Committee on Drugs 0

Clioquinol (lodochlorhydroxyquin, Vioform) and lodoquinol (Diiodohydroxyquin): Blindness and Neuropathy

Clioquinol and iodoquinol are found in topical area of the forearm (1.1% of body surface area). compounds for dermatologic use. Their application The skin was occluded with Saran Wrap and gauze. in pediatrics has been for treatment of diaper der- Approximately 40% of the dose was absorbed dur- matitis, although the current labeling for these ing the 12 hours, ie, about 60 mg of clioquinol. products advises against their use in children Plasma concentrations of 0.37 to 0.56 mg/L were younger than 2 years of age. The Table lists a few detected within 2 hours. Although the remainder of of the many agents currently available that contain the cream was removed after 12 hours, plasma levels clioquinol or iodoquinol. Some nonprescription remained elevated for an additional 12 hours.9 products also contain clioquinol. The concentrations in this study are comparable Since our 1974 commentary on the toxicity of to the clioquinol plasma levels of 0.29 to 0.52 mg/ these drugs to children,’ additional reports of tox- L measured in five dogs on whom 3% clioquinol icity following skin application have become avail- cream (5 g twice daily) was applied topically for 28 able. Both clioquinol and iodoquinol have been days.’#{176}In this study, approximately 50% of the known to cause serious and irreversible optic atro- clioquinol was absorbed during a 16-hour period. phy and peripheral neuropathy.2 This class of drugs During a 28-day observation period, all dogs were 0 was associated with several thousand cases of sub- lethargic, less responsive to stimuli, and experi- acute myelo-optic neuropathy in Japan.35 The din- enced an average weight loss of 15%. Three of the ical picture was that of a subacute onset of periph- five dogs developed dermatitis; one dog died 15 days eral weakness and sensory loss, spastic paraparesis, after treatment ended. Examination of the liver and blindness, occurring in combination in various demonstrated diffuse centrilobular and midzonal degrees. The most common symptoms were mus- cell necrosis, suggesting hepatocellular toxicity. cular weakness of the lower extremities and dyses- Partial hind limb paralysis was seen in one dog. thesia spreading to the trunk. Use of these drugs in infants carries a risk of A World Health Organization committee con- toxicity. Application of 1 g of 3% clioquinol cream vened in 1977 to prepare a list of essential drugs three times a day to the skin of an infant weighing and excluded clioquinol because it considered the 10 kg would result in a dose of 9 mg/kg per day. risks of treatment greater than the potential bene- This is similar to the 17 mg/kg per day dose applied fit.6 Other authoritative sources of drug information to the dogs, and it is more than three times greater state that “clioquinol has limited topical antibac- than the single 2.5 mg/kg dose used in the clinical terial and antifungal activity”7 and that “routine study.#{176}Of additional concern is the well-known fact use of either compound (clioquinol or iodoquinol) that greater drug absorption occurs through in- is not recommended.”8 flamed skin than through normal skin. Drug ab- A recent clinical study examined the percuta- sorption also is enhanced when applied under an neous absorption of clioquinol.9 Five healthy male occlusive dressing, such as diapers. subjects received one application (5 g) of 3% cli- Alternative topical agents for dermatitis exist oquinol cream applied for 12 hours to a 200 cm2 that have less risk of toxicity. For primary irritant dermatitis in which evidence for prostaglandin gen- eration has been obtained,12 “frequent applications of a bland protective topical agent (petrolatum or The recommendations in this statement do not indicate an zinc oxide paste) following thorough gentle clean- exclusive course of treatment to be followed. Variations, taking sing may suffice to prevent dermatitis.”3 For sec- 0 into account individual circumstances, may be appropriate. PEDIATRICS (ISSN 0031 4005). Copyright © 1990 by the ondary infection, “Polysporin (polymixin B plus American Academy of Pediatrics. bacitracin) and bacitracin are probably the two

Downloaded from www.aappublications.org/newsPEDIATRICS by guest on Vol. September 86 No. 28, 52021 November 1 990 797 TABLE. Partial List of Products Contain ing Clioquinol and Iodoquinol* Generic Name Trade Name Manufacturer

Clioquinol cream, ointment Vioform CIBA Clioquinol and hydrocortisone cream, lotion, Vioform-Hydrocortisone CIBA 0 ointment lodoquinol and hydrocortisone cream Vytone Dermik lodoquinol and hydrocortisone lodo-Cortifair Pharmafair lodoquinol tablets Yodoxin Glenwood

Source: PDR Physicians ‘ Desk Reference. 43rd ed. Oradell, NJ: Medical Economics Co; 1989.

