Teratogenic Effects

In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. Pregnancy Category C:

Pregnant rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the maximum recommended human dose [MRHD] on a mg/m basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg. Treatment caused a slight delay in fetal development, as evidenced by decreased fetal weight (30 mg/kg), undescended testes (30 mg/kg), and delayed skeletal ossification (10 mg/kg and 30 mg/kg). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 mg/kg and 30 mg/kg), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). A low incidence of diaphragmatic hernia was also seen in the fetuses exposed to 30 mg/kg. Postnatally, delayed vaginal opening was seen at 10 mg/kg and 30 mg/kg and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg. Some maternal toxicity was seen at 30 mg/kg; however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. 2

In pregnant rats receiving aripiprazole injection intravenously (3 mg/kg/day, 9 mg/kg/day, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose, which also caused some maternal toxicity.

Pregnant rabbits were treated with oral doses of 10 mg/kg/day, 30 mg/kg/day, and 100 mg/kg/day (2 times, 3 times, and 11 times human exposure at MRHD based on AUC and 6 times, 19 times, and 65 times the MRHD based on mg/m ) of aripiprazole during the period of organogenesis. Decreased maternal food consumption and increased abortions were seen at 100 mg/kg. Treatment caused increased fetal mortality (100 mg/kg), decreased fetal weight (30 mg/kg and 100 mg/kg), increased incidence of a skeletal abnormality (fused sternebrae at 30 mg/kg and 100 mg/kg), and minor skeletal variations (100 mg/kg). 2

In pregnant rabbits receiving aripiprazole injection intravenously (3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg, which produced 5 times the human exposure at the MRHD based on AUC and is 6 times the MRHD based on mg/m . 2

In a study in which rats were treated with oral doses of 3 mg/kg/day, 10 mg/kg/day, and 30 mg/kg/day (1 times, 3 times, and 10 times the MRHD on a mg/m basis) of aripiprazole perinatally and postnatally (from day 17 of gestation through day 21 postpartum), slight maternal toxicity and slightly prolonged gestation were seen at 30 mg/kg. An increase in stillbirths and decreases in pup weight (persisting into adulthood) and survival were seen at this dose. 2

In rats receiving aripiprazole injection intravenously (3 mg/kg/day, 8 mg/kg/day, and 20 mg/kg/day) from day 6 of gestation through day 20 postpartum, an increase in stillbirths was seen at 8 mg/kg and 20 mg/kg, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg. These doses produced some maternal toxicity. There were no effects on postnatal behavioral and reproductive development.

Non-teratogenic Effects

There are no adequate and well-controlled studies in pregnant women. It is not known whether aripiprazole can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

Aripiprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.