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Antiviral Therapy 9:187-195
Skin reactions in patients with influenza treated
with oseltamivir: a retrospective cohort study
Beth L Nordstrom1*, Kelly Oh1, Susan T Sacks2 and Gilbert J L’Italien1
1
Ingenix Epidemiology, Auburndale, Mass., USA
Roche Global Development, Nutley, NJ, USA
2
*Corresponding author: Tel: +1 617 552 5212; Fax: +1 617 244 9669; E-mail: [email protected]
Oseltamivir phosphate is an FDA-approved treatment
for influenza that has been available for prescription
use in the USA since 1999. The present report describes
findings from a post-marketing safety study of skin
reactions associated with oseltamivir use. All patients in
the claims-derived Ingenix Research Database with a
physician diagnosis of influenza and/or a dispensing of
oseltamivir between 1 December 1999 and 31 March
2002 were identified. Cohort eligibility criteria included
minimum baseline enrolment duration of 3 months, age
of at least 1 year and no influenza vaccination on the
date of influenza diagnosis or oseltamivir dispensing.
Patients were classified into two primary cohorts,
influenza diagnosis and oseltamivir dispensing on the
same day, and influenza diagnosis but no oseltamivir at
any time, and a cohort included for secondary analyses
comprising patients who received an oseltamivir
dispensing without an influenza diagnosis on the same
day. Outcomes included general skin reactions and
several specific skin reactions. Events occurring during
the 30 days following the date of influenza diagnosis or
oseltamivir dispensing were examined using Cox
proportional hazards models. Model covariates included
age, use of another influenza drug, month and year of
index date, and use of antitussives. Adjusted rate ratios
for the general class of skin reactions among the
primary cohort of oseltamivir users versus non-users
were 1.05 (95% CI: 0.88–1.24) for incident cases and
0.98 (95% CI: 0.77–1.24) among patients with a history
of a skin reaction. Similar results were seen for the
other skin reaction categories, and secondary analyses
investigating the oseltamivir users without influenza
revealed no elevation in risk. It is concluded that
oseltamivir use does not appear to be associated with
an increased risk of skin reactions.
Introduction
Influenza is a highly contagious illness that is associated with an average of 36 000 deaths in the USA
each year [1]. Although the primary approach to
preventing the complications of influenza is vaccination, antiviral medications can serve as an adjunct to
the vaccine for prevention and for treatment when the
illness occurs [2]. Oseltamivir phosphate is a
neuraminidase inhibitor that has been shown to be
effective in decreasing the duration and severity of
influenza symptoms [3,4].
The safety profile of oseltamivir to date has revealed
few concerns, with the most common adverse events
found to be minor upper gastrointestinal effects,
including nausea and nausea with vomiting [4,5]. A
cohort study comparing the incidence of cardiac,
neuropsychiatric and respiratory events in patients
using oseltamivir, compared with patients with
influenza who did not take oseltamivir, found no
increased risk of any of these outcomes [6]. During
post-marketing use of the drug in clinical practice,
©2004 International Medical Press 1359-6535/02/$17.00
rashes have been reported in patients using oseltamivir
[7]. Spontaneous reports of other skin reactions,
ranging from mild to severe and including, for
example, Stevens-Johnson syndrome, pruritis, urticaria
and bullous conditions, among other dermatological
diagnoses, have also been received since the drug’s
approval. Such adverse event reports raise the question
of whether the use of oseltamivir may place patients at
heightened risk of experiencing skin reactions. A
serious limitation to adverse event reporting, however,
is the inability to determine whether the drug was in
any way causally related to the reaction. Postmarketing epidemiological studies including a broader
population of patients than those included in the clinical trials can help to answer this question by
demonstrating whether the drug is associated with an
increased risk of skin reactions. The present report
describes a retrospective cohort study using medical
claims data to examine the risk of various skin reactions
associated with use of oseltamivir.
187
BL Nordstrom et al.
Materials and methods
Data source
Data for the study were obtained from the Ingenix
Research Database, which consists of demographic,
medical and prescription data from UnitedHealthcare.
UnitedHealthcare is one of the largest healthcare
companies in the USA, with more than 300000 physicians contracted to provide healthcare services to over
14 million members. The Research Database was
designed to facilitate drug safety and health outcomes
research. UnitedHealthcare members are brought into
the Ingenix Research Database if they belong to plans
in which the costs of pharmaceuticals and health
services are reimbursed to providers on an item-by-item
basis, so that it is possible to reconstruct all healthcare
utilization. Beginning with the earliest claims, in 1990,
the Research Database has detailed information on
approximately 8 000000 current and past members.
