[e-drug] Public Citizen testimony of acetaminophen (paracetemol) overdoses

["Peter Lurie" <PLURIE@citizen.org>]

E-drug: Public Citizen testimony of acetaminophen (paracetemol) overdoses
---------------------------------------------

Peter Lurie, MD, MPH
Deputy Director, Public Citizen's Health Research Group

Statement on Safety Issues Related to Acetaminophen
Before the Nonprescription Drugs Advisory Committee
September 19, 2002

In 1977, the Food and Drug Administration's (FDA's) Advisory Review 
Panel recommended the following warnings for acetaminophen-containing 
products: "Do not exceed recommended dosage because severe liver 
damage may occur" and "Do not exceed recommended dosage or take for 
more than 10 days, because severe liver damage may occur."  The FDA 
chose to ignore this wise advice.

A quarter of a century later we are facing an epidemic of fatal 
acetaminophen-associated poisonings: a near doubling from 76 in 1995 
to 141 in 1999, according to data collected by the American 
Association of Poison Control Centers through its Toxic Exposure 
Surveillance System (TESS).  TESS data also show 108,102 calls to 
Poison Control Centers in 1999, while data from the National Hospital 
Ambulatory Care Survey (NHAMCS) show an average of 56,680 Emergency 
Department Visits per year.  The National Hospital Discharge Survey 
(NHDS) indicates that there are an average of 26,256 hospitalizations 
per year related to acetaminophen overdoses.  Although the TESS data 
best indicate the time trend for acetaminophen-related mortality, the 
best estimate of the average number of deaths per year related to 
acetaminophen is 458, according to death certificate data. 
Acetaminophen is the leading cause of toxic drug ingestions in the 
U.S.  By any measure, this is a major national health problem.

The FDA has estimated that between at least 57% and 74% of ingestions 
are intentional, yet the issue before this Committee is described as 
"Unintentional Acetaminophen Hepatotoxicity," an illogical 
restriction of the debate and seemingly a capitulation to the notion 
that nothing can be done for those making suicide attempts.  This 
ignores the facts that many suicide attempts are impulsive "cries for 
help" (but may nonetheless be fatal), most are not fatal (but may 
leave significant residual disability), and fatality rates are 
related to doses consumed.

In fact, many countries have sought to address the problem of 
suicides or "intentional overdoses."  A recent experiment of this 
kind in the United Kingdom, implemented in September 1998, restricted 
the number of acetaminophen tablets per pack to 16 in supermarkets 
and 32 in pharmacies.  (Much of this was accomplished through the use 
of blister packs.)  Although one can buy several packs, prescriptions 
are required to obtain more than 100 tablets.  Early evaluations of 
the program show decreases in total and severe acetaminophen 
overdoses as well as decreases in acetaminophen-overdose liver 
transplants and deaths (Prince, et al. Lancet 2000;355:2047-8; 
Turvill, et al. Lancet 2000;355:2048-9; Robinson, et al. BMJ 
2000;321:926-7; Hawton, et al. BMJ 2001;322:1203-7), although the 
results are not completely consistent between studies.  Information 
on this critical experiment is not mentioned in the briefing material 
posted on the FDA's website.

The following is a six-point plan to address the acetaminophen 
overdose problem in all its manifestations.  While some primarily 
address intentional overdoses, many of these will also affect 
unintentional overdoses.

1. Consumer access to risk information

The currently required acetaminophen label is woefully inadequate, 
excluding even the liver-toxicity warning recommended a quarter of a 
century ago by the FDA's own advisers.  In addition to including a 
general warning about liver toxicity, the label should mention the 
early symptoms of liver toxicity and instruct patients to discontinue 
the drug and seek medical attention should such symptoms appear.  It 
should also warn against the simultaneous use of multiple 
acetaminophen-containing products.  As many of these elements as 
possible should appear, in sufficiently large typeface, on the 
container itself, as has successfully been done with children's 
aspirin in the successful attempt to prevent Reye's Syndrome.  If the 
box warning becomes unwieldy, consideration should be given to a 
system of rotating warnings, as has become standard on tobacco packs. 
A patient information leaflet in each package should also be mandated.

