Topical Ketoconazole
Derm Topics

Topical Ketoconazole Therapeutic Cheat Sheet

Posted on Nathaniel Lampley, MD

Ketoconazole is an imidazole antifungal that was initially FDA-approved in an oral formulation for the treatment of systemic fungal infections. While oral ketoconazole has largely fallen out of use due to safety concerns, including hepatotoxicity, endocrine dysregulation, and drug interactions, topical ketoconazole has proven to be a safe and effective treatment for superficial fungal infections. Ketoconazole not only exhibits broad-spectrum antifungal effects, but it also has anti-inflammatory and anti-androgenic mechanisms. We continue our series, “Therapeutic Cheat Sheet,” with a closer look at topical ketoconazole, which is FDA-approved for seborrheic dermatitis, pityriasis versicolor, cutaneous candidiasis, and dermatophyte infections.

Topical Ketoconazole Therapeutic Cheat Sheet

Compiled by: Nathaniel Lampley, MD | Reviewed by: Adam Friedman, MD

TRADE NAME7,8

    • Kuric (ketoconazole cream, 2%)
    • Xolegel (ketoconazole gel, 2%)
    • Extina, Ketodan (ketoconazole aerosol foam, 2%)
    • Nizoral A-D (ketoconazole shampoo, 1%)
    • Nizoral (ketoconazole shampoo, 2%)

MECHANISM OF ACTION8-10 

    • Inhibits lanosterol 14-a-demethylase, blocking the synthesis of ergosterol, a key structural component of fungal cell membranes.
    • Inhibits 5-lipooxygenase, decreasing the production of leukotrienes.
    • Inhibits 5-alpha-reductase, decreasing the production of DHT and sebum.
    • Inhibits hyperproliferation of keratinocytes.

FDA-APPROVED FOR1-7

    • Kuric (ketoconazole cream, 2%) Seborrheic Dermatitis
      • Pityriasis Versicolor
      • Cutaneous Candidiasis
      • Dermatophyte Infections (Tinea corporis, Tinea cruris, and Tinea pedis)
    • Xolegel (ketoconazole gel, 2%)
      • Seborrheic Dermatitis
    • Extina, Ketodan (ketoconazole aerosol foam, 2%)
      • Seborrheic Dermatitis
    • Nizoral A-D (ketoconazole shampoo, 1%)
      • Dandruff
    • Nizoral (ketoconazole shampoo, 2%)
      • Pityriasis Versicolor

OFF-LABEL DERMATOLOGIC USES8,11-13

    • Androgenetic alopecia
    • Cutaneous leishmaniasis
    • Onychomycosis
    • Acne Vulgaris
    • Seborrheic blepharitis
    • Pityrosporum folliculitis
    • Tinea Nigra
    • White Piedra

DOSING1-7

    • Ketoconazole 2% cream
      • For the treatment of seborrheic dermatitis, it should be applied to affected areas twice daily for four weeks.
      • For the treatment of pityriasis versicolor, cutaneous candidiasis, tinea corporis, and tinea cruris, it should be applied to the affected and immediate surrounding area once daily for two weeks. For tinea pedis, treatment duration should be extended to six weeks.
    • Ketoconazole 2% gel
      • For the treatment of seborrheic dermatitis, it should be applied to the affected area once daily for two weeks.
    • Ketoconazole 2% foam
      • For the treatment of seborrheic dermatitis, it should be applied to the affected area twice daily for four weeks.
    • Ketoconazole 1% shampoo
      • For the treatment of dandruff, it should be applied to wet hair, lathered, and rinsed thoroughly every three to four days for up to eight weeks.
    • Ketoconazole 2% shampoo
      • For the treatment of pityriasis versicolor, it should be applied to damp, affected skin and surrounding area, lathered, and left on the skin for five minutes before rinsing. One application should be sufficient.

