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77314 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
paragraph (f) of this AD, before further DEPARTMENT OF HEALTH AND comment period) for comments to be
flight, replace the existing bolts that HUMAN SERVICES submitted and does not plan to extend
attach the exhaust nozzle to the aft the comment period beyond this date.
engine flange with new improved bolts, Food and Drug Administration Please see section XV of this document
in accordance with part B of the for the proposed effective and
Accomplishment Instructions of 21 CFR Parts 201 and 343 compliance dates of any final rule that
Bombardier Service Bulletin 601R–78– [Docket No. 1977N–0094L]
may publish based on this proposal.
021, dated June 2, 2006. Accomplishing ADDRESSES: You may submit comments,
RIN 0910–AF36 identified by Docket No. 1977N–0094L
the bolt replacement for an engine
exhaust nozzle terminates the repetitive and Regulatory Information Number
Internal Analgesic, Antipyretic, and
inspections required by paragraph (f) of (RIN) 0910–AF36 by any of the
Antirheumatic Drug Products for Over- following methods:
this AD for that engine exhaust nozzle the-Counter Human Use; Proposed Electronic Submissions
only. Amendment of the Tentative Final Submit electronic comments in the
Note 2: Bombardier Service Bulletin 601R– Monograph; Required Warnings and following ways:
78–021, dated June 2, 2006, refers to Short Other Labeling • Federal eRulemaking Portal: http://
Brothers Service Bulletin CF34–NAC–78– AGENCY: Food and Drug Administration, www.regulations.gov. Follow the
024, Revision 4, dated November 10, 2005, as HHS. instructions for submitting comments.
an additional source of service information • Agency Web site: http://
for accomplishment of the replacement.
ACTION: Proposed rule. www.fda.gov/dockets/ecomments.
SUMMARY: The Food and Drug Follow instructions for submitting
Terminating Action Administration (FDA) is proposing to comments on the agency Web site.
Written Submissions
(h) Within 4,000 flight hours after the amend its over-the-counter (OTC)
Submit written submissions in the
labeling regulations and the tentative
effective date of this AD: For the left and following ways:
final monograph (TFM) for OTC internal • FAX: 301–827–6870.
right engine exhaust nozzles, replace the
analgesic, antipyretic, and • Mail/Hand delivery/Courier [For
existing bolts that attach the exhaust antirheumatic (IAAA) drug products to
nozzle to the aft engine flange with new, paper, disk, or CD–ROM submissions]:
include new warnings and other Division of Dockets Management (HFA–
improved bolts, in accordance with part labeling requirements advising
B of the Accomplishment Instructions of 305), Food and Drug Administration,
consumers about potential risks and 5630 Fishers Lane, rm. 1061, Rockville,
Bombardier Service Bulletin 601R–78– when to consult a doctor. FDA is also MD 20852.
021, dated June 2, 2006. Accomplishing proposing to remove the alcohol To ensure more timely processing of
the replacement for the left and right warning in its regulations and add new comments, FDA is no longer accepting
engine exhaust nozzles terminates all of warnings and other labeling for all OTC comments submitted to the agency by e-
the inspections required by paragraph IAAA drug products. The new labeling mail. FDA encourages you to continue
(f) of this AD. would be required for all OTC drug to submit electronic comments by using
products containing an IAAA active the Federal eRulemaking Portal or the
Alternative Methods of Compliance
ingredient whether marketed under an agency Web site, as described in the
(AMOCs)
OTC drug monograph or an approved Electronic Submissions portion of this
(i)(1) The Manager, New York Aircraft new drug application (NDA). FDA is paragraph.
Certification Office, FAA, has the issuing this proposal as part of its Instructions: All submissions received
authority to approve AMOCs for this ongoing review of OTC drug products must include the agency name and
AD, if requested in accordance with the after considering the advice of its Docket No. and RIN for this rulemaking.
procedures found in 14 CFR 39.19. Nonprescription Drugs Advisory All comments received may be posted
Committee (NDAC) and other available without change to http://www.fda.gov/
(2) Before using any AMOC approved information. FDA is proposing these ohrms/dockets/default.htm, including
in accordance with § 39.19 on any labeling changes because it has any personal information provided. For
airplane to which the AMOC applies, tentatively concluded they are necessary additional information on submitting
notify the appropriate principal for these ingredients to be considered comments, see the ‘‘Comments’’ heading
inspector in the FAA Flight Standards generally recognized as safe and of the SUPPLEMENTARY INFORMATION
Certificate Holding District Office. effective and not misbranded for OTC section of this document.
use. FDA will address information about Docket: For access to the docket to
Related Information
the cardiovascular risks of nonsteroidal read background documents or
(j) Canadian airworthiness directive anti-inflammatory drugs (NSAIDs) that comments received, go to http://
CF–2006–19, dated July 28, 2006, also was discussed at a February 16–18, www.fda.gov/ohrms/dockets/
addresses the subject of this AD. 2005, FDA advisory committee meeting, default.htm and insert the docket
and the ‘‘Allergy alert’’ warning for number(s), found in brackets in the
Issued in Renton, Washington, on NSAID products, in a future issue of the heading of this document, into the
December 14, 2006. Federal Register. ‘‘Search’’ box and follow the prompts
Stephen P. Boyd, DATES: Submit written or electronic and/or go to the Division of Dockets
Acting Manager, Transport Airplane comments, including comments on Management, 5630 Fishers Lane, rm.
mstockstill on PROD1PC61 with PROPOSALS
Directorate, Aircraft Certification Service. FDA’s economic impact determination, 1061, Rockville, MD 20852.
[FR Doc. E6–22043 Filed 12–22–06; 8:45 am] by May 25, 2007. The specified FOR FURTHER INFORMATION CONTACT:
BILLING CODE 4910–13–P comment period is longer than is Marina Chang, Center for Drug
normally provided for proposed rules. Evaluation and Research, Food and
Because of the complexity of the Drug Administration, 10903 New
proposed rule, FDA is providing an Hampshire Ave., Silver Spring, MD,
additional 60 days (beyond the normal 20993–0002, 301–796–2090.
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77315
SUPPLEMENTARY INFORMATION: new warnings and other labeling for all with publication of an expert panel
OTC IAAA drug products. The proposed report and continued in 1988 with
Table of Contents
warnings and other labeling publication of the TFM. The
I. Introduction requirements will advise consumers of development of labeling for OTC IAAA
II. Background potential risks and when to consult a drug products is recorded in the
A. Development of OTC IAAA Drug doctor. More specifically, FDA is following documents.
Product Warnings proposing the following changes to the
B. Completion of the OTC IAAA Drug 1. Warnings for Aspirin and
labeling:
Acetaminophen
Products Final Monograph (FM) • Requiring a new liver warning for
III. NDAC Meeting products that contain acetaminophen. In the Federal Register of July 8, 1977
A. Data and Information Reviewed • Requiring a new stomach bleeding (42 FR 35346), FDA published the
B. Acetaminophen warning for products that contain an report of the Advisory Review Panel on
C. Aspirin and Other NSAIDs NSAID (e.g., aspirin or ibuprofen). OTC Internal Analgesic, Antipyretic,
IV. Additional Data and Information • Removing the alcohol warning and Antirheumatic Drug Products (the
FDA Reviewed currently required for all OTC IAAA IAAA Panel) for OTC IAAA active
A. Pre-existing Liver Disease as a Risk drug products in § 201.322 (21 CFR ingredients: Acetaminophen, aspirin,
Factor for Acetaminophen 201.322) and incorporating an alcohol carbaspirin calcium, choline salicylate,
Hepatotoxicity warning in the new liver warning for magnesium salicylate, and sodium
B. Updated Literature about acetaminophen and the new stomach salicylate. The recommendations
Acetaminophen Toxicity bleeding warning for NSAIDs. included labeling and warnings for:
C. Aspirin and Other NSAIDs • Requiring that the ingredient • Aspirin: ‘‘Caution: Do not take this
V. FDA’s Tentative Conclusions acetaminophen be prominently product if you have stomach distress,
A. Acetaminophen identified on the product’s principal ulcers or bleeding problems except
B. Aspirin and Other NSAIDs display panel (PDP) of the immediate under the advice and supervision of a
VI. FDA’s Proposal container and the outer carton, if physician’’ (42 FR 35346 at 35387), and
A. Alcohol Warning applicable. • Acetaminophen: ‘‘Do not exceed
B. Acetaminophen • Requiring that the name of the recommended dosage because severe
C. Aspirin and other NSAIDs NSAID ingredient followed by the term liver damage may occur’’ (42 FR 35346
D. Requirements to Supplement ‘‘NSAID’’ be prominently identified on at 35415).
Approved Applications the product’s PDP of the immediate In the Federal Register of November
E. Regulatory Action container and the outer carton, if 16, 1988 (53 FR 46204), FDA published
F. Conforming Changes to the OTC applicable. a tentative monograph with the
IAAA TFM This new labeling would be required following warnings for:
VII. Additional Issues for Consideration for all OTC drug products containing an • Aspirin: ‘‘Do not take this product
A. Safe and Effective Daily IAAA active ingredient, whether if you have stomach problems (such as
Acetaminophen Dose marketed under an OTC drug heartburn, upset stomach, or stomach
B. Daily Dose Recommendations for monograph or an approved NDA. FDA pain) that persist or recur, or if you have
Alcohol Abusers bases this proposal on its reviews of the ulcers or bleeding problems, unless
C. Combinations With Methionine or medical literature, data provided to directed by a doctor’’ (53 FR 46204 at
Acetylcysteine FDA, and recommendations made by 46256), and
D. Package Size and Configuration NDAC. FDA has tentatively concluded • Acetaminophen: ‘‘Prompt medical
Limitations that new labeling for OTC IAAA drug attention is critical for adults as well as
E. Label Warning for Individuals With products is necessary for the safe and for children even if you do not notice
Human Immunodeficiency Virus effective use of these products by any signs or symptoms.’’ This warning
(HIV) consumers. follows the general overdose warnings
F. Drug Interactions Between in 21 CFR 330.1(g) (53 FR 46204 at
Acetaminophen and Warfarin II. Background 46213).
VIII. Legal Authority FDA believes that acetaminophen and 2. Warnings in the Professional Labeling
A. Statement About Warnings NSAIDs, when labeled appropriately for Aspirin
B. Marketing Conditions and used as directed, are safe and
IX. Voluntary Implementation effective OTC drug products that benefit In the Federal Register of October 23,
X. Analysis of Impacts tens of millions of consumers every 1998 (63 FR 56802), FDA published
A. Need for the Rule year. FDA believes that these products labeling for health professionals (not
B. Impact of the Rule should continue to be accessible to available in OTC drug product labeling)
C. Impact on Affected Sectors consumers in the OTC setting. that provided for cardiovascular and
D. Alternatives • Internal analgesics have long been rheumatologic indications. The labeling
E. Benefits very effective OTC drug products for the listed adverse reactions reported in the
XI. Paperwork Reduction Act of 1995 intermittent treatment of minor aches literature, e.g., hypotension (low blood
XII. Environmental Impact and pains and fever. pressure); tachycardia (rapid heart rate);
XIII. Federalism • At their recommended OTC doses, dizziness; headache; dyspepsia
XIV. Request for Comments these products are only rarely associated (indigestion); bleeding, ulceration, and
XV. Proposed Effective and Compliance with serious adverse events relative to perforation of the gastrointestinal (GI)
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Dates the number of consumers who use these tract; nausea; and vomiting. FDA
XVI. References products. determined that consumers were not
able to determine when they needed to
I. Introduction A. Development of OTC IAAA Drug take aspirin to prevent cardiovascular
FDA is proposing to: (1) Amend the Product Warnings events, such as stroke, myocardial
TFM for OTC IAAA drug products, (2) The development of a monograph for infarction (damage to the heart muscle),
remove the alcohol warning, and (3) add OTC IAAA drug products began in 1977 or other conditions. FDA did not
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77316 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
consider it possible to provide adequate Ask a doctor before use if you have: 2. Aspirin and Other NSAIDs—GI
directions and warnings to enable the • Problems or serious side effects Bleeding and Renal Toxicity
layperson to make a reasonable self- from taking pain relievers or fever
diagnosis of these cardiovascular and Aspirin and other NSAIDs are
reducers available OTC for the treatment of minor
rheumatologic conditions.
• Stomach problems that last or come aches and pain, for the treatment of
3. Alcohol Warnings for Acetaminophen back, such as heartburn, upset stomach, headaches, and for fever reduction. Per
and NSAIDs or pain aspirin’s professional labeling (not part
In the Federal Register of October 23, • Ulcers of the OTC drug product labeling),
1998 (63 FR 56789), FDA published a aspirin may be used to reduce the risk
• Bleeding problems of serious cardiovascular events when
final regulation stating that any OTC
drug product, labeled for adult use, • High blood pressure, heart or taken on a daily basis under the
containing acetaminophen, aspirin, kidney disease, are taking a diuretic, or direction of a physician. Aspirin is also
carbaspirin calcium, choline salicylate, are over 65 years of age. effective in treating a variety of
ibuprofen, ketoprofen, magnesium FDA received several comments (Refs. rheumatologic diseases under the
salicylate, naproxen sodium, and 1 and 2) about the proposed warning for direction of a physician. The
sodium salicylate must bear an alcohol kidney disease and reopened the professional labeling also includes
warning statement in its labeling. administrative record on June 4, 2003 information about the potential risk of
Section 201.322 requires the following (68 FR 33429), to allow for additional GI bleeding and renal toxicity associated
statements: public comment. FDA continues to with aspirin.
• For products containing propose a warning about kidney disease OTC nonaspirin salicylates include
acetaminophen: for ibuprofen and other NSAIDs in this the NSAIDs ibuprofen, naproxen
Alcohol Warning: If you consume 3 or document. In a future issue of the sodium, and ketoprofen. The product
more alcoholic drinks every day, ask Federal Register, we will publish our labels for these products are not
your doctor whether you should take final decision about this warning and required to contain warnings about GI
acetaminophen or other pain relievers/ the proposed inclusion of ibuprofen in bleeding and renal toxicity. These
fever reducers. Acetaminophen may the monograph. ingredients are, however, also available
cause liver damage. by prescription at strengths higher than
• For products containing aspirin, B. Completion of the OTC IAAA Drug
in OTC products and the prescription
carbaspirin calcium, choline salicylate, Products FM
product labeling contains warnings
ibuprofen, ketoprofen, magnesium In the process of completing the FM about these risks.
salicylate, naproxen sodium, and for OTC IAAA drug products, FDA
sodium salicylate: III. NDAC Meeting
reviewed a variety of data regarding the
Alcohol Warning: If you consume 3 or At a September 19 and 20, 2002,
safety of acetaminophen, aspirin, and
more alcoholic drinks every day, ask meeting, NDAC considered products
other NSAIDs. FDA continued to receive
your doctor whether you should take currently marketed with OTC IAAA
serious adverse event reports associated
(name of active ingredient) or other pain ingredients, including acetaminophen,
with the use of these products during
relievers/fever reducers. (Name of active aspirin, carbaspirin calcium, choline
this review. These serious adverse
ingredient) may cause stomach salicylate, ibuprofen, ketoprofen,
events included unintentional
bleeding. magnesium salicylate, naproxen
• For products containing acetaminophen hepatotoxicity and
NSAID-related GI bleeding and renal sodium, and sodium salicylate. FDA
acetaminophen with other IAAA active
toxicity. Although the occurrence of expressed its belief that these products
ingredients:
these events is rare, relative to the should remain available OTC given their
Alcohol Warning: If you consume 3 or
extensive use of the products, as overall effectiveness and safety, the
more alcoholic drinks every day, ask
described in the text that follows, FDA benefit to consumers of having a pain
your doctor whether you should take
believes that labeling changes are reliever and fever reducer available
(insert acetaminophen and one other
necessary for the safe and effective use OTC, and the use of these products by
IAAA active ingredient—including, but
of these products and to reduce the tens of millions of people weekly. FDA
not limited to aspirin, carbaspirin
associated morbidity. suggested that certain interventions
calcium, choline salicylate, magnesium
could decrease the frequency and
salicylate, or sodium salicylate) or other 1. Unintentional Acetaminophen morbidity of these serious adverse
pain relievers/fever reducers. Hepatotoxicity events. NDAC members were asked to
Acetaminophen and (insert name of one
Acetaminophen is widely available in consider which additional interventions
other IAAA active ingredient—
numerous single ingredient and were necessary to reduce the occurrence
including, but not limited to aspirin,
combination OTC drug products, and in of serious adverse events. The
carbaspirin calcium, choline salicylate,
many prescription drug products, as a presentations made at the meeting, and
magnesium salicylate, or sodium
pain reliever and/or fever reducer. OTC NDAC’s findings, are summarized in
salicylate) may cause liver damage and
acetaminophen drug products, as this document. More information about
stomach bleeding.
currently labeled and used, have been the September 2002 NDAC meeting is
4. Proposed Amendment to Include reported to be associated with available on the Internet and in the
Ibuprofen as a Generally Recognized unintentional overdose that may lead to Division of Dockets Management (see
Safe and Effective OTC IAAA Active ADDRESSES).
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serious hepatotoxicity (Ref. 3). The
Ingredient IAAA Panel discussed overdose-related A. Data and Information Reviewed
In the Federal Register of August 21, hepatotoxicity (42 FR 35346 at 35413 to
2002 (67 FR 54139), FDA proposed to 35414), and FDA addressed it in the FDA provided NDAC with the
include ibuprofen in the monograph for IAAA TFM (53 FR 46204 at 46213 to following data and information (Ref. 3):
OTC IAAA drug products with 46218). (See section II.A.1 of this • Applicable sections of rulemakings
additional warnings: document.) for OTC IAAA active ingredients.
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77317
• Proposed and final rules for the • Consumers are unaware of the risks • Adjustment of the maximum total
alcohol warning for OTC IAAA drug of exceeding the recommended dose of daily dose or dosing interval
products. acetaminophen with a single product, or • Changes in labeling that identify the
• Final rule for professional labeling of simultaneously using multiple population and highlight the risks
of OTC drug products containing products containing acetaminophen. • Additional research on specific
aspirin. FDA asked NDAC what additional subpopulations
• Amendment to propose inclusion of measures could be taken to better ensure • Consumer and physician education.
ibuprofen in the monograph for OTC that prescribers and other people are FDA asked NDAC whether additional
IAAA drug products. aware of the potential risks associated studies are needed to evaluate these
• For acetaminophen, FDA reviews of with exceeding the recommended dose issues. FDA suggested a number of
data, poisoning data in Toxic Exposure of prescription or OTC drug products subjects for potential research:
Surveillance System (TESS), exposure containing acetaminophen and with • Evaluation of the effectiveness of
data from poison control centers, using multiple products containing educational programs
overdose reference articles, and an acetaminophen. FDA suggested the • Evaluation of revised labeling
abstract describing trends in acute liver following possible measures for OTC • Surveillance of serious
failure in the United States. drug products: acetaminophen hepatotoxicity cases
• For aspirin/NSAIDs, FDA reviews • Consumer education • Enhanced collection of information
of data and articles from the medical • Changes in labeling that identify when medication errors occur
and highlight the risks
literature. • Better understanding of consumer
• Packaging that may enhance
NDAC also considered submissions use of these products.
appropriate use
and presentations from industry and • Consumer inserts. 2. Presentations and Submissions to
individuals during the open public For prescription products, FDA NDAC
sessions (Refs. 4 and 5). suggested:
• Unit of use packaging with labeling As a lead-in to the liver toxicity
B. Acetaminophen
on each blister pack discussion, Dr. William Lee, of the
On the first day of the meeting • Physician and pharmacist University of Texas Southwestern
(September 19, 2002), NDAC considered education Medical Center at Dallas, presented the
safety issues related to the use of • Publication of information in results of acute liver failure (ALF)
acetaminophen, unintentional overdose, professional journals studies in the United States (Ref. 6). He
and the potential for hepatotoxicity • Consumer education estimated that between 1,000 and 2,000
from both OTC and prescription • FDA publications to identify and ALF cases occur in the United States
acetaminophen products. highlight the danger and risk each year and are associated with high
1. Points for Discussion • Providing patient information mortality. Dr. Lee conducted a
leaflets and stickers when dispensing retrospective analysis of 177 cases of
FDA asked NDAC to discuss possible the prescription. ALF reported in the literature between
factors that might contribute to FDA also asked NDAC if there are 1986 and 1998. Of these, 20 percent
unintentional overdose (Ref. 3) and identifiable factors that might make were attributed to acetaminophen
provided the following points for some individuals more susceptible to toxicity. To study ALF prospectively,
consideration: hepatic toxicity (e.g., underlying liver Dr. Lee also formed a study group of 25
• Acetaminophen is available to disease, malnutrition, drug interactions, treatment centers in 1998. Details of the
consumers in many OTC and and alcohol users). If subpopulations at group’s initial 308 cases are presented
prescription drug products (i.e., single increased risk of acetaminophen- in table 1. Approximately 40 percent of
ingredient and combinations with induced hepatotoxicity could be the cases were due to acetaminophen
various other active ingredients). identified, FDA asked NDAC what toxicity, which was increased when
• Consumers fail to identify reasonable measures could be taken to compared to the rate of acetaminophen
acetaminophen as an ingredient in their decrease their risk. FDA suggested some toxicity in the cohort from Dr. Lee’s
OTC and prescription drug products. possible measures: retrospective analysis.
TABLE 1.— STUDY GROUP SERIES OF ALF CASES (N = 308)
ALF Etiology
Case Report Data All Other
Acetaminophen Induced Drug (Not Acetaminphen) Indeterminate Causes P value
(n=120) Induced (n=40) Cause (n=53) (n=95)
Sex (% Female) 79 73 60 72 NS*
Age (years) 36 41 38 43 0.02
Jaundice (days) 1 12 12 4 <0.001
Coma (%) 50 43 47 47 NS
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Alanine aminotransferase (ALT)
(International Units/Liter (IU/
L))** 4310 574 947 1060 <0.001
Bilirubin 4.3 20.2 24.5 12.6 <0.001
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77318 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
TABLE 1.— STUDY GROUP SERIES OF ALF CASES (N = 308)—Continued
ALF Etiology
Case Report Data All Other
Acetaminophen Induced Drug (Not Acetaminphen) Indeterminate Causes P value
(n=120) Induced (n=40) Cause (n=53) (n=95)
Transplant (%) 6 53 51 36 <0.001
Spontaneous survival (%) 68 25 17 33 <0.001
Overall survival (%) 73 70 64 61 NS
* Not significant ** ALT (normal range 0–35 IU/L)
Of the 120 acetaminophen toxicity acetaminophen prescription products accidental (ingestion of drugs for pain
cases identified in Dr. Lee’s series, 12 and OTC acetaminophen products at the relief, without suicidal intent) and
were omitted due to concomitant same time, some for as long as 2 to 3 suicidal (ingestion with admitted
patient issues that would have months. In 70 percent of the cases, suicidal attempt) ingestion. The type of
confounded the analysis. The remaining patients ingested more than 4 grams (g) ingestion could not be determined in 5
108 cases were analyzed and showed of acetaminophen per day cases, resulting in a comparison of 103
that alcohol use was reported in 57 (recommended maximum daily dose), cases (table 2). More than half of the
percent of the cases and alcohol abuse and 32 percent of the cases reported acetaminophen toxicity cases (57
was reported in 19 percent of the cases. ingestion of more than 10 g per day. percent) were accidental.
Individuals in 38 percent of the cases A comparison was conducted among
were taking both narcotic- the 108 cases of toxicity due to
TABLE 2.—SUICIDAL VS. ACCIDENTAL ACETAMINOPHEN ALF CASES
Accidental (n=59) Suicidal (n=44) p-value
Age 39 33 0.011
Acetaminophen total (g) 20 29 NS
Antidepressant 36% 34% NS
Alcohol (non-abuse use) 55% 61% NS
Double use* 24% 5% 0.02
Narcotic/acetaminophen 54% 14% 0.001
ALT (IU/L) 3,616 5,929 <0.001
Creatine 2.5 1.3 0.008
Survival 71% 75% NS
* Use of more than one acetaminophen containing product.
The incidence of use of databases were used to estimate the 4. Multiple Cause of Death Files—a
antidepressants and alcohol was nearly occurrence of these events: data file that contains information from
identical in the accidental and suicidal 1. National Hospital Ambulatory Care death certificates.
groups. The accidental cases included a Survey: Emergency Department (ED) Acetaminophen overdose
larger percentage of subjects who Component—a probability survey (unintentional and intentional) was
double-dosed or used a narcotic/ associated with an annual average of
sampling of visits made to emergency
acetaminophen combination product. over 56,000 emergency department
departments and short stay hospitals in
Survival rates were also similar. Lee visits (1993 to 1999) and more than
concluded that acetaminophen toxicity the United States.
26,000 hospitalizations (1990 to 1999).
accounted for about a third of all deaths 2. National Electronic Injury Between 1996 and 1998, an annual
from ALF in this case series and appears Surveillance System—collects average of 458 deaths was attributed, at
to be a growing problem in the United information on consumer product- least in part, to acetaminophen
States. related injuries treated in emergency overdose. Unintentional acetaminophen
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FDA staff presented a safety analysis departments of 66 selected hospitals. overdose was associated with an annual
of hepatotoxicity associated with 3. National Hospital Discharge average of over 13,000 emergency
acetaminophen (Ref. 7). The cases were Survey—a probability survey sampling department visits (1993 to 1999), 2,189
reported as ‘‘intentional overdose’’ and of patient discharge records from non- hospitalizations (1990 to 1999), and 100
‘‘unintentional overdose.’’ The reported Federal, short stay hospitals in the deaths (1996 to 1998). Each event in
doses were rarely within the United States. these tallies is independent from the
recommended range. Four national others. No information about associated
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77319
hepatotoxicity was available for these containing acetaminophen are available emergency department visits are most
cases. FDA reviewed the age for different age groups. The age prevalent among young people, this age
distribution for acetaminophen distribution of unintentional overdose group accounts for the lowest
overdoses. Medication use varies by age cases varies among reporting databases percentage of cases of mortality.
and different OTC drug products and is shown in table 3. While
TABLE 3.—AGE DISTRIBUTION OF UNINTENTIONAL CASES
Age (years)
<17 17—64 >65
Emergency department visit 74% 25% <1%
Hospitalization 23% 70% 7%
Mortality 1% 75% 23%
Chronic liver disease has been acetaminophen. Using the multiple unintentional and intentional overdose
postulated to be one of the factors that cause of death database, the presence of with mortality outcomes was examined
increases the risk of hepatotoxicity from chronic liver disease among cases of (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%
Other chronic liver disease 48% 8%
These findings suggest that chronic FDA also presented an analysis of hepatologists and other practitioners.
liver disease, in the presence or absence cases of hepatotoxicity associated with One case series was obtained
of alcohol, may be a risk factor for acetaminophen from the published exclusively from a consortium of liver
developing or increasing severity of literature. A MEDLINE search identified transplant centers. The number of cases
hepatotoxicity among people with all U.S. case series containing at least 10 per series ranged from 47 to 73. Two
unintentional overdose. However, this cases that had been published in the case series were largely pediatric, and
analysis has limitations. If the presence previous 10 years (Ref. 7). Eight case the remaining six case series consisted
of alcohol or alcohol use was not series were identified, four of which of largely adult populations. Six of the
mentioned on the death certificate, were derived exclusively from review of case series reported gender, and in all
alcohol related liver disease may be hospital medical charts. In two series,
six there was a preponderance of
cases were obtained from hospitals,
misclassified as other chronic liver females. Intentionality was reported in
published cases, the FDA adverse event
disease. In addition, suicide cases may reporting system, and poison control five of the series. Table 5 shows the
be misclassified as unintentional center databases. One case series was acetaminophen dose reported among in
overdose to protect privacy. from a registry of cases reported by 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.
