Considerations for relapsed multiple myeloma
Dosing Schedule for Subcutaneous or IV VELCADE® (bortezomib) in Relapsed Multiple Myeloma
- In the APEX trial,† responding patients received a median of 31 weeks of therapy (39 planned) using twice-weekly followed by weekly dosing1
- Administer VELCADE (bortezomib) (1.3 mg/m2) as a subcutaneous injection or a 3- to 5-second bolus IV injection
- Dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. In patients undergoing dialysis, VELCADE should be administered after the dialysis procedure
- In the APEX trial, discontinuations due to adverse reactions (ARs) were 25% for VELCADE and 18% for dexamethasone. In the subcutaneous vs IV trial, discontinuations due to ARs were 18% and 23%, respectively
- Please see [section 2] in the full Prescribing Information for dose modification guidelines for hematologic toxicities, nonhematologic toxicities, peripheral neuropathy, and moderate to severe hepatic impairment
Reconstitution of Subcutaneous and IV VELCADE (bortezomib)
A vial of VELCADE (bortezomib) can be used for either subcutaneous or IV administration, but reconstitution is different.
- The volume of 0.9% sodium chloride solution used to reconstitute VELCADE (bortezomib) for subcutaneous administration is different from the volume for IV administration
- The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL)
- Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered
- VELCADE contains no antimicrobial preservative
- Reconstituted VELCADE should be administered within 8 hours of preparation
Administration of VELCADE (bortezomib)
- VELCADE (bortezomib) is for subcutaneous or intravenous use only. VELCADE should not be administered by any other route
- Before VELCADE administration, visually inspect the solution for particulate matter and discoloration. If any discoloration or particulate matter is observed, do not use the reconstituted product. File a product complaint by calling 1-866-VELCADE
- Verify that the volume in the syringe is correct (refer to calculation below)
VELCADE Administration Volume Calculation
Instruction for Intravenous Administration
- Administer VELCADE (bortezomib) (1.3 mg/m2) as a 3- to 5-second bolus IV injection
VELCADE (bortezomib) can be Administered Subcutaneously in All Indications
- Administer VELCADE (bortezomib) (1.3 mg/m2) as a subcutaneous injection
- Use the abdomen or thighs as sites for subcutaneous injections
- Rotate injection sites
- Administer new injections at least 1 inch from an old site and never into areas where the skin is tender, bruised, erythematous, or indurated
Injection site reactions with subcutaneous administrations:
- In the clinical trial, the most common reaction was redness, occurring in 57% of patients.2 Injection site reactions were reported in 6% of patients as an adverse reaction, with 1% being serious and leading to dose modification or discontinuation. All events resolved in a median of 6 days
- If local injection site reactions occur following administration of VELCADE subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, consider the IV route of administration
- Please see administration precautions in the full Prescribing Information
Contraindications
- VELCADE (bortezomib) is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration
Dose Modification for Hematologic and Nonhematologic Toxicities
| Toxicity | Dose Modification or Delay | |
|
Neutropenia/Thrombocytopenia
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 | |
|
Thrombocytopenia during a cycle
If platelet count is not above 30 x 109/L or ANC is not above 0.75 x 109/L on a VELCADE (bortezomib) dosing day (other than day 1) |
Withhold VELCADE dose
|
If several doses in consecutive cycles are withheld due to toxicity, reduce VELCADE dose by 1 dose level‡ |
|
Grade 3 or higher nonhematologic toxicities (excluding peripheral neuropathy [PN] and hepatic)
|
Withhold VELCADE dose until symptoms of the toxicity have resolved to grade 1 or baseline
|
Then VELCADE may be reinitiated with 1 dose-level reduction‡ |
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- Prior to initiating any therapy with VELCADE+MP:
- Platelet count should be at least 70 x 109/L and ANC should be at least 1.0 x 109/L
- Nonhematologic toxicities should have resolved to grade 1 or baseline
‡From 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2.
- Prior to initiating any therapy with VELCADE+MP:
- Platelet count should be at least 70 x 109/L and ANC should be at least 1.0 x 109/L
- Nonhematologic toxicities should have resolved to grade 1 or baseline
Dose Modification for Peripheral Neuropathy
| Severity of PN Signs/Symptoms§ | Dose Modification or Delay | |
|
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 (bortezomib) |
|
|
Withhold VELCADE until toxicity resolves
|
When toxicity resolves, reinitiate with a reduced dose of 0.7 mg/m2 once per week | |
|
GRADE 4
(life-threatening consequences; urgent intervention indicated) |
Discontinue VELCADE | |
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Patients should be monitored for signs and symptoms of sensory and motor neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, weakness, or neuropathic pain.
§Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
||Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.
¶Self-care ADL refers to bathing, dressing and undressing, feeding self, using telephone, managing money, etc.
