Velcade

Q: Who makes Velcade?

Velcade is listed by 1 labeler in the FDA NDC directory, including Takeda Pharmaceuticals America, Inc..

bortezomib · Injection, Powder, Lyophilized, For Solution · Intravenous, Subcutaneous

Uses

1 INDICATIONS AND USAGE VELCADE is a proteasome inhibitor indicated for: treatment of adult patients with multiple myeloma ( 1.1 ) treatment of adult patients with mantle cell lymphoma ( 1.2 ) 1.1 Multiple Myeloma VELCADE is indicated for the treatment of adult patients with multiple myeloma. 1.2 Mantle Cell Lymphoma VELCADE is indicated for the treatment of adult patients with mantle cell lymphoma.

Dosage and administration

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. ( 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 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 [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. 2.2 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/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 [see Dosage and Administration (2.7) ] . 2.4 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 [see Table 5, Warnings and Precautions (5) ] .

Dosage forms and strengths

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 [see Dosage and Administration (2.10) ] . For injection: Single-dose vial contains 3.5 mg of bortezomib as lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose. ( 3 )

Contraindications

4 CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions (6.1) ] . VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. ( 4 ) Contraindicated for intrathecal administration. ( 4 )

Warnings and precautions

Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with pre-existing severe neuropathy should be treated with VELCADE 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 VELCADE therapy. ( 5.4 ) Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE 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 VELCADE therapy to assess reversibility. ( 5.9 ) Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue VELCADE if suspected. ( 5.10 ) 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 ) 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. 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 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. 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/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.

Side effects

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 Takeda Pharmaceuticals at 1-866-VELCADE or FDA at 1-800-FDA-1088 or www.fda.gov/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 9 describes safety data from 340 patients with previously untreated multiple myeloma who received VELCADE (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 VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. Table 9: Most Commonly Reported Adverse Reactions (≥10% in the VELCADE, Melphalan and Prednisone Arm) with Grades 3 and ≥4 Intensity in the Previously Untreated Multiple Myeloma Study VELCADE, Melphalan and Prednisone Melphalan and Prednisone (n=340) (n=337) Body System Total Toxicity Grade, n (%) Total Toxicity Grade, n (%) Adverse Reaction n (%) 3 ≥4 n (%) 3 ≥4 Blood and Lymphatic System Disorders Thrombocytopenia 164 (48) 60 (18) 57 (17) 140 (42) 48 (14) 39 (12) Neutropenia 160 (47) 101 (30) 33 (10) 143 (42) 77 (23) 42 (12) Anemia 109 (32) 41 (12) 4 (1) 156 (46) 61 (18) 18 (5) Leukopenia 108 (32) 64 (19) 8 (2) 93 (28) 53 (16) 11 (3) Lymphopenia 78 (23) 46 (14) 17 (5) 51 (15) 26 (8) 7 (2) Gastrointestinal Disorders Nausea 134 (39) 10 (3) 0 70 (21) 1 (<1) 0 Diarrhea 119 (35) 19 (6) 2 (1) 20 (6) 1 (<1) 0 Vomiting 87 (26) 13 (4) 0 41 (12) 2 (1) 0 Constipation 77 (23) 2 (1) 0 14 (4) 0 0 Abdominal pain upper 34 (10) 1 (<1) 0 20 (6) 0 0 Nervous System Disorders Peripheral neuropathy Represents High Level Term Peripheral Neuropathies NEC 156 (46) 42 (12) 2 (1) 4 (1) 0 0 Neuralgia 117 (34) 27 (8) 2 (1) 1 (<1) 0 0 Paresthesia 42 (12) 6 (2) 0 4 (1) 0 0 General Disorders and Administration Site Conditions Fatigue 85 (25) 19 (6) 2 (1) 48 (14) 4 (1) 0 Asthenia 54 (16) 18 (5) 0 23 (7) 3 (1) 0 Pyrexia 53 (16) 4 (1) 0 19 (6) 1 (<1) 1 (<1) Infections and Infestations Herpes Zoster 39 (11) 11 (3) 0 9 (3) 4 (1) 0 Metabolism and Nutrition Disorders Anorexia 64 (19) 6 (2) 0 19 (6) 0 0 Skin and Subcutaneous Tissue Disorders Rash 38 (11) 2 (1) 0 7 (2) 0 0 Psychiatric Disorders Insomnia 35 (10) 1 (<1) 0 21 (6) 0 0 Relapsed Multiple Myeloma Randomized Study of VELCADE vs Dexamethasone The safety data described below and in Table 10 reflect exposure to either VELCADE (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. VELCADE 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 VELCADE-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 VELCADE-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 VELCADE 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 VELCADE treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients.

Drug interactions

Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. ( 7.1 ) Strong CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) 7.1 Effects of Other Drugs on VELCADE Strong CYP3A4 Inducers Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib [see Clinical Pharmacology (12.3) ] 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 [see Clinical Pharmacology (12.3) ] 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. 7.2 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 [see Clinical Pharmacology (12.3) ] .

Use in specific populations

Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. ( 8.8 ) 8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, VELCADE can cause fetal harm when administered to a pregnant woman. There are no studies with the use of VELCADE 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 VELCADE is unknown, advise nursing women not to breastfeed during treatment with VELCADE and for two months after treatment. 8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, VELCADE 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 VELCADE treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with VELCADE and for seven months after the last dose. Males Males with female partners of reproductive potential should use effective contraception during treatment with VELCADE and for four months after the last dose. Infertility Based on the mechanism of action and findings in animals, VELCADE 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 VELCADE 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, nonrandomized 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. VELCADE 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 prespecified 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 VELCADE. There was no evidence that the addition of VELCADE had any impact on the CR rate. No new safety concerns were observed when VELCADE was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without VELCADE. 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 VELCADE arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥65 were longer on VELCADE compared to dexamethasone [5.5 mo vs 4.3 mo, and 8.0 mo vs 4.9 mo, respectively]. On the VELCADE 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 VELCADE 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 VELCADE; but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No starting dosage adjustment of VELCADE is recommended for patients with renal impairment.

