Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 2691 

1FDA continues to monitor the occurrence of 

adverse events associated with both prescription 

and OTC acetaminophen products. Any action 

relating to additional safety measures for OTC 

acetaminophen products will be taken separately 

from this notice, through rulemaking as part of the 

ongoing OTC monograph proceeding for internal 

analgesic drug products. 

2The opioid ingredient propoxyphene has also 

been widely used in combination with 

acetaminophen under the brand name Darvocet as 

well as in many generic products. On November 19, 

2010, FDA announced that Darvocet was being 

voluntarily withdrawn from the market at FDA’s 

request due to significant safety concerns about 

propoxyphene. FDA also requested that makers of 

generic propoxyphene-acetaminophen combination 

products withdraw their products from the market. 

Additional information about the status of 

propoxyphene-containing drug products can be 

found on FDA’s Web site at http://www.fda.gov/

Drugs/DrugSafety/PostmarketDrugSafety

InformationforPatientsandProviders/

ucm233800.htm. 

the amounts due and owing for the 

violations. This information collection 

request is necessary in order to inform 

the public of the process and the types 

of information needed to participate in 

the SRDP. 

The SRDP is a voluntary selfdisclosure instrument that will allow 

providers of services and suppliers to 

disclose actual or potential violations of 

section 1877 of the Act. CMS will 

analyze the disclosed conduct to 

determine compliance with section 

1877 of the Act and the application of 

the exceptions to the physician selfreferral prohibition. In addition, the 

authority granted to the Secretary under 

section 6409(b) of the ACA, and 

subsequently delegated to CMS, may be 

used to reduce the amount due and 

owing for violations. Form Number: 

CMS–10328 (OMB#: 0938–1106; 

Frequency: Once; Affected Public: 

Private Sector, Business and other forprofit and not-for-profit institutions; 

Number of Respondents: 50; Total 

Annual Responses: 50; Total Annual 

Hours: 1,175. (For policy questions 

regarding this collection contact Ronke 

Fabayo at 410–786–4460. For all other 

issues call 410–786–1326.) 

To obtain copies of the supporting 

statement and any related forms for the 

proposed paperwork collections 

referenced above, access CMS’ Web site 

at http://www.cms.hhs.gov/ 

PaperworkReductionActof1995, or email your request, including your 

address, phone number, OMB number, 

and CMS document identifier, to 

Paperwork@cms.hhs.gov, or call the 

Reports Clearance Office on (410) 786– 

1326. 

In commenting on the proposed 

information collections please reference 

the document identifier or OMB control 

number. To be assured consideration, 

comments and recommendations must 

be submitted in one of the following 

ways by March 15, 2011: 

1. Electronically. You may submit 

your comments electronically to http:// 

www.regulations.gov. Follow the 

instructions for ‘‘Comment or 

Submission’’ or ‘‘More Search Options’’ 

to find the information collection 

document(s) accepting comments. 

2. By regular mail. You may mail 

written comments to the following 

address: 

CMS, Office of Strategic Operations 

and Regulatory Affairs, Division of 

Regulations Development, Attention: 

Document Identifier/OMB Control 

Number, Room C4–26–05, 7500 Security 

Boulevard, Baltimore, Maryland 21244– 

1850. 

Dated: January 7, 2011. 

Martique Jones, 

Director, Regulations Development Group, 

Division B, Office of Strategic Operations and 

Regulatory Affairs. 

[FR Doc. 2011–737 Filed 1–13–11; 8:45 am] 

BILLING CODE 4120–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

[Docket No. FDA–2011–N–0021] 

Prescription Drug Products Containing 

Acetaminophen; Actions To Reduce 

Liver Injury From Unintentional 

Overdose 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug 

Administration (FDA) is taking steps to 

reduce the maximum dosage unit 

strength of acetaminophen in 

prescription drug products. This change 

will provide an increased margin of 

safety to help prevent liver damage due 

to acetaminophen overdosing, a serious 

public health problem. This notice 

explains the reasons for the reduction in 

dosage unit strength and describes how 

FDA is implementing it for approved 

prescription drug products that exceed 

the new maximum tablet or capsule 

strength. FDA is also requiring safety 

labeling changes, including a new boxed 

warning, for acetaminophen-containing 

prescription drug products to address 

new safety information about the risk of 

liver damage. 

DATES: Sponsors of approved 

prescription drug products containing 

more than 325 milligrams (mg) of 

acetaminophen have until January 14, 

2014 to request that FDA withdraw 

approval of the product’s application, 

after which they may be subject to 

action by FDA. 

FOR FURTHER INFORMATION CONTACT: 

Faith Dugan, Center for Drug Evaluation 

and Research, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 51, Rm. 6182, Silver Spring, 

MD 20993–0002, 301–796–3446. 

SUPPLEMENTARY INFORMATION: 

I. Acetaminophen Drug Products and 

Liver Injury 

Acetaminophen is the generic name of 

a drug used in many over-the-counter 

(OTC) oral pain-relievers such as 

Tylenol, and in prescription 

combination drug products such as 

Vicodin and Percocet. Acetaminophen 

is one of the most widely used drugs in 

the United States in both prescription 

and OTC products. This notice applies 

only to acetaminophen-containing drug 

products that are labeled for 

prescription use and marketed under 

approved new drug applications (NDAs) 

or abbreviated new drug applications 

(ANDAs). OTC acetaminophen drug 

products are not affected by this notice.1

All acetaminophen-containing 

prescription products are combinations 

with other drug ingredients, primarily 

opioids in various strengths. These 

other drug ingredients include the 

opioids hydrocodone bitartrate (e.g., 

Vicodin), oxycodone hydrochloride 

(e.g., Percocet), codeine phosphate (e.g., 

Tylenol with Codeine), dihydrocodeine, 

tramadol hydrocholoride, and 

pentazocine hydrochloride, as well as 

butalbital (a barbiturate) and caffeine (a 

stimulant).2 General references to 

‘‘acetaminophen combinations’’ or 

‘‘acetaminophen combination products’’ 

in this notice refer to all such products. 

