Bortezomib

For intravenous use only. (2.1, 2.10) The recommended starting dose of Bortezomib Injection is 1.3 mg/m 2 administered as a 3 to 5 second bolus intravenous injection. (2.2, 2.4, 2.6) Retreatment for multiple myeloma: May retreat starting at the last tolerated dose. (2.6) Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. (2.8) Dose must be individualized to prevent overdose. (2.10)

2.1 Important Dosing Guidelines Bortezomib Injection is a ready-to-use sterile solution for intravenous use only. Do not administer Bortezomib Injection by any other route. The recommended starting dose of Bortezomib Injection is 1.3 mg/m 2 . Bortezomib Injection is administered intravenously at a concentration of 1 mg/mL or 2.5 mg/mL [see Dosage and Administration (2.9 and 2.10)]. Bortezomib Injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with bortezomib and who have relapsed at least six months after completing prior bortezomib treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6)] . Administer Bortezomib Injection as a 3 to 5 second bolus intravenous injection.

2.2 Dosage in Previously Untreated Multiple Myleoma Bortezomib Injection is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1. In Cycles 1 to 4, Bortezomib Injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, Bortezomib Injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib Injection. Table 1 2.3 Dose Modification Guidelines for Bortezomib Injection When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with Bortezomib Injection in combination with melphalan and prednisone: Platelet count should be at least 70 × 10 9 /L and the absolute neutrophil count (ANC) should be at least 1 × 10 9 /L Nonhematological toxicities should have resolved to Grade 1 or baseline For information concerning melphalan and prednisone, see manufacturer's prescribing information. Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (2.7)] . Table 2 2.4 Dosage in Previously Untreated Mantle Cell Lymphoma Bortezomib Injection (1.3 mg/m 2 ) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in Table 3. Bortezomib Injection is administered first followed by rituximab. Bortezomib Injection is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 21. For patients with a response first documented at cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of Bortezomib Injection. Table 3 2.5 Dose Modification Guidelines for Bortezomib Injection When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Prior to the first day of each cycle (other than Cycle 1): Platelet count should be at least 100 × 10 9 /L and absolute neutrophil count (ANC) should be at least 1.5 × 100 9 /L Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L) Nonhematologic toxicity should have recovered to Grade 1 or baseline Interrupt Bortezomib Injection treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy [see Table 5, Warnings and Precautions (5)] . For dose adjustments, see Table 4 below. For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information. Table 4 2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Bortezomib Injection (1.3 mg/m 2 /dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21). For extended therapy of more than eight cycles, Bortezomib Injection may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day rest period (Days 23 to 35) [see Clinical Studies (14)] . At least 72 hours should elapse between consecutive doses of Bortezomib Injection. Patients with multiple myeloma who have previously responded to treatment with bortezomib (either alone or in combination) and who have relapsed at least six months after their prior bortezomib therapy may be started on Bortezomib Injection at the last tolerated dose. Retreated patients are administered Bortezomib Injection twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of Bortezomib Injection. Bortezomib Injection may be administered either as a single agent or in combination with dexamethasone [see Clinical Studies (14.1)] . Bortezomib Injection therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions (5)] . Once the symptoms of the toxicity have resolved, Bortezomib Injection therapy may be reinitiated at a 25% reduced dose (1.3 mg/m 2 /dose reduced to 1 mg/m 2 /dose; 1 mg/m 2 /dose reduced to 0.7 mg/m 2 /dose). For dose modifications guidelines for peripheral neuropathy see section 2.7.

