Antipsychotic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Two reports describing the use of ziprasidone in human pregnancy have been located, one of which described an infant with a cleft palate. The animal reproduction data suggests risk as all aspects of developmental toxicity were observed. However, the limited human pregnancy experience prevents a more complete assessment of embryo–fetal risk. Although none of the antipsychotic class of agents has been proven to cause structural anomalies, there is a concern for long-term neurobehavioral deficits. Therefore, until human pregnancy data are available, the safest course is to avoid ziprasidone in pregnancy. However, if a woman requires treatment and informed consent is obtained, ziprasidone should not be withheld because of pregnancy. If an inadvertent pregnancy does occur during treatment, the woman should be advised of the unknown risks to her embryo–fetus. If ziprasidone is used in pregnancy, healthcare professionals are encouraged to call the toll-free number 800-670-6126 for information about patient enrollment in the Motherisk study.
FETAL RISK SUMMARY
The atypical antipsychotic ziprasidone is a benzisoxazole derivative in the same subclass of antipsychotic agents as iloperidone, paliperidone, and risperidone. Ziprasidone is indicated for the treatment of schizophrenia, including acute agitation in schizophrenic patients. It also is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder. Elimination is mostly by hepatic metabolism to inactive metabolites. After oral administration, the mean terminal elimination half-life is about 7 hours, but a mean 2–5 hours after a single IM dose. Plasma protein binding to albumin and α1-acid glycoprotein is >99% (1).
Reproduction studies have been conducted in rats and rabbits. In rats, oral doses that were 0.5–8 times the maximum recommended human dose of 200 mg/day based on BSA (MRHD) given during organogenesis or throughout gestation caused embryo–fetal toxicity consisting of decreased fetal weights and delayed skeletal ossification. There was no evidence of structural anomalies. Doses that were 2 and 8 times the MRHD were maternally toxic. The developmental no-effect dose for embryo–fetal toxicity was 0.2 times the MRHD. When rats were treated throughout gestation and lactation with a dose that was half the MRHD, there was an increase in the number of pups born dead and decreased postnatal survival during the first 4 days of lactation. Developmental delays and impaired neurobehavioral function were observed in offspring with doses ≥0.2 times the MRHD. A no-effect dose for these effects was not established (1).
In pregnant rabbits during organogenesis, a dose 3 times the MRHD was associated with an increased incidence of ventricular septal defects, other cardiovascular malformations, and kidney alterations. There was no maternal toxicity at this dose. The developmental no-effect dose was equivalent to the MRHD (1).
Two-year studies for carcinogenicity were conducted in rats and mice with doses that were 0.1–0.6 and 1–5 times, respectively, the MRHD. In rats and male mice, there was no evidence of an increased incidence of tumors. However, in female mice, there were dose-related increases in the incidences of pituitary gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested. These effects have been observed in rodents with other antipsychotic agents and were thought to be prolactin-mediated. Ziprasidone was mutagenic in some tests (1).
In fertility tests with rats, doses that were 0.5–8 times the MRHD increased the time to copulation. Fertility was decreased at 8 times the MRHD, but there was no effect on fertility at 2 times the MRHD. The effect appeared to be confined to female rats as fertility was not impaired in male rats given a dose that was 8 times the MRHD and mated with untreated females. In addition, there were no treatment-related effects in the testes in a study with male rats at 10 times the MRHD for 6 months (1).
It is not known if ziprasidone crosses the human placenta. The molecular weight of the free base (about 413) and the elimination half-life suggest that the drug will cross to the embryo and/or fetus. However, the very high plasma protein binding should limit the amount crossing to the embryo/fetus.
A 2009 case report described the pregnancy of a 26-year-old woman with severe psychotic depression (2). She was treated with ziprasidone 40 mg/day and citalopram 60 mg/day throughout pregnancy. At 39 weeks’ gestation, she gave birth to a healthy, 2.64-kg male infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. No anomalies, drug-related adverse effects, or withdrawal were observed in the infant who was doing well at 6 months of age (2).
In a 2010 case report, a 33-year-old woman with paranoid schizophrenia was treated throughout pregnancy with ziprasidone (daily doses of 120 mg during first 3 months, then 80 mg for 2 months, then 40 mg until birth), fluvoxamine and diazepam (doses not specified) (3). She gave birth at term to a 3.070-kg female infant with a cleft palate. The infant’s karyotype was normal, and the mother denied smoking, drinking coffee or alcohol, taking other drugs during pregnancy (3).
BREASTFEEDING SUMMARY
A woman with schizophrenia who was breastfeeding her infant was started on ziprasidone on postpartum day 9 (4). Breastfeeding was stopped because of concerns of toxicity in the infant. Ziprasidone was not detected (limit of quantification was 10 ng/mL) until day 10 of treatment. At that time, the milk and maternal plasma concentrations were 11 and 170 ng/mL (milk:plasma ratio 0.06). The theoretical relative dose received by the infant per kg body weight based on the weight-adjusted maternal dose was 1.2% (4).
In a 2009 case (see Fetal Risk Summary), a mother taking ziprasidone and citalopram breastfed her full-term infant for 6 months. No adverse effects were noted and the infant was deemed healthy by his pediatrician (2).
Consistent with the molecular weight of the free base (about 413) and the elimination half-life (up to 7 hours), ziprasidone is excreted into breast milk but, as suggested by the very high plasma protein binding (>99%), only low levels were excreted. However, the absorption of ziprasidone in adults is increased twofold in the presence of food (1).
Although no adverse effects were observed in one case, additional data are needed before a better assessment of risk can be made. Moreover, because treatment with ziprasidone will usually be long term, there is concern for potential adverse effects involving the neurobehavior of an infant.
References
1.Product information. Geodon. Pfizer, 2007.
2.Werremeyer A. Ziprasidone and citalopram use in pregnancy and lactation in a woman with psychotic depression. Am J Psychiatry 2009;166:1298.
3.Peitl MV, Petric D, Peitl V. Ziprasidone as a possible cause of cleft palate in a newborn. Psychiatr Danub 2010;22:117–9.
4.Schlotterbeck P, Saur R, Hiemke C, Grunder G, Vehren T, Kircher T, Leube D. Low concentration of ziprasidone in human milk: a case report. Int J Neuropsychopharmacol 2009;12:437–8.