Antineoplastic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of vorinostat in human pregnancy have been located. The animal reproductive data suggest risk, but the absence of human pregnancy experience prevents a more complete assessment of embryo–fetal risk. However, the drug probably crosses the placenta and exposure of the embryo and/or fetus should be expected. In addition, although there are no other agents in this antineoplastic subclass, there are other histone deacetylase inhibitors (e.g., valproic acid [1]). If a pregnant woman requires vorinostat, avoiding the 1st trimester and obtaining informed consent are recommended. In case of an inadvertent pregnancy, the woman should be advised of the potential risk for severe adverse effects in the embryo and fetus.
FETAL RISK SUMMARY
Vorinostat is an oral histone deacetylase inhibitor that is indicated for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent, or recurrent disease on or following two systemic therapies. It is given as a daily oral dose. Vorinostat is in the same antineoplastic subclass as romidepsin. The drug is extensively metabolized to two inactive metabolites. Plasma protein binding (71%) is moderate. The mean terminal elimination half-life of vorinostat and one metabolite is about 2 hours, but the half-life of the other inactive metabolite is about 11 hours (1).
Reproductive studies have been conducted in rats and rabbits. The highest dose tested in rats, exposures about half the human exposure based on AUC (HE), caused developmental toxicity consisting of decreased mean live fetal weights; incomplete ossifications of the fetal skull, thoracic vertebra, and sternebrae; and skeletal variations (cervical ribs, supernumerary ribs, vertebral count, and sacral arch variations). The highest dose tested in rabbits, also about half the HE, was associated with reductions in mean live fetal weight and an increased incidence of incomplete ossification of the metacarpals. The no-observed-effect level in rats and rabbits was <0.1 times the HE. However, a dose-related increase in the incidence of gall bladder malformations was observed in rabbits (1,2).
Studies for carcinogenicity have not been conducted with vorinostat, but the drug was mutagenic and clastogenic in tests. No effects on reproductive performance were noted in male rats given doses resulting in exposures up to about 0.70 times the HE for 70 days before mating. Female rats were given doses resulting in exposures up to about 0.70 times the HE for 14 days before mating and through day 7 of gestation. Dose-related increases in corpora lutea, peri-implantation losses, and incidences of dead fetuses and in resorptions were observed at exposures that were ≥0.15, ≥0.36, and 0.70 times the HE, respectively (1).
It is not known if vorinostat crosses the human placenta. The molecular weight (about 264) and moderate plasma protein binding suggest that the drug will cross the human placenta, but the short elimination half-life should decrease the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of vorinostat during human lactation have been located. The molecular weight (about 264) and moderate plasma protein binding (about 71%) suggest that the drug will be excreted into breast milk. However, the short elimination half-life (about 2 hours) should decrease the amount excreted. The potential effects on a nursing infant are unknown, but toxicity is possible. In adults, the most common adverse effects were gastrointestinal (diarrhea, nausea/vomiting, anorexia, weight decrease, constipation), fatigue, chills, hematologic (thrombocytopenia, anemia), and taste disorders (dysgeusia, dry mouth) (1).
References
1.Product information. Zolinza. Merck, 2006.
2.Wise LD, Turner KJ, Kerr JS. Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague-Dawley rats and Dutch belted rabbits. Birth Defects Res (Part B) 2007;80:57–68.