeding warning''
in this paragraph.
(B) ``Ask a doctor before use if you have [heading in bold type]
[bullet] stomach problems that last or come back, such as heartburn,
upset stomach, or stomach pain [bullet] ulcers [bullet] bleeding
problems [bullet] high blood pressure [bullet] heart or kidney disease
[bullet] taken a diuretic [bullet] reached age 60 or older''.
(C) ``Ask a doctor or pharmacist before use if you are [heading in
bold type] [bullet] taking any other drug containing an NSAID
(prescription or nonprescription) [bullet] taking a blood thinning
(anticoagulant) or steroid drug''.
(D) ``Stop use and ask a doctor if [heading in bold type] [bullet]
you feel faint, vomit blood, or have bloody or black stools. These are
signs of stomach bleeding. [bullet] stomach pain or upset gets worse or
lasts''.
(iv) For products labeled only for children under 12 years of age.
Warnings. (A) The labeling of the product states the following warnings
under the heading ``Warnings'':
(1) ``Stomach bleeding warning [heading in bold type]: This product
contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause
stomach bleeding. The chance is higher if the child [bullet] has had
stomach ulcers or bleeding problems [bullet] takes a blood thinning
(anticoagulant) or steroid drug [bullet] takes other drugs containing
an NSAID (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. Sec. 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B).
(2) ``Ask a doctor before use if the child has [heading in bold
type] [bullet] stomach problems that last or come back, such as
heartburn, upset stomach, or stomach pain [bullet] ulcers [bullet]
bleeding problems [bullet] not been drinking fluids [bullet] lost a lot
of fluid due to vomiting or diarrhea [bullet] high blood pressure
[bullet] heart or kidney disease [bullet] taken a diuretic''.
(3) ``Ask a doctor or pharmacist before use if the child is
[heading in bold type] [bullet] taking any other drug containing an
NSAID (prescription or nonprescription) [bullet] taking a blood
thinning (anticoagulant) or steroid drug''.
(4) ``Stop use and ask a doctor if [heading in bold type] [bullet]
the child feels faint, vomits blood, or has bloody or black stools.
These are signs of stomach bleeding. [bullet] stomach pain or upset
gets worse or lasts''.
(B) Directions. The labeling of the product contains the following
information under the heading ``Directions'': ``this product does not
contain directions or warnings for adult use'' [in bold type].
(v) For products labeled for adults and children under 12 years of
age. Warnings. The labeling of the product states all of the warnings
in paragraphs (2)(iii)(A) through (2)(iii)(D) of this section with the
following modifications:
(A) The Stomach bleeding warning states ``Stomach bleeding warning
[heading in bold type]: This product contains a nonsteroidal anti-
inflammatory drug (NSAID), which may cause 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 an NSAID [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. Sec. 201.66(c)(5)(ii)(A) and
(c)(5)(ii)(B).
(B) The labeling states ``Ask a doctor before use if the user has
[heading in bold type] [bullet] stomach problems that last or come
back, such as heartburn, upset stomach, or stomach
[[Page 77351]]
pain [bullet] ulcers [bullet] bleeding problems [bullet] high blood
pressure [bullet] heart or kidney disease [bullet] taken a diuretic
[bullet] not been drinking fluids [bullet] lost a lot of fluid due to
vomiting or diarrhea [bullet] reached age 60 or older.''
(C) The labeling states ``Ask a doctor or pharmacist before use if
the user is [heading in bold type] [bullet] taking any other drug
containing an NSAID (prescription or nonprescription) [bullet] taking a
blood thinning (anticoagulant) or steroid drug''.
(D) The labeling states ``Stop use and ask a doctor if [heading in
bold type] [bullet] the user feels faint, vomits blood, or has bloody
or black stools. These are signs of stomach bleeding. [bullet] stomach
pain or upset gets worse or lasts''.
(vi) Active ingredient(s). The active ingredient(s) section of the
product's labeling, as defined in Sec. 201.66(c)(2), contains the term
``(NSAID)*'' after the NSAID active ingredient with an asterisk
statement at the end of the active ingredient(s) section that defines
the term ``NSAID'' and states ``* nonsteroidal anti-inflammatory
drug.''
(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
the effective date and within 12 months after the effective date of the
final rule or if relabeled at any time before the effective date of the
final rule must bear on its principal display panel (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 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).
(c) Requirements to supplement approved application. Holders of
approved applications for OTC drug products that contain internal
analgesic/antipyretic active ingredients that are subject to the
requirements of paragraph (a) of this section must submit supplements
under Sec. 314.70(c) of this chapter to include the required
information in the product's labeling. Such labeling may be put into
use without advance approval of FDA provided it includes at least the
exact information included in paragraph (a) of this section.
