VELCADE ® for Injection, a proteasome inhibitor, contains bortezomib which is an antineoplastic agent. Bortezomib is a modified dipeptidyl boronic acid. The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. Bortezomib has the following chemical structure: The molecular weight is 384.24. The molecular formula is C 19 H 25 BN 4 O 4. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5. VELCADE is available for intravenous injection or subcutaneous use. Each single-dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. It also contains the inactive ingredient: 35 mg mannitol, USP. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine. Chemical Structure

VELCADE is a proteasome inhibitor indicated for: treatment of adult patients with multiple myeloma treatment of adult patients with mantle cell lymphoma 1.1 Multiple Myeloma VELCADE is indicated for the treatment of adult patients with multiple myeloma

Mantle Cell Lymphoma VELCADE is indicated for the treatment of adult patients with mantle cell lymphoma.

For injection: Each single-dose vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder for reconstitution and withdrawal of the appropriate individual patient dose . For injection: Single-dose vial contains 3.5 mg of bortezomib as lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose.

For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. ( 2.1 , 2.10 ) The recommended starting dose of VELCADE is 1.3 mg/m 2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. ( 2.2 , 2.4 , 2.6 ) Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. Dose must be individualized to prevent overdose

Important Dosing Guidelines VELCADE is for intravenous or subcutaneous use only. Do not administer VELCADE by any other route. Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered. The recommended starting dose of VELCADE is 1.3 mg/m 2 . VELCADE is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL . VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least six months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose . When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection

Dosage in Previously Untreated Multiple Myeloma VELCADE 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, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE. Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly VELCADE (Cycles 1 to 4) Week 1 2 3 4 5 6 VELCADE (1.3 mg/m 2 ) Day 1 -- -- Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period Once Weekly VELCADE (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week 1 2 3 4 5 6 VELCADE (1.3 mg/m 2 ) Day 1 -- -- Day 8 rest period Day 22 Day 29 rest period Melphalan (9 mg/m 2 ) Prednisone (60 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period 2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone Prior to initiating any cycle of therapy with VELCADE 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 Table 2: Dose Modifications During Cycles of Combination VELCADE, Melphalan and Prednisone Therapy Toxicity Dose Modification or Delay Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle Consider reduction of the melphalan dose by 25% in the next cycle If platelet count is not above 30 × 10 9 /L or ANC is not above 0.75 × 10 9 /L on a VELCADE dosing day (other than Day 1) Withhold VELCADE dose If several VELCADE doses in consecutive cycles are withheld due to toxicity Reduce VELCADE dose by one dose level (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ) Grade 3 or higher nonhematological toxicities Withhold VELCADE therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 5 . For information concerning melphalan and prednisone, see manufacturer's prescribing information. Dose modifications guidelines for peripheral neuropathy are provided

Dosage in Previously Untreated Mantle Cell Lymphoma VELCADE (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 . VELCADE is administered first followed by rituximab. VELCADE 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 VELCADE. Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly VELCADE (6, Three Week Cycles) Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6. Week 1 2 3 VELCADE (1.3 mg/m 2 ) Day 1 -- -- Day 4 -- Day 8 Day 11 rest period Rituximab (375 mg/m 2 ) Cyclophosphamide (750 mg/m 2 ) Doxorubicin (50 mg/m 2 ) Day 1 -- -- -- -- rest period Prednisone (100 mg/m 2 ) Day 1 Day 2 Day 3 Day 4 Day 5 -- -- rest period 2.5 Dose Modification Guidelines for VELCADE 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 × 10 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 VELCADE treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy . For dose adjustments, see Table 4 below. Table 4: Dose Modifications on Days 4, 8, and 11 During Cycles of Combination VELCADE, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy Toxicity Dose Modification or Delay Hematological Toxicity Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 10 9 /L Withhold VELCADE therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L. If, after VELCADE has been withheld, the toxicity does not resolve, discontinue VELCADE. If toxicity resolves such that the patient has an ANC at or above 0.75 × 10 9 /L and a platelet count at or above 25 × 10 9 /L, VELCADE dose should be reduced by 1 dose level (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ). Grade 3 or higher nonhematological toxicities Withhold VELCADE therapy until symptoms of the toxicity have resolved to Grade 2 or better. Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m 2 to 1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 5 . For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information

Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma VELCADE (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, VELCADE 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) . At least 72 hours should elapse between consecutive doses of VELCADE. Patients with multiple myeloma who have previously responded to treatment with VELCADE (either alone or in combination) and who have relapsed at least six months after their prior VELCADE therapy may be started on VELCADE at the last tolerated dose. Retreated patients are administered VELCADE 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 VELCADE. VELCADE may be administered either as a single agent or in combination with dexamethasone . VELCADE therapy should be withheld at the onset of any Grade 3 nonhematological or Grade 4 hematological toxicities excluding neuropathy as discussed below . Once the symptoms of the toxicity have resolved, VELCADE 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