2.7 Dose Modifications for Peripheral Neuropathy Patients with preexisting severe neuropathy should be treated with Bortezomib Injection only after careful risk-benefit assessment. Patients experiencing new or worsening peripheral neuropathy during Bortezomib Injection therapy may require a decrease in the dose and/or a less dose-intense schedule. For dose or schedule modification guidelines for patients who experience Bortezomib Injection-related neuropathic pain and/or peripheral neuropathy see Table 5. Table 5 2.8 Dosage in Patients with Hepatic Impairment Do not adjust the starting dose for patients with mild hepatic impairment. Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m 2 per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m 2 or further dose reduction to 0.5 mg/m 2 based on patient tolerance (see Table 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] . Table 6 2.9 Administration Precautions The drug quantity contained in one vial may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose [see Dosage and Administration (2.10)] . Bortezomib Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 2.10 Instructions for Intravenous Administration Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of Bortezomib Injection to be administered based on the drug product concentration: A sticker that indicates the route of administration is provided with each Bortezomib Injection vial. Place this sticker directly on the syringe once the required volume of Bortezomib Injection has been withrdrawn from the vial to help alert the practitioners of the correct route of administration for Bortezomib Injection Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the product should not be used. Discard any unused portion. Stability Unopened vials of Bortezomib Injection are stable until the date indicated on the package when stored refrigerated at 2 to 8ºC (36 ºF to 46 °F) in the original package protected from light. Bortezomib Injection contains no antimicrobial preservative. Unopened vials may be stored at room temperature (20ºC to 25ºC [68 ºF to 77 ºF]) for up to 7 days prior to use. Instructions for Use

5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation. (2.7) Patients with preexisting severe neuropathy should be treated with Bortezomib 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 Injection therapy. (5.4) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib 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 Injection therapy to assess reversibility. (5.9) Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Bortezomib Injection if suspected. (5.10) Embryo-fetal Toxicity: Bortezomib 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 treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with preexisting 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 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, the incidence of Grade ≥2 peripheral neuropathy was 39% for intravenous administration. Grade ≥3 peripheral neuropathy occurred in 15% of patients in the intravenous treatment group [see Adverse Reactions (6.1)] . Patients experiencing new or worsening peripheral neuropathy during Bortezomib 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 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 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 vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib 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 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. 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 relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with bortezomib administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib 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. 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 Injection therapy in patients previously experiencing PRES is not known.

5.6 Gastrointestinal Toxicity Bortezomib 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 Injection for severe symptoms.

5.7 Thrombocytopenia/Neutropenia Bortezomib 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 Injection. Measure platelet counts prior to each dose of Bortezomib Injection. Adjust dose/schedule for thrombocytopenia [see Tables 2 and 4, Dosage and Administration (2.6)] . Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with bortezomib. Support with transfusions and supportive care, according to published guidelines. In the single-agent, relapsed multiple myeloma study of bortezomib 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 7. The incidence of bleeding (≥Grade 3) was 2% on the bortezomib arm and was <1% in the dexamethasone arm. In the combination study of bortezomib 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. Table 7 5.8 Tumor Lysis Syndrome Tumor lysis syndrome has been reported with bortezomib 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 Injection therapy to assess reversibility. There is limited re-challenge 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. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Bortezomib Injection and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting Bortezomib Injection. The safety of reinitiating Bortezomib 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 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 that they must use contraception during treatment with Bortezomib Injection and for seven months following treatment. Advise males with female partners of reproductive potential that they must use contraception during treatment with Bortezomib Injection and for four months following treatment. If Bortezomib Injection is used during pregnancy or if the patient becomes pregnant during Bortezomib 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)].

