Antifungal
PREGNANCY RECOMMENDATION: No Human Data—Potential Toxicity
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of sulconazole in human pregnancy have been located. When given orally, sulconazole was embryotoxic and prolonged gestation in one animal species, but the systemic exposures appeared to be far higher than those that could possibly be obtained after topical use. Sulconazole is partially absorbed with the amount reaching the plasma dependent on the dose and application site. The effects of this exposure are unknown. One study did find a significant increase (relative risk 1.4) in the risk of spontaneous abortion after vaginitis therapy with imidazole antifungals, clotrimazole and miconazole (1). A later study speculated that this effect might have been due to inhibition of the critical placental enzyme aromatase (2). There is no other evidence suggesting that similar topical imidazole-derivative antifungal agents cause embryo–fetal harm. However, sulconazole was a more potent inhibitor of aromatase than either of the two agents associated with the abortions (2). Until additional data are available, the best course is to avoid the use of sulconazole in the 1st trimester or the application of the antifungal to large areas of skin at any time in pregnancy.
FETAL RISK SUMMARY
Sulconazole is available as a 1% cream for topical application. It is in the same antifungal class of imidazole derivatives as butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole, and tioconazole. Sulconazole is indicated for the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccosum, Microsporum canis, and tinea versicolor (3).
In a 1988 study with seven adults, two applications (4.5 g/each) of the radiolabeled 1% cream were made on the abdominal skin at 0 and 12 hours (4). The site was then washed at 24 hours and then every 24 hours for 3 days. Radioactivity was detectable in the plasma from 8 to 96 hours, with a peak at 24 hours. The total percutaneous absorption was estimated to be 8.7%–11.3% of the total dose, the highest reported among imidazole derivatives (4).
Reproduction studies have been conducted in rats and rabbits. In rats, an oral dose 125 times the adult human dose based on body weight was embryotoxic. This dose also resulted in prolonged gestation and dystocia. No teratogenicity was observed in rats and rabbits given oral doses of 50 mg/kg/day (comparison to human dose not specified) (3).
It is not known if sulconazole crosses the human placenta. The molecular weight (about 461) suggests that exposure of the embryo–fetus will occur. However, the dose and application site will have a major role in determining the amount of drug available to cross the placenta.
A 2002 study evaluated azole antifungals commonly used in pregnancy for their potential to inhibit aromatase, a placental enzyme that is critical for the production of estrogen and for the maintenance of pregnancy (2). The authors speculated that the embryotoxicity observed in animals and humans (see also Clotrimazole and Miconazole) might be explained by inhibition of aromatase. They found that the most potent inhibitors of aromatase were (shown in order of decreasing potency) econazole, bifonazole (not available in the United States), sulconazole, clotrimazole, and miconazole. The potential plasma concentrations of sulconazole in humans were thought to be high enough to partially inhibit the enzyme (2). However, an earlier study reported a pregnancy that was maintained even when there was severe fetal and placental aromatase deficiency (<0.3% of that of controls) caused by a rare genetic defect (5). In this case, both the fetus and mother were virilized because of diminished conversion of androgens to estrogen. Because the pregnancy was maintained and the virilization, the case suggested that the main function of placental aromatase was to protect the mother and fetus from exposure to adrenal androgens (5).
BREASTFEEDING SUMMARY
No reports describing the use of sulconazole during human lactation have been located. The molecular weight (about 461) suggests that the drug will be excreted into breast milk. The drug is absorbed systemically (see above). The effect of this exposure on a nursing infant is unknown. Because the systemic absorption was the highest known among similar agents, other imidazole antifungals might be more appropriate if a nursing woman requires topical antifungal therapy.
References
1.Rosa FW, Baum C, Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987;69:751–5.
2.Kragie L, Turner SD, Patten CJ, Crespi CL, Stresser DM. Assessing pregnancy risks of azole antifungals using a high throughput aromatase inhibition assay. Endocr Res 2002;28:129–40.
3.Product information. Exelderm. Bristol-Myers Squibb, 2007.
4.Franz TJ, Lehman P. Percutaneous absorption of sulconazole nitrate in humans. J Pharm Sci 1988;77:489–91.
5.Harada N. Genetic analysis of human placental aromatase deficiency. J Steroid Biochem Mol Biol 1993;44:331–40.