Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of ziv-aflibercept in human pregnancy have been located. Animal reproduction data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment of embryo–fetal risk. However, ziv-aflibercept is given in combination with two other antineoplastics and the three agents potentially could cause embryo–fetal harm. In addition, ziv-aflibercept has caused reversible impaired fertility in male and female cynomolgus monkeys at systemic exposures that were less than those obtained in humans. Taken in sum, the drug should be considered contraindicated in pregnancy. Moreover, the manufacturer recommends that females and males of reproductive potential should use highly effective contraception during treatment and up to a minimum of 3 months after the last dose (1).
FETAL RISK SUMMARY
Ziv-aflibercept, a dimeric glycoprotein, is a recombinant fusion protein that binds to vascular endothelial growth factor-A (VEGF-A). It is indicated, in combination with 5-fluorouracil, leuvovorin, and irinotecan, for patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen (see also Fluorouracil, Irinotecan, and Leuvovorin). The metabolism and plasma protein binding were not specified, but the elimination half-life of free ziv-aflibercept was about 6 days (range 4–7 days) (1).
Reproduction studies have been conducted in rabbits. In this species, IV doses that resulted in systemic exposures that were about ≥30% of the AUC in patients at the recommended dose, given every 3 days during organogenesis resulted in adverse embryo–fetal effects. These effects included increased incidences of postimplantation losses and external (anasarca, umbilical hernia, diaphragmatic hernia and gastroschisis, cleft palate, ectrodactyly, and atresia), visceral (great vessels and arteries in the heart), and skeletal fetal anomalies (fused vertebrae, sternebrae, and ribs; supernumerary arches and ribs, and incomplete ossification). The incidence and severity of fetal anomalies increased with increasing dose (1).
Studies for carcinogenicity and mutagenicity have not been conducted. In sexually mature young cynomolgus monkeys given IV doses that were about ≥60% of the AUC in patients at the recommended dose every 2 weeks for 6 months, impaired reproductive function was noted at all doses tested. In females, the drug inhibited ovarian function and follicular development as shown by decreased ovary weight, amount of luteal tissue, and number of maturing follicles; atrophy of uterine endometrium and myometrium, vaginal atrophy, abrogation of progesterone peaks and menstrual bleeding. In males, alterations in sperm morphology and decreased sperm motility were noted. All of these effects were reversible within 18 weeks after cessation of therapy (1).
It is not known if free ziv-aflibercept crosses the human placenta. The molecular weight (about 115,000) suggests that it will not cross, at least early in gestation, but the elimination half-life is very long. Moreover, the drug did cause embryo–fetal toxicity in rabbits during organogenesis.
BREASTFEEDING SUMMARY
No reports describing the use of ziv-aflibercept during human lactation have been reported. The molecular weight (about 115,000) suggests that it will not be excreted into mature milk, but it probably will be excreted during the colostral period. However, the drug is given in combination with 5-fluorouracil, leuvovorin, and irinotecan (see also these three agents) and the two antineoplastic agents are probably excreted into breast milk. Consequently, breastfeeding should be considered contraindicated if a woman is receiving this combined therapy.
Reference
1.Product information. Zaltrap. Regeneron Pharmaceuticals, 2012.