Study population
The source population for the study included patients
from 25 UnitedHealthcare plans from the following 21
states: Alabama, Arizona, Arkansas, Florida, Georgia,
Illinois, Kentucky, Louisiana, Massachusetts, Michigan,
Mississippi, Missouri, Nebraska, North Carolina,
Ohio, Rhode Island, South Carolina, Tennessee, Texas,
Utah and Virginia. The study population included
patients who received either a dispensing of oseltamivir
or an ICD-9 diagnosis code of influenza (487.*) associated with a physician visit or hospitalization between 1
December 1999 and 31 March 2002. Oseltamivir
became available in November 1999, but was rarely
prescribed in UnitedHealthcare before 1 December
1999. Since the few people taking oseltamivir in its first
month on the market may not represent the general
population of users, we excluded any oseltamivir
dispensing and influenza diagnoses before 1 December
1999. The date of oseltamivir dispensing for those who
received oseltamivir, and of influenza diagnosis for
those who did not receive the drug, was designated as
the index date.
Oseltamivir has been approved by the FDA for use in
children over 1 year of age. We thus excluded from the
study any infants less than 1 year old on the index date.
Since influenza is a seasonal illness, we examined
only diagnoses and dispensing occurring during the
influenza season, November through March. Any
patient with oseltamivir dispensing and/or influenza
diagnoses during different influenza seasons was
allowed to enter the cohort up to once per influenza
season, for a maximum of three episodes included in
the analysis. If more than one influenza diagnosis or
oseltamivir dispensing occurred during the same
season, only the first was included in the analysis.
188
To allow assessment of baseline variables, patients
were required to have a minimum of 3 months of enrolment in the health plan before their index date. We
assumed that any diagnosis of influenza given on the
same day as an influenza vaccination did not indicate a
genuine case of influenza, and thus excluded any
patient with an influenza vaccination on the index date.
The study focused on two primary cohorts. The
influenza with oseltamivir cohort included patients
meeting the above inclusion criteria who received a
dispensing of oseltamivir on the same date as the
diagnosis of influenza. Patients who received no
dispensing of oseltamivir at any time, but who had a
diagnosis of influenza, constituted the influenza
without oseltamivir cohort. Patients who received a
dispensing of oseltamivir but did not have a diagnosis
of influenza on the date of dispensing were examined
separately from the two primary cohorts in what
must be considered an exploratory fashion only, as it
was not possible to construct an appropriate comparison group with similar baseline health status. The
oseltamivir without influenza cohort was compared
to the influenza with oseltamivir cohort to investigate
potential differences between the two groups of
patients who received oseltamivir.
Outcome definition
The outcomes assessed consisted of various categories
of skin reactions and other allergic responses. We
defined a general skin reaction outcome, including
inflammatory skin conditions and other skin diseases,
several specific skin reactions, and allergic or other
adverse reaction to a drug. The outcomes were defined
using the following ICD-9 diagnosis codes: general
skin reaction (690.*– 698.* and 700.*– 709.*), atopic
dermatitis (691.8), contact dermatitis and other
eczema (692.*), dermatitis due to substances taken
internally (693.*), dermatitis herpetiformis (694.0),
impetigo herpetiformis (694.3), pemphigus (694.4),
pemphigoid (694.5), other specified bullous
dermatoses (694.8), erythematous conditions (695.*
excluding 695.3 and 695.8), unspecified pruritic
disorder (698.9), urticaria (708.*) and adverse reaction to a drug (995.2). Appropriate diagnoses given in
conjunction with a physician visit or hospitalization
during the 30 days following the index date were
considered to be outcome events.
Baseline and covariate measures
For each patient we identified age, sex, geographic area
(northeast, southeast, midwest or west), and month
and year of influenza diagnosis. We also determined
the influenza subcode given, specifically influenza with
the fourth digit unspecified (487), influenza with pneumonia (487.0), influenza with other respiratory
©2004 International Medical Press
Oseltamivir and skin reactions
manifestations (487.1) or influenza with other manifestations (487.8). Patients were classified as using or
not using each of several classes of drugs, including
amantadine, rimantadine, zanamivir, any influenza
medication (that included any of the preceding three
drugs), ribavirin, antibiotics (also separated into
cephalosporins, macrolides, penicillins, tetracyclines,
quinolones and sulfonamides), antitussives and analgesics, during the 3-month baseline period. Pre-existing
cancer, diabetes, rheumatoid arthritis and HIV, and
history of each of the study outcomes were noted if the
patient had an appropriate diagnosis code in conjunction with a physician visit or hospitalization during the
baseline period.
All primary analyses consisted of comparisons between
the influenza with oseltamivir and influenza without
oseltamivir cohorts. Exploratory analyses compared
the oseltamivir without influenza to the influenza with
oseltamivir cohort. Differences between groups on
baseline characteristics were assessed using χ2 tests. For
the general skin reaction outcome and each of the 11
specific skin reaction outcomes, we performed Cox
proportional hazards regressions, in which adjusted
incidence rate ratios were estimated for the oseltamivir
users compared to the non-users. For statistical
reasons, proportional hazards models were computed
only for outcomes with at least 20 events. We investigated potential confounding from all baseline health
and demographic characteristics described above.
