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VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule [see DOSAGE AND ADMINISTRATION]. In the VELCADE versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥ Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies [see ADVERSE REACTIONS]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. 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. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics [see ADVERSE REACTIONS].
Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the VELCADE group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.
In a clinical trial, the first two patients given high-dose cytarabine (2g/m²per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.
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 (PRES)
Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.
VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting [see ADVERSE REACTIONS] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.
VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. 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. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 6. In the relapsed multiple myeloma study of VELCADE versus dexamethasone, the incidence of bleeding ( ≥ Grade 3) was 2% on the VELCADE arm and was < 1% in the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet count should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE [see Table 2 and DOSAGE AND ADMINISTRATION]. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.
Table 6: Severity of Thrombocytopenia Related to Pretreatment
Platelet Count in the Relapsed Multiple Myeloma Study of VELCADE versus
|Number (%) of Number of Pretreatment Platelet Count*||Patients
|Patients with Platelet Count < 10,000/μL||Number (%) of Patients with Platelet Count 10,000-25,000/μL|
|≥ 75,000/μL||309||8 (3%)||36 (12%)|
|≥ 50,000/μL- < 75,000/μL||14||2 (14%)||11 (79%)|
|≥ 10,000/μL- < 50,000/μL||7||1 (14%)||5 (71%)|
|* A baseline platelet count of 50,000/μL
was required for study eligibility
** Data were missing at baseline for 1 patient
Tumor Lysis Syndrome
Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.
Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m²based on body surface area caused post-implantation loss and a decreased number of live fetuses [see Use in Specific Populations].
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m²(one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m². VELCADE could have a potential effect on either male or female fertility.
Use In Specific Populations
Pregnancy Category D [see WARNINGS AND PRECAUTIONS].
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m²in the rat and 0.05 mg/kg; 0.6 mg/m²in the rabbit) when administered during organogenesis. These dosages are approximately half the clinical dose of 1.3 mg/m²based on body surface area.
Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05mg/kg (0.6 mg/m²) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/m²based on body surface area.
There are no adequate and well-controlled studies in pregnant women. If VELCADE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.
It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of VELCADE in children have not been established.
Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the VELCADE arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on VELCADE compared to dexamethasone [5.5 mo versus 4.3 mo, and 8.0 mo versus 4.9 mo, respectively]. On the VELCADE arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for VELCADE patients ≤ 50, 51-64 and ≥ 65 years old, respectively [see ADVERSE REACTIONS; Clinical Studies].
No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.
Patients with Renal Impairment
The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure [see CLINICAL PHARMACOLOGY].
Patients with Hepatic Impairment
The exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3x ULN) and severe (bilirubin > 3 x ULN) hepatic impairment. Starting dose should be reduced in those patients [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
Patients with Diabetes
During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral anti-diabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.
Last reviewed on RxList: 11/6/2012
This monograph has been modified to include the generic and brand name in many instances.
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