Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Conraindicated
PREGNANCY SUMMARY
No reports describing the use of vandetanib in human pregnancy have been located. In the only animal species studied, the drug was embryotoxic, fetotoxic, and teratogenic at exposures close to or less than the human exposure. However, the absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Because of the risk of fetal harm, the manufacturer recommends that women of reproductive potential use effective contraception to prevent pregnancy during treatment and for at least 4 months following the last dose.
FETAL RISK SUMMARY
Vandetanib is an oral inhibitor of tyrosine kinase. There are several other agents in this subclass (see Appendix). It is indicated for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advance or metastatic disease. Vandetanib is metabolized to apparently inactive metabolites. The mean plasma protein binding to albumin and α1-acid-glycoprotein is 93.7% and the median plasma half-life is 19 days (1).
Reproduction studies have been conducted in rats. In rats before mating and through the 1st week of pregnancy, exposures that were equal to or less than the exposure expected from the recommended human dose of 300 mg/day (HE) resulted in increases in preimplantation and postimplantation loss, including embryo–fetal death, and a significant decrease in the number of live embryos. Total litter loss occurred when the drug was given during organogenesis until expected parturition. All doses (about 0.03–1.0 times the maximum concentration [Cmax] in humans with cancer at the recommended dose) given during organogenesis caused both malformations of heart vessels and skeletal variations (delayed ossification of the skull, vertebrae, and sternum) that indicated delayed fetal development. A no-effect level for malformations was not identified in this study. In a separate study, doses identical to those used above caused maternal toxicity and, when given during gestation and/or lactation, resulted in decreased pup survival and/or reduced postnatal pup growth (1).
Carcinogenicity studies have not been conducted. Various assays for mutagenic and clastogenic effects were negative. Fertility in male rats was not impaired but, in female rats, there was a slight decrease in the number of live embryos. There also was a trend toward increased estrus cycle irregularity and a decrease in the number of corpora lutea in the ovaries (1).
It is not known if vandetanib crosses the human placenta. The molecular weight (about 475) and the long plasma half-life suggest that the drug will cross to the embryo–fetus, but high plasma protein binding might lessen the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of vandetanib during human lactation have been located. The molecular weight (about 475) and the long plasma half-life (19 days) suggest that the drug will be excreted into breast milk, but high plasma protein binding (93.7%) might lessen the exposure. The effect of this exposure on a nursing infant is unknown. However, the drug has caused serious toxicity in adults, such as skin reactions and Stevens-Johnson syndrome, pneumonitis, ischemic cerebrovascular events, and hemorrhage. The most common adverse reactions (>20%) in adults were diarrhea, rash, acne, nausea, hypertension, headache, fatigue, upper respiratory tract infections, decreased appetite, and abdominal pain. If a woman receiving the drug chooses to breastfeed, her infant should be closely monitored for these effects.
Reference
1.Product information. Caprelsa. AstraZeneca Pharmaceuticals, 2012.