Antineoplastic
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of romidepsin in human pregnancy have been located. Only one animal species was tested and a slight decrease in fetal weight was observed. The study did not expose pregnant rats to enough of the drug to evaluate adverse outcomes fully (1). Romidepsin competes with β-estradiol for binding to estrogen receptors. Because estrogen is required to maintain pregnancy throughout gestation, the competition between romidepsin and β-estradiol could cause pregnancy loss. Moreover, romidepsin may reduce the effectiveness of estrogen-containing contraceptives.
FETAL RISK SUMMARY
The antineoplastic romidepsin, a histone deacetylase inhibitor, is administered as an IV infusion on days 1, 8, and 15 of a 28-day cycle. It is in the same subclass as vorinostat. Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. The drug competes with β-estradiol for binding to estrogen receptors and may reduce the effectiveness of estrogen-containing contraceptives. Romidepsin undergoes extensive metabolism. Plasma protein binding is high (92%–94%), primarily to α1-acid-glycoprotein, and the terminal half-life is about 3 hours. No accumulation in the plasma was observed after repeated dosing (1).
A reproduction study was conducted in rats. During organogenesis, rats were given daily IV doses up to about 18% of the estimated human daily dose based on BSA. This dose resulted in a 5% reduction in fetal weight. However, embryo–fetal toxicities and other adverse developmental outcomes were not adequately assessed in this study (1).
Carcinogenicity studies have not been conducted. The drug was not mutagenic or clastogenic in various assays. Romidepsin caused impaired fertility in rats and mice. In male rats and mice, at exposures much less than those obtained in humans, the drug caused testicular degeneration. In addition, seminal vesicle and prostate organ weights were decreased in male rats. In female rats, atrophy was observed in the ovary, uterus, vagina, and mammary gland, as well as maturation arrest of ovarian follicles and decreased weight of ovaries. These toxicities occurred at doses and systemic exposures that were a small fraction of the human dose and exposure and probably resulted from the drug’s high affinity for binding to estrogen receptors (1).
It is not known if romidepsin crosses the human placenta. The molecular weight (about 541) and the elimination half-life suggest that the drug will cross, but the high plasma protein binding may limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of romidepsin during human lactation have been located. The molecular weight (about 541) and the elimination half-life (3 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (92%–94%) might limit the amount excreted. The effect of this exposure on a nursing infant is unknown but the potential for severe toxicity is a concern. Because the drug caused a wide-range of toxicity in adults that involved many systems (e.g., gastrointestinal, CNS, hematologic) and competes with β-estradiol for binding to estrogen receptors, mothers should not breastfeed while receiving this drug. However, the elimination half-life and the dosing schedule (IV infusion over 4 hours on days 1, 8, and 15 of a 28-day cycle) might allow breastfeeding on the days a dose is not given. If this strategy is chosen, the mother should “pump and dump” to maintain milk production and decrease discomfort from engorgement for at least 15 hours (i.e., five half-lives would allow about 97% of the drug to be eliminated from her blood) after the end of the infusion.
Reference
1.Product information. Istodax. Gloucester Pharmaceuticals, 2009.