8.1Pregnancy Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including RYKINDO, 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/clinicaland-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 or bipolar I disorder and with exposure to antipsychotics, including RYKINDO, during pregnancy (see Clinical Considerations ) .
Risperidone has been detected in plasma in adult subjects up to 6 weeks after a single-dose of RYKINDO [see Clinical Pharmacology (12.3) ] . The clinical significance of RYKINDO administered before or during pregnancy is unknown. Oral administration of risperidone to pregnant mice caused cleft palate at doses 3 to 4 times the maximum recommended human dose (MRHD) with maternal toxicity observed at 4 times the MRHD based on mg/m 2 body surface area.
Risperidone was not teratogenic in rats or rabbits at doses up to 6 times the MRHD based on mg/m 2 body surface area. Increased incidence of stillbirths and decreased birth weight occurred after oral risperidone administration to pregnant rats at 1.5 times the MRHD based on mg/m 2 body surface area. Learning was impaired in the offspring of dams dosed at 0.6-times the MRHD and offspring mortality increased at maternal doses 0.1 to 3 times the MRHD based on mg/m 2 body surface area.
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. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia or bipolar I disorder, including increased risk of relapse, hospitalization, and suicide.
Schizophrenia and bipolar I disorder are 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 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 show a clear association between 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: 1.02-1.56) and of cardiac malformations (RR=1.26, 95% CI: 0.88-1.81) 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 Oral administration of risperidone to pregnant mice during organogenesis caused cleft palate at 10 mg/kg/day or 3 times the MRHD of 16 mg/day based on mg/m 2 body surface area; maternal toxicity occurred at 4 times the 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 MRHD of 16 mg/day risperidone based on mg/m 2 body surface area.
Learning was impaired in the offspring of rats dosed orally throughout pregnancy at 1 mg/kg/day which is 0.6 times the MRHD and neuronal cell death increased in fetal brains of rats dosed during pregnancy at 1 and 2 mg/kg/day which are 0.6 and 1.2 times the MRHD; 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 MRHD of 16 mg/day risperidone based on mg/m 2 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 MRHD. In a rat cross-fostering study, the number of live offspring was decreased, the number of stillbirths was increased, and the offspring 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 for offspring born to control but reared by drug-treated dams. All of these effects occurred at 5 mg/kg which is 3 times the MRHD and the only dose tested in the study.