Drugs given during the baseline period were investigated both within lower-level (such as, amantadine,
cephalosporins) and higher-level groupings (such as,
influenza medications, antibiotics). The final Cox
models included any of these variables that modified
the hazard ratio for oseltamivir exposure by at least
5%. To separate incident cases of each event from
cases that may be ongoing or recurring, the adjusted
models were calculated separately for those with and
those without a history of the outcome diagnoses
during the baseline period.
oseltamivir users and 10 914 influenza patients without
oseltamivir. Only nine of the oseltamivir users were
excluded because of the age restriction, in contrast
with 1752 other influenza patients who were less than
1 year old on the index date. Fifty-two oseltamivir
users and 365 influenza patients without oseltamivir
were given an influenza vaccine on the index date,
leading to their exclusion from the study. Please note
that the same patient may have met more than one of
these exclusion criteria.
The final study cohorts included 11 625 patients
with a dispensing of oseltamivir on the same day as an
influenza diagnosis, 70 999 patients with influenza but
no oseltamivir, and 17 365 patients who received
oseltamivir without a diagnosis of influenza on the
index date. Approximately 8% (1351) of the
oseltamivir patients without an influenza diagnosis on
the date of dispensing did receive a diagnosis of
influenza on a different day than the index date. There
were 1665 patients who received a diagnosis of
influenza without oseltamivir in two different
influenza seasons and 77 patients in all three seasons
under study. A total of 66 patients received oseltamivir
with an influenza diagnosis during two different
influenza seasons, but none during all three seasons
studied, while 225 and 10 patients, respectively,
received oseltamivir without an influenza diagnosis
during two and three seasons. Some patients also
appeared in different cohorts during different influenza
seasons; 259 were diagnosed with influenza both with
and without oseltamivir, 100 received oseltamivir both
with and without an influenza diagnosis, 568 were
diagnosed with influenza without oseltamivir in one
season and received oseltamivir without influenza
during a different season, and three patients entered all
three study cohorts in the three seasons. Allowing each
patient to contribute one episode to each influenza
season in which he or she met the inclusion criteria
resulted in a total count for each cohort of 11 691
influenza with oseltamivir patients, 72 818 influenza
patients without oseltamivir, and 17 610 oseltamivir
users without influenza.
Results
Baseline characteristics
A total of 32 459 patients received one or more
dispensings of oseltamivir during the 1999 to 2002
influenza seasons. An additional 82 993 patients had
one or more physician visits or hospitalizations with
a diagnosis of influenza but did not receive a
dispensing of oseltamivir during the same influenza
season as the diagnosis.
Approximately 13% of patients were excluded
because of failure to meet the 3-month baseline enrolment criterion; this led to the exclusion of 3956
Demographic and other baseline characteristics of the
final study cohorts are presented in Table 1. Children
under the age of 13 with an influenza diagnosis were
less likely to receive oseltamivir than older individuals,
though otherwise the age distributions of the two
influenza cohorts were fairly similar, overall
χ2(6)=3090.4, P<0.001. The patients who received
oseltamivir without an influenza diagnosis were more
likely to be older than the oseltamivir users with
influenza, χ2(6)=426.0, P<0.001. There was a slightly
lower proportion of females among the influenza with
Data analysis
Antiviral Therapy 9:2
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BL Nordstrom et al.
Table 1. Demographic characteristics of study cohorts
Influenza with
oseltamivir
(n=11 691)
Influenza without
oseltamivir
(n=72 818)
Age group (years)
1–12
13–19
20–29
30–39
40–49
50–64
65+
694 (5.9%)
1059 (9.1%)
2308 (19.7%)
3108 (26.6%)
2591 (22.2%)
1844 (15.8%)
87 (0.7%)
Gender
Male
Female
Region
Northeast
Southeast
Month of index date
Season 1
December 1999
January 2000
February 2000
March 2000
Season 2
November 2000
December 2000
January 2001
February 2001
March 2001
Season 3
November 2001
December 2001
January 2002
February 2002
March 2002
P–value*
Oseltamivir without
influenza
(n=17 610)
P–value †
20 554 (28.2%)
8207 (11.3%)
9297 (12.8%)
13 066 (17.9%)
11 740 (16.1%)
9175 (12.6%)
779 (1.1%)
<0.001
657 (3.7%)
1196 (6.8%)
2662 (15.1%)
4408 (25.0%)
4618 (26.2%)
3780 (21.5%)
289 (1.6%)
<0.001
5670 (48.5%)
6021 (51.5%)
34 182 (46.9%)
38 636 (53.1%)
0.002
8231 (46.7%)
9379 (53.3%)
0.003
150 (1.3%)
7029 (60.1%)
3441 (4.7%)
30 302 (41.6%)
279 (1.6%)
10 140 (57.6%)
810 (6.9%)
2027 (17.3%)
640 (5.5%)
81 (0.7%)
10 354 (14.2%)
15 023 (20.6%)
4867 (6.7%)
1666 (2.3%)
1232 (7.0%)
3121 (17.7%)
1086 (6.2%)
255 (1.4%)
153 (1.3%)
438 (3.7%)
1677 (14.3%)
1679 (14.4%)
310 (2.7%)
1966 (2.7%)
3402 (4.7%)
8632 (11.9%)
6771 (9.3%)
2398 (3.3%)
480 (2.7%)
938 (5.3%)
2767 (15.7%)
2125 (12.1%)
610 (3.5%)
133 (1.1%)
227 (1.9%)
863 (7.4%)
1794 (15.3%)
859 (7.3%)
1495 (2.1%)
1659 (2.3%)
3470 (4.8%)
6969 (9.6%)
4146 (5.7%)
291 (1.7%)
468 (2.7%)
1052 (6.0%)
2074 (11.8%)
1111 (6.3%)
<0.001
<0.001
Values are expressed as number (%).
