Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of cabozantinib during human pregnancy have been located. The animal data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. However, based on the mechanism of action, embryo–fetal harm may occur. If a woman is pregnant or conceives during treatment, she should be informed of the potential risk to her embryo and/or fetus.
FETAL RISK SUMMARY
Cabozantinib, a substrate of CYP3A4 in vitro, is an oral inhibitor of tyrosine kinase activity. There are several other agents in this subclass (see Appendix). Cabozantinib is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer. The drug is metabolized to apparently inactive metabolites. Plasma protein binding is high (>99.7%) and the effective half-life is about 55 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats that were given the drug daily during organogenesis, embryo–fetal death was observed at doses that were <1% of the human exposure by AUC at the recommended dose (HE). The findings included delayed ossifications and skeletal variations at doses that were about ≥0.03% of the HE. In rabbits administered the drug daily during organogenesis, visceral malformations and variations including reduced spleen size and missing lung lobe were observed at a dose that was about 11% of the HE (1).
Studies evaluating the carcinogenic potential of cabozantinib have not been conducted. The drug was not mutagenic or clastogenic in various assays. Fertility was impaired in male rats (decrease in sperm counts and reproductive organ weights) and female rats (decrease in live embryos and increase in pre- and postimplantation losses, and ovarian necrosis). Impairment of fertility also was observed in male (hypospermia) and female (absence of corpora lutea) dogs (1).
It is not known if cabozantinib crosses the human placenta. The molecular weight (about 636 for the malate salt) and the long effective half-life suggest that the drug will cross to the embryo–fetus, but the high plasma protein binding might limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of cabozantinib during human lactation have been located. The molecular weight (about 636 for the malate salt) and the long effective half-life (about 55 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (≥99.7%) might limit the exposure. The effect of this exposure on a nursing infant is unknown. However, because the drug commonly (≥25%) causes toxicity in adults, such as diarrhea, stomatitis, decreased appetite and weight, nausea, fatigue, and oral and abdominal pain, the best course is to not use cabozantinib during breastfeeding.
Reference
1.Product information. Cometriq. Exelixis, 2012.