Drug Detail:Velcade (Bortezomib [ bor-tez-oh-mib ])
Generic Name: bortezomib 3.5mg
Dosage Form: injection, powder, lyophilized, for solution
Drug Class: Proteasome inhibitors
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.
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.
| 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 |
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 × 109/L and the absolute neutrophil count (ANC) should be at least 1 × 109/L
- Nonhematological toxicities should have resolved to Grade 1 or baseline
| 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 × 109/L or ANC is not above 0.75 × 109/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/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2) |
| 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/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). 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)].
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.
| Twice Weekly VELCADE (6, Three Week Cycles)* | ||||||||
|---|---|---|---|---|---|---|---|---|
| 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 |
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 × 109/L and absolute neutrophil count (ANC) should be at least 1.5 × 109/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)]. For dose adjustments, see Table 4 below.
| Toxicity | Dose Modification or Delay |
|---|---|
| Hematological Toxicity | |
|
Withhold VELCADE therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 109/L and a platelet count at or above 25 × 109/L.
|
| 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/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). 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/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.
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.
| Severity of Peripheral Neuropathy Signs and Symptoms* | 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)†) | Reduce VELCADE to 1 mg/m2 |
| Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL‡) | Withhold VELCADE therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m2 once per week. |
| Grade 4 (life-threatening consequences; urgent intervention indicated) | Discontinue VELCADE |
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/m2 per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 based on patient tolerance (see Table 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
| 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/m2 in the first cycle. Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability. |
| Severe | More than 3× ULN | Any | |
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 [see Dosage and Administration (2.10)].
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 [see Dosage and Administration (2.10)]. Alternatively, consider use of the intravenous route of administration [see Dosage and Administration (2.10)].
VELCADE is a hazardous drug. Follow applicable special handling and disposal procedures.1
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):
| 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.
