Psychotherapeutic (Miscellaneous)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although the animal data suggest risk, the absence of detailed human pregnancy experience prevents an assessment of the embryo–fetal risk. Until such data are available, the safest course is to avoid the drug in pregnancy. If the mother’s condition requires atomoxetine, the lowest effective dose, avoiding the 1st trimester if possible, should be used. However, inadvertent exposure in the 1st trimester does not appear to represent a major risk. Long-term follow-up of exposed offspring may be warranted.
FETAL RISK SUMMARY
Atomoxetine is used for the treatment of attention deficit/hyperactivity disorder (ADHD). Atomoxetine has an equipotent active metabolite, but the plasma concentration is only 1% (in normal metabolizers) of the parent drug. A second active metabolite has much less activity and its plasma levels are 5% (in normal metabolizers) of the parent drug. The plasma elimination half-life in normal (extensive) metabolizers is about 5 hours. In persons who are “poor metabolizers” (7% of whites and 2% of blacks), the drug plasma levels are much higher and the plasma elimination half-life is 24 hours. The plasma protein binding is 98%, primarily to albumin (1).
Reproduction studies have been conducted in rats and rabbits. No effects on rat fertility were observed at doses up to about 6 times the maximum human dose based on BSA (MHD). In one of two studies in which rats were treated in the diet for 2 weeks prior to mating through organogenesis and lactation with doses up to about 6 times the MHD, a decrease in pup weight (female only) and pup survival (also seen at 3 times the MHD) was observed. The no-effect dose for pup survival was about 2 times the MHD. A diet dose about 5 times the MHD given throughout the period of organogenesis resulted in a decrease in fetal weight and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses. The no-effect dose for these effects was about 2.5 times the MHD. No adverse fetal effects were observed when rats were gavage fed with doses up to 17 times the MHD throughout organogenesis (1).
In pregnant rabbits given atomoxetine by gavage, a dose about 23 times the MHD resulted in an increase in early absorptions and a decrease in live fetuses in one of three studies. In addition, slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed, as was slight maternal toxicity. The no-effect dose was about 7 times the MHD. The high dose produced plasma levels (AUC) in rabbits that were about 3.3 times (normal metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the MHD. The no-effect dose for these effects was about 7 times the MHD (1).
It is not known if atomoxetine or its active metabolites cross the human placenta. The molecular weight for the parent drug (about 256 for the free base) combined with elimination half-life suggests that atomoxetine will cross to the embryo and/or fetus. The extensive protein binding, however, will limit the amount available for transfer.
In a brief correspondence, representatives of the manufacturer and others stated that there had been three pregnancies in adult clinical trials with atomoxetine (2). Two resulted in healthy newborns, but the third pregnancy was lost to follow up. No other details were provided.
BREASTFEEDING SUMMARY
No reports describing the use of atomoxetine during human lactation have been located. The molecular weight of the parent drug (about 256 for the free base) and the relatively long elimination half-life (5 hours for normal metabolizers; 24 hours for poor metabolizers) suggest that the drug and/or its metabolites will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. If a mother chooses to breastfeed while taking atomoxetine, the infant should be monitored for potential toxicity (such as upper abdominal pain, constipation, and dyspepsia).
References
1.Product information. Strattera. Eli Lilly, 2004.
2.Heiligenstein J, Michelson D, Wernicke J, Milton D, Kratochvil CJ, Spencer TJ, Newcorn JH. Atomoxetine and pregnancy. J Am Acad Child Adolesc Psychiatry 2003;42:884–5.