AMERICAN ACADEMY OF PEDIATRICS 299

mor appearance in young women. New Eng. 3. Herbst, A. L., Ulfelder, H., and Poskanzer, D. C.: J. Med., 284:878, 1971. Registry of clear-cell carcinoma of genital 2. Greenwald, P., Barlow, J. J., Nasca, P. C., and tract in young women. New Eng. J. Med., Burnett, W. S. : Vaginal cancer after maternal 285:407, 1971. treatment with synthetic estrogens. New Eng. 4. Folkman, J. : Transplacental cardinogenesis by J. Med., 285:390, 1971. stilbestrol. New Eng. J. Med., 285:404, 1971.

ANTIHISTAMINES IN TOPICAL PREPARATIONS

NTIHISTAMINES were introduced in topically. The ethylenediamine derivatives France by Halpern in 1942 and in the include the following: antazoline phosphate United States at the end of World War II; ( Antistine ), promethazine hydrochloride they had been investigated extensively dur- ( Phenergan#{176} ), and tripelennamine ( Pyri-

ing the war for therapy of motion sickness. benzamine ) . They are particularly active in By the late 1940s, a mass of information on inducing contact dermatitis and were re- the structure activity relationship had accu- sponsible for the cases first reported.’#{176} mulated and most major drug manufactur- Ethylenediamine, because of its dibasic ens had introduced antihistamines into the structure, is widely used in various organic market for oral, parenteral, and topical ad- syntheses for the preparation of dyes, inhib- ministration. Topical use was efficacious in itors, rubber accelerators, fungicides, syn- acute dermatitis because the local anes- thetic waxes, resins, insecticides, and as- thetic activity of the drugs diminished pru- phalt-wetting agents. It is valuable for ritus. neutralizing the acidity of oils or controlling The first reports of sensitization to the alkalinity. As ethylenediaminetetracetic acid topical antihistamines, which began to ap- ( EDTA ), it is a ubiquitously used preser- pear in 1947, incriminated tnipelennamine vative in topical and systemic medications (Pyribenzamine), diphenhydramine ( Ben- of all types. The induction of contact sensi- adryl), antazoline (Antistine), and pheni- tivity to drugs of this class will result in a

ramine (Trimeton ) ,14 In the ensuing 25 dermatitis on topical or oral readministra- years, though thousands of instances of an- tion of agents of this class of antihistamines. tihistamine contact dermatitis have oc- The sensitized patient may also react to curred, many topical antihistamines remain the oral or parenteral administration of ami- on the market. The Committee is concerned nophylline, which contains theophylline about the use of topical antihistamines conjugated with ethylenediamine, as well which are sold over the counter for use in as to contact with any of the many sub- such conditions as chickenpox and poison stances containing ethylenediamines. ivy. Table I lists most of the preparations The phenothiazines include drugs em- currently available for topical use. ployed either as antihistamines or as pay- chotrophic agents. Representative members CLASSES OF ANTIHISTAMINES of this group of compounds are given in The antihistainines are classified accord- Table II. Promethazine hydrochloride ing to their chemical structure into five pri- ( Phenergan ) is available as a topical prep- mary groups as shown in Table II. Each

drug carries its own index of sensitization 0 Phenergan is both an ethlenediamine and a and other adverse effects when employed phenothiazine derivative.

The statements presented herein do not preclude alternatives which may be more appropriate, taking into account local situations and all other relevant facts. Executive Board, AAP

Downloaded from www.aappublications.org/news by guest on September 23, 2021 300 ANTIHISTAMINES IN TOPICAL PREPARATIONS aration. Phenothiazines are the worst topi- TABLE I cal offenders in the antihistamine group. ToPIcAL ANTIHISTAMINES Not only are they potent allergic contact sensitizers, but they may also evoke a pho- Brand Name Generic Antihistamine Manufocture toallergic contact dermatitis. Photoderma- Antiatine Solution Antazoline Ciba titis, due to allergic contactants, is often Antopic Cream Pyranisamine (maleate) Smith-Doraey Benadryl Cream Diphenhydramine Parke. Davis characterized by persistence long after re- Bristamine Lotion Phenyltoloxamine Bristol moval of the offending substance. Further- Caladryl Lotion and Cream Diphenhydramine Parke. Davis more, since light of 360 nm wavelength and Dermaval Cream Pyrilamine (maleate) Vale above is responsible, sunscreens and win- Histacairna Cream Methapyrilene Rexall Histadyl Ointment Thenylpyramine Lilly dow glass offer no protection. This type of Neohetramine Ointment Thonzylamine Nepra dermatitis can be debilitating for many Perazil Cream Chlorcyclizine Burroughs, Weilcome years and may be activated by both incan- Phenergan Cream Promethaxine Wyeth descent and fluorescent light. Once topical Prantal Cream Diphemanil Schering Pyribenzamine Cream sensitization to phenothiazines has oc- . and Ointment Tripelennamine Ciba curred, systemic administration of any Thenylene Cream Thenylpyramine Abbott Thephorin Lotion and member of this class may elicit a severe Ointment Phenidamine Roche dermatitis.7 Trimeton Ointment Prophenpyridamine Schering Ziradryl Lotion and The ethanolamine compounds include Cream Diphenhydramine Parke. Davis diphenhydramine ( Benadryl) and doxyla- mine succinate ( Decapryn). While this group of substances has a lower sensitizing ical antihistamines not be used because of potentialo than the other two, the extensive their sensitizing potential.9 use of topical diphenhydramine in the form The Committee on Drugs, on the basis of of Caladryl Lotion on Ointment has re- the foregoing evidence, urges pediatricians: sulted in frequent sensitization of children. 1. To discontinue the use of topical an- Because the resulting dermatitis usually

clears promptly on removal of the drug, TABLE II cases are rarely reported. CLASSES OF ArIHIsTAMINm Alkylamines and piperazine compounds

capable of inducing a contact dermatitis in- Generic Antihistamine Brand Name dude pheniramine Trimetine), phenin- ( Ethylenediamines damine (Theophorin ), and pyrilamine Tripelennamine citrate Pynbenzamine Antaxoline phosphate Antistine ( Neo-Antergan). Methapyrilene hydrochloride Histadyl

