PAMIDRONATE DISODIUM INJECTION
PAMIDRONATE DISODIUM FOR INJECTION

For Intravenous Infusion
Rx ONLY

DESCRIPTION
Pamidronate Disodium Injection is a bone resorption inhibitor available in 30 mg vials for intravenous administration. Each mL contains 3 mg of pamidronate disodium; 47 mg of mannitol USP and water for injection q.s.; phosphoric acid and/or sodium hydroxide have been added to adjust pH 6.2 to 7.0.

Pamidronate Disodium for Injection is a bone resorption inhibitor available in 30 mg and 90 mg vials for intravenous administration. Each 30 mg and 90 mg vial contains, respectively, 30 mg and 90 mg of sterile, lyophilized pamidronate disodium and 470 mg and 375 mg of mannitol USP.

Inactive Ingredients: Mannitol and phosphoric acid (for adjustment to pH 6.5 prior to lyophilization).

The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Pamidronate disodium, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as disodium dihydrogen (3-amino-1-hydroxypropylidene) diphosphonate, and its structural formula is:

Pamidronate disodium is a white-to-practically-white powder. It 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.

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, and 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 deter