occupational allergic contact dermatitis from tetrazepam in nurses
TRANSCRIPT
Contact Dermatitis 2010: 62: 303–308Printed in Singapore. All rights reserved
© 2010 John Wiley & Sons A/S
CONTACT DERMATITIS
Occupational allergic contact dermatitis fromtetrazepam in nurses
Kim Vander Hulst1, Stefan Kerre2,3 and An Goossens1
1Department of Dermatology, University Hospital, K.U.Leuven, B-3000 Leuven, 23200 Aarschot, and 3Department ofDermatology, AZ Imelda, 2820 Bonheiden, Belgium
Background: Tetrazepam is a muscle relaxant belonging to the benzodiazepine group. Drug eruptionsfollowing ingestion of tetrazepam tablets are well known.
Objective: To draw the attention to occupational airborne dermatitis and/or hand dermatitis in nursesresulting from crushing of tablets for elderly or disabled people.
Methods: Since 2003, 16 nurses with facial (eyelid) and/or hand dermatitis, suspected to be ofoccupational origin, were patch tested with the medication they handled during work.
Results: Ten nurses presented with a positive patch test reaction to tablets containing tetrazepam, 14controls remaining negative. Some of them also reacted to other drugs.
Conclusion: Occupational airborne and/or hand contact dermatitis from tetrazepam might be much morecommon than suspected by dermatologists, particularly in view of the short period in which all caseshave been observed.
Key words: airborne; allergic contact dermatitis; benzodiazepine; disabled; elderly; nurses; occupational;tetrazepam. © John Wiley & Sons A/S, 2010.
Conflict of interests: The authors have declared no conflicts.Accepted for publication 18 December 2009
Tetrazepam is a frequently used muscle relaxantbelonging to the benzodiazepine group containinga cyclohexene ring. Belgian commercial names areMyolastan® (Aktuapharma, Heverlee, Belgium;Pharmapartner, Hoegaarden, Belgium; Sanofi-Aventis, Diegem, Belgium), Epsipam® (Will-Pharma, 1301 Wavre, Belgium), and TetrazepamEG® (Eurogenerics, 1020 Brussels, Belgium).Drug eruptions are well known, but occupationalcontact dermatitis from this compound has beenoccasionally reported only.
Patients, Methods and Results
From September 2003 to August 2009, 16 nurseswith facial (mainly eyelid) (Fig. 1) and/or handdermatitis, suspected to be of occupational ori-gin, were patch tested in our Contact AllergyUnit with the baseline series (Trolab® Hermal,
Reinbek, Germany), antiseptics used, and medica-tions that were handled during work, using vander Bend chambers® (van der Bend, Brielle, theNetherlands) mounted on Micropore® (3M HealthCare, Borken, Germany), and fixed with Mefix®(Molnlycke Health Care, Goteborg, Sweden). Thisparticularly included tablets, which they sometimeshad to crush for elderly or disabled people, andwhich were tested crushed and diluted 30% in whitepetrolatum (pet.).
Ten out of the 16 patients investigated, i.e. 9geriatric nurses (or aids) and one nurse who workedin a clinic for multiple sclerosis patients, presentedwith a positive reaction to the tablets containingtetrazepam (Fig. 2).
Among them (Table 1), five suffered from air-borne facial dermatitis, two from hand dermatitis,and three from both airborne and hand dermatitis.One patient also had widespread eczema lesions on
304 VANDER HULST ET AL. Contact Dermatitis 2010: 62: 303–308
Fig. 1. Case no. 6, eczema peri-orbital, nose, and cheeks:suggestive for airborne dermatitis.
Fig. 2. Case no 4, positive patch test to tetrazepam (D2reading).
the feet, elbows, and legs. They all reported a clearrelationship with their work, with improvement ofthe lesions during holidays.
All patients were simultaneously or subsequentlytested with other benzodiazepine-containing tablets(Table 1), and cases 6, 8, 9, and 10 were alsotested with oxazepam and diazepam, and bro-mazepam as pure substances diluted 10% in pet.Lorazepam (Temesta®; Aktuapharma, Heverlee,Belgium; Wyeth, Louvain-La-Neuve, Belgium) waspositive in cases nos. 6 and 7, who also handledthis medication during work. Some patients alsoreacted positively to other medications (Table 1),among which the non-chemically related drug zolpi-dem (Stilnoct®; Aktuapharma, Heverlee, Belgium;Sanofi-Aventis, Diegem, Belgium), which cases 6and 8 needed to crush as well; however, case no. 10did not have contact with this medication.
