Race

Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and NorthAmerican (Caucasian and AfricanAmerican) patients with cancer and bone metastases.

Hepatic Insufficiency

No clinical studies were conducted to eva luate the effect of hepatic impairment on the pharmacokinetics of zoledronicacid.

Renal Insufficiency

The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for Zometa in patients with severe renal impairment (creatinine clearance less than 30mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:
CrCl = [140-age (years)] x weight (kg){x 0.85 for female patients}
[72 x serum creatinine (mg/dL)]

Zometa systemic clearance in individual patients can be calculated from the population clearance of Zometa, CL(L/h)=6.5(CLcr/90)0.4. These formulae can be used to predict the Zometa AUC in patients, where CL=Dose/AUC0-∞. The average AUC0-24 in patients with normal renal function was 0.42mg•h/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75mL/min was 0.66mg•h/L following a 4-mg dose of Zometa. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed [see Warnings And Precautions(5.2)].

13NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of zoledronicacid of 0.1, 0.5, or 2.0mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (at doses ≥0.002times a human intravenous dose of 4mg, based on a comparison of relative body surface areas). Rats were given oral doses of zoledronicacid of 0.1, 0.5, or 2.0mg/kg/day. No increased incidence of tumors was observed (at doses ≤0.2times the human intravenous dose of 4mg, based on a comparison of relative body surface areas).

Zoledronicacid was not genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese hamster gene mutation assay, with or without metabolic activation. Zoledronicacid was not genotoxic in the in-vivo rat micronucleus assay.

Female rats were given subcutaneous doses of zoledronicacid of 0.01, 0.03, or 0.1mg/kg/day beginning 15days before mating and continuing through gestation. Effects observed in the high-dose group (with systemic exposure of 1.2times the human systemic exposure following an intravenous dose of 4mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid-dose group (with systemic exposure of 0.2times the human systemic exposure following an intravenous dose of 4mg, based on an AUC comparison) and high-dose group included