Dose Modifications for Peripheral Neuropathy Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. Patients experiencing new or worsening peripheral neuropathy during VELCADE 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 VELCADE-related neuropathic pain and/or peripheral neuropathy, see Table 5 . Table 5: Recommended Dose Modification for VELCADE-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy Severity of Peripheral Neuropathy Signs and Symptoms Grading based on NCI Common Terminology Criteria CTCAE v4.0 Modification of Dose and Regimen Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function No action Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL) Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc. ) Reduce VELCADE to 1 mg/m 2 Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden ) Withhold VELCADE therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m 2 once per week. Grade 4 (life-threatening consequences; urgent intervention indicated) Discontinue VELCADE 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 . Table 6: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic Impairment Bilirubin Level SGOT (AST) Levels Modification of Starting Dose Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range. Mild Less than or equal to 1× ULN More than ULN None More than 1× to 1.5× ULN Any None Moderate More than 1.5× to 3× ULN Any Reduce VELCADE to 0.7 mg/m 2 in the first cycle. Consider dose escalation to 1 mg/m 2 or further dose reduction to 0.5 mg/m 2 in subsequent cycles based on patient tolerability. Severe More than 3× ULN Any 2.9 Administration Precautions The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose . When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated. If local injection site reactions occur following VELCADE administration subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously . Alternatively, consider use of the intravenous route of administration . VELCADE is a hazardous drug. Follow applicable special handling and disposal procedures. 1 2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration Use proper aseptic technique. Reconstitute only with 0.9% sodium chloride . The reconstituted product should be a clear and colorless solution. Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered . For each 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 7) : Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration Route of Administration Bortezomib (mg/vial) Diluent (0.9% Sodium Chloride) Final Bortezomib Concentration (mg/mL) Intravenous 3.5 mg 3.5 mL 1 mg/mL Subcutaneous 3.5 mg 1.4 mL 2.5 mg/mL 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 reconstituted VELCADE to be administered: Intravenous Administration [1 mg/mL concentration] VELCADE dose (mg/m 2 ) × patient BSA (m 2 ) =Total VELCADE volume (mL) to be administered 1 mg/mL Subcutaneous Administration [2.5 mg/mL concentration] VELCADE dose (mg/m 2 ) × patient BSA (m 2 ) =Total VELCADE volume (mL) to be administered 2.5 mg/mL Stickers that indicate the route of administration are provided with each VELCADE vial. These stickers should be placed directly on the syringe of VELCADE once VELCADE is prepared to help alert practitioners of the correct route of administration for VELCADE. 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 reconstituted product should not be used. Stability Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light. VELCADE contains no antimicrobial preservative. Administer reconstituted VELCADE within eight hours of preparation. When reconstituted as directed, VELCADE may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.

Peripheral Neuropathy: Manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy. Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt VELCADE therapy to assess reversibility. Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue VELCADE if suspected. Embryo-Fetal Toxicity: VELCADE 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. 5.1 Peripheral Neuropathy 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 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 . 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 . In the VELCADE 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

Hypotension The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8% . 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

Cardiac Toxicity 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 frequently monitored. In the relapsed multiple myeloma study of VELCADE vs 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

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 VELCADE. 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 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

Gastrointestinal Toxicity VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting 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

Thrombocytopenia/Neutropenia 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 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 VELCADE. Measure platelet counts prior to each dose of VELCADE. Adjust dose/schedule for thrombocytopenia . Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with VELCADE. Support with transfusions and supportive care, according to published guidelines. In the single agent, relapsed multiple myeloma study of VELCADE 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 VELCADE 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 VELCADE 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 VELCADE 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

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

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 VELCADE therapy to assess reversibility. There is limited rechallenge information in these patients

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 VELCADE. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop VELCADE and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing TTP/HUS is not known

Embryo-Fetal Toxicity Based on the mechanism of action and findings in animals, VELCADE 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 . Advise females of reproductive potential to use effective contraception during treatment with VELCADE and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with VELCADE and for four months following treatment. If VELCADE is used during pregnancy or if the patient becomes pregnant during VELCADE treatment, the patient should be apprised of the potential risk to the fetus .

Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. Strong CYP3A4 Inducers: Avoid concomitant use

Effects of Other Drugs on VELCADE Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib which may decrease VELCADE efficacy. Avoid coadministration with strong CYP3A4 inducers. Strong CYP3A4 Inhibitors Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib which may increase the risk of VELCADE toxicities. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors

Drugs Without Clinically Significant Interactions with VELCADE No clinically significant drug interactions have been observed when VELCADE was coadministered with dexamethasone, omeprazole, or melphalan in combination with prednisone .