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Basic Drug Info
Drug Name:Zometa
Manufacturer:Novartis Pharmaceuticals Corporation
Other Info:

Table 11 describes an overview of the efficacy population in three randomized Zometa 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 Zometa 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 Zometa is beneficial.

The optimal duration of Zometa administration is not known.      The studies were amended twice because of renal toxicity.

The Zometa 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 Zometa treatment arm were switched to 4 mg due to toxicity.

Patients who were randomized to the Zometa 8 mg group are not included in these analyses.Table 11: Overview of Efficacy Population for Phase III Studies Patient PopulationNo.

of PatientsZometa DoseControlMedian Duration (Planned Duration) Zometa 4 mg Multiple myeloma or metastatic breast cancer1,6484 and 8* mg Q3-4 weeksPamidronate 90 mg Q3-4 weeks12.0 months (13 months) Metastatic prostate cancer6434 and 8* mg Q3 weeksPlacebo10.5 months (15 months) Metastatic solid tumor other than breast or prostate cancer7734 and 8* mg Q3 weeksPlacebo3.8 months (9 months) * Patients who were randomized to the 8 mg Zometa 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 Zometa placebo-controlled studies are given in Table 12.Table 12: Zometa Compared to Placebo in Patients with Bone Metastases from Prostate Cancer or Other Solid Tumors I.

Analysis of Proportion of Patients with a SRE1II.

Analysis of Time to the First SRE StudyStudy Arm & Patient NumberProportionDifference2 & 95% CIP-valueMedian (Days)Hazard Ratio3 & 95% CIP-value Prostate CancerZometa 4 mg (n=214)33%-11% (-20%, -1%)0.02Not Reached0.67 (0.49, 0.91)0.011 Placebo (n=208)44%321 Solid TumorsZometa 4 mg (n=257)38%-7% (-15%, 2%)0.132300.73 (0.55, 0.96)0.023 Placebo (n=250)44%163 1SRE=Skeletal-Related Event2Difference for the proportion of patients with a SRE of Zometa 4 mg versus placebo.3Hazard ratio for the first occurrence of a SRE of Zometa 4 mg versus placebo.       In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zometa 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 Zometa compared to pamidronate are given in Table 13.Table 13: Zometa Compared to Pamidronate in Patients with Multiple Myeloma or Bone Metastases from Breast Cancer I.

Analysis of Proportion of Patients with a SRE1II.

Analysis of Time to the First SRE StudyStudy Arm & Patient NumberProportionDifference2 & 95% CIP-valueMedian (Days)Hazard Ratio3 & 95% CIP-value Multiple Myeloma & Breast CancerZometa 4 mg (n=561)Pamidronate (n=555)44%46%-2% (-7.9%, 3.7%)0.463733630.92 (0.77, 1.09)0.32 1SRE=Skeletal-Related Event2Difference for the proportion of patients with a SRE of Zometa 4 mg versus pamidronate 90 mg.3Hazard ratio for the first occurrence of a SRE of Zometa 4 mg versus pamidronate 90 mg.



Clinical Trials:


Indications and Usage

Zometa is a bisphosphonate indicated for the treatment of:Hypercalcemia of malignancy (1.1)Patients with multiple myeloma and patients with 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 (1.2)Important limitation of use: The safety and efficacy of Zometa has not been established for use in hyperparathyroidism or nontumor-related hypercalcemia (1.3)
Hypercalcemia -- Abnormally high level of calcium in the blood.

Multiple Myeloma -- A malignancy of mature PLASMA CELLS engaging in monoclonal immunoglobulin production. It is characterized by hyperglobulinemia, excess Bence-Jones proteins (free monoclonal IMMUNOGLOBULIN LIGHT CHAINS) in the urine, skeletal destruction, bone pain, and fractures. Other features include ANEMIA; HYPERCALCEMIA; and RENAL INSUFFICIENCY.

Secondary malignant neoplasm of bone and bone marrow -- Cancer that has spread from the original (primary) tumor to the bone.

solid tumor -- Cancer of body tissues other than blood, bone marrow, or the lymphatic system.

Malignant neoplasm of prostate -- A primary or metastatic malignant tumor involving the prostate gland. The vast majority are carcinomas. -- 2003

Prostate carcinoma -- One of the most common malignant tumors afflicting men. The majority of carcinomas arise in the peripheral zone and a minority occur in the central or the transitional zone of the prostate gland. Grossly, prostatic carcinomas appear as ill-defined yellow areas of discoloration in the prostate gland lobes. Adenocarcinomas represent the overwhelming majority of prostatic carcinomas. Prostatic-specific antigen (PSA) serum test is widely used as a screening test for the early detection of prostatic carcinoma. Treatment options include radical prostatectomy, radiation therapy, androgen ablation and cryotherapy. Watchful waiting or surveillance alone is an option for older patients with low-grade or low-stage disease. -- 2002

Hyperparathyroidism -- WHAT: Hyperparathyroidism. Hyperparathyroidism: a condition due to an increase in the secretion of the parathyroids, causing generalized osteitis fibrosa cystica, elevated serum calcium, decreased serum phosphorus, and increased excretion of both calcium and phosphorus. WHY: Several rheumatological disorders are associated with hyperpara- thyroidism. First, hyperuricemia and gouty arthritis (which may mimic hyperparathyroidism with renal stone formation and colic) have an increased incidence in patients with hyperparathyroidism. Second, patients with primary hyperparathyroidism show an increased incidence of chondrocalcinosis with episodes of calcium pyrophosphate crystal induced synovitis. Approximately 25% of patients with hyperparathyroidism will show radiographic evidence of calcification of articular cartilage and joint capsules. Finally, there can be a synovial and cartilaginous lesion ("osteogenic synovitis") in patients with hyperparathyroidism which may mimic other primary rheumatic diseases such as rheumatoid arthritis. In osteogenic synovitis there is softening and collapse of subchondral bone. Eventually the cartilage overlying this area erodes and is replaced by an irregular fibrocartilage. Eventually the articular surface of the joint is destroyed and secondary degenerative arthritis may develop. REFS: 1) Zvaifler, NJ; Reefe, WE and Black, RL: Articular manifestations in primary hyperparathyroidism. Arthritis Rheum 5:237, 1962. 2) Scott, JT; Dixon, ASJ and Bywaters, EGL: Association of hyperuricemia and gout with hyperparathyroidism. Br Med J 1:1070, 1964. 3) Bywaters, EGL and Scott, JT : Joint lesions of hyperparathyroidism. Ann Rheum Dis 22:171-87, 1963.

Contraindications
Hypersensitivity to any component of Zometa (4)
Hypersensitivity -- Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen.


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