CIBA-GEIGY’s AREDIA (PAMIDRONATE) RECOMMENDED FOR APPROVAL IN TREATMENT OF HYPERCALCEMIA OF MALIGNANCY; LABELING SHOULD STRESS PATIENT MONITORING

Ciba-Geigy's Aredia I.V. (pamidronate disodium) was unanimously recommended for approval in treating hypercalcemia associated with malignancy by FDA's Endocrinologic and Metabolic Drugs Advisory Committee at its Oct. 22 meeting. In response to FDA's question whether Ciba-Geigy's data provides substantial evidence of safety and efficacy, committee acting chair Douglas Greene, MD, University of Michigan, said: "I'd vote 'yes'...and point out that the amount of safety data that has been accumulated over the years is much in excess of that which is usually seen with a drug that's only [in the body] for a short period of time." Hypercalcemia occurs in approximately 10% to 20% of patients with malignancies, such as lytic malignant bone disease or tumors of the lung, head and neck, ovary, bladder, and renal cell. FDA noted that although the "etiology is not clearly understood, in most patients there is a relative increase in bone resorption over bone formation." Aredia may work by inhibiting bone resorption. The committee review of Ciba-Geigy's Aredia studies was presented by outside consultant Ethel Siris, MD, College of Physicians and Surgeons of Columbia University. Siris said she believed "that these protocols, which have been carefully done and which come in the context of some less carefully, but nonetheless interesting acquired data from Europe, would indicate that this is an efficacious agent for the lowering of the serum calcium in hypercalcemia of malignancy." She added that "there are some mild adverse effects that may be seen" but "the risk/benefit relationship for this agent is a very, very favorable one in the direction of benefit." Aredia appears to have a relatively strong safety profile. In the trials presented, the only drug-related adverse experiences were low rates of transient fever and infusion site inflammation. Also, Siris noted that "the duration of response in this first set of studies was consistent with what has been seen with other drugs with such severely ill patients." Although the committee recommended approval of Aredia, the panel made several suggestions on how the proposed labeling might be improved. Committee member Lewis Kuller, MD, University of Pittsburgh, suggested that the labeling should have "clarified further in terms of whether this should be given [in or out] of the hospital." He added that labeling "probably should restrict...use [of the drug to] the hospital, but obviously [there is] future potential to use it out of the hospital." Several members suggested that labeling include statements about the necessity of rehydration and of monitoring electrolyte levels, which generally drop as result of hypercalcemia. Panel member Barry Bercu, MD, University of South Florida, noted that physicians need information about the use of Aredia in children. Ciba-Geigy's NDA for Aredia, filed in December 1989, contains the results of two multicenter trials in which all hypercalcemic patients were hydrated with saline before treatment. The primary efficacy parameter was normalization of calcium levels. Secondary parameters included duration of complete response, time to relapse, and symptoms of hypercalcemia. One study was a double-blind, randomized, parallel study comparing three different doses of Aredia: 30 mg, 60 mg, and 90 mg given as a single 24-hour infusion. Presenting the results, Henry Bone, III, MD, Henry Ford Hospital, Detroit, said that "there was a 100% complete response rate with the 90 mg dose -- that is all patients became normocalcemic." For the patients who had a complete or partial response, "about a week and a half to two weeks was the time to relapse," Bone noted. The second study compared the efficacy of a single 60 mg Aredia I.V. infusion with etidronate I.V. (7.5 mg/kg over two hours) for three days in 64 patients. "Both patient groups improved but the degree of improvement was greater for Aredia and this was statistically significant during the latter half of the week at endpoint," Bone said. Retreatment of hypercalcemia with Aredia is being looked at in open-label extension phases of the two studies. Bone said that about 60% of the patients who received the retreatment dose of 60 mg "had a complete or partial response."