Lotilaner

8.1 Pregnancy Risk Summary There are no available data on XDEMVY use in pregnant women to inform any drug associated risk; however, systemic exposure to lotilaner from ocular administration is low [see Clinical Pharmacology (12.3) ] . In animal reproduction studies, lotilaner did not produce malformations at clinically relevant doses.

Data Animal Data In an oral embryofetal developmental study in pregnant rats dosed during organogenesis from gestation days 6-19, increased post-implantation loss, reduced fetal pup weight, and incomplete skeletal ossification were observed at 50 mg/kg/day (approximately 1390 times the recommended human ophthalmic dose (RHOD) on a body surface area basis) in the presence of maternal toxicity (i.e., decreased body weight and food consumption). A rare malformation of situs inversus of the thoracic and abdominal viscera occurred in 1 fetus from a pregnant rat receiving 50 mg/kg/day; whether this finding was treatment-related could not be excluded.

No maternal or embryofetal toxicity was observed at 18 mg/kg/day (approximately 501 times the RHOD on a body surface area basis). In an oral embryofetal development study in pregnant rabbits dosed during organogenesis from gestation days 7-19, no embryofetal toxicity or teratogenic findings were observed at 20 mg/kg/day (approximately 580-times the RHOD on an AUC basis), even in the presence of maternal toxicity (i.e., decreased food consumption and body weight). In an oral two-generation reproductive toxicity study, F0 male and female rats were administered lotilaner at doses up to 40 mg/kg/day for 10 weeks before pairing and during the 2-week pairing period (3 weeks for males).

Dosing for F0 females continued through lactation day 22. F1 male and female rats were administered lotilaner at 1 and 5 mg/kg/day post-weaning from day 23 for 10 weeks before pairing and during the 2-week pairing period (3 weeks for males). Dosing for F1 parenteral females continued through lactation day 22. There were no clear adverse effects on the F1 generation, and a slightly lower mean body weight during lactation was noted for F2 pups at 5 mg/kg/day. The no observed adverse effect level (NOAEL) was determined to be 5 mg/kg/day (approximately 139 times the RHOD on a body surface area basis).