Food and Drug Administration
Science Background:
Safety Concerns Associated with Over-the-Counter Drug Products
Containing Analgesic/Antipyretic Active Ingredients for Internal Use
January 22, 2004
This
Science Paper is intended to raise the awareness of healthcare
professionals about the important educational role that they can play
in preventing unintentional acetaminophen induced hepatotoxicity and
NSAID-related gastrointestinal bleeding and renal toxicity in their
adult and pediatric patients. The FDA Nonprescription Advisory
Committee (NDAC) reviewed safety data related to the use of these pain
relievers on September 19-20, 2002, and made recommendations regarding
ways to better educate patients and consumers in order to reduce the
risk of these rare, but potentially serious adverse events.
1
History
Acetaminophen has been marketed in
the United States as an over-the-counter (OTC) antipyretic/analgesic
agent since 1960. It is widely available in a variety of strengths
and formulations for children and adults as a single-ingredient
product, and can also be found in numerous combination OTC and
prescription drug products.
Chemically acetaminophen is a para-aminophenol
derivative that is also the active metabolite of the analgesic drug
phenacetin.2 Its effectiveness as an antipyretic agent has
been attributed to its effect on the hypothalamic heat center, while
its analgesic efficacy is due to its ability to raise the pain
threshold.2
Acetaminophen’s ability to cause
fulminant hepatic failure in acute intentional overdose situations or
when used in combination with alcohol is well known. The latter
resulted in the addition of an alcohol warning on all OTC
acetaminophen-containing products since 1998. An internal review of
post-marketing case reports collected by the FDA’s Adverse Event
Reporting System (AERS) identified 307 cases of hepatoxicity in both
adults and children during the period from January 1998 to July 2001,
where at least one acetaminophen containing product was considered to
be a suspect drug. The agency review focused on cases of
unintentional overdose (not related to a suicide attempt) of
acetaminophen leading to hepatotoxicity. The agency also reviewed
data from liver failure transplant lists and other information
submitted to the agency. Many of these cases are consistent with
published reports in the worldwide literature, and provided the basis
for public discussion of the drug’s safety profile at the September
2002 NDAC meeting.
NSAIDs include aspirin, which
irreversibly acetylates cyclooxygenase (COX), and several other
classes of organic acids, including propionic acid derivatives
(ibuprofen, naproxen, etc.), acetic acid derivatives (indomethacin,
etc.), and enolic acid acids (e.g., piroxicam), all of which are
reversible competitors with arachidonic acid at the active site of
cyclooxygenase 3. There are two forms of cyclooxygenase,
COX-1 found in blood vessels, stomach and kidney, and COX-2, which is
induced in settings of inflammation by cytokines and inflammatory
mediators. All currently available OTC NSAIDs are non-selective COX
inhibitors. The antipyretic, analgesic, and antiinflammatory actions
of NSAIDs are related to their ability to inhibit COX-2. Side effects
such as gastrointestinal (GI) bleeding and renal toxicity are a result
of the inhibition of COX-1 and are well-known complications of NSAID
therapy 3,4,5.
Review of post-marketing case
reports collected by the FDA’s Adverse Event Reporting System (AERS)
between 1998 and 2001 identified a total of 279 cases of GI bleeding
associated with the OTC use of NSAIDs: 197 cases for ibuprofen,
ketoprofen and naproxen, and 82 cases for aspirin. The cases were
screened for the use of these analgesic products, or for mention of
OTC use in the narrative of the report. These reports are consistent
with published case studies from the worldwide literature.
Data supporting a nephrotoxic risk
associated with use of OTC NSAIDs was compiled from adverse events
reported to the FDA’s AERS database and large population studies.
Cases of acute renal failure with the use of OTC NSAIDs are rare.
Individuals with conditions where renal perfusion is more dependent on
prostaglandins (e.g. congestive heart failure, hepatic cirrhosis with
ascitis, chronic renal disease, or hypovolemia such as occurs with
dehydration) are at particular risk for acute renal
failure.
Considering the wide spread use of
OTC analgesic/antipyretic drug products, the FDA acknowledges that the
serious adverse event rate is low. However, it is clear that many of
the serious adverse events are preventable.
What are the factors that
contribute to these cases?