There are no prescription drug products 

that contain only acetaminophen. 

Prescription combination drugs 

account for approximately 20 percent of 

the total acetaminophen drug market, 

and include some of the most widely 

prescribed and sold prescription drug 

products in the United States. (The 

remaining 80 percent of the 

acetaminophen drug market consists of 

OTC products.) Acetaminophenhydrocodone combinations account for 

more than half of all prescriptions for 

acetaminophen combination drug 

products in the United States, and for 

many years, have also been the mostprescribed products in the U.S. retail 

market (Ref. 1). Unlike other drugs 

commonly used to reduce pain and 

fever (e.g., nonsteroidal antiinflammatory drugs (NSAIDS) such as 

aspirin, ibuprofen, and naproxen), at 

recommended doses acetaminophen 

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2692 Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 

3These include, among others: Emergency 

department data from the National Electronic Injury 

Surveillance System All Injury Program and the 

National Hospital Ambulatory Medical Care 

Survey–Emergency Department; hospitalization 

data from the National Hospital Discharge Survey; 

and mortality data from the National Multiple 

Cause of Death File. 

4The NPDS data include all acetaminophenrelated calls, including calls relating to both 

prescription and OTC products, and calls that do 

not involve liver damage. ‘‘Serious injury’’ includes, 

but is not limited to, serious liver damage caused 

by acetaminophen. 

does not cause gastro-intestinal 

discomfort and/or bleeding. However, 

despite its wide use, long acceptance, 

and therapeutic utility, acetaminophen 

does pose risks. Acetaminophen 

overdose can cause liver damage 

(hepatotoxicity), ranging in severity 

from abnormalities in liver function to 

acute liver failure (ALF), and even death 

(Ref. 1). Acetaminophen overdose has 

become the leading cause of ALF as well 

as a leading cause of death from ALF in 

the United States (Refs. 2, 3, and 4). 

Based on extrapolation from regional 

results in the first population-based 

study of ALF conducted in the United 

States, an estimated national total of 

1,600 cases of ALF may occur each year 

(Ref. 3). 

Acetaminophen-induced liver injury 

is caused by the effects of a toxic 

metabolite of acetaminophen, N-acetylp-benzoquinone imine (NAPQI) that is 

produced when acetaminophen is 

broken down by the body (Ref. 5). With 

low doses of acetaminophen, the 

amount of NAPQI produced is low and 

an individual’s body usually has 

sufficient intracellular glutathione 

levels to bind to the NAPQI and prevent 

toxicity (Ref. 6). With higher 

acetaminophen levels and greater 

NAPQI production, NAPQI binds to 

liver proteins, causing cellular injury 

that can lead to liver failure and death 

(Refs. 4 and 7). 

The likelihood and severity of liver 

injury is influenced by the amount of 

acetaminophen that is ingested and the 

ability of an individual’s liver to 

effectively remove it from the body. In 

most cases, glutathione levels are more 

than sufficient to conjugate the small 

amount of NAPQI produced by 

therapeutic doses of acetaminophen 

(Ref. 6). However, some people may 

have increased risk for liver injury 

following exposure to therapeutic doses 

or overdoses of acetaminophen due to 

reduced glutathione stores, induced 

cytochrome P450 enzymatic activity, or 

states of oxidative stress. Increased risk 

may be associated with a wide variety 

of conditions, such as Acquired Immune 

Deficiency Syndrome, chronic 

alcoholism, acute excess alcohol use, 

and use of anticonvulsant or 

antituberculosis medications (Refs. 8 

and 9). Acetaminophen poisoning is 

treated with the drug N-acetylcysteine 

(NAC), which helps prevent toxicity by 

inactivating NAPQI. However, NAC 

does not reverse liver cell damage that 

has already occurred (Ref. 10). 

The public health burden of 

acetaminophen-associated overdoses 

has been estimated using data from a 

variety of national databases and other 

resources.3 A summary of data from four 

different surveillance systems indicates 

that there were an estimated 56,000 

emergency room visits, 26,000 

hospitalizations, and 458 deaths per 

year related to acetaminophenassociated overdoses during the 1990s 

(Ref. 10). Within these estimates, 

unintentional acetaminophen overdose 

accounted for nearly 25 percent of the 

emergency department visits, 10 percent 

of the hospitalizations, and 25 percent 

of the deaths (Ref. 10). 

Prescription products contribute 

significantly to the toll of liver damage 

from both unintentional and intentional 

acetaminophen overdoses. For example, 

in the study of ALF patients by Larson 

et al., 63 percent of the unintentionally 

overdosed subjects and 18 percent of 

intentionally overdosed subjects had 

taken prescription acetaminophen 

combination products prior to injury 

(Ref. 4). According to data from the 

Toxic Exposure Surveillance System 

(now named the National Poison Data 

System (NPDS)), 30 percent of all 

acetaminophen-associated calls to 

poison centers in 2005 involved 

prescription acetaminophen 

combination products (41,999 of 

138,602 calls). Prescription 

acetaminophen combination products 

were involved in approximately 44 

percent of acetaminophen-associated 

calls that resulted in serious injury 

(1,470 of 3,310 calls) and 48 percent 

(161 of 333 calls) of acetaminophenassociated calls that resulted in fatalities 

(Ref. 11).4

In addition, there is a high incidence 

of cases of unintentional acetaminophen 

overdose, which should be preventable. 

In a population-based study of ALF 

conducted in the United States, 45 

percent of adult ALF cases were 

associated with acetaminophen use and 

55 percent of those were related to 

unintentional overdose (Ref. 3). In 

another study, similarly, approximately 

half of the cases of acetaminopheninduced ALF were due to unintentional 

overdose (Ref. 4). 