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Nine people in the Johnston case the recommended dose, while 13 people in one case and 4 to 6 g/day in two
series and three people in the Schiodt used between 4.1 and 6 g/day. In the cases). In the Broughan case study, none
case series ingested 4 g/day or less of Whitcomb case series, 3 people used of the people took acetaminophen at the
acetaminophen. In the Zimmerman case acetaminophen at, or slightly above, the recommended dose.
series, 27 people used acetaminophen at recommended dose (i.e., 3.5 to 5 g/day
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Table 6 compares the number of Intentionality could only be compared outcomes were defined as hepatic coma,
deaths and serious outcomes for the in the adult case series. Serious acute liver failure, and liver transplant.
unintentional and intentional groups.
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 acetaminophen product simultaneously. concentrated drops containing
TESS of the American Association of These AAPCC data may underreport the acetaminophen 100 mg/milliliter (mL)
Poison Control Centers (AAPCC). At actual number of acetaminophen were reportedly ingested in seven cases.
that time, AAPCC had a repository of toxicity cases, because serious cases that In 20 of the pediatric cases, 1 or more
over 27 million human poison go directly to emergency departments, medication errors were reported. In
exposures reported by over 60 and chronic users of acetaminophen, are three cases, the wrong product was
participating centers. These centers unlikely to generate poison control used, i.e., the concentrated drops
covered over 90 percent of the U.S. center contacts. instead of the children’s acetaminophen
population. Examination of AAPCC’s FDA staff reviewed spontaneous liquid formulation. In four cases,
annual reports from 1995 to 1999 of reports of hepatoxicity in FDA’s adverse incorrect measuring devices were used,
cases listing acetaminophen as the event reporting system (AERS). U.S. i.e., teaspoonfuls instead of dropperfuls.
primary (first) agent showed cases were identified that had been Five cases reported instances of
acetaminophen to be the leading cause received by FDA between January 1998 misinterpretation of labeled dosing
of poisonings. In 1999, acetaminophen- and July 2001 and in which one or more guidelines or misinterpretation of
related calls represented 10 percent of acetaminophen containing products had instructions provided by a health care
all calls to AAPCC. There was a been ingested. Of 633 reports, 43 were provider.
decrease in calls between 1995 duplicates. Another 283 were excluded Sixty percent of the 282 adult cases
(111,175) and 1999 (108,102). In 1999, for various reasons, primarily to exclude (15 to 85 years old) were female and 229
nearly 50 percent of the poison victims cases in which there was apparent required hospitalization. A total of 169
associated with the calls received suicidal intent. A total of 307 cases were adults experienced severe, life-
treatment in health care facilities. Two included in FDA’s analysis (25 pediatric threatening liver injury; 124 of these
percent of these victims were reported and 282 adult cases). patients died and 7 required a liver
to have developed major effects Pediatric cases (of children age 1 day transplant. One hundred ninety-nine (71
resulting from the poisoning, i.e., the to 8 years) consisted primarily of males percent) adults reported using an
signs or symptoms occurring as a result (approximately 70 percent), although acetaminophen product for a
of acetaminophen exposure were life- gender was not reported in each case. therapeutic indication, primarily
threatening or resulted in significant Fifteen of the 25 pediatric cases analgesia. In 74 (26 percent) cases, the
residual disability. Fifty percent of the involved severe, life-threatening liver indication for use was unknown, and in
calls involved children and adolescents injury. Of the 25 children, 10 died, 21 9 (3 percent) cases, abuse of a narcotic-
(19 years of age or under). Of the were hospitalized, and 2 required only acetaminophen prescription product
acetaminophen related calls regarding treatment in an emergency department. was reported. One hundred thirty-eight
children under 6 years of age The dose was estimated, based upon (38 percent) cases listed an unspecified
(approximately 40,000 calls), 22 percent reported daily doses and weight, in 10 acetaminophen product (unknown
occurred in children who ingested adult cases to be 106 to 375 milligrams/ whether single ingredient or
formulations of acetaminophen. kilogram (mg/kg) per day. The combination product and whether OTC
In 1995, there were at least 76 recommended pediatric dose is 75 mg/ or prescription), 122 (33 percent) cases
acetaminophen-related fatalities. By kg/day (Ref. 7). Twenty-two of the involved the use of a narcotic-
1999, the number of acetaminophen- children (88 percent) took only 1 acetaminophen prescription product,
related fatalities increased to 141. Of product containing acetaminophen and and 76 (21 percent) cases reported use
these, 92 (65 percent) were a result of 3 children (12 percent) took 2 or more of an OTC single ingredient
suicidal intent, 43 (30 percent) were products containing acetaminophen. acetaminophen product. Approximately
unintentional, and the dosing intent for Sixteen of the cases (53 percent) 25 percent of all adult cases reported
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6 (4 percent) was undetermined. Among reported ingestion of a single ingredient use of more than one acetaminophen
the 43 unintentional fatalities, 28 (65 acetaminophen product (APAP), 12 product. When more than one
percent) took one OTC drug product cases (40 percent) reported ingestion of acetaminophen product was reported, a
containing only acetaminophen; 4 (9 an ‘‘unspecified APAP product’’ and the narcotic-acetaminophen prescription
percent) took one prescription product remainder of the cases reported product in combination with an OTC
containing acetaminophen, and 11 (26 ingestion of combination products. Of product containing acetaminophen was
percent) took more than one the single ingredient products, used more often than any other
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combination of acetaminophen showed a mean and median daily dose reports was highly variable. Alcohol use
products. These cases also used higher of 7.1 and 6.23 g, respectively. Twenty- in these cases was defined by FDA as
doses than people who took only one three of the 65 cases with severe liver alcoholism or alcohol abuse in 64 cases;
acetaminophen-containing product. injury reported doses of less than 4 g/ regular, daily, or moderate use in 23
Dosing amounts were reported in 132 day. People who used more than one cases; occasional use in 10 cases;
of the 282 adult cases. The mean and acetaminophen product reported taking previous use in 6 cases; and 13 cases
median daily dose were 6.5 and 5 g, higher doses than people who took a did not provide a description. Eighty-six
respectively, but ranged from 650 mg to single product. Qualitative dosing (74 percent) of the 116 alcohol users
30 g/day. Where the dosage strength was information was provided for an developed severe liver injury. For those
known, 500 mg acetaminophen was additional 43 (15 percent) cases with
cases with acetaminophen dose
reported most often. If a dose range was terms such as ‘‘excessive doses’’ or
reported in the case, the mid-point was information, the mean dose associated
‘‘recommended doses.’’ Two out of three
used in the analysis. If the strength was of these cases suggest that greater than with toxicity was lower for alcohol
unknown, a 500-mg strength was recommended doses were used. users compared to nonalcohol users
assumed. Dosing in the 65 adults with Alcohol use was reported in 116 of (table 7).
severe liver injury from this group the adult cases and the content of the
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 the 70 cases with pre-existing liver liver injury) that reported dosing
possible underlying liver disease, was disease, 49 percent (70 percent) information. The second row shows a
reported in 70 cases. In at least 20 of developed severe liver injury. Table 8 dose comparison in people who
these cases, the pre-existing liver shows the dose that was associated with experienced severe liver injury after
disease was reportedly due to alcohol. liver injury for cases with and without acetaminophen exposure.
Twenty-three people reported a history pre-existing liver disease. The first row
of, or possible, viral hepatitis. Among includes all cases (all degrees of acute
TABLE 8.—ACETAMINOPHEN DOSE AND LIVER DISEASE
Cases With Pre-existing Liver Dis- Cases With No Pre-existing Liver
Category of Liver Injury Associated With Acetaminophen Dosing ease (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 provide certainty that acetaminophen identified and may have increased the
contributed to the development of was the cause of any of the reported risk for hepatotoxicity.
hepatotoxicity in these adults. Use of adverse event. Furthermore, incidence FDA presented NDAC with several
other medications that may have rates cannot be determined, because the questions that remained unaddressed by
contributed to hepatotoxicity was numerator or denominator descriptors FDA’s review:
reported in 93 cases, including 63 cases for the entire population are not • Do users lack knowledge of the
that involved products that are labeled available. Overall, spontaneous reports potential for and symptoms of
with warnings about potential may be subject to significant hepatotoxicity when using a product
hepatotoxicity. A small number of underreporting. containing acetaminophen?
reports also mentioned the existence of The AERS cases strongly suggest that • Does malnutrition or fasting affect
concomitant malnutrition or decreased particular circumstances were likely to severity of hepatoxicity?
oral intake. have led to hepatotoxicity. Some • What is the contribution of
FDA noted that there are limitations examples of those circumstances follow: concomitant hepatotoxic medication?
to interpreting the AERS data. Dosing • Errors related to product confusion • What additional factors place a
information may be unreliable. were mostly observed in pediatric cases. small number of individuals at risk for
Acetaminophen products are generally These errors primarily involved severe hepatotoxicity at various dose
taken on an as-needed basis, so the confusion over varying product levels (i.e., under, at, or above the
actual dose ingested can be difficult to formulations and strengths and use of recommended dose)?
ascertain. There is no certainty that all inappropriate measuring devices. It is clear that unintentional
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of the adult cases included in this • Many adults were taking more than acetaminophen doses are associated
analysis were unintentional. Stigma the recommended dose of with a large number of emergency
may be associated with reporting acetaminophen and, in some cases, use department and hospital admissions
suicide, so cases may be reported as of multiple products likely contributed and are related to an estimated 100
unintentional when they were to hepatotoxicity. deaths each year. Using a number of
intentional overdoses. In addition, • Risk factors, such as alcohol use or data sources, analyses have shown that
spontaneous reporting systems cannot pre-existing liver disease, were circumstances leading to
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77322 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
acetaminophen hepatotoxicity are acetaminophen reported by the AAPCC More patients were evaluated for
multifactorial. FDA asked the committee is approximately 20 times that for transplants (11 versus 9), received
to consider the contribution of each of ibuprofen. transplants (2 versus 0), and died (3
the following in producing 2 . Unintentional overdose of versus 0) as a result of unintentional
unintentional overdose toxicity: acetaminophen can put consumers in a overdoses.
• Product—the ingredient is present life-threatening situation due to the 3. Compared to the intentional
in multiple prescription and OTC drug delayed onset of clinical symptoms of overdose group, the unintentional
products and in multiple oral toxicity. overdose group was more likely to have
formulation strengths 3. Advertising portrays one or more of the following risk factors
• Knowledge—since a number of acetaminophen as a totally safe for acetaminophen toxicity: (1) Hepatic
cases have occurred from multiple ingredient. This portrayal may disease, (2) acute or chronic alcohol use,
product use and overuse, there is likely exacerbate use and contribute to the (3) drug abuse, or (4) concomitant
a lack of knowledge about safe use of silent danger resulting from overdose. disease. Ninety-six percent of cases in
acetaminophen • One individual presented a review the unintentional overdose group had
• Risk factors—multiple data sources of acetaminophen overdose admissions one or more of these risk factors, as
identify alcohol and underlying liver at the University of Pennsylvania compared to 70 percent in the
disease as risk factors that may increase hospital over a 4-year period. Fifty-four intentional group. Acute and chronic
the potential for hepatotoxicity. reports of acetaminophen overdose were alcohol use was present in 87 percent of
Several drug manufacturers and other found in the hospital’s database. Of the unintentional overdose cases, as
interested parties provided additional 47 cases reviewed to date, 23 (50 compared to 61 percent of the
comment (Ref. 4): percent) were reported to be intentional overdose cases. Thus, the
• One major manufacturer of unintentional overdoses. In 13 of these
existence of risk factors may have an
acetaminophen OTC drug products 23 cases, the reviewer was able to
impact on toxicity in unintentional
provided the following comments: document that an attending physician or
ingestions.
1. The precise incidence of harmful, a psychiatry consultant concluded that
• One individual described the
unintentional overuse cannot be there had been no suicidal intent.
1. The median and average doses were untimely death of her son who initially
accurately determined from the current
between 6 and 8 g/day. These values are used a prescription product. When the
databases. Forty-eight million American
above the recommended maximum prescription was finished, he purchased
adults use products containing
daily dose (4 g/day), but below the 10 an OTC acetaminophen product and
acetaminophen in any single week;
to 15 g dosage usually considered to be developed flu like symptoms. Another
thus, harm is rare and is caused by
toxic. There were three cases of OTC acetaminophen product was
inadvertent overdose.
2. There are limitations to the AERS intentional overdose and three cases of subsequently used to treat the flu
data set for assessing hepatic events. unintentional overdose involving symptoms, resulting in hepatotoxicity.
Patients consistently underestimate the prescription acetaminophen products. He was hospitalized and ultimately
dose taken, and suicide attempts are OTC products were associated with 20 died.
often not recorded in patients who are intentional and 21 unintentional • A professional pharmaceutical
found unconscious or intoxicated. The overdoses. More patients in the association encouraged consumers to
AERS reports found to be definitely unintentional overdose group used carefully read product labeling. The
associated with acetaminophen single ingredient acetaminophen (i.e., association also recommended: (1) Clear
involved substantial overdose in not a combination product). The labeling on all prescription and OTC
individuals with self-abusive behaviors primary reason reported for exceeding drug products containing
(e.g., alcohol abuse, bulimia). Causality the maximum dose was to treat acetaminophen with special statements
cannot be ascertained using unrelieved pain. Many patients stated (e.g., ‘‘contains acetaminophen’’ on the
retrospective data, especially case that they knew they were exceeding the product’s PDP), and (2) pharmacists
reports, because the dose history is often recommended dose and did so because placing auxiliary labels on the vial of
inaccurate. they thought it was a safe drug. Thirty prescription drug products containing
3. Formulations most commonly percent of the patients used the drug acetaminophen to identify this
reported were OTC single-ingredient over a period of greater than 7 days. ingredient.
and prescription combination 2. The unintentional overdose group • A consumer public health
acetaminophen products. OTC experienced greater morbidity and organization described a consumer
acetaminophen combination products mortality than the intentional overdose survey showing that many consumers
were rarely reported. group. The peak acetaminophen levels do not recognize the potential for harm
4. Serious hepatotoxicity occurs in the intentional overdose group were from: (1) Taking more than the
following substantial overdose (a single much lower compared to the recommended dose, (2) taking more
dose of approximately 15 g or use of unintentional overdose group (27.8 than one product containing
approximately 12 g for multiple days). versus 115.1 mg/L). The unintentional acetaminophen, or (3) inappropriately
5. FDA focused on unintentional overdose group had much higher peak combining OTC and prescription drug
misuse. The manufacturer noted they levels of Alanine aminotransferase products containing acetaminophen.
had implemented labeling changes to (ALT) (5,193 versus 3,065 units/L), • A member of a national health
minimize the inadvertent overuse of Aspartate aminotransferase (AST) (6,819 foundation expressed concern that
analgesics. The manufacturer versus 2,742 units/L), International present marketing practices make it very
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recommended an organ specific Normalized Ratio (INR) (4 versus 2.5), difficult to find the standard 325-mg
overdose warning. and total bilirubin (5.87 versus 1.87 mg/ acetaminophen dosage unit. As a result,
• One manufacturer of ibuprofen OTC dL). Patient outcomes were generally many consumers believe that the 500-
drug products provided the following worse in the unintentional overdose mg product is the only one available.
comments: group, in which more patients failed to This failure to more broadly market the
1. In overdose situations, in any given have resolution of the liver problems lower dose may contribute to increased
year, the number of deaths for from the overdose (31 versus 4 percent). adverse events. The individual
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77323
advocated educational efforts to help susceptibility to acetaminophen- (Ref. 5 Tab D). Consumers need to know
minimize this problem. associated hepatotoxicity at the type of medication and the dose of
• A spokesperson for a national unexpectedly low doses of OTC analgesic in every combination
consumer organization described acetaminophen. The manufacturer product to ensure safe and effective use.
marketing limitations that are employed provided arguments that the existence
in the United Kingdom and intended to 3. NDAC Deliberations and
of any of these factors in a case report
limit the potential for overdose. In Recommendations Concerning
may each inherently interfere, for
September 1998, a restriction was Acetaminophen
various reasons, with establishing the
placed on the number of tablets in correct assessment of a hepatotoxic dose NDAC unanimously agreed that the
acetaminophen packages for sale of acetaminophen. evidence of risk associated with
without a prescription. If sold in a • An expert panel sponsored by a unintentional overdose of
supermarket, the maximum is 16 tablets manufacturer of acetaminophen acetaminophen warrants FDA labeling
per package. If sold in a pharmacy, the products reviewed all 281 adult reports changes, without awaiting the outcome
maximum is 32 tablets per package. in AERS and assigned a probability of further studies. NDAC noted the
There is also an overall restriction that category relating the reported hepatic following four major areas of concern:
a maximum of 100 tablets can be adverse events to acetaminophen 1. Unintentional use of multiple
purchased at one time. The exposure. In 3 reports the adverse event acetaminophen containing products
representative stated that early and exposure were considered 2. Exceeding the recommended dose
evaluations of this program have shown ‘‘definitely’’ related, in 74 reports they without recognizing the consequences
decreases in (1) total and severe were ‘‘probably’’ related, 47 reports they 3. Improper dosing of infants
acetaminophen overdoses and (2) were ‘‘possibly’’ related, in 53 reports 4. The unknown consequences of use
overdoses related to liver transplant and they were unlikely to be related, and in in special populations, such as alcohol
death. 27 reports they were definitely not abusers.
Several drug manufacturers and related. Data were considered NDAC recommended that the
others submitted additional information insufficient in 73 reports, 3 reports were minimum requirements for change
for the committee to review (Ref. 5): not able to be evaluated and there was should include, for all products
• One major manufacturer of no consensus regarding the evaluation containing acetaminophen (including
acetaminophen OTC drug products of 1 report. those available by prescription), the
provided the following comments (Ref. Based on an assessment of several addition of distinctive labeling
5, Tab A): databases, a sponsor calculated that the (highlighted or bold type) on the front
1. AERS serves as a signal generating worst case scenario of deaths from panel or PDP to state that the products
system for rare, unexpected adverse acetaminophen overdose is estimated to contain acetaminophen. FDA noted that
events in marketed products. It cannot be 213 deaths per year (Ref. 5, Tab A). the nonproprietary name of prescription
be used to determine event rates, dose • One manufacturer submitted an drugs must appear in labeling in letters
ingested, or patient dosing intent. analysis of data from TESS (Ref. 5, Tab at least half the size of the brand name
2. FDA’s review of the AERS data set B). The manufacturer made the (see 21 CFR 201.10(g)(2)). NDAC
was intended to exclude obvious following conclusions from these data: recommended that a similar provision
suicide, usually associated with very 1. The majority of hepatotoxicity also be applied to OTC drug products
large drug ingestion. Thus, the reported cases (65 percent of cases in the year containing acetaminophen, such as a
dosage (which could only be estimated 2000) involved use of one standard to ensure prominence of
in 48 percent of the reports in the data acetaminophen-containing analgesic important information. NDAC stated
set) is skewed significantly toward product. that consumers need to be informed that
labeled directions for use, so cases may 2. Acetaminophen-containing cough/ combining products containing
falsely appear to be consistent with cold medications were not a significant acetaminophen can result in exceeding
inadvertent misuse. contributor to the total number of the recommended dose.
3. The selective data in FDA’s AERS reports of acetaminophen associated NDAC commented that there are
review cannot be used to determine an hepatotoxicity (2 percent of cases in the insufficient data in the OTC setting on
acetaminophen toxicity threshold year 2000). risk management, understanding
associated with any patient condition 3. Only 1 percent of the reported cases consumer behavior, and the
(i.e., concomitant drug, alcohol history, of hepatotoxicity in 2000 involved use effectiveness of warnings on labels. This
or pre-existing concomitant disease). of an OTC acetaminophen-containing lack of data makes it difficult to
4. The quality of the 281 adult reports cough/cold product concomitantly with determine which factors contribute to
in AERS was evaluated by the other acetaminophen-containing liver injury. Although these factors are
manufacturer. The manufacturer product(s). not clearly understood, NDAC
concluded that 168 reports (24 percent) • One physician stated that 3 to 4 g concluded that labeling revisions are
contained insufficient information to of acetaminophen per day is the upper needed to help minimize any risks.
estimate the dose taken and 212 reports range of a safe dose (Ref. 5 Tab C). For • Separate liver toxicity and alcohol
(88 percent) contained no liver an individual who is a regular user of warnings. NDAC recommended a liver
pathology information. AST and ALT alcohol, in a prolonged fasting or in a toxicity statement, separate from the
levels were not reported in 108 cases (38 rapid weight loss program, the upper alcohol warning, be added to the label
percent). Only 61 reports (25 percent) limit of a safe dose is unknown, but so that the potential for liver toxicity
had information about viral hepatitis unlikely to not exceed 2 g of would not appear to be applicable only
mstockstill on PROD1PC61 with PROPOSALS
testing and, of these, 29 reports were acetaminophen. No data were provided to consumers who drink alcohol. NDAC
positive for hepatitis A, B, or C. to support these observations. noted that alcohol is not the only risk
5. There are flaws in the derivation of • Several organizations urged that factor for hepatotoxicity. It was also felt
FDA’s theory that alcohol use, labeling be improved to provide clear to be important to warn consumers of
underlying/history of liver disease, and directions about the appropriate doses the consequences of taking multiple
potentially the use of hepatotoxic for use and frequency of administration, products containing acetaminophen and
concomitant medications, may increase especially for combination products that toxicity can be related to the total
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77324 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
dose of acetaminophen taken during a potential toxicity, but noted that there is C. Aspirin and Other NSAIDs
given period of time. NDAC felt it a lack of information to support such On the second day of the meeting
would be more prudent to describe labeling. (September 20, 2002), NDAC considered
these risks in a separate warning to One NDAC member mentioned that
safety issues related to the use of aspirin
more fully inform consumers who do although some evidence appeared to
and other OTC NSAIDs. The primary
not abuse alcohol. show an association of increased
areas for discussion included the
NDAC did not propose exact acetaminophen toxicity for patients
potential for GI bleeding and renal
language. It was believed that it was with pre-existing liver disease, this
toxicity from using these drugs. The
important that the message not refer to finding is contrary to hepatologists’
‘‘overdose,’’ but rather to a statement experience with acetaminophen. prescription labeling for NSAIDs and
such as ‘‘do not take more’’ or ‘‘do not Generally, acetaminophen is considered the professional labeling for aspirin
exceed the recommended dose.’’ NDAC safe for use in patients with liver have warnings for GI bleeding and
believed that the term ‘‘overdose’’ disease, including people awaiting liver possible renal toxicity. Aside from the
would not be understood to be pertinent transplantation. Most hepatologists alcohol warning required on all OTC
to consumers whose intent was to use recommend acetaminophen for such NSAID drug products, current OTC
the product safely. One NDAC member patients, but at reduced doses, such as labeling does not have warnings about
stated the term ‘‘exceed’’ is not part of 2 g maximum in a 24-hour period. damage to specific organs.
consumers’ common vocabulary and NDAC urged more studies, not only of 1. Points for Discussion
proposed that it would be more useful risk factors, but of a plan to reduce risk.
to inform consumers of a specific • Consumer and healthcare provider FDA asked NDAC to consider the
allowable total dose (e.g., not to take education. NDAC concluded that FDA relative risks for GI bleeding and renal
more than a specified number of tablets and manufacturers have a joint toxicity associated with OTC doses of
in a given period). responsibility to reduce the occurrence NSAIDs, including aspirin, and to
NDAC re-examined the currently of unintentional overdoses from consider the following issues:
required alcohol warning for acetaminophen. NDAC considered it • How should the relative risk of GI
acetaminophen, which states: ‘‘Alcohol essential that consumer and bleeding or renal toxicity be described
Warning: If you consume 3 or more professional educational programs to consumers who use the maximum
alcoholic drinks every day, ask your heighten awareness of the risk, recommended daily OTC dose?
doctor whether you should take particularly to certain populations. • Are there subpopulations of
acetaminophen or other pain relievers/ NDAC believed consumers are consumers who are at a greater risk for
fever reducers. Acetaminophen may unfamiliar with the term developing GI bleeding or renal toxicity
cause liver damage.’’ NDAC inquired ‘‘acetaminophen’’ and are more likely to with OTC doses?
why ‘‘three drinks’’ were used in the know the brand names. NDAC stated • If additional warnings are
alcohol warning. FDA responded that that an effort should be made to create recommended, should such warnings
the number is from recommendations of a broader educational campaign to inform consumers about the risk,
the American Heart Association as to inform consumers that acetaminophen provide information on the at-risk
what constitutes excessive alcohol use. is an analgesic, because most people are populations, or provide expanded
FDA stated that it recognized this may familiar with aspirin and not with information to all consumers about
seem arbitrary and asked NDAC to acetaminophen. NDAC also suggested symptoms of toxicity?
provide further recommendations. that the packaging, display, format, and • Should the warnings that are
NDAC questioned whether doctors are wording recommendations in OTC drug currently in professional labeling for
well-informed with proper information product labeling should also be aspirin be conveyed to consumers as
about the relationship between alcohol extended to all product advertisements, part of the OTC labeling?
and acetaminophen use and whether both in print and media, because • If yes, which warnings should be
educational efforts should also include advertising is an educational tool for conveyed and how should they appear
educational efforts directed at health many consumers. in OTC drug product labeling?
care professionals and consumers. NDAC stated that many physicians • Are any additional studies needed
NDAC was concerned about the lack of and pharmacists may not be aware of to evaluate subpopulations at risk for
available data on which to base such the risks of unintentional overdose. serious adverse events, labeling
advice, noting that there is a lack of NDAC added that, along with consumer revisions, and any other issues?
