Antipsychotic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of asenapine in human pregnancy have been located. There is no evidence of embryo–fetal harm with other agents in this subclass. However, because of the very limited human pregnancy experience with atypical antipsychotics, the American College of Obstetricians and Gynecologists does not recommend the routine use of these agents in pregnancy, but a risk benefit assessment may indicate that such use is appropriate (1). Until human data are available, the use of other antipsychotics in pregnancy should be considered. Nevertheless, asenapine is indicated for severe debilitating mental disease and the benefits to the mother will probably outweigh the unknown embryo–fetal risk. A 1996 review on the management of psychiatric illness concluded that patients with histories of chronic psychosis represent a high-risk group (for both the mother and the fetus) and should be maintained on pharmacologic therapy before and during pregnancy (2). 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 (3).
FETAL RISK SUMMARY
Asenapine is an atypical antipsychotic agent that is available for sublingual administration. It is indicated for the acute treatment of schizophrenia in adults. Asenapine belongs to the antipsychotic subclass of dibenzapine derivatives that includes clozapine, loxapine, olanzapine, and quetiapine. It is metabolized and eliminated as inactive metabolites. The mean terminal half-life is about 24 hours. Asenapine is highly bound (95%) to plasma proteins, including albumin and α1-acid glycoprotein (4).
Animal reproduction studies have been conducted in rats and rabbits. In these species, asenapine was not teratogenic at IV doses up to 0.7 and 0.4 times, respectively, the maximum recommended human dose of 10 mg twice daily given sublingually based on BSA (MRHD). In rabbits, the highest dose produced plasma levels (AUC) that were twice the human levels resulting from the MRHD. Increases in post-implantation loss and early pup deaths were observed in rats given daily IV doses that were 0.15–0.7 times the MRHD from gestation day 6 through postpartum day 21. Decreases in pup survival and weight gain were seen at IV doses that were 0.4 and 0.7 times the MRHD. Oral dosing had the same effects. The decreases in pup survival were largely due to prenatal drug effects (4).
Lifetime carcinogenicity studies have been conducted in mice and rats. In female mice given SC doses resulting in plasma levels (AUC) that were about 5 times the human levels resulting from the MRHD, an increased incidence of malignant lymphomas was observed. However, the mouse strain used had a high and variable incidence of this cancer, and the significance of this finding to humans is unknown. The no-effect dose was about 1.5 times the human levels resulting from the MRHD. No tumors were observed in male mice or in rats. No evidence of genotoxic potential was found in several tests. In rats, doses up to 10 times the MRHD had no effect on fertility (4).
It is not known if asenapine crosses the human placenta. The molecular weight (about 286 for the free base) and the long terminal elimination half-life suggest that the drug will cross to the embryo–fetus, even though the high plasma protein binding may limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of asenapine during human lactation have been located. The molecular weight (about 286 for the free base) and the long terminal elimination half-life (about 24 hours) suggest that the drug will be excreted into breast milk, even though the high (95%) plasma protein binding might limit the exposure. The effect of this exposure on a nursing infant is unknown, but they should be monitored for the most common adverse reactions observed in adults (somnolence, dizziness, akathisia, and oral hypoesthesia).
The manufacturer recommends women receiving asenapine should not breastfeed (4). Moreover, the American Academy of Pediatrics classifies other atypical antipsychotics (e.g., see Clozapine) as drugs whose effect on the nursing infant is unknown but may be of concern (5).
Because of the very limited human experience with atypical antipsychotics, the American College of Obstetricians and Gynecologists does not recommend the routine use of these agents during lactation, but a risk–benefit assessment may indicate that such use is appropriate (1).
References
1.American College of Obstetricians and Gynecologists. Use of psychiatric medications during pregnancy and lactation. ACOG Practice Bulletin. Number 92, April 2008. Obstet Gynecol 2008;111:1001–19.
2.Althuler LL, Cohen L, Szuba MP, Burt VK, Gitlin M, Mintz J. Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines. Am J Psychiatry 1996;153:592–606.
3.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.
4.Product information. Saphris. Organon Pharmaceuticals USA, 2013.
5.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.