Antineoplastic (Miscellaneous)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of vismodegib in human pregnancy have been located. In the one animal species studied, the drug caused embryo and fetal death, as well as structural anomalies at systemic exposures that were close to or below the predicted human exposure. The absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. In clinical trials in women of reproductive potential, amenorrhea has been observed (1). The manufacturer recommends a negative pregnancy test within 7 days before starting therapy and a highly effective form of contraception before the first dose and for 7 months after the last dose.
FETAL RISK SUMMARY
Vismodegib is an inhibitor of the Hedgehog pathway that is given orally. It is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advance basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. The drug undergoes limited metabolism with >98% of the total circulating drug-related components being the parent drug. Plasma protein binding to albumin and α1-acid-glycoprotein is high (>99%) and the elimination half-life is 4 days (1).
Reproduction studies have been conducted in rats. In this species, oral doses that resulted in exposures that were about ≥2 times the systemic exposure at the recommended dose based on AUC (SERD) caused preimplantation and postimplantation losses, which included early resorption of 100% of the fetuses. Exposures that were about 0.2 times the RD resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws).
Carcinogenicity studies have not been conducted. Vismodegib was not mutagenic or clastogenic in multiple assays. Fertility impairment studies have not been done. However, data from repeat-dose toxicology studies in rats and dogs indicated that the drug may impair male and female reproductive function and fertility (1).
It is not known if vismodegib crosses the human placenta. The molecular weight (about 421) and long elimination half-life suggest that the drug will cross to the embryo–fetus, but the high plasma protein binding might limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of vismodegib during human lactation have been located. The molecular weight (about 421) and long elimination half-life (4 days) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (>99%) might limit the exposure. The effect of the exposure on a nursing infant is unknown. Some of the most common adverse reactions (≥10%) in adults were muscle spasms, alopecia, diarrhea or constipation, nausea, vomiting, weight loss, decreased appetite, and fatigue. If a woman receiving the drug chooses to breastfeed, her infant should be closely monitored for these effects.
Reference
1.Product information. Erivedge. Genentech USA, 2012.