The following clinically significant adverse reactions are also discussed in other sections of the labeling: Peripheral Neuropathy [see Warnings and Precautions (5.1)] Hypotension [see Warnings and Precautions (5.2)] Cardiac Toxicity [see Warnings and Precautions (5.3)] Pulmonary Toxicity [see Warnings and Precautions (5.4)] Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.5)] Gastrointestinal Toxicity [see Warnings and Precautions (5.6)] Thrombocytopenia/Neutropenia [see Warnings and Precautions (5.7)] Tumor Lysis Syndrome [see Warnings and Precautions (5.8)] Hepatic Toxicity [see Warnings and Precautions (5.9)] Thrombotic Microangiopathy [see Warnings and Precautions (5.10)] Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact MAIA Pharmaceuticals, Inc. at 1-888-877-9064 or FDA at 1-800-FDA-1088 or www.fda.g ov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma Table 8 describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m 2 ) administered intravenously in combination with melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) in a prospective randomized study. The safety profile of Bortezomib Injection in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone The safety data described below and in Table 9 reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m 2 twice weekly for two out of three weeks (21 day cycle). After eight 21 day cycles patients continued therapy for three 35 day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients <65 and ≥65 years of age. Most patients were Caucasian [see Clinical Studies (14.1)] . Among the 331 bortezomib-treated patients, the most commonly reported (>20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (>20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each). A total of 145 patients, including 84 (25%) of 331 patients in the bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 bortezomib treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each). Four deaths were considered to be bortezomib-related in this relapsed multiple myeloma study: one case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: two cases of sepsis, one case of bacterial meningitis, and one case of sudden death at home. Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 9. All adverse reactions with incidence ≥10% in the bortezomib arm are included. Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study [see Clinical Studies (14.1)] . Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma Table 10 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received bortezomib (1.3 mg/m 2 ) administered intravenously in combination with rituximab (375 mg/m 2 ), cyclophosphamide (750 mg/m 2 ), doxorubicin (50 mg/m 2 ), and prednisone (100 mg/m 2 ) (VcR-CAP) in a prospective randomized study. Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% vs R-CHOP 5%). The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment. The incidences of Grade ≥3 bleeding events were similar between the two arms (four patients in the VcR-CAP arm and three patients in the R-CHOP arm). All of the Grade ≥3 bleeding events resolved without sequelae in the VcR-CAP arm. Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; three patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (<1%; two patients). Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma) Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m 2 /dose twice weekly for two weeks followed by a ten day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (>20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). In the Phase 2 relapsed multiple myeloma clinical trials of bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of bortezomib was not associated with tissue damage. Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each). Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each). In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis. Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety The most common adverse reactions are shown in Table 11. All adverse reactions occurring at ≥10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows. Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 Relapsed Mantle Cell Lymphoma Studies Gastrointestinal Toxicity A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia. Grade 3 adverse reactions occurred in 14% of patients; ≥Grade 4 adverse reactions were ≤1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%). Thrombocytopenia Across the studies, bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (Days 1 to 11) and a return toward baseline during the ten day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in bortezomib discontinuation in 2% of patients [see Warnings and Precautions (5.7)] . Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%). Peripheral Neuropathy Overall, peripheral neuropathies occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and ≥Grade 4 for <1% of patients. Eight percent (8%) of patients discontinued bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%). In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, among the 62 bortezomib-treated patients who experienced ≥Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset. In the Phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one Grade or more from the last dose of bortezomib. Hypotension The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥Grade 4 in <1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, <1% of patients experienced hypotension associated with a syncopal reaction. Neutropenia Neutrophil counts decreased during the bortezomib dosing period (Days 1 to 11) and returned toward baseline during the ten day rest period during each treatment cycle. Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in <1% of patients and <1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%). Asthenic conditions (Fatigue, Malaise, Weakness, Asthenia) Asthenic conditions were reported in 54% of patients. Fatigue was reported as Grade 3 in 7% and ≥Grade 4 in <1% of patients. Asthenia was reported as Grade 3 in 2% and ≥Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma. Pyrexia Pyrexia (> 38°C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥Grade 4 in <1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to bortezomib discontinuation in <1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥Grade 3 pyrexia was 1% in patients with multiple myeloma and <1% in patients with mantle cell lymphoma. Herpes Virus Infection Consider using antiviral prophylaxis in subjects being treated with Bortezomib Injection. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between 6 to 11%) than in the control groups (3 to 4%). Herpes simplex was seen in 1 to 3% in subjects treated with bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%). Retreatment in Relapsed Multiple Myeloma A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in Tables 10, 11, and 13; no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of ≥Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of ≥Grade 3 peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each). Adverse reactions leading to discontinuation occurred in 13% of patients. The reasons for discontinuation included peripheral neuropathy (5%) and diarrhea (3%). Two deaths considered to be bortezomib-related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis. Additional Adverse Reactions from Clinical Studies The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors. Blood and Lymphatic System Disorders: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia Cardiac Disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes , ventricular tachycardia Ear and Labyrinth Disorders: Hearing impaired, vertigo Eye Disorders: Diplopia and blurred vision, conjunctival infection, irritation Gastrointestinal Disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux General Disorders and Administration Site Conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis Hepatobiliary Disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure Immune System Disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema Infections and Infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter related infection Injury, Poisoning and Procedural Complications: Catheter related complication, skeletal fracture, subdural hematoma Investigations: Weight decreased Metabolism and Nutrition Disorders: Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremity Nervous System Disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack Psychiatric Disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation Renal and Urinary Disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension Skin and Subcutaneous Tissue disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus. Vascular Disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension Table 8 Table 9 Table 10 Table 11 6.2 Postmarketing Experience The following adverse reactions have been identified from the worldwide postmarketing experience with bortezomib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Cardiac Disorders: Cardiac tamponade Ear and Labyrinth Disorders: Deafness bilateral Eye Disorders: Optic neuropathy, blindness, chalazion/blepharitis Gastrointestinal Disorders: Ischemic colitis Infections and Infestations: Progressive multifocal leukoencephalopathy (PML), ophthalmic herpes, herpes meningoencephalitis Nervous System Disorders: Posterior reversible encephalopathy syndrome (PRES, formerly RPLS), Guillain-Barré syndrome, demyelinating polyneuropathy Respiratory, Thoracic and Mediastinal Disorders: Acute diffuse infiltrative pulmonary disease Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute febrile neutrophilic dermatosis (Sweet's syndrome)

