Dosing and uses of Velcade (bortezomib)
Adult dosage forms and strengths
powder for injection
- 3.5mg/vial
Mantle Cell Lymphoma
Indicated for the treatment of patients with mantle cell lymphoma as first-line in previously untreated patients or those who have relapsed
Previously untreated MCL
- 1.3 mg/m²/dose IV twice weekly for 2 weeks (days 1, 4, 8, 11) followed by a 10-day rest period (days 12 to 21) for six 3-week cycles; may continue for 8 cycles if response is first seen at cycle 6
- Give with rituximab 375 mg/m² IV, cyclophosphamide 750 mg/m² IV, and doxorubicin 50 mg/m² IV on day 1, plus prednisone 100 mg/m² IV on days 1-5
Relapsed MCL
- 1.3 mg/m²/dose IV/SC twice weekly for 2 weeks (days 1, 4, 8, 11) followed by a 10-day rest period (days 12 to 21)
- Therapy extending beyond 8 cycles: Give standard schedule
Multiple Myeloma
Previously untreated multiple myeloma
- Administer in combination with prednisone and melphalan as part of 6-wk treatment cycles for 9 cycles
- Cycles 1-4 (twice weekly): 1.3 mg/m² IV/SC on Days 1, 4, 8, 11, 22, 25, 29, and 32
- Cycles 5-9 (once weekly): 1.3 mg/m² IV/SC on Days 1, 8, 22, and 29
Relapsed multiple myeloma
- 1.3 mg/m²/dose IV/SC twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21)
- Therapy extending beyond 8 cycles: Standard schedule or maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35)
Retreatment
- Indicated for retreatment of adults with multiple myeloma who had previously responded to bortezomib and relapsed at least 6 months following completion of prior bortezomib treatment
- Treatment may be started at the last tolerated dose
- Administer twice weekly for 2 weeks (days 1, 4, 8, 11) followed by a 10-day rest period (days 12 to 21)
Dosage modification
Bortezomib, melphalan, and prednisone regimen
- Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle, consider reducing melphalan dose by 25% in the next cycle
- Platelet ≤30 x 10^9/L or ANC ≤0.75 x 10^9/L on bortezomib dosing day (other than day 1): Withhold bortezomib
- If several bortezomib doses in consecutive cycles are withheld due to toxicity: Reduce bortezomib by 1 dosage level (eg, 1.3 mg/m² to 1 mg/m², or from1 mg/m² to 0.7 mg/m² ≥Grade 3 nonhematological toxicities: Withhold bortezomib until symptoms resolve to Grade 1 or baseline; then, may be reinitiated with 1 dosage level reduction (eg, from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²)
Relapsed multiple myeloma and mantle cell lymphoma
- Grade 3 nonhematological or grade 4 hematological toxicities (excluding neuropathy): Withhold at the onset; once symptoms have resolved, may reinitiate bortezomib at a 25% reduced dose (eg, 1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose)
Peripheral neuropathy
- Starting therapy with SC administration 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 bortezomib only after careful risk-benefit assessment
- 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: Reduce dose to 1 mg/m²
- Grade 2 with pain or Grade 3: Withhold drug until toxicity symptoms resolve; may reinitiate at 0.7 mg/m² qWeek
- Grade 4: Discontinue bortezomib
Hepatic impairment
- Moderate-to-severe (bilirubin >1.5x ULN): Reduce 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 tolerability
Orphan Designations
Follicular non-Hodgkin lymphoma
Acute lymphoblastic leukemia
Treatment of neurofibromatosis type 2 (NF2)
Sponsors
- Millennium Pharmaceuticals, Inc; 40 Landsdowne Street; Cambridge, MA 02139
- 3 BioXcel Corporation; 780 East Main St, Ste 2; Branford, CT 06405
Pediatric dosage forms and strengths
Safety and efficacy not established
Velcade (bortezomib) adverse (side) effects
>10%
Asthenia (61-65%)
Nausea (61-65%)
Diarrhea (51-55%)
Anorexia (41-45%)
Constipation (41-45%)
Thrombocytopenia (41-45%)
Peripheral neuropathy (IV: 16-41%; SC: 6-24%)
Pyrexia (36-40%)
Vomiting (36-40%)
Anemia (31-35%)
Arthralgia (26-30%)
Headache (26-30%)
Insomnia (26-30%)
Limb pain (26-30%)
Dizziness (21-25%)
Dyspnea (21-25%)
Edema (21-25%)
Neutropenia (21-25%)
Paresthesia (21-25%)
Rash (21-25%)
Cough (15-20%)
Dehydration (15-20%)
URI (15-20%)
Rigors, grade 4 toxicity (10-15%)
Frequency not defined
Hypotension
Anxiety
Pain
Pruritis
Abdominal pain
Dyspepsia
Back pain
Bone pain
Myalgia
Muscle spasms
