[Federal Register Volume 76, Number 10 (Friday, January 14, 2011)]
[Notices]
[Pages 2691-2697]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-709]
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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.
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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\
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\1\ FDA 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.
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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.
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\2\ The 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/PostmarketDrugSafetyInformationforPatientsandProviders/ucm233800.htm.
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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.) Acetaminophen-hydrocodone 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 most-prescribed products in the U.S. retail market
(Ref. 1). Unlike other drugs commonly used to reduce pain and fever
(e.g., nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin,
ibuprofen, and naproxen), at recommended doses acetaminophen
[[Page 2692]]
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-acetyl-p-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
acetaminophen-associated 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).
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\3\ These 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.
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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
acetaminophen-associated calls that resulted in fatalities (Ref.
11).\4\
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\4\ The NPDS data include all acetaminophen-related 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.
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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 acetaminophen-
induced 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-para-
aminophenol), 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
[[Page 2693]]
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
science-based 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).
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\5\ Meeting 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.
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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
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\
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\8\ Among 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).
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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 safety-related labeling changes based on new
[[Page 2694]]
safety information that becomes available after approval of the
drug.\9\
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\9\ Section 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.
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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 benefit-to-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\
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\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.
\11\ The 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).
Table 1--Overview of Currently Marketed Prescription Acetaminophen Products
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N*_Acetaminophen
N*_All Acetaminophen strengths N*_Acetaminophen Acetaminophen strengths strengths >325
Ingredient combination acetaminophen <=325 mg strengths >325 mg mg
strengths <=325 mg
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Acetaminophen; Butalbital............... 4 325 mg; 50 mg Tablets....... 2 650 mg; 50 mg Tablets....... 1
[[Page 2695]]
650 mg; 50 mg Capsules...... 1
Total: 2 Total: 2
Acetaminophen; Butalbital; Caffeine..... 16 300 mg; 50 mg; 40 mg 1 500 mg; 50 mg; 40 mg Tablets 6
Capsules.
325 mg; 50 mg; 40 mg Tablets 6 500 mg; 50 mg; 40 mg 1
Capsules.
325 mg; 50 mg; 40 mg 1 750 mg; 50 mg; 40 mg Tablet. 1
Capsules.
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 2 650 mg; 5 mg Tablets........ 4
Solution.
Total: 25 650 mg; 10 mg Tablets....... Total: 24
Acetaminophen; Pentazocine HCl.......... 2 None........................ 0 650 mg; EQ 25 mg BASE 2
Tablets.
Total: 2
Acetaminophen; Tramadol HCL............. 6 325 mg; 37.5 mg Tablets..... 6 None........................ 0
Total: 6 Total: 0
GRAND TOTAL TOTAL 86 TOTAL 103
189
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* N = number of approved applications.
[[Page 2696]]
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
Sec. 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 Sec. 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.
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\12\ For 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 Sec. 314.94(a)(3)(iii), must be approved
before the reformulated product may be marketed.
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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 Sec.
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 Sec. 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/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/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., ``Acetaminophen-Induced 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 N-acetyl-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 N-Acetylcysteine in
the Treatment of Acetaminophen Overdose, Analysis of the National
Multicenter Study (1976 to
[[Page 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