VELCADE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VELCADE (VELCADE).
Bortezomib is a reversible inhibitor of the 26S proteasome, a protease complex that degrades ubiquitinated proteins. By blocking proteasome activity, it disrupts cellular homeostasis, leading to cell cycle arrest and apoptosis, particularly in malignant cells.
| Metabolism | Primarily metabolized by cytochrome P450 enzymes, mainly CYP3A4 and to a lesser extent CYP2C19 and CYP1A2. |
| Excretion | Primarily via hepatic metabolism; renal excretion accounts for <15% of the dose; biliary/fecal excretion accounts for 50-80% of the dose. |
| Half-life | Terminal elimination half-life is 40-100 hours (mean ~77 hours) after intravenous administration; extensive tissue binding results in prolonged terminal phase. |
| Protein binding | Approximately 83% bound to human plasma proteins, primarily albumin and α2-macroglobulin. |
| Volume of Distribution | Volume of distribution at steady state (Vdss) is >500 L (≥ 7.1 L/kg in adults), indicating extensive extravascular distribution and tissue binding. |
| Bioavailability | Not applicable; only available for intravenous (IV) or subcutaneous (SC) administration; bioavailability is 100% for IV; SC administration has approximately 100% bioavailability relative to IV (based on area under the curve, AUC). |
| Onset of Action | Intravenous: Clinical effect (e.g., response in multiple myeloma) typically seen within 2-4 weeks. |
| Duration of Action | Duration of action is variable; proteasome inhibition persists for 48-72 hours post dose, but clinical effects last for the dosing interval (twice weekly for 2 weeks followed by 1 week rest). |
| Action Class | Proteasome inhibitor |
1.3 mg/m^2 intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of a 21-day cycle for up to 8 cycles.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for CrCl ≥20 mL/min. For CrCl <20 mL/min or hemodialysis, reduce initial dose to 0.7 mg/m^2 and monitor closely. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: 0.7 mg/m^2 initially, may escalate to 1.0 mg/m^2 if tolerated. Child-Pugh C: 0.5 mg/m^2 initially, may escalate to 0.7 mg/m^2. |
| Pediatric use | Not approved for pediatric use. No established dosing guidelines. |
| Geriatric use | No specific dose adjustment based on age alone. Monitor for peripheral neuropathy and cardiac toxicity more frequently. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for VELCADE (VELCADE).
| Breastfeeding | No data on the presence of bortezomib in human milk, effects on the breastfed infant, or effects on milk production. The M/P ratio is unknown. Due to potential serious adverse reactions in the breastfed infant, advise women not to breastfeed during treatment and for 2 months after the last dose. |
| Teratogenic Risk | VELCADE (bortezomib) is a Pregnancy Category D drug. In animal studies, bortezomib caused embryo-fetal lethality and teratogenicity at doses lower than the clinical dose. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy is contraindicated unless the potential benefit justifies the potential risk to the fetus. First trimester: High risk of major malformations. Second and third trimesters: May cause fetal growth restriction and oligohydramnios. |
■ FDA Black Box Warning
VELCADE should be used with caution in patients with pre-existing peripheral neuropathy or at high risk of developing it, as it may cause severe peripheral neuropathy. Also, there is a risk of cardiac arrest, congestive heart failure, and QT prolongation.
| Serious Effects |
Hypersensitivity to bortezomib, boron, or mannitol. Contraindicated in patients with severe hepatic impairment (Child-Pugh class C).
| Precautions | Peripheral neuropathy, cardiac toxicity (including heart failure and QT prolongation), hypotension, pulmonary toxicity, tumor lysis syndrome, thrombocytopenia, hepatotoxicity, and gastrointestinal toxicity. |
Loading safety data…
| Fetal Monitoring | Monitor complete blood counts (CBC) with differential, platelet count, and hepatic function (AST, ALT, bilirubin) regularly. Assess for peripheral neuropathy, cardiac function (ECG), and signs of hypotension. In pregnant patients, perform fetal ultrasound monitoring for growth and amniotic fluid volume. |
| Fertility Effects | Based on animal studies, bortezomib may impair male fertility. No human data available on fertility. Women of childbearing potential should use effective contraception during treatment and for at least 6 months after the last dose. Men with partners of childbearing potential should use effective contraception during treatment and for 3 months after the last dose. |