Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including PERSERIS, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/. 

Risk Summary

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations). Overall available data from published epidemiologic studies of pregnant women exposed to risperidone have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including PERSERIS, during pregnancy (see Clinical Considerations). 

Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the oral maximum recommended human dose (MRHD) of 16 mg/day with maternal toxicity observed at 4 times the MRHD based on mg/m2 body surface area. Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the oral MRHD based on mg/m2 body surface area. Increased stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the oral MRHD based on mg/m2 body surface area. Learning was impaired in offspring of rats when the dams were dosed at 0.6 times the oral MRHD and offspring mortality increased at doses 0.1 to 3 times the oral MRHD based on mg/m2 body surface area. 

Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused developmental toxicity that included post-implantation loss, decreased number of live fetuses, decreased fetal weight and fetal malformations (external, skeletal, and visceral), at doses that are 52 (rat) and 43 (rabbit) times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area. These effects could be attributed to N-methyl-2-pyrrolidone (NMP) an excipient in the delivery system based on information in the published literature (see Data). Subcutaneous administration of the delivery system to pregnant and lactating rats had no effect on embryofetal and postnatal development at doses up to 17 times the delivery system amount present in 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area. 

The estimated background risks 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. 

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia is associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. 

Fetal/neonatal adverse reactions

Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including risperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. 

Data

Human Data

Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone demonstrated placental passage of risperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR = 1.26, 95% CI 1.02 to 1.56) and of cardiac malformations (RR = 1.26, 95% CI 0.88 to 1.81) in a subgroup of 1566 women exposed to risperidone during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. 

Animal data

No developmental toxicity studies were conducted with subcutaneous risperidone suspension. 

Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day which is 3 times the oral MRHD of 16 mg/day based on mg/m2 body surface area; maternal toxicity occurred at 4 times the oral MRHD. Risperidone was not teratogenic when administered orally to rats at 0.6 to 10 mg/kg/day and rabbits at 0.3 to 5 mg/kg/day, which are up to 6 times the oral MRHD of 16 mg/day risperidone based on mg/m2 body surface area. Learning was impaired in offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the oral MRHD and neuronal cell death increased in fetal brains of offspring of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the oral MRHD based on mg/m2 body surface area; postnatal development and growth of the offspring were also delayed. 

Rat offspring mortality increased during the first 4 days of lactation when pregnant rats were dosed throughout gestation at 0.16 to 5 mg/kg/day which are 0.1 to 3 times the oral MRHD of 16 mg/day based on mg/m2 body surface area. It is not known whether these deaths were due to a direct effect on the fetuses or pups or to effects on the dams; a no-effect dose could not be determined. The rate of stillbirths was increased at 2.5 mg/kg or 1.5 times the oral MRHD based on mg/m2 body surface area. In a rat cross-fostering study the number of live offspring was decreased, the number of stillbirths increased, and the birth weight was decreased in offspring of drug-treated pregnant rats. In addition, the number of deaths increased by Day 1 among offspring of drug-treated pregnant rats, regardless of whether or not the offspring were cross-fostered. Risperidone also appeared to impair maternal behavior in that offspring body weight gain and survival (from Day 1 to 4 of lactation) were reduced in offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the oral MRHD based on mg/m2 and the only dose tested in the study. 

Subcutaneous administration of the delivery system to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity (decreased body weight, weight gain and food intake), post-implantation loss, decrease in number of live fetuses and decrease in fetal weight at doses that are 52 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area. Developmental toxicity in both rat and rabbit included skeletal and visceral malformations at doses 35 (rat), and 43 (rabbit) times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area. The NOAEL dose for these effects in both species is 17 times the delivery system amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area. These effects could be related to N-methyl-2-pyrrolidone (NMP), an excipient present in the delivery system. In published animal developmental toxicity studies, NMP administered orally daily to pregnant rats during organogenesis produced developmental toxicity below maternally toxic levels and resulted in dose-dependent decrease in fetal body weights, increased incidence of post-implantation loss, incomplete ossification and increased incidence of external, visceral and skeletal malformations. These toxicities occurred at doses that are ~3 to 12 times the NMP amount present in monthly 120 mg risperidone subcutaneous injectable suspension based on mg/m2 body surface area.