DERMATOLOGICA SINICA 30 (2012) 11e15

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ORIGINAL ARTICLE

Fixed-drug eruption: A retrospective study in a single referral center

in northern Taiwan
Cheng-Han Lee 1, Yi-Chun Chen 2, Yung-Tsu Cho 1, Chia-Ying Chang 1, Chia-Yu Chu 1, *
1
2

Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
Department of Dermatology, Cathay General Hospital, Taipei, Taiwan

a r t i c l e i n f o

a b s t r a c t

Article history:
Received: Jul 19, 2011
Revised: Oct 4, 2011
Accepted: Feb 9, 2012

Background/Objective: Fixed drug eruption (FDE) is a dermatosis characterized by recurrent patches or

plaques at exactly the same sites with each administration of the causative drug. Vesicles or bullae may
sometimes be found, and generalized bullous xed drug eruption (GBFDE) may be confused with
Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). This study aimed to investigate the
clinical and pathologic features of FDE in Taiwan.
Methods: A retrospective analysis evaluated patients with FDE in a referral center in Taiwan covering
a period of 11 years. Clinical data, suspected etiologies, and pathology/patch test results were collected.
We also compared the GBFDE cases with SJS/TEN overlap or TEN cases to nd differentiating clues.
Results: There were 39 FDE patients, including nine GBFDE cases. The most frequent causative drugs were
non-steroidal anti-inammatory drugs (ve cases, 12.8%) and antibiotics (four cases, 10.3%). Extremities
other than the hands (71.8%) were the most frequently affected sites, followed by the trunk (51.3%),
mucosa (38.5%), and hands (33.3%). The average age of FDE patients was 52.2 years (median, 56 years;
range, 4e86 years). Patients with GBFDE were signicantly older than non-GBFDE patients (69.1
19.7
vs. 47.2
23.6, p 0.0124) and the trunk was more likely to be involved in GBFDE cases (88.9% vs. 40.0%,
p 0.0197). GBFDE cases also showed tendency to have more mucosal involvement (66.7% vs. 30.0%,
p 0.0631). Although similar to SJS/TEN, GBFDE cases had fewer constitutional symptoms, less mucosal
involvement but had previous episodes. Histopathologically, the presence of more than two aggregated
dyskeratotic keratinocytes (re ag sign) in the epidermis was more frequently observed in SJS/TEN,
whereas GBFDE had supercial and deep dermal inltration of eosinophils and melanophages.
Conclusion: FDE is one of the specialized cutaneous drug reactions and GBFDE should be kept in mind and
differentiated from SJS/TEN.
Copyright 2012, Taiwanese Dermatological Association.
Published by Elsevier Taiwan LLC. All rights reserved.

Keywords:
generalized bullous xed drug eruption
xed drug eruption
Stevens-Johnson syndrome
toxic epidermal necrolysis

Introduction
Fixed drug eruptions (FDEs) are dened as recurrent lesions at
the same skin or mucosal sites after repeated intake of the causative agent.1 FDEs usually present as itching or burning, wellcircumscribed, erythematous macules, patches, or plaques that
leave hyperpigmentation after resolving. Vesicles or bullae may
occasionally be seen. There are many causative agents and the
incidence of FDE for a particular drug depends on the frequency of
its use. Therefore, the list of etiologic drugs varies from one place to
another and from time to time.2

* Corresponding author. Chia-Yu Chu, Department of Dermatology, National

Taiwan University Hospital, Number 7, Chung-Shan South Road, Taipei, Taiwan.
E-mail address: chiayu@ntu.edu.tw (C.-Y. Chu).

Generalized bullous xed drug eruption (GBFDE) may be

confused with toxic epidermal necrolysis (TEN) or Stevens-Johnson
syndrome (SJS). The present study aimed to investigate the clinical
and pathologic features of FDE in Taiwan and identify several
differentiating features between GBFDE and non-GBFDE, as well as
between GBFDE and SJS/TEN.
Methods
Patients
From January 2000 to February 2011, cases with suspected diagnosis
of FDE recorded in the patch-testing database or skin pathology
database of the Department of Dermatology of the National Taiwan
University Hospital in Taipei, Taiwan, were recruited. FDE was
diagnosed according to the typical clinical features: erythematous,

1027-8117/$ e see front matter Copyright 2012, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.dsi.2012.02.002