information about how to determine the education, professional programs are • Should the labeling and packaging
amount of alcohol that may be harmful important, because prescription of these products more prominently
to any individual. NDAC noted that products containing acetaminophen are state that the product contains aspirin or
reducing the risk of drug adverse events widely used. Education of pharmacists the specific NSAID?
is the goal, but believed that more data would be needed to support the use of
2. Presentations and Submissions to
are essential for them to make specific additional labeling information (stick-on
NDAC
recommendations. labels, etc.) attached to prescription
FDA asked NDAC to comment on containers. NDAC stated that auxiliary GI bleeding
whether the current maximum labeling is critical to conveying FDA staff described cases of GI
allowable daily dose of acetaminophen information that the prescription bleeding (spontaneous reports from
should be used by individuals product contains acetaminophen. AERS received by FDA between 1998
consuming three or more drinks per • Pediatric dosage. NDAC also and 2001) in individuals who used OTC
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day. One NDAC member agreed that expressed concern about the lack of NSAIDS (including aspirin) as an
was prudent to lower the dose, however, standardized pediatric dosage analgesic and/or antipyretic (Ref. 8).
the majority of NDAC members believed information, especially for infants under The review was limited to cases that
that more information is needed before 2 years of age. FDA stated that a mentioned ‘‘OTC’’ in the narrative of the
dose reductions could be implemented separate rulemaking on this issue was in report. Any cases that appeared to
for this population. NDAC stated that, progress and will be addressed in a involve prescription NSAID products
intuitively, a lower dose would decrease future Federal Register publication. were excluded. A total of 279 cases of
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77325
GI bleeding were included: 82 for the incidence of complicated aspirin every day. The study showed
aspirin and 197 for nonaspirin NSAIDs ulcerations (specifically, bleeding that there is an increased risk of upper
(i.e., ibuprofen, ketoprofen, and ulcers) has increased in the past few GI bleeding in patients who combine
naproxen). The mean age was 59 years years. This is likely due to increased low dose aspirin and other NSAIDs
(ranging from 1 to 99 years). There were NSAID exposure, possibly from OTC compared to the incidence of GI
138 (49.5 percent) males, 119 (42.7 use. Gastric ulceration (15 percent bleeding events in the general
percent) females, and 22 cases (7.9 prevalence) associated with NSAIDs (at population (RR 5.6; 95% confidence
percent) in which gender was not recommended doses) is much more interval (CI) 4.4—7.0). The risk of GI
reported. common than duodenal ulceration (5 bleeding among patients taking more
Cases that specified the location in percent prevalence). Clinically relevant than one NSAID was approximately
the GI tract of the bleed included: ulceration (i.e., ulcers that present with double the risk among patients taking
Stomach (63 cases), duodenum (35 bleeding), has a prevalence of aspirin alone.
cases), unspecified upper GI site (15 approximately 2 percent. • In an American College of
cases), esophagus (13 cases), and • A history of prior bleeding, Gastroenterology Bleeding Registry (Ref.
rectum/colon/small intestine (9 cases). anticoagulant use, corticosteroid use, 18), cases of GI bleeding were assessed
For nonaspirin NSAIDs, the median and increasing age are factors that for use of aspirin or OTC NSAIDs and
time to onset was 7 days. Time to onset increase the risk of bleeding associated concomitant use of alcohol. These cases
was defined as the time between each with NSAIDs (Refs. 10 through 13). were compared to data from a control
person’s first use of the drug and the • The prevalence of upper GI cohort of cases with no GI bleeding. The
time that bleeding occurred. For aspirin, bleeding from aspirin use is different results suggest an increased risk of
time to onset was about 30 days. For than for nonaspirin NSAID use. A study bleeding when alcohol is used while
both aspirin and nonaspirin NSAIDs, evaluated the prevalence of aspirin and taking an OTC NSAID (odds ratio 4.47;
there was a wide range in time to onset. nonaspirin NSAID use in 421 patients 95 percent CI 2.73 -7.32) compared to
FDA reviewed the cases for common evaluated for upper GI bleeding (Ref. the use of either alcohol or OTC NSAIDs
risk factors for GI bleeding that are 14). Patients were asked at the time of alone (odds ratio for alcohol alone 2.07;
recognized in the medical literature, hospital admission whether they were 95 percent CI 1.48—2.88/ odds ratio for
including previous GI bleed or history using prescription or OTC products and NSAID alone 2.76; 95 percent CI 2.03—
of an ulcer, social history (alcohol or whether they were using nonaspirin
3.74). Dr. Cryer noted that the results of
tobacco use), concomitant use of other NSAIDs or aspirin. The results show
the study were confounded because 12
drugs (NSAIDs, aspirin, anticoagulants, that 42 percent of GI bleeding was
percent of the subjects in the registry
corticosteroids), use of doses higher associated with aspirin use. Fourteen
had gastric or esophageal varices
than recommended, and advanced age percent of patients admitted to the
(enlarged veins). He suggested that there
(65 years and older). The results hospital were using prescription
may be an increased risk particularly to
included 195 (70 percent) cases with at NSAIDs and 9 percent were using OTC
patients with an extensive history of
least one risk factor, 112 (40 percent) NSAIDs.
• A recent study suggests that up to alcohol use who are exposed to OTC
cases with more than one risk factor, NSAIDs.
80 percent of people with GI bleeding
and 81 (29 percent) cases with no risk
are taking an NSAID, primarily low dose • Another report (Ref. 19) evaluated
factors apparent in the report. The most subjects who regularly or occasionally
aspirin (Ref. 15). The relative risk (RR)
commonly reported risk factors were: used aspirin or ibuprofen and compared
• Concomitant use of another NSAID (i.e., the probability of an event in the
active group divided by the probability the RR of GI bleeding between those
or aspirin (50 percent) who never used alcohol and those who
• Advanced age (40 percent) of the event in the control group) was
2.4 for a low/medium NSAID dose and used alcohol. The results suggest a
• History of a previous GI bleed (18 modest increase in RR of upper GI
percent) 4.9 for a high dose.
• Using NSAID doses above the • Another study compared the use of bleeding in alcohol users; however, the
OTC aspirin, ibuprofen, naproxen, and statistical analyses did not provide a
recommended OTC dose (14 percent)
• Alcohol or tobacco use (5 percent). acetaminophen between two case strong distinction between alcohol users
In the aspirin cases, only one person groups, one group who experienced GI and non-users.
was reported to have exceeded the OTC bleeding events and a control group of Dr. Marie Griffin of Vanderbilt
recommended dose. Of the 279 aspirin cases who did not experience GI University discussed additional
and nonaspirin cases, 212 people (76 bleeding (Ref 16). The patients in the GI information obtained from large
percent) were hospitalized. Most bleeding group were more likely to be population studies regarding GI
recovered; however, 13 (4.7 percent) taking aspirin or OTC NSAIDs prior to complications associated with the use of
people died. the GI bleeding event than were patients NSAIDs (Ref. 20). She made the
FDA indicated that these reports in the control group. The extent of use following points:
suggest that serious GI bleeding events of acetaminophen was comparable • The risk of ulcer disease was shown
can occur with NSAID and aspirin use between the two groups. This study to increase 10-fold in older people and
at OTC dosage strengths, within the included people with chronic disease this risk is increased further by use of
duration of use described in the OTC and chronic analgesic exposure, NSAIDs (Ref. 21). This ulcer
labeling. providing information about a subgroup hospitalization study found the absolute
Dr. Byron Cryer, of the University of of patients that may be different from risks to increase from approximately 4
Texas Southwestern Medical School, relatively healthy individuals exposed hospitalizations per 1,000 person-years
mstockstill on PROD1PC61 with PROPOSALS
provided an overview of the GI risks to OTC analgesics for acute, short-term, in older non-users of NSAIDs to
from NSAID use (Ref. 9). His review was or intermittent use. approximately 16 hospitalizations per
not limited to OTC dosing of NSAIDs • The risk of combining low dose 1,000 person-years in older users of
and extended to all NSAIDs. He made aspirin with nonaspirin NSAIDs was NSAIDs. In general, consumers taking
the following points: examined in a large national cohort NSAIDs for a year at moderate doses
• Despite the overall decrease in study in Denmark (Ref. 17) in which have about a 1 to 2 percent chance of
prevalence of uncomplicated ulceration, 27,000 people were given 100 to 150 mg being hospitalized with a complication.
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77326 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
• The risk of hospitalization for low risk. Results of prevention studies sold), of fatalities associated with
peptic ulcer disease (PUD), and risk of of secondary and acute myocardial acetaminophen overdose in the United
GI complications, increases with infarction have shown that for people States significantly exceeds the
increasing NSAID doses (Refs. 20, 22, whose 10-year risk of having a corresponding figures for aspirin
and 23). subsequent cardiovascular event is overdose.
• Data obtained from the Tennessee between 20 and 50 percent, the • One manufacturer stated that the
Medicaid database indicate that the cardiovascular benefit of aspirin far occurrence of GI adverse events with
greatest absolute risk for hospitalization outweighs the risks. The relative and naproxen/naproxen sodium at single
for PUD occurs in the first 30 days of absolute risks of aspirin are low. low dose (220 mg), at multiple doses (up
NSAID use among patients older than • One consumer advocacy to 880 mg), and as needed OTC doses,
65 years of age (Ref. 23). For older organization stated that GI bleeding are comparable to the occurrence
patients, there were 26.3 caused by NSAIDs (reference to associated with use of placebo (Ref. 5,
hospitalizations for PUD per 1,000 prescription or OTC products was not Tab H). Nausea, dyspepsia, and
NSAID users per year within 30 days of specified) is now recognized as the most vomiting are the most common GI
starting NSAID therapy, 20.9 common serious adverse drug reaction adverse events.
hospitalizations between 31 and 180 in the United States and accounts for as Renal effects
days of use, and 16.2 hospitalizations many as 16,000 deaths a year. The FDA staff presented information about
for use longer than 180 days. In contrast, organization requested that: (1) Product the potential for OTC NSAIDs to cause
there were 4.2 hospitalizations per 1,000 labeling contain a clear organ-specific nephrotoxicity (Ref. 24) and made the
NSAID non-users per year. Overall, warning about GI bleeding, (2) following points:
people of all ages have a 1 to 2 percent packaging include consumer education • NSAID-induced nephrotoxicity at
chance of being hospitalized with a on GI bleeding, such as a leaflet inside prescription doses is characterized by
complication when using NSAIDs for the packaging listing specific symptoms fluid and electrolyte disturbances
over a year at moderate doses. and factors associated with increased leading to sodium retention, edema
• Surveys in the 1980s showed that risk, and (3) a separate warning, about (accumulation of watery fluid in cells
approximately 1 to 3 percent of people increased risk of GI bleeding associated and tissues), and hyperkalemia (high
65 and older take a prescription with alcohol use, be added and directed concentration of potassium in the
corticosteroid drug. The concomitant at consumers who drink some alcohol. blood). These drugs can also cause
use of an OTC NSAID with a Several drug manufacturers submitted blood pressure to increase. The majority
corticosteroid increases the risk of ulcer additional information (Ref. 5): of healthy people who are exposed to
complication 13- to 15-fold over NSAID • One manufacturer stated that the therapeutic doses of NSAIDs for a
non-users. The ulcer hospitalization rate safety profile for OTC ibuprofen, limited time tolerate these drugs
in people using both drugs was about 5 generated over 18 years of OTC use by without untoward renal effects. Some
to 6 per 100 people per year. millions of consumers, indicates that subsets of the population are more
• In the 1980s, 1 to 2 percent of the the current labeling has been effective in susceptible to potentially life-
elderly population were co-prescribed informing consumers of the appropriate threatening nephrotoxicity (e.g., acute
warfarin (an anticoagulant drug) and use of the drug (Ref. 5, Tab E). The renal failure and serious fluid and
NSAIDs. The risk of GI bleeding manufacturer stated that FDA has electrolyte disorders), including people
increased by 12 fold in patients who received an average of 18 reports per who have volume depletion, underlying
used both therapies compared to NSAID year of GI perforations, ulcers, or kidney disease, congestive heart failure,
non-users. The risk of hospitalization hemorrhage associated with OTC use. or liver dysfunction with ascites
for GI bleeding is approximately 3 per • One manufacturer stated that no (accumulation of fluid in the peritoneal
100 per year in patients who use antidote is available for aspirin or cavity of the abdomen), and the elderly.
warfarin and NSAIDs. ibuprofen overdose (Ref. 5 Tab F). Acute The use of NSAIDs in the last trimester
Several drug manufacturers and overdose and chronic aspirin toxicity of pregnancy has been associated with
others provided additional comments are associated with significant significant neonatal nephrotoxicity.
(Ref. 4): morbidity (as high as 25 percent). If • Ideally, an assessment of the
• One drug manufacturer of ibuprofen acetaminophen was restricted, aspirin nephrotoxic risk associated with OTC
OTC drug products stated that the OTC and other NSAID use would increase. NSAIDs should rely on data derived
ibuprofen daily regimen is 1,200 mg/day Available data suggest that more people from prospective, randomized, placebo-
versus 2,400 to 3,200 mg a day for would die from aspirin and other controlled and adequately powered
prescription use. Unlike NSAID-related GI bleeding. The net studies in healthy, as well as at-risk,
acetaminophen, the OTC directions public health impact of changing populations. However, such data are not
clearly state to take one 200-mg tablet labeling for OTC IAAA drug products available. In 1995, the National Kidney
and, only if necessary, a second tablet should be taken into consideration in Foundation (NKF) convened a group of
may be taken. OTC use of NSAIDs is the formulation of any regulatory policy. investigators and clinicians to consider
limited to a maximum of 10 days, • One manufacturer stated that the and develop recommendations on the
whereas prescription use is chronic. risk patterns associated with use of issue of analgesic-related kidney
• One drug manufacturer stated that acetaminophen and aspirin are distinct disease. The database used to make their
each analgesic ingredient requires from one another and support different recommendations was comprised of 556
appropriate labeling for its pattern of product labeling for the various articles published in the medical
use and that it is inappropriate to label ingredients in OTC IAAA drug products literature on aspirin, acetaminophen,
mstockstill on PROD1PC61 with PROPOSALS
OTC products with risks associated with (Ref. 5, Tab G). There are no data to aspirin-acetaminophen combinations,
chronic, long-term prescription dosing. support the view that a balanced and NSAID-related nephrotoxicity. The
The prescription and OTC uses of warning for acetaminophen will cause a NKF recommended ‘‘[t]here should be
NSAIDs are distinct and these two dose significant number of patients to switch an explicit label warning people taking
levels have different risk-benefit to another OTC analgesic. Available over-the-counter NSAIDs of the
profiles. The OTC use is short-term for data indicate that both the absolute potential renal risks of consuming the
pain relief and fever reduction, with a number, and the rate (per billion tablets drugs.’’
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77327
• FDA staff identified all cases in the OTC dosages and/or an OTC NSAID and nine died. Renal failure occurred
AERS database reporting acute renal product had a role in the adverse within less than 7 days of exposure to
failure, chronic renal failure, and renal reaction. People with pre-existing the drug. Fourteen ibuprofen cases were
failure in association with the use of conditions were not included. Table 9 within the pediatric age group. For
OTC doses of NSAIDs. The time period shows the number of cases of renal naproxen sodium, 25 people were
reviewed was from the OTC approval failure reported, including 94 cases for hospitalized, 4 required dialysis, and 3
date for ibuprofen (1984), naproxen ibuprofen, 26 cases for naproxen died. The single ketoprofen case was
sodium (1994), and ketoprofen (1995) sodium, and 1 case for ketoprofen. Fifty- hospitalized.
through August 10, 1999. FDA’s review six people who used ibuprofen required
included cases that specified that either hospitalization; nine needed dialysis;
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—Total 94 26 1
Renal Failure Cases—Adult 80 26 1
Renal Failure Cases—Pediatric 14 0 0
Next, Dr. Griffin discussed renal Several drug manufacturers submitted warning. One NDAC member suggested
complications from the use of NSAIDs additional information suggesting that the heading ‘‘bleeding alert’’ because
obtained from large population studies (Ref. 5): aspirin and the other NSAIDs can cause
(Ref. 20). A study of patients 65 years • The number of renal side effects more than stomach bleeding, and it is
of age and older in the Tennessee that have been reported with OTC very important to stop using an OTC
Medicaid database (Ref. 23) included ibuprofen are minimal (less than two IAAA active ingredient when signs of
the following information: cases of renal failure per year), bleeding are present (e.g., vomiting
confirming that the drug is well- blood or bloody or black stools). Most
• Eighteen percent of the patients
tolerated. NDAC members felt that stomach
presenting with acute renal failure used • The renal safety profile of
NSAIDs at either prescription or OTC bleeding was the major safety problem
naproxen/naproxen sodium is and should be the focus of the warning
doses. A RR for acute renal failure in consistent with other currently
NSAID users was calculated to be 1.58 statement.
marketed NSAIDs with which it has NDAC found that low dose aspirin,
compared to NSAID non-users. been compared. Even at prescription combined with another NSAID, will
• The RR for acute renal failure with doses, reports of adverse events increase the risk for GI bleeding two to
ibuprofen was dose related. The RR of involving the kidney have been rare. four times more than use of an NSAID
acute renal failure associated with use
3. NDAC Deliberations and alone. From the data reviewed, enteric-
of daily doses of less than 1,200 mg was
Recommendations Concerning Aspirin coated or buffered aspirin preparations
approximately 1 compared to use of no
and Other NSAIDs do not change the risk associated with
ibuprofen. Daily doses of 1,200 to 2,400
• GI bleeding. NDAC members agreed use of multiple NSAID products. NDAC
mg (above the OTC range of 1,200 mg
that NSAIDs increase the risk for GI recommended that the labeling for
per day or less) increased the RR of
adverse events. The risk appears to be aspirin and other NSAIDs include a
renal failure to 1.89.
related to dose. Aspirin, even at lower stomach bleeding warning advising
• The greatest risk for renal failure consumers of the risks of taking more
doses, has some GI risks. However, the
was within the first 30 days of therapy than directed or using more than one
benefits from use far exceed any risks.
with an NSAID. The RR was 2.83. NSAID. In addition, NDAC concluded
NDAC stated that low dose aspirin
Several drug manufacturers and should be available OTC for the elderly that the warning should advise
others provided additional comments for cardiovascular prophylaxis as consumers that the risk is greater for
(Ref. 4). One drug manufacturer stated described in the professional labeling. individuals who are over 65 years of
that the incidence of renal failure and NDAC believed that the absolute risk of age, have a history of ulcers, stomach,
other serious renal events are rare with GI bleeding from use of low dose aspirin or bleeding problems, or are taking
use of either prescription or OTC is probably comparable to the risk from steroids or anticoagulants (blood
ibuprofen. One drug manufacturer using aspirin at analgesic doses. thinners).
claimed that there was an average of Therefore, NDAC recommended that the A majority of NDAC members
approximately five reports of renal information on risk provided in OTC believed that there were insufficient
failure per year from FDA’s safety aspirin labeling to consumers need not data and a lack of a scientific rationale
surveillance data. The manufacturers be categorized by dose. to support a warning about using
also suggested that serious renal events NDAC agreed that the data support a alcohol while taking NSAIDs.
mstockstill on PROD1PC61 with PROPOSALS
are almost always reversible, even in the separate and distinct stomach bleeding Recognizing that the data are mixed and
elderly or chronically ill. It was stated warning and suggested that the heading not conclusive, the members believed
that serious renal events following ‘‘stomach bleeding warning’’ be used. that a majority of the trials reviewed
NSAID therapy almost always occur in NDAC recommended that this heading failed to show a direct and convincing
patients with pre-existing renal be in bold type and that the warning be association with alcohol. NDAC urged
dysfunction, congestive heart failure, or included as one of the first warnings in FDA to remove the existing alcohol
compromised hepatic function. labeling along with the Reye’s syndrome warning from labeling and encouraged
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77328 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
FDA to examine future cases of GI IV. FDA’s Review of Additional Data NDAC meeting, FDA conducted a
bleeding in individuals who consume and Information literature review (1966 to January 2003)
alcohol and are alcohol abusers to and determined that the following
A. Pre-existing Liver Disease as a Risk
explore the impact of concomitant use factors may place patients with pre-
Factor for Acetaminophen
of NSAIDs. existing liver disease at a greater risk for
Hepatotoxicity
acetaminophen toxicity (Ref. 26).
• Renal effects. NDAC considered Following publication of the OTC • Depletion of hepatic GSH has been
particular groups at risk for short-term IAAA TFM in 1988, FDA received found in both alcoholic and
adverse renal consequences from NSAID comments urging adoption of a warning nonalcoholic liver diseases, suggesting
use. While NDAC agreed that small to advise consumers with pre-existing that the diseased liver may have less
increases in blood pressure of limited liver disease against using capacity to inactivate the toxic
duration (e.g., several days) in acetaminophen, unless directed by a metabolite of acetaminophen. (Refs. 27
normotensive or hypertensive doctor. The comments cited reports in through 34)
individuals is not a significant risk, the the medical literature concerning • The hepatic cytochrome P450
labeling for NSAIDs should warn about toxicity in persons with liver disease. enzyme, P450–2E1, metabolizes
the potential association of long-term Other comments asserted that there is acetaminophen to the toxic metabolite
use and renal failure in individuals who no evidence to warrant a warning. At that causes hepatotoxicity. Expression
have high blood pressure, heart or that time, FDA believed the evidence of hepatic P450–2E1 tends to increase in
kidney disease, use diuretics, or are over was insufficient to propose a warning. stable chronic liver diseases.
65 years of age. NDAC agreed with the NDAC briefly discussed this issue in • Studies have shown that the
OTC labeling proposed for ibuprofen in September 2002, but concluded that clearance of acetaminophen from the
the Federal Register of August 21, 2002, there were not sufficient data to make body is impaired in people with chronic
including the warning to ask a doctor specific recommendations. liver disease (Refs. 35, 36, and 37). The
before use in the presence of high blood FDA has reconsidered its previous disease status of the liver alters drug
pressure, heart or kidney disease, if also position on this issue and now believes metabolism and drug metabolites made
using a diuretic, or if over 65 years of that the current evidence supports a by each metabolic pathway (Refs. 38
age. warning. At the NDAC meeting, FDA and 39).
reported information derived from • In chronic liver disease, hepatic
Labeling. NDAC members agreed that mortality data of acetaminophen glucuronide and sulfate conjugation are
labeling continues to be a major factor overdose (intentional and decreased (Refs. 40 through 43).
in promoting the safe and effective use unintentional). Among patients with • Significant impairment of total
of OTC NSAID products. NDAC chronic alcoholic or other chronic liver hepatic P450 expression is found only
expressed concern that consumers do disease, death associated with in people with severe liver disease
not read labels adequately and are often unintentional acetaminophen overdose (hepatitis with liver failure and
unaware of the names of the medicines was reported far more frequently than in decompensated cirrhosis) (Ref. 38).
that they are taking. This lack of association with intentional overdose Recent studies indicate that different
awareness is especially problematic for (see table 4 of this document). In the types (viral, chemical, or immunological
people who are also taking prescription series of 282 AERS cases of hepatoxicity factors) and/or states (acute, chronic, or
medicines concomitantly with OTC associated with acetaminophen use severe) of liver disease selectively
drug products. NDAC expressed presented at the meeting, 70 cases were influence expression of different P450
concern about the ability to reported as having underlying liver isozymes.
communicate meaningful information in disease. • Chronic alcohol use significantly
the confines of a small package label, Metabolic activation and deactivation induces hepatic P450–2E1 and increases
especially to the elderly. NDAC are involved in acetaminophen this enzyme’s ability to metabolize
suggested that patient information be elimination (Ref. 25). At a therapeutic acetaminophen to NAPQI (Ref. 44). In
included in a package insert to provide dose, the majority (greater than 90 other types of human liver disease,
expanded information beyond what percent) of acetaminophen combines changes in expression and activity of
could be presented clearly on a small with glucuronic acid (the major P450–2E1, as well as other P450
label. metabolic pathway for adults) and isozymes (1A2 and 3A4) involved in
sulfuric acid (the major metabolic acetaminophen metabolism, are variable
NDAC strongly recommend that the pathway for children). There is also a (Refs. 38, 45, 46, and 47). Both human
term ‘‘NSAID’’ be used throughout OTC second, minor metabolic pathway in and animal studies show that hepatic
product labeling. The term NSAID is which a small portion of acetaminophen P450–2E1 expression is significantly
becoming more widely recognized and undergoes cytochrome P450 phase I increased in a nonalcoholic fatty liver
is often found in drug information metabolism to the toxic acetaminophen (Refs. 48 and 49).
leaflets. NDAC suggested that meaning metabolite, N-acetyl-p- Few clinical trials directly assess the
of the NSAID acronym could be spelled benzoquinoneimine (NAPQI). This toxic hepatotoxicity of acetaminophen in
out somewhere on the label. metabolite is normally inactivated people with nonalcoholic liver disease.