*P-value obtained from χ2 test comparing influenza without oseltamivir to influenza with oseltamivir.
† P-value obtained from χ2 test comparing oseltamivir without influenza to influenza with oseltamivir.
oseltamivir cohort than the influenza without
oseltamivir, χ2(1)=9.80, P=0.002, and oseltamivir
without influenza cohorts, χ2(1)=8.71, P=0.003.
Regional differences were seen, with a higher proportion of oseltamivir users with influenza in the
southeast, and a lower proportion in the midwest and
northeast compared with non-users, χ2(3)=1537.6,
P<0.001, and oseltamivir users without influenza,
χ2(3)=24.98, P<0.001. Use of oseltamivir peaked in
January and February of each year, with the peaks
somewhat sharper than the peaks in influenza diagnoses in the same months, χ2(13)=1579.1, P<0.001.
The decline in numbers of patients with influenza
across the three seasons reflects the patterns seen in the
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USA as a whole, with the highest incidence of influenza
occurring during the 1999–2000 season [8–10].
Table 2 presents the frequency of diagnoses and
drugs given during the 91-day period from 3 months
before the index date through the index date. Most
influenza diagnoses given on the index date were coded
as 487.1, influenza with other respiratory manifestations. The oseltamivir users with influenza were
somewhat less likely to receive a diagnosis of influenza
with pneumonia than were the non-users, overall
χ2(3)=88.70, P<0.001.
Most influenza patients did not receive any
influenza medication. Most patients who did use an
influenza drug used only one antiviral. Approximately
©2004 International Medical Press
Oseltamivir and skin reactions
17% of the non-users received an influenza drug other
than oseltamivir, whereas only 0.5% of the influenza
with oseltamivir group received another antiviral in
addition to oseltamivir, χ2(1)=2250.2, P<0.001.
Amantadine was the most frequently dispensed of the
other three influenza drugs. The oseltamivir users
without influenza were about twice as likely to receive
another influenza medication in addition to
oseltamivir than the primary oseltamivir cohort,
χ2(1)=25.26, P<0.001, though prevalence of use
within this group was still only 1%. Ribavirin was
very rarely used in any cohort (results not shown). The
oseltamivir users with influenza were somewhat less
likely to use antibiotics than were the non-users,
χ2(1)=23.31, P<0.001 and the oseltamivir users
without influenza, χ2(1)=4.81, P=0.03. The influenza
patients receiving oseltamivir were more likely than
the comparison influenza patients, χ2(1)=1046.0,
P<0.001, and than the oseltamivir users without
influenza, χ2(1)=767.3, P<0.001, to receive antitussives during the baseline period. The primary
oseltamivir cohort was also more likely than non-users
to receive analgesics, χ2(1)=207.7, P<0.001. The
oseltamivir without influenza cohort showed a similar
prevalence of analgesic use to the oseltamivir with
influenza cohort, χ2(1)=1.58, P=0.21.