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C.-H. Lee et al. / Dermatologica Sinica 30 (2012) 11e15

bright red or dusky red macules that might evolve into an edematous
plaque with residual grayish or slate-colored hyperpigmentation
(Figure 1A).3 GBFDE was dened as typical or nonpigmented FDE
lesions with bulla formation involving at least three of the following
different anatomic sites: head and neck (including lips), anterior
trunk, back, upper limbs, lower limbs, and genitalia (Figure 1B).4e7
Patch tests were performed according to ICDRG regulations
and literature after obtaining informed consent.8,9 Due to ethical
issues, oral challenge tests were not performed. Clinical data, suspected etiologies, and pathology/patch test results were collected
from chart records. Pathology-proved TEN or SJS/TEN overlap
patients in the same period were included to compare with GBFDE
patients. These TEN or SJS/TEN overlap patients were diagnosed
according to the criteria proposed by the European Registry of
Severe Cutaneous Adverse Reactions (EuroSCAR) group.10 Pathologic features such as supercial or supercial and deep inammation, basal vacuolization, pigment incontinence, and presence of
dyskeratotic (apoptotic) keratinocytes were recorded. Eosinophil
and neutrophil numbers were also assessed on a four-point scale
[score of 0 indicated no specied cell in the specimen; score 1, < 2
cells in every 400 high power eld (HPF); score 2, 2e10 cells in
one HPF; and score 3, > 10 cells in one HPF].
Statistical analysis
Two-sided Wilcoxon rank sum test was used to compare the age
difference of GBFDE and non-GBFDE patients. Chi-square tests or

Fishers exact tests were conducted to compare differences in sex,

frequency of previous events, and lesion locations between the two
groups. All of the statistical analyses were performed using the SAS
software (ver. 9.1.3, SAS Institute, Cary, NC, USA).
Results
FDE patients, including GBFDE and non-GBFDE
Of the 39 FDE patients recruited in this study, 30 were non-GBFDE
and nine were GBFDE cases (Table 1). The average age of FDE
patients was 52.2
24.4 years (median, 56 years; range, 4e86
years). The average and median ages of non-GBFDE were younger
than those of GBFDE (47.2
23.6 vs. 69.1
19.7 years, p 0.0124
and 46 vs. 74 years). There was no signicant sex preference,
although a trend of male predominance was noted (22 men and 17
women). A total of 20 of the 39 FDE patients (51.3%) had previous
events, including 14 (46.7%) non-GBFDE and six (66.7%) GBFDE
(p 0.4506).
Fifteen FDE patients (38.5%) had mucosal involvement. GBFDE
cases seemed more likely to have mucosal lesions (66.7% vs. nonGBFDE 30.0%, p 0.0631). GBFDE patients were also more likely
to have trunk involvement (88.9% in GBFDE vs. 40.0% in non-GBFDE,
p 0.0197). These results are shown in Table 1.
Etiologic agents
Nonsteroidal anti-inammatory drugs (NSAIDs) were the most
common causative agents, accounting for 12.8% of cases (ve cases,
including four non-GBFDE and one GBFDE). Four cases (10.3%) were
caused by antibiotics (one non-GBFDE and three GBFDE). Other
cases were caused by miscellaneous agents, including computed
tomography contrast and unknown Chinese herbal drugs (Table 2).
During this period, only 12 of the 39 patients received patch testing
of the suspected causative agents on the previous lesion sites, four
(33.3%) of whom had a positive reaction to the suspected drugs.
GBFDE and TEN
Four TEN patients and two SJS/TEN overlap patients were included
for comparison with GBFDE patients (Table 3). The GBFDE patients
were older than the SJS/TEN overlap or TEN patients (69.1
19.7 vs.
58.7
26.1 years; median, 74 vs. 57.5 years). Previous events were
noted in six GBFDE patients (66.7%) but none in the SJS/TEN overlap
or TEN patients. There was mucosal involvement in six GBFDE

Table 1 Demographic data of patients with non-GBFDE and GBFDE.

Figure 1 (A) Fixed drug eruption: round erythematous plaque with central dusky red
to grayish hyper-pigmentation; (B) generalized bullous xed drug eruption: large areas
of accid blisters or erosions involving the abdomen, thighs, and glans penis.

