PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
No reports describing the use of clofarabine in human pregnancy have been located. The animal pregnancy data suggest risk, as does the potential for impaired fertility. The absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Women of reproductive age should use effective contraceptive methods to prevent pregnancy while receiving this drug (1). However, lymphoblastic leukemia is a potential fatal disease. Thus, if a woman does conceive and informed consent is obtained, clofarabine should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Clofarabine is a purine nucleoside antimetabolite antineoplastic that is sequentially metabolized intracellularly to the active 5′-triphosphate metabolite that inhibits DNA synthesis. The drug is classified as an antimetabolite in the same subclass of purine analogs and related agents as cladribine, fludarabine, pentostatin, mercaptopurine, and thioguanine. Clofarabine is indicated for the treatment of pediatric patients (1–21 years of age) with relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. Plasma protein binding, primarily to albumin, is 47%. The terminal half-life is about 5.2 hours with 49%–60% of the drug excreted unchanged in the urine within 24 hours (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats and rabbits, doses that were about equal to and 0.23 times, respectively, the recommended human clinical dose based on BSA (RHCD) resulted in increased incidences of malformations and variations (gross external, soft tissue, skeletal and retarded ossification) and developmental toxicity (reduced fetal body weight and increased postimplantation loss) (1).
Studies for carcinogenicity have not been conducted with clofarabine. Although not mutagenic in one assay, the drug was clastogenic in two assays. Fertility studies have been conducted in mice, rats, and dogs. Toxicity was observed in male reproductive organs in these species at doses that were about 0.17, 3, and 0.14 times, respectively, the RHCD. In female mice, a dose 4 times the RHCD resulted in ovarian atrophy or degeneration and uterine mucosal apoptosis (1).
It is not known if clofarabine crosses the human placenta. The molecular weight (about 304), plasma protein binding, and elimination half-life suggest that exposure of the embryo and fetus will occur.
No reports describing the use of clofarabine during human lactation have been located. The molecular weight (about 304), plasma protein binding (47%), and elimination half-life (5.2 hours) suggest that the drug will be excreted into breast milk. The effects of this exposure on a nursing infant are unknown, but severe toxicity potentially involving multiple systems throughout the body is a concern. Thus, the best course is to not breastfeed while receiving clofarabine therapy.
1.Product information. Clolar. Genzyme, 2007.