Additionally, NDAC recommended that through combination with hepatic One double-blind, placebo controlled,
this term should be included on the glutathione (GSH). Any factors that can crossover study was conducted in 20
front panel or PDP, advising consumers change GSH availability (by decreasing people with stable chronic liver disease
that the product contains an NSAID, synthesis and/or increasing utilization (including Laennec’s cirrhosis, alcoholic
mstockstill on PROD1PC61 with PROPOSALS
especially if the product is a or interfering with the conjugation liver cirrhosis, primary biliary cirrhosis,
combination containing an NSAID. enzyme) could potentially influence the or chronic hepatitis) (Ref. 50). The
Finally, NDAC members agreed that hepatotoxicity of acetaminophen. Any subjects received 1 g of acetaminophen
there is a need for additional label factors that disturb the balance between or placebo every 4 hours (a total of 4 g/
comprehension studies to identify ways these two metabolic pathways may day) for 13 days. The author stated that
to improve communication with affect the amount of acetaminophen there were no significant changes in
consumers. metabolized by each pathway. After the laboratory tests or clinical status in the
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77329
acetaminophen and placebo treatments. • 48% were designated as (Ref. 54). NSAID use is so widespread
The author concluded that underlying unintentional injury, 44% were that NSAID-induced gastropathy has
liver disease does not increase patient designated as an intentional injury and been identified by some as one of the
sensitivity to the hepatotoxic effects of 8% could not be classified to either most prevalent, serious drug toxicities
acetaminophen at a therapeutic dose. group; in the United States (Ref. 55). NSAID-
Because of the small sample size and • 147 (53%) used an OTC product, associated serious GI complications are
crossover study design, FDA believes including 6 of 147 who used more than estimated to result in over 200,000
this study is inadequate to make any one OTC product at the same time and hospitalizations per year in the United
conclusions regarding the risk for 41 of 147 who also used a prescription States. Although these adverse event
acetaminophen hepatotoxicity in combination product; rates are for prescription and OTC
patients with chronic liver disease. • 120 (44%) reported use of a NSAID formulations combined, there is
In summary, the single prospective narcotic/acetaminophen combination; a significant prevalence of OTC NSAID
clinical study found by FDA in the • 55% had a history of alcohol use use among people presenting to
literature that evaluated the and 35% had a history of alcohol abuse; hospitals with upper GI bleeding (Ref.
susceptibility of the diseased liver to • 108 (39%) also used a 56). The rate of consumption of OTC
acetaminophen toxicity was not antidepressant; NSAIDs by consumers is estimated to be
definitive. Analyses of an • 65% survived without transplant; as much as seven times that of
acetaminophen overdose database and a and prescribed NSAIDs (Ref. 54).
review of the AERS case reports suggest, • 22% used more than one • The American College of
however, that people with a history of acetaminophen product. Gastroenterology guideline for treatment
liver disease may have increased The authors also compared and prevention of NSAID-induced
susceptibility to acetaminophen- characteristics between those classified ulcers indicates an increased risk of
induced hepatotoxicity. In addition, the as unintentional versus intentional liver NSAID-associated GI complications for
depletion of hepatic GSH has been injury. Females predominate in both people greater than 60 years of age (Ref.
found in both alcoholic and groups. The clinical outcomes are 56). A United Kingdom (UK)
nonalcoholic liver diseases, suggesting similar for both groups. Narcotic/ population-based, retrospective case-
that the diseased liver may have less acetaminophen use was more prevalent control study evaluated the risk of
capacity to inactivate the toxic in the unintentional injury group (63% various NSAIDs (Ref. 10). The study
metabolite of acetaminophen. vs. 18%). The unintentional injury reported a RR of 3.7 for upper GI
Expression of hepatic P450–2E1, a major group had a greater percentage with bleeding (UGIB) and GI perforation in
enzyme for metabolic activation of stage 3-4 hepatic coma score at people under 60 years old exposed to
acetaminophen, tends to be increased in admission and at peak during the NSAIDs, 13.2 in people 60 years and
stable chronic liver diseases, hospitalization. FDA believes that these older exposed to NSAIDs, and 2.8 in
particularly in nonalcoholic fatty liver data support the previous NDAC people 60 years and older not exposed
disease. FDA believes that these data conclusion that acetaminophen to NSAIDs.
hepatotoxicity is an important public • FDA analyzed a series of studies
collectively establish that it is necessary
health consideration and that additional that used the Medicaid population in
to alert patients with chronic liver
labeling is necessary for it to continue Tennessee (Refs. 12, 13, 56, 57, and 58).
disease that they may be at risk for
to be generally recognized as safe and These case-controlled retrospective
developing acetaminophen
effective. studies were based on hospitalizations
hepatotoxicity, as an important factor in
for GI bleeds. The study population
the safe and effective use of C. Aspirin and Other NSAIDs totaled 103,954 individuals, about 15
acetaminophen products.
1. GI Bleeding percent of Tennessee’s elderly
B. Updated Literature About population, with 209,066 person-years
Acetaminophen Hepatoxicity Following the NDAC meeting, FDA of followup. There were 1,371
reviewed additional data and hospitalizations for PUD. These studies
The Acute Liver Study Group recently information related to the use of OTC found increased risk of GI bleeds in
published an update of the prospective NSAIDs and GI bleeding. people who were:
data in patients diagnosed with ALF at • One individual asserted in a citizen • Over 65 years old (RR of 4.7),
22 tertiary care centers. Over a 6-year petition that incomplete information • Taking an increased NSAID dose
period from January 1, 1998, to about aspirin reaches consumers and (RR of 2.8 for the lowest dose vs. RR
December 31, 2003, 662 patients increases the danger that aspirin will be of 8 for the highest dose category),
fulfilled standard criteria for ALF. Of misused with serious consequences or
these cases, 275 were attributed to (Ref. 52). The citizen petition suggested • Taking concomitant corticosteroid
acetaminophen hepatotoxicity. The that additional labeling for aspirin (RR of 4.4) or anti-coagulant (RR
criteria for attribution to acetaminophen should be implemented without delay 12.7) drug products.
included one or more of the following: to state: ‘‘CAUTION: This product can In addition, the risk of GI bleeds
(1) A history of potentially toxic cause severe hemorrhaging and should among people taking NSAIDs was
acetaminophen ingestion (> 4 g/day) not be taken for more than five days greatest within the first 30 days of use
within 7 days of presentation; (2) except under the supervision of a (RR of 7.2).
detection of any level of acetaminophen physician. When used for fever, if • A multicenter, case-control study of
in the serum; or (3) a serum alanine symptoms persist more than three days, 550 people with UGIB admitted to a
mstockstill on PROD1PC61 with PROPOSALS
aminotransferase (ALT) > 1,000 IU/L consult a physician.’’ hospital with bloody stools or vomiting
with a history of acetaminophen • NSAIDs are being used by an blood and 1,202 controls identified from
ingestion, irrespective of acetaminophen estimated 17 million Americans on a census lists, compared risks of major GI
level (Ref. 51). daily basis (Ref. 53). The estimated rate bleeding for plain, coated, and buffered
Of the 275 cases attributed to of serious adverse events is about 1 formulations of low-dose aspirin (Ref.
acetaminophen, the following percent for clinically significant GI 59). Each of these types of low-dose
observations were made: bleeding in the first 3 months of use aspirin formulations (less than 325 mg
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77330 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
per day) had about a 2.5 to 3 times existing renal problems were prescribed interstitial nephritis, which the authors
increased risk of major UGIB. ibuprofen for the treatment of fever due attributed to beta-lactam antibiotic use.
• A double-blind, randomized, to acute illness. Both had a recovery of These case reports demonstrate the
placebo-controlled, ulcer prevention renal function on withdrawal of the variety of situations in which ibuprofen-
study in 8,843 people with rheumatoid drug. The third child (a 7.5-year-old associated renal toxicity can occur. In
arthritis identified several risk factors girl) developed progressive chronic many of the cases, the children were
for upper GI complications from NSAID renal failure. She had underlying hyper already at risk for renal adverse effects
use: (1) Age 75 years or older (odds ratio Ig-E syndrome and was treated with a because of underlying disease states,
2.48), (2) prior peptic ulcer (odds ratio single dose of ibuprofen 5 mg /kg for concomitant medications, or
2.29), (3) prior GI bleeding (odds ratio fever due to severe pulmonary infection. dehydration. Children with underlying
2.56), and (4) history of cardiovascular Her illness was also complicated by illnesses or those dehydrated are at
disease (odds ratio 1.84) (Ref. 60). moderate dehydration. Her renal biopsy greatest risk for this injury. FDA
• A case control study of 1,122 showed evidence of kidney damage currently requires all OTC pediatric
subjects admitted consecutively for consistent with loss of blood products containing ibuprofen marketed
UGIB to four hospitals in Spain and circulation. under new drug applications to include
2,231 controls from the same geographic • Ibuprofen-induced acute renal warnings for children ages 2 to 11 years
area, showed that a prior history of failure was reported in a 9-month-old to ask a doctor before use if the child
UGIB is a risk factor (odds ratio 3.7) for girl (Ref. 67). A family practitioner has ‘‘not been drinking fluids’’ or has
UGIB in people who used NSAIDs (Ref. treated the infant for diarrhea, vomiting, ‘‘lost a lot of fluid due to continued
61). and fever. She was given oral vomiting or diarrhea.’’
In summary, results of several large- rehydration therapy and acetaminophen b. Alcohol use. Binge drinking of
scale clinical studies, conducted in the alcohol reduces the production of
and was sent home. Symptoms persisted
United States and worldwide, have antidiuretic hormone causing increased
for 48 hours and the acetaminophen was
established that use of OTC NSAIDs is urine production. Two cases of
changed to ibuprofen 50 mg (5 mg/kg/
an important risk factor for serious GI reversible acute deterioration in renal
dose) three times a day. Seven doses of
adverse events, especially bleeding. The function following binge drinking of
ibuprofen were given over a 40-hour
risk is higher for people age 60 or older, beer with use of NSAIDs have been
period, but the child’s clinical state
who have a history of stomach ulcers or reported in adults (Ref. 69):
deteriorated. She was admitted to an • The authors reported a case of a 22-
bleeding problems, or who use emergency facility 18 hours after the last
corticosteroids or anticoagulants. year old male admitted to the hospital
dose with a creatinine concentration of with low back pain and worsening renal
2. Renal Effects 2.1 mg/deciliter (dL). For the first 12 function. Four days prior to admission,
NSAIDs decrease renal prostaglandin hours after admission, the infant’s he had consumed an unknown amount
production, which may result in acute kidneys failed to secrete urine in spite of beer; 2 days later as the pain
reduction in renal blood flow and of receiving adequate hydration and an intensified he had taken six doses of
glomerular filtration, leading to fluid intravenous diuretic (furosemide). The 400-mg ibuprofen with no relief. Upon
retention, edema, and elevation of creatinine concentration increased to admission, his serum creatinine was 3.1
serum creatinine (Ref. 62). Marked 2.4 mg/dL. Renal function slowly mg/dL. Biopsy of the kidney was
reduction in renal blood flow may result recovered; 4 days after admission her consistent with the diagnosis of acute
in renal failure. creatinine was 0.9 mg/dL and 3 weeks kidney failure. The subject’s serum
NSAID use may also result in higher later was 0.5 mg/dL. Clinical diagnosis creatinine increased to a peak of 6.5 mg/
than normal levels of potassium in the was kidney damage secondary to dL on the fourth day and decreased to
bloodstream. This occurs most ibuprofen use in a dehydrated child. 1.4 mg/dL 6 days later.
commonly in people with diabetes • Primack, et al. reported acute renal • In a second case, a 20-year old male
mellitus or mild to moderate renal failure with use of ibuprofen in an 11- was admitted because of flank and back
insufficiency as well as in people taking year-old boy (Ref. 68). The child was pain of 24 hours’ duration. Four days
beta-blocker, angiotensin-converting diagnosed with possible sinusitis and before admission, the subject drank 8 to
enzyme inhibitor, or potassium-sparing given an antibiotic; on the third day 10 bottles of beer (355 mL per bottle).
diuretic drugs. symptoms worsened with associated On the evening of admission, he had
By inhibiting the production of headaches, fatigue and anorexia, and his taken 6 to 8 tablets of 325-mg aspirin for
vasodilatory prostaglandins, NSAIDs serum creatinine was 0.7 mg/dL. The pain relief. The laboratory data showed
may decrease renal blood flow and the antibiotic was continued and ibuprofen a 2.0 mg/dL serum creatinine level.
rate of glomerular filtration in subjects 200 mg was added, alternating with Following intravenous fluid
with congestive heart failure, liver acetaminophen every 4 hours for fever. administration, the subject urinated
failure with ascites, chronic renal He received a total of 24 200-mg frequently for over 16 hours. Followup
disease, or those who are hypovolemic ibuprofen tablets during the 12 days serum creatinine 1 week later was 1.2
(abnormal volume decrease of prior to hospitalization. The fever mg/dL. The authors concluded that
circulating fluid (plasma) in the body) persisted with improvement in the other dehydration is a frequent consequence
(Refs. 63, 64, and 65). symptoms. The child became of heavy alcohol ingestion due to water
a. Pediatric population. The medical progressively weaker and began diuresis. The volume contraction may
literature includes sporadic reports of vomiting. Approximately 2 weeks after be further aggravated by nausea and
acute renal failure in pediatric subjects his illness began, the child was vomiting.
mstockstill on PROD1PC61 with PROPOSALS
taking ibuprofen within the OTC dose admitted with a serum creatinine of 7.6 In the proposed rule to amend the
range, including the following cases: milliequivalent/L. After 3 days of TFM for OTC IAAA drug products to
• One article describes three cases in symptomatic treatment, his serum include ibuprofen, FDA included the
children 5-, 6.5-, and 7.5-years-old in creatinine was 4.1 mg/dL and 1 week results of the agency’s evaluation of the
which ibuprofen treatment led to later his serum creatinine was 2.2 mg/ adverse renal effects of OTC doses of
varying degrees of renal failure (Ref. 66). dL. Findings of renal biopsy on the third ibuprofen (67 FR 54139 at 54144). Based
Two subjects with dehydration and pre- hospital day were consistent with acute on its evaluation of the data, FDA
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77331
concluded that OTC doses of ibuprofen • Propose revised OTC labeling for FDA also tentatively concludes that a
can exert a variety of adverse renal these products new warning is needed to advise
effects, particularly in those who are • Continue a consumer and health consumers who have liver disease to
dependent on adequate prostaglandin provider educational campaign consult a doctor before using OTC drug
levels to maintain renal hemodynamic • Continue to monitor AERS in products that contain acetaminophen.
perfusion (i.e., congestive heart failure, various databases FDA notes that many of the case reports
liver failure with ascites, etc.). It was in the databases involved people who
• Examine available data to
further noted that although the sporadic had pre-existing liver disease (the rate of
determine whether other measures may
nature of idiosyncratic drug-induced the number of cases in the databases
be needed in the future to try to
ibuprofen nephrotoxicity makes it exceeds the rate of underlying liver
decrease morbidity associated with OTC
impossible to predict which group of disease in the general population). This
acetaminophen and NSAIDs.
individuals is at risk for developing this observation may also be due to a
event, this is not the case with In addition to the changes to the difference in the use of acetaminophen
individuals who experience IAAA TFM proposed in this document, by people with chronic liver disease or
prostaglandin-dependent hemodynamic FDA encourages manufacturers of these that they are at greater risk to develop
changes. The latter, if recognized, is products to undertake education liver failure in general. As described in
reversible upon discontinuation of the initiatives regarding safe use of OTC section IV.A of this document, people
drug (67 FR 54139 at 54145). products containing acetaminophen and with chronic liver disease can have
NSAIDs. FDA plans to increase its changes in the liver enzymes
V. FDA’s Tentative Conclusions monitoring of AERS in various responsible for the metabolism of
FDA has carefully considered NDAC’s databases to see how this new proposed acetaminophen. It is not clear whether
recommendations and other available labeling, if implemented, is working to these changes increase the risk in these
data and information and determined reduce injuries resulting from OTC individuals. It was noted at NDAC that
that labeling revisions are necessary for acetaminophen and NSAID drug some physicians who treat patients with
OTC IAAA drug products to advise products and to determine whether chronic liver disease recommend lower
consumers of potential health risks and further measures need to be proposed. total daily doses. FDA believes this
to recommend, under certain additional warning will alert patients
A. Acetaminophen
circumstances, that they consult a with chronic liver disease to ask their
doctor for advice about taking products 1. Hepatotoxicity doctor before using acetaminophen.
containing OTC IAAA active FDA recognizes there is limited
FDA tentatively concludes that
ingredients. information supporting the need for
FDA continues to believe that additional new labeling is needed for
OTC drug products that contain different dose recommendations in
acetaminophen and NSAIDs, when people with liver disease. FDA seeks
labeled appropriately and used as acetaminophen. Data from Lee (Ref. 6),
a case series from the University of comment on the information this
directed, are generally recognized as warning should provide and encourages
safe and effective OTC IAAA drugs for Pennsylvania Hospital (Ref. 4), and the
FDA AERS database show that healthcare providers and researchers
consumer self-use. However, the who treat patients with chronic liver
available evidence clearly indicates that unintentional overuse of acetaminophen
is associated with severe hepatic injury. disease to provide information on how
both drugs can cause serious side much they recommend as an
effects. When taken in excess amounts, One manufacturer provided calculations
appropriate dose and the basis for their
acetaminophen can cause liver injury. of a ‘‘worst case’’ scenario for
recommendation.
NSAIDs have the potential to cause GI acetaminophen hepatic failure deaths
bleeding and renal (kidney) injury even using estimates by Lee (Ref. 70) and 2. Other Labeling
at OTC dosing levels. calculated 213 deaths per year. FDA FDA also tentatively concludes that
When compared to the extensive use does not know the exact number of the name ‘‘acetaminophen’’ on the PDP
of OTC acetaminophen and NSAID drug cases of liver failure or deaths related to should be enhanced to allow consumers
products, the incidence of injury unintentional acetaminophen overdose. to better identify acetaminophen
appears relatively low. However, based FDA thinks that improved labeling may containing products among the many
on the available evidence and the help prevent events that are catastrophic products currently available on the OTC
seriousness of the risks, FDA believes it to the unintentional victims and their market. First, FDA is proposing that the
is necessary for consumers to be made family members. FDA has determined name be highlighted (e.g., in fluorescent
aware of the possible serious side effects that adding a liver warning is necessary or color contrast to other information on
associated with using these products. for safe and effective use of the drug and the PDP) or in bold type so that the
For many people, the risks are quite low to reduce the number of unintentional name is prominent and stands out from
because they use these products only overdoses. Thus, FDA is proposing a other text. Second, FDA is proposing
occasionally. The risks may be greater ‘‘liver warning’’ stating use factors that that the name have a size that is
for people who use these products more could lead to liver injury. prominent compared to other printed
frequently, have certain risk factors, FDA notes that NDAC recommended matter on the PDP. FDA’s regulation for
and/or do not follow the labeling both an alcohol warning and a liver the statement of identity for OTC drug
information on the package. FDA toxicity statement separate from the products in § 201.61(c) (21 CFR
believes that providing additional alcohol warning for OTC drug products 201.61(c)) states that ‘‘the statement of
labeling information about how to containing acetaminophen. FDA has identity shall be presented in bold face
mstockstill on PROD1PC61 with PROPOSALS
correctly use OTC drug products combined this information because it is type on the PDP, shall be in a size
containing acetaminophen and NSAIDs interrelated and a shorter warning saves reasonably related to the most
could reduce injuries and is necessary label space on products that already prominent printed matter on such panel
for the products to be considered contain extensive labeling information. ***.’’ FDA is proposing that
generally recognized as safe and FDA believes that two, separate manufacturers determine the
effective and not misbranded. warnings may be less likely to be read prominence of the name
FDA plans to act on several fronts: and understood by consumers. ‘‘acetaminophen’’ on the PDP by
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77332 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
selecting, from the two options that or older, who have had stomach ulcers acute reduction in renal blood flow and
follow, the print size option that is or bleeding problems, or who use glomerular filtration, leading to renal
greater: corticosteroids or anticoagulants (Refs. insufficiency. These cases are often
• The name ‘‘acetaminophen’’ is at 10 and 55). Based on these studies, FDA reversible. Although the
least one-quarter as large as the size of believes that people 60 years of age and epidemiological data are limited and the
the most prominent printed matter on older are at increased risk and is number of reported cases are rare
the PDP; or proposing to include this age group in relative to their use, FDA believes it is
• The name ‘‘acetaminophen’’ is at the warning. important to alert consumers about
least as large as the size of the ‘‘Drug In September 1993, NDAC concluded underlying conditions that may increase
Facts’’ title, as required in § 201.66(d)(2) that the use of aspirin, ibuprofen, and their risk if they take an NSAID without
(21 CFR 201.66(d)(2)). naproxen sodium increases the risk of first asking a doctor because of potential
Finally, FDA notes that NDAC UGIB in people who are heavy alcohol serious side effects.
expressed concern about the lack of users or abusers. At the September 2002 NDAC agreed with the OTC labeling
standardized pediatric dosage meeting, during discussion of the proposed for ibuprofen in the Federal
information, especially for infants under relative risks for GI bleeding associated Register of August 21, 2002, including
2 years of age. FDA intends to address with the use of OTC NSAIDs, some the warning to ask a doctor before use
this issue in another Federal Register NDAC members questioned whether the in the presence of high blood pressure,
publication. incidence of GI bleeding is increased by heart or kidney disease, concomitant
the concurrent use of NSAIDs and use of a diuretic, or if they are over 65
B. Aspirin and Other NSAIDs alcohol. NDAC members were divided years of age. Based upon a further
1. GI Bleeding almost equally. Some members thought review of the literature that indicates
that there was no clear evidence that that the risk is higher for people age 60
FDA tentatively concludes that alcohol potentiates the risk of bleeding or older, FDA is proposing to lower the
epidemiological data indicate a dose- in NSAID or aspirin users. They age from 65 years of age to 60 years of
related risk for GI bleeding with proposed removal of the existing age.
NSAIDs. The data demonstrate a slight alcohol warning. Other NDAC members Children’s NSAID products marketed
increase in risk for GI bleeding at OTC suggested that the alcohol warning under an NDA already have warnings
daily doses. Because many people use should remain in effect, but be regarding dehydration and fluid loss.
OTC NSAIDs intermittently, the risk for separated from the GI bleeding warning. FDA tentatively concludes that similar
bleeding for the average person is quite Subsequently, FDA considered language is needed for children’s
low. People who use NSAIDs for several NDAC’s recommendations and NSAIDs products marketed under the
days may be at greater risk but it is still evaluated the alcohol warning for OTC OTC drug monograph. There are,
low compared to chronic NSAID users. drug products containing an NSAID. however, few case reports suggesting a
People who have certain identifiable FDA did a new literature search, problem in adults. FDA is seeking
risk factors (e.g., stomach ulcers or selecting new articles describing the comment on the need for similar
bleeding problems, taking certain other relationship between alcohol use and language for adults. Although there are
drugs or alcohol concurrently) are at the risk of GI bleeding in OTC IAAA few reported cases in adults, it is
greater risk of GI bleeding when they users. After reviewing these articles anticipated that prostaglandin has
take a product containing an NSAID. (Ref. 71), FDA finds that these studies, similar effects on renal physiology.
FDA believes that additional warnings despite some flaws in their design and
alerting these people about these 3. Other Labeling
methodology, suggest that combining
potential risks and some of the NSAIDs with alcohol increases the risks FDA agrees with NDAC that the term
symptoms associated with GI bleeding of a GI bleed. FDA has determined that ‘‘NSAID’’ should be prominently
could reduce morbidity from using it is necessary to retain a warning displayed in OTC drug product labeling
these OTC NSAID drug products. regarding use of OTC NSAID drug so consumers are aware of the presence
Based on the NDAC’s products with alcohol. FDA tentatively of the ingredient in the product. The
recommendations and the agency’s concludes that a warning about this risk term should also be defined in the
review of the literature, FDA has should be incorporated in a ‘‘Stomach labeling as ‘‘nonsteroidal anti-
determined that additional new warning bleeding warning’’, in place of the inflammatory drug.’’ FDA tentatively
labeling is needed to continue to current alcohol warning. Although concludes that the presence of an
consider OTC NSAID products generally NDAC recommended that a GI bleeding ‘‘NSAID’’ ingredient in an OTC drug
recognized as safe and effective. Such warning be distinct from a warning product should be prominently stated
warnings should advise people not to against alcohol ingestion with NSAIDs, on the PDP and in the Drug Facts
take more than one product containing FDA is proposing to combine these two labeling.
NSAIDs (aspirin, ibuprofen, naproxen, warnings to conserve labeling space and In section V.A.2 of this document,
or others) and not to take more drug or avoid redundancy. FDA discusses its proposed
take the drug for a longer time than requirements for the name
recommended in product labeling. 2. Renal Effects ‘‘acetaminophen’’ to be prominently
NDAC also acknowledged that people FDA tentatively concludes that people presented on the PDP. FDA considers
age 65 and older are at increased risk for who get acute renal insufficiency from the same degree of prominence
GI bleed. using NSAIDs generally have a pre- necessary to identify the presence of an
FDA subsequently reviewed the existing condition that will predispose ‘‘NSAID’’ ingredient in an OTC IAAA
mstockstill on PROD1PC61 with PROPOSALS
results of several large-scale clinical them to this insufficiency. There is a drug product. Accordingly, FDA is
studies, conducted in the United States pharmacological basis for this to occur. proposing that the name of the NSAID
and worldwide, and has established that Normal renal blood flow depends on ingredient and the word ‘‘(NSAID)’’ be
use of NSAIDs is an important risk prostaglandin metabolism. NSAIDs highlighted (e.g., fluorescent or color
factor for serious GI adverse events, inhibit renal prostaglandin production. contrast) or in bold type, be in lines
especially bleeding. These studies show In predisposed people, suppression of generally parallel to the base on which
that the risk is higher for people age 60 prostaglandin production may result in the package rests as it is designed to be
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77333
displayed, and be in one of the • The presence of acetaminophen in 3. For Acetaminophen Products Labeled
following sizes, whichever is greater: (1) the product must be prominently stated Only for Children Under 12 Years of
At least one-quarter as large as the size on the PDP. The word ‘‘acetaminophen’’ Age
of the most prominent printed matter on must appear highlighted (e.g., Under proposed § 201.325(a)(1)(iv),
the PDP, or (2) at least as large as the fluorescent or color contrast) or in bold the labeling would be required to
size of the ‘‘Drug Facts’’ title, as type, be in lines generally parallel to the include the following statement:
required in § 201.66(d)(2). In the Drug base on which the package rests as it is Liver warning: This product contains
Facts labeling, FDA is proposing that designed to be displayed, and be in one acetaminophen. Severe liver damage
the active ingredient(s) section, as of the following sizes, whichever is may occur if the child takes
defined in § 201.66(c)(2), be required to greater: (1) At least one-quarter as large • more than 5 doses in 24 hours
contain the term ‘‘(NSAID)’’ after the as the size of the most prominent • with other drugs containing
NSAID active ingredient with an printed matter on the PDP, or (2) at least acetaminophen.
asterisk statement at the end of the as large as the size of the ‘‘Drug Facts’’ This ‘‘Liver warning’’ must be the first
active ingredient(s) section that defines title, as required in § 201.66(d)(2). warning under the ‘‘Warnings’’ heading.
the term ‘‘NSAID’’ as a ‘‘ * nonsteroidal • The presence of acetaminophen The labeling would also be required
anti-inflammatory drug.’’ must appear as part of the established
In addition, FDA has conducted a to include the statements ‘‘Do not use
name of the drug, as defined in § 299.4 with any other drug containing
detailed review of available data (21 CFR 299.4).
regarding the potential risks of serious acetaminophen (prescription or
cardiovascular events in patients • Combination products containing nonprescription). Ask a doctor or
receiving COX–2 selective and non- acetaminophen and a non-analgesic pharmacist before using with other
selective NSAIDs. FDA also held a joint ingredient(s) (e.g., cough-cold) must drugs if you are not sure’’ and ‘‘Ask a
meeting of its Arthritis and Drug Safety include the name ‘‘acetaminophen’’ and doctor before use if the child has liver
and Risk Management on February 16– the names of the other active ingredients disease.’’
