
[Federal Register Volume 79, Number 59 (Thursday, March 27, 2014)]
[Notices]
[Pages 17156-17163]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-06802]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-N-0021]


AbbVie Inc., et al.; Proposal To Withdraw Approval of Abbreviated 
New Drug Applications for Prescription Pain Medications Containing More 
Than 325 Milligrams of Acetaminophen; Opportunity for a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity to request a hearing on the Agency's proposal to withdraw 
approval of abbreviated new drug applications (ANDAs) from multiple 
sponsors for prescription pain medications containing more than 325 
milligrams (mg) of acetaminophen. The basis for this proposal is that 
the Agency has determined that fixed-combination 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.

DATES: Submit written requests for a hearing by April 28, 2014; submit 
data and information in support of the hearing request by May 27, 2014.

ADDRESSES: Identify your requests for a hearing, supporting data, and 
other comments with Docket No. FDA-2011-N-0021 and submit this 
information to the Division of Dockets Management (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Rachel Turow, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6236, Silver Spring, MD 20993-0002, 301-
796-5094.

SUPPLEMENTARY INFORMATION: In the Federal Register of January 14, 2011 
(76 FR 2691), FDA published a notice announcing its plans to reduce the 
maximum dosage unit strength of acetaminophen in prescription drug 
products. The notice announced FDA's conclusion that, based on a 
reevaluation of the relative risks and benefits of prescription 
acetaminophen products, fixed-combination 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 asked product sponsors to limit the maximum amount of 
acetaminophen per dosage unit to 325 mg and, for those products 
containing more than 325 mg of acetaminophen per dosage unit, to submit 
requests that FDA withdraw approval of their applications under Sec.  
314.150(d) (21 CFR 314.150(d)). FDA asked that all such requests be 
made before January 14, 2014, after which date the Agency would use its 
authority under section 505(e) of the Federal Food, Drug, and Cosmetic 
Act (the FD&C Act) (21 U.S.C. 355(e)) to initiate approval withdrawal 
proceedings for any prescription drug products containing more than 325 
mg of acetaminophen per dosage unit that remain on the market. The full 
text of that notice is provided in this document, and provides a 
detailed description and analysis of the specific facts resulting in 
today's action.
    FDA did not receive a request for withdrawal of approval of an 
application containing more than 325 mg of acetaminophen per dosage 
unit from one sponsor. In addition, FDA received requests for 
withdrawal of approval of applications for products containing more 
than 325 mg of acetaminophen per dosage unit for which sponsors either 
submitted requests under Sec.  314.150(c) or failed to cite a relevant 
regulatory provision. FDA contacted all of these sponsors on multiple 
occasions to ask that they submit a request that FDA withdraw approval 
of their applications under Sec.  314.150(d), but they failed to 
respond.
    With respect to those applications for which FDA received no 
request for withdrawal, FDA is proceeding under Sec.  314.150(a) and 
(b) to withdraw approval. With respect to requests for withdrawal of 
approval submitted under Sec.  314.150(c), the Agency notes that 
because FDA has made a determination under Sec.  314.150(a) that 
approval of these applications should be withdrawn for reasons of 
safety, application holders may not withdraw their applications 
pursuant to Sec.  314.150(c). The text of Sec.  314.150(c) expressly 
precludes withdrawal of an application under the subsection if FDA has 
made a safety determination under Sec.  314.150(a). Similarly, when a 
request for withdrawal is made without a citation to any regulation, 
FDA is not appropriately notified that an application holder has 
voluntarily waived the opportunity for a hearing. Accordingly, FDA has 
determined to proceed with withdrawal of approval of applications for 
which sponsors either submitted requests under Sec.  314.150(c) or 
failed to cite a relevant regulatory provision pursuant to the 
withdrawal procedures outlined in Sec. Sec.  314.150 (a) and (b).
    Table 1 lists the applications for products for which FDA received 
no request for withdrawal, a request for withdrawal citing Sec.  
314.150(c), or a request for withdrawal with no regulatory citation.

 Table 1--Applications for Fixed-Combination Prescription Drugs Containing More Than 325 mg of Acetaminophen per
                   Dosage Unit That Have Not Been Voluntarily Withdrawn as of January 14, 2014
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     Application No.             Drug product(s)            Applicant or holder                 Reason
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ANDA 40117..............  Vicodin HP (Acetaminophen     AbbVie Inc., 1 N. Waukegan   Submitted a voluntary
                           and Hydrocodone Bitartrate    Rd., North Chicago, IL       request for withdrawal
                           Tablets), 660 mg/10 mg.       60064.                       under Sec.   314.150(c).
ANDA 88058..............  Vicodin (Acetaminophen and    AbbVie Inc.................  Submitted a voluntary
                           Hydrocodone Bitartrate                                     request for withdrawal
                           Tablets), 500 mg/5 mg.                                     under Sec.   314.150(c).
ANDA 89736..............  Vicodin ES (Acetaminophen     AbbVie Inc.................  Submitted a voluntary
                           and Hydrocodone Bitartrate                                 request for withdrawal
                           Tablets), 750 mg/7.5 mg.                                   under Sec.   314.150(c).

