Velcade

VELCADE is a proteasome inhibitor indicated for:

• treatment of adult patients with multiple myeloma (
  1.1 Multiple Myeloma

  VELCADE is indicated for the treatment of adult patients with multiple myeloma.
  )
• treatment of adult patients with mantle cell lymphoma (
  1.2 Mantle Cell Lymphoma

  VELCADE is indicated for the treatment of adult patients with mantle cell lymphoma.
  )

• 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 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/m². VELCADE is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL

  [see Dosage and Administration (2.10)]

  .

  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

  [see Dosage and Administration (2.6)]

  .

  When administered intravenously, administer VELCADE as a 3 to 5 second bolus intravenous injection.
  ,
  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

  [see Dosage and Administration (2.9)]

  .

  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/m2) × patient BSA (m2)	=Total VELCADE volume (mL) to be administered
    1 mg/mL

  • Subcutaneous Administration [2.5 mg/mL concentration]

    VELCADE dose (mg/m2) × patient BSA (m2)	=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.
  )
• The recommended starting dose of VELCADE is 1.3 mg/m² administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. (
  2.2 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/m2)	Day 1	--	--	Day 4	Day 8	Day 11	rest period	Day 22	Day 25	Day 29	Day 32	rest period
  Melphalan (9 mg/m2) Prednisone (60 mg/m2)	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/m2)	Day 1	--	--		Day 8		rest period	Day 22		Day 29		rest period
  Melphalan (9 mg/m2) Prednisone (60 mg/m2)	Day 1	Day 2	Day 3	Day 4	--	--	rest period	--	--	--	--	rest period
  ,
  2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

  VELCADE (1.3 mg/m²) 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/m2)	Day 1	--	--	Day 4	--	Day 8	Day 11	rest period
  Rituximab (375 mg/m2) Cyclophosphamide (750 mg/m2) Doxorubicin (50 mg/m2)	Day 1	--	--			--	--	rest period
  Prednisone (100 mg/m2)	Day 1	Day 2	Day 3	Day 4	Day 5	--	--	rest period
  ,
  2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

  VELCADE (1.3 mg/m²/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)

  [see Clinical Studies (14)]

  . 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

  [see Clinical Studies (14.1)]

  .

  VELCADE 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, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose).

  For dose modifications guidelines for peripheral neuropathy, see section 2.7.
  )
• Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. (
  2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

  VELCADE (1.3 mg/m²/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)

  [see Clinical Studies (14)]

  . 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

  [see Clinical Studies (14.1)]

  .

  VELCADE 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, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose).

  For dose modifications guidelines for peripheral neuropathy, see section 2.7.
  )
• Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. (
  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/m²per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m²or further dose reduction to 0.5 mg/m²based on patient tolerance

  (see Table 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]

  .

  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/m2in the first cycle. Consider dose escalation to 1 mg/m2or further dose reduction to 0.5 mg/m2in subsequent cycles based on patient tolerability.
  Severe	More than 3× ULN	Any
  )
• Dose must be individualized to prevent overdose. (
  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

  [see Dosage and Administration (2.9)]

  .

  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/m2) × patient BSA (m2)	=Total VELCADE volume (mL) to be administered
    1 mg/mL

  • Subcutaneous Administration [2.5 mg/mL concentration]

    VELCADE dose (mg/m2) × patient BSA (m2)	=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.
  )

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

Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. (

• Peripheral Neuropathy: Manage with dose modification or discontinuation. (
  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 SymptomsGrading 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/m2
  Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADLSelf 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/m2once per week.
  Grade 4 (life-threatening consequences; urgent intervention indicated)	Discontinue VELCADE
  ) Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. (
  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 SymptomsGrading 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/m2
  Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADLSelf 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/m2once per week.
  Grade 4 (life-threatening consequences; urgent intervention indicated)	Discontinue VELCADE
  ,
  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

  [see Adverse Reactions (6.1)]

  . Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

  Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule

  [see Dosage and Administration (2.7)]

  . 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: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. (
  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.
  )
• 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 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

  [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 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 syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy. (
  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 VELCADE. Some of these events have been fatal.

  In a clinical trial, the first two patients given high-dose cytarabine (2 g/m²per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.

  There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

  In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt and comprehensive diagnostic evaluation is conducted.
  )
• Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. (
  5.5 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: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. (
  5.6 Gastrointestinal Toxicity

  VELCADE 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 VELCADE for severe symptoms.
  )
• Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. (
  5.7 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

  [see Dosage and Administration (2.6)]

  . 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 CountA 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: Closely monitor patients with high tumor burden. (
  5.8 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: Monitor hepatic enzymes during treatment. Interrupt VELCADE therapy to assess reversibility. (
  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 VELCADE therapy to assess reversibility. There is limited rechallenge information in these patients.
  )
• Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue VELCADE if suspected. (
  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 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: 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. (
  5.11 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/m²based 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 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

  [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)]

  .
  )