Renal Safety of Zoledronic Acid in Patients With Breast Cancer

2 ASCO Guidelines for Use of IV Bisphosphonates in Breast Cancer  Recommended for patients with – Evidence of bone destruction on plain radiographs  Reasonable to initiate IV bisphosphonate therapy in patients with bone destruction through imaging, but who have normal plain radiographs  Initiate IV zoledronic acid (4 mg via 15-minute infusion) or pamidronate (90 mg via 2-hour infusion) every 3 to 4 weeks – Oral bisphosphonates not recommended Hillner B, et al. J Clin Oncol. 2003;21: Zometa and Aredia Product Information Major PP, et al. Cancer 88:6-14, 2000.

3 ASCO Guidelines for IV Bisphosphonate Use in Patients With Breast Cancer  Once initiated, IV bisphosphonates should be continued as long as tolerated or until evidence of substantial decline in performance status  Serum creatinine should be monitored before each dose according to product information  No changes in dose, infusion duration or interval is necessary for patients with pre-existing renal disease if serum creatinine is < 3.0 mg/dL (265 µmol/L) Hillner B, et al. J Clin Oncol. 2003;21: Zometa and Aredia Product Information

4 Recommendations for Zoledronic Acid Treatment in Patients With Breast Cancer  Zoledronic acid (4 mg) should be infused over no less than 15 minutes every 3 to 4 weeks  Withhold treatment for patients with – Notable serum creatinine increase until it returns to within 10% of baseline  Not recommended for patients with severe renal impairment: – Creatinine levels > 400 micromol/L for patients with tumour induced hypercalcaemia (TIH) – Creatinine levels > 265 micromol/L for patients with bone metastases  Ensure adequate hydration  Patients should also receive – Oral calcium supplement of 500mg daily – Multi-vitamin containing 400 IU of vitamin D daily Zometa ® product information.

5 Phase III Randomized Trial in Breast Cancer and Multiple Myeloma (Study 010)  Stratification – Durie-Salmon stage III MM with  1 osteolytic bone lesion – Stage IV BC with  1 osteolytic, osteoblastic, or mixed metastatic bone lesion – Patient stratification: those receiving chemotherapy (with or without hormonal therapy) those receiving hormonal treatment  Appropriate antineoplastic therapy at baseline and during the course of the trial  Baseline serum creatinine  3.0 mg/dL (265 µmol/L)  Patients randomized to zoledronic acid (4 or 8 mg) versus pamidronate (90 mg) every 3 to 4 weeks for up to 24 months  Protocol amendments for renal safety – Increased zoledronic acid infusion time from 5 to 15 minutes – Reduced dose from 8 to 4 mg (8/4 mg group) Rosen LS, et al. Cancer. 2003;98:

6 Notable Serum Creatinine Increase  Definition – Increase of > 44 micromol/L ( >0.5 mg/dL) in patients with normal baseline serum creatinine (< 125 micromol/L/ < 1.4 mg/dL) – Increase of > 88 micromol/L (>1.0 mg/dL) in patients with abnormal baseline serum creatinine (≥ 125 micromol/L/  1.4 mg/dL/) or – Doubling of serum creatinine from baseline value  If serum creatinine was notably increased according to above criteria, dose was held until serum creatinine returned to within 10% of baseline Rosen LS, et al. Cancer. 2003;98: Zometa ® and Aredia product information.

7 Breast Cancer Patients*—Time to First Notable Serum Creatinine Increase Was Similar in the Zoledronic Acid and Pamidronate Groups Kaplan-Meier Estimate of Time to First Notable Serum Creatinine Increase nHazard ratioP value Zol 4 mg Pam 90 mg184 *Safety-evaluable patients treated post–15-minute infusion amendment. Lipton A, et al. Presented at: 4th European Breast Cancer Conference. 2004: Poster 296. Zol 4 mg Pam 90 mg

8 Percent of BC Patients* With Notable Serum Creatinine Increase Was Similar in the Zoledronic Acid and Pamidronate Groups n = 181 n = 184 *Safety-evaluable patients treated post–15-minute infusion amendment. Lipton A, et al. Presented at: 4th European Breast Cancer Conference. 2004: Poster 296.

9 No NCI Grade 3 or 4 Serum Creatinine Increases Occurred in Breast Cancer Patients Treated With Zoledronic Acid* Patients, n (%) Zol 4 mgPam n = 181n = 184 Grade 3 (>  ULN)00 Grade 4 (> 6.0  ULN)01 (0.5) NCI = National Cancer Institute; ULN = Upper limit of normal (1.2 mg/dL). *Safety-evaluable patients treated post–15-minute infusion amendment. Lipton A, et al. Presented at: 4th European Breast Cancer Conference. 2004: Poster 296.

10 Conclusions  Zoledronic acid (4 mg via 15-minute infusion) has a renal safety profile comparable to that of pamidronate (90 mg via 2-hour infusion) in patients with breast cancer  There was a low incidence of NCI Common Toxicity Criteria grade 3 or 4 serum creatinine increase – No patient with breast cancer treated with 4 mg zoledronic acid via 15-minute infusion experienced grade 3 or 4 serum creatinine elevation NCI = National Cancer Institute. Lipton A, et al. Presented at: 4 th European Breast Cancer Conference. 2004: Poster 296.

11 Serum Creatinine After 3 Months of IV Bisphosphonate Therapy in Patients With BC Mean serum creatinine  SD,  mol/L nBaselineMonth 3 Ibandronate   2.2 (6 mg over 1 hr) Placebo   3.0 Zoledronic acid*   15.0 (4 mg over 15 min) Pamidronate   16.4 (90 mg over 2 hrs) *Within the first 3 months of treatment, no patient treated with zoledronic acid (4 mg over 15 minutes) experienced a notable serum creatinine increase (based on defined criteria). Lipton A, et al. Presented at: 4th European Breast Cancer Conference. 2004: Poster 296. Lyubimova NV, et al. Clin Drug Invest, 2003; 23:

12 TGA approved indications:  Prevention of skeletal-related events (pathological fracture, spinal cord compression, radiation to bone or surgery to bone) in patients with advanced malignancies involving bone.  Treatment of tumour-induced hypercalcaemia. Please review full Product Information before prescribing. For further information please contact Novartis, ABN Waterloo Road North Ryde NSW 2113.

13 PBS LISTING: Bone metastases from hormone-resistant prostate cancer, with demonstration of biochemical progression of disease despite maximal therapy with hormonal treatments; Multiple Myeloma Bone metastases from Breast Cancer Treatment of hypercalcaemia of malignancy refractory to anti-neoplastic therapy PBS Information: Zometa is listed on the PBS (Section 100) for the treatment of patients with multiple myeloma, bone metastases from breast cancer and bone metastases from hormone- resistant prostate cancer. Refer to PBS schedule for full information. Please review full Product Information before prescribing. For further information please contact Novartis, ABN Waterloo Road North Ryde NSW 2113.