Based on findings from animal studies, isavuconazonium may cause fetal harm when administered to a pregnant woman. There are no available human data on the use of isavuconazonium in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, perinatal mortality was increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at approximately 0.5 times the clinical exposure during pregnancy through the weaning period. In animal studies when isavuconazonium chloride was administered by oral gavage to pregnant rats and rabbits during organogenesis at exposures corresponding to less than the human maintenance dose increases in the incidences of multiple skeletal abnormalities, including rudimentary cervical ribs and fused zygomatic arches were observed.^L49211

During clinical studies, total daily isavuconazonium doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in a thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhea, oral hypoesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Adverse reactions leading to discontinuation of the study drug occurred in 7 of 39 (17.9%) subjects in the supratherapeutic dose group.^L49211

Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring.^L49211

In a 2-year rat carcinogenicity study and a 2-year mouse carcinogenicity study, dose-related increases in hepatocellular adenomas and/or carcinomas were observed in male and female B6C3F1/Crl mice and male, but not female Han Wistar rats at doses as low as 0.1 times the exposure seen in humans administered the maintenance dose. Hepatic hemangiomas were increased in female mice at 300 mg/kg, at an exposure similar to the maintenance dose. Hepatoblastoma was increased in male mice at 100 mg/kg, about 0.4 times the systemic exposures based on AUC comparisons. Thyroid follicular cell adenomas were observed in male and female rats at doses as low as 60 mg/kg in male rats (about 0.2 times the human clinical maintenance dose). The relevance of rat thyroid tumors to human carcinogenic risk remains unclear.^L49211

A significant increase in the incidence of skin fibromas was seen in male rats at 300 mg/kg, exposures 0.8 times the human exposure at the human clinical maintenance dose. Uterine adenocarcinomas were observed in female rats at 200 mg/kg, at systemic exposures similar to the human exposure at the human clinical maintenance dose.^L49211

No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats.^L49211

Oral administration of isavuconazonium sulfate did not affect fertility in male or female rats treated at doses up to 90 mg/kg/day (approximately 0.3 times the systemic exposure at the human clinical maintenance dose).^L49211