Although fluconazole is used extensively, serious toxicity is rarely associated with the drug. Nausea, vomiting, anorexia, rash, and mild elevation of liver function test results are the most commonly recognized adverse events [10]. In 1993, one of us noted several patients who developed alopecia while receiving fluconazole for blastomycosis as part of an NIAID Mycoses Study Group (MSG) protocol. We report on 33 persons who developed reversible alopecia temporally associated with extended fluconazole use.

Methods

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Members of the MSG who had participated in fluconazole trials were surveyed by a brief questionnaire to determine whether they had recognized patients who had developed alopecia while receiving fluconazole. Twenty-six MSG members at different sites were selected on this basis and were sent the questionnaire by mail. Information requested included patient demographic characteristics, the type of fungal disease being treated, the underlying disease, other medications being received, the time alopecia was reported, the pattern of alopecia, the time until resolution of alopecia, and other toxicities possibly related to fluconazole use. After completing the questionnaire, respondents were asked to return the completed form to one of the investigators (CAK) by mail or facsimile.

Results

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All 26 MSG investigators responded; 11 (42%) reported that they had seen a total of 33 patients with alopecia as an adverse event probably associated with fluconazole therapy for fungal disease (Table 1). Twenty-five patients (patients 1 to 25) had participated in protocols involving the use of fluconazole to treat blastomycosis, histoplasmosis, and sporotrichosis in patients not infected with the human immunodeficiency virus (HIV) (MSG study 13) or to treat histoplasmosis in patients with AIDS (MSG study 23). The other 8 patients had not been involved in MSG protocols but had been treated and observed by the investigators for other fungal infections.

Seventeen of the 136 patients (12.5%) enrolled in MSG study 13 and 8 of the 40 patients (20%) enrolled in MSG study 23 developed substantial alopecia while receiving fluconazole therapy. All patients in the protocol were followed monthly while receiving fluconazole and every 1 to 3 months when not receiving therapy. Fifteen of 33 patients (45%) were female. Twenty-nine of 33 patients (88%) received at least 400 mg of fluconazole daily (range, 100 mg weekly to 800 mg daily) for a mean of 7.1 months (range, 2 to 24 months). Alopecia was first noted a mean of 3.2 months (range, 2 weeks to 7 months) and a median of 3 months after initiation of fluconazole therapy, and all patients had varying degrees of scalp hair loss, noted by both patient and investigator. In at least 3 patients, hair loss was so substantial that wigs were necessary. In addition, 10 patients (30%) had substantial loss of facial, axillary, public, leg, or chest hair. Although no patient prematurely stopped receiving fluconazole because of alopecia, doses were reduced for 3 patients because of substantial hair loss presumed to be secondary to fluconazole therapy.

Alopecia resolved in 32 patients when fluconazole therapy was discontinued or when the daily dose was reduced by at least 50%. In one patient (patient 10), alopecia began to resolve despite the continuation of fluconazole therapy at the original dose (800 mg/d). The time to complete resolution of alopecia was available for 28 patients; in these patients, alopecia resolved within 6 months of stopping fluconazole therapy or reducing the dose. Common concomitant drug-related toxicities included dry skin and chapped lips, but few other important toxicities were seen. Twenty of 33 patients (61%) received concomitant medications during fluconazole therapy. The most common concomitant medications included azidothymidine, trimethoprim-sulfamethoxazole, dideoxyinosine, dideoxycytidine, nonsteroidal anti-inflammatory drugs, and prednisone; none of these drugs is commonly associated with substantial alopecia.

Discussion

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Fluconazole is associated with few life-threatening adverse events, but less serious toxicities, such as nausea, vomiting, anorexia, headache, rash, and mild elevation of liver function test results, are not uncommon [10]. Alopecia has rarely been reported [11]. In this report, we describe 33 patients who developed alopecia while receiving fluconazole and who had resolution of this complication when therapy was discontinued or when the daily dose was reduced. Ours is the only report describing reversible alopecia commonly associated with extended fluconazole therapy. Most of the patients in our study were receiving at least 400 mg of fluconazole daily. However, alopecia was seen in 2 patients receiving as little as 100 mg of fluconazole weekly for long-term prophylaxis of recurrent candida vulvovaginitis. All patients received fluconazole for at least 2 months, and alopecia developed within 3 months of initiation of therapy in more than 60% of cases. The scalp was involved in all patients, and other sites were involved in almost one third of patients. Thus, substantial alopecia may develop as an adverse event in patients receiving fluconazole. Moreover, this appears to be a common adverse event; in two separate studies, alopecia developed in 12.5% and 20% of patients receiving at least 400 mg of fluconazole daily.

