Drugs in Pregnancy and Lactation: Tenth Edition

BOSUTINIB

Antineoplastic (Tyrosine Kinase Inhibitor)

PREGNANCY RECOMMENDATION: Contraindicated

BREASTFEEDING RECOMMENDATION: Contraindicated

PREGNANCY SUMMARY

No reports describing the use of bosutinib in pregnancy have been located. The animal data cannot be interpreted because in one species inadequate doses were used and, in the other, fetal toxicity occurred with maternal toxic doses. Nevertheless, the manufacturer warns that the drug can cause fetal harm based on the drug’s mechanism of action (1). Thus, use of bosutinib should be avoided in pregnancy, especially during the 1st trimester.

FETAL RISK SUMMARY

Bosutinib is an oral tyrosine kinase inhibitor. There are several other agents in this subclass (see Appendix). Bosutinib is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive chronic myelogenous leukemia with resistance or intolerance of prior therapy. It is metabolized to inactive metabolites and is highly (96%) bound to plasma protein. The mean terminal phase elimination half-life is 22.5 hours (1).

Reproduction studies have been conducted in rats and rabbits. Rats were given daily oral doses during organogenesis that resulted in exposures that were about <3 times the human exposure at 500 mg/day based on AUC (HE). However, the study did not expose the rats to sufficient drug to fully evaluate adverse outcomes. In rabbits given daily doses during organogenesis, a maternal toxic dose that resulted in exposures that were about 4 times the HE, fetal anomalies (fused sternebrae and various visceral anomalies), and an approximate 6% decrease in fetal body weight were observed (1).

A 2-year carcinogenicity study in male and female rats was negative, as were tests and assays for mutagenic and clastogenic effects. Reduced fertility was observed in male rats given high doses of the drug that resulted in exposures about equal to the HE. Although fertility (number of pregnancies) was not affected in female rats, doses resulting in exposures less than the HE were associated with increased resorptions and decreased implantations and number of viable embryos (1).

It is not known if bosutinib crosses the human placenta. The molecular weight (about 530 for the anhydrous form) and long elimination half-life suggest that the drug will cross to the embryo–fetus. However, the high plasma protein binding might limit the exposure.

BREASTFEEDING SUMMARY

No reports describing the use of bosutinib during human lactation have been located. The molecular weight (about 530 for the anhydrous form) and long elimination half-life (22.5 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (96%) might limit the amount in milk. The effect on a nursing infant from this exposure is unknown. If a woman receiving the drug chooses to nurse, her infant should be closely monitored for the most common adverse effects observed in adults (diarrhea, nausea, vomiting, thrombocytopenia, abdominal pain, rash, anemia, pyrexia, and fatigue).

Reference

1.Product information. Bosulif. Pfizer, 2012.