There is no single factor that accounts 

for the high incidence of unintentional 

acetaminophen overdose. Multiple 

distinct factors appear to contribute to 

the problem, including the following: 

• Given the large number and wide 

array of OTC and prescription 

acetaminophen products and 

indications, consumers may 

unintentionally overdose by taking more 

than one acetaminophen product at the 

same time without realizing that 

acetaminophen is a common ingredient. 

• Patients may be unaware that their 

prescription pain relief products contain 

acetaminophen because the ingredient 

is often identified on pharmacy drug 

containers only as ‘‘APAP,’’ an acronym 

based on the chemical name of 

acetaminophen (N-acetyl-paraaminophenol), or by an abbreviation 

such as ‘‘ACET.’’ Such terms are not 

generally understood by the public to 

mean that a product contains 

acetaminophen. 

• Patients may take more than the 

maximum number of labeled or 

prescribed doses seeking additional 

therapeutic benefit, unaware that they 

are taking too much acetaminophen. 

• Experts agree that taking a large 

amount of acetaminophen over a short 

period of time causes liver injury, but a 

specific threshold dose for toxicity has 

not been established and may not be the 

same for all persons. Based on available 

information, we cannot currently 

identify all of the factors that might 

increase an individual’s risk of 

acetaminophen toxicity, particularly at 

doses near the current recommended 

total daily dose of 4,000 mg per day 

(Refs. 5 and 7). 

• NAC, the antidote for 

acetaminophen poisoning, is most 

effective when given in the first 8 hours 

after an acute overdose and has been 

shown to have benefit up to 24 hours 

and possibly later (Ref. 10). Victims of 

unintentional acetaminophen overdose 

may not be treated within that time 

because the symptoms of liver damage 

can take several days to emerge, even in 

severe cases, and are not readily 

associated by patients or clinicians with 

acetaminophen poisoning (Ref. 5). 

• Patients do not realize that 

acetaminophen can cause severe liver 

injury if the recommended dose is 

exceeded. In 2004, FDA launched a 

public education program to help 

inform consumers about the potential 

for acetaminophen to cause liver injury. 

Since that time, FDA has provided 

materials for use in a wide variety of 

media and tailored for users of both 

prescription and OTC acetaminophen 

products. The continued occurrence of 

liver injury associated with prescription 

acetaminophen combinations 

notwithstanding those efforts suggests 

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Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 2693 

5Meeting of the Non-Prescription Drug Advisory 

Committee with members from the Anesthetic and 

Life Support Drugs Advisory Committee, Arthritis 

Advisory Committee, Drug Safety and Risk 

Management Advisory Committee, and 

Gastrointestinal Drugs Advisory Committee, 

September 19 and 20, 2002, (2002 Advisory 

Committee). Detailed information on this meeting 

can be viewed electronically at http://www.fda.gov/ 

ohrms/dockets/ac/ 

cder02.htm#NonprescriptionDrugs. 

6 2002 Advisory Committee Transcript, 

September 19, 2002, discussion at 160–182. 

7 2002 Advisory Committee Transcript, supra at 

182–221. 

8Among other recommendations, 24 of the 37 

Advisory Committee members recommended 

reducing the amount of acetaminophen per single 

adult dose in OTC products to 650 milligrams per 

dose (i.e., two 325 mg tablets or capsules). With 

respect to prescription products, the Advisory 

Committee overwhelmingly voted to require a 

boxed warning for prescription acetaminophen 

combinations, and slightly more than half favored 

eliminating prescription acetaminophen 

combinations entirely (with the option of 

prescribing single-entity opioids instead). While not 

offered as a voting option, the alternative of 

reducing the amount of acetaminophen per dosage 

unit in prescription combination products was 

recommended by a number of Advisory Committee 

members. See FDA, Joint Meeting of the Drug Safety 

and Risk Management Advisory Committee, 

Nonprescription Drugs Advisory Committee, and 

the Anesthetic and Life Support Drugs Advisory 

Committee to Address the Public Heath Problem of 

Liver Injury Related to the Use of Acetaminophen 

in Both Over-the-Counter and Prescription Drugs, 

June 30, 2009, at 658–672 (Vote on Question 2), 

771–801 (Vote on Question 7), 802–842 (Vote on 

Question 9 and Discussion of Question 11). 

that additional interventions are 

needed. 

II. FDA’s Acetaminophen Safety 

Initiatives 

FDA has been working to reduce the 

incidence of acetaminophen-related 

liver injury since the early 1990s, when 

the scope of the problem began to 

become evident. In addition to the 

scientific activities described in section 

I of this document, we have been active 

in acetaminophen safety education for 

consumers and health care 

professionals. In particular, we are 

currently working with the National 

Association of State Boards of 

Pharmacy, to urge state authorities to 

adopt rules replacing the term ‘‘APAP’’ 

and other abbreviations with 

‘‘acetaminophen’’ on pharmacy 

containers. Our dedicated Web page on 

acetaminophen safety provides access to 

educational information along with 

links to additional scientific and 

regulatory resources. This information 

can be viewed at http://www.fda.gov/ 

Drugs/DrugSafety/ 

InformationbyDrugClass/ 

ucm165107.htm. 

Most importantly, as the Federal 

Agency responsible for the sciencebased regulatory oversight of drug 

products, we have continued to identify 

and pursue additional regulatory 

measures to reduce the risk of 

acetaminophen-induced liver injury. 

Rulemaking initiatives to date have 

focused largely on OTC acetaminophen 

products under our ongoing monograph 

proceeding for OTC internal analgesic, 

anti-inflammatory and antipyretic drug 

products. In 2002, we conducted a 

comprehensive review of the available 

data on acetaminophen and liver injury. 

