Antineoplastic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Only one report describing the use of fludarabine in human pregnancy has been located. In that report, exposure occurred in the 2nd trimester and no fludarabine-induced toxicity was thought to have occurred. However, the animal reproduction data suggest risk if the drug is used during organogenesis. Thus, if indicated, avoiding exposure during the 1st trimester would be the best course. The manufacturer states that women of childbearing potential and fertile males must take contraceptive measures during and at least for 6 months after the cessation of therapy (1,2).
FETAL RISK SUMMARY
Fludarabine phosphate, available in oral and IV formulations, is a synthetic purine antimetabolite that is rapidly dephosphorylated in the plasma to an active metabolite. It is a fluorinated nucleotide analog of vidarabine. Fludarabine is in the same antineoplastic subclass of purine analogs and related agents as cladribine, clofarabine, mercaptopurine, pentostatin, and thioguanine. It is indicated as a single agent for the treatment of adult patients with B-cell chronic lymphocytic leukemia whose disease has not responded to or has progressed during or after treatment with at least one standard alkylating-agent containing regimen. Plasma protein binding of the active metabolite is about 19%–29% and the terminal half-life is about 20 hours (1,2).
Reproduction studies have been conducted in rats and rabbits. In rats during organogenesis, repeated IV doses that were 1.5 and 4.5 times the recommended human oral dose based on BSA (RHOD) caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and vertebrae deformities), and decreased body weights. The highest dose was maternal toxic (slight body weight decreases). In rabbits, repeated IV doses that were ≥0.3 times the RHOD were associated with a significant increase in malformations, including cleft palate, hydrocephaly, adactyly, brachydactyly, fusion of the digits, diaphragmatic hernia, heart and great vessel defects, and vertebrae and rib anomalies. At 2.4 times the RHOD, increases in embryo (increased resorptions) and fetal (decreased live fetuses) lethality were observed (1,2).
Studies for carcinogenesis have not been conducted. Both the parent drug and the active metabolite were clastogenic but not mutagenic. Fertility studies in mice, rats, and dogs have shown dose-related adverse effects on the male reproductive system that included decreases in testicular weights and degeneration and necrosis of spermatogenic epithelium in the testes (1,2).
It is not known if fludarabine crosses the human placenta. The molecular weights of the parent drug and active metabolite, 365 and 269, respectively, the low plasma protein binding, and the elimination half-life suggest that both compounds will cross to the embryo–fetus.
In a 2009 case report, a woman with relapse of acute myeloid leukemia at 22 weeks’ gestation was treated with fludarabine, cytarabine, mitoxantrone, idarubicin, and gemtuzumab ozogamicin (3). The fetus developed signs of idarubicin-induced cardiomyopathy, transient cerebral ventriculomegaly, anemia, and intrauterine growth restriction. The newborn, delivered at 33 weeks by cesarean section, showed no congenital malformations.
A 20-year-old woman with Fanconi anemia became pregnant 93 months after allogeneic stem cell transplantation from an unrelated donor (4). The preparative regimen for the transplantation consisted of fludarabine, cyclophosphamide, methotrexate, tacrolimus, and antithymocyte globulin. She gave birth at 38 weeks’ gestation to a normal, 2828-g male infant after an uncomplicated pregnancy.
BREASTFEEDING SUMMARY
No reports describing the use of fludarabine during human lactation have been located. The molecular weights of the parent drug and active metabolite, 365 and 269, respectively, the low plasma protein binding (19%–29%), and the elimination half-life (20 hours) suggest that both compounds will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, in patients treated with the drug, clinically significant toxicities were observed that involved the hematopoietic, nervous, pulmonary, gastrointestinal, cardiovascular, and genitourinary systems, as well as the skin. Taken in sum, the potential risks suggest that if a woman is receiving fludarabine, she should not breastfeed her infant.
References
1.Product information. Oforta. Sanofi-Aventis, 2009.
2.Product information. Fludarabine Phosphate. Antisoma Research Limited, 2009.
3.Baumgartner AK, Oberhoffer R, Jacobs VR, Ostermayer E, Menzel H, Voigt M, Schneider KT, Pildner von Steinburg S. Reversible foetal cerebral ventriculomegaly and cardiomyopathy under chemotherapy for maternal AML. Onkologie 2009;32:40–3.
4.Yabe H, Koike T, Shimizu T, Ishiguro H, Morimoto T, Hyodo H, Akiba T, Kato S, Yabe M. Natural pregnancy and delivery after unrelated bone marrow transplantation using fludarabine-based regimen in a Fanconi anemia patient. Int J Hematol 2010;91:350–1.