Pregnancy

8.1 Pregnancy Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) ] and findings in animals, VELCADE can cause fetal harm when administered to a pregnant woman. There are no studies with the use of VELCADE 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.

Pediatric use

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. The activity and safety of VELCADE 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, nonrandomized 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. VELCADE 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 prespecified 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 VELCADE. There was no evidence that the addition of VELCADE had any impact on the CR rate. No new safety concerns were observed when VELCADE was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without VELCADE. The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.

Geriatric use

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 VELCADE arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥65 were longer on VELCADE compared to dexamethasone [5.5 mo vs 4.3 mo, and 8.0 mo vs 4.9 mo, respectively]. On the VELCADE 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 VELCADE 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 VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Overdosage

There is no known specific antidote for VELCADE overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given. Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m 2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m 2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at one hour postadministration, with progression to death in 12 to 14 hours following drug administration.

Description

11 DESCRIPTION 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

Mechanism of action

12.1 Mechanism of Action Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro . Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING VELCADE ® (bortezomib) for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder. NDC 63020-049-01 3.5 mg single-dose vial Unopened vials may be stored at controlled room temperature 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Retain in original package to protect from light. Follow guidelines for handling and disposal for hazardous drugs, including the use of gloves and other protective clothing to prevent skin contact 1 .

Storage

Unopened vials may be stored at controlled room temperature 25°C (77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Retain in original package to protect from light. Follow guidelines for handling and disposal for hazardous drugs, including the use of gloves and other protective clothing to prevent skin contact 1 .

Patient information

Discuss the following with patients prior to treatment with VELCADE: Peripheral Neuropathy Advise patients to report the development or worsening of sensory and motor peripheral neuropathy to their healthcare provider [see Warnings and Precautions (5.1) ] . Hypotension Advise patients to drink adequate fluids to avoid dehydration and to report symptoms of hypotension to their healthcare provider [see Warnings and Precautions (5.2) ] . Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps. Cardiac Toxicity Advise patients to report signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3) ] . Pulmonary Toxicity Advise patients to report symptoms of ARDS, pulmonary hypertension, pneumonitis, and pneumonia immediately to their healthcare provider [see Warnings and Precautions (5.4) ] . Posterior Reversible Encephalopathy Syndrome (PRES) Advise patients to seek immediate medical attention for signs or symptoms of PRES [see Warnings and Precautions (5.5) ] . Gastrointestinal Toxicity Advise patients to report symptoms of gastrointestinal toxicity to their healthcare provider and to drink adequate fluids to avoid dehydration. Instruct patients to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells, or muscle cramps [see Warnings and Precautions (5.6) ] . Thrombocytopenia/Neutropenia Advise patients to report signs or symptoms of bleeding or infection immediately to their healthcare provider [see Warnings and Precautions (5.7) ] . Tumor Lysis Syndrome Advise patients of the risk of tumor lysis syndrome and to drink adequate fluids to avoid dehydration [see Warnings and Precautions (5.8) ] . Hepatic Toxicity Advise patients to report signs or symptoms of hepatic toxicity to their healthcare provider [see Warnings and Precautions (5.9) ] . Thrombotic Microangiopathy Advise patients to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur [see Warnings and Precautions (5.10) ] . Ability to Drive or Operate Machinery or Impairment of Mental Ability VELCADE may cause fatigue, dizziness, syncope, orthostatic/postural hypotension. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Warnings and Precautions (5.2 , 5.5) ] . Embryo-Fetal Toxicity Advise females of the potential risk to the fetus and to use effective contraception during treatment with VELCADE and for seven months following the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VELCADE and for four months following the last dose. Instruct patients to report pregnancy to their physicians immediately if they or their female partner becomes pregnant during treatment or within seven months following last dose [see Warnings and Precautions (5.11) ] . Lactation Advise women not to breastfeed while receiving VELCADE and for two months after last dose [see Use in Specific Populations (8.2) ] . Concomitant Medications Advise patients to speak with their physicians about any other medication they are currently taking. Diabetic Patients Advise patients to check their blood sugar frequently if using an oral antidiabetic medication and to notify their physicians of any changes in blood sugar level. Dermal Advise patients to contact their physicians if they experience rash, severe injection site reactions [see Dosage and Administration (2.9) ] , or skin pain. Discuss with patients the option for antiviral prophylaxis for herpes virus infection [see Adverse Reactions (6.1) ] . Other Instruct patients to contact their physicians if they develop an increase in blood pressure, bleeding, fever, constipation, or decreased appetite.

Label text from the FDA structured product label by Takeda Pharmaceuticals America, Inc. (revised Aug 28, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Bortezomib in 1 product

Velcade NDC products (1)

NDC	Strength & form	Labeler	Type
63020-049	Bortezomib 3.5 mg/1 Injection, Powder, Lyophilized, For Solution	Takeda Pharmaceuticals America, Inc.	NDA

Frequently asked questions

What is Velcade used for?

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Who makes Velcade?

Velcade is listed by 1 labeler in the FDA NDC directory, including Takeda Pharmaceuticals America, Inc..