1. Renal Safety of Zoledronic Acid in Patients With Breast Cancer

2. 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;21:4042-4057. Zometa and Aredia Product Information Major PP, et al. Cancer 88:6-14, 2000.

3. 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;21:4042-4057. Zometa and Aredia Product Information

4. 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. 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;98:1735-1744.

6. 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;98:1735-1744. Zometa ® and Aredia product information.

7. 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 mg1811.401.371 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 18115012695493812 Pam 90 mg18414212088504219

8. 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. 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 (> 3.0 - 6.0  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. 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. 11 Serum Creatinine After 3 Months of IV Bisphosphonate Therapy in Patients With BC Mean serum creatinine  SD,  mol/L nBaselineMonth 3 Ibandronate2880.9  2.084.8  2.2 (6 mg over 1 hr) Placebo2383.4  3.989.1  3.0 Zoledronic acid*18181.4  13.678.9  15.0 (4 mg over 15 min) Pamidronate18481.9  17.280.8  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: 707-716.

12. 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, 1800 814 667. ABN 18 004211 160. 54 Waterloo Road North Ryde NSW 2113.

13. 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, 1800 814 667. ABN 18 004211 160. 54 Waterloo Road North Ryde NSW 2113.