warnings and cautions
5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with pre-existing severe neuropathy should be treated with Bortezomib for Injection only after careful risk-benefit assessment. ( 2.7 , 5.1 ) Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ( 5.2 ) Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ( 5.3 ) Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting Bortezomib for Injection therapy. ( 5.4 ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for Injection if suspected. ( 5.5 ) Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ( 5.6 ) Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. ( 5.7 ) Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. ( 5.8 ) Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt Bortezomib for Injection therapy to assess reversibility. ( 5.9 ) Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Bortezomib for Injection if suspected. ( 5.10 ) Embryo-Fetal Toxicity: Bortezomib for Injection can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 ) 5.1 Peripheral Neuropathy Bortezomib for Injection 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 Bortezomib for Injection. 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 Bortezomib for Injection subcutaneous vs 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 [see Adverse Reactions (6.1) ] . Starting Bortezomib for Injection subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during Bortezomib for Injection therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2.7) ] . In the Bortezomib for Injection vs 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. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. 5.2 Hypotension The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8% [see Adverse Reactions (6.1) ] . These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. 5.3 Cardiac Toxicity Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during Bortezomib for Injection therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction [see Adverse Reactions (6.1) ] . Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of Bortezomib for Injection vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the Bortezomib for Injection 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 Bortezomib for Injection 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. 5.4 Pulmonary Toxicity 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 Bortezomib for Injection. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m 2 per day) by continuous infusion with daunorubicin and Bortezomib for Injection for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with Bortezomib for Injection administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib for Injection until a prompt and comprehensive diagnostic evaluation is conducted. 5.5 Posterior Reversible Encephalopathy Syndrome (PRES) Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving Bortezomib for Injection. 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 for Injection. The safety of reinitiating Bortezomib for Injection therapy in patients previously experiencing PRES is not known. 5.6 Gastrointestinal Toxicity Bortezomib for Injection treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions (6.1) ] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib for Injection for severe symptoms. 5.7 Thrombocytopenia/Neutropenia Bortezomib for Injection 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 remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied. Monitor complete blood counts (CBC) frequently during treatment with Bortezomib for Injection. Measure platelet counts prior to each dose of Bortezomib for Injection. Adjust dose/schedule for thrombocytopenia [see Dosage and Administration (2.6) ] . Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with Bortezomib for Injection. Support with transfusions and supportive care, according to published guidelines. In the single agent, relapsed multiple myeloma study of Bortezomib for Injection vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 8 . The incidence of bleeding (≥Grade 3) was 2% on the Bortezomib for Injection arm and was <1% in the dexamethasone arm. Table 8: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib for Injection vs Dexamethasone Pretreatment Platelet Count A baseline platelet count of 50,000/µL was required for study eligibility Number of Patients (N=331) Data were missing at baseline for one patient Number (%) of Patients with Platelet Count <10,000/µL Number (%) of Patients with Platelet Count 10,000 to 25,000/µL ≥75,000/µL 309 8 (3%) 36 (12%) ≥50,000/µL to <75,000/µL 14 2 (14%) 11 (79%) ≥10,000/µL to <50,000/µL 7 1 (14%) 5 (71%) In the combination study of Bortezomib for Injection with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥Grade 4) was 32% vs 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 12 . The incidence of bleeding events (≥Grade 3) was 1.7% in the VcR-CAP arm (four patients) and was 1.2% in the R-CHOP arm (three patients). 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 R-CHOP arm. The incidence of febrile neutropenia (≥Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm. 5.8 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with Bortezomib for Injection therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. 5.9 Hepatic Toxicity 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 Bortezomib for Injection therapy to assess reversibility. There is limited rechallenge information in these patients. 5.10 Thrombotic Microangiopathy Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received Bortezomib for Injection. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Bortezomib for Injection and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting Bortezomib for Injection. The safety of reinitiating Bortezomib for Injection therapy in patients previously experiencing TTP/HUS is not known. 5.11 Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, Bortezomib for Injection can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area caused postimplantation loss and a decreased number of live fetuses [see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bortezomib for Injection and for four months following treatment. If Bortezomib for Injection is used during pregnancy or if the patient becomes pregnant during Bortezomib for Injection treatment, the patient should be apprised of the potential risk to the fetus [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ] .