8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1)] and findings in animals, Bortezomib Injection can cause fetal harm when administered to a pregnant woman. There are no studies with the use of bortezomib in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data) . Advise pregnant women of the potential risk to the fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data 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/m 2 in the rat and 0.05 mg/kg; 0.6 mg/m 2 in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately 0.5 times the clinical dose of 1.3 mg/m 2 based on body surface area). Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/m 2 ) experienced significant postimplantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight.

8.2 Lactation Risk Summary There are no data on the presence of bortezomib or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Bortezomib Injection is unknown, advise nursing women not to breastfeed during treatment with Bortezomib Injection and for two months after treatment.

8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, Bortezomib Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Conduct pregnancy testing in females of reproductive potential prior to initiating Bortezomib Injection treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Bortezomib Injection and for seven months after the last dose. Males Males with female partners of reproductive potential should use effective contraception during treatment with Bortezomib Injection and for four months after the last dose. Infertility Based on the mechanism of action and findings in animals, Bortezomib Injection may have an effect on either male or female fertility [see Nonclinical Toxicology (13.1)] .

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. The activity and safety of bortezomib in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, non-randomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in three blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; Block 2 included cyclophosphamide, etoposide and methotrexate; Block 3 included high dose cytosine arabinoside and asparaginase. Bortezomib was administered at a dose of 1.3 mg/m 2 as a bolus intravenous injection on Days 1, 4, 8, and 11 of Block 1 and Days 1, 4, and 8 of Block 2. There were 140 patients with ALL or LL enrolled and evaluated for safety. The median age was ten years (range 1 to 26), 57% were male, 70% were white, 14% were black, 4% were Asian, 2% were American Indian/ Alaska Native, 1% were Pacific Islander. The activity was evaluated in a pre-specified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL ≤21 years and relapsed <36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without bortezomib. There was no evidence that the addition of bortezomib had any impact on the CR rate. No new safety concerns were observed when bortezomib was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without bortezomib. The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.

8.5 Geriatric Use Of the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the bortezomib arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥65 were longer on bortezomib compared to dexamethasone [5.5 mo vs 4.3 mo, and 8.0 mo vs 4.9 mo, respectively]. On the bortezomib arm, 40% (n=46) of evaluable patients aged ≥65 experienced response (CR+PR) vs 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for bortezomib patients ≤50, 51 to 64 and ≥65 years old, respectively [see Adverse Reactions (6.1); Clinical Studies (14.1)] . No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving bortezomib; but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment No starting dosage adjustment of Bortezomib Injection is recommended for patients with renal impairment. In patients requiring dialysis, Bortezomib Injection should be administered after the dialysis procedure [see Clinical Pharmacology (12.3)] .

8.7 Hepatic Impairment No starting dosage adjustment of Bortezomib Injection is recommended for patients with mild hepatic impairment (total bilirubin ≤1× ULN and AST > ULN, or total bilirubin >1 to 1.5× ULN and any AST). The exposure of bortezomib is increased in patients with moderate (total bilirubin ≥1.5 to 3× ULN and any AST) and severe (total bilirubin >3× ULN and any AST) hepatic impairment. Reduce the starting dose in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.8), Clinical Pharmacology (12.3)] .

8.8 Patients with Diabetes During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib Injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.