Acute Phase Reaction-like Events

Symptoms consistent with acute phase reaction (APR) can occur with intravenous bisphosphonate use. Fever has been the most commonly associated symptom, occurring in 44% of patients treated with Zometa 4mg and 33% of patients treated with Pamidronate 90mg. Occasionally, patients experience a flu-like syndrome consisting of fever, chills, flushing, bone pain and/or arthralgias, and myalgias.

Mineral and Electrolyte Abnormalities

Electrolyte abnormalities, most commonly hypocalcemia, hypophosphatemia and hypomagnesemia, can occur with bisphosphonate use.

Grade3 and Grade 4laboratory abnormalities for serum creatinine, serum calcium, serum phosphorus, and serum magnesium observed in two clinical trials of Zometa in patients with HCM are shown in Table5 and6.

Table 5: Grade 3 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM  Grade 3
Laboratory Parameter Zometa Pamidronate
 4mg 90mg
 n/N (%) n/N (%)
Serum Creatinine1 2/86 (2%) 3/100 (3%)
Hypocalcemia2 1/86 (1%) 2/100 (2%)
Hypophosphatemia3 36/70 (51%) 27/81 (33%)
Hypomagnesemia4 0/71 — 0/84 —
Table 6: Grade 4 Laboratory Abnormalities for Serum Creatinine, Serum Calcium, Serum Phosphorus, and Serum Magnesium in Two Clinical Trials in Patients with HCM  Grade 4
Laboratory Parameter Zometa Pamidronate
 4mg 90mg
 n/N (%) n/N (%)
Serum Creatinine1 0/86 — 1/100 (1%)
Hypocalcemia2 0/86 — 0/100 —
Hypophosphatemia3 1/70 (1%) 4/81 (5%)
Hypomagnesemia4 0/71 — 1/84 (1%)
1 Grade3 (greater than 3x Upper Limit of Normal); Grade4 (greater than 6x Upper Limit of Normal)
2 Grade3 (less than 7mg/dL); Grade4 (less than 6mg/dL)
3 Grade3 (less than 2mg/dL); Grade4 (less than 1mg/dL)
4 Grade3 (less than 0.8 mEq/L); Grade4 (less than 0.5mEq/L)

Injection Site Reactions

Local reactions at the infusion site, such as redness or swelling, were observed infrequently. In most cases, no specific treatment is required and the symptoms subside after 24-48 hours.

Ocular Adverse Events

Ocular inflammation such as uveitis and scleritis can occur with bisphosphonate use, including Zometa. No cases of iritis, scleritis or uveitis were reported during these clinical trials. However, cases have been seen in postmarketing use [see Adverse Reactions (6.2)].

Multiple Myeloma and Bone Metastases of Solid Tumors

The safety analysis includes patients treated in the core and extension phases of the trials. The analysis includes the 2,042patients treated with Zometa 4mg, pamidronate 90mg, or placebo in the three controlled multicenter bone metastases trials, including 969patients completing the efficacy phase of the trial, and 619patients that continued in the safety extension phase. Only 347patients completed the extension phases and were followed for 2years (or 21months for the other solid tumor patients). The median duration of exposure for safety analysis for Zometa 4mg (core plus extension phases) was 12.8months for breast cancer and multiple myeloma, 10.8months for prostate cancer, and 4.0months for other solid tumors.

Table7 describes adverse events that were reported by 10% or more of patients. Adverse events are listed regardless of presumed cau