Total (%)

Non-GBFDE (%)

GBFDE (%)

p value

Number
Age (mean
SD), y
Median age
Sex (W/M)
Previous events

39
52.2
24.4
56
17/22
20 (51.3)

30
47.2
23.6
46
14/16
14 (46.7)

9
69.1
19.7
74
3/6
6 (66.7)

NA
0.0124
NA
0.7042
0.4506

Location
Mucosal involvement
Lip or oral mucosa
Genital area

15 (38.5)
12 (30.8)
8 (20.5)

9 (30.0)
8 (26.7)
5 (16.67)

6 (66.67)
4 (44.4)
3 (33.33)

0.0631
0.4161
0.3548

Extremities
Hands
Other extremities
Trunk
Face
Patch test (/)

13 (33.3)
28 (71.8)
20 (51.3)
6 (15.4)
4/8

9 (30.0)
20 (66.7)
12 (40.0)
3 (10.0)
3/5

4 (44.4)
8 (88.89)
8 (88.89)
3 (33.3)
1/3

0.4472
0.3994
0.0197
0.1225
NA

GBFDE generalized bullous xed drug eruption; NA not applicable; SD

standard deviation.

C.-H. Lee et al. / Dermatologica Sinica 30 (2012) 11e15

13

Table 2 Suspected etiologies of FDE.

NSAIDs
Antibiotics
Other drugs
Multiple drugs

Other etiologies
Unknown

Non-GBFDE (n 30)

GBFDE (n 9)

Total

4 (mefenamic acid,a,b sulindac,a,b piroxicam,a,b acemetacin)

1 (cephalosporin)
6 (rabeprazole,b,c levamisole,b allopurinol,b propranolol, Andrographis paniculata,b
dicyclomine or mepenzolateb)
7 [(doxycycline, acetaminophenb,c,), (sulfamethoxazole and trimethoprim,
diclofenacb,c), (sulfamethoxazole and trimethoprim, diclofenacb,c), (clindamycin,
sulfamethoxazole and trimethoprim, ibuprofen, pseudoephedrineb), (amoxicillin,
mefenamic acidb), (cephalexin, levocetirizineb),(diclofenac, indomethacin, colchicin,
allopurinolb)]
5 [computed tomography contrast, unknown Chinese herbal drugs,b drug for headache,
drugs for upper respiratory tract infection (two cases)]
7

1 (ibuprofenb)
3 (ceftriaxonea, cefpiromeb, tetracyclineb)
1 (allopurinolb)

5
4
7

2 [(sulindac, cimetidine, calcium carbonateb,c),

(amoxicillin, hydroxyzine, mefenamic acida)]

FDE xed-drug eruption; GBFDE generalized bullous xed drug eruption; NSAID nonsteroidal anti-inammatory drug.
a
Positive patch test.
b
Previous events ().
c
Negative patch test.

patients (66.7%) and in all six SJS/TEN overlap or TEN patients.

Constitutional symptoms (e.g. fever, chills, or malaise) were more
common in SJS/TEN overlap or TEN patients [three patients (50%)
vs. one in GBFDE (11.1%)].
To avoid examining secondary changes of skin pathology due to
blister formation or epidermal necrosis, only biopsy specimens
taken from the perilesional skin or early stage lesions were used
for comparison of histopathologic features between GBFDE and
SJS/TEN. Seven and six histologic specimens were available for
evaluation in GBFDE and SJS/TEN overlap or TEN patients, respectively. The pathologic features of SJS/TEN overlap or TEN specimens
showed supercial perivascular inammation (100%), basal
vacuolization (100%), presence of re ag sign3,11,12 (more than two
aggregated dyskeratotic keratinocytes, 100%), less pigment incontinence (33.3%), and lower eosinophil score (0e1). These results are
shown in Figure 2A and B.

Table 3 Comparison of clinical and pathologic features GBFDE and SJS/TEN overlap
or TEN.
GBFDE (%)

SJS/TEN overlap or TEN (%)

Clinical features
Average age (mean
SD), y
Median age, y
Sex (W/M)
Previous events
Mucosal involvement
Constitutional symptoms

n9
69.1
19.7
74
3/6
6 (66.7)
6 (66.7)
1 (11.1)

n6
58.7
26.1
57.5
3/3
0 (0)
6 (100)
3 (50)

Pathologic features
Perivascular inammation
Supercial
Supercial and deep
Basal vacuolization
Fire ag signa
Eosinophil scoreb
0
1
2
Neutrophil scoreb
0
1
2
Pigment incontinence

n7

n6

5
2
7
0

6
0
6
6

(71.4)
(28.6)
(100)
(0)