18, 2005, to consider these issues. FDA in the product on the PDP. Only the FDA is aware that products labeled
is currently considering whether name ‘‘acetaminophen’’ must appear for children only are sometimes used by
additional labeling changes related to highlighted (e.g., fluorescent or color adults who cannot take solid oral dosage
these risks are warranted, and will contrast) or in bold type, and be in one forms or who are taking a product
address this in a future issue of the of the following sizes, whichever is marketed in children’s strengths.
Federal Register. greater: (1) At least one-quarter as large Accordingly, FDA is proposing to
as the size of the most prominent include the statement ‘‘this product
VI. FDA’s Proposal printed matter on the PDP, or (2) at least does not contain directions or warnings
Based on the available evidence, FDA as large as the size of the ‘‘Drug Facts’’ for adult use’’ in bold type in the
is proposing to amend its regulations title, as required in § 201.66(d)(2). labeling of these products under the
and the OTC IAAA TFM to make a 2. For Acetaminophen Products Labeled heading ‘‘Directions’’.
number of changes. FDA is proposing for Adults Only 4. For Acetaminophen Products Labeled
new labeling for OTC IAAA drug
for Adults and Children Under 12 Years
products (proposed § 201.325). This Under proposed § 201.325(a)(1)(iii),
of Age
labeling includes a number of important the labeling would be required to
new warnings. To alert consumers to include the following statement: Under proposed § 201.325(a)(1)(v), the
these new warnings, FDA is proposing Liver warning: This product contains labeling would be required to include
to require that the statement ‘‘See new acetaminophen. Severe liver damage all of the warnings for adults with the
warnings information’’ appear on the may occur if you take following modifications:
PDP of all OTC IAAA drug products for • more than (insert maximum number Liver warning: This product contains
a limited time after the effective date of of daily dosage units) in 24 hours acetaminophen. Severe liver damage
a final rule based on this proposal may occur if
• with other drugs containing
(proposed § 201.325(b)). • adult takes more than [insert
The labeling statements in this acetaminophen
maximum number of daily dosage units]
proposed rule are in the OTC Drug Facts • 3 or more alcoholic drinks every in 24 hours
labeling format (see § 201.66), which is day while using this product. • child takes more than 5 doses in 24
being implemented for all OTC drug This ‘‘Liver warning’’ would be the hours
products. For ease of reading, the first warning under the ‘‘Warnings’’ • taken with other drugs containing
following descriptions of the proposed heading. For products that contain both acetaminophen.
labeling statements do not include the acetaminophen and aspirin, the ‘‘Liver • adult has 3 or more alcoholic drinks
bracketed formatting instructions warning’’ would appear after the every day while using this product.
included in the codified portion of this ‘‘Reye’s syndrome’’ and ‘‘Allergy alert’’ This ‘‘Liver warning’’ must be the first
document. warnings in § 201.66(c)(5)(ii)(A) and warning under the ‘‘Warnings’’ heading.
(c)(5)(ii)(B) and before the NSAID FDA is proposing to use the term ‘‘the
A. Alcohol Warning ‘‘Stomach bleeding warning’’ in user’’ instead of ‘‘you or the child’’ for
FDA is proposing to remove § 201.322 proposed § 201.325(a)(2)(iii)(A). warnings applying to both children and
of the regulations entitled ‘‘Over-the- The labeling would also be required adults. The ‘‘ask a doctor’’ statement is
counter drug products containing to include the statements ‘‘Do not use modified to read: ‘‘Ask a doctor before
internal analgesic/antipyretic active
mstockstill on PROD1PC61 with PROPOSALS
with any other drug containing use if the user has liver disease.’’
ingredients required alcohol warning.’’ acetaminophen (prescription or
nonprescription). Ask a doctor or C. Aspirin and Other NSAIDs
B. Acetaminophen
pharmacist before using with other The NSAID category includes, but is
1. For All Acetaminophen Products drugs if you are not sure’’ and ‘‘Ask a not limited to, aspirin, carbaspirin
Proposed § 201.325(a)(1)(i) includes doctor before use if you have liver calcium, choline salicylate, ibuprofen,
the following provisions: disease.’’ ketoprofen, magnesium salicylate,
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77334 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
naproxen sodium, and sodium 2. For NSAID Products Labeled for inflammatory drug (NSAID), which may
salicylate. In the Federal Register of Adults Only cause stomach bleeding. The chance is
August 21, 2002 (67 FR 54139 at 54159), Warnings for NSAIDS are proposed in higher if the child:
FDA proposed a number of warnings for • has had stomach ulcers or bleeding
§ 201.325(a)(2)(iii). Some of the
products containing ibuprofen if added problems
proposed warning statements are
to the OTC IAAA drug products • takes a blood thinning
discussed here.
monograph. FDA is adding information (anticoagulant) or steroid drug
Stomach bleeding warning: This • takes other drugs containing an
and further revising portions of some of product contains a nonsteroidal anti-
those warnings in this document and NSAID (aspirin, ibuprofen, naproxen, or
inflammatory drug (NSAID), which may others)
proposing these warnings be applicable cause stomach bleeding. The chance is
to all OTC NSAIDs. • takes more or for a longer time than
higher if you: directed.
1. For All Products Containing NSAIDs • are age 60 or older The ‘‘Stomach bleeding warning’’
• have had stomach ulcers or would appear after the ‘‘Reye’s
Proposed § 201.325(a)(2)(i) includes bleeding problems syndrome’’ and ‘‘Allergy alert’’
the following provisions: • take a blood thinning warnings in § 201.66(c)(5)(ii)(A) and
• The presence of an NSAID (anticoagulant) or steroid drug (c)(5)(ii)(B).
ingredient in the product must be • take other drugs containing an The labeling would be required to
prominently stated on the PDP. The NSAID (aspirin, ibuprofen, naproxen, or include the following statement:
name of the NSAID ingredient and the others) Ask a doctor before use if the child
word ‘‘(NSAID)’’ must appear • have 3 or more alcoholic drinks has
highlighted (e.g., fluorescent or color every day while using this product • stomach problems that last or come
contrast) or in bold type, be in lines • take more or for a longer time than back, such as heartburn, upset stomach,
generally parallel to the base on which directed. or stomach pain
the package rests as it is designed to be This ‘‘Stomach bleeding warning’’ • ulcers
displayed, and be in one of the would appear after the ‘‘Reye’s • bleeding problems
following sizes, whichever is greater: (1) syndrome’’ and ‘‘Allergy alert’’ • not been drinking fluids
At least one-quarter as large as the size warnings in § 201.66(c)(5)(ii)(A) and • lost a lot of fluid due to vomiting
of the most prominent printed matter on (c)(5)(ii)(B). For products that contain or diarrhea
the PDP, or (2) at least as large as the both acetaminophen and aspirin, the • high blood pressure
size of the ‘‘Drug Facts’’ title, as acetaminophen ‘‘Liver warning’’ would • heart or kidney disease
required in § 201.66(d)(2). appear before the NSAID ‘‘Stomach • taken a diuretic.
bleeding warning.’’ The labeling would be required to
• For single ingredient products, the include the statement:
word ‘‘(NSAID)’’ must appear as part of The labeling would be required to
include the following statement: Ask a doctor or pharmacist before use
the established name of the drug, as if the child is
defined in § 299.4 of this chapter, or as Ask a doctor before use if you have
• stomach problems that last or come • taking any other drug containing an
part of the statement of identity of the NSAID (prescription or
drug, as defined in § 201.61 of this back, such as heartburn,
nonprescription)
upset stomach, or stomach pain
chapter. For example, either of the • taking a blood thinning
following would be acceptable: • ulcers
(anticoagulant) or steroid drug
• bleeding problems The labeling would also be required
• Ibuprofen Tablets (NSAID) • high blood pressure to include the statement:
Pain reliever/ fever reducer • heart or kidney disease Stop use and ask a doctor if
or • taken a diuretic • the child feels faint, vomits blood,
• Ibuprofen Tablets • reached age 60 or older. or has bloody or black stools. These
The labeling would be required to are signs of stomach bleeding.
Pain reliever/ fever reducer (NSAID) include the statement: • stomach pain or upset gets worse or
• Combination products containing Ask a doctor or pharmacist before use lasts
an NSAID and a non-analgesic if you are FDA is aware that products labeled
ingredient(s) (e.g., cough-cold) must • taking any other drug containing an only for children are sometimes used by
include the name of the NSAID NSAID (prescription or nonprescription) adults who cannot take solid oral dosage
ingredient and the names of the other • taking a blood thinning forms or who are taking a product
active ingredients in the product on the (anticoagulant) or steroid drug marketed in children’s strengths.
PDP. The word ‘‘(NSAID)’’ must appear The labeling would be required to Accordingly, FDA is proposing to
after either the name of the NSAID include the statement: include the statement ‘‘this product
ingredient or the general Stop use and ask a doctor if does not contain directions or warnings
pharmacological (principal intended) • you feel faint, vomit blood, or have for adult use’’ in bold type in the
action of the NSAID ingredient (see bloody or black stools. These are signs labeling of these products under the
previous examples). Only the name of of stomach bleeding. heading ‘‘Directions’’.
the NSAID ingredient and the word • stomach pain or upset gets worse or
‘‘(NSAID)’’ must appear highlighted lasts 4. For NSAID Products Labeled for
(e.g., fluorescent or color contrast) or in Adults and Children Under 12 Years of
3. For NSAID Products Labeled Only for Age
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bold type, and be in one of the following
sizes, whichever is greater: (1) At least Children Under 12 Years of Age
Under proposed § 201.325(a)(2)(v), the
one-quarter as large as the size of the Under proposed § 201.325(a)(2)(iv), labeling would be required to include
most prominent printed matter on the the labeling would be required to all of the warnings for adults with the
PDP, or (2) at least as large as the size include the following statement: following modifications:
of the ‘‘Drug Facts’’ title, as required in Stomach bleeding warning: This Stomach bleeding warning: This
§ 201.66(d)(2). product contains a nonsteroidal anti- product contains a nonsteroidal anti-
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77335
inflammatory drug (NSAID), which may D. Requirements to Supplement effective than a single 650-mg dose. One
cause stomach bleeding. The chance is Approved Applications of the other studies failed to
higher if the user: Holders of approved applications for demonstrate a dose response between
• has had stomach ulcers or bleeding OTC IAAA drug products who the two doses, and the last study failed
problems voluntarily implement the proposed to show separation of the active
• takes a blood thinning labeling changes in proposed treatments from placebo. The overall
(anticoagulant) or steroid drug § 201.325(a) would be required to safety profile for the 1,000-mg dose was
• takes other drugs containing an submit supplements under § 314.70(c) similar to the 650-mg dose, with the
NSAID (aspirin, ibuprofen, naproxen, or (21 CFR 314.70(c)), but could exception of a higher incidence of
others) implement the proposed labeling dizziness. In 1975, FDA approved a 500-
• takes more or for a longer time than without advance approval from FDA, mg immediate-release tablet. Data from
directed provided the labeling includes the two crossover bioequivalence studies
• is age 60 or older information in proposed § 201.325(a). comparing two 500-mg capsules to two
• has 3 or more alcoholic drinks 500-mg tablets demonstrated the
See section IX of this document on
everyday while using this product. bioequivalence of the two formulations
voluntary implementation.
The ‘‘Stomach bleeding warning’’ (Ref. 3).
would appear after the ‘‘Reye’s E. Regulatory Action The IAAA Panel further evaluated
syndrome’’ and ‘‘Allergy alert’’ Proposed § 201.325(c) sets out the acetaminophen and recommended in its
warnings in § 201.66(c)(5)(ii)(A) and implementation dates for the proposed 1977 report (42 FR 35346) that
(c)(5)(ii)(B). labeling changes after publication of any acetaminophen be generally recognized
FDA is proposing to use the term ‘‘the final rule based on this proposal. See as safe and effective. The IAAA Panel’s
user’’ instead of ‘‘you or the child’’ for section VIII.B of this document on evaluation of effectiveness was based on
warnings applying to both children and marketing conditions. data from a number of controlled and
adults in the above and following uncontrolled studies of the effectiveness
F. Conforming Changes to the OTC of a variety of acetaminophen doses, i.e.,
modified statements.
IAAA TFM 300, 325, 330, 500, 600, 1,000, and 1,200
The labeling would be required to
include the following statement: This proposed rule includes changes mg (42 FR 35346 at 35412). However,
to the OTC IAAA TFM in proposed the IAAA Panel’s evaluation did not
Ask a doctor before use if the user has
include an assessment of the relative
• stomach problems that last or come § 343.50. Proposed § 343.50(c)(1)(i),
(c)(1)(iii), (c)(1)(iv)(A), (c)(1)(v)(A), effectiveness of each of the dosage
back, such as heartburn, upset stomach,
(c)(1)(v)(B), (c)(1)(v)(C), (c)(1)(ix)(A), strengths. The Panel determined the
or stomach pain
maximum daily safe dosage to be not
• ulcers (c)(1)(ix)(B), (c)(1)(ix)(C), (c)(1)(ix)(E),
(c)(2)(i), (c)(2)(iii), (c)(2)(iv)(A), greater than 4 g in a 24-hour period.
• bleeding problems Upon publication of that document,
• high blood pressure (c)(2)(v)(A), (c)(2)(v)(B) and (c)(2)(v)(C)
(as proposed in 53 FR 46204 and 67 FR FDA permitted OTC marketing without
• heart or kidney disease an NDA provided the product was
• taken a diuretic 54139) would be amended and new
paragraphs (b)(4)(i)(c) and (c)(3)(i) consistent with the IAAA Panel’s
• not been drinking fluids recommended labeling. FDA’s 1988
• lost a lot of fluid due to vomiting through (c)(3)(v)(C) would be added to
either include references to proposed TFM for OTC IAAA drug products
or diarrhea proposed to include acetaminophen as a
• reached age 60 or older § 201.325 and/or additional language to
conform to that section. monograph ingredient (53 FR 46204 at
The labeling would be required to 46255). FDA revised the IAAA Panel’s
include the statement: VII. Additional Issues for Consideration recommended dosing regimens but
Ask a doctor or pharmacist before use maintained the maximum limit of 4 g in
if the user is A. Safe and Effective Daily
a 24-hour period.
• taking any other drug containing an Acetaminophen Dose To determine the maximum daily safe
NSAID (prescription or nonprescription) In 1960, FDA first approved (under dosage (4 g of acetaminophen in a 24-
• taking a blood thinning the NDA process) a 325-mg immediate- hour period), the Panel reviewed
(anticoagulant) or steroid drug release acetaminophen tablet numerous references that describe cases
The labeling would also be required formulation for OTC marketing in the of serious liver damage associated with
to include the statement: United States. The recommended dose excessive use of acetaminophen (42 FR
Stop use and ask a doctor if was one to two tablets every 4 to 6 35346 at 35413). Most of these cases
• the user feels faint, vomits blood, or hours, with a maximum daily dose of were associated with single dose oral
has bloody or black stools. These are 3,900 mg in a 24-hour period (Ref. 3). ingestions of greater than 15 g of
signs of stomach bleeding. In 1973, FDA approved (under the acetaminophen. Based on this
• stomach pain or upset gets worse or NDA process) a 500-mg immediate- information, the Panel concluded that a
lasts. release acetaminophen capsule single dose less than 15 g is not usually
formulation for OTC marketing in the associated with serious liver injury. The
5. Active Ingredients United States. The sponsor’s rationale Panel also noted that 15 g is 23 times
Under proposed § 201.325(a)(2)(v), the for this product was that the higher the usual recommended dose of 650 mg
active ingredient(s) section of the strength would have greater analgesic and approximately 4 times the
product’s labeling, as defined in efficacy. Four double-blind, placebo- maximum recommended daily dose of 4
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§ 201.66(c)(2), would be required to controlled, post partum pain studies g. In estimating the safety margin, the
contain the term ‘‘(NSAID)*’’ after the evaluated the effectiveness of a single Panel decided the comparison with the
NSAID active ingredient with an dose of two 500-mg capsules (1,000 mg) single dose (650 mg) was probably more
asterisk statement at the end of the to a single dose of two 325-mg tablets appropriate than the comparison with
active ingredient(s) section that defines (650 mg) in 338 subjects. Two of the the daily therapeutic dose (4 g). The
the term ‘‘NSAID’’ as a ‘‘* nonsteroidal studies demonstrated that a single current information on unintentional
anti-inflammatory drug.’’ 1,000-mg dose was significantly more overdose suggests that the margin of
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77336 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
safety may be less than originally was unable to recommend a reduced enabled a better evaluation of chronic
determined. The data on liver failure maximum daily acetaminophen dose for alcohol use and underlying alcohol-
presented by Dr. Lee at the September alcohol abusers, because of a lack of induced liver abnormalities. Subjects
2002 NDAC meeting and the adverse specific data. with AST and ALT higher than 120 IU/
event reports in the FDA AERS data One drug manufacturer issued a ‘‘Dear L were excluded from the study, so no
suggest daily doses less than 10 g, Doctor’’ letter to inform health evaluation of subjects with underlying
ingested on consecutive days, presents a professionals about the September 2002 liver damage evidenced by slight
risk for liver injury in some individuals. NDAC meeting (Ref. 72). The letter elevations of liver function tests could
FDA invites comment on whether stated: ‘‘The NDAC proceedings may be assessed. Such subjects may respond
there are subpopulations of individuals generate media interest and, as a result, differently than those with more
who are more susceptible to developing people may contact you with questions substantial hepatic impairment. Other
liver injury when taking about OTC pain relievers such as investigators have similarly criticized
acetaminophen. The dosing information acetaminophen.’’ The letter summarized the studies (Refs. 76 and 77). Assessing
included in the AERS cases of the existing data that support the safety the change in liver function tests after
hepatotoxicity reported for of acetaminophen, including the drug administration may not adequately
acetaminophen suggest that the median statement: ‘‘Prospective data indicate support a conclusion that the drug is
daily dose is in the 5- to 6-g range. FDA that chronic alcoholics can take without risk of liver injury in this
recognizes, however, that dosing recommended doses of acetaminophen population. If subpopulations of chronic
information in the AERS reports is up to 4,000 mg/day without risk of liver alcoholics are sensitive to lower doses
sometimes inaccurate and is difficult to injury.’’ The letter cited two references of acetaminophen, this type of study
validate. The information in the AERS from the medical literature to support would be inadequate to make any
cases of hepatotoxicity is adequate to the statement (Refs. 73 and 74). The assessment of risk.
raise concerns that there may be letter continued: ‘‘Acetaminophen can FDA also finds that a 2-day treatment
subpopulations at risk for developing be used safely, at recommended doses, period may be too short to deplete the
hepatotoxicity with doses lower than by the occasional moderate consumer of lowered hepatic gluthianone capacity in
the currently labeled maximum daily alcohol.’’ alcoholic people. The 2-day regimen
dose of 4 g. If such subpopulations can FDA has reviewed the two references
cannot be extrapolated into the
be identified, the maximum daily dose (studies of hepatotoxicity of the
recommended 10-day dosing regimen in
of 4 g may no longer be considered safe therapeutic dose of acetaminophen in
OTC drug product labeling. One
for those individuals and should be people with alcohol abuse, conducted
individual agreed, stating that the
lowered. If the at risk subpopulations by the same investigators). One (Ref. 73)
investigators gave no rationale for
cannot be identified, or addressed is a full study report of 201 people (102
on acetaminophen and 99 on placebo). dosing acetaminophen for only 2
through appropriate labeling, and cases
The other (Ref. 75) was an abstract consecutive days while the drug is
of liver injury continue to be reported,
describing a pilot trial with 60 people approved for 4 g/day for 10 consecutive
FDA may reconsider whether the
(30 each on acetaminophen and days and commonly used for prolonged
labeled maximum daily dose is still
placebo). A full report of this study is periods of time (Ref. 78). Further, the
generally recognized as safe and
not available (Ref. 75). individual stated that the lack of
effective for use in the general
Both studies were randomized, elevation in liver enzyme values after
population.
double-blind, placebo-controlled only 2 days of acetaminophen lends
B. Daily Dose Recommendation for clinical trials conducted in an alcohol little support to the authors’ conclusion
Alcohol Abusers detoxification center to evaluate the regarding its safety in alcoholic people.
Following publication of the IAAA hepatotoxicity of maximum therapeutic FDA’s detailed assessment of these
TFM in 1988, FDA received a comment dosing of acetaminophen in long-term studies is on file in the Division of
recommending that the maximum daily alcoholic subjects. In both studies, the Dockets Management (Ref. 79).
dose of acetaminophen be reduced from subjects were treated with the maximum FDA concludes that these studies do
4 to 2 g per day for alcohol abusers. The therapeutic dose of acetaminophen (1g not provide reliable evidence that
comment did not provide any data to four times a day) for 2 days, followed by people with chronic alcohol use can
support a reduced maximum daily dose. a 2-day observation. The results showed safely take 4 g/day of acetaminophen,
In June 1993, NDAC considered: (1) that acetaminophen treatment did not particularly for up to 10 days in
Identifying a population at risk in terms significantly increase serum ALT, accordance with OTC drug product
of alcohol consumption, e.g., people Aspartate Aminotransferase (AST), and labeling. Based on the data presented by
who rarely drink, social drinkers, or International Normalized Ratio (INR), as Dr. Lee on liver failure, the experience
alcohol abusers, (2) whether the data are compared to the placebo control. The in the University of Pennsylvania
sufficient to support a reduced authors concluded that there was no Hospital series, and data from the AERS
maximum daily dose for alcohol evidence that the daily maximum database, FDA believes that alcohol
abusers, and (3) if yes, what the reduced therapeutic dose of acetaminophen users are a significant percentage of
maximum daily dose should be. NDAC caused liver injury in alcoholics. persons who develop severe liver injury.
found the data insufficient and was However, FDA finds the data Acetaminophen products already have
unable to recommend a reduced insufficient to support this conclusion. an alcohol warning to alert consumers
maximum daily acetaminophen dose for Neither study included an assessment of the risk for developing
alcohol abusers. of the quantity, frequency, and duration hepatotoxicity. It is important to
mstockstill on PROD1PC61 with PROPOSALS
At the September 19, 2002, NDAC of alcohol use by the subjects. Alcoholic determine whether the labeling should
meeting, FDA described cases of detoxification history and information include a lower daily dose for chronic
hepatotoxicity involving the use of on alcohol-related disorders, including alcohol users. At this time, FDA is
prescription combination (narcotic/ more specific hepatic evaluations (such seeking both comments and data to
acetaminophen) products (Refs. 6 and as hepatic CYP2E1 p450 enzyme levels, support a specific dosage for
7). Many of these cases involved people glutathione levels, or biopsy), were not acetaminophen as safe and effective in
with a history of alcohol abuse. NDAC reported. That information would have people who consume alcohol.
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77337
C. Combinations With Methionine or methionine would prevent or reduce impaired survival in persons with HIV
Acetylcysteine acetaminophen-induced liver toxicity. disease, and (5) the effect of NAC
FDA is currently evaluating different FDA seeks comments and data on this replacement therapy on clinical
safety measures to reduce the relative issue. outcomes in persons with HIV disease.
A comment (Ref. 88) disagreed with
risks for hepatotoxicity associated with D. Package Size and Configuration the petitioner’s assertions for the
the use of acetaminophen. Limitations following reasons:
Theoretically, one method might be to At the September 19, 2002, NDAC • The available data do not
administer acetaminophen and N- meeting, a representative from a demonstrate that acetaminophen
acetylcysteine (NAC) together. NAC is a national consumer organization reduces total body or circulating GSH
chemical produced by the body that reported that the UK implemented when taken as recommended.
enhances the production of the enzyme package size restrictions on • There currently are no studies that
glutathione. A small portion of acetaminophen. He noted that an early demonstrate that acetaminophen has
acetaminophen undergoes cytochrome assessment of the effect of the package any impact on the survival of HIV
P450-mediated N-hydroxylation to form size restrictions in the UK shows patients.
N-acetyl-p-benzoquinoneimine (NAPQI, decreases in total and severe • The depletion of hepatic GSH that
a toxic metabolite of acetaminophen). acetaminophen overdoses, as well as occurs after acetaminophen overdose is
Liver toxicity from acetaminophen decreases in acetaminophen related not related to plasma GSH levels.
overdose depends in part on production toxicity leading to liver transplant or • The source of plasma GSH in
of NAPQ to levels that exceed the ability death. The representative did not humans is not clearly defined.
of the normal hepatic detoxification provide any data to support his FDA finds that although data from in
pathway to eliminate NAPQ. comments. FDA seeks comments on vitro and in vivo studies (Refs. 89
Glutathione is produced predominantly package size and package configuration through 96) have documented low
in the liver and is an important limitations as a mechanism to increase levels of GSH and its precursors in HIV
detoxifier of NAPQ. In the event of safe use of acetaminophen products by infection, the effect of this deficiency on
acetaminophen overdose in people with reducing overdose. Comments should survival has not been clearly
enhanced activity of CYP 2E1 address the possible impact of such established. Data from in vitro studies
(alcoholics, or people using measures on unintentional and (Refs. 97 through 100) have
anticonvulsants), glutathione liver intentional overdose. demonstrated improvement in healthy
stores are depleted. One substrate for and HIV-infected T-cell functioning post
glutathione synthesis is cysteine. NAC E. Label Warning for Individuals With exposure to NAC. However, these
protects against liver damage in early Human Immunodeficiency Virus (HIV) findings have not been correlated with
acetaminophen poisoning by production A citizen petition (Refs. 86 and 87) survival from in vivo studies. While
of cysteine, a glutathione precursor. The requested that FDA consider the need some studies of the effects of NAC
administration of precursors of cysteine, for a warning about the increased risk of administration in HIV-infected
such as NAC or methionine, may liver injury from the use of individuals (Refs. 89, 90, and 101
prevent depletion of glutathione and, acetaminophen by individuals infected through 104) have demonstrated an
thus, liver injury (Refs. 80 and 81). with HIV. The request is based on the increase in GSH, the majority of studies
Scientific data supports the efficacy of following reasoning: were not designed to assess survival.
treating acute acetaminophen overdose • Glutathione (GSH) deficiency is Herzenberg, et al. (Ref. 102) discussed
with early administration of NAC (Refs. frequent in HIV-infected individuals. results from several studies in HIV-
82 through 85). To determine whether • Acetaminophen depletes GSH infected patients that evaluated the
there is any usage data of (essential for the detoxification of relationship between GSH levels and
acetaminophen with NAC or acetaminophen’s toxic metabolite) and survival, the administration of NAC in
methionine for the purposes of is potentially more toxic to GSH- patients with low GSH levels in whole
prevention of liver toxicity, FDA deficient individuals. blood and in CD4 T cells, and the effect
examined the literature from 1975 to • GSH deficiency is associated with of NAC on survival in patients with low
December 2002. FDA did not find any impaired survival in persons with HIV GSH levels in CD4 T cells. The
articles that specifically addressed disease, and acetaminophen may further presentation of data in the report made
whether either combination (when used reduce survival by depleting GSH. it difficult to understand the study
at the therapeutic dose level) would In support of this request, the design details. Other problems based on
prevent liver toxicity. petitioner (Ref. 86) provided published the information presented included:
The UK is the only country where a studies of: (1) GSH and cysteine levels Survival data was not collected in a
combination product containing in plasma, peripheral blood monocytes significant proportion of the population
acetaminophen and methionine is and lymphocytes, and in the pleural (17 percent), baseline characteristics of
available. The marketed product fluid of HIV-positive individuals, and the individuals in all of the trials were
contains 500 mg acetaminophen and (2) the effects of GSH replacement in not presented, the use of antiviral
100 mg methionine. One published model systems and HIV-infected treatments and other medications before
study summarized the issues related to individuals. A subsequent submission and during the studies was not
combining acetaminophen and (Ref. 87) provided a search of the provided, and NAC administration after
methionine (Ref. 85). The authors worldwide literature that included 8 weeks was not randomized. In their
acknowledge that there are no data studies of: (1) Nonhepatic GSH levels in conclusions, the authors recommend
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available on the relative efficacy or the numerous disease states, (2) the effects that excessive exposure to
prophylactic antidotal dose of of treatment with NAC or other GSH- acetaminophen be avoided in HIV-
methionine for protecting the liver after replenishing drugs in diseases and infected individuals. The report
acetaminophen overdose in humans. conditions in which GSH is decreased, references acetaminophen overdose
At this time, FDA finds insufficient (3) the causes of GSH deficiency in leading to GSH deficiency as a basis to
evidence that combinations of persons with HIV disease, (4) an support their recommendation.
acetaminophen with NAC or association between GSH deficiency and However, it does not provide sufficient
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77338 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
information suggesting that intermittent period of time (several months to years), warfarin interaction occurs has yet to be
or short-term use presents a problem in and used acetaminophen ‘‘regularly’’ clearly identified (Refs. 119 and 120).
