Animal studies have revealed evidence of dose-related maternal toxicity, embryotoxicity, and teratogenicity; these events occurred in rats at doses of about 40 to 160 mg/kg/day (5 to 20 times the maximum recommended human dose [MRHD]) and in mice at doses of about 80 mg/kg/day (10 times the MRHD). The teratogenicity consisted of major skeletal defects in rats and encephaloceles and/or macroglossia in mice. Placental transfer has been observed in a rat model. There are no controlled data in human pregnancy.

During postmarketing experience, cases of congenital abnormalities have been reported including skeletal, genitourinary tract, cardiovascular, and ophthalmic malformations as well as chromosomal and multiple malformations; causal relationship with this drug has not been established.

Published prospective and retrospective cohort studies of women exposed to short courses of this drug during the first trimester of pregnancy (sample size 198 to 687) reported no increase in the rate of major birth defects; the most important methodological limitation of these studies was the short duration of exposure during pregnancy (mean duration 6.9 to 8.5 days), or the lack of data on duration of therapy. The risk of prolonged exposure in pregnancy is not known.

Published prospective and retrospective cohort studies of pregnant women exposed to this drug (sample size 131 to 198) reported inconsistent findings regarding risk of miscarriage; available data were inconclusive and limited by possible bias due to earlier enrollment and possible residual confounding in the exposed group compared to the unexposed group.

Pregnant women exposed to this drug were matched with control subjects not exposed to any known teratogens in a prospect cohort study. A total of 198 women who used this drug during the first trimester (mostly for short-term vulvovaginal candidiasis) were reported to the manufacturer and were compared to controls. The rate of major malformations in the study group (156 live births) was 3.2% and in the control group (187 live births) it was 4.8%. The rate of any pregnancy loss was higher in the exposed group and birth weight was found to be lower; this finding may not be clinically significant. Gestational age at birth, rate of preterm delivery, Apgar scores at 1 and 5 minutes, and neonatal complications were comparable for the 2 groups.

AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Use is contraindicated during pregnancy, except in life-threatening cases when the benefit outweighs the risk to the fetus.
-According to some authorities:
---Onychomycosis: Use is contraindicated in pregnant patients and women contemplating pregnancy.
---Systemic fungal infections and oropharyngeal/esophageal candidiasis: This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

AU TGA pregnancy category: B3
US FDA pregnancy category: Not assigned.

Risk summary: No data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-Highly effective contraception is recommended during therapy and for up to 2 months after the last dose; local protocol should be consulted regarding contraception timing.
-According to some authorities: This drug should not be used to treat onychomycosis in patients of childbearing potential unless they are using effective contraceptive measures to prevent pregnancy and they begin therapy on the second or third day after the onset of menses.

See references

An alternative agent may be preferred, especially while breastfeeding newborn or preterm infants.
-According to some authorities: Expected benefits of therapy should outweigh the potential risk of nursing; breastfeeding is not recommended if there is doubt.
-According to some authorities: Use of the oral solution and pulse therapy are not recommended.

Excreted into human milk: Yes (small amount)

Comments:
-No data available on the clinical use of this drug during breastfeeding.
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug.
-The effects in the nursing infant are unknown; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.
-The US CDC advises HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.

Limited data indicate maternal dosing produces levels in milk that are less than the 5 mg/kg daily doses recommended to treat infants.

Exposure to this drug in the nursing infant has been calculated at about 450 times lower than in the mother.

In an unpublished study, 2 healthy subjects took 200 mg orally every 12 hours for 2 doses. Milk samples were collected with a breast pump at 4, 24, and 48 hours after the second dose; drug levels in milk averaged 70.2, 27.7, and 16.2 mcg/L, respectively, and at 72 hours, the milk level was 20.1 mcg/L in 1 woman and not detectable (less than 5 mcg/L) in the other. Steady-state was probably not attained at the time of sampling, and metabolites (including the active hydroxyitraconazole) were not measured.

It has been estimated using data reported in the literature (including the above study) that fully breastfed infants between 3 and 12 months of age would receive 1.48% of the mother's weight-adjusted dosage and reach a plasma level of 0.77% of the mother's plasma level.

See references