Drugs in Pregnancy and Lactation: Tenth Edition



PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk

BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity


No reports describing the use of paliperidone, the active metabolite of risperidone, in human pregnancy have been located. Developmental toxicity, in the absence of maternal toxicity, was not observed in two animal species. Risperidone was carcinogenic in rodents, but the relationship of this effect to humans has not been studied. Although there are no human pregnancy data with paliperidone, there are limited data for risperidone. (See Risperidone.) However, the absence of specific information for paliperidone prevents a complete assessment of the embryo–fetal risk. Nevertheless, if the mother’s disease requires the use of paliperidone, the benefits to her probably outweigh any fetal risk. Folic acid 4 mg/day has been recommended for women taking atypical antipsychotics because they may have a higher risk of neural tube defects due to inadequate folate intake and obesity (1). If paliperidone is used in pregnancy, health care professionals are encouraged to call the toll-free number 800-670-6126 for information about patient enrollment in the Motherisk study.


Paliperidone (9-hydroxyrisperidone), an atypical antipsychotic, is the major active metabolite of risperidone. (See also Risperidone.) It is a benzisoxazole derivative in the same antipsychotic subclass as iloperidone, risperidone, and ziprasidone. Paliperidone is indicated for the acute and maintenance treatment of schizophrenia. The plasma protein binding is 74%, and the metabolites are inactive. The terminal elimination half-life is about 23 hours (2).

Reproduction studies have been conducted in rats and rabbits. No increases in fetal abnormalities were observed in these species at oral doses that were 8 times the maximum recommended human dose based on BSA (MRHD) (2).

Carcinogenicity studies have not been performed with paliperidone. However, in mice and rats, the parent compound risperidone produced pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. This effect in rodents from risperidone and other antipsychotics is thought to be mediated by prolonged dopamine D2 antagonism and hyperprolactinemia. The no-observed-effect-level (NOEL) for these tumors was equal to or less than the maximum recommended human dose of risperidone based on BSA (2).

Paliperidone was not mutagenic in three assays. Fertility of male and female rats was not affected by oral doses up to about 2 times the MRHD. However, preimplantation and postimplantation losses were increased at the maximum dose that also caused slight maternal toxicity. No decrease in live embryos was observed at a dose that was about 0.5 times the MRHD (2).

It is not known if paliperidone crosses the human placenta. The molecular weight (about 426), moderate plasma protein binding, and long elimination half-life suggest that the drug will cross to the embryo–fetus.

Antipsychotics, especially those classified as high potency, can cause extrapyramidal reactions (e.g., acute dystonia, akathisia, parkinsonism, and tardive dyskinesia) in those taking the drug and, if large doses are taken by the mother, also in the newborn. The American Academy of Pediatrics (AAP) classifies risperidone as high potency; its active metabolite should be classified similarly. However, the AAP did note that high-potency antipsychotics were preferred to minimize maternal anticholinergic, hypotensive, and antihistamine adverse effects (3).


No reports describing the use of paliperidone during human lactation have been located.

However, risperidone and its active metabolite, 9-hydroxyrisperidone (paliperidone), are excreted into breast milk (46). (See also Risperidone.)

A 21-year-old mother with a 2-year history of bipolar disorder stopped all medication when her pregnancy was diagnosed (4). She did well during pregnancy and delivered a healthy infant at 38 weeks’ gestation. When her disease relapsed, she was admitted to the hospital 2.5 months after birth of her infant, stopped breastfeeding, and started on risperidone, eventually reaching a steady-state dose of 6 mg/day. Concentrations of risperidone and paliperidone were determined in the plasma and milk. The milk:plasma ratios, based on AUC0–24, were 0.42 and 0.24, respectively. Based on a daily milk intake of 150 mL/kg, a nursing infant would have received 0.84% of the mother’s risperidone dose (mg/kg/day) and an additional 3.46% from the paliperidone (as risperidone equivalents), or about 4.3% of the weight-adjusted maternal dose. Although the combined amounts of risperidone and paliperidone measured in breast milk appear to be too low to cause extrapyramidal effects, concern was expressed for other effects, such as neuroleptic malignant syndrome, and effects on cognitive development (4).