HIV patients. FDA concludes that this instead of ‘‘intermittently’’ for The second updated literature review
report does not provide a sufficient approximately 3 to 14 days prior to the (Ref. 127) noted two additional case
basis to restrict that use of discovery of their abnormally prolonged controlled studies generated from
acetaminophen in patients infected with INR or PT. The dosages of patient cohorts followed in
HIV. acetaminophen reportedly ingested by anticoagulation clinics that were
Further, a search of FDA’s AERS these individuals ranged from 1.2 to published in the European literature
database for hepatic adverse events in 4.5g/day. FDA’s epidemiologists (Refs. 123 and 124). Both of these
HIV-infected individuals who took attribute the small number of studies failed to document the existence
acetaminophen failed to identify any postmarketing case reports collected to of a possible drug-drug interaction in
case reports which fit the search underreporting. We believe that the stable anticoagulated people treated
parameters, i.e., acetaminophen, HIV actual number of cases is much higher, with the warfarin analogues
infection, and hepatotoxicity. Thus, based on the numbers of people who are phenprocoumon or acenocoumarol and
there is no clinical evidence of toxicity treated with anticoagulant therapy. using acetaminophen concomitantly.
or decrease survival that can be FDA’s epidemiologists also conducted The data generated from the literature
attributed to the recommended use of two literature searches on this topic. In searches are conflicting. Although many
acetaminophen in HIV-infected the first (Ref. 126), FDA reviewed 11 of the studies controlled for other
individuals since GSH levels were never published articles describing three variables known to potentate warfarin’s
validated to predict survival. anticoagulant effect, it is not known if
double-blind, placebo-controlled,
Given these facts, FDA does not they all also controlled for life style
randomized studies that demonstrated a
consider the current data a sufficient factors such as diet, the use of vitamins
basis for a warning. However, the issues prolongation of warfarin’s anticoagulant
effect when acetaminophen was used and herbal medications, physical
raised by the petition highlight the need activity, concurrent illness, or liver
for additional information or research to concomitantly in a chronic manner
(Refs. 110, 112, and 113). Two status. Extrapolating the clinical
clarify whether acetaminophen poses findings generated from the study by
additional risk for certain population additional published double-blind,
crossover studies showed that people on Fattinger, et al. may not be applicable to
subgroups (e.g., conditions in which real life situations, since this trial was
GSH is reduced). Therefore, FDA invites a stable warfarin dose who were acutely
dosed with acetaminophen did not conducted in people where background
the submission of data and comments life style factors such as diet and
on this issue. experience any changes in their
anticoagulant status (Refs. 111 and 117). physical activity did not come into play
F. Drug Interactions Between A prospective, case-control study due to the controlled study environment
Acetaminophen and Warfarin looked at a cohort of people from an (Ref. 124). The study by van den Bemt,
anticoagulant clinic, each of whom were et al. may have also failed to
The labeling for a currently marketed
noted to have an INR greater than 6 on demonstrate the existence of an adverse
warfarin-containing prescription drug
a routine followup clinic visit. The drug-drug interaction associated with
product lists acetaminophen as a drug
study found that after controlling for the concomitant use of acetaminophen
that can increase warfarin’s
other risk factors associated with with either of the warfarin analogues
anticoagulant effect (Ref. 105). A
reciprocal warning is not currently prolongation of anticoagulant status phenprocoumon or acenocoumarol,
included on the consumer labeling for (i.e., medication use, recent diet, illness, because these drugs may be metabolized
any OTC drug products that contain alcohol consumption, and actual differently than warfarin (Ref. 123). FDA
acetaminophen. To evaluate the need warfarin use), the use of acetaminophen believes that the current available data
for a consumer warning regarding co- was an independent dose-dependent do not demonstrate sufficient evidence
administration of warfarin-containing risk factor for having an INR over 6 (P- to warrant a consumer warning for
drugs with acetaminophen, FDA value for trend <0.001). Other warfarin-acetaminophen interaction.
considered postmarketing adverse event independent variables associated with However, we are seeking comments or
case reports in our AERS database, the development of a prolonged INR data on whether additional labeling
studies published in the worldwide were identified and included: Advanced about this drug-drug interaction is
literature (Refs. 106 through 125), and malignancy (odds ratio [OR], 16.4; 95 warranted at this time.
three consultative reviews (Ref. 126, percent confidence interval [CI], 2.4 to VIII. Legal Authority
127, and 128). 111.0), recent diarrheal illness (OR, 3.5;
In the consultative reviews, FDA 95 percent CI, 1.4 to 8.6), decreased oral A. Statement About Warnings
epidemiologists identified a cumulative intake (OR, 3.6; 95 percent CI, 1.3 to Mandating warnings in an OTC drug
total of 20 (3 probable and 17 possible) 9.7), ingesting a higher dose of warfarin monograph does not require a finding
postmarketing adverse event case than prescribed (OR, 8.1; 95 percent CI, that any or all of the OTC drug products
reports of prolongation of laboratory 2.2 to 30.0), and taking new medications covered by the monograph actually
tests that monitor the ability of the known to interact with warfarin (OR, caused an adverse event, and FDA does
blood to clot. These tests are the INR or 8.5; 95 percent CI, 2.9 to 24.7) (Ref. 113). not so find. Nor does FDA’s requirement
Prothrombin Time (PT). These reports The validity of this study’s findings was of warnings repudiate the prior OTC
occur in individuals treated chronically subsequently questioned when it was drug monographs and monograph
with warfarin who concomitantly took publicly criticized in the literature for rulemakings under which the affected
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acetaminophen and had minor or severe its flawed methodological design, such drug products have been lawfully
bleeding events. Of note, the only as the overlapping of risk factors in the marketed. Rather, as a consumer
background characteristics that were population studied (i.e., fever and the protection agency, FDA has determined
identifiable in these case reports were use of acetaminophen), and the lack of that warnings are necessary to ensure
that the individuals involved were reported adverse events (Refs. 115, 116, that these OTC drug products continue
generally elderly, had been on stable and 118). Additionally, the mechanism to be safe and effective for their labeled
anticoagulant therapy for a prolonged by which a possible acetaminophen- indications under ordinary conditions
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77339
of use as those terms are defined in the drug products may implement the or more (adjusted annually for inflation)
Federal Food, Drug, and Cosmetic Act proposed labeling without advance FDA in any one year.’’
(the act). This judgment balances the approval provided the labeling includes FDA tentatively concludes that this
benefits of these drug products against the information in proposed § 201.325. proposed rule is consistent with the
their potential risks (see 21 CFR A supplement must be submitted under principles set out in Executive Order
330.10(a)). § 314.70(c) to provide for the 12866 and in these two statutes. This
FDA’s decision to act in this instance implementation of such labeling. The proposed rule is not a significant
need not meet the standard of proof supplement and its mailing cover regulatory action as defined by the
required to prevail in a private tort should be clearly marked: ‘‘Special Executive Order and so is not subject to
action (Glastetter v. Novartis Supplement—Changes Being Effected.’’ review under the Executive Order. As
Pharmaceuticals Corp., 252 F. 3d 986, FDA considers the proposed labeling discussed in this section, FDA has
991 (8th Cir. 2001)). To mandate in this document to be important to the tentatively determined that this
warnings, or take similar regulatory safe use of OTC IAAA drug products proposed rule will not have a significant
action, FDA need not show, nor do we and strongly encourages manufacturers economic impact on a substantial
allege, actual causation. For an of these products to voluntarily number of small entities. Because the
expanded discussion of case law implement the proposed labeling rule does not impose any mandates on
supporting FDA’s authority to require changes before FDA issues a final rule. state, local or tribal governments, or the
such warnings, see the final rule on However, voluntary compliance with private sector that will result in an
‘‘Labeling of Diphenhydramine- the proposed labeling in this document expenditure in any one year of $100
Containing Drug Products for Over-the is subject to the possibility that FDA million or more, FDA is not required to
Counter Human Use’’ (67 FR 72555, may revise the wording of some of the perform a cost-benefit analysis
December 6, 2002). proposed statements or changes, or not according to the Unfunded Mandates
require the statement or change, as a Reform Act. The current threshold after
B. Marketing Conditions result of comments filed in response to adjustment for inflation is about $110
This proposal applies to all OTC this proposal. Because FDA wishes to million.
internal analgesic/antipyretic drug encourage the voluntary use of the FDA estimates that manufacturers and
products that contain an ingredient proposed labeling statements and marketers of OTC IAAA drug products
included in proposed § 201.325(a). changes, FDA advises that would incur one-time compliance costs
Upon issuance of a final rule, any new manufacturers will be given 18 months of $32 million in the first year to revise
labeling will apply to any product that after publication of a final rule to use up labeling to conform to the proposed
is initially introduced or initially any labeling implemented in rule. The benefits of this proposed rule
delivered for introduction into interstate conformance with this proposal (see are based on estimated annual
commerce. Such products would be section XV of this document). reductions from 1 to 3 percent in serious
misbranded under section 502 of the act illnesses and related hospital and
X. Analysis of Impacts emergency room costs and in deaths
(21 U.S.C. 352) and would be subject to
regulatory action unless: FDA has examined the impacts of this related to unintentional overdosing. If 1
• Products marketed without an NDA proposed rule under Executive Order to 3 percent of these adverse events are
include the required labeling within 12 12866 and the Regulatory Flexibility Act avoided, the monetized benefits would
months after any final rule that is issued (5 U.S.C. 601–612), and the Unfunded be $6 million to $17 million per year,
based on this proposal. Mandates Reform Act of 1995 (Public respectively. The present value of the
• Products marketed with an NDA Law 104–4). Executive Order 12866 monetized benefits over a 10-year
include the required labeling within 12 directs agencies to assess all costs and period is $41 million to $126 million
months after any final rule that is issued benefits of available regulatory assuming a 7-percent discount rate,1
based on this proposal. The labeling alternatives and, when regulation is and $49 million to $147 million at a 3-
may be put into use without advance necessary, to select regulatory percent discount rate. If we assume only
FDA approval provided it includes the approaches that maximize net benefits a 1 percent reduction in the illnesses
information described in the final rule. (including potential economic, and fatalities analyzed, the benefits of
Manufacturers should submit a environmental, public health and safety, this proposed rule outweigh the costs.
supplement under § 314.70(c). and other advantages; distributive We summarize the impacts in Table 10
If companies voluntarily implement impacts; and equity). Under the of this document.
the labeling in this proposal before a Regulatory Flexibility Act, if a rule may FDA notes that we lack the data
final rule issues, FDA intends to provide have a significant economic impact on needed to confidently predict a percent
those companies 18 months to a substantial number of small entities, reduction in serious cases related to
implement the labeling in the final rule. an agency must analyze regulatory unintentional overdosing. Because of
options that would minimize any the uncertainty in these estimates, we
IX. Voluntary Implementation significant impact of the rule on small estimated an annual average number of
The labeling proposed in this entities. Section 202(a) of the Unfunded adverse events that would need to be
document represents a change from the Mandates Reform Act of 1995 requires avoided over a 10-year period to reach
current labeling required for OTC IAAA that agencies prepare a written a breakeven point. Social benefits would
drug products. Although FDA considers statement, which includes an equal the costs of compliance if the
these proposed labeling changes to be assessment of anticipated costs and proposed rule prevented about 1 fatality
very important, holders of approved benefits, before proposing ‘‘any rule that each year (0.9 and 0.7 fatalities over 10
mstockstill on PROD1PC61 with PROPOSALS
NDAs for OTC IAAA drug products will includes any Federal mandate that may years at a 7-percent and a 3-percent
not be required to implement the result in the expenditure by State, local, discount rate, respectively).
proposed labeling at this time. However, and tribal governments, in the aggregate, Alternatively, if no fatalities are
holders of approved NDAs for these or by the private sector of $100 million avoided, the proposed rule would need
1Per the Office of Management and Budget (OMB)
Circular A4, revised in 2003.
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77340 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
to prevent about 475 hospitalizations discount rate, an average reduction of
per year over the 10-year period at a 7- 410 hospitalizations per year is needed.
percent discount rate. At a 3-percent
TABLE 10.—SUMMARY OF IMPACTS
Benefits: ($ Million)
Monetized 1 and 3-percent reduction in illnesses and mortality, per year $5—$17
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 immediate prescription container may for certain populations. Based on the
In September 2002, FDA’s NDAC not state that the product contains evidence discussed in this document,
recommended changes to the labeling of acetaminophen or state the maximum FDA further finds that NSAIDs increase
OTC IAAA drug products to better daily dose limit. Consumers may often the risk for GI adverse events and that
inform consumers about the active fail to recognize the presence and without a new stomach bleeding
ingredients and possible side effects amount of acetaminophen ingredients in warning in the labeling for aspirin and
caused by improper use. Although FDA OTC and prescription drug products. other NSAIDs the products would no
considers acetaminophen to be safe and This lack of knowledge can result in a longer be considered generally
effective when labeled and used person taking two different products recognized as safe and effective and not
correctly, taking too much can lead to containing acetaminophen misbranded for OTC use.
liver damage and death. Similarly, the simultaneously. Moreover, many
consumers are unaware that exceeding The purpose of this proposed rule is
use of NSAIDs can lead to GI bleeding to amend FDA’s OTC drug labeling
and renal toxicity. The number of cases the recommended dosage for
acetaminophen can lead to regulations and the TFM for OTC IAAA
of injury reported is a very low
unintentional overdosing and cause drug products to include new warnings
percentage of the total use of OTC
potential harm. Based on the evidence and other labeling requirements to
acetaminophen and NSAID drug
products. For many people, the risks are discussed in this document, FDA finds advise consumers of potential risks and
quite low because they use these that there is sufficient incidence of liver when to consult a doctor. FDA is also
products only occasionally. The risks damage associated with acetaminophen proposing to remove the alcohol
may be greater for people who use these to warrant new labeling, and that warning in § 201.322 and incorporate
products more frequently and/or do not without the new labeling, new alcohol-related warnings and other
follow the labeling information on the acetaminophen products would no labeling for all OTC IAAA drug
package. The risk of injury may be longer be considered generally products. FDA is proposing certain
increased for certain populations and recognized as safe and effective and not warning information targeted to age
under certain conditions of use. misbranded for OTC use. specific populations. In addition, FDA
There are multiple reasons for Results of several large-scale clinical is proposing that the presence of
unintentional acetaminophen studies performed in the United States acetaminophen or any NSAID would
overdoses. First, acetaminophen is an and in other countries have established appear prominently on the products’
active ingredient in a wide variety of that the use of NSAIDs is an important PDP. Table 11 presents an overview of
both OTC and prescription drug risk factor for serious GI adverse events, the proposed changes by type of
products. For prescription products, the especially bleeding. The risk is higher 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 phar-
macological (principal intended) action of the NSAID ingredient.
Combination products containing acetaminophen or an Include the name acetaminophen or the name of the NSAID ingredient [highlighted
NSAID and a nonanalgesic ingredient or in bold type, and in a prominent print size] and the names of the other active
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ingredients on the PDP. Products containing an NSAID ingredient must include
the word ‘‘(NSAID)’’ as stated under NSAIDS.
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77341
TABLE 11.—OVERVIEW OF THE PROPOSED LABEL CHANGES BY PRODUCT TYPE—Continued
Type of Product Proposed Change
All IAAA drug products Remove the current alcohol warning in § 201.322, and incorporate new alcohol-re-
lated warnings format. For a specific period of time, add to the PDP the state-
ment ‘‘See new warnings information’’. We are proposing that this statement ap-
pear highlighted in the same way that the name ‘‘acetaminophen’’ or the pres-
ence 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 § 201.66(d)(2).
B. Impact of the Rule quantities) have been granted extensions assumptions and methods for
FDA contracted with Eastern Research on compliance dates, many packaging calculating costs.
Group, Inc. (ERG) to assess the costs and alternatives now exist to assure ERG visited five stores—two major
benefits of this proposed rule. The compliance. chain drug stores and three convenience
following is a summary of ERG’s Manufacturers routinely change labels stores—to collect information on the
analysis; the full report, including at varying intervals and have distribution of types of OTC IAAA drug
details on assumptions, cost standardized procedures in place for product packaging. Roughly 80 percent
calculations, and findings, is on file in complying with FDA requirements. The of OTC IAAA drug products were
the Division of Dockets Management packaged in cartons and 20 percent in
analysis assumes that one-half of the
(Ref. 129). containers. To assess the increase in
manufacturers of OTC IAAA drug
Manufacturers and marketers of OTC label space requirements, ERG
products typically redesign their label
IAAA drug products would incur one- purchased 45 affected products, with an
every 2 years, the remainder every 3 emphasis on smaller packages.
time costs to revise affected product
years, based on consultant input. For
labeling to comply with the proposed 1. Label Area Changes
this analysis, ERG assumed that
labeling changes. We assumed an
implementation period of 12 months for manufacturers whose label redesign ERG collected and recorded
one-time costs for a major labeling cycle is less than the implementation descriptive packaging information on
revision. We estimated one-time costs period will not incur any regulatory the sampled products and measured
for a major labeling revision using a costs. For example, if a company existing font size, labeling area and
pharmaceutical labeling revision cost routinely revises its product labeling labeling text on packages, and the area
model. This labeling model is described annually and is given at least that long needed for replacement text. ERG then
in detail in Appendix A of the ERG to incorporate the required changes, calculated the percentage increase in
report (Ref. 129). ERG judged that the regulatory revision square millimeters (mm2) needed to
To develop the original model, FDA can be made at essentially no cost. accommodate the proposed labeling
and ERG interviewed pharmaceutical The costs of labeling change depend changes. In all cases, ERG determined
representatives from regulatory, legal, on the type of labeling (e.g., carton and that the requirement to add active
manufacturing controls, and labeling container label) and whether there is ingredient names on the PDP, while
departments to collect information on sufficient labeling space to requiring major redesign in some cases,
labeling change cost components, type accommodate the proposed changes. did not impose a change in the size of
of personnel affected, and costs. The There are an estimated 22,500 OTC the PDP or the addition of non-standard
model incorporates data on average IAAA drug product stockkeeping units labeling (such as adding a fifth carton
industry costs by company size, (SKUs), split evenly among branded and panel or peelback label). ERG estimates
including, where applicable, private labels, according to an industry that the increase in existing label area
modifications to packaging consultant.2 FDA assumes branded needed to accommodate the additional
configurations. Industry consultants SKUs are distributed by firm size: 50 proposed label warnings and text ranges
also provided information on model percent small, 17 percent medium, and from 8 percent (acetaminophen) to 32
inputs related to the OTC IAAA 33 percent large. Based on consultant percent (ibuprofen).
industry, the labeling revision process, input, we assumed the distribution of 2. Package size or type changes
the costs of modifying labeling, and the SKUs among OTC IAAA drug products
frequency of packaging reconfiguration ERG measured the available panels
as follows: Acetaminophen, 45 percent;
changes. and white space on the 45 packages
The baseline for this proposed action NSAIDS (except ibuprofen), 38 percent; sampled. If the available white space
is full compliance with the format and ibuprofen, 15 percent; and combinations was greater than the estimated increase
content requirements for OTC drug of IAAAs (i.e., contain acetaminophen in space necessary to accommodate the
product labeling in 21 CFR 201.66. In and aspirin), 2 percent. Cost estimates new label warnings, ERG determined
the final rule that established these are for small, medium, and large the product would not require an
requirements on March 17, 1999 (64 FR branded companies, private label increase in carton or container size.
companies, and by affected product
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13254), FDA accounted for the total Based on this review, ERG assumed that
incremental costs to comply with group. The ERG report presents model all current packaging can accommodate
requirements, including 6.0 font size the required changes in this proposal
2Estimates of affected SKUs are 18,000 (CDER)
and related costs for increased package without altering label sizes, package
and from 20,000 to 25,000 (per industry consultant).
size and longer labeling where This number of SKUs includes products marketed
sizes, or adding non-standard labels.
applicable. FDA notes that although by manufacturers, repackers, relabelers, and Therefore, ERG did not assign costs for
some forms of packaging (for small distributors. adjustments to packaging. Although
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77342 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
finding only a few small foil packs that Table 12 presents the estimated total over the relevant relabeling period is
did not comply with the OTC Drug and annualized costs of compliance $15.2 million at a 7-percent discount
Facts labeling requirements, ERG noted with the OTC IAAA drug product rate. The estimated average annualized
that alternative types of packaging are proposed rule. The total estimated one- cost per SKU is $677 ($15.2 million/
now available to replace the older time costs to revise labeling are $32.6 22,500 SKUs).
packages. million. The estimated annualized cost
TABLE 12.—ESTIMATED TOTAL AND ANNUALIZED COSTS OF COMPLIANCE ($ MILLION)
Product Type
NSAID (except Combinations of
Company Type Acetaminophen Ibuprofen
Ibuprofen) IAAAs
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 0.9 0.3 0.05 2.7
Medium Brand 1.0 0.8 0.3 0.04 2.2
Large Brand 2.8 2.4 0.9 0.1 6.2
Private Label 2.0 1.7 0.7 0.09 4.5
Total 6.9 5.8 2.3 0.3 15.2
C. Impact on Affected Sectors sales under $23 million. Generally, only labeling costs are absorbed by chain
Manufacturers of OTC drug products the largest supermarket and drug store stores and calculate impacts.
are classified in North American chains (263 firms) or superstores (9 To assess the impact on entities in the
Industry Classification System (NAICS) firms) would have their own private pharmaceutical-manufacturing sector
325412, pharmaceutical preparation label. ERG included only those largest (NAICS 325412), ERG adjusted SBA
manufacturing. This classification code retail chains with annual sales of $100 data on firm size and revenues to
includes all manufacturers of million or more as having their own
estimate average receipts per firm for
prescription and OTC pharmaceutical private labels. Thus, FDA believes that
the affected sector. ERG applied
preparations, but does not include there are no small entities in these retail
modeling assumptions to estimate the
relabelers, repackers, and distributors. sectors that are affected. Marketers of
private label OTC drug products are number of large and small affected
The Small Business Administration firms. ERG further assumed the
(SBA) defines a small business in this classified as follows:
NAICS 446110, Pharmacies and drug distribution of all 22,500 affected SKUs
industry classification code as one with is one-third for large firms (producing
fewer than 750 employees. In NAICS stores
NAICS 445110, Supermarkets and either branded or private label products)
325412, over 90 percent are considered
other grocery stores and two-thirds for small firms. To
small entities. The affected industry is
a subset of the OTC pharmaceutical NAICS 452910, Warehouse clubs and estimate the share of total compliance
industry. This proposed rule affects an superstores. costs for each size category, ERG
estimated 258 manufacturers (of which Packaging and labeling services that distributed the SKUs attributed to small
200 are small) of OTC IAAA drug contract with pharmaceutical businesses in the same proportion as
products. manufacturing firms may also be employment. The distribution of SKUs
Manufacturers often package private affected, but we assume manufacturers determines the distribution of
label products, although some chains bear the costs of any labeling changes. compliance costs by employment size
package their own brands. SBA Both the manufacturing and marketing category. Table 13 summarizes the
considers the following to be small: (1) sectors will most likely share costs, but estimated impacts for pharmaceutical
Any pharmacy or drug store with the extent is not known. Therefore, this manufacturers, the total cost per firm
mstockstill on PROD1PC61 with PROPOSALS
annual sales under $6 million, and (2) impact analysis first assumes that based on $677 per SKU, and the
supermarkets and other grocery stores manufacturers absorb all of the labeling compliance costs as a percent of
and warehouses and superstores with costs. We then assume that all private revenues.
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TABLE 13.—ESTIMATED IMPACTS ON PHARMACEUTICAL PREPARATION MANUFACTURING FIRMS BY SIZE (NAICS 325412)
Average Receipts Assumed No. of Total Firm Cost Compliance Cost
Employment Size SKUs per Firm
per Firm ($mil) SKUs ($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%
1Number of SKUs x $677 per SKU.
Source: SBA, 1999 and ERG estimates.
