title: Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases.
abstract: OBJECTIVE
  This article summarizes data submitted to the United States Food and Drug Administration for marketing approval of zoledronic acid (Zol; Novartis Pharmaceuticals, East Hanover, NJ), a bisphosphonate drug for treating patients with bone metastases.
  
  
  METHODS
  We review the chemistry, toxicology, pharmacology, and clinical study results submitted to support the supplemental New Drug Application for Zol for treatment of patients with bone metastases. Four- and 8-mg Zol doses were selected for Phase III trials based on bone resorption markers and clinical efficacy parameters. Patients with bone metastases were randomized in three Phase III studies (prostate cancer, solid tumors, and multiple myeloma or breast cancer) to receive 4 or 8 mg of Zol or to a control arm. The control was a placebo in the prostate cancer study and the other solid tumor study and was 90 mg of pamidronate (Pam) in the study of breast cancer and multiple myeloma. Studies were amended twice because of renal toxicity, initially to increase Zol infusion time from 5 to 15 min and later to decrease the dose in the Zol 8-mg arm to 4 mg. The efficacy end point was skeletal-related events (SREs), a composite end point consisting of pathologic fracture, radiation therapy to bone, changes in antineoplastic therapy for bone pain (prostate cancer only), surgery to bone, or spinal cord compression. This end point was analyzed either as the proportion of patients with SRE or time to first SRE. The breast cancer and myeloma study used a noninferiority statistical analysis methods to determine efficacy.
  
  
  RESULTS
  In prostate cancer, both the proportions analysis and time-to-SRE analysis showed significantly less bone morbidity on Zol (4 mg) than placebo, but no significant difference between Zol (8 mg) and placebo in either analysis. In the solid tumor study, the time to SRE analysis but not the proportions analysis showed significantly less skeletal morbidity on Zol (4 mg) than placebo, and Zol (8 mg) was significantly better than placebo in both analyses. The breast cancer and myeloma study demonstrated noninferiority of Zol compared with Pam, with Zol retaining at least 49.3% of the Pam treatment effect previously demonstrated in placebo-controlled trials. Zol was approved on February 22, 2002, by the United States Food and Drug Administration for the "treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy." The recommended dose and schedule is 4 mg of Zol infused over 15 min every 3-4 weeks. Increased Zol doses and shorter infusions are not recommended because of potential renal toxicity.
authors.affiliation: Division of Oncology Drug Products, Center for Drug Evaluation and Research, Rockville, Maryland 20857, USA. ibrahima@cder.fda.gov
authors.forename: Amna
authors.initials: A
authors.lastname: Ibrahim
authors.forename: Nancy
authors.initials: N
authors.lastname: Scher
authors.forename: Grant
authors.initials: G
authors.lastname: Williams
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sridhara
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Leighton
authors.forename: Brian
authors.initials: B
authors.lastname: Booth
authors.forename: Jogarao V S
authors.initials: JV
authors.lastname: Gobburu
authors.forename: Atiqur
authors.initials: A
authors.lastname: Rahman
authors.forename: Yung
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wood
authors.forename: Debra
authors.initials: D
authors.lastname: Vause
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D004164:Diphosphonates / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009362:Neoplasm Metastasis; D010919:Placebos; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D013997:Time Factors; D014481:United States; D014486:United States Food and Drug Administration; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D010919:Placebos; D000077211:Zoledronic Acid