Central Stimulant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Other than the three cases reported by the manufacturer, no reports describing the use of armodafinil in human pregnancy have been located. Developmental toxicity was observed in two animal species at systemic exposures that were equal to or less than human plasma exposures. The near absence of human pregnancy experience prevents a better assessment of the embryo–fetal risk. Avoiding armodafinil during pregnancy is the best course. Inadvertent exposure does not appear to represent a major risk of embryo–fetal harm but, because of the two cases of intrauterine growth restriction, closer attention than usual to fetal growth might be appropriate.
FETAL RISK SUMMARY
Armodafinil is the R-enantiomer of modafinil which is a mixture of the R- and S-enantiomers (see also Modafinil). It is indicated to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome, narcolepsy, and shift-work sleep disorder. Armodafinil is a lipophilic agent that is extensively metabolized to apparently inactive metabolites. The drug is moderately bound (about 60%) to plasma proteins, primarily albumin, and the terminal half-life is about 15 hours (1).
Reproduction studies with armodafinil have been conducted in rats and, with modafinil, in rats and rabbits. In rats, daily oral doses of armodafinil given throughout the period of organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weights. The no-effect dose for rat embryo–fetal developmental toxicity was associated with a plasma exposure (AUC) that was about 0.03 times the AUC in humans at the maximum recommended daily dose of 250 mg (MRDD) (1).
Daily oral doses of modafinil given to rats throughout organogenesis caused an increase in resorptions and increased incidences of visceral and skeletal variations. The no-effect dose for embryo–fetal developmental toxicity was associated with a plasma exposure (AUC) that was about 0.5 times the AUC in humans at the recommended daily dose of 200 mg (RHD). In another study, no developmental toxicity was observed at plasma modafinil exposure about 2 times the AUC at the RHD. However, when modafinil was given to rats throughout gestation and lactation, decreased viability in the offspring occurred with plasma exposures that were about 0.1 times the AUC at the RHD. No effects on postnatal developmental and neurobehavioral parameters were observed in surviving offspring (1).
In rabbits, daily oral doses of modafinil given throughout organogenesis caused increased incidences of fetal structural alterations and embryo–fetal death at the highest dose. The highest no-effect dose for developmental toxicity was associated with a plasma modafinil exposure that was about equal to the AUC at the RHD (1).
Carcinogenicity studies conducted with modafinil in mice and rats were negative. No evidence of mutagenic or clastogenic potential was found in multiple assays with armodafinil. Fertility studies in male and female rats with modafinil observed an increase in time to mate at the highest dose. The no-effect dose resulted in a plasma exposure that was about equal to the AUC in humans at the RHD (1).
It is not known if armodafinil crosses the human placenta. The molecular weight (about 273), lipophilic nature, moderate plasma protein binding, and long terminal half-life suggest that the drug will cross to the embryo–fetus.
The manufacturer mentioned two cases of intrauterine growth restriction, and one spontaneous abortion had been reported in association with armodafinil and modafinil, but it was not known if the outcomes were drug-related (1). (See also Modafinil.)
BREASTFEEDING SUMMARY
No reports describing the use of armodafinil during human lactation have been located. The molecular weight (about 273), lipophilic nature, moderate plasma protein binding (about 60%), and long terminal half-life (about 15 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. If a lactating woman uses armodafinil, her infant should be closely observed for adverse effects that are commonly seen in adults (i.e., headache, nausea, dizziness, anxiety, and insomnia).
Reference
1.Product information. Nuvigil. Cephalon, 2010.