Federal Register / Vol. 74, No. 78 / Friday, April 24, 2009 / Notices 18731 

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. 

2Larson, 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. 

3Bower, 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. 

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. 

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: 

elaine.ferguson@fda.hhs.gov, 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 overthe-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). 

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 selfpoisoning. 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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18732 Federal Register / Vol. 74, No. 78 / Friday, April 24, 2009 / Notices 

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. 

5 ‘‘APAP’’ is an acronym based on the chemical 

name of acetaminophen, N-acetyl-paraaminophenol. 

6Stumpf 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. 

7See http://www.fda.gov/OHRMS/DOCKETS/ 

98fr/082002c.htm. 

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

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 nonspecific 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. 

• 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

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. 

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 

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Federal Register / Vol. 74, No. 78 / Friday, April 24, 2009 / Notices 18733 

8Letter 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.) 

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). 

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. 

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. 

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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Centers for Disease Control and 

Prevention 

National Center for Injury Prevention 

and Control, Initial Review Group, 

(NCIPC, IRG) 

In accordance with section 10(a)(2) of 

the Federal Advisory Committee Act 

(Pub. L. 92–463), CDC announces the 

following meeting of the 

aforementioned review group: 

Times and Dates: 

10 a.m.–10:10 a.m., May 18, 2009 (Open). 

10:10 a.m.–4 p.m., May 18, 2009 (Closed). 

Place: Teleconference, Toll Free: (877) 

468–4185, Participant Passcode: 4475689. 

Status: Portions of the meetings will be 

closed to the public in accordance with 

provisions set forth in Section 552b(c)(4) and 

(6), Title 5, U.S.C., and the Determination of 

the Director, Management Analysis and 

Services Office, CDC, pursuant to Section 

10(d) of Public Law 92–463. 

Purpose: This group is charged with 

providing advice and guidance to the 

Secretary, Department of Health and Human 

Services, and the Director, CDC, concerning 

the scientific and technical merit of grant and 

cooperative agreement applications received 

from academic institutions and other public 

and private profit and nonprofit 

organizations, including State and local 

government agencies, to conduct specific 

research that focuses on prevention and 

control. 

Matters To Be Discussed: The meeting will 

include the review, discussion, and 

evaluation of applications submitted in 

response to Fiscal Year 2009 Requests for 

Applications related to the following 

individual research announcement: TS09001, 

Libbey Montana Amphibole Epidemiology 

Research Program (R01) and TS09002, 

Disease Progression in persons Exposed to 

Asbestos Contaminated Vermiculite Ore in 

Marysville, Ohio (R01). 

Agenda items are subject to change as 

priorities dictate. 

Contact Person for More Information: Lisa 

T. Garbarino, B.S., NCIPC, Division of Injury 

Response, CDC, 4770 Buford Highway, NE., 

M/S F62, Atlanta, Georgia 30341, Telephone 

(440) 723–1527. The Director, Management 

Analysis and Services Office has been 

delegated the authority to sign Federal 

Register notices pertaining to 

announcements of meetings and other 

committee management activities for both 

CDC and the Agency for Toxic Substances 

and Disease Registry. 

Dated: April 16, 2009. 

Elaine L. Baker, 

Director, Management Analysis and Services 

Office, Centers for Disease Control and 

Prevention. 

[FR Doc. E9–9470 Filed 4–23–09; 8:45 am] 

BILLING CODE 4163–18–P 

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