WARNINGS AND PRECAUTIONS1-7,14 

    • Topical formulations of ketoconazole are not for ophthalmic use. Contact with the eyes should be avoided even with ketoconazole shampoo, as it can irritate the mucous membrane of the eyes.
    • Ketoconazole gel and foam formulations should not be used orally or intravaginally.
    • Ketoconazole cream contains a sulfite that can cause allergic reactions including anaphylactic symptoms and asthmatic episodes in individuals with sulfite sensitivity and thus should be avoided in these individuals.
    • Cases of allergic and photoallergic contact dermatitis to topical ketoconazole have been reported in the literature. If such reactions occur, ketoconazole should be discontinued.
    • Ketoconazole foam and gel formulations contain flammable contents. Fire, flames, and smoking should be avoided during and immediately following application.

SIDE EFFECTS8

The most common side effects of topical ketoconazole include pruritus, dry skin, and burning sensation, which occurred at a low rate of 5-32% in a systematic review of 40 randomized clinical trials, including 4566 patients.

DRUG INTERACTIONS

There are no known drug interactions with topical ketoconazole.

CONTRAINDICATIONS1-7

Contraindicated in individuals with known hypersensitivity to ketoconazole or any excipient ingredients in the topical formulations.

PREGNANCY AND BREASTFEEDING1-8,15 

    • Ketoconazole is pregnancy risk category C
    • No adequate and well-controlled studies of topical ketoconazole in pregnant women exist.
    • Plasma concentrations are not detectable after application of ketoconazole 2% cream or after chronic use of ketoconazole 2% shampoo.
    • Topical ketoconazole should only be used in pregnant women if the potential therapeutic benefit justifies the potential risk to the fetus.
    • It is unknown whether topical ketoconazole results in enough systemic absorption to be excreted in breast milk.
    • Caution should be taken when using topical ketoconazole in nursing mothers.
    • Application of topical ketoconazole on the breast or nipples should be avoided in nursing mothers to prevent potential oral ingestion by the infant.

MONITORING

None

Ketoconazole
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FURTHER READING

If you would like to learn more about topical ketoconazole, check out the following articles in the Journal of Drugs in Dermatology:

Long-term Safety of Ketoconazole Foam, 2% in the Treatment of Seborrheic Dermatitis: Results of a Phase IV, Open-Label Study

Draelos Z, Feldman S, Butners V, et al.

Abstract

Background: Ketoconazole foam, 2%, is approved in the United States for seborrheic dermatitis therapy in immunocompetent patients aged ≥12 years. While short-term trials have demonstrated its safety and efficacy, seborrheic dermatitis often requires long-term treatment.

Objective: To assess the long-term safety of ketoconazole foam, 2%, twice daily, as required.

Methods: A 12-month, open-label, multicenter study. Subjects were evaluated at baseline and at weeks 4, 8, 16, 26, 39, and 52 (or early termination [ET]) for adverse events (AEs), serious AEs (SAEs), target lesion erythema, scaling, and pruritus, as well as Investigator’s Static Global Assessment (ISGA) scores. Physical examinations were performed at baseline and at week 52/ET, and laboratory evaluations at baseline and at weeks 8, 26, and 52. A poststudy product-preference questionnaire was completed.

Results: Of 500 subjects enrolled, 498 were included in the safety population, and 363 completed the study. Overall, 57% of subjects reported ≥1 AE. Treatment-related AEs occurred in 14% of subjects, including application-site irritation (8%), application-site pain (4%), application-site pruritus (1%), and increased alanine aminotransferase (1%). Seven subjects were withdrawn because of treatment-related AEs. No SAEs (21 in 17 subjects) were considered to be related to study drug. Mean target lesion erythema, scaling, and pruritus scores improved by 2 units from baseline at all study visits; mean ISGA score improved by 1 unit at week 4 and by 2 units at subsequent visits. The foam vehicle was preferred by 67% of subjects.

Conclusion: The long-term safety profile of ketoconazole foam, 2%, in subjects with seborrheic dermatitis was favorable and efficacy was maintained. This trial was registered at clinicaltrials.gov (NCT00703846).

J Drugs Dermatol. 2013;12(1):e1-e6.

Efficacy and Safety of a New Once-Daily Topical Ketoconazole 2% Gel in the Treatment of Seborrheic Dermatitis: A Phase III Trial

Elewski B, Ling M, Phillips T

Abstract

Background: The first gel formulation of ketoconazole has been tested in 2-week treatment courses.