The data were presented for 

consideration by the Non-Prescription 

Drug Advisory Committee (2002 

Advisory Committee) 5 whose members 

unanimously agreed that the evidence of 

risk associated with the unintentional 

overdose of acetaminophen warranted 

labeling changes.6 The 2002 Advisory 

Committee also considered whether a 

lower dose that would be safe for 

alcohol users or other sensitive 

subpopulations could be identified, but 

concluded that current data were 

insufficient for this purpose.7 Based in 

part on the 2002 Committee’s 

recommendations, in 2009 the Agency 

issued a new final rule requiring 

specific liver injury warnings and 

related labeling for OTC acetaminophen 

drugs (final rule, 74 FR 19385, April 29, 

2009; and technical amendment, 74 FR 

61512, November 25, 2009). 

In 2007, the Director of FDA’s Center 

for Drug Evaluation and Research 

(CDER) convened a multidisciplinary 

working group in CDER to update, 

review, and report on the full range of 

medical data and to propose additional 

regulatory options for both prescription 

and OTC acetaminophen drug products. 

On June 29 and 30, 2009, FDA held a 

joint meeting of the Drug Safety and 

Risk Management Advisory Committee, 

the Nonprescription Drugs Advisory 

Committee, and the Anesthetic and Life 

Support Drugs Advisory Committee 

(2009 Advisory Committee) to consider 

the collected data and related public 

testimony and make recommendations 

concerning further regulatory options 

for both prescription and OTC 

acetaminophen drugs. Detailed 

information on the 2009 Advisory 

Committee’s deliberations and the 

evidence it considered are available on 

FDA’s Web site at http://www.fda.gov/ 

AdvisoryCommittees/Calendar/ 

ucm143083.htm. After reviewing and 

discussing the evidence presented, the 

2009 Advisory Committee 

recommended a range of additional 

regulatory actions such as adding a 

boxed warning to prescription 

acetaminophen products, withdrawing 

prescription combination products from 

the market, or reducing the amount of 

acetaminophen in each dosage unit.8

FDA has determined that reducing the 

dosage unit strength of acetaminophen 

in prescription products is necessary to 

reduce the risk of liver injury associated 

with prescription acetaminophen 

combinations, and to ensure safe use of 

acetaminophen combinations. FDA is 

issuing this notice as the first step 

towards implementing this change. In 

deciding to take this step, we 

considered the 2009 Advisory 

Committee’s recommendations and the 

Agency’s evaluation of the available 

data on both prescription and OTC 

products. The data and the 2009 

Advisory Committee’s 

recommendations on OTC products are 

relevant to prescription acetaminophen 

combinations for several reasons. The 

mechanism of acetaminophen-related 

liver injury is the same for both OTC 

and prescription drug products. In 

addition, while the range of 

acetaminophen strengths is much 

greater for prescription than for OTC 

products, the most widely used 

acetaminophen dosage unit in both 

prescription and OTC products is 500 

mg. All acetaminophen products 

likewise share the same maximum 

recommended daily dose (4,000 mg). As 

a result, our safety evaluation of 

prescription acetaminophen products 

draws on the common body of evidence 

and expert advice about all 

acetaminophen products, as well as 

important factors that are specific to the 

prescription products and how they are 

used. 

III. FDA’s New Safety Measures for 

Prescription Acetaminophen Drug 

Products 

A. Safety Labeling Changes 

Consistent with the advice of the 2009 

Advisory Committee, FDA today is 

issuing letters to holders of approved 

NDAs and ANDAs (if the same drug 

approved under section 505(b) of the 

Federal Food, Drug, and Cosmetic Act 

(the FD&C Act) (21 U.S.C. 355(b)) is not 

currently marketed) for prescription 

acetaminophen drugs, notifying them of 

the need to modify the labeling of 

prescription acetaminophen drugs to 

reflect new safety information about 

acetaminophen and liver toxicity. Our 

authority for this action is section 

505(o)(4) of the Federal Food, Drug, and 

Cosmetic Act (FD&C Act), which was 

added to the FD&C Act by the Food and 

Drug Administration Amendments Act 

of 2007. This provision authorizes FDA 

to require certain holders of approved 

new drug applications to make safetyrelated labeling changes based on new 

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2694 Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 

9Section 505(o)(4) of the FD&C Act also 

establishes the procedures for implementing safety 

labeling changes. The procedures include an 

opportunity for application holders to question the 

need for or specific wording of the labeling changes. 

10 Detailed Orange Book listings, including 

specific application numbers and sponsors, can be 

viewed electronically by accessing FDA’s Web site 

at http://www.accessdata.fda.gov/scripts/cder/ob, 

electing ‘‘Search by Active Ingredient,’’ and entering 

‘‘acetaminophen’’ in the search form. 11The figures in table 1 of this document do not 

include approved applications for combination 

products that are subject to the recently announced 

market withdrawal due to safety concerns related to 

propoxyphene. The table also excludes various 

approved combinations that are not currently 

marketed. These include: 

acetaminophen;butalbital;caffeine;codeine (1 

approved application with acetaminophen strength 

≤ 325 mg;) acetaminophen;caffeine;dihydrocodeine 

bitartrate (5 applications with acetaminophen 

strengths > 325 mg;) acetaminophen;codeine 

phosphate (1 application with acetaminophen 

strength over 325 mg); acetaminophen;hydrocodone 

in solution dosage form (3 applications with 

acetaminophen strengths ≤ 325 mg; 6 with 

acetaminophen strengths > 325 mg). 

safety information that becomes 

available after approval of the drug.9

The letters issued today propose that 

the sponsors of prescription 

acetaminophen drugs make various 

modifications to their drugs’ approved 

labeling, including adding the following 

as a boxed warning: 

Hepatotoxicity 

[DRUG NAME] contains acetaminophen 

and [INGREDIENT]. Acetaminophen has 

been associated with cases of acute liver 

failure, at times resulting in liver transplant 

and death. Most of the cases of liver injury 

are associated with the use of acetaminophen 

at doses that exceed 4,000 milligrams per 

day, often in combination with other 

acetaminophen-containing products. 

