Antineoplastic Cytoprotectant
PREGNANCY RECOMMENDATION: Compatible—Maternal Benefit >> Embryo–Fetal Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of dexrazoxane in human pregnancy have been located. Developmental toxicity was observed in two animal species, but the doses studied were greater than the dose causing maternal toxicity. Nevertheless, the absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. However, dexrazoxane is intended to protect the patient from doxorubicin-induced cardiomyopathy. Thus, if a pregnant woman requires dexrazoxane and gives informed consent, the maternal benefit from the drug appears to outweigh the potential embryo–fetal risk. If inadvertent exposure occurs during pregnancy, the woman should be advised of the potential risk for adverse effects in the embryo and fetus.
FETAL RISK SUMMARY
Dexrazoxane, a cyclic derivative of ethylenediaminetetraacetic acid (EDTA) that readily penetrates cell membranes, is given as an IV dose immediately prior to a dose of doxorubicin. It is indicated for reducing the incidence and severity of cardiomyopathy associated with doxorubicin in women with metastatic breast cancer who have received a cumulative doxorubicin dose of 300 mg/m2 and who will continue to receive doxorubicin therapy to maintain tumor control. Dexrazoxane is partially metabolized to inactive metabolites and is not bound to plasma proteins. The mean dose-related plasma elimination half-lives were 2.1 and 2.5 hours (1).
Reproduction studies have been conducted in rats and rabbits, but the route of administration was not specified in either species. Maternal toxicity was observed in pregnant rats given a dose that was about 0.025 times the human dose based on BSA (HD). When given daily to rats during organogenesis, a dose that was about 0.1 times the HD was embryotoxic and teratogenic. Teratogenic effects were imperforate anus, microphthalmia, and anophthalmia. In rabbits, a daily dose during organogenesis that was about 0.1 times the HD caused maternal toxicity. A higher dose, about 0.5 times the HD, was embryotoxic and teratogenic, including skeletal malformations (short tail, rib, and thoracic defects), soft tissue variations (subcutaneous, eye, and cardiac hemorrhagic areas), and agenesis of the gallbladder and of the intermediate lobe of the lung (1).
Long-term studies for carcinogenic potential have been conducted. Dexrazoxane was not mutagenic in one test but was clastogenic in two other tests. Fertility was impaired in mature male and female rats exposed in utero during organogenesis to doses that were about 0.1 times the HD. Testicular atrophy was observed in rats given a dose that was about 0.33 times the HD for 6 weeks, and in dogs given a dose about equal to the HD for 13 weeks (route of administration not specified) (1).
It is not known if dexrazoxane crosses the human placenta. The molecular weight (about 268), lack of plasma protein binding, and elimination half-life suggest that the drug will cross to the embryo and/or fetus.
BREASTFEEDING SUMMARY
No reports describing the use dexrazoxane during human lactation have been located.
The molecular weight (about 268), lack of plasma protein binding, and elimination half-life (2.1 or 2.5 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, because the drug is given as a short IV infusion immediately before doxorubicin, and breastfeeding would be unlikely at this time, the risk of exposing an infant to dexrazoxane when nursing is later resumed appears to be nil.
Reference
1.Product information. Zinecard. Pharmacia & Upjohn, 2007.