Antineoplastic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of capecitabine during human pregnancy have been located. Studies have observed developmental toxicity in mice (structural anomalies and death) and rabbits (death) at systemic exposures less than those observed with the maximum recommended dose in humans. The drug is converted intracellularly to the active metabolite 5-FU. Although there are no human pregnancy data, capecitabine should be avoided in pregnancy. If it must be used for the mother’s benefit, consideration should be given to avoiding the period of organogenesis.
FETAL RISK SUMMARY
Capecitabine, a fluoropyrimidine carbamate, is an oral prodrug that, upon absorption from the gut, is converted in the liver to a precursor (5′-DFUR) of 5-fluorouracil (5-FU). The final metabolic step to 5-FU, the active agent, occurs in tumor and normal cells. (See also Fluorouracil.) Capecitabine is classified as an antimetabolite in the subclass of pyrimidine analogs. In addition to fluorouracil, other antineoplastic agents in the subclass are cytarabine, floxuridine, and gemcitabine. Capecitabine is indicated for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor, as first-line treatment of patients with metastatic colorectal carcinoma, and, either alone or in combination (see Ixabepilone) in some cases of breast cancer. Plasma protein binding of capecitabine and its metabolites is low (<60%). The elimination half-life of capecitabine and 5-FU is very short (about 0.75 hours) (1).
Reproduction studies have been conducted in mice and monkeys. During organogenesis in mice, a dose that resulted in systemic exposures of 5′-DFUR AUC that were about 0.2 times the human exposure from the recommended daily dose (HERDD) produced cleft palate, anophthalmia, microphthalmia, oligodactyly, polydactyly, syndactyly, kinky tail, and dilation of cerebral ventricles. In monkeys, during organogenesis, a dose that resulted in systemic exposures of 5′-DFUR AUC that were about 0.6 times HERDD caused fetal death (1).
The carcinogenic potential of capecitabine has not been evaluated. The drug was not mutagenic in two assays but was clastogenic in one test. However, 5-FU causes mutations in bacteria and yeast and chromosomal abnormalities in mice. In mice, a capecitabine dose resulting in exposures that were about 0.7 times the HERDD caused a reversible decrease in fertility in females and degenerative changes in the testes of males. No fetuses survived this dose in mice that became pregnant (1).
It is not known if capecitabine or the precursor 5′-DFUR crosses the human placenta. The molecular weight of capecitabine (about 359) and the low plasma protein binding suggest that the drug will cross to the embryo–fetus, but the very short elimination half-life should limit the exposure. The molecular weight of 5′-DFUR was not specified, but if it or the parent drug were to cross the placenta, intracellular metabolism in normal tissues could expose the embryo–fetus to 5-FU.
BREASTFEEDING SUMMARY
No reports describing the use of capecitabine during human lactation have been located. The molecular weight of capecitabine (about 359) and the low plasma protein binding (<60%) of capecitabine and 5′-DFUR (molecular weight not specified) suggest that the drugs will be excreted into breast milk, but the very short elimination half-life of capecitabine (about 0.75 hours; unspecified for 5′-DFUR) should limit the exposure. The effects of this exposure on a nursing infant are unknown. However, metabolism of the parent drug and the precursor would expose the infant to 5-FU. The mother should not breastfeed if she is being treated.
Reference
1.Product information. Xeloda. Roche Laboratories, 2006.