Central Stimulant
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Only one report, in addition to the nine cases mentioned by the manufacturer, describing the use of modafinil in human pregnancy has been located. The animal data suggest moderate risk, but the limited human pregnancy experience prevents a full assessment of the embryo–fetal risk. Avoiding modafinil during pregnancy is the best course, but inadvertent exposure does not appear to represent a major risk of embryo–fetal harm.
FETAL RISK SUMMARY
Modafinil is a mixture of R- and S-enantiomers and the R-enantiomer, armodafinil, also is available (see Armodafinil). Modafinil is indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. Its pharmacologic profile is not identical to that of sympathomimetic agents. Plasma protein binding, primarily to albumin, is moderate (about 60%). Modafinil is extensively (>90%) metabolized by the liver. After chronic dosing, the elimination half-life is about 15 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats, doses 10 times the maximum recommended human daily dose of 200 mg based on BSA (MRHDD) given throughout organogenesis were associated with increased resorptions, hydronephrosis, and skeletal variations. No maternal toxicity was observed at this dose. The no-effect dose for these effects was 5 times the MRHDD. Doses up to 4.8 times the MRHDD given to male and female rats before and during gestation had no effect on fertility. In rabbits, no embryotoxicity was observed at doses up to 10 times the MRHDD during organogenesis. However, the sample sizes and doses were inadequate to assess the toxic effects on fertility or reproduction (1). (See Armodafinil for additional animal data.)
It is not known if modafinil crosses the human placenta. The molecular weight (about 273), moderate plasma protein binding, and long elimination half-life suggest that the drug will cross to the embryo–fetus.
The manufacturer cited the outcomes of nine pregnancies that were exposed to modafinil, but few details were given. There were seven normal births, one healthy male infant delivered 3 weeks before the expected range of delivery dates (based on ultrasound), and one spontaneous abortion (woman had history of previous spontaneous abortions) (1).
A 16-year-old primigravid woman with narcolepsy, cataplexy, and glutaric aciduria type II, an autosomal recessive disorder, was treated throughout pregnancy with modafinil 200 mg/day, fluoxetine 20 mg/day, L-carnitine, and riboflavin (2). Because the episodes of narcolepsy and cataplexy increased in frequency, a cesarean section was conducted at 38 weeks’ to deliver 2.360-kg infant (sex not specified) with Apgar scores of 7, 8, and 9. No signs of withdrawal or abnormalities in vital signs or behaviour were noted in the infant. The infant was discharged home with the mother after 3 days (2).
BREASTFEEDING SUMMARY
No reports describing the use of modafinil during human lactation have been located. The relatively low molecular weight (about 273), moderate plasma protein binding (about 60%), and long elimination half-life (about 15 hours) suggest that the drug will be excreted in breast milk. The effects of this exposure on a nursing infant are unknown. However, if a lactating woman uses modafinil, her infant should be closely observed for adverse effects that are commonly seen in adults (i.e., headache, nausea, nervousness, anxiety, and insomnia).
References
1.Product information. Provigil. Cephalon, 2004.
2.Williams SF, Alvarez JR, Pedro HF, Apuzzio JJ. Glutaric aciduria type II and narcolepsy in pregnancy. Obstet Gynecol 2008;111:522–4.