(100)
(0)
(100)
(100)

0 (0)
3 (42.9)
4 (57.1)

3 (50)
3 (50)
0 (0)

6
0
1
7

4
2
0
2

(85.7)
(0)
(14.3)
(100)

(66.7)
(33.3)
(0)
(33.3)

GBFDE generalized bullous xed drug eruption; HPF high power eld; NA, not
applicable; SD standard deviation; SJS Stevens-Johnson syndrome; TEN toxic
epidermal necrolysis.
a
Fire ag sign, more than two aggregated dyskeratotic keratinocytes.
b
0, no specied cell in the specimen; 1, specied cell present but < 2 cells in
every 400 HPF; 2, 2e10 cells in one HPF; 3, > 10 cells in one HPF.

By contrast, GBFDE specimens showed no aggregated dyskeratotic keratinocytes in the epidermis (re ag sign) (0%), frequent
pigment incontinence (100%), more common supercial and deep
perivascular inammation (28.6%), and higher eosinophil scores
(1e2). These results are shown in Figure 2C and D. Such results
indicated that detailed histopathologic examination from early
stage lesions or perilesional skin, along with clinical information
of previous episodes, constitutional symptoms, and mucosal
involvement, were useful in differentiating GBFDE from SJS/TEN.
Discussion
This study collected 39 cases of FDE from a referral center in
northern Taiwan. NSAIDs and antibiotics are the most common
drugs causing FDE among many other etiologies. Patients with
GBFDE are older and have higher chances of trunk and mucosal
involvement than non-GBFDE patients. Patients with GBFDE are
also more likely to have previous events but less likely to have
constitutional symptoms than patients with SJS/TEN overlap or
TEN. The presence of eosinophils and pigment incontinence with
absent re ag sign is an important clue to differentiate GBFDE
from SJS/TEN.
Although the rst case of FDE was described by Bourns in
1889,13 the term FDE was rst proposed in 1894 by Brocq to
describe a special type of reaction to antipyrine.14 The phenomenon
of lesions recurring at the previous involved sites has intrigued
many dermatologists. Intraepidermal CD8 T cells with effectormemory phenotype resident in FDE lesions are considered very
important in the disease pathogenesis. FDE predisposing sites (i.e.
lips, genital areas, or hands) are frequent regions of herpes simplex
virus (HSV) reactivation.15 Previous studies have found that the vast
majority of FDE patients are asymptomatic HSV seropositive individuals and their anti-HSV immunoglobin G (IgG) titers are much
higher than in patients with HSV recurrences.15 FDE lesions found
at previously traumatized sites, such as burn scars and insect bites,
were also well documented.15 Moreover, these T cells are found at
the site of repeated pathogen entry, such as the lungs. Thus,
intraepidermal CD8 T cells with an effector-memory phenotype
resident in FDE lesions may mediate protective immunity.15 Additional recruitment of other inammatory cells occurs in the late
stage of the disease, and then disease activity is down regulated by
regulatory T cells.15
A recent French study16 recruited 59 cases from 17 hospitals
over three years, which indicate that FDE is not a common cutaneous adverse drug reaction (roughly one case per year per
hospital). However, FDEs are the most frequent cutaneous reactions

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C.-H. Lee et al. / Dermatologica Sinica 30 (2012) 11e15

Figure 2 Pathologic features of toxic epidermal necrolysis (TEN) and generalized bullous xed drug eruption (GBFDE). (A, B) TEN: supercial perivascular lymphocytic inammation, aggregation of more than two dyskeratotic keratinocytes (re ag sign, arrows), and basal vacuolization (hematoxylin-eosin, 40 and 100); (C) GBFDE: discrete
dyskeratosis, basal vacuolization, and supercial perivascular lymphocytic inammation (hematoxylin-eosin, 100; (D) GBFDE: pigment incontinence and eosinophils in the upper
dermis (hematoxylin-eosin, 200).