The safety labeling changes will be 

required for all prescription drug 

products containing acetaminophen. In 

accordance with section 505(o)(4)(B) of 

the FD&C Act, within 30 days of the 

date of the letters, the holders of 

approved applications for prescription 

acetaminophen drugs must submit to 

FDA a supplement proposing labeling 

changes that reflect the new safety 

information about acetaminophen and 

liver toxicity, or a statement detailing 

the reasons why such a change is not 

warranted. 

However, we do not believe that these 

safety labeling changes alone will 

adequately address the ongoing problem 

of liver injury associated with 

prescription acetaminophen 

combinations. Accordingly, we are 

taking additional steps to reduce the 

amount of exposure to acetaminophen 

from these products, as described in the 

following discussion. 

B. Limiting the Amount of 

Acetaminophen in Prescription 

Combination Products 

1. How and Why We Are Limiting 

Acetaminophen Content 

In light of the information described 

previously, we have re-evaluated the 

relative risks and benefits of 

prescription acetaminophen products 

and have concluded that acetaminophen 

prescription drugs containing more than 

325 mg of acetaminophen per dosage 

unit (tablet or capsule) do not provide 

a sufficient margin of safety to protect 

the public against the serious risk of 

acetaminophen-induced liver injury. 

Accordingly, we are asking product 

sponsors to limit the maximum amount 

of acetaminophen per dosage unit of the 

combination product (‘‘acetaminophen 

strength’’) to 325 mg. We are basing this 

change on multiple considerations, 

including the following: 

• The significant contribution made 

by prescription products to the 

continued and unacceptably high 

incidence of acetaminophen-related 

liver injury; 

• The need to establish an adequate 

margin of safety given the current 

inability to identify precise toxicity 

thresholds and/or specific populations 

for whom currently recommended 

dosages are not safe; 

• The high potential for unintentional 

overdosing; and 

• The lack of evidence from which to 

conclude that the benefit of increased 

pain relief or dosing convenience from 

higher acetaminophen strengths 

outweighs the risk of liver damage from 

unintentional overdose. 

The intended effect of reducing the 

amount of acetaminophen to 325 mg per 

dosage unit is to reduce the potential for 

exceeding the toxic threshold of the 

drug that could cause liver injury. This 

change is intended to reduce the risk of 

unintentional acetaminophen overdose 

by providing an additional margin of 

safety for all users, including 

individuals who, for a variety of reasons 

(e.g., existing liver disease, chronic 

alcohol use) are particularly susceptible 

to liver injury from acetaminophen. The 

change is consistent with the 

fundamental principle that the benefitto-risk ratio of a drug must be 

considered in determining safety and 

effectiveness, and the safety of a drug 

can only be established if its benefits 

outweigh its known and potential risks. 

Additionally, as discussed in the 

following section, many acetaminophen 

combinations are already approved at 

the 325-mg acetaminophen strength and 

thus can provide a basis for further 

generic approvals at the new maximum 

dosage unit strength. 

It is not possible, based on currently 

available information, to quantify 

precisely to what extent reducing the 

maximum acetaminophen strength of 

acetaminophen combination drugs will 

reduce the incidence of liver injury. 

However, data from Larson et al. (Ref. 4) 

suggest that the effect could be 

considerable. In that study, the median 

dose of acetaminophen taken by 77 

people with an unintentional overdose 

was 7,500 mg per day. Assuming that 

they took 500 mg tablets (currently the 

most common prescription and OTC 

dosage strength), the total median dose 

for this group from taking the same 

number (15) of 325-mg tablets or 

capsules would have been only 4,875 

mg, a level at which death or liver 

failure is unlikely to occur in most 

people. 

2. How FDA Is Implementing the 

Limitation on Acetaminophen Strength 

We have identified prescription 

acetaminophen drug products and 

product sponsors potentially affected by 

this notice based on information in the 

list of Approved Drug Products With 

Therapeutic Equivalence Evaluations 

(the Orange Book).10 Table 1 of this 

document provides an overview of 

approved new drug applications for 

currently marketed acetaminophen 

combination products grouped 

according to their active ingredients and 

acetaminophen strengths.11

TABLE 1—OVERVIEW OF CURRENTLY MARKETED PRESCRIPTION ACETAMINOPHEN PRODUCTS

Ingredient combination 

N*—All 

acetaminophen 

strengths 

Acetaminophen 

strengths 

≤325 mg 

N*—Acetaminophen 

strengths 

≤325 mg 

Acetaminophen 

strengths 

>325 mg 

N*—Acetaminophen 

strengths 

>325 mg 

Acetaminophen; 

Butalbital.

4 325 mg; 50 mg Tablets .............. 2 650 mg; 50 mg Tablets .............. 1 

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Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 2695 

TABLE 1—OVERVIEW OF CURRENTLY MARKETED PRESCRIPTION ACETAMINOPHEN PRODUCTS—Continued 

Ingredient combination 

N*—All 

acetaminophen 

strengths 

Acetaminophen 

strengths 

≤325 mg 

N*—Acetaminophen 

strengths 

≤325 mg 

Acetaminophen 

strengths 

>325 mg 

N*—Acetaminophen 

strengths 

>325 mg 

650 mg; 50 mg Capsules ........... 1 

Total: 2 Total: 2 

Acetaminophen; 

Butalbital; Caffeine.

16 300 mg; 50 mg; 40 mg Capsules 1 500 mg; 50 mg; 40 mg Tablets .. 6 

325 mg; 50 mg; 40 mg Tablets .. 6 500 mg; 50 mg; 40 mg Capsules 1 

325 mg; 50 mg; 40 mg Capsules 1 750 mg; 50 mg; 40 mg Tablet .... 1 

Total: 8 Total: 8 

Acetaminophen Codeine 

Phosphate.

