[Federal Register Volume 74, Number 78 (Friday, April 24, 2009)]
[Notices]
[Pages 18731-18733]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-9380]



[[Page 18731]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0138]


Joint Meeting of the Drug Safety and Risk Management Advisory 
Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic 
and Life Support Drugs Advisory Committee; Notice of Meeting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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    This notice announces a forthcoming meeting of a public advisory 
committee of the Food and Drug Administration (FDA). The meeting will 
be open to the public.
    Name of Committees: Drug Safety and Risk Management Advisory 
Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic 
and Life Support Drugs Advisory Committee.
    General Function of the Committees: To provide advice and 
recommendations to the agency on FDA's regulatory issues.
    Date and Time: The meeting will be held on June 29 and 30, 2009, 
from 8 a.m. to 5 p.m.
    Addresses: Electronic comments should be submitted to http://www.regulations.gov. Enter ``FDA-2009-N-0138 Liver Injury Related to 
the Use of Acetaminophen'' and follow the prompts to submit your 
statement. Written comments should be submitted to the Division of 
Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852. All comments received will 
be posted without change, including any personal information provided. 
Comments received on or before June 8, 2009, will be provided to the 
committee before the meeting.
    Location: Marriott Conference Centers, University of Maryland, 
University College Inn and Conference Center, 3501 University Blvd. 
East, Adelphi, MD. The Conference Center telephone number is 301-985-
7300.
    Contact Person: Elaine Ferguson, Center for Drug Evaluation and 
Research (HFD-21), Food and Drug Administration, 5600 Fishers Lane (for 
express delivery, 5630 Fishers Lane, rm. 1093), Rockville, MD 20857, 
301-827-7001, FAX: 301-827-6776, e-mail: [email protected], 
or FDA Advisory Committee Information Line, 1-800-741-8138 (301-443-
0572 in the Washington, DC area), codes 3014512535, 3014512541, and 
3014512529. Please call the Information Line for up-to-date information 
on this meeting. A notice in the Federal Register about last minute 
modifications that impact a previously announced advisory committee 
meeting cannot always be published quickly enough to provide timely 
notice. Therefore, you should always check the agency's Web site and 
call the appropriate advisory committee hot line/phone line to learn 
about possible modifications before coming to the meeting.
    Agenda: The primary topic area for discussion is how to address the 
public health problem of liver injury related to the use of 
acetaminophen in both over-the-counter (OTC) and prescription (Rx) 
products. FDA recognizes that acetaminophen is an important drug used 
to treat pain and fever in both settings and is not seeking to remove 
it from the market. The risk of developing liver injury to the 
individual patient who uses the drug according to directions is very 
low. However, acetaminophen containing products are used extensively 
making the absolute number of liver injury cases a public health 
concern.
    More complete information about the topics on which FDA will seek 
public input will be available by or around May 22, 2009, at http://www.fda.gov/ohrms/dockets/ac/acmenu.htm, click on the year 2009 and 
scroll down to the appropriate advisory committee link.
    FDA intends to make background material available to the public no 
later than 2 business days before the meeting. If FDA is unable to post 
the background material on its Web site prior to the meeting, the 
background material will be made publicly available at the location of 
the advisory committee meeting, and the background material will be 
posted on FDA's Web site after the meeting. Background material is 
available at http://www.fda.gov/ohrms/dockets/ac/acmenu.htm, click on 
the year 2009 and scroll down to the appropriate advisory committee 
link.
    Background: Acetaminophen is one of the most commonly used drugs in 
the United States,\1\ yet it is also an important cause of serious 
liver injury. Acetaminophen is the generic name of a drug found in many 
common brand name over-the-counter (OTC) products, such as Tylenol, and 
Prescription (Rx) products, such as Vicodin and Percocet. Acetaminophen 
is an important drug, and its effectiveness in relieving pain and fever 
is widely known. Unlike other commonly used drugs to reduce pain and 
fever (e.g., nonsteroidal antinflammatory drugs (NSAIDs), such as 
aspirin, ibuprofen, and naproxen), at recommended doses acetaminophen 
does not cause adverse effects, such as stomach discomfort and 
bleeding, and acetaminophen is considered safe when used according to 
the directions on its OTC or Rx labeling. However, taking more than the 
recommended amount can cause liver damage, ranging from abnormalities 
in liver function blood tests, to acute liver failure, and even death. 
Many cases of overdose are caused by patients inadvertently taking more 
than the recommended dose (i.e., 4 grams a day) of a particular 
product, or by taking more than one product containing acetaminophen 
(e.g., an OTC product and an Rx drug containing acetaminophen).
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    \1\ Kaufman, D.W., J.P. Kelly, L. Rosenberg, et al., ``Recent 
Patterns of Medication Use in the Ambulatory Adult Population of the 
United States: The Slone Survey,'' The Journal of the American 
Medical Association 2002, Jan 16;287(3) 337-44.
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    The mechanism of liver injury is not related to acetaminophen 
itself, but to the production of a toxic metabolite. The toxic 
metabolite binds with liver proteins, which cause cellular injury. The 
ability of the liver to remove this metabolite before it binds to liver 
protein influences the extent of liver injury. In a study that combined 
data from 22 specialty medical centers in the United States, 
acetaminophen-related liver injury was the leading cause of acute liver 
failure for the years 1998 through 2003.\2\ Patients in this study were 
found to have taken too much acetaminophen from OTC, Rx products, or 
both. Almost half of these cases involved overdose in which the patient 
had not intended to take too much acetaminophen (unintentional 
overdoses), although many cases of liver injury with acetaminophen 
result from self-harm, i.e., intentional self-poisoning. The high 
percentage of cases of liver failure related to unintentional 
acetaminophen overdose was also observed in a study published in 
2007.\3\ The extent of liver failure cases reported in the medical 
literature provides an important signal of concern. However, the types 
of databases available to identify cases make it difficult to determine 
the full extent of the problem or whether interventions have been 
successful.
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    \2\ Larson, A.M., J. Polson, R.J. Fontana, et al., Acute Liver 
Failure Study Group (ALFSG), ``Acetaminophen-Induced Acute Liver 
Failure: Results of a United States Multicenter, Prospective 
Study,'' Hepatology 2005, Dec;42(6):1364-72.
    \3\ Bower, W.A., M. Johns, H.S. Margolis, et al., ``Population-
Based Surveillance for Acute Liver Failure,'' The American Journal 
of Gastroenterology 2007;102:2459-63.

