Invega Hafyera Use In Pregnancy & Lactation

Pregnancy: 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 as follows).
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.
INVEGA HAFYERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data as follows). There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including INVEGA HAFYERA during pregnancy (see Clinical Considerations as follows). Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of 3-month paliperidone palmitate prolonged-release suspension for injection [see Pharmacology: Pharmacokinetics under Actions]. The clinical significance of INVEGA HAFYERA administered before pregnancy or anytime during pregnancy is not known.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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.
In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate or when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis. Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone (see Data: Animal Data as follows).
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 INVEGA HAFYERA, 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, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. 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 the parent compound of paliperidone, 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 the 6-month paliperidone palmitate prolonged-release suspension for injection.
There were no treatment-related effects on the offspring when pregnant rats were injected intramuscularly with 1-month paliperidone palmitate prolonged-release suspension for injection during the period of organogenesis at doses up to 250 mg/kg, which is ~10 times the MRHD of 234 mg of the 1-month paliperidone palmitate prolonged-release suspension for injection based on mg/m² body surface area. 234 mg paliperidone palmitate equivalent to 150 mg paliperidone.
In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the oral MRHD of 12 mg based on mg/m² body surface area.
Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m² body surface area; maternal toxicity occurred at 4 times the MRHD. There was no evidence of teratogenicity in embryo-fetal developmental toxicity studies with risperidone in rats and rabbits at doses up to 6 times the MRHD of 16 mg/day risperidone based on mg/m² body surface area. When the offspring of pregnant rats, treated with risperidone at 0.6 times the MRHD based on mg/m² body surface area, reached adulthood, learning was impaired. Increased neuronal cell death occurred in the fetal brains of the offspring of pregnant rats treated at 0.5 to 1.2 times the MRHD; the postnatal development and growth of the offspring was delayed.
In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone 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.
Lactation: Risk Summary: Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations as follows). Paliperidone has been detected in plasma in adult subjects up to 18 months after a single-dose administration of 3-month paliperidone palmitate prolonged-release suspension for injection. The clinical significance on the breastfed infant is not known [see Pharmacology: Pharmacokinetics under Actions]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for INVEGA HAFYERA and any potential adverse effects on the breastfed child from INVEGA HAFYERA or from the mother's underlying condition.
Clinical Considerations: Infants exposed to INVEGA HAFYERA through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements).
Females and Males of Reproductive Potential: Infertility: Females: Based on the pharmacologic action of paliperidone (D₂ receptor antagonism), treatment with INVEGA HAFYERA may result in an increase in serum prolactin levels, which may lead to a reversible reduction in fertility in females of reproductive potential [see Hyperprolactinemia under Precautions].