Patch tests with crushed Myolastan® tabletsdiluted in white pet. at 30% dilution were negative
in 14 control patients, which included six nurseswho also contacted this drug at work.
After 1–66 months, nine subjects were contactedby telephone for a follow-up interview (Table 1).All, but one, had improvement in their dermatitisby avoiding contact with tetrazepam, by avoidinghandling medication or by using protective measures(gloves, masks, goggles) when in contact. Subjectno. 2, who only suffered from hand dermatitis, hadno improvement, despite the use of gloves. Thiscould be explained by an insufficient avoidance,as tetrazepam was still used in her department,or by other contributing factors (irritant dermatitis,other – undetected – contact allergies).
The Belgian Centre for Pharmacovigilance wasinformed about these cases.
Discussion
Both allergic contact dermatitis and drug erup-tions following ingestion of tetrazepam have beendescribed in the literature. In our search (PubMed)we found seven cases of occupational allergiccontact dermatitis from tetrazepam: one occurredin a mother crushing Myolastan® tablets for herdaughter (1), three in nurses (2–4), and three inpharmaceutical manufacturing workers (5, 6). Allpatients suffered from airborne contact dermatitiswith lesions on the face and neck, and three of themalso had erythema or eczema on the fingers and dor-sum of the hands. One technician had developeda widespread eczematous dermatitis every time herepaired a machine manufacturing Myolastan® (6).
Patch tests have proven to be of great value toinvestigate the role of tetrazepam, both in allergiccontact dermatitis and in drug eruptions (7–9).
The patch test concentrations for patch testingmedication, proposed by the European Society ofContact Dermatitis, are 30% pet. or aq. for thecommercialized drug and 10% pet. or aq. whentesting with the pure substance (10), as we did. Thepreparations used in the literature vary from crushedtablets containing tetrazepam (mainly Myolastan®)and tetrazepam pure powder as is, in dilutions1–30% aq or 0.1–30% pet. However, tetrazepamhas poor water solubility.
In our series, 14 control patients tested negativelywith crushed Myolastan® tablets diluted with whitepet. at 30%. In the literature, patch tests with one ormore of the tests, tetrazepam pure powder, 0.1–30%pet., or 1% aq. or Myolastan® crushed tablet as is,1% aq. and ≥10% pet., were negative in 155 controlpatients (3, 6–8, 11–16).
Case nos. 6 and 7 of our series presented witha positive patch test to another benzodiazepinewhich they handled during work, namely lorazepam(Temesta®). In the literature, 12 tetrazepam-allergic
