Zometa Dose Reductions Required in Patients With Renal Impairment

Yael Waknine

Disclosures

March 25, 2005

March 25, 2005 — The U.S. Food and Drug Administration (FDA) and Novartis Pharmaceuticals have advised healthcare professionals via letter of required dose reductions for zoledronic acid injection (Zometa) when treating advanced cancer in patients with mild to moderate renal impairment, according to an alert sent today from MedWatch, the FDA's safety information and adverse event reporting program.

Dose reductions for patients with a creatinine clearance of 60 mL per minute or less are calculated to achieve a target area under the curve (AUC) equal to that of patients with a clearance of 75 mL per minute (target AUC, 0.66 mg/L · one hour).

Due to the risk of clinically significant deterioration in renal function that may progress to renal failure, single doses of zoledronic acid for the treatment of multiple myeloma and metastatic bone lesions from solid tumors should not exceed 4 mg, and the duration of infusion should be no less than 15 minutes, in patients with creatinine clearance greater than 60 mL per minute.

In patients with a baseline creatinine clearance of 50 to 60 mL per minute, the dose should be reduced to 3.5 mg (4.4 mL). Further reductions are required in patients with baseline clearances ranging from 40 to 49 mL per minute (3.3 mg; 4.1mL) and 30 to 29 mL per minute (3.0 mg; 3.8 mL). Doses should be diluted in 100 mL of sterile 0.9% NaCl or 5% dextrose injection.

The FDA recommends that serum creatinine be measured prior to administration of each dose of zoledronic acid. Treatment should be withheld in the event of renal deterioration, defined as an increase in creatinine of 0.5 mg/dL for patients with normal baseline levels and an increase of 1.0 mg/dL in patients with abnormal baseline levels.

Treatment should be resumed at the same dose used prior to treatment interruption and upon return of creatinine levels to within 10% of the baseline value.

The FDA notes that preexisting renal insufficiency and multiple cycles of zoledronic acid or other bisphosphonates are risk factors for subsequent renal deterioration during therapy. Factors predisposing to renal deterioration, including dehydration or administration of other nephrotoxic drugs, should be identified and managed if possible.

Healthcare professionals are encouraged to report adverse events related to use of zoledronic acid to Novartis Pharmaceuticals by phone at 1-888-NOW NOVARTIS (1-888-669-6682), online at www.us.zometa.com/contact/hcp/emailh.jsp or www.us.zometa.com/hcp/tools/medicalinquiry.jsp, or by mail to 1 Health Plaza, East Hanover, NJ 07936.

Alternatively, this information can be reported to the FDA's MedWatch program by phone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at https://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.

Reviewed by Gary D. Vogin, MD

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