Herpes zoster
Pneumonia
Blurred vision
Postmarketing Reports
Cardiovascular: Atrioventricular block complete, cardiac tamponade
GI: Ischemic colitis, hepatitis, acute pancreatitis
CNS: Encephalopathy, dysautonomia, progressive multifocal leukoencephalopathy (PML), acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), herpes meningoencephalitis
Hematologic: Disseminated intravascular coagulation
Pulmonary: Acute diffuse infiltrative pulmonary disease
Skin: Toxic epidermal necrolysis, acute febrile neutrophilic dermatosis (Sweet’s syndrome)
Sensory: Optic neuropathy, deafness bilateral, blindness, and ophthalmic herpes
Warnings
Contraindications
Hypersensitivity to any component or boron or mannitol; intrathecal administration
Cautions
Fatal events with inadvertent intrathecal administration reported
Syncope history
Dehydration
Use caution in hepatic impairment (reduce starting dose); monitor hepatic enzymes during treatment
Diabetes mellitus
Heart disease
High tumor load (risk of tumor lysis syndrome)
Acute respiratory syndromes have occurred; monitor closely for new or worsening symptoms
Risks of: CHF; severe lung disease (eg, ARDS, pneumonitis)
Closely monitor patients with high tumor burden
Acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS)
Monitor complete blood counts regularly throughout treatment
Hypotension (antihypertensive dosages may need modification)
Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement
Consider MRI imaging for onset of visual or neurological symptoms; discontinue therapy if suspected
Worsening of and development of cardiac failure reported; closely monitor patients with existing heart disease or risk factors for heart disease
Women should avoid becoming pregnant while on therapy; advise pregnant women of potential embryo-fetal harm
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
Peripheral neuropathy
- Treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported
- Pre-existing symptoms (numbness, pain or burning in feet or hands) and/or signs of peripheral neuropathy may worsen during treatment
- In a comparative trial of SC and IV administration, the incidence of grade 2 or greater peripheral neuropathy was 24% for SC compared with 41% for IV; grade 3 or higher occurred in 6% when administered SC vs 16% for IV administration
- New or worsening peripheral neuropathy may require a decreased dose or altered dose schedule (see Dosage modification)
Pregnancy and lactation
Pregnancy category: D; avoid becoming pregnant while being treated; when administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/sq.meter, bortezomib caused post-implantation loss and a decreased number of live fetuses
Lactation: excretion in milk unknown/not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Velcade (bortezomib)
Mechanism of action
Reversible inhibitor of chymotrypsin-like activity at the 26-S proteasome, which in turn causes cell cycle arrest and apoptosis
Absorption
Pleak plasma level: 509 ng/mL
Distribution
Protein bound: 83%
Vd: 498-1884 L/m²
Metabolism
Hepatic P450 enzyme CYP3A4 (major); also CYP1A2, 2C9, 2C19, 2D6 (minor)
Enzymes inhibited: CYP2C19
Elimination
Half-Life: 9-15 hr (single dose IV); 40-193 (multiple 1 mg/m² doseing); 76-108 hr (multiple 1.3 mg/m² dosing)
Administration
Preparation
Reconstitute vial with 0.9% NaCL
IV administration: Add 3.5 mL to vial for final concentration of 1 mg/mL
SC administration: 2.5 mg/mL: Add 1.4 mL to vial for final concentration of 2.5 mg/mL
If local injection site reactions occur following SC administration, a less concentrated solution (1 mg/mL) may be administered subcutaneously
IV or SC administration
Not for intrathecal (IT) use; inadvertent IT has resulted in death and is contraindicated
Separate consecutive doses by at least 72 hr
Give IV as a bolus over 3-5 seconds or as SC injection
Give SC injection in thigh or abdomen; rotate injection site with each dose
Monitor hydration status
Use cytotoxic handling procedures for preparation, administration, and disposaL
Storage
Store vial at controlled room temperature (25°C [77°F]) protected from light
Contains no antimicrobial preservative; administer within 8 hr of preparation
Do not store reconstituted solution in a syringe for >3 hr