Patients should be monitored for signs and symptoms of sensory and motor neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, weakness, or neuropathic pain.
Dose Modification for Hepatic Impairment
| Bilirubin and SGOT (AST) Levels | Modification of Starting Dose |
| None | |
|
MODERATE
Bilirubin level more than 1.5–3 x ULN and any SGOT (AST) level |
Reduce VELCADE (bortezomib) to 0.7 mg/m2 in the first cycle Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2in subsequent cycles based on patient tolerability |
|
SEVERE Bilirubin level more than 3 x ULN and any SGOT (AST) level |
|
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#Upper limit of normal range.
**Serum glutamic oxaloacetic transaminase.
††Aspartate aminotransferase.
Indications and Important Safety Information for VELCADE® (bortezomib)
INDICATIONS: VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.
WARNINGS AND PRECAUTIONS
VELCADE (bortezomib) is for subcutaneous or IV administration only. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.Peripheral neuropathy, including severe cases, may occur. Patients should be monitored for symptoms and managed with dose modification or discontinuation. Patients with preexisting symptoms may experience worsening peripheral neuropathy (includingâ„grade 3). Starting with VELCADE subcutaneously may be considered for patients who either have preexisting or are at high risk for peripheral neuropathy.
Hypotension: Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated.
Cardiac toxicity, including acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction, has occurred. Isolated cases of QT-interval prolongation have been reported. Patients with risk factors for, or existing, heart disease should be closely monitored.
Pulmonary toxicity: Acute respiratory distress syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology have occurred (sometimes fatal). Pulmonary hypertension, in the absence of left heart failure or significant pulmonary disease, has been reported. 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 has occurred. Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected.
Gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting, has occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement. Interrupt VELCADE (bortezomib) for severe symptoms.
Thrombocytopenia/Neutropenia: Manage with dose and/or schedule modifications. Complete blood counts should be monitored frequently during treatment. There have been reports of gastrointestinal and intracerebral hemorrhage. Transfusions may be considered.
Tumor lysis syndrome: Closely monitor patients with high tumor burden and take appropriate precautions.
Hepatic toxicity: Monitor hepatic enzymes during treatment. Upon occurrence, interrupt therapy with VELCADE to assess reversibility.
Embryo-fetal risk: Women should avoid breast-feeding or becoming pregnant while on VELCADE.
Patients with diabetes may require close monitoring and adjustment of the antidiabetic medications.
DRUG INTERACTIONS: Closely monitor patients receiving VELCADE (bortezomib) in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.
ADVERSE REACTIONS
Previously untreated multiple myeloma (MM): In the phase 3 study of VELCADE administered intravenously with melphalan and prednisone (MP) vs MP alone, the most commonly reported adverse reactions (ARs) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), and leukopenia (32% vs 28%).
Relapsed MM and mantle cell lymphoma: In the integrated analysis of 1163 patients in phase 2 and 3 studies of VELCADE (bortezomib) administered intravenously, the most commonly reported ARs were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathy NEC (38%), and thrombocytopenia (32%). A total of 26% of patients experienced serious ARs. The most commonly reported serious ARs included diarrhea, vomiting, and pyrexia (each 3%); nausea, dehydration, and thrombocytopenia (each 2%); and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (each 1%).
Relapsed MM subcutaneous vs IV: In the phase 3 study of VELCADE administered subcutaneously vs intravenously in relapsed MM, safety data were similar between the two treatment groups. The most commonly reported ARs in the subcutaneous vs IV treatment groups were peripheral neuropathy (37% vs 50%) and thrombocytopenia (30% vs 34%). The incidence of serious ARs was similar in the subcutaneous treatment group (20%) and the IV treatment group (19%). The most commonly reported serious ARs were pneumonia and pyrexia (each 2%) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (each 3%) in the IV treatment group.
- Please see full Prescribing Information available at www.VELCADE.com
View full U.S. Prescribing Information
*VELCADE (bortezomib) (Vc) in combination with melphalan+prednisone (MP).
†APEX TRIAL: a randomized, open-label trial (N=669) evaluating the efficacy and safety of VELCADE (bortezomib) administered intravenously vs dexamethasone in patients with relapsed/refractory multiple myeloma. The primary endpoint was TTP. Secondary endpoints were overall survival, ORR, and safety. The APEX trial was terminated at a preplanned interim analysis of TTP. All dexamethasone patients were offered VELCADE. Median TTP was 6.2 months with VELCADE vs 3.5 months with dexamethasone (p<0.0001). An updated analysis was performed.
‡From 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2.
§Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
||Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.
¶Self-care ADL refers to bathing, dressing and undressing, feeding self, using telephone, managing money, etc.
#Upper limit of normal range.
**Serum glutamic oxaloacetic transaminase.
††Aspartate aminotransferase.
References: 1. Data on file 12, Millennium Pharmaceuticals, Inc. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomized, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.
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