Table 2. Diagnoses and drugs given during the 3-month baseline period
Influenza with
oseltamivir
(n=11 691)
Influenza without
oseltamivir
(n=72 818)
Influenza ICD-9 diagnosis code
Influenza, no fourth digit (487)
Influenza with pneumonia (487.0)
Influenza with other respiratory manifestations (487.1)
Influenza with other manifestations (487.8)
300 (2.6%)
243 (2.1%)
10822 (92.6%)
326 (2.8%)
Drug use history
Amantadine
Rimantadine
Zanamivir
Any influenza medication
Cephalosporins
Macrolides
Penicillins
Tetracyclines
Quinolones
Sulfonamides
Any antibiotic
Antitussives
Analgesics
Diagnostic history
Diabetes (250)
Cancer (140–209)
Rheumatoid arthritis (714)
HIV (042, V08)
General skin reaction (690–698, 700–709)
Atopic dermatitis (691.8)
Contact dermatitis and other eczema (692)
Dermatitis due to substance taken internally (693)
Erythematous conditions
(695 excluding 695.3 and 695.8)
Unspecified pruritic disorder (698.9)
Urticaria (708)
Adverse reaction to drug (995.2)
P–value*
Oseltamivir without
influenza
(n=17 610)
P–value †
1670 (2.3%)
2593 (3.6%)
65999 (90.6%)
2556 (3.5%)
<0.001
N/A
N/A
N/A
N/A
N/A
21 (0.2%)
25 (0.2%)
7 (0.1%)
53 (0.5%)
941 (8.0%)
2458 (21.0%)
1613 (13.8%)
370 (3.2%)
684 (5.9%)
9 (0.1%)
5012 (42.9%)
4701 (40.2%)
1557 (13.3%)
5435 (7.5%)
3877 (5.3%)
3343 (4.6%)
12616 (17.3%)
6250 (8.6%)
14644 (20.1%)
14162 (19.4%)
1778 (2.4%)
3068 (4.2%)
81 (0.1%)
32960 (45.3%)
18771 (25.8%)
6609 (9.1%)
<0.001
<0.001
<0.001
<0.001
0.06
0.02
<0.001
<0.001
<0.001
0.29
<0.001
<0.001
<0.001
55 (0.3%)
66 (0.4%)
54 (0.3%)
172 (1.0%)
1391 (7.9%)
3963 (22.5%)
2295 (13.0%)
568 (3.2%)
1441 (8.2%)
18 (0.1%)
7778 (44.2%)
4389 (24.9%)
2436 (13.8%)
0.03
0.02
<0.001
<0.001
0.64
0.003
0.06
0.77
<0.001
0.49
0.03
<0.001
0.21
261 (2.2%)
77 (0.7%)
29 (0.2%)
6 (0.1%)
681 (5.8%)
30 (0.3%)
143 (1.2%)
9 (0.1%)
5 (0.04%)
1711 (2.3%)
465 (0.6%)
154 (0.2%)
41 (0.1%)
4484 (6.2%)
308 (0.4%)
1221 (1.7%)
78 (0.1%)
49 (0.07%)
0.44
0.80
0.43
0.83
0.16
0.008
<0.001
0.35
0.33
529 (3.0%)
227 (1.3%)
52 (0.3%)
34 (0.2%)
1075 (6.1%)
37 (0.2%)
211 (1.2%)
13 (0.1%)
10 (0.06%)
<0.001
<0.001
0.36
0.001
0.32
0.41
0.85
0.92
0.60
6 (0.05%)
31 (0.3%)
25 (0.2%)
83 (0.11%)
333 (0.5%)
145 (0.2%)
0.05
0.003
0.74
17 (0.10%)
53 (0.3%)
36 (0.2%)
0.18
0.58
0.86
Values are expressed as number (%).
*P-value obtained from χ2 test comparing influenza without oseltamivir to influenza with oseltamivir.
† P-value obtained from χ2 test comparing oseltamivir without influenza to influenza with oseltamivir.
Antiviral Therapy 9:2
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BL Nordstrom et al.
History of diabetes, cancer, rheumatoid arthritis,
HIV and each of the skin reaction outcomes did not
differ markedly among the cohorts, though some
comparisons did achieve statistical significance at the
0.05 level. The prevalence of diabetes, cancer and HIV
were similar between the two influenza cohorts, but
the oseltamivir without influenza group showed a
higher prevalence of each, χ2(1)=15.94, P<0.001 for
diabetes, χ2(1)=27.20, P<0.001 for cancer and
χ2(1)=10.36, P=0.001 for HIV. Although the general
skin reaction was seen in approximately 6% of
patients, the frequency of each of the specific reactions
investigated was low, with all diagnoses except contact
dermatitis and other eczema present in less than 1% of
patients. Compared with the oseltamivir users with
influenza, the non-users showed a somewhat higher
prevalence of atopic dermatitis, χ2(1)=7.00, P=0.008,
contact dermatitis and other eczema, χ2(1)=13.05,
P<0.001, unspecified pruritic disorder, χ2(1)=3.76,
P=0.05 and urticaria, χ2(1)=8.67, P=0.003. In contrast,
baseline rates of each skin reaction were similar
between the two oseltamivir cohorts. Diagnoses of
dermatitis herpetiformis, impetigo herpetiformis,
pemphigus, pemphigoid and other specified bullous
dermatoses were seen in almost no patients in the baseline or follow-up period, so the results for these skin
reactions are not shown.
Skin reaction outcomes
Table 3 shows the frequency of each skin reaction
outcome during the 30 days following the index date
for the two primary study cohorts, along with crude
and adjusted incidence rate ratios obtained from Cox
proportional hazards models. The adjusted incidence
rate ratios were computed separately for those with
and without a history of the outcome diagnoses
during the 3-month baseline period. Age, grouped
into the categories shown in Table 1, and use of
another influenza medication during the baseline
period were found to be important predictors of
almost all of the skin reaction outcomes, so we
included these two variables in all models.