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A. Why Acetaminophen Overdoses Occur

    There are few data available describing consumer behavior with 
acetaminophen products or consumer understanding of acetaminophen 
toxicity. However, based on the prevalence of liver injury, it appears 
that there are distinct factors associated with acetaminophen and 
acetaminophen products that contribute to this public health problem. 
These factors are listed below.
     Taking just a small amount of acetaminophen over the 
recommended total daily dose (4 grams per day) may lead to liver 
injury.\4\
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    \4\ Data from both FDA's Adverse Event Reporting System (AERS) 
and the ALFSG show that the median daily dose of acetaminophen 
related to liver injury was 5 to 7.5 grams/day, very near the 
current maximum daily dose of 4 grams/day.
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Currently recommended doses and tablet strengths of acetaminophen leave 
little room for error and the onset of liver injury can be hard to 
recognize. There is scientific agreement that taking a large amount of 
acetaminophen over a short period of time causes liver injury, but 
there is limited agreement as to the specific threshold dose for 
toxicity. In addition, the onset of symptoms associated with 
acetaminophen liver injury can take several days, even in severe cases. 
The symptoms of liver injury may not be readily identified by an 
individual because they may be non-specific and mimic flu symptoms. The 
antidote for acetaminophen poisoning, N-acetylcysteine, is less 
effective when liver injury has progressed too far.
     Some individuals may be especially sensitive to liver 
injury from acetaminophen. The maximum safe dose may not be the same 
for all persons. Individuals with increased sensitivity may experience 
toxic effects at lower acetaminophen doses. Available information 
suggests that some individuals, such as those who use alcohol or have 
liver disease, may have a greater sensitivity to the effects of the 
toxic metabolite because they produce more or are unable to clear it 
from the body as easily. More research is needed to understand whether 
ethnicity, genetics, nutrition, or other factors might have a role in 
making some individuals more sensitive.
     There is a wide array of OTC and Rx acetaminophen products 
used in a range of doses for various indications.
For some people, it may be difficult to identify the appropriate 
product to use. Acetaminophen is in many widely used OTC single 
ingredient products, such as those to treat headaches, and multiple 
ingredient (combination) products, such as those to treat symptoms of 
the common cold, like aches and fever. Acetaminophen is also a 
component of a number of Rx drug products in combination with narcotic 
pain medicines. So, consumers may reasonably attempt to treat different 
conditions or symptoms with multiple choices among products containing 
acetaminophen, but may not realize that acetaminophen is an ingredient 
common to each.
     It can be difficult to identify acetaminophen as an 
ingredient.
Rx products that contain acetaminophen (usually with codeine or 
oxycodone) are often labeled as containing ``APAP'' on pharmacy 
dispensed containers.\5\ Without clear labeling, patients may take more 
than one product containing acetaminophen (e.g., a Rx product and an 
OTC product) without realizing it, and in some cases take a harmful 
overdose.
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    \5\ ``APAP'' is an acronym based on the chemical name of 
acetaminophen, N-acetyl-para-aminophenol.
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     Multiple products exist for children containing different 
strengths.
Liquid acetaminophen formulations intended for use in infants are 
typically more concentrated (i.e., stronger) to enable proper dosing 
using less liquid. However, failure to distinguish between the two 
strengths of liquid can result in an accidental overdose where the 
parent gives a higher dose of the concentrated drops to a younger 
child.
     The association between acetaminophen and liver injury is 
not common knowledge.\6\
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    \6\ Stumpf J.L., A.J. Skyles, C. Alaniz, et al., ``Knowledge of 
Appropriate Acetaminophen Doses and Potential Toxicities in an Adult 
Clinic Population, Journal of the American Pharmacists Association 
(2003), 2007 Jan-Feb; 47(1): 35-41.
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Consumers are not sufficiently aware that acetaminophen can cause 
serious liver injury, and their perceptions may be influenced by the 
marketing of the products. Finding ways to educate consumers about the 
risk of liver injury from acetaminophen has been difficult. Current 
labeling on OTC products may be overlooked, as can the patient 
information provided with dispensed prescriptions. Programs to educate 
the public about safe use of acetaminophen have been small and 
encountered a number of obstacles. Advertisements of OTC drugs often 
emphasize the effectiveness of products, but are not subject to the 
same requirements to offset such messages by providing warning 
information as prescription products. Also, acetaminophen is available 
in retail outlets in large quantities (e.g., 500 tablets per bottle) 
which may contribute to the perception that the ingredient is unlikely 
to be harmful.

