DESCRIPTION

Pamidronate Disodium is a sterile bone-resorption inhibitor available in 30 mg and 90 mg vials for intravenous administration. The pamidronate disodium obtained by combining pamidronic acid and sodium hydroxide is provided in a sterile, ready to use solution for injection. Each mL of the 30 mg vial contains, 3 mg Pamidronate Disodium, 47 mg Mannitol, USP; Water for Injection, USP, q.s.; Phosphoric acid to adjust pH. Each mL of the 90 mg vial contains, 9 mg Pamidronate Disodium, 37.5 mg Mannitol, USP; Water for Injection, USP, q.s.; Phosphoric acid to adjust pH. The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Pamidronate, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, and its structural formula is:

Pamidronate disodium is soluble in water and in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in organic solvents. Its molecular formula is C3H9NO7P2Na2 and its molecular weight is 279.1 (calculated as the anhydrous form).

Inactive Ingredients: Mannitol, Phosphoric acid (for adjustment to pH range of 6.0 to 7.0) and Water for Injection.

CLINICAL PHARMACOLOGY

The principal pharmacologic action of pamidronate disodium is inhibition of bone resorption. Although the mechanism of antiresorptive action is not completely understood, several factors are thought to contribute to this action. Pamidronate disodium adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. In animal studies, at doses recommended for the treatment of hypercalcemia, pamidronate disodium inhibits bone resorption apparently without inhibiting bone formation and mineralization. Of relevance to the treatment of hypercalcemia of malignancy is the finding that pamidronate disodium inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various tumors in animal studies.

Pharmacokinetics

Cancer patients (n=24) who had minimal or no bony involvement were given an intravenous infusion of 30, 60, or 90 mg of pamidronate disodium over 4 hours and 90 mg of pamidronate disodium over 24 hours (Table 1).

Distribution

The mean ± SD body retention of pamidronate was calculated to be 54 ± 16% of the dose over 120 hours.

Metabolism

Pamidronate is not metabolized and is exclusively eliminated by renal excretion.

Excretion

After administration of 30, 60, and 90 mg of pamidronate disodium over 4 hours, and 90 mg of pamidronate disodium over 24 hours, an overall mean ± SD of 46 ± 16% of the drug was excreted unchanged in the urine within 120 hours. Cumulative urinary excretion was linearly related to dose. The mean ± SD elimination half-life is 28 ± 7 hours. Mean ± SD total and renal clearances of pamidronate were 107 ± 50 mL/min and 49 ± 28 mL/min, respectively. The rate of elimination from bone has not been determined.

Special Populations

There are no data available on the effects of age, gender, or race on the pharmacokinetics of pamidronate.

Pediatric

Pamidronate is not labeled for use in the pediatric population.

Renal Insufficiency

The pharmacokinetics of pamidronate were studied in cancer patients (n=19) with normal and varying degrees of renal impairment. Each patient received a single 90 mg dose of pamidronate disodium infused over 4 hours. The renal clearance of pamidronate in patients was found to closely correlate with creatinine clearance (see Figure 1). A trend toward a lower percentage of drug excreted unchanged in urine was observed in renally impaired patients. Adverse experiences noted were not found to be related to changes in renal clearance of pamidronate. Given the recommended dose, 90 mg infused over 4 hours, excessive accumulation of pamidronate in renally impaired patients is not anticipated if pamidronate disodium is administered on a monthly basis.

Figure 1. Pamidronate renal clearance as a function of creatinine clearance in patients with normal and impaired renal function.

The lines are the mean prediction line and 95% confidence intervals.

Hepatic Insufficiency

The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=7). Each patient received a single 90 mg dose of pamidronate disodium infused over 4 hours. Although there was a statistically significant difference in the pharmacokinetics between patients with normal and impaired hepatic function, the difference was not considered clinically rele