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9/14/2001

New Bisphosphonic Acid Approved by FDA

Cheryl A. Thompson

Novartis Pharmaceuticals Corp. has received FDA’s approval to market zoledronic acid (Zometa) for the treatment of cancer-related hypercalcemia, an indication shared with the company's other phosphonic acid analogue, pamidronate disodium.

The efficacy of zoledronic acid, which inhibits bone resorption, was compared with that of pamidronate disodium 90 mg in two identical multicenter, double-blind, randomized studies involving a total of 275 patients with hypercalcemia of malignancy who received a single dose of one of the drugs or a placebo.1 All of the patients initially had a corrected (to account for possible hypoalbuminemia) serum calcium concentration of >12 mg/dL.

By day 10 of the studies, 88% of the patients who received a 4-mg i.v. dose of zoledronic acid over five minutes had a corrected serum calcium concentration of <10.8 mg/dL, a level defined as a complete response. For half of these patients, this effect lasted at least 32 days. Seventy percent of the patients who received pamidronate disodium as a two-hour i.v. infusion completely responded to the treatment by day 10. Patients who received 8 mg of zoledronic acid responded similarly to those who received the lower dose but had a significantly higher risk of renal toxicity, defined on the basis of the serum creatinine concentration. None of the patients in the two studies had an initial serum creatinine concentration of >4.5 mg/dL.

In other studies, the infusion time of zoledronic acid was found to influence patients' risk of renal toxicity. Administration of the drug over 15 minutes instead of 5 minutes decreased the risk.

The most commonly reported adverse effect of treatment with zoledronic acid during the two major studies was fever (44.2%). Nausea, constipation, anemia, or dyspnea occurred in 22.1–29.1% of the patients.

The pharmacokinetic profile of zoledronic acid was determined in patients with cancer and bone metastases, not hypercalcemia. After i.v. infusion, the drug disappeared from the plasma in three phases; the half-lives of the first two phases were less than two hours each, and the half-life of the terminal phase was seven days. Zoledronic acid is not metabolized in vivo.

As with other bisphosphonates, zoledronic acid should be used cautiously in patients with aspirin-sensitive asthma.

The recommended dosage of zoledronic acid is 4 mg administered intravenously over 15 minutes. Measures should be undertaken to ensure that the patient is adequately hydrated and that urine output is >2 L/day. A loop diuretic should not be administered until the patient is adequately hydrated. Renal function should be assessed before and after treatment with zoledronic acid.

Treatment may be repeated but not sooner than seven days. If, in the two weeks preceding a repeat dose, the patient's serum creatinine concentration has increased by >0.5 mg/dL and is no longer in the normal range, the dose should be withheld until the laboratory value returns to within 10% of baseline. The same procedure should be followed if the patient initially had a higher-than-normal serum creatinine concentration and it increased by >1 mg/dL.

Short-term therapy with a calcium, phosphate, or magnesium supplement may be necessary to correct for treatment-related hypocalcemia, hypophosphatemia, or hypomagnesemia.

Zometa is supplied in vials containing 4 mg of the drug and a buffering agent. A dose is prepared by adding 5 mL of sterile water for injection to the vial and transferring the contents to a 100-mL container of 0.9% sodium chloride injection or 5% dextrose injection. The drug must not be mixed with a calcium-containing solution.

Soon after FDA approved the initial marketing of zoledronic acid, Novartis announced it was seeking an additional indication: treatment of bone metastases associated with multiple myeloma and prostate, lung, and breast cancer. Pamidronate disodium is indicated for the treatment of bone metastases associated with multiple myeloma and breast cancer but not prostate or lung cancer.

1. Major P, Lortholary A, Hon J et al. J Clin Oncol. 2001; 19:558-67.