Other modes of communication should also be used to warn consumers. 
Advertising for acetaminophen- containing over-the-counter products 
(regulated by the Federal Trade Commission, not the FDA) should also 
require the warnings mentioned above.  The FDA should also write 
articles in medical and lay journals to increase health professional 
and consumer awareness of the problem.  Public Service Announcements 
are also an important part of such a strategy.

2. Reduce maximum daily doses

Among unintentional adult acetaminophen-related liver toxicity cases 
reported to the FDA or published in the medical literature (a total 
of 282 between January 1, 1998 and July 25, 2001), the median daily 
dose was 5 g/day (range: 0.65-30 g/day), not much above the 
FDA-recommended maximum of 4 g/day.  Among those with a history of 
alcohol use, the median dose was 4.6 g/day, compared with 5.8 g/day 
among those without such a history.  This argues strongly for a 
reduction in the maximum daily dose for alcohol users.  Patients with 
liver toxicity and underlying liver disease also had consumed low 
daily doses of acetaminophen (median: 4 g/day) as did those taking 
potentially liver-toxic medications in addition to acetaminophen 
(median: 3.9 g/day); this argues for similar maximum daily dose 
restrictions in these populations.  The margin of safety is even 
small for patients without these underlying conditions.  Restrictions 
on daily doses should be considered for them too.

3. Reduce per-tablet doses

Because there is a strong relationship between the amount of drug 
consumed and the incidence of serious overdose and death, and because 
there is a practical limit on how many pills a suicidal patient can 
take, it is logical that a reduction in the strength of individual 
dosage forms to 325 mg per tablet would yield benefits.  Such a 
restriction is likely to also benefit pediatric patients who ingest 
acetaminophen-containing products as well as those unknowingly taking 
multiple acetaminophen-containing products.  There is precedent for 
such a restriction.  Over-the-counter ibuprofen contains only 200 mg 
of the drug, compared with up to 800 mg in the prescription versions.

4. Standardize liquid formulations

Cases of liver toxicity reported to the FDA or reported in the 
medical literature between January 1, 1998 and July 25, 2001 included 
25 pediatric cases.  In at least four of these, teaspoonfuls of 
medication were administered, instead of dropperfuls.  While 
acetaminophen  suspension contains 32 mg/ml, the drops contain 100 
mg/ml, ample opportunity for unintentional overdose.  All liquid 
forms of the drug should be required to have the same concentration.

5. Remove irrational acetaminophen-containing combinations from the market

Forty-nine percent of over-the-counter acetaminophen sales is in the 
form of combination products.  Most, if not all, of these 
combinations are irrational.  Patients (and their parents) should be 
encouraged to use only the medication they need, not lapse into this 
shotgun approach to drug therapy.  The use of combination products 
with elaborate (often misleading) brand names discourages patients 
from learning the generic names of active ingredients, potentially 
leading to overdoses when taken with other acetaminophen-containing 
drugs.  Approximately 25% of patients with liver toxicity collected 
by the FDA had taken more than one acetaminophen-containing product.

6. More research

It has been suggested that all acetaminophen-containing products be 
combined with N-acetylcysteine, the drug used to treat acetaminophen 
overdose.  While we are aware of no studies documenting the 
effectiveness of this approach, it does merit further study.  The 
impact of any interventions to reduce acetaminophen-related liver 
toxicity adopted by the FDA should also be measured so that new 
measures can be added if appropriate.

None of these approaches will be enough on its own to eliminate 
acetaminophen overdoses.  Only a multidimensional approach is likely 
to significantly reduce the enormous burden of suffering and the 
expenditure of scarce health care resources currently represented by 
this in-large-part preventable problem.

Peter Lurie, MD, MPH
Deputy Director
Public Citizen's Health Research Group
1600 20th Street, NW
Washington, DC 20009
Phone: (202)588-7781
Fax: (202)588-7796
Email: plurie@citizen.org
Web address: http://www.citizen.org
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