Antipsychotic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
There is limited human pregnancy experience with loxapine. Animal reproductive data suggest risk. 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). Because loxapine is indicated for severe debilitating mental disease, the benefits to the mother appear to outweigh the unknown 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 NTDs due to inadequate folate intake and obesity (3). Moreover, neonates exposed to antipsychotic drugs in the 3rd trimester are at risk of extrapyramidal and/or withdrawal symptoms (4).
FETAL RISK SUMMARY
Loxapine is an atypical antipsychotic that is indicated for the treatment of schizophrenia (4). The drug is extensively metabolized to apparently inactive metabolites. The manufacturer did not state the amount of plasma protein binding or the elimination half-life, but did state that loxapine was rapidly removed from the plasma and distributed in tissues (4). Loxapine belongs to the antipsychotic subclass of dibenzapine derivatives that includes asenapine, clozapine, olanzapine, and quetiapine.
In reproductive studies with rats, rabbits, and dogs, no embryotoxicity or teratogenicity was observed. However, with the exception of one rabbit study, the dose used was ≤2 times the maximum recommended human dose (presumably based on weight) (4,5). Renal papillary abnormalities were found in offspring of rats treated from mid-gestation with doses approximately equivalent to the usual human dose (4).
It is not known if loxapine crosses the human placenta. The molecular weight (about 328 for the free base) suggests that it will cross to the embryo–fetus.
A 2009 review cited information received from the manufacturer regarding the outcomes of three pregnancies exposed to loxapine (6). The retrospective outcomes were one baby with achondroplasia; one with multiple unspecified anomalies; and one infant, exposed throughout pregnancy, with tremors at 15 weeks of age (6). However, achondroplasia is a known autosomal dominant inheritance defect and is not related to drug exposure.
BREASTFEEDING SUMMARY
No reports describing the use of loxapine during human lactation have been located. The relatively low molecular weight of loxapine (about 328 for the free base) suggests that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. The American Academy of Pediatrics classifies other antipsychotics (e.g., see Clozapine) as drugs whose effect on the nursing infant is unknown but may be of concern (7). 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. No. 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. Loxitane. Watson Laboratories, 2010.
5.Mineshita T, Hasewaga Y, Inoue Y, Kozen T, Yamamoto A. Teratological studies on fetuses and suckling young mice and rats of S-805. Oyo Yakuri 1970;4:305–16. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:378.
6.Einarson A, Boskovic R. Use and safety of antipsychotic drugs during pregnancy. J Psychiatr Pract 2009;15:183–92.
7.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.