ese studies is the short duration of exposure in pregnancy (mean duration 6.9 to8.5 days), or the lack of information on treatment duration. The risk of prolonged exposure inpregnancy is not known.
Published prospective and retrospective cohort studies of pregnant women exposed toitraconazole (sample size 131-198) have reported inconsistent findings on the risk ofmiscarriage. Available data are inconclusive and limited by possible bias due to earlierenrollment and possible residual confounding in the exposed group compared to the unexposedgroup.
Animal Data
Itraconazole has been shown to cross the placenta in a rat model. In animal reproduction studies,itraconazole administration to rats and mice during organogenesis resulted in maternal toxicity,embryotoxicity and teratogenicity at and above 40 and 80 mg/kg respectively (doses equivalentto 6- and 12-times the MRHD of 390 mg/day, based on mg/kg comparisons). In rats, theteratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/ormacroglossia.
8.2 Lactation
Risk Summary
Itraconazole is excreted in human milk; however, there are no data on the amount of itraconazolein human milk, the effects on the breastfed child, or the effects on milk production. Thedevelopmental and health benefits of breastfeeding should be considered along with the mother’sclinical need for TOLSURA and any potential adverse effects on the breastfed child fromTOLSURA or from the underlying maternal condition.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
The long-term effects of itraconazole on bone growth in children are unknown. Bone lesionswere observed in the young adult rats dosed with oral itraconazole for 3 to 12 months [seeNonclinical Toxicology (13.2)].
8.5 Geriatric Use
Clinical studies of itraconazole did not include sufficient numbers of subjects aged 65 years andover to determine whether they respond differently from younger subjects. It is advised to useTOLSURA Capsules in these patients only if it is determined that the potential benefit outweighsthe potential risks. In general, it is recommended that the dose selection for an elderly patientshould be taken into consideration, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.
Reversible or permanent hearing loss has been reported in elderly patients receiving treatmentwith itraconazole. Several of these reports included concurrent administration of quinidine whichis contraindicated [see Boxed Warning, Contraindications (4.1) and Drug Interactions (7.1)].
8.6 Renal Impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. It isrecommended that patients with renal impairment be carefully monitored when takingTOLSURA [see Clinical Pharmacology (12) and Warnings and Precautions (5.1)].
8.7 Hepatic Impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. It is recommended that patients with impaired hepatic function be carefully monitored when takingTOLSURA. It is recommended that the prolonged elimination half-life of itraconazole observedin the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be consideredwhen deciding to initiate therapy with other medications metabolized by CYP3A4 [see Cli |