B. FDA's Previous Actions

    In the late 1990s, research began to show that acetaminophen was a 
major cause of acute liver failure in the United States, with up to 
half of the cases due to accidental overdose. Responding to these 
concerns, FDA took a number of steps to reduce the incidence of liver 
injury related to acetaminophen.
    In 1998, FDA finalized a regulation that required all OTC 
acetaminophen products to include an alcohol warning in labeling. The 
warning stated: Acetaminophen. ``Alcohol Warning'' [heading in boldface 
type]: ``If you consume 3 or more alcoholic drinks every day, ask your 
doctor whether you should take acetaminophen or other pain relievers/
fever reducers. Acetaminophen may cause liver damage.''
    In 2002, FDA convened an Advisory Committee meeting to discuss 
unintentional liver toxicity related to the use of OTC 
acetaminophen.\7\ The Advisory Committee recommended a specific liver 
toxicity warning and distinctive labeling on OTC packages so that 
products containing acetaminophen could be more easily identified. FDA 
and manufacturers were also advised to educate consumers and health 
professionals about the risk of liver injury from acetaminophen.
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    \7\ See http://www.fda.gov/OHRMS/DOCKETS/98fr/082002c.htm.
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    In early 2004, FDA launched a public education campaign to help 
consumers use acetaminophen more safely. By most standards, the 
campaign would be considered small, due to budgetary constraints. It 
was also limited by reluctance on the part of some commercial outlets 
to provide a venue for FDA's message about acetaminophen toxicity as 
the product was sold or promoted in those outlets. Nonetheless, FDA has 
continued to expand efforts to improve public education about 
acetaminophen overdosing and liver injury and has recently updated the 
acetaminophen information on FDA's Web site.
    In 2004, FDA sent letters to every state board of pharmacy asking 
them to consider requiring labeling on the immediate container of Rx 
products containing acetaminophen that: (1) uses the term 
acetaminophen, not APAP, (2) instructs patients to avoid concurrent use 
of other acetaminophen containing drugs, (3) instructs patients not to 
exceed the maximum daily recommended acetaminophen dose, and (4) 
instructs patients to avoid drinking

