Antiemetic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of aprepitant in human pregnancy have been located. The animal data suggest low risk, even though low doses relative to the human dose were studied. Use of higher doses was not possible because of saturation of absorption in the animals. The absence of human pregnancy experience prevents a full assessment of the risk. Until additional data are available, the use of aprepitant, if indicated, should be restricted to the 2nd and 3rd trimesters. However, if inadvertent exposure does occur during organogenesis, the embryo–fetal risk appears to be low.
FETAL RISK SUMMARY
Aprepitant is an oral antiemetic indicated, in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy, such as cisplatin. It is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1). Protein binding to plasma protein is >95%. Aprepitant is extensively metabolized to relatively inactive compounds by cytochrome P450 isoenzymes (primarily CYP3A4). The elimination half-life ranges from 9 to 13 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats, oral doses up to about 1.6 times the human exposure in nonpregnant patients at the recommended dose based on AUC0–24 h (HERD) revealed no evidence of impaired fertility or fetal harm. Similar results were observed in rabbits at doses up to about 1.4 times the HERD. Higher doses were not used because of saturation of absorption. In 2-year carcinogenicity studies, oral doses up to 0.4–1.4 times the HERD were carcinogenic in male and female rats. Oral doses up to 2.2–2.7 times the HERD were carcinogenic in male mice. No mutagenicity was observed in various assays (1).
It is not known if aprepitant crosses the human placenta. The drug crosses the placenta in rats and rabbits and crosses the blood–brain barrier in humans (1). Although protein binding is high, the molecular weight (about 534) and elimination half-life suggest that the drug will cross the human placenta to the embryo and/or fetus.
BREASTFEEDING SUMMARY
No reports describing the use of aprepitant during human lactation have been located. The molecular weight (about 534) and elimination half-life (9–13 hours) suggest that the drug will be excreted into breast milk. However, the high plasma protein binding (>95%) should attenuate the amount excreted. The potential effect of this exposure on a nursing infant is unknown, but consideration should be given, especially if the exposure is prolonged, to the carcinogenic effects observed in animal studies.
Reference
1.Product information. Emend. Merck, 2005.