Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of nilotinib in human pregnancy have been located.
In animal studies, developmental toxicity (embryo–fetal death) without maternal toxicity was observed in one species. The absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. However, the drug should be avoided in pregnancy. If it must be given for the mother’s benefit, avoiding the 1st trimester should be considered.
FETAL RISK SUMMARY
Nilotinib is an oral tyrosine kinase inhibitor. It is in the same subclass as several other agents (see Appendix). Nilotinib is indicated for the treatment of chronic-phase and accelerated-phase Philadelphia chromosome-positive chronic myelogenous leukemia in adults resistant to or intolerant to prior therapy that include imatinib. It is metabolized to inactive metabolites. Serum protein binding is about 98%, and the apparent elimination half-life is about 17 hours (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, doses producing systemic exposures that were about ≥1.7 times the exposure (AUC) from the recommended human dose (RHD) resulted in increased resorptions and postimplantation losses. Maternal toxicity (decreased body weight, uterine weight, weight gain, and food consumption) was evident at exposures that were about 5.7 times the RHD. At this exposure, there was a decrease in viable fetuses. In pregnant rabbits, a dose about half of the RHD was maternal toxic (death and decreased weight and food consumption) and was associated with embryo death (resorptions) and minor skeletal anomalies. Nilotinib did not cause structural anomalies in these two species (1).
Carcinogenicity studies have not been conducted with nilotinib. The drug was not mutagenic or clastogenic in multiple assays. Nilotinib had no effect on mating or fertility in male and female rats at doses up to about 4–7 times the RHD or in female rabbits at doses that were about half the RHD. When male and female rats were given doses that were about 1–6.6 times the RHD during pre-mating and mating and then continued in pregnant rats through gestation day 6, there was an increase in postimplantation loss and early resorption, and a decrease in the number of viable fetuses and litter size at all doses tested (1).
It is not known if nilotinib crosses the human placenta. Although the serum protein binding is high, the molecular weight (about 512 for the nonhydrated free base) and long elimination half-life suggest that the drug will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of nilotinib during human lactation have been located. Although the serum protein binding (98%) is high, the molecular weight (about 512 for the nonhydrated free base) and long elimination half-life (about 17 hours) suggest that the drug will be excreted into breast milk. The effects of this exposure on a nursing infant are unknown, but there is potential for severe toxicity based on the adult data. The most common adverse reactions in adults were rash, pruritus, nausea, vomiting, fatigue, headache, and constipation and/or diarrhea. Thrombocytopenia and neutropenia also have been observed (1). Because of the risk, women receiving nilotinib should not breastfeed.
Reference
1.Product information. Tasigna. Novartis Pharmaceuticals, 2007.