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FDA arthritis advisory committee meetingPostmarketing surveillance of nonsteroidal antiinflammatory drugs.

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I168
GOVERNMENT AFFAIRS
FDA ARTHRITIS ADVISORY COMMITTEE MEETING:
POSTMARKETING SURVEILLANCE OF
NONSTERQIDAL ANTIINFLAMMATORY DRUGS
HAROLD E. PAULUS
This communication reports on the FDA Arthritis Advisory Committee meeting of April 29-30,
1985.
Between August 16, 1983 and August 24, 1984,
16,911 adverse drug reactions (ADR) associated with
nonsteroidal antiinflammatory drugs (NSAIDs) were
entered into the United States voluntary adverse reaction reporting system or reported to the manufacturers. Summary tables were prepared by the Food and
Drug Administration (FDA) reviewer with the cooperation of the manufacturers, after eliminating multiple
adverse reaction terms and cases judged to have only a
remote possibility of being causally related to the
NSAID. With the understanding that the numerator
data consist of reports of adverse reactions rather than
the number of adverse reactions that actually occurred, and that the denominator data consist of
millions of prescriptions filled rather than number of
patients, some of the information presented to the
Committee is included here because it is the best
available on this subject and because it illustrates
some of the problems associated with the voluntary
adverse reaction reporting system (Tables 1 and 2).
Additional information included summaries of
ADRs related to specific organ systems. The FDA
reviewer pointed out some “blips” in the data, which
were then discussed by the manufacturers. For example, nonfatal acute allergic reactions were reported for
tolmetin in 36.52 cases per million prescriptions,
whereas each of the other NSAIDs had fewer than 9
~Harold E. Paulus, MD, American Rheumatism Association
Liaison to the FDA Arthritis Advisory Committee, UCLA School of
Medicine, Department of Medicine, Division of Rheumatology, LOS
Angeles, CA 90024.
Arthritis and Rheumatism, Vol. 28, No. 10 (October 1985)
similar reports per million prescriptions. The manufacturer presented Medicaid data from 3 states which
indicated that the incidence of allergic reactions to
tolmetin was lower than that for 5 comparison
NSAIDs, suggesting that the “blip” was a reporting
aberration that may have been stimulated by the
withdrawal of a similar drug, zomepirac, because of
allergic reactions.
Diflunisal and piroxicam ranked at or near the
top of most of the summaries for specific ADRs (Table
2). However, the manufacturers pointed out that these
drugs were first introduced in the United States in
April 1982, and the summaries were prepared from
data collected during their second year of marketing.
Information on ADR duriug the life-cycle of other
Table 1. Summary of reported US ADR cases per million
prescriptions (August 1983 to August 1984)*
NSAID
Phenylbutazone
Diflunisal
Piroxicam
Sulindac
Fenoprofen
Indomethacin
Tolmetin
Meclqfenamate
Naproxen
Ibuprofen
Aspirin
Acetaminophen
Fatal
ADR
Nonfatal
Millions Fatal cases
cases
of Rxs ADR per lo6 Nonfatal
per lo6
(or units) cases Rxs ADR cases
Rxs
2.81
2.50
7.53
5.47
3.26
9.02
2.57
1.80
11.86
20.45
241.0t
211.0t
14
10
20
11
6
15
4
2
8
9
NA
NA
4.99
4.00
2.66
2.01
1.84
1.66
1.55
1.11
0.67
0.44
NA
NA
71
238
686
255
81
229
152
86
246
209
NA
NA
25.29
95.31
91. I6
46.61
24.85
25.39
59.05
47.72
20.75
10.22
NA
NA
* ADR = adverse drug reaction; NSAID = nonsteroidal antiinflammatory drug; Rxs = prescriptions; NA = not available.
t Number of 100-tablet units sold x 10’.
1169
GOVERNMENT AFFAIRS
Table 2. Reported cases of nonfatal uppel-gastrointestinal perforations, bleeding, and ulcers per million daily doses*
NSAID
Difluni sal
Piroxicam
Phenylbutazone
Indomethacln
Sulindac
Meclofenamate
Naproxen
Tolmetin
Ibuprofen
Fenoprofen
Perforation
Bleeding
Ulcer
6
29
57
22
51
44
8
33
3
19
6
6
84
7
7
4
2
9
14
1
8
1
0
3
0
4
1
4
10
2
Cases per
miI1ion
daily doses
0.96
0.90
0.53
0.23
0. I7
0.15
0.14
0.08
0.06
0.05
* NSA.ID = nonsteroidal antiinflammatory drug; 1983 data for
piroxicam, 1982 and 1983 data for all others.
drugs indicates that the reporting rate during the
second year is about 5 times greater than that after the
fifth year of marketing. When this correction was
applied, these drugs ranked near the bottom of the
summaries comparing them with other, more mature
NSAlDs.
Attention was called to other apparent abberations in the data, but in each case the manufacturers
were able to provide rational explanations, such as:
more careful examination of the data might demonstrate that the same case was counted more than once,
or that cases were incorrectly classified and should be
excluded; some companies were more diligent or
effective in their use of detail persons to identify
ADRs; published case reports stimulated more ADR
reports: etc.
The explanations illustrate some of the many
problems associated with the interpretation of data
collected by the voluntary ADR reporting system. It
must be noted, however, that this system provides the
largest, and frequently the only, summary data of
ADRs for marketed drugs. The FDA believes that
major (threefold or greater) deviations from the norm,
after appropriate corrections, provide useful signals of
possibly important adverse reactions that should
prompt more vigorous investigations using other approaches.
In the past, 2 NSAIDs, meclofenamate and
indomethacin, have been labeled “not for initial use”
because of perceptions of increased risk of adverse
effects associated with their use. Since their use now
appears to entail no greater risk than that of the other
NSAIDs, the Committee advised the FDA to remove
the “not for initial use” restriction from the labels.
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