[[Page 17157]]

 
ANDA 89166..............  SYNALGOS-DC-A                 Leitner Pharmaceuticals      Did not submit a voluntary
                           (Acetaminophen, Caffeine,     LLC, 340 Edgemont Ave.,      request for withdrawal.
                           and Dihydrocodeine            Bristol, TN 37620.
                           Bitartrate Capsules), 356.4
                           mg/30 mg/16 mg.
ANDA 40366..............  Acetaminophen and             Nesher Pharmaceuticals USA   Submitted a voluntary
                           Hydrocodone Bitartrate Oral   LLC, 13910 St. Charles       request for withdrawal
                           Solution, 500 mg/15 mL; 7.5   Rock Rd., Bridgeton, MO      under Sec.   314.150(c).
                           mg/15 mL.                     63044.
ANDA 40182..............  Acetaminophen and             Pharmaceutical Associates,   Submitted a voluntary
                           Hydrocodone Bitartrate Oral   Inc., 201 Delaware St.,      request for withdrawal,
                           Solution, 500 mg/15 mL; 7.5   Greenville, SC 29605.        but failed to cite the
                           mg/15 mL.                                                  appropriate regulatory
                                                                                      provision.
ANDA 40825..............  Acetaminophen and             Ranbaxy Laboratories Inc.,   Submitted a voluntary
                           Hydrocodone Bitartrate        C/O Ranbaxy Inc., 600        request for withdrawal,
                           Tablets, 500 mg/5 mg.         College Rd. East,            but failed to cite the
                                                         Princeton, NJ 08540.         appropriate regulatory
                                                                                      provision.
ANDA 40824..............  Acetaminophen and             Ranbaxy Laboratories Inc.,   Submitted a voluntary
                           Hydrocodone Bitartrate        C/O Ranbaxy Inc., 600        request for withdrawal,
                           Tablets, 500 mg/10 mg.        College Rd., East,           but failed to cite the
                                                         Princeton, NJ 08540.         appropriate regulatory
                                                                                      provision.
ANDA 40822..............  Acetaminophen and             Ranbaxy Laboratories Ltd.,   Submitted a voluntary
                           Hydrocodone Bitartrate        C/O Ranbaxy Inc., 600        request for withdrawal,
                           Tablets, 750 mg/7.5 mg.       College Rd. East, Ste.       but failed to cite the
                                                         2100, Princeton, NJ 08540.   appropriate regulatory
                                                                                      provision.
ANDA 040637.............  Acetaminophen, Caffeine, and  West-Ward Pharmaceutical     Submitted a voluntary
                           Dihydrocodeine Bitartrate     Corp., 435 Industrial Way    request for withdrawal,
                           Tablets, 712.8 mg/60 mg/32    West, Eatontown, NJ 07724.   but failed to cite the
                           mg.                                                        appropriate regulatory
                                                                                      provision.
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    Under section 505(e) of the FD&C Act (21 U.S.C. 355(e)) and Sec.  
314.150(a) (21 CFR 314.150(a)), and under authority delegated to her by 
the Commissioner of Food and Drugs, the Director, Center for Drug 
Evaluation and Research (CDER), has evaluated the information discussed 
in this notice and in the January 14, 2011, Federal Register notice 
and, on the grounds stated, is proposing to withdraw approval of the 
applications listed in table 1 of this document and all amendments and 
supplements thereto for unit dose strengths greater than 325 mg. This 
proposal is made on the grounds that, based on consideration of new 
evidence together with the evidence available to FDA when the 
applications were approved, the drugs are no longer safe for use under 
the conditions of use upon the basis of which they were approved.
    Therefore, in accordance with section 505(e) of the FD&C Act and 
Sec. Sec.  314.150 and 314.200 (21 CFR 314.150(a) and 314.200)), notice 
is given to the holders of the ANDAs listed in table 1, and to all 
other interested persons, that FDA is hereby providing the holders the 
opportunity to request a hearing to show why approval of the 
applications listed should not be withdrawn.
    Any holder that decides to seek a hearing must file: (1) On or 
before April 28, 2014, a written notice of appearance and request for a 
hearing; and (2) on or before May 27, 2014, the data, information, and 
analyses relied on to demonstrate that there is a genuine and 
substantial issue of material fact that requires a hearing to resolve, 
as specified in Sec.  314.200.
    Any other interested person may also submit comments on this notice 
on or before May 27, 2014. The procedures and requirements governing 
this notice of opportunity for a hearing, notice of participation and 
request for a hearing, information and analyses to justify a hearing, 
other comments, and a grant or denial of a hearing are contained in 
Sec.  314.200 and in 21 CFR part 12.
    The failure of a holder to file a timely written notice of 
participation and request for a hearing, as required by Sec.  314.200, 
constitutes an election by that holder not to avail itself of the 
opportunity to request a hearing concerning the action proposed and 
constitutes a waiver of any contentions concerning the legal status of 
that holder's drug products. In such instance, FDA intends to withdraw 
approval of the applications and to take other appropriate action. Any 
new drug product marketed without an approved new drug application is 
subject to regulatory action at any time.
    A request for a hearing may not rely upon allegations or denials, 
but must present specific facts showing that there is a genuine and 
substantial issue of fact that requires a hearing. If it conclusively 
appears from the face of the data, information, and factual analyses in 
the request that there is no genuine and substantial issue of fact, the 
Commissioner of Food and Drugs will enter summary judgment against the 
person who requests the hearing, making findings and conclusions, and 
denying a hearing.
    All submissions under this notice of opportunity for a hearing must 
be filed in four copies. Except for data and information prohibited 
from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 1905, the 
submissions may be seen in the Division of Dockets Management (see 
ADDRESSES) between 9 a.m. and 4 p.m., Monday through Friday.
    The following is the text of the January 14, 2011, Federal Register 
notice entitled ``Prescription Drug Products Containing Acetaminophen; 
Actions to Reduce Liver Injury From Unintentional Overdose.''

