ZOLEDRONIC (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (at doses ≥0.002 times a human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Rats were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. No increased incidence of tumors was observed (at doses ≤0.2 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas).

Zoledronic acid was not genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese hamster gene mutation assay, with or without metabolic activation. Zoledronic acid was not genotoxic in the in-vivo rat micronucleus assay.

Female rats were given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation. Effects observed in the high-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid-dose group (with systemic exposure of 0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and high-dose group included an increase in preimplantation losses and a decrease in the number of implantations and live fetuses.

14 CLINICAL STUDIES

14.1 Hypercalcemia of Malignancy

Two identical multicenter, randomized, double-blind, double-dummy studies of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.1 and 5.2) and Dosage and Administration (2.4) ].The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.

In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of greater than or equal to 12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.

To assess the effects of Zoledronic acid Injection versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zoledronic acid Injection 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for Zoledronic acid Injection 8 mg over Zoledronic acid Injection 4 mg; however, the risk of renal toxicity of Zoledronic acid Injection 8 mg was significantly greater than that seen with Zoledronic acid Injection 4 mg. Figure 1

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Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value less than 11.6 mg/dL (less than 2.90 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8 mg/dL (2.70 mmol/L). The results of these secondary analyses for Zoledronic acid Injection 4 mg and pamidronate 90 mg are shown in Table 10.

Table 10: Secondary Efficacy Variables in Pooled HCM Studies
Zoledronic acid Injection 4 mg Pamidronate 90 mg
Complete Response N Response Rate N Response Rate
By Day 4 8645.3%9933.3%
By Day 7 8682.6%*9963.6%
Duration of Response N Median Duration (Days) N Median Duration (Days)
Time to Relapse 8630*9917
Duration of Complete Response 76326918
* P less than 0.05 versus pamidronate 90 mg.

14.2 Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors


Table 11 describes an overview of the efficacy population in three randomized Zoledronic acid Injection trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zoledronic acid Injection effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zoledronic acid Injection is beneficial. The optimal duration of Zoledronic acid Injection administration is not known.The studies were amended twice because of renal toxicity. The Zoledronic acid Injection infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zoledronic acid Injection treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the Zoledronic acid Injection 8 mg group are not included in these analyses.

Table 11: Overview of Efficacy Population for Phase III Studies
Patient Population No. of Patients Zoledronic acid Injection Dose Control Median Duration (Planned Duration) Zoledronic acid Injection 4 mg
Multiple myeloma or metastatic breast cancer 1,648 4 and 8* mg Q3-4 weeks Pamidronate 90 mg Q3-4 weeks 12.0 months (13 months)
Metastatic prostate cancer 643 4 and 8* mg Q3 weeks Placebo 10.5 months (15 months)
Metastatic solid tumor other than breast or prostate cancer 773 4 and 8* mg Q3 weeks Placebo 3.8 months (9 months)
* Patients who were randomized to the 8 mg Zoledronic acid Injection group are not included in any of the analyses in this package insert.

Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zoledronic acid Injection placebo-controlled studies are given in Table 12.

Table 12: Zoledronic acid Injection Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors
I. Analysis of Proportion of Patients with a SRE 1 II. Analysis of Time to the First SRE
Study Study Arm & Patient Number Proportion Difference 2 & 95% CI P-value Median (Days) Hazard Ratio 3 & 95% CI P-value
Prostate Cancer Zoledronic acid Injection 4 mg (n=214) 33% -11% (-20%, -1%) 0.02 Not Reached 0.67 (0.49, 0.91) 0.011
Placebo (n=208) 44% 321
Solid Tumors Zoledronic acid Injection 4 mg (n=257) 38% -7% (-15%, 2%) 0.13 230 0.73 (0.55, 0.96) 0.023
Placebo (n=250) 44% 163
1 SRE=Skeletal-Related Event2 Difference for the proportion of patients with a SRE of Zoledronic acid Injection 4 mg versus placebo.3 Hazard ratio for the first occurrence of a SRE of Zoledronic acid Injection 4 mg versus placebo.

In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zoledronic acid Injection to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with Zoledronic acid Injection compared to pamidronate are given in Table 13.

Table 13: Zoledronic acid Injection Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer
I. Analysis of Proportion of Patients with a SRE 1 II. Analysis of Time to the First SRE
Study Study Arm & Patient Number Proportion Difference 2 & 95% CI P-value Median (Days) Hazard Ratio 3 & 95% CI P-value
Multiple Myeloma & Breast Cancer Zoledronic acid Injection 4 mg (n=561) Pamidronate (n=555) 44% 46% -2% (-7.9%, 3.7%) 0.46 373 363 0.92 (0.77, 1.09) 0.32
1 SRE=Skeletal-Related Event2 Difference for the proportion of patients with a SRE of Zoledronic acid Injection 4 mg versus pamidronate 90 mg.3 Hazard ratio for the first occurrence of a SRE of Zoledronic acid Injection 4 mg versus pamidronate 90 mg.

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