Zometa (zoledronic acid)

Zometa 4 mg (zoledronic acid for injection) has been approved for the treatment of hypercalcemia of malignancy (HCM), a common life-threatening metabolic complication associated with cancer. Zometa is an intravenous bisphosphonate that works by inhibiting the breakdown of bone (resorption).

HCM affects more than 10% of all cancer patients and occurs most frequently with breast cancer, multiple myeloma and non-small cell lung cancer. This condition occurs when factors made by cancer cells over-stimulate osteoclasts, which are cells responsible for bone resorption. The over-stimulation results in an increased rate of bone breakdown and the release of excess calcium into the bloodstream. The kidneys are unable to cope with the excessively high calcium levels and the calcium remains in the blood, leading to complications such as dehydration, fatigue, nausea, vomiting, confusion and coma.

Zometa was evaluated in two multicenter, randomized, double-blind trials in which it was compared to Aredia (pamidronate) 90 mg. The trials included 275 evaluable subjects, and treatment groups were generally well balanced in terms of age, sex, race and tumor types. Treatment with a single dose of either Zometa 4 mg or 8 mg was compared to a single dose of Aredia 90 mg.

Data revealed that the proportion of subjects with normalization of corrected serum calcium (CSC) by day 10 were 88% and 70% for Zometa 4 mg and Aredia 90 mg, respectively. The risk of renal toxicity with Zometa 8 mg was shown to be significantly greater than that seen with Zometa 4 mg - notably, no additional benefit was seen with the higher dosage.

Zometa also demonstrated positive results in secondary efficacy variables. Results showed that time to relapse was 30 days for Zometa 4 mg and 17 days for Aredia 90 mg. Duration of complete response, or the maintenance of normalized calcium levels, was 32 days for Zometa 4 mg and 18 days for Aredia 90 mg.

In general, adverse reactions to Zometa were mild and short-lived. Adverse events reported by subjects in clinical trials include (but are not limited to) the following:

• Fever
• Nausea
• Constipation
• Diarrhea
• Vomiting
• Abdominal pain
• Anemia

The principle pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. (from Zometa Prescribing Information)

Zometa has been approved for the treatment of HCM in several countries, including Switzerland, Brazil, Canada and Australia.

Novartis also plans to submit a supplemental application to the FDA for Zometa in the treatment of bone metastasis.

For additional information on Zometa, please visit the product web site at www.zometa.com.