Download FDA`s Acetaminophen Notice: A Snapshot of the Current Regulatory

QUALITY & COMPLIANCE
FDA’s Acetaminophen Notice: A Snapshot of the
Current Regulatory Environment
By Kevin D. Healy, PhD, RAC
As part of an ongoing safety initiative, the US
Food and Drug Administration (FDA) recently
announced that it is asking manufacturers to
limit the maximum amount of acetaminophen
allowed in prescription products to 325 mg/
unit.1 Acetaminophen is an active ingredient
found in many common over-the-counter (OTC)
products (e.g., Tylenol, Excedrin, Nyquil) and
prescribed combination products (e.g., Percocet,
Vicodin). FDA’s action will directly impact
several highly prescribed drug products in the
US, and it is possible that future FDA actions
will impact the substantial OTC acetaminophen
market. The regulatory activity surrounding
acetaminophen illustrates FDA’s continued focus
on drug safety and exemplifies the tools and tactics being utilized in the wake of Food and Drug
Administration Amendments Act (FDAAA) of 2007.
As summarized in an FDA Advisory
Committee briefing document, nearly 20 billion
OTC doses of acetaminophen-containing products are sold in the US per year. About half of
these are single-ingredient products and half are
combination products.
On the prescription side, combination drugs
containing acetaminophen include some of the
most highly prescribed drug products—11 billion
doses of drugs containing acetaminophen were
prescribed in the US in 2005, and the hydrocodone/
acetaminophen combination has been the most
highly prescribed product in the US since 1997.2
Acetaminophen is widely recognized as
an effective and well-tolerated drug when used
as directed, and has been used successfully to
treat ailments in millions of patients. Notably,
acetaminophen use is not associated with gastrointestinal problems that are associated with
many other pain drugs, such as aspirin and
other non-steroidal anti-inflammatory drugs
(NSAIDs).3 However, acetaminophen safety concerns, primarily related to overdose, date back
to the early 1990s. Specifically, acetaminophen
overdose (more than 4000 mg/day) can lead to
hepatotoxicity and, in the most severe cases, lead
to acute liver failure (ALF) or death. In the 1990s,
acetaminophen poisoning was responsible for
56,000 emergency room visits per year, approximately 1,600 annual cases of ALF, and about
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450 deaths annually.4 A 2006 study concluded
that unintentional acetaminophen overdose
accounted for about one-quarter of the ER visits
and deaths, and other studies have concluded
that unintentional overdose contributes to about
half of the cases of acetaminophen-induced
ALF.5,6,7 An array of factors can contribute to
unintentional overdosing (See Box 1).
FDA’s Acetaminophen Safety Initiative was
created in the early 1990s to reduce acetaminophen-related injuries, and recent activities serve
as an example of the agency’s expanded authority and focus on safety in the post-FDAAA era.
The 2007 FDAAA granted FDA the authority to
require safety-related labeling changes to prescription drugs based upon safety information
that becomes available postapproval.
In January 2011, FDA published a notice
in the Federal Register requesting manufacturers to reduce the maximum dosage strength of
acetaminophen in prescribed products to 325
mg/unit and requiring safety labeling changes,
including a new black box warning. Per the
notice, the agency determined that the scientific
literature provided new safety information that
acetaminophen overdose is a major cause of ALF
in the US, and that postmarketing reports and
Box 1: Overdose Factors
Nearly 500 Americans per year die as a
result of acetaminophen-related poisoning. FDA has outlined several possible
contributing factors:8
• large number of products
ŊŊ simultaneous use of multiple
acetaminophen-containing
products
• varying dosage forms (liquids,
tablets, etc)
• varying dosage concentrations
(250 – 750 mg/tablet)
• confusing prescription labeling
(use of abbreviations such as
“APAP” and “ACET”)
• lack of public awareness of which
products contain acetaminophen
the scientific literature contained additional new
safety information—cases of hypersensitivity
reactions and anaphylaxis associated with acetaminophen. Consistent with Section 505(o)(4)(B)
of the Federal Food, Drug, and Cosmetic Act (FD&C
Act), sponsors were given 30 days from their
receipt of a Safety Labeling Change Notification
to submit revised labeling or a response detailing the reasons that such a labeling change is
unwarranted.
Based on Section 505(e)(2) of the FD&C
Act, the agency has authority to withdraw
approval of New Drug Applications (NDAs) or
Abbreviated NDAs (ANDAs) based on the consideration of new evidence. However, consistent
with recent practice, in this instance, FDA has
chosen to rely on voluntary sponsor activity for
product withdrawals of any prescription acetaminophen-containing products.
At the time of publication of the Federal
Register notice, there were 189 approved active
applications containing acetaminophen in the
list of Approved Drug Products with Therapeutic
Equivalence Evaluations (Orange Book), spanning
seven different combinations from 26 sponsors.
The majority of these applications, including the
most highly prescribed products, have more than
325 mg acetaminophen/unit,9 and, thus, limiting the maximum unit dosage strength to 325
mg has widespread implications. In an apparent
effort to minimize the regulatory burden while
focusing on patient safety and access, the agency
opted to request that sponsors voluntarily withdraw their products containing more than 325
mg acetaminophen/unit over the next three
years, after which time they may be subject to
FDA action.10 Further, the Federal Register notice
advised sponsors on appropriate steps for developing and obtaining approval for reformulated,
lower-strength products, and directly welcomed
related consultations.
