A well-characterized safety profile in relapsed multiple myeloma
Adverse Reactions in Relapsed Multiple Myeloma
(APEX† Trial)
VELCADE® (bortezomib) should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.
| Most Commonly Reported (≥20%) Adverse Reactions | VELCADE® (bortezomib) (n=331), % |
Dexamethasone (n=332), % |
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| MedDRA System Organ Class Preferred Term | All | Grade 3 | Grade 4 | All | Grade 3 | Grade 4 |
| Adverse Reactions | 98 | 58 | 8 | 89 | 33 | 9 |
| Nausea | 52 | 2 | 0 | 9 | 0 | 0 |
| Diarrhea NOS | 52 | 7 | 0 | 11 | <1 | 0 |
| Fatigue | 39 | 5 | 0 | 25 | 2 | 0 |
| Peripheral Neuropathies NEC | 35 | 7 | <1 | 4 | 0 | <1 |
| Thrombocytopenia | 33 | 24 | 4 | 3 | 2 | <1 |
| Constipation | 30 | 2 | 0 | 8 | <1 | 0 |
| Vomiting NOS | 29 | 2 | 0 | 3 | <1 | 0 |
| Anorexia | 21 | 2 | 0 | 2 | <1 | 0 |
| Pyrexia | 20 | <1 | 0 | 6 | <1 | <1 |
- The most commonly reported serious ARs in the VELCADE (bortezomib) treatment group were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious ARs were pneumonia (4%), hyperglycemia (3%), and pyrexia and psychotic disorder (2% each)
- Discontinuations due to adverse reactions were 25% for VELCADE and 18% for dexamethasone
- Treatment-related deaths were similar between VELCADE and dexamethasone treatment groups (1% each)
Characteristics of Peripheral Neuropathy in APEX Trial
In relapsed multiple myeloma, VELCADE (bortezomib)-associated peripheral neuropathy was reversible or completely resolved in the majority of patients with dose modification or discontinuation.1
- In the APEX trial, 37% of patients experienced treatment-emergent peripheral neuropathy (PN)1
- For the patients who experienced PN, the onset of PN generally occurred by week 15 and the actuarial overall incidence of grade ≥3 peripheral neuropathy reached a plateau at approximately 24 weeks1
- Discontinuation rate due to PN was 8%
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Dose modification guidelines available for peripheral neuropathy, moderate to severe hepatic impairment, and other hematologic and nonhematologic toxicities View guidelines |
Neurotoxicity Assessment Tool |
Additional Safety Considerations for VELCADE (bortezomib)
- Antiviral prophylaxis should be considered for patients treated with VELCADE (bortezomib). Herpes zoster reactivation was more common in patients treated with VELCADE
- Thrombocytopenia and neutropenia were predictable, transient, and cyclical
- Complete blood counts should be monitored regularly throughout treatment
- Low incidence of thromboembolic events with VELCADE2
- Grade 3/4 DVT 0%
- Grade 3/4 pulmonary embolism 0%
- The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia
- The mean platelet count nadir measured was approximately 40% of baseline
- In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (grade ≥3) was 2% in the VELCADE treatment group and was <1% in the dexamethasone treatment group
- Thrombocytopenia or neutropenia can occur; complete blood counts should be monitored regularly throughout treatment
- Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE
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.
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 (includingâ„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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*VELCADE (bortezomib) (Vc) in combination with melphalan+prednisone (MP).
†APEX TRIAL: a randomized, open-label trial (N=669) evaluating the efficacy and safety of VELCADE (bortezomib) 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.
‡Severity reduction of at least 1 NCI CTC grade.
References: 1. Richardson PG, Sonneveld P, Schuster MW, et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol. 2009;144:895-903. 2. Data on file 50, Millennium Pharmaceuticals, Inc. 3. Lonial S, Richardson PG, San Miguel J, et al. Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol. 2008;143(2):222-229.
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