Drug Interactions
Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium.

Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs.

In multiple myeloma patients, the risk of renal dysfunction may be increased when pamidronate disodium is used in combination with thalidomide.

Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 104 week carcinogenicity study (daily oral administration) in rats, there was a positive dose response relationship for benign adrenal pheochromocytoma in males (P<0.00001). Although this condition was also observed in females, the incidence was not statistically significant. When the dose calculations were adjusted to account for the limited oral bioavailability of pamidronate disodium in rats, the lowest daily dose associated with adrenal pheochromocytoma was similar to the intended clinical dose. Adrenal pheochromocytoma was also observed in low numbers in the control animals and is considered a relatively common spontaneous neoplasm in the rat. Pamidronate disodium (daily oral administration) was not carcinogenic in an 80 week study in mice.

Pamidronate disodium was nonmutagenic in six mutagenicity assays: Ames test, Salmonella and Escherichia/liver-microsome test, nucleus-anomaly test, sister-chromatid-exchange study, point-mutation test, and micronucleus test in the rat.

In rats, decreased fertility occurred in first-generation offspring of parents who had received 150 mg/kg of pamidronate disodium orally; however, this occurred only when animals were mated with members of the same dose group. Pamidronate disodium has not been administered intravenously in such a study.

Animal Toxicology

In both rats and dogs, nephropathy has been associated with intravenous (bolus and infusion) administration of pamidronate disodium.

Two 7-day intravenous infusion studies were conducted in the dog wherein pamidronate disodium was given for 1, 4, or 24 hours at doses of 1 to 20 mg/kg for up to 7 days. In the first study, the compound was well tolerated at 3 mg/kg (1.7 x highest recommended human dose [HRHD] for a single intravenous infusion) when administered for 4 or 24 hours, but renal findings such as elevated BUN and creatinine levels and renal tubular necrosis occurred when 3 mg/kg was infused for 1 hour and at doses of ≥10 mg/kg. In the second study, slight renal tubular necrosis was observed in 1 male at 1 mg/kg when infused for 4 hours. Additional findings included elevated BUN levels in several treated animals and renal tubular dilation and/or inflammation at ≥1 mg/kg after each infusion time. Pamidronate disodium was given to rats at doses of 2, 6, and 20 mg/kg and to dogs at doses of 2, 4, 6, and 20 mg/kg as a 1-hour infusion, once a week, for 3 months followed by a 1-month recovery period. In rats, nephrotoxicity was observed at ≥6 mg/kg and included increased BUN and creatinine levels and tubular degeneration and necrosis. These findings were still present at 20 mg/kg at the end of the recovery period. In dogs, moribundity/death and renal toxicity occurred at 20 mg/kg as did kidney findings of elevated BUN and creatinine levels at ≥6 mg/kg and renal tubular degeneration at ≥4 mg/kg. The kidney changes were partially reversible at 6 mg/kg. In both studies, the d