se group included 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 included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2times the human systemic exposure following an intravenous dose of 4mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.
In pregnant rabbits given subcutaneous doses of zoledronicacid of 0.01, 0.03, or 0.1mg/kg/day during gestation (≤0.5times the human intravenous dose of 4mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05times the human intravenous dose of 4mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.
8.3 Nursing Mothers
It is not known whether zoledronic acid is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zometa, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.
8.4 Pediatric Use
Zometa is not indicated for use in children.
The safety and effectiveness of zoledronicacid was studied in a one-year active-controlled trial of 152pediatric subjects (74receiving zoledronicacid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55%male, 84%Caucasian, with a mean lumbar spine BMD of 0.431gm/cm2, which is 2.7standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronicacid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zometa use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy or bone metastases. However, adverse reactions seen more commonly in pediatric patients included pyrexia(61%), arthralgia(26%), hypocalcemia(22%) and headache(22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zometa should only be used in children if the potential benefit outweighs the potential risk.
Plasma zoledronicacid concentration data was obtained from 10patients with severe osteogenesis imperfecta (4in the age group of 3-8 years and 6in the age group of 9-17 years) infused with 0.05mg/kg dose over 30min. Mean Cmax and AUC(0-last) was 167ng/mL and 220ng.h/mL, respectively. The plasma concentration time profile of zoledronicacid in pediatric patients represent a multi-exponential decline, as observed in a
