Antineoplastic (Alkylating Agent)
PREGNANCY RECOMMENDATION: Contraindicated—1st Trimester
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of the alkylating antineoplastic agent bendamustine in human pregnancy have been located. Other agents in this class (see below) are known to cause human teratogenicity and, combined with the animal data strongly suggest that bendamustine should not be given in the 1st trimester. If a woman is inadvertently exposed to the drug during the 1st trimester, she should be informed of the potential risk.
FETAL RISK SUMMARY
Bendamustine is an alkylating antineoplastic agent that is a bifunctional mechlorethamine derivative given by IV infusion. It is in the same subclass of antineoplastics as busulfan, chlorambucil, cyclophosphamide, carmustine, dacarbazine, ifosfamide, mechlorethamine, melphalan, and streptozocin. Bendamustine is indicated for the treatment of patients with chronic lymphocytic leukemia. It also is indicated for indolent B-cell non-Hodgkin’s lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Bendamustine is metabolized to two minor active metabolites (M3 and M4) that have low plasma concentrations (10% and 1% of the parent compound concentrations, respectively). Plasma protein binding of bendamustine is 94%–96%. The elimination half-lives of the parent compound and the two active metabolites are about 40 minutes, 3 hours, and 30 minutes, respectively (1).
Reproduction studies have been conducted in mice and rats. In mice, an intraperitoneal dose about 2.1 times the recommended human dose based on BSA (RHD) given during organogenesis caused an increase in resorptions, decreased fetal body weights, and skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities). The dose did not cause apparent maternal toxicity. Repeat intraperitoneal dosing on gestational days 7–11 resulted in increased resorptions and similar malformations. In rats, intraperitoneal doses about 1.2 times the RHD given 5 times during gestational days 4–13 caused embryo and fetal death. A significant increase also was observed in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations (1).
Bendamustine was carcinogenic in mice, producing peritoneal sarcomas in females after 4 days of intraperitoneal injections and mammary carcinomas and pulmonary adenomas after 4 days of oral dosing. The drug also was mutagenic and clastogenic in several assays. In human males, impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported after treatment with other alkylating agents and might occur with bendamustine (1).
Although it is apparent that bendamustine crosses the placenta in animals, it is not known if it or the active metabolites cross the human placenta. The molecular weight of the parent compound (about 359 for the free base) is low enough for passage, but the short elimination half-life combined with high plasma protein binding should reduce the amount transferred to the embryo or fetus. A similar conclusion can be reached for M4, which has a shorter half-life and a serum concentration that is only 1% of the parent compound’s concentration. M3 has a longer half-life and its serum concentration is 10% of the parent compound’s concentration.
Occupational exposure of the mother to antineoplastic agents during pregnancy may present a risk to the fetus. A position statement from the National Study Commission on Cytotoxic Exposure and a research article involving some antineoplastic agents are presented in the monograph for cyclophosphamide. (See Cyclophosphamide.)
BREASTFEEDING SUMMARY
No reports describing the use of bendamustine during human lactation have been located. The molecular weight of the parent compound (about 359 for the free base) and the presence of two active metabolites suggest that excretion into breast milk will occur. Because of the potential for serious toxicity in a nursing infant, breastfeeding should be discontinued while the mother is receiving therapy. Pumping and discarding the milk for at least 24 hours after a dose should prevent exposure of the nursling.
Reference
1.Product information. Treanda. Cephalon, 2008–2009.