Objective: To evaluate the efficacy and safety of a new, once-daily, 2-week ketoconazole 2% gel treatment in moderate to severe seborrheic dermatitis.

Methods: Four hundred fifty-nine subjects with moderate to severe seborrheic dermatitis were randomized to receive ketoconazole 2% gel or vehicle gel once daily for 14 days. The primary efficacy was the proportion of successfully treated subjects at day 28 (cleared and almost cleared).

Results: A significantly greater percentage of subjects were successfully treated with ketoconazole 2% gel compared with vehicle (25.3% vs. 13.9%, P = .0014). Ketoconazole 2% gel improved erythema, scaling (P = .0022 vs. vehicle), and pruritus. Mean overall symptom severity was reduced by 53% and 39% with ketoconazole gel and vehicle, respectively. Adverse events were few, generally mild or moderate, and similar between treatment groups.

Conclusion: Once-daily ketoconazole 2% gel is an effective, well-tolerated, convenient, and cosmetically acceptable treatment for moderate to severe seborrheic dermatitis.

J Drugs Dermatol. 2006;5(7):646-650.

References

    1. Drug label information. Nizoral (Ketoconazole) 1% Shampoo. Updated December 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020310Orig1s023lbl.pdf
    2. Drug label information. Nizoral (Ketoconazole) 2% Shampoo. Updated October 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019927s032lbl.pdf
    3. Encube Ethicals Private Limited. Drug Label Information. Ketoconazole Cream 2%. Updated May 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=59188ef 7-5bc9-4acc-bbff-8712c41e5f77
    4. Drug label information. Xolegel (Ketoconazole) 2% Gel. Updated November 2010. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021946s004lbl.pdf
    5. Drug label information. Extina (Ketoconazole) 2% Foam. Updated June 2007. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021738lbl.pdf
    6. Medimetriks Pharmaceuticals, Inc. Drug Label Information . Ketodan (Ketoconazole) 2% Foam. Updated October 2023. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=62f19bd8-926e-4e6b-9097-d81b894b95cc
    7. (Ketoconazole). In: Merative Micromedex® DRUGDEX® (electronic version). Merative Healthcare Solutions/EBSCO Information Services, Greenwood Village, Colorado; Cambridge, Massachusetts, USA. Available at: https://www.dynamed.com
    8. Choi FD, Juhasz MLW, Atanaskova Mesinkovska N. Topical ketoconazole: a systematic review of current dermatological applications and future developments. J Dermatolog Treat. 2019;30(8):760-771. doi:10.1080/09546634.2019.1573309
    9. De Pedrini P, Rapisarda R, Spanò G. The effect of ketoconazole on sebum secretion in patients suffering from acne and seborrhoea. Int J Tissue React. 1988;10(2):111-113.
    10. Borgers M, Degreef H. The role of ketoconazole in seborrheic dermatitis. Cutis. 2007;80(4):359-363.
    11. Chottawornsak N, Chongpison Y, Asawanonda P, Kumtornrut C. Topical 2% ketoconazole cream monotherapy significantly improves adult female acne: A double-blind, randomized placebo-controlled trial. J Dermatol. 2019;46(12):1184-1189. doi:10.1111/1346-8138.15113
    12. Green M, Feschuk AM, Kashetsky N, Maibach HI. Clinical characteristics and treatment outcomes of Pityrosporum folliculitis in immunocompetent patients. Arch Dermatol Res. 2023;315(6):1497-1509. doi:10.1007/s00403-022-02506-0
    13. Bonifaz A, Tirado-Sánchez A, Araiza J, et al. White Piedra: Clinical, Mycological, and Therapeutic Experience of Fourteen Cases. Skin Appendage Disord. 2019;5(3):135-141. doi:10.1159/000493374
    14. Lazzarini R, Hafner MFS, Miguel BAF, Kawakami NT, Nakagome BHY. Allergic contact dermatitis caused by topical ketoconazole: a relevant issue? Review of ketoconazole-positive patch tests. Contact Dermatitis. 2018;78(3):234-236. doi:10.1111/cod.12919
    15. Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006-. Ketoconazole. [Updated 2023 May 15]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501228/

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