24 300 mg; 15 mg Tablets .............. 6 None ........................................... 0 

300 mg; 30 mg Tablets .............. 10 

300 mg 60 mg Tablets ............... 8 

Total: 24 Total: 0 

Acetaminophen; 

Hydrocodone.

88 300 mg; 5 mg Tablets ................ 1 400 mg; 5 mg Tablets ................ 1 

300 mg; 7.5 mg Tablets ............. 1 400 mg; 7.5 mg Tablets ............. 1 

300 mg; 10 mg Tablets .............. 1 400 mg; 10 mg Tablets .............. 1 

325 mg; 2.5 mg Tablets ............. 1 500 mg; 2.5 mg Tablets ............. 4 

325 mg; 5 mg Tablets ................ 500 mg; 5 mg Tablets ................ 12 

325 mg; 7.5 mg Tablets ............. 500 mg; 7.5 mg Tablets ............. 7 

325 mg; 10 mg Tablets .............. 7 500 mg; 10 mg Tablets .............. 7 

Total: 21 

500 mg; 5 mg Capsules ............. 2 

650 mg; 5 mg Tablets ................ 1 

650 mg; 7.5 mg .......................... 7 

7 

6 

9 

2 

Total: 67 

Acetaminophen; 

Hydrocodone.

300 mg; 5 mg Tablets ................ 1 400 mg; 5 mg Tablets ................ 1 

300 mg; 7.5 mg Tablets ............. 1 400 mg; 7.5 mg Tablets ............. 1 

300 mg; 10 mg Tablets .............. 1 400 mg; 10 mg Tablets .............. 1 

325 mg; 2.5 mg Tablets ............. 1 500 mg; 2.5 mg Tablets ............. 4 

325 mg; 5 mg Tablets ................ 5 500 mg; 5 mg Tablets ................ 12 

325 mg; 7.5 mg Tablets ............. 5 500 mg; 7.5 mg Tablets ............. 7 

325 mg; 10 mg Tablets .............. 7 500 mg; 10 mg Tablets .............. 7 

Total: 21 

500 mg; 5 mg Capsules ............. 2 

650 mg; 5 mg Tablets ................ 1 

650 mg; 7.5 mg Tablets ............. 7 

650 mg; 10 mg Tablets .............. 7 

660 mg; 10 mg Tablets .............. 6 

750 mg; 7.5 mg Tablets ............. 9 

750 mg; 10 mg Tablets .............. 2 

Total: 67 

49 300 mg; 2.5 mg Tablets ............. 1 400 mg; 2.5 mg Tablets ............. 1 

Acetaminophen; 

Oxycodone HCl.

300 mg; 5 mg Tablets ................ 1 400 mg; 5 mg Tablets ................ 1 

300 mg; 7.5 mg Tablets ............. 1 400 mg; 7.5 mg Tablets ............. 1 

300 mg; 10 mg Tablets .............. 1 400 mg; 10 mg Tablets .............. 1 

325 mg; 2.5 mg Tablets ............. 2 500 mg; 5 mg Tablets ................ 1 

325 mg; 5 mg Tablets ................ 8 500 mg; 75 mg Tablets .............. 5 

325 mg; 7.5 mg Tablets ............. 4 500 mg; 10 mg Tablets .............. 1 

325 mg; 10 mg Tablets .............. 5 500 mg; 5 mg Capsules ............. 8 

325 mg/5 ml; 5 mg/5 ml Oral Solution.2 650 mg; 5 mg Tablets ................ 4 

Total: 25 650 mg; 10 mg Tablets .............. Total: 24 

Acetaminophen; 

Pentazocine HCl.

2 None ........................................... 0 650 mg; EQ 25 mg BASE Tablets.2 

Total: 2 

Acetaminophen; 

Tramadol HCL.

6 325 mg; 37.5 mg Tablets ........... 6 None ........................................... 0 

Total: 6 Total: 0 

GRAND 

TOTAL 189 

TOTAL 86 TOTAL 103 

* N = number of approved applications. 

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2696 Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 

12For historical reasons, virtually all currently 

approved applications for prescription 

acetaminophen combination products are ANDAs 

rather than NDAs. Unlike NDAs, which may be 

supplemented to reflect changes in unit dosage 

strength or other product characteristics, products 

marketed under an approved ANDA must maintain 

the same strength as the RLD. Accordingly, if the 

acetaminophen strength of such a product is 

reformulated from, e.g., 500 mg to 325 mg, a new 

ANDA listing either an appropriate RLD having the 

new lower strength or an appropriate approved 

suitability petition as described in 

§ 314.94(a)(3)(iii), must be approved before the 

reformulated product may be marketed. 

As shown in table 1 of this document, 

there are 7 different prescription 

acetaminophen combinations currently 

marketed under a total of 189 approved 

active applications. The applications are 

held by a total number of 26 sponsors. 

Products with approved acetaminophen 

strengths of 325 mg or less per dosage 

unit (‘‘lower acetaminophen strengths’’) 

account for slightly fewer than half (86) 

of the approved applications but are 

much less widely marketed and 

prescribed than products with higher 

acetaminophen strengths. 

We anticipate that drug sponsors who 

request that FDA withdraw approval of 

their higher acetaminophen strength 

applications under § 314.150(d) (21 CFR 

314.150(d)) will wish to market the 

same combination of active ingredients 

with lower acetaminophen strength. For 

example, a sponsor that requests that 

FDA withdraw approval of its 

application for 500 mg of 

acetaminophen combined with 5 mg of 

hydrocodone in tablet dosage form 

presumably would want to remain on 

the market with a tablet product 

containing 5 mg of hydrocodone and no 

more than 325 mg of acetaminophen. 

Such a change will not require 

submission of an application by 

sponsors who already have approved 

applications for the lower strength 

product, as often is the case. However, 

sponsors who do not already have such 

approval would need to develop a new 

formulation with the lower 

acetaminophen strength, submit an 

appropriate application, and obtain FDA 

approval before marketing. 