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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[[Page 17158]]

    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 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. 2-4). 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, 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. 8-9). 
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

[[Page 17159]]

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 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 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 Health 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

[[Page 17160]]

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 
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

[[Page 17161]]

(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\
---------------------------------------------------------------------------

    \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, selecting ``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 2--Overview of Currently Marketed Prescription Acetaminophen Products
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                          N *--All
       Ingredient combination           Acetaminophen        Acetaminophen         N *--Acetaminophen         Acetaminophen         N *--Acetaminophen
                                          strengths       strengths <=325 mg      strengths <= 325 mg       strengths >325 mg         strengths >325
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acetaminophen; Butalbital...........                 4  325 mg; 50 mg Tablets.  2......................  650 mg; 50 mg Tablets.  1.
                                                                                                         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    6.
                                                         Capsules.                                        Tablets.
                                                        325 mg; 50 mg; 40 mg    6......................  500 mg; 50 mg; 40 mg    1.
                                                         Tablets.                                         Capsules.
                                                        325 mg; 50 mg; 40 mg    1......................  750 mg; 50 mg; 40 mg    1.
                                                         Capsules.                                        Tablet.
                                                                                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..  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.
                                                                                                                                 .......................
                                                                                                                                 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

[[Page 17162]]

 
                                                                                                         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.
Acetaminophen; Oxycodone HCI........                49  300 mg; 2.5 mg Tablets  1......................  400 mg; 2.5 mg Tablets  1.
                                                        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  2......................  650 mg; 5 mg Tablets..  4.
                                                         Oral Solution.
                                                                                Total: 25..............  650 mg; 10 mg Tablets.  1.
                                                                                                                                 Total: 24.
Acetaminophen; Pentazocine HCI......                 2  None..................  0......................  650 mg; EQ 25 mg BASE   2.
                                                                                                          Tablets.
                                      ................  ......................  Total: 0...............  ......................  Total: 2.
Acetaminophen; Tramadol HCL.........                 6  325 mg; 37.5 mg         6......................  ......................  0.
                                                         Tablets.
                                      ................  ......................  Total: 6...............  None..................  Total: 0.
                                     -------------------------------------------------------------------------------------------------------------------
                                      Grand Total: 189  ......................  Total: 86..............  ......................  Total: 103.
--------------------------------------------------------------------------------------------------------------------------------------------------------
* N = number of approved applications.

    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

[[Page 17163]]

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.
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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

    FDA has verified the Web site address in this reference section, 
but we are not responsible for any subsequent changes to the Web site 
after this document publishes in the Federal Register.

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, L. P. 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 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: March 24, 2014.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 2014-06802 Filed 3-26-14; 8:45 am]
BILLING CODE 4160-01-P


