Antifungal
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
The human pregnancy experience suggests that the risk of itraconazole-induced structural anomalies is low. However, another triazole antifungal agent, fluconazole, has demonstrated a possible dose-related relationship with major malformations (see Fluconazole). For itraconazole, the animal data cannot be adequately interpreted because maternal toxicity was evident and comparisons with the human dose appeared to be based on body weight. Therefore, the safest course is to avoid itraconazole, if possible, during organogenesis. If inadvertent exposure does occur during the 1st trimester, or if itraconazole must be used during early pregnancy, the woman can be reassured that the risk to her embryo or fetus is low, if it exists at all.
FETAL RISK SUMMARY
Itraconazole is a triazole antifungal agent that is structurally related to a number of other antifungal agents, including the imidazole derivatives butoconazole, clotrimazole, and ketoconazole, and to the triazoles, fluconazole and terconazole (1). Other triazole antifungals are posaconazole and voriconazole.
A dose-related increase in toxicity and teratogenicity was found in both rats and mice (2). In pregnant rats treated with a dose 5–20 times the maximum recommended human dose (MRHD), maternal and embryo toxicity was observed, as were major skeletal malformations. In mice given 10 times the MRHD, maternal toxicity, embryo toxicity, and malformations consisting of encephaloceles or macroglossia occurred.
It is not known if itraconazole crosses the human placenta. The molecular weight (about 706) is low enough that passage to the fetus should be expected.
Cohort data presented at a 1996 meeting on single-dose fluconazole or itraconazole exposures during organogenesis did not demonstrate adverse outcomes in approximately 70 exposed pregnancies (3). However, the FDA has received 14 case reports of malformations following use of itraconazole, 4 of which involved limb defects (includes 1 case of agenesis of the fingers and toes (3).
A 1998 noninterventional observational cohort study described the outcomes of pregnancies in women who had been prescribed one or more of 34 newly marketed drugs by general practitioners in England (4). Data were obtained by questionnaires sent to the prescribing physicians one month after the expected or possible date of delivery. In 831 (78%) of the pregnancies, a newly marketed drug was thought to have been taken during the 1st trimester, with birth defects noted in 14 (2.5%) singleton births of the 557 newborns (10 sets of twins). In addition, two birth defects were observed in aborted fetuses. However, few of the aborted fetuses were examined. Itraconazole was taken during the 1st trimester in 41 pregnancies. The outcomes of these pregnancies included 1 ectopic pregnancy, 2 spontaneous abortions (SABs), 6 elective abortions (EABs), 2 cases lost to follow-up, and 30 normal newborns (1 premature) (4). One of the normal, full-term newborns, however, had a minor congenital anomaly consisting of a thin, prominent, protruding left ear. Although no major congenital malformations were observed, the study lacked the sensitivity to identify minor anomalies because of the absence of standardized examinations. Late-appearing major defects may also have been missed due to the timing of the questionnaires.
A prospective cohort study published in 2000 evaluated the pregnancy outcomes of 198 women exposed to itraconazole in the 1st trimester (5). The pregnancy exposures had been reported to the manufacturer, before the outcomes were known, between April 1989 and June 1998. The median itraconazole dose was 200 mg (range 50–800 mg) with mean therapy duration of 8.5 days (range 1–90 days). A matched control group (N = 198) was formed from pregnant women who had contacted the Motherisk Program, a teratogen information service in Toronto, Canada. The control group had not been exposed to any known teratogens (acceptable exposures were acetaminophen, penicillins, prenatal vitamins, dental radiography, or no exposures). There were no statistical differences between the groups in gravidity, parity, alcohol use, or cigarette smoking, but the maternal age in the study group was significantly less than controls (30.1 vs. 31.0 years, p = 0.02). Among pregnancy outcomes, there were no statistical differences between the groups in delivery method, rates of term, preterm, and postterm deliveries, 1- and 5-minute Apgar scores, sex ratios, and rates of neonatal complications. Significantly more pregnancy losses occurred in the exposed group than in controls (relative risk 1.75, 95% confidence interval 1.47–2.09), including SABs (12.6% vs. 4.0%), EABs (7.5% vs 0.5%), and fetal deaths (1.5% vs. 1.0%). The authors attributed these differences to group differences, rather than to effects of itraconazole exposure (5). In addition, the birth weight of exposed newborns was significantly lower than controls (3.33 vs. 3.46 kg. p = 0.048), but this finding was probably not clinically significant (5). There was no statistical difference between the groups in major congenital malformations. Among the 156 live births in the study group, there were five infants (3.2%) with major anomalies (microphthalmia, dysplasia of the right hand, pyloric stenosis, hip joint dysplasia, and congenital heart disease [type not specified]). There were nine newborns (4.8%) with major defects among the 187 controls with live births (congenital heart disease [three cases—two with ventricular septal defect and one not specified], hypospadias requiring surgery [two cases], and one each of oversized tongue, congenital hip dislocation, cleft palate, and Down’s syndrome with atrioventricular canal). The study had 80% power to detect a threefold increased risk of major defects (5), but no evaluation was conducted for minor defects.
