Key words: antihistamines, contact dermatitis,
cross-reactions
Topical
antihistamine preparations are available as creams, lotions, eye drops, nasal
preparations, aerosols, and suppositories.
Antihistamines or H1-receptor antagonists have anti-pruritic properties
and mild, local anesthetic effects and may also diminish capillary,
permeability. They can be classified
into 6 groups in function of their chemical structure (1): alkylamines,
ethanolamines, ethylenediamines, phenothiazines, piperazines, and other
H1-receptor antagonists. Application to
the skin is generally considered to carry an unacceptably high risk of
sensitization (e.g. 1, 2). Recently,
several cases have been reported of allergic contact dermatitis to topically
applied doxepin hydrochloride, a tricyclic antidepressant that has a very
potent antihistaminic activity (3-5).
Here
we report on the antihistamines that produced positive patch test reactions in
the Contact Allergy Unit of our Department over the last 20 years and discuss
the results in the light of the literature.
Between
January 1978 and December 1997, 12.460 patients were tested for contact
allergy. For each, a detailed history
was taken and the results of the patch tests analyzed. The allergens tested were supplied by Trolab
(Hermall Chemie, Reinbek, Germany), Chemotechnique,Diagnostics (Malmö, Sweden),
or were prepared in-house. When a
contact allergy to topical antihistamine preparations was suspected, the
individual ingredients
- including the antihistamines obtained as raw materials from the
manufacturing companies - were tested whenever possible. In view of the frequent use of promethazine
preparations in Belgium, this substance was included to the Belgian standard
series from January 1978 until May 1981 and tested in 1823 subjects. Two subjects with a positive reaction to
diphenhydramine were further tested with its chemical derivatives to check for
cross-sensitivity. Chlorpromazine (a
phenothiazine neuroleptic drug) was also tested in some of the subjects
suspected of promethazine sensitivity.
The
antihistamines with positive reactions were observed during a 20-year
period. Of the 14 patients who reacted
to promethazine, 12 had a contact allergic reaction, 1 a photo-allergic
reaction, and one a photo-aggravation of the positive patch test.
Among
the 1823 subjects routinely tested between January 1978 and May 1981, 8
(0.4 %) reactions to promethazine were noted (including one photo-allergic
reaction). Three patients tested with
chlorpromazine reacted positively to this substance as well. In the two patients allergic to
diphenhydramine and tested with chemically related derivatives, two positive
reactions were observed to bromodiphenhydramine, two to medrylamine
(4methoxy-diphenhydramine) and one to dimenhydrinate (diphenhydramine teoclate)
and p-methyldiphenhydramine, respectively.
In
the literature, contact allergic reactions in patients exposed to antihistamine
preparations were reported to be due mainly to antazoline, mepyramine and
tripelennamine (ethylenediamines), diphenhydramine (ethanolamines),
promethazine (phenothiazines), and phenindamine (unclassified H1-receptor
antagonists). Moreover, occupational
exposure to antihistamines and/or their chemical intermediates has caused
eczema in laboratory technicians, industrial chemists, and pharmacists as well
as in medical doctors and nurses who handle these drugs (see 6 for a review).
Cross-sensitivity
occurs not only between chemically related antihistamines but also with other
related drugs or chemicals. For
example, the ethylenediamine derivatives may cross react to ethylenediamine,
their parent substance. We were able to
demonstrate cross-reactions between diphenhydramine and some of its derivatives
as well as between promethazine and chlorpromazine.
Systemic
eczematous contact-type dermatitis reactions may be observed when chemically
related drugs are administered systemically in previously sensitized
individuals. Photo-allergic reactions
may also occur, and photo-toxic reactions are common, particularly with the
phenothiazines.
We
found that promethazine caused most of the reactions, followed by
diphenhydramine, and clemizole, the last of which caused reactions when used in
topical, anti-hemorrhoidal preparations.
Two patients with a photo-contact allergy -one to promethazine, the
other to mequitazine - reacted to systemic administration of preparations
containing them.
Notwithstanding the widespread use of topical
antihistamines and the apparently general opinion that they are strong
sensitizers, the number of positive reactions observed in our series is very
low. The reason may be that, in
general, antihistamines were only tested when contact allergy was suspected
from the clinical history. However,
even when promethazine, a widely used topical antihistamine was routinely
tested during a 4-year period, few positive reactions occurred. This is in agreement with Szolar-Platzer and
Maibach (6), who concluded from an extensive review of the literature on
contact allergic reactions to antihistamines observed during the period
1940-1995 that systematic reports on the incidence of sensitization are scarce
and that their reputation as potent sensitizers appears to be based on clinical
impressions rather than controlled observations. Moreover, most reports and studies dealing with contact allergies
to such preparations date back to before the 1970s and in many cases, the
potential allergenic or irritant role of the vehicle was not ruled out. The incidence of sensitivity to individual
antihistamine preparations, of course, may differ from country to country
because of prescription and self-medication habits. Contact allergic and photo-allergic reactions to topical
antihistamines are rare relative to their use.
Photo-toxic reactions seem to be more common and are mainly due to
promethazine.
1.
Martindale, The Extra Pharmacopoeia. London, The Pharmaceutical Press, 30th
Edition, 1993, pp. 926-947.
2.
de Groot AC, Weyland JW and Vater JP. Unwanted Effects of Cosmetics and Drugs Used
in Dermatology. Amsterdam, Elsevier,
1994, pp. 83-85.
3.
Aguirre A, Vicente JM, Zabala R et al. Eccema alérgico de contacto por doxepina
tópica. Boletin informativo del
G.E.I.D.C. 1996, 24:33-34.
4.
Greenberg JH.
Allergic contact dermatitis from topical doxepin. Contact Dermatitis 1995, 33:281.
5.
Shelly WB, Shelly ED, Talanin NY. Self-potentiating allergic contact
dermatitis caused by doxepin hydrochloride cream. J. Am. Acad. Dermatol. 1996, 34:143-4.
6.
Szolar-Platzer C, Maibach H. Allergic contact dermatitis to topically
applied antihistamines. Dermatosen
1996, 44:205-212.