The analysis of the general skin reaction outcome
included only age and use of another influenza drug as
covariates. For this broad class of events, we observed
little difference in risk between the two groups, either
with or without a history of the outcome. Figure 1
presents Kaplan-Meier curves showing the cumulative
incidence of this event for the two groups. It is clear
from the figure that the risk of a general skin reaction
was much higher among those with a history of a skin
reaction than among those who had not received a skin
reaction diagnosis during the 3 months prior to the
index date. The figure also reveals that the skin reactions occurred at a relatively constant rate across the
192
month of follow-up; if influenza and/or oseltamivir
caused skin reactions concurrent with the illness or
drug use, the curves should have shown a sharper
increase during the first several days followed by a
levelling off as patients recovered from influenza and
stopped using oseltamivir.
Atopic dermatitis occurred in a total of 82 patients in
the two cohorts. For this outcome, use of antitussives
during the baseline period modified the hazard ratio for
exposure by more than 5%, so this variable was
included in the model along with age and use of another
influenza medication. The adjusted incidence rate ratio
for the patients without a history of atopic dermatitis
was 0.81, though the confidence interval for this rate
ratio was fairly wide. Since there were fewer than 20
events among those with a history of the outcome, we
did not construct a Cox model for this subgroup.
Contact dermatitis and other eczema occurred
more frequently, so we were able to perform adjusted
analyses for both patients with and without a history
of this outcome. Only age group and use of another
influenza drug were included in these models. For the
patients without a history of the outcome, the
adjusted incidence rate ratio was 0.79. The confidence interval was narrower than in the analysis of
atopic dermatitis, but it still included one, suggesting
that the apparently lower risk in the oseltamivir
group may not reflect a true difference. The rate ratio
for the group with a history of contact dermatitis and
other eczema was close to one.
Dermatitis due to a substance taken internally is of
particular interest in this study, because a skin reaction
ascribed by the physician to oseltamivir may be
assigned this code. There were, however, only 43 of
these events, which limits the power of our analysis.
Fewer than 20 events occurred in the group with a
history of the event, so an adjusted incidence rate ratio
is shown only for the group without a history of
dermatitis due to a substance. Month (November
through March) and use of antitussives during the
baseline period were important predictors in the
model, so these two variables were added as covariates.
The adjusted incidence rate ratio for oseltamivir exposure was somewhat greater than one, but the
confidence interval was very wide, so we cannot
conclude that oseltamivir was associated with an
increased risk of this event.
Erythematous conditions were seen only among the
non-users. The model for this event, computed only for
the group without a history of the outcome, included
only the age and other influenza drug covariates. The
incidence rate ratio was zero and the exact confidence
limit crossed one but closely approached statistical
significance. With so few events, however, these results
must be interpreted with caution.
©2004 International Medical Press
Oseltamivir and skin reactions
Table 3. Incidence rate ratios of skin reactions for influenza cohorts in 30 days following index date
Number of outcomes
General skin reaction
Atopic dermatitis
Contact dermatitis and other eczema
Dermatitis due to substance taken internally
Erythematous conditions
Unspecified pruritic disorder
Urticaria
Adverse reaction to drug
Influenza
with
oseltamivir
(n=11 691)
Influenza
without
oseltamivir
(n=72 818)
Crude incidence
rate ratio*
Adjusted
incidence rate
ratio, no history
Adjusted
incidence rate
ratio, history
247
7
47
7
0
5
18
16
1440
75
356
36
29
24
132
74
1.06 (0.93, 1.22)
0.58 (0.27, 1.26)
0.82 (0.60, 1.11)
1.21 (0.54, 2.71)
0 (0.00, 0.84)
1.29 (0.49, 3.39)
0.85 (0.52, 1.38)
1.35 (0.78, 2.31)
1.05 (0.88, 1.24) †
0.81 (0.36, 1.84) §
0.79 (0.56, 1.12) †
1.26 (0.53, 3.01) ‡
0 (0.00, 1.03) †
1.27 (0.45, 3.56) ¢
1.27 (0.72, 2.25) §
1.10 (0.60, 1.99) #
0.98 (0.77, 1.24) †
N/A
0.94 (0.46, 1.91) †
N/A
N/A
N/A
1.01 (0.30, 3.42) §
N/A
*Incidence rate ratios are presented as rate ratio (95% CI).
† Rate ratio adjusted for age and use of another influenza drug.
§ Rate ratio adjusted for age, use of another influenza drug and use of antitussives.
‡ Rate ratio adjusted for age, use of another influenza drug, month of index date and use of antitussives.
¢ Rate ratio adjusted for age, use of another influenza drug and year of index date.
# Rate ratio adjusted for age, use of another influenza drug and month of index date.
A total of 29 patients had a diagnosis of unspecified
pruritic disorder during the outcome period. Again the
analyses were computed only for the group without a
history of the outcome. Year of index date was found
to modify the hazard ratio for exposure, so it was
added to age and use of another influenza drug as a
covariate. The adjusted incidence rate ratio was
slightly over one but again was made questionable
because of low power; the confidence interval ranged
from less than 0.5 to 3.5.
