Sinecatechins

8.1 Pregnancy Risk Summary There are no available data on Veregen use 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, sinecatechins did not cause malformations, but did affect the developing fetus in the presence of maternal toxicity when given to pregnant rabbits and rats by intravaginal or systemic routes of administration during the period of organogenesis ( see Data ).

The available data do not allow the calculation of relevant comparisons between the systemic exposure of sinecatechins observed in the animal studies to the systemic exposure that would be expected in humans after topical use of Veregen. Data Embryo-fetal development studies were conducted in rats and rabbits using intravaginal and systemic routes of administration, respectively. Oral administration of sinecatechins during the period of organogenesis (gestational Days 6 to 15 in rats or 6 to 18 in rabbits) did not cause treatment-related malformations or effects on embryo-fetal development at doses of up to 1,000 mg/kg/day.

In the presence of maternal toxicity (characterized by marked local irritation at the administration sites and decreased body weight and food consumption) in pregnant female rabbits, subcutaneous doses of 12 and 36 mg/kg/day of sinecatechins during the period of organogenesis (gestational Days 6 to 19) resulted in corresponding influences on fetal development including reduced fetal body weights and delays in skeletal ossification. No treatment-related effects on embryo-fetal development were noted at 4 mg/kg/day. No malformations were noted at any of the doses evaluated in this study.

A combined fertility and embryo-fetal development study using daily vaginal administration of Veregen to rats from Day 4 before mating and throughout mating until Day 17 of gestation did not show treatment-related effects on fertility, malformations, or embryo-fetal development at doses up to 0.15 mL/rat/day. This dose corresponds to approximately 150 mg/rat/day. A pre- and post-natal development study was conducted in rats using vaginal administration of Veregen at doses of 0.05, 0.10 and 0.15 mL/rat/day from Day 6 of gestation through parturition and lactation.

The high and intermediate dose levels of 0.15 and 0.10 mL/rat/day resulted in an increased mortality of the F 0 dams, associated with indications of parturition complications. The high dose level of 0.15 mL/rat/day also resulted in an increased incidence of stillbirths. There were no other treatment-related…