COMMENT Phenothiazine, Methadilaxine Tacaryl Recently, the National Academy of Sci- Promethazine hydrochloride Phenergan Tripelennamine tartrate Temaril ences-National Research Council Drug Effi- cacy Study group evaluated a group of over Elhanolamines Diphenhydramine hydrochloride Benadryl the counter topical antihistamines. Based Carbinoxamine maleate Clistin on their report, the Food and Drug Admin- Doxylamine succinate Decapryn Succinate

istration concluded that these drugs are in- .4llcylamines effective for prophylaxis against dermatitis Brompheniramine maleate Dimetane Chlorpheniramine maleate Chlor-Trimetal. Ilistaspan, caused by poison ivy and other plants of Teldnn the rhus genus. It further classified these Dexbrompheniramine maleate Disomer Dexchlorpheniramine maleate Polaramine drugs as “possibly effective” for other la- Dimethindene maleate Forhistal Maleate beled indications for dermatologic use, Tripolidine hydrochloride Actidil

placing the onus on the manufacturer to Piperazines prove their efficacy.8 The American Medical Cyclizine hydrochloride Marezitie Medicine hydrochloride Bonine Association has also recommended that top-

Downloaded from www.aappublications.org/news by guest on September 23, 2021 AMERICAN ACADEMY OF PEDIATRICS 301 tihistamine preparations because their tox- apy with tripelennamine hydrochloride icity exceeds their limited benefit. (“Pyribenzamine Hydrochloride”). JAMA, 134:782, 1947. 2. To discourage parents from purchas- 3. Harris, M. C., and Shure, N.: Eczematoid der- ing over the counter topical antihistamines, matitis following ingestion of “Pyribenzamine especially Benadryl, Caladryl, Ziradryl, and Hydrochloride” N.N.R. tablets. J. Allerg., 18: Pyribenzamine for use in treating chicken- 408, 1947. 4. Peck, S. M.: The role of the antihistaminic pox, poison ivy, poison oak, and other types drugs in producing cross-sensitization derma- of dermatitis. titis. New York J. Med., 50 (supplement): 3. To keep in mind the frequency of con- 2690, 1950. tact dermatitis resulting from such agents 5. Hjorth, N., and Fregert, S.: Contact dermatitis. in the evaluation of a dermatitis of un- in Rook, A., Wilkinson, D. S., and Ebling, J. C., eds.: Textbook of Dermatology. Oxford: known etiology. Blackwell Scientific Publications. 1968, pp. The Committee further urges that a 238-322. warning about the sensitizing potential of 8. Fisher, A. A. : Systemic eczematous “contact- these agents be placed on the label of these type” dermatitis medicametosa. In Fisher, preparations. A. A., ed.: Contact Dermatitis. Philadelphia: Lea & Febiger, p. 233, 1967. COMMITrEE ON DRUGS 7. Epstein, S., and Rowe, R. J.: Photoallergy and SUMNER YArn, M.D., Chairman J. photocross-sensitivity to phenergan. J. Invest. Ciirns W. BIERMAN, M.D. Derm., 29:319, 1957. Howiw M. CN, M.D. 8. Food and Drug Administration: Certain OTC ARNOLD P. GoLD, M.D. topical antihistamines, drugs for human use; drug efficacy study implementation. Federal Fiiuc M. KENNY, M.D. Register, 36:18021, 1971. Hms D. RILEY, JR., M.D. 9. Antihistamines. in AMA Drug Evaluations, ed. IRwmr ScHAFER, M.D. 1. Chicago: American Medical Association, LEO STERN, M.D. 1971, pp. 367-368.

REFERENCES Acknowledgment 1. Sulzberger, M., Baer, R. L., and Levin, H. B.: The Committee wishes to acknowledge the gen- Local therapy Pyribenzamine Hydrochloride. erous assistance of Dr. Don Warren Printz of the J. Invest. Derm., 10:41, 1948. Center for Disease Control, Atlanta, Georgia, in 2. Epstein, E. : Dermatitis occurring during ther- the preparation of this statement.

Downloaded from www.aappublications.org/news by guest on September 23, 2021 ANTIHISTAMINES IN TOPICAL PREPARATIONS Sumner J. Yaffe, Charles W. Bierman, Howard M. Cann, Arnold P. Gold, Frederic M. Kenny, Harris D. Riley, Jr., Irwin Schafer and Leo Stern Pediatrics 1973;51;299

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Downloaded from www.aappublications.org/news by guest on September 23, 2021 ANTIHISTAMINES IN TOPICAL PREPARATIONS Sumner J. Yaffe, Charles W. Bierman, Howard M. Cann, Arnold P. Gold, Frederic M. Kenny, Harris D. Riley, Jr., Irwin Schafer and Leo Stern Pediatrics 1973;51;299

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1973 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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