Urticaria was more common, with 150 patients
receiving this diagnosis. Use of antitussives in the
baseline period was an important predictor and was
added to the models both for those with and those
without a history of the outcome. For patients
without a history of urticaria during the baseline
period, the adjusted incidence rate ratio was 1.27, but
again the confidence interval is sufficiently wide that
we cannot conclude that oseltamivir was associated
with an increased risk of this outcome. For those with
Figure 1. General skin reaction between the two influenza cohorts for 30 days after the index date
0.14
Oseltamivir, with
history of outcome
Proportion of patients with event
0.12
0.10
No oseltamivir, with
history of outcome
0.08
0.06
0.04
Oseltamivir, no
history of outcome
0.02
No oseltamivir, no history of outcome
0.00
0
5
10
15
20
25
30
Days since index date
Plots are separate for patients with and without claims indicating a history of the outcome diagnoses given during the 3-month period prior to the index date.
Antiviral Therapy 9:2
193
BL Nordstrom et al.
a history of the outcome, the rate ratio was approximately one.
Adverse reaction to a drug occurred in a total of 90
patients during follow-up. Month of the index date
modified the hazard ratio for exposure, so this variable
was added to the model. The adjusted incidence rate
for patients without a history of the diagnosis was
slightly greater than one but with a wide confidence
interval, so that again there is no clear sign of an
increase in risk of this outcome with oseltamivir.
Five of the specific outcomes, dermatitis herpetiformis,
impetigo
herpetiformis,
pemphigus,
pemphigoid and other specified bullous dermatoses,
were extremely rare in both cohorts, so we were unable
to perform survival analyses of these outcomes. There
were no incident cases of any of these disorders in the
oseltamivir cohort, so there was clearly no indication of
an elevation of risk associated with oseltamivir.
Comparisons of the skin reaction outcomes between
the two oseltamivir groups are presented in Table 4.
Many outcomes failed to reach the 20 event minimum
we had set for performing Cox regressions. For all events
that we were able to analyse, including the general skin
reaction, contact dermatitis and other eczema, urticaria
and adverse reaction to a drug, the oseltamivir without
influenza cohort showed no sign of any increase in risk
compared with the primary oseltamivir cohort. All confidence intervals were one or less, though none were
significantly (P<0.05) less than one.
Discussion
The skin reactions investigated as outcomes after
oseltamivir and/or influenza diagnosis were found to
be uncommon in the present cohorts. The broadest
class of diagnoses, consisting of a wide range of
inflammatory skin conditions and other skin diseases,
was seen in approximately 2% of patients during the
month following the index date. The more specific
reactions examined were overall very rare.
We found no indication of an increase in risk of any
of these events associated with use of oseltamivir. We
must, however, question the frequency with which
these skin reactions, especially mild to moderate reactions of fairly brief duration, are reported on medical
claims. Under-reporting of such events seems likely to
occur similarly across patients who did and those who
did not receive a dispensing of oseltamivir, so that the
effect of this under-reporting is most likely to reduce
the statistical power of our comparisons rather than to
bias the size of the effect.
Although severe reactions including StevensJohnson syndrome have been reported with
post-marketing use of oseltamivir, we did not find a
heightened risk of these reactions among patients
receiving oseltamivir in the present database. StevensJohnson syndrome cannot be identified in claims data
with any precision, because there is no unique ICD-9
code associated with it. In our skin reaction categories,
this reaction would fall under the heading of erythematous conditions, of which we identified none in the
primary oseltamivir cohort and only four among the
oseltamivir users without influenza. The power of this
study may have been inadequate to detect a very rare
event. If the true incidence of erythematous conditions
among users of oseltamivir was one in 10 000, the likelihood of our detecting such events in the primary
oseltamivir cohort would be 0.69, but if the true incidence was one in 100 000, the probability of detecting
the events would be only 0.11. We cannot, therefore,
Table 4. Incidence rate ratios of skin reactions for oseltamivir cohorts in 30 days following index date
Number of outcomes
General skin reaction
Atopic dermatitis
Contact dermatitis and other eczema
Dermatitis due to substance taken internally
Erythematous conditions
Unspecified pruritic disorder
Urticaria
Adverse reaction to drug
Influenza
with
oseltamivir
(n=11 691)
Oseltamivir
without
influenza
(n=17 610)
Crude incidence
rate ratio*
Adjusted
incidence rate
ratio, no history
Adjusted
incidence rate
ratio, history
247
7
47
7
0
5
18
16
341
10
63
4
4
10
15
18
0.92 (0.78, 1.08)
N/A
0.89 (0.61, 1.30)
N/A
N/A
N/A
0.55 (0.28, 1.10)
0.75 (0.38, 1.46)
0.99 (0.81, 1.21) †
N/A
1.00 (0.66, 1.51) †
N/A
N/A
N/A
0.57 (0.26, 1.23) §
0.88 (0.43, 1.79) ‡
0.77 (0.57, 1.03) †
N/A
N/A
N/A
N/A
N/A
N/A
N/A
*Incidence rate ratios are presented as rate ratio (95% CI).