We anticipate that in virtually all 

cases the fastest and least burdensome 

route to approval for new lower 

acetaminophen strength versions of 

existing higher acetaminophen strength 

products will be through new ANDA 

submissions using another 

manufacturer’s existing lower 

acetaminophen strength product as the 

reference listed drug (RLD).12 For nearly 

all of the higher acetaminophen strength 

combinations, there is at least one 

appropriate RLD with an 

acetaminophen strength at or below 325 

mg in the Orange Book. For a small 

minority of higher acetaminophen 

strength combinations, there is no 

approved lower acetaminophen strength 

product with the same active 

ingredients that could serve as the RLD. 

We believe that reformulations of these 

products, however, could be approved 

as ANDAs upon approval of an ANDA 

suitability petition (see section 

505(j)(2)(C) of the FD&C Act and 

§ 314.93 (21 CFR 314.93)) permitting the 

submission of an ANDA for a drug 

product that is not identical to the RLD 

in an active ingredient or unit dosage 

strength, or could be approved as NDAs 

following submission of applications 

with appropriate clinical studies. 

We are establishing a timeframe for 

responding to this notice that takes into 

account the estimated time needed for 

sponsors to obtain necessary approvals 

and begin to market new products with 

lower acetaminophen strengths. We 

believe that a period of 3 years from 

publication of this notice in the Federal 

Register will provide adequate time for 

drug sponsors to prepare to withdraw 

existing products with higher 

acetaminophen strengths, and to 

develop and obtain approval for lower 

acetaminophen strength versions of 

those products. We also anticipate that 

this will provide sufficient time for drug 

sponsors with approved lower 

acetaminophen strength products to 

expand their production to meet the 

expected increase in demand for lower 

acetaminophen strength products when 

the higher strength products become 

unavailable. 

We strongly encourage sponsors of 

combination prescription products with 

acetaminophen strengths greater than 

325 mg to submit requests for 

withdrawal of those products’ approved 

applications under § 314.150(d) within 

the 3-year period described previously. 

Sponsors who intend to seek approval 

of one or more new products with 

acetaminophen strengths of 325 mg or 

less are encouraged to submit 

appropriate applications for such 

products in time to obtain approval 

within the same period. To that end, we 

welcome inquiries and requests for 

consultation from sponsors relating to 

specific existing or proposed products 

in connection with this notice. Any 

such requests from sponsors of currently 

approved products affected by this 

notice should be made as 

correspondence under the affected 

application(s) and should reference this 

notice. 

We are issuing this notice because we 

believe that voluntary action on the part 

of product sponsors to reduce the 

acetaminophen strengths of prescription 

acetaminophen combinations can 

achieve the needed increase in patient 

safety substantially sooner and with less 

burden on public and private resources 

than alternative regulatory measures. 

However, FDA has authority under 

section 505(e)(2) of the FD&C Act to 

withdraw approval of an NDA or ANDA 

if the Agency determines that the 

‘‘* * * drug is not shown to be safe for 

use under the conditions of use upon 

the basis of which the drug was 

approved * * *’’ based on consideration 

of ‘‘* * * new evidence * * * together 

with the evidence available to [FDA] 

when the application was approved 

* * *.’’ FDA regulations describe the 

procedures for withdrawing approval of 

an application. (See § 314.150 and 21 

CFR 314.151, 314.200, 314.201, and 

314.235). We intend to use our authority 

under section 505(e) of the FD&C Act to 

initiate withdrawal proceedings for any 

prescription acetaminophen 

combination products with 

acetaminophen strengths greater than 

325 mg that remain on the market 3 

years after the date of publication of this 

notice. 

IV. References 

1. FDA Center for Drug Evaluation and 

Research, Acetaminophen Overdose and 

Liver Injury—Background and Options 

for Reducing Injury, Available on FDA’s 

Web site at http://www.fda.gov/Advisory

Committees/CommitteesMeeting

Materials/Drugs/DrugSafetyandRisk

ManagementAdvisoryCommittee/

ucm126014.htm. 

2. Schiodt, F.V. et al., ‘‘Acetaminophen 

Toxicity in an Urban County Hospital,’’ 

New England Journal of Medicine, 

337:1112–7, 1997. 

3. Bower, W.A. et al., ‘‘Population-Based 

Surveillance for Acute Liver Failure,’’ 

American Journal of Gastroenterology, 

(102(11)):2459–63, 2007. 

4. Larson, A.M. et al., ‘‘AcetaminophenInduced Acute Liver Failure: Results of 

a United States Multicenter, Prospective 

Study,’’ Hepatology, 42:1364–72, 2005. 

5. Larson, A.M., ‘‘Acetaminophen 

Hepatotoxicity,’’ Clinical Liver Disease, 

11:525–48, vi, 2007. 

6. Holme J.A. et al., Cytotoxic Effects of Nacetyl-p-Benzoquinone Imine, a 

Common Arylating Intermediate of 

Paracetamol and N-hydroxyparacetamol, 

Biochemical Pharmacology, Feb. 1:33(3), 

1984. 

7. James, LP et al., ‘‘Pharmacokinetics of 

Acetaminophen—Protein Adducts in 

Adults With Acetaminophen Overdose 

and Acute Liver Failure,’’ Drug 

Metabolism and Disposition 37: 1779– 

1784, 2009. 

8. Lee W., Drug-Induced Hepatotoxicity, New 

England Journal of Medicine, 349:474– 

485, 2003. 

9. Smilkstein, M.J. et al., ‘‘Efficacy of Oral NAcetylcysteine in the Treatment of 

Acetaminophen Overdose, Analysis of 

the National Multicenter Study (1976 to 

mstockstill on DSKH9S0YB1PROD with NOTICES

Federal Register / Vol. 76, No. 10 / Friday, January 14, 2011 / Notices 2697 

1985),’’ New England Journal of 

Medicine, 319:1557–62, 1988. 