It is not clear why this complication of fluconazole therapy has not been recognized and reported more frequently. Most clinicians who use fluconazole probably treat patients for considerably shorter periods of time, particularly for uncomplicated infections caused by Candida species. Few immunologically normal patients receive fluconazole for extended periods of time. Further, patients receiving fluconazole for extended periods frequently have underlying diseases associated with hair loss, such as advanced HIV disease and hematologic malignant disorders requiring cytotoxic chemotherapy. Thus, fluconazole-induced alopecia might be easily overlooked in these groups. Twelve of our patients (36%) had underlying disorders that have been associated with alopecia: Eleven had advanced HIV disease and 1 had systemic lupus erythematosus. Although these conditions cannot be excluded as contributing factors in the development of alopecia, the temporal relation of hair loss to the use of fluconazole and the resolution of alopecia once the drug was withdrawn strongly support an association between fluconazole and reversible alopecia in these patients. Similarly, none of the concomitant drugs used in these patients is commonly associated with alopecia.

The mechanism of hair loss with fluconazole is not understood. Ketoconazole has been associated with alopecia in as many as 8% of persons receiving 400 mg to 2000 mg/d [12]. Although ketoconazole has been associated with inhibition of glucocorticoid and testosterone synthesis and male impotence [13], no clear relation has been noted between ketoconazole-associated hormonal abnormalities and hair loss. Fluconazole does not substantially inhibit cortisol and testosterone synthesis, nor is it commonly associated with impotence. Our observations suggest that alopecia is not associated with changes in hormone synthesis. Although fluconazole achieves excellent levels in the skin [14], the concentration of drug in fingernail keratin is minimal, and there are no data on fluconazole concentration in hair follicles. Other cutaneous toxicities, especially dry skin and cracked lips, were commonly seen in patients receiving long-term fluconazole therapy [8], but we cannot correlate these observations with alopecia in this group. Itraconazole, the newest triazole antifungal agent, is structurally similar to ketoconazole but has rarely been associated with alopecia [15].

In summary, substantial alopecia appears to be much more commonly associated with fluconazole than was previously recognized, particularly when the drug is given at larger doses (400 mg/d) and for prolonged periods (2 months). The pattern of hair loss almost always involves the scalp and may involve other sites. The alopecia reverses with discontinuation of fluconazole therapy or dose reduction. This adverse event does not appear to be linked to other toxicities, such as liver function abnormalities, impotence, or gastrointestinal disturbances. Although alopecia is not a life-threatening toxicity, the implications to the patient are substantial, and clinicians should be aware of the association of prolonged higher-dose fluconazole therapy with reversible alopecia.

Dr. Kauffman: Infectious Diseases Section, Veterans Administration Medical Center, Room 839-A, 2215 Fuller Road, Ann Arbor, MI 48105.

Dr. Perfect: Duke University Medical Center, Box 3353, Durham, NC 27710.

Dr. Johnson: Department of Medicine, University of Texas School of Medicine, 6431 Fannin 1. 122 MSB, Houston, TX 77030.

Dr. McKinsey: Infectious Diseases Associates of Kansas City, 2316 East Meyer Boulevard, Kansas City, MO 64132.

Dr. Bamberger: Division of Infectious Diseases, University of Missouri School of Medicine, 2411 Holmes Red 4 Unit, Kansas City, MO 64108-2792.

Dr. Hamill: Infectious Diseases Section, Veterans Administration Medical Center, Building 100, Room 4B-370C, 2002 Holcomb Boulevard, Houston, TX 77030.

Dr. Sharkey: Division of Infectious Diseases, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7881.

Dr. Chapman: Division of Infectious Diseases, University of Mississippi, 2500 North State Street, Jackson, MS 39216-4505.

Dr. Sobel: Division of Infectious Diseases, Harper Hospital, Suite 202, Harper Professional, 4160 John R, Detroit, MI 48201.