Bisphosphonate
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
One report has described the use of zoledronic acid use in human pregnancy. The animal data suggest risk, but the limited human pregnancy experience prevents a complete assessment of the embryo–fetal risk. The amount of zoledronic acid incorporated into bone and eventually released back into the systemic circulation is directly related to the total dose and duration of treatment. Because zoledronic acid probably crosses the placenta, the use of the drug shortly before or during gestation could expose the embryo and/or fetus to a potentially toxic agent. Thus, administration before pregnancy may result in low-level, continuous exposure throughout gestation. The use of zoledronic acid in women who may become pregnant or during pregnancy is not recommended. However, based on the animal and limited human data, inadvertent exposure during early pregnancy does not appear to represent a major risk to the embryo–fetus.
FETAL RISK SUMMARY
Zoledronic acid is given by IV infusion. It is indicated for the treatment of hypercalcemia of malignancy. Other agents in this pharmacologic class are alendronate, etidronate, ibandronate, pamidronate, risedronate, and tiludronate. Only about 3% of an oral dose is absorbed into the systemic circulation. Zoledronic acid is not metabolized, and plasma protein binding is only 22%. The postinfusion half-life in the plasma is 1.87 hours, whereas the terminal elimination half-life is 146 hours, correlating with the low concentrations in the plasma observed up to 28 days postdose (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, daily SC doses producing exposures 1.2, 2.4, and 4.8 times the human systemic exposure after an IV dose of 4 mg based on AUC (HSE) were associated with adverse fetal effects. At 1.2 times the HSE, fetal skeletal variations were noted. Doses producing exposures 2.4 and 4.8 times the HSE caused pre- and postimplantation losses; decreases in viable fetuses; and fetal skeletal, visceral, and external malformations. The fetal skeletal effects observed at 4.8 times the HSE were unossified or incompletely ossified bones; thickened, curved, or shortened bones; wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group were reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction or absence of lung lobes, vessel dilation, cleft palate, and edema, but maternal toxicity (reduced body weight and food consumption) also was observed (1).
In female rats given SC doses producing exposures ≥ 0.2 times the HSE for 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased. Higher exposure (1.2 times the HSE) inhibited ovulation, resulting in a decrease in the number of pregnant rats. Maternal toxicity (dystocia and periparturient mortality) was observed at all exposures ≥ 0.7 times the HSE. This toxicity was thought to be secondary to drug-induced inhibition of skeletal calcium mobilization, resulting in hypocalcemia, a bisphosphonate class effect (1).
In pregnant rabbits, SC doses resulting in exposures ≤ 0.5 times the HSE did not cause fetal harm. However, exposures >0.05 times the HSE were associated with maternal mortality and abortion in all treatment groups. The maternal toxicity may have been caused by drug-induced hypocalcemia (1).
Long-term carcinogenicity studies with oral zoledronic acid were positive in male and female mice but not in rats. Various assays for mutagenicity were negative (1).
It is not known if zoledronic acid crosses the human placenta. The molecular weight (about 290 for the hydrated form), lack of metabolism, low plasma protein binding, plasma half-life, and the prolonged terminal elimination half-life all suggest that exposure of the embryo and/or fetus will occur. Moreover, detectable amounts of the drug can be measured in plasma for up to 28 days postdose (1).
A 33-year-old woman with metastatic breast cancer was treated with zoledronic acid (two IV courses 28 days apart; dose not specified) and tamoxifen in the 2nd and 3rd trimesters (2). She also received five cycles of 5-fluorouracil, epirubicin, and cyclophosphamide before conception and during the 1st trimester, as well as radiotherapy at 17 weeks’ gestation. Her pregnancy was diagnosed at 28 weeks. A cesarean section at 35 weeks’ delivered a 2070-g female infant with Apgar scores of 10 at 1 and 5 minutes, respectively. All hematologic and biochemistry parameters were normal for age. The healthy infant apparently was developing normally at 12 months of age (2).
A 2008 review described 51 cases of exposure to bisphosphonates before or during pregnancy: alendronate (N = 32) pamidronate (N = 11), etidronate (N = 5), risedronate (N = 2), and zoledronic acid (N = 1) (3). They concluded that although these drugs may affect bone modeling and development in the fetus, no such toxicity has yet been reported.
BREASTFEEDING SUMMARY
No reports describing the use of zoledronic acid during human lactation have been located. The molecular weight (about 290 for the hydrated form), lack of metabolism, low plasma protein binding, plasma half-life, and the prolonged terminal elimination half-life suggest that the drug will be excreted into breast milk. Detectable amounts of the drug are measured in adult plasma for up to 28 days postdose (1). Although the low lipid solubility of zoledronic acid may limit the amount present in milk, and maternal treatment may be compatible with nursing, the best course is to not breastfeed until data are available.
References
1.Product information. Zometa. Novartis Pharmaceuticals, 2006.
2.Andreadis C, Charalampidou M, Diamantopoulos N, Chouchos N, Mouratidou D. Combined chemotherapy and radiotherapy during conception and first two trimesters of gestation in a woman with metastatic breast cancer. Gynecol Oncol 2004;95:252–5.
3.Djokanovic N, Klieger-Grossmann C, Koren G. Does treatment with bisphosphonates endanger the human pregnancy? J Obstet Gynaecol Can 2008;30:1146–8.