A 2004 study measured the steady-state plasma and milk concentrations of risperidone and 9-hydroxyrisperidone in two breastfeeding women and one woman with risperidone-induced galactorrhea (5). A 29-year-old woman with galactorrhea was taking risperidone 3 mg at night (37.5 mcg/kg/day) for schizophrenia. The galactorrhea was attributed to elevated prolactin concentrations due to the D2 antagonist effects of risperidone. Milk and plasma samples were collected 20 hours postdose, and then milk only on days 2 and 3, each at 21 hours postdose. The plasma concentrations of risperidone and the metabolite were <1 and 14 mcg/L, respectively. All milk risperidone concentrations were <1 mcg/L, whereas the mean concentration of the metabolite was 5.1 mcg/L (range 4.4–5.6 mcg/L). Although the woman was not nursing, the absolute and relative infant doses were 0.88 mcg/kg/day or 2.3% (as risperidone equivalents) (5).

The two women who were breastfeeding were treated for psychosis with risperidone doses of 42.1 (2 mg every 12 hours) and 23.1 mcg/kg/day (0.5 mg in the morning and 1 mg at night), respectively (5). The nursing infants were a 3.3-month-old female and a 6-week-old male, respectively. In the first woman, milk concentrations of the parent drug and metabolite were 49 and 142 mcg•hr/L (AUC), respectively, whereas the average concentrations were 2.1 and 6 mcg/L, respectively. The absolute infant doses were 0.32 and 0.9 mcg/kg/day, respectively. In the second woman, milk concentrations were 3.1 and 56.5 mcg•hr/L (AUC), respectively, whereas the average concentrations over 24 hours were 0.39 and 7.06 mcg/L, respectively. The absolute infant doses were 0.06 and 1.06 mcg/kg/day, respectively. The milk:plasma ratios were 0.1 and 0.5, respectively. Neither risperidone nor the metabolite was detected in the plasma of the infants and both were developing normally at 9 and 12 months, respectively (5).

A 23-year-old woman, nursing a 4.2-kg male infant 6 times daily, was diagnosed with paranoid schizophrenia 1 week after birth (6). She was hospitalized and started on risperidone 1 mg twice daily. The dose was changed to 2 mg every evening on day 7 and then to 3 mg every evening on day 10. Milk (fore and hind) and maternal plasma concentrations of risperidone and paliperidone were determined on days 6, 10, and 20. No drug accumulation was observed and the concentrations of paliperidone always exceeded those of risperidone. The ranges of risperidone and paliperidone milk concentrations were 0–3 and 1.2–11 ng/mL, respectively, whereas the plasma concentrations were 0.4–10 and 4–43 ng/mL, respectively. Moreover, the concentrations in fore- and hind-milk were comparable. On day 10, 15 hours after a 2 mg dose, the concentrations of risperidone and paliperidone in infant plasma were 0 and 0.1 ng/mL, respectively. The mother was discharged home on risperidone after 5 weeks. The psychomotor development of the infant during the mother’s hospitalization was normal and no adverse effects or sedation in the infant were observed. The mother and infant were doing well 2 months after discharge (6).

The AAP classifies other antipsychotic drugs as agents for which the effect on nursing infants is unknown but may be of concern, especially when given for long periods (7). Neither risperidone nor paliperidone was mentioned, but the AAP noted that antipsychotics are excreted into breast milk and could conceivably alter both short-term and long-term CNS function (7). Although no adverse effects from exposure to risperidone and paliperidone have been observed, studies have not been conducted to determine if there are long-term effects.


1.Koren G, Cohn T, Chitayat D, Kapur B, Remington G, Myles-Reid D, Zipursky RB. Use of atypical antipsychotics during pregnancy and the risk of neural tube defects in infants. Am J Psychiatry 2002;159:136–7.

2.Product information. Invega. Janssen, 2008.

3.Committee on Drugs, American Academy of Pediatrics. Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Pediatrics 2000;105:880–7.

4.Hill RC, McIvor RJ, Wojnar-Horton RE, Hackett LP, Ilett KF. Risperidone distribution and excretion into human milk: case report and estimated infant exposure during breast-feeding. J Clin Psychopharmacol 2000;20:285–6.

5.Ilett KF, Hackett LP, Kristensen JH, Vaddadi KS, Gardiner SJ, Begg EJ. Transfer of risperidone and 9-hydroxyrisperidone into human milk. Ann Pharmacother 2004;38:273–6.

6.Aichhorn W, Stuppaeck C, Whitworth AB. Risperidone and breast-feeding. J Psychopharmacol 2005;19:211–3.

7.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.