Drugs in Pregnancy and Lactation: Tenth Edition

AXITINIB

Antineoplastic (Tyrosine Kinase Inhibitor)

PREGNANCY RECOMMENDATION: Contraindicated

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

No reports describing the use of axitinib during human pregnancy have been located. In one animal species, the drug was teratogenic, embryotoxic, and fetotoxic at maternal exposures that were lower than human exposures. Moreover, axitinib impairs fertility in both female and male animals. Although the human risk is unknown, women taking this drug should be informed of the potential risk to their embryo–fetus if they become pregnant.

FETAL RISK SUMMARY

Axitinib, available as oral tablets, is an inhibitor of receptor tyrosine kinases including vascular endothelial growth factor receptors that are implicated in pathologic angiogenesis, tumor growth, and cancer progression. There are several other agents in this subclass (see Appendix). It is indicated for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy. The drug is metabolized to relatively inactive metabolites and is highly bound (>99%) to plasma proteins with preferential binding to albumin and moderate binding to a1-acid glycoprotein. The plasma half-life is 2.5–6.1 hours (1).

Reproduction studies have been conducted in mice. An increase in post-implantation loss was observed when mice were given twice-daily doses up to about 10 times the systemic exposure (AUC) from the recommended human starting dose (RHSD) before mating and through the first week of pregnancy. In mice given twice-daily doses during organogenesis, embryo–fetal toxicities were observed, in the absence of maternal toxicity, that included cleft palate and variation in skeletal ossification at about 0.5 and 0.15 times, respectively, the exposure from the RHSD (1).

Carcinogenicity studies have not been conducted with axitinib. The drug was not mutagenic or clastogenic in two in vitro assays, but was genotoxic in an in vivo assay. In fertility studies with male mice and dogs, testes/epididymis toxicity was observed that included decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, and reduced sperm density and count. Findings in the female reproductive tracts of these species included delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights, and uterine atrophy (1).

It is not known if axitinib crosses the human placenta. The molecular weight (about 387) and plasma half-life suggest that the agent will cross to the embryo–fetus, but the high plasma protein binding might limit the amount crossing.

BREASTFEEDING SUMMARY

No reports describing the use of axitinib during human lactation have been located. The molecular weight (about 387) and plasma half-life (2.5–6.1 hours) suggest that the agent will be excreted into breast milk, but the high plasma protein binding (>99%) might limit the amount in milk. However, the drug is given orally and, if excreted into milk, it could be absorbed into the systemic circulation by a nursing infant. The effect of this exposure on a nursing infant is unknown, but severe toxicity is a potential concern. Consequently, mothers taking this drug should not breastfeed.

Reference

1.Product information. Inlyta. Pfizer Laboratories, 2012.



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