Total estimated compliance costs per considered but rejected the following products. We used a value of $5 million
firm ranged from $6,000 for firms with alternatives: (1) Not adding the new to represent the premature loss of a
fewer than 20 employees to $152,000 for information to OTC IAAA drug product statistical life in previous analyses (see
firms with 500 to 749 employees. The labeling, and (2) a longer 66 FR 6137, January 19, 2001). We
compliance cost as a percent of receipts implementation period. FDA does not quantified the related hospital and
is less than 1 percent for all firms; 0.18 consider either of these approaches emergency room costs, estimated related
percent for all small firms and 0.01 for acceptable because they do not assure morbidity costs, applied a value of $5
large firms. This estimate of impacts is that consumers will have the most million to the premature loss of a
somewhat understated because the current labeling information needed for statistical life, and estimated annual
census data used to derive estimates the safe and effective use of these savings if 1 to 3 percent of these adverse
includes both OTC and prescription products. FDA considers this proposed events and deaths are avoided (Ref.
drug manufacturers. However, no rule the least burdensome alternative 129).
alternative revenue and employment that meets the public health objectives
size information for affected product of this rule. We lack evidence to predict with
lines is available. We tentatively certainty a specific level of reduction in
conclude that this estimate of the E. Benefits adverse events. Nonetheless, we believe
impacts of the proposed rule does not FDA’s proposed requirements are that presenting consumers with
constitute a significant economic impact intended to enhance consumer improved label warnings and more
on a substantial number of small awareness and knowledge of the active prominently displaying the active
entities. ingredient in OTC IAAA drug products. ingredients on the PDP will promote
In a similar analysis, we assume chain These new proposals include: safer use of OTC IAAA drug products.
stores absorb costs for all 11,250 private • New label warnings Specifically, prominent display of the
label SKUs. Compliance costs as a • Age specific information active ingredients on the PDP would
percent of receipts are less than 0.001 • Advising consumers of potential alert consumers to the presence of the
percent for all of the affected sectors: risks and when to consult a doctor active ingredients in OTC IAAA drug
Pharmacies, drug stores, superstores, • Prominent display of active products and help minimize the risks of
supermarkets, and other grocery stores. ingredients on the PDP unintentional overdosing. The revised
No small entities are affected. The revised alcohol statements are warnings are intended to assist
Manufacturers routinely change labels intended to provide clearer warnings to consumers, including higher risk
at varying intervals and have high-risk individuals about product use. individuals, to use OTC IAAA drug
standardized procedures in place for The overall intent of these proposed products more safely and lead to at least
complying with FDA requirements. The requirements is to reduce the liver
a modest reduction in unintentional
proposed rule would not require any damage and GI bleeding episodes that
overdosing.
new reporting and record keeping occur due to unintentional overdosing
activities and no additional professional with these drugs. The proposed Table 14 summarizes the baseline and
skills are needed. There are no other requirements are also intended to estimates of the number of avoidable
Federal rules that duplicate, overlap, or reduce the incidence of adverse health hospitalizations and emergency room
conflict with the proposed rule; FDA is outcomes among high-risk visits, the average cost per case, and
proposing to remove the existing subpopulations consuming proper doses potential savings from events avoided.
alcohol warning in § 201.322. of OTC IAAA drug products (e.g., These data do not include reported
people with liver disease or prone to GI cases of intentional overdosing. Based
D. Alternatives bleeding). on the total monetized costs per adverse
mstockstill on PROD1PC61 with PROPOSALS
FDA does not believe that there are To estimate the benefits of this health outcome and the number of cases
any alternatives to the proposed rule proposed rule, we developed baseline estimated to be avoided each year (from
that would adequately provide for the information on the frequency of 1 to 3 percent), the total monetized
safe and effective use of OTC drug hospitalizations, emergency room visits, benefits of illness avoided range from
products containing IAAA active and deaths related to unintentional $0.6 million to $1.8 million per year
ingredients. Nonetheless, FDA overdosing with OTC IAAA drug ($592,600 to $1,777,900).
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77344 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
TABLE 14. —SUMMARY OF ANNUAL MONETIZED BENEFITS OF ILLNESSES AVOIDED ASSOCIATED WITH THE PROPOSED
RULE (2001 $)
Total Monetized Potentially Pre- Annual Number of Total Annual Mone-
Adverse Willing to Pay
Hospital Costs Value of Illness ventable Baseline Cases Avoided Due to tized Benefits of Ill-
Health Event to Avoid Illness Avoided Cases per Year(1) Proposed Rule(2) ness Avoided ($000)
Minor drug
toxicity or
emergency
room visits $209 $301 $510 3,380 34–101 $17.2–$51.7
Acetamino-
phen poi-
soning epi-
sode with
hospitaliza-
tion $8,579 $2,000 $10,579 3,424 34–103 $362.2–$1,086.8
NSAID poi-
soning epi-
sode with
hospitaliza-
tion $8,579 $357 $8,936 2,269 23–68 $202.8–$608.3
Acute renal
failure with
hospitaliza-
tion $22,251 Not Estimated $22,251 5 0.05–0.15 $1.1–$3.3
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 mone-
tized ben-
efit of ill-
ness avoid-
ed NA NA NA NA NA $592.6–$1,777.9
(1) The number of potentially preventable baseline cases per year is derived from data on emergency department and hospital cases of over-
dosing, 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 benefits associated with preventing 1 to from reduced hospital costs and deaths
preventing adverse drug events that 3 fatalities to be $5 to $15 million avoided, from $5.6 to $16.8 million,
result in emergency department or annually ($2001). would accrue each year. Over a 10-year
hospitalization, we consider the annual If the proposed improved labeling and period, the $5.6 to $16.8 million per
number of deaths related to warnings reduced serious adverse year in benefits has a present value of
unintentional acetaminophen events by 1 to 3 percent each year, the $41.2 to $126.1 million at a discount
overdoses. FDA estimates that from total monetized value of preventing rate of 7 percent, and a present value of
1996 to 1998, an annual average of 99 illness and fatalities because of $49.1 to $147.4 million at a discount
improved labeling and warnings would
adult deaths were related to rate of 3 percent. Thus, the benefits of
be $5.6 million to $16.8 million per
unintentional acetaminophen overdoses this proposed rule, assuming a 1-percent
year, respectively. These benefits are
(see section III.B.2 of this document and presented in 2001 dollars. reduction in current levels of adverse
the ERG report (Ref. 129)). We assume Benefit Cost Comparison. Industry health outcomes associated with the use
the proposed rule would reduce would incur the one-time costs of the of OTC IAAA drug products, will more
fatalities by 1 to 3 percent annually. proposed rule of $32.6 million in the than offset the costs of the proposed
Applying a value of $5 million for each first year. In 2001, the costs were $32.0 rule. Table 15 summarizes the estimated
fatality prevented, we estimate the total million. However, the estimated savings benefits and costs of this proposed rule.
TABLE 15.—SUMMARY OF IMPACTS
mstockstill on PROD1PC61 with PROPOSALS
Benefits/Costs ($Million)
Benefits:
Monetized 1 and 3 percent reduction in illnesses and mortality, per year $5.6–$16.8
Present value over 10 years at 7 percent $41–$126
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77345
TABLE 15.—SUMMARY OF IMPACTS—Continued
Benefits/Costs ($Million)
Present value over 10 years at 3 percent $49–$147
Costs:
One-time label revision, first year $32.6
Break-even Analysis. FDA notes that evaluate any comments and supporting 503(f)(1)(A); and (2) that is different from or
we lack the data needed to confidently data that are received and will reassess in addition to, or that is otherwise not
predict a percent reduction in serious the economic impact of this rulemaking identical with, a requirement under this Act,
cases related to unintentional in the preamble to any final rule. the Poison Prevention Packaging Act of 1970
overdosing. Because of the uncertainty (15 U.S.C. 1471 et seq.), or the Fair Packaging
XI. Paperwork Reduction Act of 1995 and Labeling Act (15 U.S.C. 1451 et seq.). *
in these estimates, we estimated an
annual average number of adverse FDA tentatively concludes that the **
events that would need to be avoided labeling requirements proposed in this Currently, this provision operates to
over a 10-year period to reach a document are not subject to review by preempt States from imposing
breakeven point (i.e., the cost of the Office of Management and Budget requirements related to the regulation of
compliance/present value of avoiding because they do not constitute a
nonprescription drug products. (See
one death each year for 10 years). The ‘‘collection of information’’ under the
section 751(b), (c), (d), and (e) of the act
proposed rule would need to prevent Paperwork Reduction Act of 1995 (44
U.S.C. 3501 et seq.). Rather, the for the scope of the express preemption
about 1 fatality each year over 10 years provision, the exemption procedures,
[0.9 fatality ($32/$37.6 million at a 7- proposed labeling statements are public
disclosures of information originally and the exceptions to the provision.)
percent discount rate) and 0.7 fatality This proposed rule, if finalized as
($32/$43.9 million at a 3 percent supplied by the Federal Government to
the recipient for the purpose of proposed, would amend the labeling for
discount rate)]. Alternatively, if no
disclosure to the public (5 CFR over-the-counter IAAA drug products to
fatalities are avoided, the proposed rule
1320.3(c)(2)). include new warnings and other
would need to prevent about 476
labeling requirements advising
hospitalizations ($32 million/$67,000) XII. Environmental Impact
each year over the 10-year period. This consumers about potential risks and
estimate uses the present value of the FDA has determined under 21 CFR when to consult a doctor. Although any
lowest benefit category of poisoning 25.31(a) that this proposed action is of final rule would have preemptive effect,
episode with hospitalizations, $8,936 a type that does not individually or in that it would preclude States from
per episode over 10 years at a 7-percent cumulatively have a significant effect on issuing requirements related to the
discount rate. At a 3 percent discount the human environment. Therefore, labeling of IAAA drug products that are
rate, an average of 407 hospitalizations neither an environmental assessment different from or in addition to, or not
($32 million/$79,000) would need to be nor an environmental impact statement otherwise identical with a requirement
avoided annually over the period. is required. in the final rule, this preemptive effect
Although we lack evidence to predict XIII. Federalism is consistent with what Congress set
with certainty a specific level of forth in section 751 of the act. Section
FDA has analyzed this proposed rule
reduction in adverse events, if we 751(a) of the act displaces both state
in accordance with the principles set
assume only a 1-percent reduction in forth in Executive Order 13132. FDA legislative requirements and state
the illnesses and fatalities analyzed, the has determined that the proposed rule, common law duties. We also note that
benefits of this proposed rule outweigh if finalized as proposed, would have a even where the express preemption
the costs. FDA finds that this proposed preemptive effect on State law. Section provision is not applicable, implied
rule will enhance public health and 4(a) of the Executive Order requires preemption may arise. See Geier v.
promote the safer use of OTC IAAA agencies to ‘‘construe* * *a Federal American Honda Co., 529 U.S. 861
drug products. statute to preempt State law only where (2000).
This economic analysis, together with
the statute contains an express FDA believes that the preemptive
other relevant sections of this
preemption provision or there is some effect of the proposed rule, if finalized
document, serves as FDA’s initial
other clear evidence that the Congress as proposed, would be consistent with
regulatory flexibility analysis, as
intended preemption of State law, or Executive Order 13132. Section 4(e) of
required under the Regulatory
where the exercise of State authority the Executive Order provides that
Flexibility Act.
FDA invites public comment conflicts with the exercise of Federal ‘‘when an agency proposes to act
regarding any significant economic authority under the Federal statute.’’ through adjudication or rulemaking to
impact that this rulemaking would have Section 751 of the Federal Food, Drug, preempt State law, the agency shall
on affected manufacturers of these OTC and Cosmetic Act (act) (21 U.S.C. 379r) provide all affected State and local
IAAA drug products. Comments is an express preemption provision that officials notice and an opportunity for
applies to nonprescription drugs.
mstockstill on PROD1PC61 with PROPOSALS
regarding the impact of this rulemaking appropriate participation in the
should be accompanied by appropriate Section 751(a) of the act (21 U.S.C. proceedings.’’ FDA is providing an
documentation. FDA is providing 150 379r(a)) provides that: opportunity for State and local officials
* * no State or political subdivision of a
days from the date of publication of this State may establish or continue in effect any
to comment on this rulemaking, and
proposed rule in the Federal Register requirement— * * * (1) that relates to the will conduct outreach to State and local
for comments on this subject to be regulation of a drug that is not subject to the governments or organizations
developed and submitted. FDA will requirements of section 503(b)(1) or representing them.
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77346 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
XIV. Request for Comments mailed comments, except that dockets/ac/02/slides/3882S1_05_Nourjah-
individuals may submit one paper copy. Ahmad-Karwoski_files/frame.htm.
In addition to requesting general 8. Weaver, J. P., ‘‘OTC NSAID and ASPIRIN
comments on the proposal and the Comments are to be identified with the
GI Bleeding: Analysis of Spontaneous
economic analysis, we are seeking docket number found in brackets in the
Reports,’’ presentation at September 20,
comment on the following specific heading of this document and may be 2002, NDAC meeting, transcript http://
issues identified in the description of accompanied by a supporting www.fda.gov/ohrms/dockets/ac/02/
the proposed rule (presented here for memorandum or brief. Received transcripts/3882T2.htm and slides http://
the convenience of the reader): comments may be seen in the Division www.fda.gov/ohrms/dockets/ac/02/slides/
of Dockets Management between 9 a.m. 3882S2_03_Weaver_files/frame.htm.
1. Both comment and data on whether 9. Cryer, B., ‘‘Risks of NSAIDS: Focus on
adult NSAID products should contain a and 4 p.m., Monday through Friday.
GI Risks of Over-the-Counter NSAIDs,’’
warning regarding fluid loss or XV. Proposed Effective and Compliance presentation at September 20, 2002, NDAC
dehydration similar to children NSAID Dates meeting, transcript http://www.fda.gov/
products (see section V.B.2 of this ohrms/dockets/ac/02/transcripts/3882T2.htm
document). Because of the importance of the and slides http://www.fda.gov/ohrms/
2. Appropriate approaches to reduce proposed labeling to the safe use of OTC dockets/ac/02/slides/
unintentional acetaminophen overdose IAAA drug products, FDA is proposing 3882S2_04_CRYER_files/frame.htm.
that any final rule that may publish 10. Garcia Rodriguez, L. A. et al, ‘‘Risk of
(see section VII.A of this document).
based on this proposal become effective Upper Gastrointestinal Bleeding and
3. Whether more specific directions, Perforation Associated With Individual Non-
such as those currently required for 12 months after its date of publication
Steroidal Anti-Inflammatory Drugs,’’ Lancet,
OTC drug products containing in the Federal Register. Manufacturers 343: 769–772, 1994, correction 343: 1048,
ibuprofen, should be considered for who voluntarily implement the labeling 1994.
acetaminophen (see section VII.A of this included in this proposal before the 11. Gutthann, S. P., L. A. Rodriquez, and
document). final rule is published will have 18 D. S. Raiford, ‘‘Individual Nonsteroidal Anti-
4. Both comment and data on whether months after the date of publication of inflammatory Drugs and Other Risk Factors
there are specific populations of people the final rule in the Federal Register to for Upper Gastrointestinal Bleeding and
for whom the maximum daily dose for be in compliance with that final rule. Perforation,’’ Epidemiology, 8(1):18–24, 1997.
12. Shorr, R. I. et al, ‘‘Concurrent Use of
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and should be lowered (see section Oral Anticoagulants Places Elderly Persons at
VII.A of this document). The following references are on High Risk for Hemorrhagic Peptic Ulcer
5. Both comment and data on specific display in the Division of Dockets Disease,’’ Archives of Internal Medicine,
dosage for safe and effective use of Management (see ADDRESSES), under 153:1665–1670, 1993.
acetaminophen in people who consume Docket No. 1977N–0094L, unless 13. Piper, J. M. et al, ‘‘Corticosteroid Use
alcohol (see section VII.B of this otherwise indicated, and may be seen by and Peptic Ulcer Disease: Role of
document). interested persons between 9 a.m. and 4 Nonsteroidal Anti-Inflammatory Drugs,’’
6. Both comment and data on whether p.m., Monday through Friday. (FDA has Annals of Internal Medicine, 114(9):735–740,
1991.
combinations of acetaminophen with verified the Web site addresses, but we 14. Wilcox, C. M. et al, ‘‘Striking
NAC or methionine would prevent or are not responsible for subsequent Prevalence of Over-the-Counter Nonsteroidal
reduce acetaminophen-induced liver changes to the Web sites after this Anti-Inflammatory Drug Use in Patients With
toxicity (see section VII.C of this document publishes in the Federal Upper Gastrointestinal Hemorrhage,’’
document). Register.) Archives of Internal Medicine, 154:42–46,
7. Both comment and data on package 1. Comment No. C1, Docket No. 1977N– 1994.
size or package configuration limitations 0094I (formerly Docket No. 77N–094I). 15. Garcia-Rodriguez, L. A. and S.
on the sale of acetaminophen (see 2. Comment No. C2, Docket No. 1977N– Hernandez-Diaz, ‘‘Relative Risk of Upper
section VII.D of this document). 0094I (formerly Docket No. 77N–094I). Gastrointestinal Complications Among Users
3. FDA background information for of Acetaminophen and Nonsteroidal Anti-
8. Both comment and data on whether
September 19–20, 2002, NDAC meeting, Inflammatory Drugs,’’ Epidemiology,
acetaminophen poses additional risk for http://www.fda.gov/ohrms/dockets/ac/02/ 12(5):570–576, 2001.
certain population subgroups (e.g., briefing/3882b1.htm. 16. Blot, W. J. and J. K. McLaughlin, ‘‘Over
conditions in which GSH is reduced) 4. NDAC meeting September 19–20, 2002 the Counter Non-steroidal Anti-Inflammatory
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9. Both comment and data on whether dockets/ac/02/transcripts/3882T1.htm. and Journal of Epidemiology and Biostatistics,
additional labeling is necessary http://www.fda.gov/ohrms/dockets/ac/02/ 5(2):137–142, 2000.
regarding acetaminophen-warfarin drug- transcripts/3882T2.htm. 17. Sorensen, H. T. et al., ‘‘Risk of Upper
drug interaction (see section VII.F of 5. Additional information submitted for Gastrointestinal Bleeding Associated With
consideration at the NDAC meeting Use of Low-Dose Aspirin,’’ American Journal
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10. Comment on the proposal to 6. Lee, W. M., ‘‘Acute Liver Failure in the 18. Peura, D. A. et al., ‘‘The American
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to ask their doctor for advice. Also, transcript, http://www.fda.gov/ohrms/ Journal of Gastroenterology, 92(6):924–928,
request information and data on the dockets/ac/02/transcripts/3882T1.htm and 1997.
current dosing practices of health slides http://www.fda.gov/ohrms/dockets/ac/ 19. Kaufman, D. W. et al., ‘‘The Risk of
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7. Nourjah, P., S. A. Ahmad, and C. B. Among Users of Aspirin and Ibuprofen at
mstockstill on PROD1PC61 with PROPOSALS
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Interested persons may submit to the Karwoski, ‘‘ Safety Analysis of Various Levels of Alcohol Consumption,’’
Acetaminophen A.P.A.P.-Associated American Journal of Gastroenterology,
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Submit a single copy of electronic ohrms/dockets/ac/02/transcripts/3882T1.htm 20, 2002, NDAC meeting, transcript http://
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162:1194, 2002. 95. Ehret, A. et al., ‘‘Resistance of 507, 1968.
78. Oviedo, J. and M. M. Wolfe, ‘‘Alcohol, Chimpanzee T Cells to Human 111. Antlitz, A. M., and L. F. Awalt, ‘‘A
Acetaminophen , and Toxic Effects on the Immunodeficiency Virus Type 1 TAT- Double-Blind Study of Acetaminophen Used
Liver,’’ Archives of Internal Medicine, Enhanced Oxidative Stress and Apoptosis,’’ in Conjunction With Oral Anticoagulant
Journal of Virology, 70 (9):6502–6507, 1996. Therapy, ‘‘ Current Therapeutic Research,
162:1194–1195, 2002.
96. Aukrust, P. et al., ‘‘Tumor Necrosis 11(6):360–361, 1969.
79. Chen, J., ‘‘Literature Review of One
Factor (TNF) System Levels in Human 112. Boeijinga, J. J. et al., ‘‘Interaction
Article and One Abstract That Assess
Immunodeficiency Virus-Infected Patients Between Paracetamol and Coumarin
Hepatotoxicity of Acetaminophen (4g/day for
During Highly Active Antiretroviral Therapy: Anticoagulants [letter],’’ Lancet, 1(8270):506,
2 days) in Alcoholic Patients,’’ FDA review
Persistent TNF Activation is Associated With 1982.
dated June 18, 2003. Virologic and Immunologic Treatment 113. Rubin, R. N., R. L. Mentzer, and A. Z.
80. Lauterburg, B. H., ‘‘Analgesic and Failure,’’ Journal of Infectious Diseases, Budzynski, ‘‘Potentiation of Anticoagulant
Glutathione,’’ American Journal of 179(1):74–82, 1999. Effect of Warfarin by Acetaminophen
Therapeutics, 9: 25–233, 2002. 97. Malorni, W. et al., ‘‘The Role of (Tylenol) [abstract],’’ Clinical Research,
81. Roberts, L. I. and M. E. Mortensen, Oxidative Imbalance in Progression to AIDS: 32(3):698A, 1984.
‘‘Analgesic-Antipyretic and Anti- Effect of the Thiol Supplier N- 114. Hylek, E. M. et al., ‘‘Acetaminophen
Inflammatory Agents,’’ Goodman & Gilman’s Acetylcystiene,’’ AIDS Research and Human and Other Risk Factors for Excessive
The Pharmacological Basis of Therapeutics, Retroviruses, 14(17):1589–1596, 1998. Warfarin Anticoagulation,’’ The Journal of
9th ed. Hardman, J. and Limbird L. E., 98. Roberts, R. L. et al., ‘‘N-Acetylcysteine the American Medical Association, 279(9):
editors. McGraw-Hill, pp. 631–633, 2001. Enhances Antibody-Dependent Cellular 657–662, 1998.
82. Jones, A. L., ‘‘Mechanism of Action and Cytotoxicity in Neutrophils and Mononuclear 115. Amato, M. G. et al., ‘‘Acetaminophen
Value of N-Acetylcysteine in the Treatment Cells From Healthy Adults and Human and Risk Factors for Excess Anticoagulation
of Early and Late Acetaminophen Poisoning: Immunodeficiency Virus-Infects Patients,’’ With Warfarin [letter],’’ The Journal of the
A Critical Review,’’ Clinical Toxicology, Journal of Infectious Diseases, 172(6): 1492– American Medical Association, 280(8): 695–
36(4): 277–285, 1998. 1502, 1995. 696, 1998.
83. Buckley, N. A. et al., ‘‘Oral or 99. Eylar, E. et al, ‘‘N-Acetylcysteine 116. Riser, J. et al., ‘‘Acetaminophen and
intravenous N-acetylcysteine: Which is the Enhances T Cell Functions and T Cell Risk Factors for Excess Anticoagulation With
Treatment of Choice for Acetaminophen Growth in Culture,’’ International Warfarin [letter],’’ The Journal of the
(Paracetamol) Poisoning?,’’ Journal of Immunology, 5(1):97–101, 1993. American Medical Association, 26; 280(8):
Toxicology and Clinical Toxicology, 100. Droge, W. et al., ‘‘Modulation of 696, 1998.
37(6):759–767, 1999. Lymphocyte Functions and Immune 117. Kwan, D., W. R. Bartle, and S. E.
84. Burgunnder, J. M., A. Varriale, and B. Responses by Cysteine and Cysteine Walker, ‘‘The Effects of Acetaminophen on
H. Lauterburg, ‘‘Effect of N-Acetylcysteine on Derivatives,’’ American Journal of Medicine, Pharmacokinetics and Pharmacodynamics of
Plasma Cysteine and Glutathione Following 91(Supplement C):140S–144S, 1991. Warfarin,’’ Journal of Clinical Pharmacology,
Paracetamol Administration, ’’ European 101. DeRosa, S. C. et al., ‘‘N-Acetylcysteine 39:68–75, 1999.
Journal of Clinical Pharmacology, 36(2):127– (NAC) Replenishes Glutathione in HIV 118. Shek, K. L. A., L. N. Chan, and E.
131, 1989. Infection,’’ European Journal of Clinical Nutescu, ‘‘Warfarin-Acetaminophen Drug
85. Jones, A. L. et al., ‘‘Controversies in Investigation, 30:841–856, 2000. Interaction Revisited,’’ Pharmacotherapy,
Management: Should Methionine be Added 102. Herzenberg, L. A. et al., ‘‘Glutathione 19(10):1153–1158, 1999.
to Every Paracetamol Tablet?,’’ British Deficiency is Associated With Impaired 119. Lehmann, D. F., ‘‘Enzymatic Shunting:
Medical Journal, 315:301–303, 1997. Survival in HIV Disease,’’ Proceedings of the Resolving the Acetaminophen-Warfarin
86. Comment No. CP1, Docket No. 1997P– National Academy of Sciences, 94:1967–72, Controversy,’’ Pharmacotherapy,
0102 (formerly Docket No. 97P–0102).
mstockstill on PROD1PC61 with PROPOSALS
1997. 20(12):1464–1468, 2000.
87. Comment No. C4, Docket No. 1997P– 103. Holroyd, K. J. et al., ‘‘Correction of 120. Whyte, I. M. et al., ‘‘Acetaminophen
0102 (formerly Docket No. 97P–0102). Glutathione Deficiency in the Lower Causes an Increased International
88. Comment No. C1, Docket No. 1997P– Respiratory Tract of HIV Seropositive Normalized Ratio by Reducing Functional
0102 (formerly Docket No. 97P–0102). Individuals by Glutathione Aerosol Factor VII,’’ Therapeutic Drug Monitoring,
89. Akerlund, B. et al., ‘‘Effects of N- Treatment,’’ Thorax, 48(10):985–89, 1993. 22(6):742–748, 2000.
Acetylcysteine (NAC) Treatment in HIV–1 104. Jahoor, F., ‘‘Erythrocyte Glutathione 121. Bell, W. R., ‘‘Acetaminophen and
Infection: A Double-Blind Placebo Controlled Deficiency in Symptom-Free HIV Infection is Warfarin: Undesirable Synergy [editorial],’’
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77349
The Journal of the American Medical I 2. Section 201.66 is amended by cold) must include the name
Association, 279(9): 702–703, 1998. revising paragraph (c)(5)(ii)(E) to read as ‘‘acetaminophen’’ and the name(s) of the
122. Caraco, Y., J. Sheller, and A. J. Wood, follows: other active ingredient(s) in the product
‘‘Pharmacogenetic determination of the on the PDP in accord with this
effects of codeine and prediction of drug § 201.66 Format and content requirements
interactions,’’ Journal of Pharmacology and
paragraph. Only the name
for over-the-counter (OTC) drug product
Experimental Therapeutics, 278(3):1165– labeling. ‘‘acetaminophen’’ must appear
1174, 1996. highlighted or in bold type, and in a
* * * * * prominent print size, as described in
123. van den Bemt, P. M. et al., ‘‘The (c) * * *
potential interaction between oral (5) * * * this paragraph.
anticoagulants and acetaminophen in (iii) For products labeled for adults
(ii) * * *
everyday practice,’’ Pharmaceutical World only. Warnings. The labeling of the
(E) Liver warning set forth in
Science, 24(5):201–204, 2002. product states the following warnings
124. Fattinger, K. et al., ‘‘No clinically § 201.325(a)(1)(iii) and/or stomach
bleeding warning set forth in under the heading ‘‘Warnings’’:
relevant drug interaction between
paracetamol and phenoprocoumon based on § 201.325(a)(2)(iii). The liver warning (A) ‘‘Liver warning [heading in bold
a pharmacoepidemiological cohort study in shall follow the subheading ‘‘Liver type]: This product contains
medical in people,’’ European Journal of warning:’’ and the stomach bleeding acetaminophen. Severe liver damage
Clinical Pharmacology, 57(12): 863–867, warning shall follow the subheading may occur if you take [bullet] more than
2002. ‘‘Stomach bleeding warning:’’ [insert maximum number of daily
125. La Grenad, L., D. J. Graham, and P. dosage units] in 24 hours [bullet] with
Nourjah, ‘‘Underreporting of hemorrhagic * * * * *
other drugs containing acetaminophen
stroke associated with § 201.322 [Removed] [bullet] 3 or more alcoholic drinks every
phenylpropanolamine,’’ The Journal of the
American Medical Association; 286: 3081, 3. Section 201.322 is removed. day while using this product’’. This
2001. 4. Section 201.325 is added to subpart ‘‘Liver warning’’ must be the first
126. Phelan, K., ‘‘OPDRA Postmarketing G to read as follows: warning under the ‘‘Warnings’’ heading.
Safety Review: Acetaminophen and For products that contain both
§ 201.325 Over-the-counter drug products
Coumadin (drug interaction affecting acetaminophen and aspirin, this ‘‘Liver
containing internal analgesic/antipyretic
anticoagulation),’’ FDA review dated April
active ingredients; required warnings and warning’’ must appear after the ‘‘Reye’s
20, 2001. syndrome’’ and ‘‘Allergy alert’’
other labeling.
