Antifungal
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of voriconazole in human pregnancy have been located. The animal data are suggestive for a risk of toxicity and teratogenicity. However, inhibition of estrogen synthesis was observed in rats. This effect also has been noted in rats treated with another triazole agent, fluconazole. In those studies, the anti-estrogen action was thought to be responsible for the observed cleft palate and bone abnormalities (see Fluconazole). Whether this mechanism also applies to voriconazole is unknown. Nevertheless, based only on the animal data, one review concluded that voriconazole should be avoided in pregnancy (1). Although there are currently no human data, the close relationship with fluconazole, a suspected teratogen in high doses, is reason enough to avoid voriconazole in the 1st trimester. If advertent exposure has occurred, the patient should be advised of the potential but unknown risk to the embryo.
FETAL RISK SUMMARY
The antifungal drug voriconazole is indicated for the treatment of various systemic fungal infections (2). It is a triazole antifungal in the same class as fluconazole, itraconazole, posaconazole, and terconazole.
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, a dose 0.3 times the recommended human maintenance dose or higher based on BSA (RHMD) was teratogenic (cleft palates, hydronephrosis, and hydroureter). Toxic effects observed at this dose were reduced ossification of sacral and caudal vertebrae, skull, and pubic and hyoid bones, super numerary ribs, anomalies of the sternebrae, and dilatation of the ureter/renal pelvis. Treatment later in gestation resulted in increased gestational length and dystocia with a subsequent increase in perinatal pup mortality. Plasma estradiol in pregnant rats was reduced at all dose levels. In pregnant rabbits, toxic effects, noted at 6 times the RHMD, consisted of increased embryo mortality, reduced fetal weight, and increased incidences of skeletal variations, cervical ribs, and extra sternebrae ossification sites (2).
In 2-year studies, hepatocellular adenomas were observed in female rats at an oral dose 1.6 times the RHMD, and hepatocellular carcinomas were seen in male rats at oral doses 0.2 and 1.6 times the RHMD. In mice, hepatocellular adenomas were observed in male and female mice and hepatocellular carcinomas in male mice at oral doses that were 1.4 times the RHMD. Voriconazole was clastogenic in an in vitro assay with human lymphocytes, but was not genotoxic in four other assays (2).
It is not known if voriconazole crosses the placenta to the fetus. The molecular weight (about 349) is low enough that exposure of the embryo and/or fetus should be expected.
BREASTFEEDING SUMMARY
No reports describing the use of voriconazole during lactation have been located. The molecular weight (about 349) suggests that the agent will be excreted into breast milk. There is potential for toxicity in nursing infants, especially during the neonatal period when hepatic function is immature. Therefore, women taking this drug should not breastfeed.
References
1.Moudgal VV, Sobel JD. Antifungal drugs in pregnancy: a review. Expert Opin Drug Saf 2003;2:475–83.
2.Product information. Vfend. Pfizer, 2004.