Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of pazopanib in human pregnancy have been located. The animal reproduction data suggest risk because developmental toxicity (growth restriction, structural anomalies, and death) was observed in two species at systemic exposures that were much lower than those in humans. The absence of human pregnancy experience prevents a full assessment of the embryo–fetal risk. The manufacturer advises women to avoid becoming pregnant while taking pazopanib (1). However, renal cell carcinoma may be fatal without appropriate treatment. If a woman becomes pregnant while receiving everolimus she should be advised of the potential for embryo–fetal harm. If possible, avoiding the 1st trimester should be considered.
FETAL RISK SUMMARY
Pazopanib is a tyrosine kinase inhibitor antineoplastic that is available as oral tablets. It is indicated for the treatment of advanced renal cell carcinoma. Pazopanib is in the same subclass as several other agents (see Appendix). The drug is metabolized, but the activity of the metabolites (assumed to be inactive) was not stated. Plasma protein binding is >99% and the mean elimination half-life is about 31 hours (1).
Reproduction studies have been conducted in rats and rabbits. In rats, doses given during organogenesis that resulted in exposures that were about 0.1 times the human clinical exposure based on AUC (HCE) caused cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossification. Other toxicities were reduced fetal body weight, and pre- and postimplantation embryolethality. In rabbits, doses resulting in exposures that were about 0.007 times the HCE caused maternal toxicity (reduced food consumption, increased postimplantation loss, and abortion). At 0.02 times the HCE, severe maternal body weight loss and 100% litter loss were observed. Fetal body weight was reduced at a dose 1% (AUC not calculated) of the dose causing 100% litter loss (1).
Carcinogenicity studies have not been conducted, but in a 13-week mouse study, proliferative lesions in the liver including eosinophilic foci in two females and a single case of adenoma in another female were noted. The drug was not mutagenic or clastogenic in various assays. In female fats, various doses all resulting in exposures less than the HCE, caused decreased fertility, increased pre- and postimplantation losses, and decreased fetal body weight. Decreased corpora lutea and increased cysts were noted in mice given a dose that was about 1.3 times the HCE for 13 weeks, and in a 26-week study, ovarian atrophy was seen in rats at a dose that was about 0.85 times the HCE. Decreased corpora lutea were also noted in monkeys given a dose that was about 0.4 times the HCE for up to 34 weeks. The drug did not affect mating or fertility in male rats, but did cause decreases in sperm production and concentrations, as well as decreased testicular and epididymal weights. In a 6-month toxicity study with male rats, atrophy and degeneration of the testes with aspermia, hypospermia, and cribiform change in the epididymis were observed (1).
It is not known if pazopanib crosses the human placenta. The molecular weight (about 438 for the free base) and long elimination half-life suggest that the drug will cross, but the high plasma protein binding might limit the amount crossing.
BREASTFEEDING SUMMARY
No reports describing the use of pazopanib during human lactation have been located. The molecular weight (about 438 for the free base) and long elimination half-life (about 31 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (>99%) might limit the amount. The effect of this exposure on a nursing infant is unknown. In adults, adverse reactions occurring in ≥10% of patients were diarrhea, hypertension, hair color changes, nausea and vomiting, anorexia, fatigue, asthenia, abdominal pain, and headache. Other serious toxicities, such as hepatotoxicity, were also observed (1). Because the potential for severe toxicity in a nursing infant is a concern, women receiving pazopanib should not breastfeed.
Reference
1.Product information. Votrient. GlaxoSmithKline, 2009.