Zoledronic Acid (ZA)- Associated Nephrotoxicity: An Analysis of Adverse Drug Reaction (ADR) Reports by the Research on Adverse Drug Events and Reports (RADAR) Project.

Abstract Background-The FDA originally approved zoledronic acid (ZA) in August 2001 for the treatment of hypercalcemia of malignancy and subsequently for prevention of skeletal related events among patients with multiple myeloma (MM), breast, and prostate cancer. Since its approval, the FDA has received several reports of nephrotoxicity. Many of these individuals have myeloma, a malignancy associated with renal damage. Herein, RADAR investigators reviewed the clinical characteristics of ZA-induced nephrotoxicity among cancer patients with multiple myeloma versus other malignancies. We investigated the clinical characteristics and reporting quality of all adverse event (AE) reports describing ZA-associated neprotoxicity. Methods- We analyzed reports of ZA-associated nephrotoxicity from the FDA’s Adverse Event Reporting System, which included a total of 141 AE reports, with exclusion of cases/trials reported in duplicate. Results- Overall, 141 cases of ZA-associated renal failure (RF) were identified: 92 case reports were from the United States and 44 were from non-United States countries. Reporting completeness was generally poor, with respect to serum creatinine levels and frequency of ZA administration, especially in reports from Canada and Great Britain respectively. Two thirds of the patients with scheduling information had received ZA every 4 weeks. Infusion rate was reported for 21%, and was usually 15 minutes or longer. NSAIDS and Cox-II inhibitor exposures were reported in 25%, and 20% of the patients who had prior diagnoses of renal insufficiency. Patients with MM (n=82) had similar mean age as patients with other cancers (n= 54) (72.05 versus 72.9 years). For patients for whom data was available (n=62), pamidronate was used by 97.8% in the MM group versus 86.9% in the non-myeloma group. The onset of RF occurred after a mean of 67.9 days in the MM group (range, 3–366) versus 73.7 days in the non-myeloma group (range, 0–546 days) post initiation of ZA; after a mean number of ZA doses (2.5 vs. 1.8 doses). Only one dose of ZA was received by 24.4% and 25.4% of MM versus non-myeloma patients respectively, which occurred after an average of 14.7 days and 30 days. RF manifestations included serum Cr > 2 for 59.7% of the MM and 83.1% of the other cancer patients. Outcomes of RF in MM and non-myeloma patients, respectively, included hospitalization (61% and 71%) and dialysis, (38% and 22%). Conclusions- Close monitoring of serum creatinine prior to ZA, is important for both MM and other cancer patients; completeness of current case reporting efforts of ZA-associated renal insufficiency is poor in both US and non-US countries; and information about the potential occurrence of renal toxicity should be prominently described in the packet insert for ZA.

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