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IMPORTANT SAFETY INFORMATION
Contraindications, warnings, and precautions derived from an integrated analysis evaluating
VELCADE® (bortezomib) for Injection dosed at 1.3 mg/m2 at the same schedule in multiple myeloma and MCL clinical trials.
INDICATIONS
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VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 1 prior therapy. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
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CONTRAINDICATIONS
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VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol
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WARNING
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VELCADE should be administered under the supervision of a physician experienced in the use of
antineoplastic therapy
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PREGNANCY CATEGORY D AND NURSING
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Women of childbearing potential should avoid becoming pregnant while being treated with
VELCADE. Patients should be advised to use effective contraceptive measures. Women should
be advised against breast-feeding
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PRECAUTIONS
Peripheral Neuropathy
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VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However,
cases of severe sensory and motor neuropathy have been reported
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Patients with preexisting symptoms and/or signs of peripheral neuropathy may experience
worsening peripheral neuropathy (including greater than or equal to grade 3) during treatment
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Patients should be monitored for symptoms of neuropathy, such as a burning sensation,
hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness
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Improvement or resolution of peripheral neuropathy was reported in 51% of patients with
greater than or equal to grade 2 peripheral neuropathy in the phase 3 multiple myeloma study and in 73% of patients
in phase 2 multiple myeloma studies who discontinued due to grade 2 neuropathy or had greater than or equal to grade 3 neuropathy
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The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma
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Hypotension
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In phase 2 and 3 studies, the incidence of hypotension (postural, orthostatic, and hypotension NOS)
was 13%. These events were observed throughout therapy
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Caution should be used when treating patients with a history of syncope, patients receiving
medications known to be associated with hypotension, and patients who are dehydrated
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Management may include adjustment of antihypertensive medications, hydration, and
administration of mineralocorticoids and/or sympathomimetics
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Cardiac Disorders
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Acute development or exacerbation of congestive heart failure, and/or new onset of decreased
left ventricular ejection fraction has been reported, including reports in patients with few or no risk
factors for decreased left ventricular ejection fraction
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Patients with risk factors for, or existing, heart disease should be closely monitored. In the phase 3
multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% with
VELCADE® and 13% with dexamethasone
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The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive heart failure,
cardiogenic shock, pulmonary edema) was 5% with VELCADE and 4% with dexamethasone
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There have been isolated cases of QT interval prolongation in clinical studies; causality has not
been established
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Pulmonary Disorders
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There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology
such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress
Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. A higher
proportion of these events have been reported in Japan
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In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous
infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS
early in the course of therapy
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There have been rare reports of pulmonary hypertension associated with VELCADE administration
in the absence of left heart failure or significant pulmonary disease
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In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic
evaluation should be conducted
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Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
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There have been rare reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible,
neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion,
blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI
(Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS,
discontinue VELCADE
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The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known
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Laboratory Tests
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Complete blood counts (CBCs) should be frequently monitored throughout treatment with VELCADE
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Gastrointestinal Adverse Events
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VELCADE causes nausea, diarrhea, constipation, and vomiting, sometimes requiring antiemetic
and antidiarrheal medication
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Fluid and electrolyte replacement should be administered to prevent dehydration
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Thrombocytopenia/Neutropenia
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VELCADE is associated with thrombocytopenia and neutropenia. Platelets and neutrophils were
lowest at day 11 of each cycle of treatment and typically recovered to baseline by the next cycle
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The cyclical pattern of platelet and neutrophil count decrease and recovery remained consistent
over the 8 cycles of twice weekly dosing. There was no evidence of cumulative thrombocytopenia
or neutropenia. The mean platelet nadir measured was approximately 40% of baseline
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The severity of thrombocytopenia is related to pretreatment platelet counts. Two percent of patients in
studies discontinued treatment due to thrombocytopenia
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In the phase 3 multiple myeloma study, the incidence of significant bleeding events (greater than or equal to grade 3) was 4% with
VELCADE and 5% with dexamethasone
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Platelet counts should be monitored prior to each dose of VELCADE
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VELCADE therapy should be held when the platelet count is less than 25,000/µL and reinitiated at a
reduced dose
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Transfusions may be considered
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There have been reports of gastrointestinal and intracerebral hemorrhage in association
with VELCADE
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The incidence of febrile neutropenia was less than 1% across phase 2 and 3 studies
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Hepatic Events
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Rare cases of acute liver failure have been reported in patients receiving multiple concomitant
medications and with serious underlying medical conditions
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Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and
hepatitis which may be reversible upon discontinuation of VELCADE. There is limited rechallenge
information in these patients
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Patients with Hepatic or Renal Impairment
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Patients with hepatic or renal impairment should be closely monitored for toxicities. Bortezomib
is metabolized by liver enzymes and clearance of bortezomib may decrease in patients with
hepatic impairment
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No clinical information is available on the use of bortezomib in patients with CrCl less than 13 mL/min and
patients on hemodialysis
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Tumor Lysis Syndrome
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Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of
tumor lysis syndrome may occur. Patients with high tumor burden prior to treatment should be
monitored closely and appropriate precautions taken
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IMPORTANT FINDINGS IN THE OVERALL VELCADE SAFETY POPULATION
In the integrated analysis across phase 2 and 3 studies (N = 1163), the most commonly
reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) (64%),
nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy (including peripheral
sensory neuropathy and peripheral neuropathy aggravated) (39%), thrombocytopenia and appetite
decreased (including anorexia) (each 36%), pyrexia (34%), vomiting (33%), and anemia (29%). Twenty
percent (20%) of patients experienced at least 1 episode of greater than or equal to grade 4 toxicity, most commonly
thrombocytopenia (5%) and neutropenia (3%). Fifty percent (50%) of patients reported serious adverse
events (SAEs). The most commonly reported SAEs were pneumonia (7%), pyrexia (6%), diarrhea (5%),
vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).
For full Prescribing Information click here. (pdf) (74KB) For further information about VELCADE® (bortezomib) for Injection, call 1-866-VELCADE (U.S. clinicians only).
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