Antineoplastic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of ixabepilone in human pregnancy have been located. Teratogenicity was not observed in two animal species. However, embryo death (in the absence of maternal toxicity) was noted in one species. Because of maternal toxicity, the highest doses that could be given were about 10% of the human exposure or dose. The absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk, but the drug should be avoided in pregnancy. If it must be administered for the mother’s benefit, avoiding the 1st trimester should be considered.
FETAL RISK SUMMARY
Ixabepilone is a semisynthetic analog of epothilone B, a polypeptide macrolide isolated from the myxobacterium Sorangium cellulosum. There are no other agents in this antineoplastic subclass. Ixabepilone is a microtubule inhibitor that is given as an IV infusion every 3 weeks. It is indicated in combination with capecitabine (see Capecitabine) for the treatment of metastatic or locally advanced breast cancer resistant to an anthracycline and a taxane, or in patients whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. It also is indicated as monotherapy for the treatment of metastatic or locally advanced breast cancer resistant to anthracyclines, taxanes, and capecitabine. The drug is extensively metabolized in the liver to inactive compounds. Binding to human serum proteins ranges between 67% and 77%, and the terminal elimination half-life is about 52 hours (1).
Reproductive studies have been conducted in rats and rabbits. No teratogenic effects were observed in rats with doses producing exposures up to about 0.1 times the human clinical exposure based on AUC (HCE). The highest dose was maternal toxic and resulted in fetal death and decreased fetal weight. In rabbits, no teratogenicity was observed at doses up to about 0.1 times the human clinical dose based on BSA, but maternal and fetal toxicity (death in both) was noted at the highest dose (1).
Carcinogenicity studies with ixabepilone have not been conducted. The drug was not mutagenic in one assay but was clastogenic in one of two tests. No effect on the fertility of male and female rats was observed with doses producing exposures that were about 0.07 times the HCE. However, when female rats were given an IV infusion at this dose during breeding and through the first 7 days of gestation, a significant increase in resorptions and pre- and postimplantation loss, and a decrease in the number of corpora lutea were observed. Testicular atrophy or degeneration was observed in male rats when IV doses that were 2.1 times the HCE were given every 21 days for 6 months. Similar toxicity was observed in male dogs when IV doses that were ≥0.2 times the HCE were given every 21 days for 9 months (1).
It is not known if ixabepilone crosses the human placenta. The molecular weight (about 507), the moderate serum protein binding, and the very long elimination half-life suggest that the drug will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of ixabepilone during human lactation have been located. The molecular weight (about 507), the moderate serum protein binding (67%–77%), and the very long elimination half-life (about 52 hours) suggest that the drug will be excreted into breast milk. The effects of this exposure on a nursing infant are unknown, but there is potential for severe toxicity. The most common adverse reactions in adults were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain (1). Because of the risk, women receiving ixabepilone should not breastfeed.
Reference
1.Product Information. Ixempra. Bristol-Myers Squibb, 2007.