Acetaminophen Hepatotoxicty
The acetaminophen safety review
update identified four factors, which have resulted in potentially
fatal or life threatening unintentional overdoses in the adults:
-
failure by consumers to recognize the ingredients
contained in OTC drug products and/or the potential for harm due to
exceeding the recommended dose
-
the wide variety and availability of both OTC and
prescription drug products that contain acetaminophen (e.g., single
ingredient, combinations, and multiple formulations)
-
the lack of consumer awareness for the potential to
develop serious adverse events from taking two or more different
products containing acetaminophen concomitantly
-
the failure of prescription container labels to list
acetaminophen as an ingredient
Four
situations were identified which resulted in unintentional overdoses
in children:
-
administering the wrong pediatric
acetaminophen formulation [i.e., substituting the concentrated
infant drops (80mg/0.8ml) for the less concentrated children’s
suspension (160 mg/5 ml)]
-
administering the adult instead of the
age-appropriate children’s formulation
-
incorrectly calculating the weight-appropriate dose
of acetaminophen
-
using the wrong dosing device (e.g., tablespoon
instead of teaspoon, dropper versus syringe)
NSAIDs Gastrointestinal Bleeding and Renal Toxicity
The NSAID safety data review
identified the following risk factors for GI bleeding for OTC and
prescription NSAIDs:
-
use of concomitant medications such as
anticoagulants and/or corticosteroids
-
concomitant use of low dose aspirin and other NSAIDs
-
increasing age (> 60 years)
-
increasing dose
-
previous history of GI bleeding
-
concomitant use of alcohol
The following at-risk populations
for NSAID-induced nephrotoxicity were identified:
Discussion
The unintentional acetaminophen
overdoses resulting in liver failure, and the cases of GI bleeding and
renal toxicity attributable to the use of OTC NSAIDs underscore the
need for better consumer education about which products contain
acetaminophen or an NSAID and conditions for safe product use. Many
of these adverse events are preventable. Consumers need to recognize
that serious health consequences can result from unsafe use of
over-the-counter analgesics.
Recommendations
Health care providers should prescribe adequate pain medication
regimens for patients and provide instructions regarding the use of
other pain medications, including appropriate warnings about use of
multiple and combination products containing the same active
ingredient. The FDA encourages healthcare providers to help prevent
the morbidity and mortality of acetaminophen-induced hepatotoxicity
and NSAID-related GI and renal effects by educating their patients
about the following:
-
that any OTC analgesic is a drug and
appropriate safety precautions need to be taken when using or
storing it
-
the wide variety of different strengths,
formulations, and combinations of acetaminophen- and NSAID-containing
products that are available OTC and by prescription
-
the correct dosing frequency for each of the
acetaminophen or the NSAID formulations
-
the correct weight-based dose for each child
-
the use of the correct measuring device for liquid
formulations
-
drinking more than 3 alcoholic drinks every day is
not compatible with safe acetaminophen or NSAID use
-
risks of taking OTC analgesics with other
prescription or non-prescription medications
-
signs and symptoms of self-recognizable side effects
-
the potential problems associated with using more
than one pain reliever product simultaneously
The
FDA is also recommending that all U.S. Boards of Pharmacy implement
changes to the container labeling for all prescription drugs
containing acetaminophen or NSAIDs so that all active ingredients
(such as acetaminophen or NSAID), their strengths, recommended single
and daily dose, and warnings appear on the prescription label.
Most importantly health care
professionals should remind their patients to always read their OTC
and prescription medication labels and carefully follow the
directions.
References
1 Nonprescription Drug
Advisory Committee Meeting, September 2002 transcripts located at
www.fda.gov/ohrms/dockets/ac/02/transcripts/3882T1.htm
2 Woodbury DM, Fingl E:
Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed
in the Treatment of Gout. In Hardman JG, Gilman AG, Limbird LE
(eds): Goodman’s &Gilman’s The Pharmaceutical Basis of Therapeutics, 5th
ed. New York, Mcgraw-Hill, 1970: 325-58.
3 Insel P:
Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed
in the Treatment of Gout. In Hardman JG, Gilman AG, Limbird LE
(eds): Goodman’s & Gilman’s The Pharmaceutical Basis of Therapeutics, 5th
ed. New York, Mcgraw-Hill, 1996: 617-43.
4Lanza FL, et al: A
guideline for treatment and prevention of NSAID-induced ulcers. Am J
Gastroenterol 1998; 93(11):2037-46.
5Altman RD, et al:
Recommendations for the medical management of osteoarthritis of the
hip and knee; 2000 update. Arthritis Rheum 2000; 43(9): 1905-15.
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Date created: January 22, 2004  |
