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There have been fatal cases of inadvertent intrathecal administration of BORTEZOMIB. BORTEZOMIB is for IV and subcutaneous use only. DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY.
Overall, the safety profile of patients treated with BORTEZOMIB in monotherapy was similar to that observed in patients treated with BORTEZOMIB in combination with melphalan and prednisone.
Peripheral Neuropathy: BORTEZOMIB treatment causes a peripheral neuropathy (PN) that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory 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 BORTEZOMIB. 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 study comparing BORTEZOMIB IV vs SC the incidence of Grade ≥2 peripheral neuropathy events was 24% for SC and 41% for IV (p=0.0124). Grade ≥3 peripheral neuropathy occurred in 6% of subjects in the SC treatment group, compared with 16% in the IV treatment group (p=0.0264) (Table 23). Therefore, patients with pre-existing PN or at high risk of peripheral neuropathy may benefit from starting BORTEZOMIB subcutaneously.
Patients experiencing new or worsening peripheral neuropathy may require a change in dose, schedule or route of administration to SC (see Method of Administration under Dosage & Administration).
Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the single agent phase 3 multiple myeloma study of BORTEZOMIB vs dexamethasone. 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.
The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
Hypotension: In phase 2 and 3 single agent multiple myeloma studies, the incidence of hypotension (postural, orthostatic, and Hypotension Not Otherwise Specified) was 11% to 12%. 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, or administration of mineralocorticoids and/or sympathomimetics (see Adverse Reactions).
Cardiac Disorders: 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. Patients with risk factors for, or existing heart disease should be closely monitored. In the single agent phase 3 multiple myeloma study of BORTEZOMIB vs dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% respectively. The incidence of heart failure events (acute pulmonary oedema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary oedema) was similar in the BORTEZOMIB and dexamethasone groups, 5% and 4%, respectively.
There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Hepatic Events: Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of BORTEZOMIB. There is limited re-challenge information in these patients.
Pulmonary Disorders: 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 BORTEZOMIB. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. In the event of new or worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and patients treated appropriately.
In a clinical trial, two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and BORTEZOMIB for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
Laboratory Tests: Complete blood counts (CBC) should be frequently monitored throughout treatment with BORTEZOMIB.
Thrombocytopenia/Neutropenia: BORTEZOMIB is associated with thrombocytopenia and neutropenia (see Adverse Reactions).
Platelets were lowest at Day 11 of each cycle of BORTEZOMIB treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet count decrease and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in any of the regimens studied.
Platelet counts should be monitored prior to each dose of BORTEZOMIB. BORTEZOMIB therapy should be held when the platelet count is <25,000/uL (see Method of Administration under Dosage & Administration and Adverse Reactions). There have been reports of gastrointestinal and intracerebral hemorrhage in association with BORTEZOMIB. Transfusion and supportive care may be considered.
In the single-agent multiple myeloma study of BORTEZOMIB vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pre-treatment platelet count is shown in Table 20. The incidence of significant bleeding events (≥ Grade 3) was similar on both the BORTEZOMIB (4%) and dexamethasone (5%) arms. (See Table 20.)
Click on icon to see table/diagram/imageIn the combination study of BORTEZOMIB with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia adverse events (≥ Grade 4) was 32% versus 2% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm. The incidence of bleeding adverse events (≥ Grade 3) was 1.7% (4 patients) in the VcR-CAP arm and was 1.2% (3 patients) in the R-CHOP arm.
There were no deaths due to bleeding events in either arm. There were no CNS bleeding events in the VcR-CAP arm; there was 1 bleeding event in the R-CHOP arm. Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm.
The incidence of neutropenia (≥ Grade 4) was 70% in the VcR-CAP arm and was 52% in the RCHOP arm. The incidence of febrile neutropenia (≥ Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Colony-stimulating factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm.
Gastrointestinal Adverse Events: BORTEZOMIB treatment can cause nausea, diarrhea, constipation, and vomiting (see Adverse Reactions) sometimes requiring use of antiemetics and antidiarrheal medications. Fluid and electrolyte replacement should be administered to prevent dehydration. Since patients receiving BORTEZOMIB therapy may experience vomiting and/or diarrhea, patients should be advised regarding appropriate measures to avoid dehydration. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.
Tumor Lysis Syndrome: Because BORTEZOMIB is a cytotoxic agent and can rapidly kill malignant cells the complications of tumor lysis syndrome may occur. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Patients with Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with BORTEZOMIB at reduced starting doses and closely monitored for toxicities. See Method of Administration under Dosage & Administration and Pharmacology: Pharmacokinetics under Actions.
Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving BORTEZOMIB. 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 BORTEZOMIB. The safety of reinitiating BORTEZOMIB therapy in patients previously experiencing PRES is not known.
Effects on Ability to Drive and Use Machines: BORTEZOMIB may cause tiredness, dizziness, fainting, or blurred vision. Patients should be advised not to drive or operate machinery if they experience these symptoms.
