Zometa for Hypercalcemia of Malignancy

October 1, 2001

ROCKVILLE, Maryland-Zometa (zoledronic acid for injection) has received marketing approval from the US Food and Drug Administration for the treatment of hypercalcemia of malignancy. Zoledronic acid represents a new generation of intravenous bisphosphonates. It is currently approved for treating hypercalcemia of malignancy in more than 30 countries.

ROCKVILLE, Maryland—Zometa (zoledronic acid for injection) has received marketing approval from the US Food and Drug Administration for the treatment of hypercalcemia of malignancy. Zoledronic acid represents a new generation of intravenous bisphosphonates. It is currently approved for treating hypercalcemia of malignancy in more than 30 countries.

Novartis has also filed an application with the FDA seeking approval for the drug in treating bone metastases that occur as a result of a number of cancers. These malignancies include prostate and lung cancer, for which no bisphosphonate therapy is currently approved.

Hypercalcemia of malignancy is the most common life-threatening metabolic complication associated with cancer, Novartis noted. Excessively high calcium levels—which result when factors produced by tumor cells overstimulate osteoclasts—affect more than 10% of cancer patients, generally in the late stages of their disease.

Zoledronic acid inhibits increased osteoclastic activity and the release of skeletal calcium. If hypercalcemia of malignancy recurs, patients can be treated again with the same zoledronic acid protocol.

The company submitted two pivotal studies comparing the drug with pamidronate disodium for injection (Aredia), the current treatment standard for hypercalcemia of malignancy.

The two international, multicenter trials enrolled a total of 287 patients (275 evaluable). Patients were infused with a single dose of zoledronic acid, at either 4 mg or 8 mg, or a single 90-mg dose of pamidronate delivered over 2 hours. Researchers measured clinical response by the normalization of corrected serum calcium by day 10.

Pooled results of the two studies showed that by day 10, 88% of the patients who received zoledronic acid 4 mg had normal corrected serum calcium concentrations, compared with 70% of those treated with pamidronate (P = .002).

The median duration of complete response was 32 days for zoledronic acid vs 18 days for pamidronate, and the time to relapse was 30 days vs 17 days. There were no differences in outcomes between the 4-mg and 8-mg doses.

Bisphosphonates, including zoledronic acid, are associated with kidney toxicity, reduced renal function, and potential renal failure. The risk of renal dysfunction was significantly increased in patients on the 8-mg dose of Zometa, compared with the 4-mg dose. Other clinical trials have shown a significantly increased risk for patients receiving Zometa over 5 minutes, compared with those getting the same dose over 15 minutes.

Thus, the drug’s labeling warns that "due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa should not exceed 4 mg and the duration of infusion should be no less than 15 minutes."

According to Novartis, reactions to zoledronic acid are usually mild and transient. The most common adverse events were fever (44.2%), nausea (29.1%), constipation (26.7%), anemia (22.1%), and dyspnea (22.1%). Occasionally, patients had electrolyte and mineral disturbances, such as low serum levels of phosphate, calcium, magnesium, and potassium. The company cautioned that zoledronic acid should be used with caution in patients with aspirin-sensitive asthma and also in those receiving loop diuretics, due to an increased risk of hypocalcemia.