Contact Dermatitis 2010: 62: 303–308 OCCUPATIONAL ALLERGIC CONTACT DERMATITIS 305
Tabl
e1.
Occ
upat
iona
lal
lerg
icco
ntac
tde
rmat
itis
from
tetr
azep
amin
nurs
es
Tetr
azep
ampa
tch
test
s
Cas
eSe
xA
ge(y
ears
)A
topy
Loc
atio
nan
ddu
rati
onof
derm
atiti
s
Prev
ious
posi
tive
patc
hte
sts
D2
D4
Oth
erbe
nzo-
diaz
epin
este
sted
a ,D
4
Oth
erpo
sitiv
ete
sts,
D4
Follo
w-u
p
1W
L09
-200
3M
40−
Arm
s,ha
nds,
peri
-orb
ital;
1ye
ar
ND
++
Alp
razo
lam
−–
66m
onth
s;fr
eeof
lesi
ons;
crus
hing
tabl
ets
inpl
astic
bags
2SS
04-2
005
F52
−H
ands
;1
year
Neg
ativ
e,5
mon
ths
earl
ier
++
++
++
Bro
maz
epam
−lo
praz
olam
−cl
otia
zepa
m−
diaz
epam
−lo
raze
pam
−flu
nitr
azep
am−
−48
mon
ths;
stil
lha
ndec
zem
a,us
esgl
oves
whe
nha
ndli
ngdr
ugs;
oral
inge
stio
nlo
raze
pam
,w
itho
utan
ypr
oble
m3
SS09
-200
7F
28+
(ecz
ema)
Face
;2
mon
ths
Pota
ssiu
m−d
ichr
omat
e,th
iom
ersa
l,1
mea
rlie
r+
++A
lpra
zola
m−
Sodi
umva
lpro
ate
+at
orva
stat
ine
+18
mon
ths;
free
ofle
sion
s;av
oidi
ngM
yola
stan
,ha
ndli
ngm
edic
atio
nw
itho
utpr
otec
tive
mea
sure
s4
DB
08-2
008
F44
+(e
czem
a)Pe
ri-o
rbita
l;3
mon
ths
ND
++
++
Lop
razo
lam
−cl
otia
zepa
m−
alpr
azol
am−
lorm
etaz
epam
−ox
azep
am−
lora
zepa
m−
p-ph
enyl
ened
iam
ine
+di
sper
sem
ix+
p-to
luen
edia
min
e+
at72
hr
8m
onth
s;le
ssle
sion
s,av
oids
crus
hing
ofm
edic
atio
n
5D
M09
-200
8F
45+
(hay
feve
r)R
elap
sing
eryt
hem
aof
the
face
;se
vera
lye
ars
Pota
ssiu
m–
dich
rom
ate,
coba
lt,
nick
el,
thiu
ram
-m
ix;
4ye
ars
earl
ier
++
Alp
razo
lam
−ox
azep
am−
lorm
etaz
epam
−flu
nitr
azep
am−
diaz
epam
−lo
raze
pam
−lo
praz
olan
−
–7
mon
ths;
noco
ntac
tw
ithm
edic
atio
n;st
illsw
ellin
gof
eyel
ids
duri
ngde
mol
ition
wor
kin
hous
e
6FP
10-2
008
M39
−R
etro
-aur
icul
ar,
peri
-orb
ital,
para
nasa
l,ne
ck,
hand
s;1
year
Pota
ssiu
m–
dich
rom
ate
and
thio
mer
sal
+++
++
Lor
azep
am+
alpr
azol
am−
lorm
etaz
epam
−lo
praz
olan
−ox
azep
amb
−di
azep
amb
−br
omaz
epam
b−
clot
iaze
pam
−
Zol
pide
m+
++
6m
onth
s;no
lesi
ons
sinc
ech
ange
ofw
ork
(no
mor
ecr
ushi
ngof
med
icat
ion)
306 VANDER HULST ET AL. Contact Dermatitis 2010: 62: 303–308
Tabl
e1.
Con
tinu
ed
Tetr
azep
ampa
tch
test
s
Cas
eSe
xA
ge(y
ears
)A
topy
Loc
atio
nan
ddu
rati
onof
derm
atiti
s
Prev
ious
posi
tive
patc
hte
sts
D2
D4
Oth
erbe
nzo-
diaz
epin
este
sted
a ,D
4
Oth
erpo
sitiv
ete
sts,
D4
Follo
w-u
p
7SC
01-2
009
F51
−Fa
ce,
hand
s,ar
ms
HIC
C,
3m
onth
sea
rlie
r+
++Fl
unit
raze
pam
−lo
raze
pam
+lo
rmet
azep
am−
oxaz
epam
−di
azep
am−
Nic
kel+
coba
lt+
frag
ranc
em
ix1
+fr
agra
nce
mix
2++
dich
loro
benz
ylal
coho
l+
3m
onth
s;le
ssle
sion
sw
ithpr
otec
tion
mea
sure
s(g
love
s,m
ask,
gogg
les)
8B
M06
-200
9F
59−
Ecz
ema
hand
s,fe
et,
arm
s,le
gs,
ears
;1.
