sNDA 21-386, ZometaSafety Review

Nancy S. Scher, M.D.

Oncology Drug Products

CDER, FDA

Protocol Amendments Affecting Safety

• Changes in infusion (June 1999)– infusion time increased from 5 to 15 minutes– infusion volume increased from 50 to 100 ml

• Dose reduced for 8 mg arm (June 2000)– subsequent doses were 4 mg (8/4 mg group)

• Creatinine monitoring required (June 2000)– Assess prior to each dose– Hold Zometa for renal deterioration– Resume if creatinine within 10% of baseline

Renal Deterioration by Baseline Creatinine15-Minute Infusion, Study 010, Breast and Myeloma

Zol 4 mgN (%)

Zol 8/4 mgN (%)

Aredia 90 mgN (%)

Patients with normalbaseline Cr

23/246(9.3%)

43/242(17.8%)

20/246(8.1%)

Patients withabnormal baseline Cr

1/26(3.8%)

6/21(28.6%)

2/22(9.1%)

All patients 24/272(8.8%)

49/263(18.6%)

22/268(8.2%)

Summary of SafetyStudy 010 (Zometa 4 vs. Aredia)

• Incidence of adverse events similar – More patients with >25% decrease in Hb

• Higher incidence of Zometa renal function deterioration before 15-minute amendment

• Incidence of renal function deterioration similar post amendment

• Time to first renal deterioration similar

Renal Deterioration by Baseline Creatinine 15-Minute Infusion, Study 039, Prostate

Zol 4 mgN (%)

Zol 8/4 mgN (%)

PlaceboN (%)

Patients with normalbaseline Cr

10/82(12.2%)

14/68 (20.6%)

7/68(10.3%)

Patients withabnormal baseline Cr

4/10(40.0%)

4/19(21.1%)

2/20(10.0%)

All patients 14/92(15.2%)

18/87 (20.7)

9/78(11.5%)

Renal Deterioration by Baseline Creatinine15 Minute Infusion, Study 011, Solid Tumors

Zol 4 mgN (%)

Zol 8/4 mgN (%)

PlaceboN (%)

Patients with normalbaseline Cr

17/154(11.0%)

19/160(11.9%)

10/143(7.0%)

Patients withabnormal baseline Cr

1/11(9.1%)

2/21(9.5%)

1/20(5.0%)

All patients 18/165(10.9%)

21/181(11.6%)

11/163(6.7%)

Summary of SafetyStudies 039 and 011

• More bisphosphonate-associated AEs for Zometa than placebo– fever, arthralgias, electrolyte abnormalities

• Anemia more common for Zometa

• Increased incidence of renal function deterioration for Zometa – related to duration of therapy

Safety Conclusions• Administration and dosage

– 4 mg i.v. over 15 minutes

– Q 3-4 weeks

• Acceptable safety profile

– more toxic than placebo (039 and 011)

– similar to Aredia 90 mg i.v. over 2 hours (010)

• Caution: Renal issues

– trials excluded creatinine > 3 mg/dL

– renal excretion

– monitor serum creatinine all patients