The voluntary withdrawal route is analogous to a previous high-profile change in
the pain arena. In 2004 and 2005, the COX-2
antagonists Vioxx and Bextra were withdrawn
by Merck and Pfizer, respectively. In each case,
the sponsor voluntarily withdrew the product
following communications with FDA regarding new postmarketing clinical trial data. Thus,
while FDA has long had the authority to withdraw drug approvals, the preferred path appears
to be suggesting voluntary withdrawals on the
part of sponsors, an approach more likely to
reduce legal and regulatory burden.
Another trend evident in recent regulatory activity is FDA’s increased use of Advisory
Committees, particularly the Drug Safety and
Risk Management (DSRM) Advisory Committee.
FDA has long relied upon Advisory Committees
to provide independent expert advice; there are
currently 49 separate committees and panels that
periodically meet and discuss regulatory matters.11
At least two Advisory Committee
meetings have played prominent roles in
the Acetaminophen Safety Initiative. A
Nonprescription Drugs Advisory Committee
meeting in September 2002 led to labeling
changes for OTC acetaminophen products in
2009, and a DSRM Advisory Committee meeting
in June 2009 held jointly with the Anesthetic and
Life Support Drugs Advisory Committee was
cited as a primary driver of the recent changes to
prescription acetaminophen products. FDA has
acknowledged its growing reliance on the DSRM
Committee, which convened for 13 days last year
as opposed to six days in 2009.12 FDA’s Center
for Drug Evaluation and Research convened 51
days of Advisory Committee meetings per year
in 2009 and 2010, approximately double the
number of meeting days held per year from 2006
to 2008.13
In summary, FDA’s actions of January 2011
will not only affect several of the most highly
prescribed drug products in the US, but also
illustrate the safety-oriented regulatory environment and broad range of tools and tactics that
the agency is employing. FDA is focused on
ensuring the public’s health, while also striving to work with pharmaceutical companies to
minimize disruptions to the healthcare system.
This balancing act is exemplified by the acetaminophen case: While stating that prescription
acetaminophen products should no longer contain greater than 325 mg/unit and strengthening
Regulatory Focus
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label warnings, FDA is also utilizing potential
voluntary withdrawals, an extended timeframe
of three years, and offering consultation with
manufacturers on product reformulation issues.
Future changes are possible, as FDA continues to evaluate ways to reduce the risk of
acetaminophen-related liver injury from OTC
products.14 Once again, FDA likely will give
great weight to recommendations of the DSRM
Advisory Committee; a majority of its members previously recommended reducing the
amount of acetaminophen per dose to 650 mg.15
Implementing changes to OTC products would
require altering the OTC monograph and FDA
drawing upon another set of tools from its regulatory toolbox. If acetaminophen-containing
OTC product changes are determined necessary,
recent trends indicate FDA will work diligently
to make any changes to that massive market
as smooth as possible for the American public,
the healthcare system and the pharmaceutical
industry.
Box 2: The Regulatory Toolbox
FDA can rely on a number of tools to help
ensure the public’s health. Several different tactics have been utilized to ensure
safe use of acetaminophen.
• Acetaminophen Safety Initiative
Ŋ
Ongoing umbrella program
• Advisory Committee Meetings
Ŋ
Nonprescription Drugs
Advisory Committee
(September 2002)
Ŋ
Drug Safety and Risk
Management Advisory
Committee (June 2009)
• Safety Labeling Updates
Ŋ
Authority granted through
FDAAA 2007
• Sponsor Withdrawals of NDAs /
ANDAs
Ŋ
Section 505(e)(2) grants
authority of FDA to withdraw applications
Ŋ
Voluntary withdrawals
appear to be the preferred
route
References
1.
Federal Register Docket No. FDA-2011-N-0021, 14 Jan 2011.
2.
Briefing Information for the June 29-30, 2009
Joint Meeting of the Drug Safety and Risk
Management Advisory Committee with the
Anesthetic and Life Support Drugs Advisory
Committee and the Nonprescription Drugs Advisory
Committee. www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
DrugSafetyandRiskManagementAdvisoryCommittee/
ucm161515.htm
Op cit 1.
Nourjah P et al. ”Estimates of Acetaminophen
(Paracetamol)-induced Overdoses in the United States.’’
Pharacoepidemiological Drug Safety, 6: 406-409, 2006.
Op cit 4
Bower WA et al. “Population-Based Surveillance for
Acute Liver Failure.” American Journal of Gastroenterology,
(102(11)):2459-63, 2007.
Larson, AM et al. “Acetaminophen-Induced Acute
Liver Failure: Results of A United States Multicenter,
Prospective Study.” Hepatology, 42:1364-72, 2005.
Op cit 1.
Op cit 1.
Op cit 1.
www.fda.gov/AdvisoryCommittees/default.htm
The Pink Sheet, “Where FDA Is Paying The Most
Attention: Drug Safety Advisory Committee Had The
Most Meetings In 2010.” Sue Sutter. 20 Jan 2011.
Op cit 11.
www.fda.gov/ForConsumers/ConsumerUpdates/
ucm239747.htm
Summary Minutes of the Joint Meeting of the
Drug Safety and Risk Management Advisory
Committee, Nonprescription Drugs Advisory
Committee, and the Anesthetic and Life Support
Drugs Advisory Committee, June 29 and 30,
2009. www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/
DrugSafetyandRiskManagementAdvisoryCommittee/
ucm126014.htm.
Author
Kevin Healy, PhD, RAC, is a manager of regulatory affairs
within the specialty pharmaceuticals division at Covidien, a
global healthcare company that develops pharmaceuticals,
medical devices and medical supplies. Healy has extensive
experience with drug development in a number of therapeutic
areas, and has supported products from the pre-IND stage
through postapproval. He is currently focused on advancing
innovative products intended for the management of pain.
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June 2011