5ye
ars
Thi
uram
-m
ix,
met
hyl-
(chl
oro)
-is
othi
azol
inon
e,ca
rbam
ix,
rani
tidi
ne,
hand
soap
++++
Bro
maz
epam
b −cl
otia
zepa
m−
oxaz
epam
b −lo
raze
pam
−di
azep
amb −
lorm
etaz
epam
−lo
praz
olam
−flu
nitr
azep
am−
Zol
pide
m+
rani
tidin
e++
cycl
ohex
ylth
ioph
tali
mid
e+
2m
onth
s;le
ssle
sion
s,av
oids
crus
hing
ofm
edic
atio
n
9M
G08
-200
9F
58−
Eye
lids
,fa
ce,
neck
;8
mon
ths
Frag
ranc
em
ix1
+++
Dia
zepa
mb−
alpr
azol
am−
lora
zepa
m−
lorm
etaz
epam
−br
omaz
epam
b −ox
azep
amb −
clot
iaze
pam
−
Cin
nam
ical
coho
l+
ND
10PI
08-2
009
F33
−E
yelid
s,lip
s,ne
ck;
4m
onth
s
ND
++++
Dia
zepa
mb−
alpr
azol
am−
lora
zepa
m−
lorm
etaz
epam
−br
omaz
epam
b−
oxaz
epam
b−
Zol
pide
m++
risp
erdo
n+
1m
onth
;no
mor
ele
sion
s;no
cont
act
with
med
icat
ion
F,fe
mal
e;M
,m
ale;
ND
,no
tdo
ne;
h,ho
urs;
HIC
C,
hydr
oxyi
sohe
xyl
3-cy
cloh
exen
eca
rbox
alde
hyde
.a Fo
rea
chco
mpo
und
the
resp
ecti
veta
blet
was
crus
hed
and
dilu
ted
30%
inpe
t.bPu
resu
bsta
nce
dilu
ted
10%
inpe
t.
Contact Dermatitis 2010: 62: 303–308 OCCUPATIONAL ALLERGIC CONTACT DERMATITIS 307
Cl
NH
N
O
Tetrazepam with cyclohexene substituent
Cl
NH
N
O
Diazepam with phenyl substituent
Cl
NH
N
O
OH
Cl
Lorazepam with chlorophenyl structure
NCH3
NCH3
N
O
CH3
CH3
Zolpidem
Fig. 3. Chemical structures of tetrazepam, diazepam,lorazepam, and zolpidem.
patients tested negative to this compound (2,15–18).
Skin reactions to benzodiazepines other thantetrazepam have been less frequently described.Although tetrazepam and diazepam (Valium®)have similar chemical structures, cross-reactionsare rarely seen (Fig. 3). In the literature, we foundonly two case reports regarding a positive patchtest to diazepam in patients with cutaneous reactionto tetrazepam (1, 8): the first patient was sufferingfrom an occupational contact dermatitis and also
had to crush tablets containing diazepam; the sec-ond case reported a maculopapular eruption afteringestion of tetrazepam tablets and denied previousintake of diazepam. In several other reports (2, 4,11, 12, 14–20), patch tests (and oral provocationtests) with diazepam remained negative, which wasalso the case in our patients, as diazepam (Valium®crushed tablet 30% pet. or diazepam pure substance10% pet.) tested negatively in the seven cases tested(Table 1).
Recently, Barbaud et al. suggested that differ-ences in chemical structures between tetrazepam andother benzodiazepines could explain the absenceof cross-reactions observed in patients with acutaneous adverse reaction from tetrazepam. Theyhypothesize that the non-aromatic cyclohexene sub-stituent of tetrazepam versus the aromatic sub-stituent of the other benzodiazepines could eitherinduce a selectivity at the T-cell receptor level oraccount for a higher reactivity towards proteins (18).
Some subjects of our series also showed positivepatch tests to drugs other than benzodiazepines(Table 1), among which zolpidem that has beenreported only once in the literature as a cause ofoccupational airborne contact dermatitis (21).
Most nurses handled several medications at workand thus could suffer from multiple contact allergies,being the expression of concomittant sensitization.However, the metabolism of drugs being complex,a cross-reaction cannot always be ruled out com-pletely (J-P Lepoittevin, personal communication).
Conclusion
We describe here 10 cases of occupational allergiccontact dermatitis from tetrazepam in nurses whohad to crush tetrazepam containing tablets for geri-atric or disabled people who were unable to swal-low. In nurses with airborne dermatitis and/or handeczema, one should indeed consider the possibilityof drug-induced contact dermatitis and not just con-sider contact with antiseptics and other allergenic orirritant compounds.
In order to prevent sensitization and elicitation ofallergic contact dermatitis from drugs, nurses shoulduse crushing devices and take protective measures(gloves and masks) when handling medication.
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Address:An GoossensDepartment of DermatologyUniversity HospitalK.U. LeuvenB-3000 Leuven, BelgiumTel: +00 32 16 33 78 60Fax: +00 32 16 33 70 12e-mail: [email protected]