The authors of the above study, in a letter correspondence that predated that study, demonstrated that retrospective reports to the manufacturer, at least for itraconazole, involved reporting bias (6). The rates for retrospective vs. prospective outcomes, all of which were significant, were live births (64% vs. 79%), EABs (15% vs. 8%), SABs (18% vs. 13%), major anomalies (13% vs. 3%), and major anomalies including EABs (15% vs. 3%). The authors concluded that women with poor outcomes were more likely to report the event than those with good outcomes (6).
A prospective cohort study involving itraconazole pregnancy exposure was published in 2009 (7). The data were collected by two teratology information services in Italy. During the period 2002–2006, 206 women called the services because of 1st trimester exposure to the drug and their pregnancy outcomes were compared with 207 controls. The rates of major congenital anomalies in the two groups were not significant (1.8% vs. 2.1%, respectively). The three anomalies in the exposed group and the maternal daily dose were cerebral calcification and hepatomegaly (200 mg), unilateral hydronephrosis (100 mg), and interatrial defect (100 mg). There were no significant differences in the rates of vaginal delivery, premature births, low birth weight, and high birth weight. However, significant differences were found for live births (79.1% vs. 91.8%), SABs (11.2% vs. 4.8%), and EABs (9.2% vs. 3.4%). The lower live birth rate was obviously due to the higher rates of abortion (7).
BREASTFEEDING SUMMARY
Itraconazole is excreted into breast milk. Two healthy lactating women each took two oral doses of 200 mg 12 hours apart (total dose 400 mg) (personal communication, EK Cazzaniga and A Chanlam, Janssen Pharmaceuticals, 1996). Neither infant was allowed to nurse during the study. At 4, 24, and 48 hours after the second dose, the average milk concentrations of itraconazole were 70, 28, and 16 ng/mL, respectively. At 72 hours, the milk level was 20 ng/mL in one woman and not detectable (<5 ng/mL) in the other. The average milk:plasma ratios at 4, 24, and 48 hours were 0.51, 1.61, and 1.77, respectively. Based on the 4-hour concentration (the approximate time of the peak plasma level), and assuming that the infants consumed 500 mL of milk/day, the maximum 24-hour average dose the infants would have received was 35 mcg.
Although the above amount seems small, peak plasma concentrations in healthy male volunteers taking itraconazole 200 mg twice daily were not reached until about 15 days (2). The mean peak concentration of the parent compound in these volunteers was 2282 ng/mL, or about 15 times the average peak concentration measured in the two women above. Moreover, the mean plasma concentration of one of the metabolites (hydroxyitraconazole) exceeded that of the parent compound. Continuous daily dosing, even with lower doses, should result in milk levels of the drug much higher than those found above and could result in widespread tissue accumulation in nursing infants. Because the potential effects of this exposure have not been studied, women taking itraconazole should probably not breastfeed.
References
1.American Hospital Formulary Service. Drug Information 1997. Bethesda, MD: American Society of Health-System Pharmacists, 1997:93–5.
2.Product information. Sporanox. Janssen Pharmaceutica, 2001.
3.Rosa F. Azole Fungicide Pregnancy Risks. Presented at the Ninth International Conference of the Organization of Teratology Information Services, May 2–4, 1996, Salt Lake City, Utah.
4.Wilton LV, Pearce GL, Martin RM, Mackay FJ, Mann RD. The outcomes of pregnancy in women exposed to newly marketed drugs in general practice in England. Br J Obstet Gynaecol 1998;105:882–9.
5.Bar-Oz B, Moretti ME, Bishai R, Mareels G, Van Tittelboom T, Verspeelt J, Koren G. Pregnancy outcome after in utero exposure to itraconnazole: a prospective cohort study. Am J Obstet Gynecol 2000;183:617–20.
6.Bar-Oz B, Moretti ME, Mareels G, Van Tittelboom T, Koren G. Reporting bias in retrospective ascertainment of drug-induced embryopathy. Lancet 1999;354:1700–1.
7.De Santis M, Gianantonio ED, Cesari E, Ambrosini G, Straface G, Clementi M. First-trimester itraconazole exposure and pregnancy outcome; a prospective cohort study of women contacting teratology information services in Italy. Drug Safety 2009;32:239–44.