(d) Regulatory action. Any drug product subject to this section
that is not labeled as required and that is initially introduced or
initially delivered for introduction into interstate commerce after
[date 12 months after date of publication of the final rule in the
Federal Register] is misbranded under section 502 of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 352) and is subject to
regulatory action. Any drug product for which the labeling required in
this section was voluntarily implemented before the date of publication
of the final rule that is initially introduced or initially delivered
for introduction into interstate commerce after [date 18 months after
date of publication of the final rule in the Federal Register] and that
is not labeled as required is misbranded under section 502 of the act
and is subject to regulatory action.
PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
4. The authority citation for 21 CFR part 343 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
5. Section 343.50, as proposed at 53 FR 46255, November 16, 1988,
and 67 FR 54158, August 21, 2002, is further amended by revising
paragraphs (c)(1)(i), (c)(1)(iii), (c)(1)(iv)(A), (c)(1)(v)(A) through
(c)(1)(v)(C), (c)(1)(ix)(A), (c)(1)(ix)(B), (c)(1)(ix)(C),
(c)(1)(ix)(E), (c)(2)(i), (c)(2)(iii), (c)(2)(iv)(A), (c)(2)(v)(A)
through (c)(2)(v)(C)\3\ and adding new paragraphs (b)(4)(i)(C) and
(c)(3)(i) through (c)(3)(v)(C) to read as follows:
---------------------------------------------------------------------------
\3\The warnings in these sections are revised to conform with
Sec. 201.66 (Drug Facts format). Other warnings remain as proposed
in the TFM and will be revised into the Drug Facts format in a
future issue of the Federal Register.
---------------------------------------------------------------------------
Sec. 343.50 Labeling of analgesic-antipyretic drug products.
* * * * *
(b) * * *
(4) * * *
(i) * * *
(C) The product states the following statement under the heading
``Directions,'' ``this product does not contain directions or warnings
for adult use''. This statement is not required for products containing
ibuprofen as identified in Sec. 343.10 (g).
* * * * *
(c) * * *
(1) * * *
(i) For products containing any ingredient in Sec. 343.10 (a)
through (f) The labeling states ``Stop use and ask a doctor if [heading
in bold type] [bullet]\1\ pain gets worse or lasts more than 10 days
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or
swelling is present [bullet] any new symptoms appear''.
---------------------------------------------------------------------------
\1\See Sec. 201.66(b)(4) of this chapter for definition of
bullet symbol.
---------------------------------------------------------------------------
* * * * *
(iii) For products containing acetaminophen identified in Sec.
343.10(a). The labeling states the warnings in Sec.
201.325(a)(1)(iii)(A), (a)(1)(iii)(B), and (a)(1)(iii)(C) and the
following statement must follow the general warning identified in Sec.
330.1(g) of this chapter: ``Prompt medical attention is critical for
adults as well as for children even if you do not notice any signs or
symptoms.''
(iv) * * *
(A) The labeling states the warning in paragraph (c)(1)(v)(B) plus
the bulleted statement ``asthma''.
* * * * *
(v) * * *
(A) The labeling states the warning in paragraph (c)(1)(i) of this
section plus ``[bullet] you feel faint, vomit blood, or have bloody or
black stools. These are signs of stomach bleeding. [bullet] stomach
pain or upset gets worse or lasts [bullet] ringing in the ears or loss
of hearing occurs''.
(B) The labeling states ``Ask a doctor before use if you have
[heading in bold type] [bullet] stomach problems that last or come
back, such as heartburn, upset stomach, or stomach pain [bullet] ulcers
[bullet] bleeding problems [bullet] high blood pressure [bullet] heart
or kidney disease [bullet] taken a diuretic [bullet] reached age 60 or
older''.
(C) The labeling states ``Ask a doctor or pharmacist before use if
you are [heading in bold type] [bullet] taking any other drug
containing an NSAID (prescription or nonprescription) [bullet] taking a
blood thinning (anticoagulant) or steroid drug [bullet] taking a
prescription drug for diabetes, gout, or arthritis''.
* * * * *
(ix) * * *
(A) The stomach bleeding warning set forth in Sec.
201.325(a)(2)(iii)(A), (a)(2)(iv)(A), or (a)(2)(v)(A) of this chapter
appears after the subheading ``Stomach bleeding warning:''.
(B) The labeling states ``Ask a doctor before use if you have
[heading in bold type] [bullet] problems or serious side effects from
taking pain relievers or fever reducers [bullet] stomach problems that
last or come back, such as
[[Page 77352]]
heartburn, upset stomach, or stomach pain [bullet] ulcers [bullet]
bleeding problems [bullet] high blood pressure [bullet] heart or kidney
disease [bullet] taken a diuretic [bullet] reached age 60 or older''.