10. Nourjah P. et al, ‘‘Estimates of 

Acetaminophen (Paracetamol)-induced 

Overdoses in the United States,’’ 

Pharacoepidemiological Drug Safety, 6: 

406–409, 2006. 

11. Lai, M.W. et al., ‘‘2005 Annual Report 

of the American Association of Poison 

Control Centers’ National Poisoning and 

Exposure Database,’’ Clinical Toxicology, 

44:803–932, 2006. 

Dated: January 10, 2011. 

Leslie Kux, 

Acting Assistant Commissioner for Policy. 

[FR Doc. 2011–709 Filed 1–13–11; 8:45 am] 

BILLING CODE 4160–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Health Resources and Services 

Administration 

Agency Information Collection 

Activities: Proposed Collection: 

Comment Request 

In compliance with the requirement 

for opportunity for public comment on 

proposed data collection projects 

(section 3506(c)(2)(A) of Title 44, United 

States Code, as amended by the 

Paperwork Reduction Act of 1995, Pub. 

L. 104–13), the Health Resources and 

Services Administration (HRSA) 

publishes periodic summaries of 

proposed projects being developed for 

submission to the Office of Management 

and Budget (OMB) under the Paperwork 

Reduction Act of 1995. To request more 

information on the proposed project or 

to obtain a copy of the data collection 

plans and draft instruments, e-mail 

paperwork@hrsa.gov or call the HRSA 

Reports Clearance Officer on (301) 443– 

1129. 

Comments are invited on: (a) The 

proposed collection of information for 

the proper performance of the functions 

of the Agency; (b) the accuracy of the 

Agency’s estimate of the burden of the 

proposed collection of information; (c) 

ways to enhance the quality, utility, and 

clarity of the information to be 

collected; and (d) ways to minimize the 

burden of the collection of information 

on respondents, including through the 

use of automated collection techniques 

or other forms of information 

technology. 

Proposed Project: Children’s Hospitals 

Graduate Medical Education Payment 

Program (CHGME Payment Program) 

(OMB No. 0915–0247)—[Revision] 

The CHGME Payment Program was 

enacted by Public Law 106–129 and 

reauthorized by Public Law 109–307 to 

provide federal support for graduate 

medical education (GME) to 

freestanding children’s hospitals. This 

legislation attempts to provide support 

for GME comparable to the level of 

Medicare GME support received by 

other, non-children’s hospitals. The 

legislation indicates that eligible 

children’s hospitals will receive 

payments for both direct and indirect 

medical education. Direct payments are 

designed to offset the expenses 

associated with operating approved 

graduate medical residency training 

programs and indirect payments are 

designed to compensate hospitals for 

expenses associated with the treatment 

of more severely ill patients and the 

additional costs relating to teaching 

residents in such programs. The 

CHGME Payment Program application 

forms received OMB clearance on June 

30, 2010. Centers for Medicare and 

Medicaid Services (CMS) final rule 

regarding Sections 5503, 5504, 5505 and 

5506 of the Affordable Care Act of 2010, 

Public Law 111–148, published in the 

Federal Register on Wednesday, 

November 24, 2010, requires some 

modification of the data collection 

within the CHGME Payment Program 

application. The CHGME Payment 

Program application forms have been 

adjusted to accommodate CMS policy 

and require OMB approval. 

Data are collected on the number of 

full-time equivalent residents in 

applicant children’s hospitals’ training 

programs to determine the amount of 

direct and indirect medical education 

payments to be distributed to 

participating children’s hospitals. 

Indirect medical education payments 

will also be derived from a formula that 

requires the reporting of discharges, 

beds, and case mix index information 

from participating children’s hospitals. 

Hospitals will be requested to submit 

such information in an annual 

application. Hospitals will also be 

requested to submit data on the number 

of full-time equivalent residents a 

second time during the federal fiscal 

year to participate in the reconciliation 

payment process. 

The estimated annual burden is as 

follows: 

Form Number of 

respondents 

Responses per 

respondent 

Total number of 

responses 

Hours per 

response 

Total burden 

hours 

HRSA 99–1 (Initial Application) ..................... 60 1 60 26 .5 1,590 

HRSA 99–1 (Reconciliation Application) ....... 60 1 60 6 .5 390 

HRSA 99–2 (Initial Application) ..................... 60 1 60 11 .33 679.8 

HRSA 99–2 (Reconciliation Application) ....... 60 1 60 3 .67 220.2 

HRSA 99–3 (Initial Application) ..................... 60 1 60 0 .5 30 

HRSA 99–3 (Reconciliation Application) ....... 60 1 60 0 .5 30 

HRSA 99–4 (Reconciliation Application) ....... 60 1 60 12 .5 750 

HRSA 99–5 (Initial Application) ..................... 60 1 60 .33 19.8 

HRSA 99–5 (Reconciliation Application) ....... 60 1 60 .33 19.8 

Total ........................................................ 60 ............................ 60 .............................. 3729.6 

E-mail comments to 

paperwork@hrsa.gov or mail them to the 

HRSA Reports Clearance Officer, Room 

10–33, Parklawn Building, 5600 Fishers 

Lane, Rockville, MD 20857. Written 

comments should be received within 60 

days of this notice. 

Dated: January 10, 2011. 

Robert Hendricks, 

Director, Division of Policy and Information 

Coordination. 

[FR Doc. 2011–713 Filed 1–13–11; 8:45 am] 

BILLING CODE 4165–15–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

National Institutes of Health 

National Institute on Drug Abuse; 

Notice of Meeting 

Pursuant to section 10(d) of the 

Federal Advisory Committee Act, as 

amended (5 U.S.C. App.), notice is 

mstockstill on DSKH9S0YB1PROD with NOTICES