ALERT-REDUCE BORTEZOMIB DOSE FOR PATIENTS WITH LIVER IMPAIRMENT

January 26, 2010 — The US Food and Drug Administration (FDA) and Takeda Oncology issued a notification today to healthcare providers about Velcade (bortezomib), informing them that the starting dose for patients with multiple myeloma and moderate-to-severe hepatic impairment should be reduced.

The notification reads "dose-normalized mean [area-under-the-curve] values were increased by approximately 60% in patients with moderate or severe hepatic impairment."

Section 5.11, "Patients with Hepatic Impairment," now reads, "Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities."

New labeling will include full prescribing information for bortezomib for injection, with recommended dosages for patients with compromised liver function. Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated according to the current recommendations.

Patients with moderate or severe hepatic impairment (bilirubin levels > 1.5 - 3.0 × upper limit of normal) should be started on bortezomib at a reduced dose of 0.7 mg/m² per injection during the first cycle, with a subsequent dose escalation to 1.0 mg/m². Dose reduction to 0.5 mg/m² may be considered based on patient tolerance.

The new labeling will also include updated survival data at a median 36.7 months follow-up in patients with previously untreated multiple myeloma. The overall survival hazard ratio is 0.65 (95% confidence interval, 0.51 - 0.84; P = .00084). Median survival was 46.2 months for bortezomib compared with 34.8 months for melphalan and prednisone.

Bortezomib is indicated for the treatment of patients with multiple myeloma and for patients with mantle cell lymphoma who have received at least one prior therapy.

More information is available on the FDA's MedWatch Web site.

Adverse events related to Velcade should be communicated to MedWatch by telephone at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, Maryland 20852-9787.