* More than 50 other products containing clioquinol or iodoquinol are registered with the Food and Drug Administration. most useful preparations for pyoderma.”13 Topi- Sumner J. Yaffe, MD, National In- cally applied nystatin is specific for Candida super- stitute of Child Health and Hu- ficial fungal skin infections. Haloprogin, micona- man Development zole, clotrimazole, and econazole are active against AAP Section Liaison Candida, Pityrosporum orbiculare, and the derma- Cheston M. Berlin, MD, Section on tophytes. Topical antibiotic combinations with Clinical Pharmacology other agents, such as corticosteroids, in general are inadvisable.’3 Consultants Mary Ellen Mortensen, MD Anthony R. Temple, MD CONCLUSION

Clioquinol and iodoquinol are neurotoxic. Their use for topical application poses a potential risk of REFERENCES toxicity to infants and children. Since alternative 1. American Academy of Pediatrics, Committee on Drugs. effective treatments for dermatitis are available, we Blindness and neuropathy from diiodohydroxyquin-like drugs. Pediatrics. 1974;54:378-379 recommend that drug products containing cli- 2. Oakley GP. The neurotoxicity of the halogenated hydroxy- oquinol or iodoquinol not be used. quinolines. JAMA. 1973;225:395-397 3. Kono R. Review of subacute myelo-optic neuropathy (SMON) and studies done by the SMON research commis- COMMITTEE ON DRUGS, 1989-1990 sion. Jpn J Med Sci Biol. 1975;28(suppl):1-21 0 Ralph E. Kauffman, MD, Chairman 4. Shigematsu I. Subacute myelo-optic neuropathy (SMON) William Banner, Jr, MD and clioquinol. Jpn J Med Sci Biol. 1975;28(suppl):35-55 5. Rose FC, Gawel M. Clioquinol neurotoxicity: an overview. Jeffrey L. Blumer, MD Acta Neurol Scand. 1984;70(suppl 100):137-145 Richard L. Gorman, MD 6. World Health Organization. The selection ofessential drugs. George H. Lambert, MD WHO Tech Rep Ser. 1977;615:14 7. Bennett DR, Cranston JW, Evans RM, et al. Topical anti- Wayne Snodgrass, MD infective agents: drugs used on skin and mucous membranes. Liaison Representatives In: Drug Evaluations. 6th ed. Chicago, IL: American Medical Association; 1986:1511 Donald R. Bennett, MD, PhD, 8. Webster LT. Drugs used in the chemotherapy of protozoal American Medical Association infections. In: Gilman AG, Goodman LS, Rail TW, Murad Jose F. Cordero, MD, MPH, Cen- F, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 7th ed. New York, NY: Macmillan Publishing ters for Disease Control Co; 1985 Sharon Dooley, MD, American Col- 9. Stohs SF, Ezzedeen FW, Anderson AK, et al. Percutaneous lege of Obstetricians and Gyne- absorption of iodochlorhydroxyquin in humans. J Invest Dermatol. 1984;82:195-198 cologists 10. Ezzedeen FW, Stohs SJ, Kilzer KL, et a!. Percutaneous Sam A. Licata, MD, National absorption anddisposition of iodochlorhydroxyquin in dogs. Health & Welfare, Health Pro- J Pharm Sci. 1984;73:1369-1372 11. Kahn G. Principles oftreatment. In: Schachner LA, Hansen tection Branch, Canada RC, eds. Pediatric Dermatology. New York, NY: Churchill Robert Peterson, MD, Canadian Livingstone; 1988:196-197 Paediatric Society 12. Brain SD, Williams TJ. Prostaglandins, leukotrienes, re- lated compounds and their inhibitors. In: Greaves MW, John C. Petricciani, MD, Pharma- Shuster 5, eds. Pharmacology of the Skin 1. New York, NY: ceutical Manufacturers’ Associa- Springer-Verlag; 1989:352 tion 13. Esterly NB. The skin: diseases of the skin. In: Behrman RE, Vaughan VC, Nelson WE, et al, eds. Nelson Textbook of Gloria Troendle, MD, Food and Pediatrics. 13th ed. Philadelphia, Pa: WB Saunders Co; Drug Administration 1987:1405, 1445

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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 © 1990 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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