(C) The labeling states ``Ask a doctor or pharmacist before use if
you are [heading in bold type] [bullet] taking any other drug
containing an NSAID (prescription or nonprescription [bullet] taking a
blood thinning (anticoagulant) or steroid drug [bullet] under a
doctor's care for any serious condition [bullet] taking any other
drug''.
* * * * *
(E) In addition to the warning required in Sec. 201.324(c) of this
chapter after the subheading ``Stop use and ask a doctor if'' [heading
in bold type], the following statements also appear: ``[bullet] you
feel faint, vomit blood, or have bloody or black stools. These are
signs of stomach bleeding. [bullet] pain gets worse or lasts more than
10 days [bullet] fever gets worse or lasts more than 3 days [bullet]
stomach pain or upset gets worse or lasts [bullet] redness or swelling
is present in the painful area [bullet] any new symptoms appear``.
* * * * *
(2) * * *
(i) For products containing any ingredient in Sec. 343.10 (a)
through (f) The labeling states ``Stop use and ask a doctor if [heading
in bold type] [bullet] pain gets worse or lasts more than 5 days
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or
swelling is present [bullet] any new symptoms appear ''.
* * * * *
(iii) For products containing acetaminophen identified in Sec.
343.10(a). The labeling states the warnings in Sec.
201.325(a)(1)(iv)(A)(1), (a)(1)(iv)(A)(2), and (a)(1)(iv)(A)(3) and the
following statement must follow the general warning identified in Sec.
330.1(g) of this chapter: ``Prompt medical attention is critical even
if you do not notice any signs or symptoms.''
(iv) * * *
(A) The labeling states the warning in paragraph (c)(2)(v)(B) plus
the bulleted statement ``asthma''.
* * * * *
(v) * * *
(A) The labeling states the warning in paragraph (c)(2)(i) of this
section plus ``[bullet] the child feels faint, vomits blood, or has
bloody or black stools. These are signs of stomach bleeding. [bullet]
stomach pain or upset gets worse or lasts [bullet] ringing in the ears
or loss of hearing occurs''.
(B) The labeling states ``Ask a doctor before use if the child has
[heading in bold type] [bullet] stomach problems that last or come
back, such as heartburn, upset stomach, or stomach pain [bullet] ulcers
[bullet] bleeding problems [bullet] not been drinking fluids [bullet]
lost a lot of fluid due to vomiting or diarrhea [bullet] high blood
pressure [bullet] heart or kidney disease [bullet] taken a diuretic''.
(C) The labeling states ``Ask a doctor or pharmacist before use if
the child is [heading in bold type] [bullet] taking any other drug
containing an NSAID (prescription or nonprescription) [bullet] taking a
blood thinning (anticoagulant) or steroid drug [bullet] taking a
prescription drug for diabetes, gout, or arthritis''.
* * * * *
(3) * * *
(i) For products containing any ingredient in Sec. 343.10 (a)
through (f). The labeling states ``Stop use and ask a doctor if
[heading in bold type] [bullet] adult's pain gets worse or lasts more
than 10 days [bullet] child's pain gets worse or lasts more than 5 days
[bullet] fever gets worse or lasts more than 3 days [bullet] redness or
swelling is present [bullet] any new symptoms appear''.
(ii) The warning in Sec. 343.50(c)(1)(ii), if applicable.
(iii) For products containing acetaminophen identified in Sec.
343.10(a). The labeling states the warnings in Sec. 201.325(a)(1)(v)
of this chapter. The warning in Sec. 201.325 (a)(1)(v)(B) is modified
to read: `` Ask a doctor before use if the user [heading in bold type]
[bullet] has liver disease [bullet] is a child with pain of
arthritis''. The following statement must follow the general warning
identified in Sec. 330.1(g) of this chapter: ``Prompt medical
attention is critical for adults as well as for children even if you do
not notice any signs or symptoms.''
(iv) The warnings in Sec. 343.50(c)(1)(iv), if applicable.
(v) For products containing aspirin, carbaspirin calcium, choline
salicylate, magnesium salicylate, or sodium salicylate identified in
Sec. Sec. 343.10(b), (c), (d), (e) and ( f).
(A) The labeling states the warning in paragraph (c)(3)(i) of this
section plus ``[bullet] the user feels faint, vomits blood, or has
bloody or black stools. These are signs of stomach bleeding. [bullet]
stomach pain or upset gets worse or lasts [bullet] ringing in the ears
or loss of hearing occurs''.
(B) The labeling states the warning in Sec. 201.325(a)(2)(v)(B)
plus ``[bullet] is a child with pain of arthritis''.
(C) The labeling states the warning in Sec. 201.325(a)(2)(v)(C)
plus ``[bullet] taking a prescription drug for diabetes, gout, or
arthritis''.
Dated: November 22, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-21855 Filed 12-19-06; 8:45 am]
BILLING CODE 4160-01-S