in one report from India, accounting for 30% of all cutaneous

adverse drug reactions (61 cases over a 10-year study).17 There
were a total of 39 cases over an 11-year period in one referral center
for drug eruption and patch testing in northern Taiwan. It seems
that the incidence rate of FDE in Taiwan is similar to that of India.
There may be some evidence of genetic predisposition to FDEs.1
The average age of the patients in the current study is 52.2 years,
which is older than those of previous reported series (around the
fourth decade).18e20 However, the median age of one recent study
(58 years) is close to the present ndings.16 The average age of
GBFDE patients is higher than those of non-GBFDE patients. This
may be explained by the fact that GBFDE patients have more
previous episodes than non-GBFDE patients, even though the
difference is not statistically signicant. It is possible that some
patients may overlook or forget prior episodes.
Some studies, including the present one, show a trend toward
a male predominance,2 although female predominance has also
been reported.16 In the present study, extremities (not including
hands)(71.8%) were the most frequently affected sites, followed by
trunk (51.3%), mucosa (38.5%), and hands (33.3%). In a study of site
involvement in FDE from 105 patients from Turkey, genital mucosa
(50.5%) was the most frequently involved site, followed by the
trunk (38.1%), lips (37.1%), and hands (32.4%).20 However, some
studies show that the lips are the most frequently affected
site.18,19,21
The etiology of FDE varies depending on the drugs in vogue at
the time in different regions.2 The list of causative drugs is long,
including non-narcotic analgesics, antibacterial agents, antifungal
agents, antipsychotics, other miscellaneous drugs, and even ultraviolet radiation, emotional and psychiatric factors, heat, menstrual
abnormalities, pregnancy, fatigue, cold, and undue effort.2 There is
even one report describing a male patient with postcoital FDE after
his wife took the causative drug trimethoprim/sulfamethoxazole.22

In the present study, the etiologies are diverse. It is very common

that patients take several drugs at one time and, in this study, nine
patients took multiple possible drugs. Therefore, it is difcult to
identify the true etiology. Furthermore, it is difcult to pinpoint
a culprit drug in subsequent episodes considering cross- and
polysensitivity.2 Verbov23 reported a case of FDE caused by
paracetamol-chlormezanone combination, but not by either drug
alone. Drug interactions may lead to formation of chemicals
causing FDE. Although oral challenge with subtherapeutic dose
remains the most reliable method for dening the etiology, it may
cause severe are-up reactions. Thus, only patch tests were done on
the previously involved sites in this study.
Because there is no clear denition of GBFDE in the literature,
we proposed that it should fulll the description of typical FDE or
nonpigmented lesions and have at least bullae involving at least
three of the following different anatomic sites: head and neck
(including the lips), anterior trunk, back, upper limbs, lower
limbs, and genitalia.4e7 GBFDE is sometimes confused with SJS/
TEN.12 There have been reports of patients surviving from recurrent TEN episodes but such cases are rare. Some authors even
suspect that some of these cases are actually GBFDE rather than
TEN.12
The present study shows that GBFDE patients are older than SJS/
TEN patients and may have previous episodes. Mucosal involvement and constitutional symptoms are less frequent. Commonly
incriminated drugs for bullous FDE are rifampicin, metronidazole,
paracetamol, paclitaxel, vinburnine, erythromycin, and ibuprofen.3
This study showed antibiotics (three cases) are the most frequent
causative drugs in GBFDE. Histopathologically, FDE and SJS/TEN
both showed basal vacuolization and dyskeratosis. However, the
presence of eosinophils, neutrophils, or melanophages in the
supercial and deep inltrates favors GBFDE over SJS/TEN.12
The absence of re ag sign and higher eosinophil scores further

C.-H. Lee et al. / Dermatologica Sinica 30 (2012) 11e15

differentiate FDE from SJS/TEN.3,11,12 Unfortunately, because of the

limited number of cases, further investigations are warranted.
In conclusion, NSAIDs and antibiotics are the most frequent
causative drugs of FDEs in Taiwan. Patients with GBFDE are older
than non-GBFDE patients, have more involvement of the trunk,
and are easily misdiagnosed as TEN. They are less likely to have
constitutional symptoms and mucosal involvement, and may have
previous episodes. Skin biopsy is important because the absence of
re ag sign and eosinophils and melanophages in the supercial
and deep inltration favors GBFDE. Detailed histopathologic
examination from early stage lesions or perilesional skin, along
with clinical information of previous episode, constitutional
symptoms and mucosal involvement, will be useful in differentiating GBFDE from SJS/TEN.
Acknowledgments
The authors thank Yu-Hsian Tseng for her assistance in the statistical computations.
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