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Indications and Important Safety Information for VELCADE® (bortezomib)

  • INDICATIONS: VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

  • CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE.

  • WARNINGS AND PRECAUTIONS
    VELCADE (bortezomib) is for subcutaneous or IV administration only. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.

    • Peripheral neuropathy, including severe cases, may occur. Patients should be monitored for symptoms and managed with dose modification or discontinuation. Patients with preexisting symptoms may experience worsening peripheral neuropathy (including ≥grade 3). Starting with VELCADE subcutaneously may be considered for patients who either have preexisting or are at high risk for peripheral neuropathy.

    • Hypotension: Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated.

    • Cardiac toxicity, including acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction, has occurred. Isolated cases of QT-interval prolongation have been reported. Patients with risk factors for, or existing, heart disease should be closely monitored.

    • Pulmonary toxicity: Acute respiratory distress syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology have occurred (sometimes fatal). Pulmonary hypertension, in the absence of left heart failure or significant pulmonary disease, has been reported. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt and comprehensive diagnostic evaluation is conducted.

    • Posterior reversible encephalopathy syndrome has occurred. Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected.

    • Gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting, has occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement. Interrupt VELCADE (bortezomib) for severe symptoms.

    • Thrombocytopenia/Neutropenia: Manage with dose and/or schedule modifications. Complete blood counts should be monitored frequently during treatment. There have been reports of gastrointestinal and intracerebral hemorrhage. Transfusions may be considered.

    • Tumor lysis syndrome: Closely monitor patients with high tumor burden and take appropriate precautions.

    • Hepatic toxicity: Monitor hepatic enzymes during treatment. Upon occurrence, interrupt therapy with VELCADE to assess reversibility.

    • Embryo-fetal risk: Women should avoid breast-feeding or becoming pregnant while on VELCADE.

    • Patients with diabetes may require close monitoring and adjustment of the antidiabetic medications.

  • DRUG INTERACTIONS: Closely monitor patients receiving VELCADE (bortezomib) in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

  • ADVERSE REACTIONS

    • Previously untreated multiple myeloma (MM): In the phase 3 study of VELCADE administered intravenously with melphalan and prednisone (MP) vs MP alone, the most commonly reported adverse reactions (ARs) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), and leukopenia (32% vs 28%).

    • Relapsed MM and mantle cell lymphoma: In the integrated analysis of 1163 patients in phase 2 and 3 studies of VELCADE (bortezomib) administered intravenously, the most commonly reported ARs were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathy NEC (38%), and thrombocytopenia (32%). A total of 26% of patients experienced serious ARs. The most commonly reported serious ARs included diarrhea, vomiting, and pyrexia (each 3%); nausea, dehydration, and thrombocytopenia (each 2%); and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (each 1%).

    • Relapsed MM subcutaneous vs IV: In the phase 3 study of VELCADE administered subcutaneously vs intravenously in relapsed MM, safety data were similar between the two treatment groups. The most commonly reported ARs in the subcutaneous vs IV treatment groups were peripheral neuropathy (37% vs 50%) and thrombocytopenia (30% vs 34%). The incidence of serious ARs was similar in the subcutaneous treatment group (20%) and the IV treatment group (19%). The most commonly reported serious ARs were pneumonia and pyrexia (each 2%) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (each 3%) in the IV treatment group.

  • Please see full Prescribing Information available at www.VELCADE.com

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*Melphalan+prednisone.

VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE® (bortezomib) administered intravenously in combination with melphalan+prednisone (MP) vs MP in previously untreated multiple myeloma. After progressive disease was established, all patients were eligible to receive subsequent therapies.3 The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted, and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.

APEX TRIAL: a randomized, open-label trial (N=669) evaluating the efficacy and safety of VELCADE administered intravenously vs dexamethasone in patients with relapsed/refractory multiple myeloma. The primary endpoint was TTP. Secondary endpoints were overall survival, ORR, and safety. The APEX trial was terminated at a preplanned interim analysis of TTP. All dexamethasone patients were offered VELCADE. Median TTP was 6.2 months with VELCADE vs 3.5 months with dexamethasone (p<0.0001). An updated analysis was performed.

§Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

||SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial that compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed multiple myeloma. Patients who did not obtain a CR after 4 cycles were allowed oral dexamethasone. The primary endpoint was ORR at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival, and safety.

82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone.

References: 1. Richardson PG, Sonneveld P, Schuster MW, et al; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487-2498. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440. 3. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

Important Safety Information for VELCADE® (bortezomib)