Moxidectin

7 DRUG INTERACTIONS

7.1 Midazolam (CYP3A4 substrate) In healthy subjects, concomitant administration of a single 8 mg oral dose of Moxidectin Tablets did not have an effect on the pharmacokinetics of midazolam [ see Clinical Pharmacology ( 12.3 ) ]. Moxidectin can be co-administered with CYP3A4 substrates.

8.1 Pregnancy Risk Summary Available data from clinical trials on the use of Moxidectin Tablets in pregnant women are insufficient to establish whether there is a moxidectin-associated risk for major birth defects and miscarriage . Moxidectin administered orally to pregnant rats during the period of organogenesis was not associated with significant embryo-fetal developmental effects at doses of approximately 15 times the recommended human dose based on body surface area (BSA) comparison.

When moxidectin was dosed orally to pregnant rabbits during the period of organogenesis, no embryo-fetal developmental effects were observed at oral doses of moxidectin up to 24 times the recommended human dose based on BSA comparison ( see Data ) . Daily administration of moxidectin by oral gavage to maternal female rats during organogenesis and through lactation was associated with decreased survival, adverse clinical signs, and decreased body weights in first-generation offspring during the lactation period at a moxidectin dose less than 2-times the recommended human dose based on BSA comparison.

Additional findings in first-generation offspring at the same dose included delays in pinna unfolding, eye opening, and vaginal opening. Other parameters, including reproduction and neurological development in first-generation offspring were not affected at any moxidectin dose ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data In a rat embryo-fetal development study, daily oral administration of moxidectin at 12 mg/kg/day (approximately 15 times the recommended human dose of 8 mg based on BSA comparison) during Gestation Days (GDs) 6 to 15 significantly increased the fetal incidence, but not the litter incidence of cleft palate and the fetal and litter incidence of a skeletal variation, wavy ribs, at a maternally toxic dose. Mean maternal food consumption, body weights, and body weight gain were significantly decreased at moxidectin doses of 10 and 12 mg/kg/day compared to control values.

The no observed adverse effect level (NOAEL) value for maternal and fetal toxicity was considered to be 5 and 10 mg/kg/day respectively (approximately 6 and 12 times, respectively, the recommended human dose based on BSA comparison). In…