† Rate ratio adjusted for age and use of another influenza drug.
§ Rate ratio adjusted for age, use of another influenza drug and use of antitussives.
‡ Rate ratio adjusted for age, use of another influenza drug and month of index date.
194
©2004 International Medical Press
Oseltamivir and skin reactions
be confident that such an extremely rare event as
Stevens-Johnson syndrome is likely to be would have
appeared in the present study.
For other severe reactions that can be ascertained
from medical claims, such as pemphigus and
pemphigoid, we found no incident cases among
oseltamivir users. Unlike many mild reactions, severe
reactions should be given some form of medical care
that will ensure that the diagnosis appears on health
insurance claims, making it unlikely that such events
were missed in the present study. Given the limitations
of the diagnostic coding system, however, it is difficult
to determine which events may be considered severe.
Over half of the patients who received a dispensing
of oseltamivir did so without having a diagnosis of
influenza noted in their medical claims at any time
during the same influenza season. The resulting
oseltamivir without influenza cohort probably
consisted of patients using oseltamivir prophylactically, patients who did have influenza but simply called
their physicians rather than making an office visit, and
patients who received an oseltamivir dispensing on a
different day from the date of diagnosis of influenza.
The proportion of patients in the former two categories is impossible to determine using claims data
alone, as telephone calls do not result in medical
claims. The finding of similar risks of each outcome
between the primary oseltamivir cohort and the
oseltamivir cohort without an influenza diagnosis
provides reassurance that the influenza with
oseltamivir group was fairly representative of all
oseltamivir users, and hence that the principal comparisons between influenza patients with and without
oseltamivir were valid.
Please note that oseltamivir exposure may have been
misclassified for some patients, as those who received
a pharmacy dispensing of the drug may not have taken
it, while those with no claims for oseltamivir
dispensing in the database may have obtained the drug
through a different source than a pharmacy dispensing
processed by their healthcare insurer (such as, samples
provided in the physician’s office).
In conclusion, the skin reactions investigated
occurred infrequently in this claims-based study of
influenza patients. Oseltamivir use appears not to be
associated with an increase in risk of any of the skin
reactions examined. This finding holds both for incident cases and for recurring reactions, suggesting that
oseltamivir is likely to be safe with respect to skin reactions even among those with a history of skin disorders.
Source of support
Supported by a contract between Roche Global
Development and Ingenix Epidemiology.
References
1.
Centers for Disease Control and Prevention. Update:
Influenza activity – United States, 2002–03 season.
Morbidity & Mortality Weekly Report 2003; 52:26–28.
2
Centers for Disease Control and Prevention. Prevention
and control of influenza: recommendations of the Advisory
Committee on Immunization Practices (ACIP). Morbidity
& Mortality Weekly Report 2001; 50:1–46.
3. Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller
M, Kinnersley N, Mills RG, Ward P & Straus SE. Use of
the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for
prevention and treatment. Journal of the American
Medical Association 1999; 282:1240–1246.
4. Nicholson KG, Aoki FY, Osterhaus AD, Trottier S,
Carewicz O, Mercier CH, Rode A, Kinnersley N & Ward
P. Efficacy and safety of oseltamivir in treatment of acute
influenza: a randomised controlled trial. Lancet 2000;
355:1845–1850.
5. Treanor JJ, Hayden FG, Vrooman PS, Barbarash R, Bettis
R, Riff D, Singh S, Kinnersley N, Ward P & Mills RG.
Efficacy and safety of the oral neuraminidase inhibitor
oseltamivir in treating acute influenza: a randomized
controlled trial. Journal of the American Medical
Association 2000; 283:1016–1024.
6. Enger C, Nordstrom BL, Thakrar B, Sacks S & Rothman
KJ. Health outcomes among patients receiving oseltamivir.
Pharmacoepidemiology & Drug Safety (In Press).
7. Roche Laboratories, Inc. Tamiflu (oseltamivir phosphate)
capsules and for oral suspension (Package insert). Roche
Laboratories, Inc.: Nutley, NJ, USA. 2001.
8. Centers for Disease Control and Prevention. Update:
Influenza activity – United States and worldwide, 19992000 season and composition of the 2000–2001 influenza
vaccine. Morbidity & Mortality Weekly Report 2000;
49:375–381.
9. Centers for Disease Control and Prevention. Update:
Influenza activity – United States and worldwide, 2000-01
season, and composition of the 2001–2002 influenza
vaccine. Morbidity & Mortality Weekly Report 2001;
50:466–470.
10. Centers for Disease Control and Prevention. Update:
Influenza activity – United States and worldwide, 20012002 season and composition of the 2002–2003 influenza
vaccine. Morbidity & Mortality Weekly Report 2002;
51:503–506.
Received 20 August 2003; accepted 31 October 2003
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