Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of sunitinib in human pregnancy have been located. The animal reproduction data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment. However, there are limited human pregnancy data for imatinib, a drug in the same subclass and with same mechanism of action as dasatinib. (See Imatinib.) Nevertheless, agents in this subclass inhibit angiogenesis, a critical component of embryonic and fetal development. Women of reproductive age should use effective contraception. However, gastrointestinal cancers can be fatal, so if a woman requires imatinib and informed consent is obtained, treatment should not be withheld because of pregnancy. If an inadvertent pregnancy occurs, the woman should be advised of the potential risk for severe adverse effects in the embryo and fetus.
FETAL RISK SUMMARY
Sunitinib is an oral tyrosine kinase inhibitor that inhibits tumor growth, pathologic angiogenesis, and metastatic progression of cancer. There are several other agents in this subclass (see Appendix). Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib. It is extensively metabolized by the liver. One of the metabolites is active and comprises 23%–37% of the total exposure. The terminal elimination half-lives of sunitinib and the active metabolite are 40–60 and 80–110 hours, respectively, whereas the binding to human plasma proteins is 95% and 90%, respectively. Elimination is primarily in the feces (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, doses producing systemic exposures that were about 5.5 times than the systemic exposure in humans from the recommended daily dose of 50 mg based on AUC (SE-RDD) caused significant increases in the incidences of embryo death and structural anomalies (malformations of the ribs and vertebrae). The no-effect exposure in rats was 2.3 times the SE-RDD. In pregnant rabbits, an exposure about 2.7 times the SE-RDD caused a significant increase in embryo death and in cleft lips and palates. A lower exposure, about 0.3 times the SE-RDD, caused cleft lip only (1).
Studies for carcinogenicity have not been conducted with sunitinib. The drug did not cause genotoxicity in multiple tests. In a 3-month study in monkeys, with a dose producing systemic exposures that were about 5.1 times the SE-RDD, ovarian changes (decreased follicular development) were noted, while an exposure about 0.4 times the SE-RDD caused uterine changes (endometrial atrophy). When the study period was lengthened to 9 months, an exposure 0.8 times the SE-RDD caused vaginal atrophy, as well as the ovarian and uterine changes. A no-effect dose was not determined in the 3-month study but, in the 9-month study, it was about 0.2 times the SE-RDD. No effects on fertility were observed in male and female rats (1).
It is not known if sunitinib or its active metabolite crosses the human placenta. The molecular weight (about 399 for the free base) of the parent compound and the long elimination half-lives for sunitinib and the metabolite suggest that the agents will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of sunitinib during human lactation have been located. The molecular weight (about 399 for the free base) of the parent compound and the long elimination half-lives for sunitinib and its active metabolite suggest that the agents will be excreted into breast milk. The risk to a nursing infant is unknown, but there is potential for severe toxicity affecting multiple systems.
Reference
1.Product information. Sutent. Pfizer, 2007.