[[Page 18733]]

alcohol during prescription use.\8\ FDA was informed by the National 
Association of Boards of Pharmacy that, as of February 2008, no states 
had implemented regulations related to the request.
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    \8\ Letter from Steven Galson to State Boards of Pharmacy, 
Acetaminophen Hepatotoxicity and Nonsteroidal Anti-Inflammatory Drug 
(NSAID)-Related Gastrointestinal and Renal Toxicity (January 22, 
2004), available on FDA's Web site at http://www.fda.gov/cder/drug/analgesics/letter.htm.)
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    In December 2006, FDA issued proposed regulations for OTC labeling 
for acetaminophen containing products to require inclusion of new 
safety information and that the container and outer carton identify 
acetaminophen when it is an ingredient.\9\ The final version of the 
regulation is currently under review.
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    \9\ Internal Analgesic, Antipyretic, and Antirheumatic Drug 
Products for Over-the Counter Human Use: Proposed Amendment of the 
Tentative Final Monograph: Required Warnings and Other Labeling, 71 
FR 77314-52 (December 26, 2006) (Docket No.1977N-0094L) (amending 21 
CFR 201.66, 201.322, 201.325, 343.50).
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    In 2007, the Director of FDA's Center for Drug Evaluation and 
Research (CDER) convened a multidisciplinary working group in CDER to 
continue to evaluate the issues associated with acetaminophen-related 
liver injury and consider additional steps FDA could take to decrease 
the number of cases of acetaminophen-related liver injury. The working 
group considered detailed reviews of the issues from the Office of 
Nonprescription Products, the Office of Surveillance and Epidemiology 
and the Division of Anesthesia and Analgesic and Rheumatology Drug 
Products as part of its deliberations. The working group considered the 
full range of options proposed and made recommendations to the Center 
Director regarding which should be considered for implementation. Given 
the complex nature of the underlying problem of acetaminophen liver 
toxicity, the Center Director and the Working Group agreed that the 
options should be presented for public discussion prior to taking 
further action. The report of the Working Group will be available by or 
around May 22, 2009, at http://www.fda.gov/ohrms/dockets/ac/acmenu.htm, 
click on the year 2009 and scroll down to the appropriate advisory 
committee link.
    Procedure: Interested persons and Sponsors (representatives from 
industry) may present data, information, or views, orally or in 
writing, on issues pending before the committee.
    All electronic and written submissions submitted to the Docket (see 
above section: Addresses) on or before June 8, 2009, will be provided 
to the committees.
    Oral presentations from the public (excluding Sponsors) will be 
scheduled between approximately 1 p.m. to 2 p.m. on both days. Persons 
desiring to make formal oral presentations during this time should 
notify the contact person and submit a brief statement of the general 
nature of the evidence or arguments they wish to present, the names and 
addresses of proposed participants, and an indication of the 
approximate time requested to make their presentation on or before June 
1, 2009. Time allotted for each presentation may be limited. If the 
number of registrants requesting to speak is greater than can be 
reasonably accommodated during the scheduled open public hearing 
session, FDA may conduct a lottery to determine the speakers for the 
scheduled open public hearing session. The contact person will notify 
interested persons regarding their request to speak at the open public 
hearing session by June 3, 2009.
    FDA will work with sponsors of acetaminophen products who wish to 
make presentations to ensure that adequate time, separate from the 1 
p.m. to 2 p.m. time slots for the general Open Public Hearing, is 
provided. Sponsors interested in making formal presentations to the 
committees should notify the contact person on or before June 1, 2009. 
Sponsors with common interest are urged to coordinate their oral 
presentations.
    Persons attending FDA's advisory committee meetings are advised 
that the agency is not responsible for providing access to electrical 
outlets.
    FDA welcomes the attendance of the public at its advisory committee 
meetings and will make every effort to accommodate persons with 
physical disabilities or special needs. If you require special 
accommodations due to a disability, please contact Elaine Ferguson at 
least 7 days in advance of the meeting.
    FDA is committed to the orderly conduct of its advisory committee 
meetings. Please visit our Web site at http://www.fda.gov/oc/advisory/default.htm for procedures on public conduct during advisory committee 
meetings.
    Notice of this meeting is given under the Federal Advisory 
Committee Act (5 U.S.C. app.).

    Dated: April 16, 2009.
Randall W. Lutter,
Deputy Commissioner for Policy.
[FR Doc. E9-9380 Filed 4-23-09; 8:45 am]
BILLING CODE 4160-01-S