Reproduction toxicity studies with pamidronate.

Peroral Segment I, II and III reproduction toxicity studies in rats and peroral Segment II studies in rabbits were conducted with pamidronate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate, CGP 23339 A, CAS 57248-88-1). In addition, intravenous Segment II studies were carried out in rats and rabbits. Only about 2% of a peroral dose of pamidronate is absorbed from the gastro-intestinal tract. However, with both modes of administration, it was evident that after equivalent dosing peroral and parenteral studies yielded similar results. The most relevant consistent findings in the rat were failure of the dams to complete and/or survive a protracted parturition and a reduced number of viable pups. There was evidence that the distressed state of the dams shortly before parturition was associated with acutely reduced serum calcium concentrations. In both species, at daily doses about ten times higher than the recommended human therapeutic dose, maternal toxicity, embryolethality or severe general underdevelopment and a marked skeletal retardation of the fetuses were observed. There was no evidence that pamidronate has a teratogenic potential, nor did it affect reproductive performance. Nevertheless, in view of the effects of pamidronate on parturition and the fact that it crosses the placenta and binds to fetal bone, use of the drug in pregnancy should be avoided unless there is a life-saving medical need.