127. Karwoski, C. B., ‘‘Office of Drug Safety warnings in § 201.66(c)(5)(ii)(A) and
Postmarketing Safety Review (DO30283) (a) Labeling. The labeling for all over-
the-counter (OTC) drug products (c)(5)(ii)(B) and before the ‘‘Stomach
Drugs—Acetaminophen and Warfarin,
Reaction: Drug Interaction affecting containing any internal analgesic/ bleeding warning’’ in paragraph
Anticoagulation (update),’’ FDA review dated antipyretic active ingredients (a)(2)(iii)(A) of this section.
June 27, 2003. (including, but not limited to, (B) ‘‘Do not use [heading in bold type]
128. Neuner, R., ‘‘Potentiation of acetaminophen, aspirin, carbaspirin with any other drug containing
Anticoagulaton Status Due to a Possible calcium, choline salicylate, ibuprofen, acetaminophen (prescription or
Adverse Drug Interaction Between Warfarin nonprescription). Ask a doctor or
ketoprofen, magnesium salicylate,
and Acetaminophen,’’ FDA review dated July pharmacist before using with other
9, 2003. naproxen sodium, and sodium
salicylate) alone or in combination must drugs if you are not sure.’’
129. Eastern Research Group, Inc. ‘‘Cost (C) ‘‘Ask a doctor before use if you
Benefit Analysis of Proposed FDA Rule on bear the following labeling in
Over-the-Counter Internal Analgesic, accordance with §§ 201.60, 201.61, and have [heading in bold type] liver
Antipyretic, and Antirheumatic Drug 201.66. disease’’.
Products; Required Warnings’’, Final Report, (1) Acetaminophen. (iv) For products labeled only for
October 6, 2004. (i) Principal display panel. The children under 12 years of age. (A)
presence of ‘‘acetaminophen’’ in the Warnings. The labeling of the product
List of Subjects states the following warnings under the
product must be prominently stated on
21 CFR Part 201 the principal display panel (PDP), as heading ‘‘Warnings’’:
defined in § 201.60. (1) ‘‘Liver warning [heading in bold
Drugs, Labeling, Reporting and (ii) Statement of identity. The type]: This product contains
recordkeeping requirements. statement of identity appears in accord acetaminophen. Severe liver damage
21 CFR Part 343 with §§ 201.61, 299.4, and 343.50(a) of may occur if the child takes [bullet]
this chapter. The ingredient name more than 5 doses in 24 hours [bullet]
Labeling, Over-the-counter drugs. acetaminophen must appear highlighted with other drugs containing
Therefore, under the Federal Food, (e.g., fluorescent or color contrast) or in acetaminophen’’. This ‘‘Liver warning’’
Drug, and Cosmetic Act and under bold type, be in lines generally parallel must be the first warning under the
authority delegated to the Commissioner to the base on which the package rests ‘‘Warnings’’ heading.
of Food and Drugs, it is proposed that as it is designed to be displayed, and be (2) ‘‘Do not use [heading in bold type]
21 CFR parts 201 and 343 (as proposed in one of the following sizes, whichever with any other drug containing
in the Federal Register of November 16, is greater: (1) At least one-quarter as acetaminophen (prescription or
1988 and August 21, 2002) be amended large as the size of the most prominent nonprescription). Ask a doctor or
as follows: printed matter on the PDP, or (2) at least pharmacist before using with other
as large as the size of the ‘‘Drug Facts’’ drugs if you are not sure.’’
mstockstill on PROD1PC61 with PROPOSALS
PART 201—LABELING title, as required in § 201.66(d)(2). The (3) ‘‘Ask a doctor before use if the
presence of acetaminophen must appear child has [heading in bold type] liver
1. The authority citation for 21 CFR as part of the established name of the disease’’.
part 201 continues to read as follows: drug, as defined in § 299.4 of this (B) Directions. The labeling of the
Authority: 21 U.S.C. 321, 331, 351, 352, chapter. Combination products product contains the following
353, 355, 358, 360, 360b, 360g–360s, 371, containing acetaminophen and a information under the heading
374, 379e; 42 U.S.C. 216, 241, 262, 264. nonanalgesic ingredient(s) (e.g., cough- ‘‘Directions’’: ‘‘this product does not
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77350 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
contain directions or warnings for adult ingredient and the word ‘‘(NSAID)’’ takes other drugs containing an NSAID
use’’ [in bold type]. need to appear highlighted or in bold (aspirin, ibuprofen, naproxen, or others)
(v) For products labeled for adults type, and in a prominent print size, as [bullet] takes more or for a longer time
and children under 12 years of age. described in this paragraph. than directed’’. The ‘‘Stomach bleeding
Warnings. The labeling of the product (iii) For products labeled for adults warning’’ must appear after the ‘‘Reye’s
states all of the warnings in paragraphs only. Warnings. The labeling of the syndrome’’ and ‘‘Allergy alert’’
(a)(1)(iii)(A), (a)(1)(iii)(B), and product states the following warnings warnings in §§ 201.66(c)(5)(ii)(A) and
(a)(1)(iii)(C) of this section with the under the heading ‘‘Warnings’’: (c)(5)(ii)(B).
following modifications: (A) ‘‘Stomach bleeding warning (2) ‘‘Ask a doctor before use if the
(A) The Liver warning states ‘‘Liver [heading in bold type]: This product child has [heading in bold type] [bullet]
warning [heading in bold type]: This contains a nonsteroidal anti- stomach problems that last or come
product contains acetaminophen. inflammatory drug (NSAID), which may back, such as heartburn, upset stomach,
Severe liver damage may occur if cause stomach bleeding. The chance is or stomach pain [bullet] ulcers [bullet]
[bullet] adult takes more than [insert higher if you [bullet] are age 60 or older bleeding problems [bullet] not been
maximum number of daily dosage units] [bullet] have had stomach ulcers or drinking fluids [bullet] lost a lot of fluid
in 24 hours [ bullet] child takes more bleeding problems [bullet] take a blood due to vomiting or diarrhea [bullet] high
than 5 doses in 24 hours [bullet] taken thinning (anticoagulant) or steroid drug blood pressure [bullet] heart or kidney
with other drugs containing [bullet] take other drugs containing an disease [bullet] taken a diuretic’’.
acetaminophen [bullet] adult has 3 or NSAID [aspirin, ibuprofen, naproxen, or (3) ‘‘Ask a doctor or pharmacist before
more alcoholic drinks everyday while others] [bullet] have 3 or more alcoholic use if the child is [heading in bold type]
using this product.’’ drinks every day while using this [bullet] taking any other drug containing
(B) ‘‘Ask a doctor before use if the product [bullet] take more or for a an NSAID (prescription or
user [heading in bold type] has liver longer time than directed’’. This nonprescription) [bullet] taking a blood
disease.’’ ‘‘Stomach bleeding warning’’ must thinning (anticoagulant) or steroid
(2) Nonsteroidal anti-inflammatory appear after the ‘‘Reye’s syndrome’’ and drug’’.
analgesic/antipyretic active ‘‘Allergy alert’’ warnings in (4) ‘‘Stop use and ask a doctor if
ingredients—including, but not limited § 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B). For [heading in bold type] [bullet] the child
to, aspirin, carbaspirin calcium, choline products that contain both feels faint, vomits blood, or has bloody
salicylate, ibuprofen, ketoprofen, acetaminophen and aspirin, the or black stools. These are signs of
magnesium salicylate, naproxen acetaminophen ‘‘Liver warning’’ in stomach bleeding. [bullet] stomach pain
sodium, and sodium salicylate. § 201.325(a)(1)(iii) must appear before or upset gets worse or lasts’’.
(i) Principal display panel. The the ‘‘Stomach bleeding warning’’ in this (B) Directions. The labeling of the
presence of an ‘‘NSAID’’ ingredient in paragraph. product contains the following
the product must be prominently stated (B) ‘‘Ask a doctor before use if you information under the heading
on the principal display panel (PDP), as have [heading in bold type] [bullet] ‘‘Directions’’: ‘‘this product does not
defined in § 201.60. stomach problems that last or come contain directions or warnings for adult
(ii) Statement of identity. The back, such as heartburn, upset stomach, use’’ [in bold type].
statement of identity appears in accord or stomach pain [bullet] ulcers [bullet] (v) For products labeled for adults
with §§ 201.61, 299.4, and 343.50(a) of bleeding problems [bullet] high blood and children under 12 years of age.
this chapter. The name of the NSAID pressure [bullet] heart or kidney disease Warnings. The labeling of the product
ingredient and the word ‘‘(NSAID)’’ [bullet] taken a diuretic [bullet] reached states all of the warnings in paragraphs
must appear highlighted (e.g., age 60 or older’’. (2)(iii)(A) through (2)(iii)(D) of this
fluorescent or color contrast) or in bold (C) ‘‘Ask a doctor or pharmacist before section with the following
type, be in lines generally parallel to the use if you are [heading in bold type] modifications:
base on which the package rests as it is [bullet] taking any other drug containing (A) The Stomach bleeding warning
designed to be displayed, and be in one an NSAID (prescription or states ‘‘Stomach bleeding warning
of the following sizes, whichever is nonprescription) [bullet] taking a blood [heading in bold type]: This product
greater: At least one-quarter as large as thinning (anticoagulant) or steroid contains a nonsteroidal anti-
the size of the most prominent printed drug’’. inflammatory drug (NSAID), which may
matter on the PDP, or at least as large (D) ‘‘Stop use and ask a doctor if cause stomach bleeding. The chance is
as the size of the ‘‘Drug Facts’’ title, as [heading in bold type] [bullet] you feel higher if the user [bullet] has had
required in § 201.66(d)(2). The word faint, vomit blood, or have bloody or stomach ulcers or bleeding problems
‘‘(NSAID)’’ must appear as part of the black stools. These are signs of stomach [bullet] takes a blood thinning
established name of the drug, as defined bleeding. [bullet] stomach pain or upset (anticoagulant) or steroid drug [bullet]
in § 299.4 of this chapter, or after the gets worse or lasts’’. takes other drugs containing an NSAID
general pharmacological (principal (iv) For products labeled only for [aspirin, ibuprofen, naproxen, or others]
intended) action of the NSAID children under 12 years of age. [bullet] takes more or for a longer time
ingredient. For example, either of the Warnings. (A) The labeling of the than directed [bullet] is age 60 or older
following would be acceptable: product states the following warnings [bullet] has 3 or more alcoholic drinks
Ibuprofen Tablets (NSAID) or Pain under the heading ‘‘Warnings’’: everyday while using this product’’. The
reliever/ fever reducer (NSAID). (1) ‘‘Stomach bleeding warning ‘‘Stomach bleeding warning’’ must
Combination products containing an [heading in bold type]: This product appear after the ‘‘Reye’s syndrome’’ and
mstockstill on PROD1PC61 with PROPOSALS
NSAID and a nonanalgesic ingredient(s) contains a nonsteroidal anti- ‘‘Allergy alert’’ warnings in
(e.g., cough-cold) must include the inflammatory drug (NSAID), which may §§ 201.66(c)(5)(ii)(A) and (c)(5)(ii)(B).
name of the NSAID ingredient and the cause stomach bleeding. The chance is (B) The labeling states ‘‘Ask a doctor
word ‘‘(NSAID)’’ in accord with this higher if the child [bullet] has had before use if the user has [heading in
paragraph, and the name(s) of the other stomach ulcers or bleeding problems bold type] [bullet] stomach problems
active ingredient(s) in the product on [bullet] takes a blood thinning that last or come back, such as
the PDP. Only the name of the NSAID (anticoagulant) or steroid drug [bullet] heartburn, upset stomach, or stomach
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Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules 77351
pain [bullet] ulcers [bullet] bleeding information included in paragraph (a) of (i) For products containing any
problems [bullet] high blood pressure this section. ingredient in § 343.10 (a) through (f) The
[bullet] heart or kidney disease [bullet] (d) Regulatory action. Any drug labeling states ‘‘Stop use and ask a
taken a diuretic [bullet] not been product subject to this section that is doctor if [heading in bold type] [bullet]1
drinking fluids [bullet] lost a lot of fluid not labeled as required and that is pain gets worse or lasts more than 10
due to vomiting or diarrhea [bullet] initially introduced or initially days [bullet] fever gets worse or lasts
reached age 60 or older.’’ delivered for introduction into interstate more than 3 days [bullet] redness or
(C) The labeling states ‘‘Ask a doctor commerce after [date 12 months after swelling is present [bullet] any new
or pharmacist before use if the user is date of publication of the final rule in symptoms appear’’.
[heading in bold type] [bullet] taking the Federal Register] is misbranded * * * * *
any other drug containing an NSAID under section 502 of the Federal Food, (iii) For products containing
(prescription or nonprescription) Drug, and Cosmetic Act (the act) (21 acetaminophen identified in § 343.10(a).
[bullet] taking a blood thinning U.S.C. 352) and is subject to regulatory The labeling states the warnings in
(anticoagulant) or steroid drug’’. action. Any drug product for which the § 201.325(a)(1)(iii)(A), (a)(1)(iii)(B), and
(D) The labeling states ‘‘Stop use and labeling required in this section was (a)(1)(iii)(C) and the following statement
ask a doctor if [heading in bold type] voluntarily implemented before the date must follow the general warning
[bullet] the user feels faint, vomits of publication of the final rule that is identified in § 330.1(g) of this chapter:
blood, or has bloody or black stools. initially introduced or initially ‘‘Prompt medical attention is critical for
These are signs of stomach bleeding. delivered for introduction into interstate adults as well as for children even if you
[bullet] stomach pain or upset gets commerce after [date 18 months after do not notice any signs or symptoms.’’
worse or lasts’’. date of publication of the final rule in (iv) * * *
(vi) Active ingredient(s). The active the Federal Register] and that is not (A) The labeling states the warning in
ingredient(s) section of the product’s labeled as required is misbranded under paragraph (c)(1)(v)(B) plus the bulleted
labeling, as defined in § 201.66(c)(2), section 502 of the act and is subject to statement ‘‘asthma’’.
contains the term ‘‘(NSAID)*’’ after the regulatory action. * * * * *
NSAID active ingredient with an (v) * * *
asterisk statement at the end of the PART 343—INTERNAL ANALGESIC,
ANTIPYRETIC, AND ANTIRHEUMATIC (A) The labeling states the warning in
active ingredient(s) section that defines paragraph (c)(1)(i) of this section plus
the term ‘‘NSAID’’ and states ‘‘* DRUG PRODUCTS FOR OVER-THE-
COUNTER HUMAN USE ‘‘[bullet] you feel faint, vomit blood, or
nonsteroidal anti-inflammatory drug.’’ have bloody or black stools. These are
(b) New warnings information 4. The authority citation for 21 CFR signs of stomach bleeding. [bullet]
statement. The labeling of any drug part 343 continues to read as follows: stomach pain or upset gets worse or
product subject to this section that is lasts [bullet] ringing in the ears or loss
Authority: 21 U.S.C. 321, 351, 352, 353,
initially introduced or initially 355, 360, 371. of hearing occurs’’.
delivered for introduction into interstate 5. Section 343.50, as proposed at 53 (B) The labeling states ‘‘Ask a doctor
commerce before the effective date and FR 46255, November 16, 1988, and 67 before use if you have [heading in bold
within 12 months after the effective date FR 54158, August 21, 2002, is further type] [bullet] stomach problems that last
of the final rule or if relabeled at any amended by revising paragraphs or come back, such as heartburn, upset
time before the effective date of the final (c)(1)(i), (c)(1)(iii), (c)(1)(iv)(A), stomach, or stomach pain [bullet] ulcers
rule must bear on its principal display (c)(1)(v)(A) through (c)(1)(v)(C), [bullet] bleeding problems [bullet] high
panel (PDP), as defined in § 201.60, the (c)(1)(ix)(A), (c)(1)(ix)(B), (c)(1)(ix)(C), blood pressure [bullet] heart or kidney
statement ‘‘See new warnings (c)(1)(ix)(E), (c)(2)(i), (c)(2)(iii), disease [bullet] taken a diuretic [bullet]
information.’’ This statement must (c)(2)(iv)(A), (c)(2)(v)(A) through reached age 60 or older’’.
appear highlighted (e.g., fluorescent or (c)(2)(v)(C)3 and adding new paragraphs (C) The labeling states ‘‘Ask a doctor
color contrast) or in bold type, be in (b)(4)(i)(C) and (c)(3)(i) through or pharmacist before use if you are
lines generally parallel to the base on (c)(3)(v)(C) to read as follows: [heading in bold type] [bullet] taking
which the package rests as it is designed any other drug containing an NSAID
to be displayed, and be in one of the § 343.50 Labeling of analgesic-antipyretic (prescription or nonprescription)
following sizes, whichever is greater: drug products. [bullet] taking a blood thinning
(1) At least one-quarter as large as the * * * * * (anticoagulant) or steroid drug [bullet]
size of the most prominent printed (b) * * * taking a prescription drug for diabetes,
matter on the PDP, or (4) * * * gout, or arthritis’’.
(2) At least as large as the size of the (i) * * *
* * * * *
‘‘Drug Facts’’ title, as required in (C) The product states the following
(ix) * * *
§ 201.66(d)(2). statement under the heading
(A) The stomach bleeding warning set
(c) Requirements to supplement ‘‘Directions,’’ ‘‘this product does not
forth in § 201.325(a)(2)(iii)(A),
approved application. Holders of contain directions or warnings for adult
(a)(2)(iv)(A), or (a)(2)(v)(A) of this
approved applications for OTC drug use’’. This statement is not required for
chapter appears after the subheading
products that contain internal analgesic/ products containing ibuprofen as
‘‘Stomach bleeding warning:’’.
antipyretic active ingredients that are identified in § 343.10 (g).
(B) The labeling states ‘‘Ask a doctor
subject to the requirements of paragraph * * * * * before use if you have [heading in bold
mstockstill on PROD1PC61 with PROPOSALS
(a) of this section must submit (c) * * * type] [bullet] problems or serious side
supplements under § 314.70(c) of this (1) * * * effects from taking pain relievers or
chapter to include the required fever reducers [bullet] stomach
3The warnings in these sections are revised to
information in the product’s labeling. problems that last or come back, such as
conform with § 201.66 (Drug Facts format). Other
Such labeling may be put into use warnings remain as proposed in the TFM and will
without advance approval of FDA be revised into the Drug Facts format in a future 1See § 201.66(b)(4) of this chapter for definition
provided it includes at least the exact issue of the Federal Register. of bullet symbol.
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77352 Federal Register / Vol. 71, No. 247 / Tuesday, December 26, 2006 / Proposed Rules
heartburn, upset stomach, or stomach bold type] [bullet] stomach problems taking a prescription drug for diabetes,
pain [bullet] ulcers [bullet] bleeding that last or come back, such as gout, or arthritis’’.
problems [bullet] high blood pressure heartburn, upset stomach, or stomach Dated: November 22, 2006.
[bullet] heart or kidney disease [bullet] pain [bullet] ulcers [bullet] bleeding
taken a diuretic [bullet] reached age 60 problems [bullet] not been drinking Jeffrey Shuren,
or older’’. fluids [bullet] lost a lot of fluid due to Assistant Commissioner for Policy.
(C) The labeling states ‘‘Ask a doctor vomiting or diarrhea [bullet] high blood [FR Doc. E6–21855 Filed 12–19–06; 8:45 am]
or pharmacist before use if you are pressure [bullet] heart or kidney disease BILLING CODE 4160–01–S
[heading in bold type] [bullet] taking [bullet] taken a diuretic’’.
any other drug containing an NSAID (C) The labeling states ‘‘Ask a doctor
(prescription or nonprescription [bullet] or pharmacist before use if the child is
taking a blood thinning (anticoagulant) [heading in bold type] [bullet] taking DEPARTMENT OF THE TREASURY
or steroid drug [bullet] under a doctor’s any other drug containing an NSAID
care for any serious condition [bullet] (prescription or nonprescription) Internal Revenue Service
taking any other drug’’. [bullet] taking a blood thinning
* * * * * (anticoagulant) or steroid drug [bullet] 26 CFR Part 1
(E) In addition to the warning taking a prescription drug for diabetes,
required in § 201.324(c) of this chapter gout, or arthritis’’. [REG–136806–06]
after the subheading ‘‘Stop use and ask * * * * *
a doctor if’’ [heading in bold type], the (3) * * * RIN 1545–BF87
following statements also appear: (i) For products containing any
‘‘[bullet] you feel faint, vomit blood, or ingredient in § 343.10 (a) through (f). Treatment of Payments in Lieu of
have bloody or black stools. These are The labeling states ‘‘Stop use and ask a Taxes Under Section 141
signs of stomach bleeding. [bullet] pain doctor if [heading in bold type] [bullet]
gets worse or lasts more than 10 days adult’s pain gets worse or lasts more AGENCY: Internal Revenue Service (IRS),
[bullet] fever gets worse or lasts more than 10 days [bullet] child’s pain gets Treasury.
than 3 days [bullet] stomach pain or worse or lasts more than 5 days [bullet]
upset gets worse or lasts [bullet] redness fever gets worse or lasts more than 3 ACTION: Change of location of public
or swelling is present in the painful area days [bullet] redness or swelling is hearing.
[bullet] any new symptoms appear‘‘. present [bullet] any new symptoms
* * * * * appear’’. SUMMARY: On October 19, 2006, on page
(2) * * * (ii) The warning in § 343.50(c)(1)(ii), if 61693 of the Federal Register (71 FR
(i) For products containing any applicable. 61693), a notice of proposed rulemaking
ingredient in § 343.10 (a) through (f) The (iii) For products containing and notice of public hearing announced
labeling states ‘‘Stop use and ask a acetaminophen identified in § 343.10(a). that a public hearing concerning
doctor if [heading in bold type] [bullet] The labeling states the warnings in applying the private security or
pain gets worse or lasts more than 5 § 201.325(a)(1)(v) of this chapter. The payment test for State and local
days [bullet] fever gets worse or lasts warning in § 201.325 (a)(1)(v)(B) is governmental issuers of tax-exempt
more than 3 days [bullet] redness or modified to read: ‘‘ Ask a doctor before bonds will be held February 13, 2007 in
swelling is present [bullet] any new use if the user [heading in bold type] the auditorium of the New Carrollton
symptoms appear ’’. [bullet] has liver disease [bullet] is a Federal Building, 5000 Ellin Road,
* * * * * child with pain of arthritis’’. The Lanham, MD 20706. The location of the
(iii) For products containing following statement must follow the public hearing has changed.
acetaminophen identified in § 343.10(a). general warning identified in § 330.1(g)
The labeling states the warnings in of this chapter: ‘‘Prompt medical ADDRESSES: The public hearing will be
§ 201.325(a)(1)(iv)(A)(1), (a)(1)(iv)(A)(2), attention is critical for adults as well as held in the IRS Auditorium, Internal
and (a)(1)(iv)(A)(3) and the following for children even if you do not notice Revenue Building, 1111 Constitution
statement must follow the general any signs or symptoms.’’ Avenue, NW., Washington, DC.
warning identified in § 330.1(g) of this (iv) The warnings in § 343.50(c)(1)(iv),
FOR FURTHER INFORMATION CONTACT:
chapter: ‘‘Prompt medical attention is if applicable.
Concerning submissions of comments,
critical even if you do not notice any (v) For products containing aspirin,
carbaspirin calcium, choline salicylate, the hearing, and/or to be placed on the
signs or symptoms.’’
(iv) * * * magnesium salicylate, or sodium building access list to attend the hearing
(A) The labeling states the warning in salicylate identified in §§ 343.10(b), (c), Kelly Banks, (202) 622–0392 (not a toll-
paragraph (c)(2)(v)(B) plus the bulleted (d), (e) and ( f). free number).
statement ‘‘asthma’’. (A) The labeling states the warning in LaNita Van Dyke,
* * * * * paragraph (c)(3)(i) of this section plus Branch Chief, Publications and Regulations,
(v) * * * ‘‘[bullet] the user feels faint, vomits Associate Chief Counsel, Legal Processing
(A) The labeling states the warning in blood, or has bloody or black stools. Division, (Procedure and Administration).
paragraph (c)(2)(i) of this section plus These are signs of stomach bleeding. [FR Doc. E6–22017 Filed 12–22–06; 8:45 am]
‘‘[bullet] the child feels faint, vomits [bullet] stomach pain or upset gets
mstockstill on PROD1PC61 with PROPOSALS
BILLING CODE 4830–01–P
blood, or has bloody or black stools. worse or lasts [bullet] ringing in the ears
These are signs of stomach bleeding. or loss of hearing occurs’’.
[bullet] stomach pain or upset gets (B) The labeling states the warning in
worse or lasts [bullet] ringing in the ears § 201.325(a)(2)(v)(B) plus ‘‘[bullet] is a
or loss of hearing occurs’’. child with pain of arthritis’’.
(B) The labeling states ‘‘Ask a doctor (C) The labeling states the warning in
before use if the child has [heading in § 201.325(a)(2)(v)(C) plus ‘‘[bullet]
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