Bortezomib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection [preservative free]:

Velcade: 3.5 mg (1 ea)

Solution Reconstituted, Intravenous [preservative free]:

Generic: 3.5 mg (1 ea)

Pharmacology

Mechanism of Action

Bortezomib inhibits proteasomes, enzyme complexes which regulate protein homeostasis within the cell. Specifically, it reversibly inhibits chymotrypsin-like activity at the 26S proteasome, leading to activation of signaling cascades, cell-cycle arrest, and apoptosis.

Pharmacokinetics/Pharmacodynamics

Distribution

~498 to 1,884 L/m²; distributes widely to peripheral tissues

Metabolism

Hepatic primarily via CYP2C19 and 3A4 and to a lesser extent CYP1A2; forms metabolites (inactive) via deboronization followed by hydroxylation

Half-Life Elimination

Single dose: IV: 9 to 15 hours; Multiple dosing: 1 mg/m²: 40 to 193 hours; 1.3 mg/m²: 76 to 108 hour

Protein Binding

~83%

Use in Specific Populations

Special Populations: Hepatic Function Impairment

Dose-normalized mean AUC levels were increased by ~60% in patients with moderate or severe hepatic impairment.

Special Populations: Elderly

Patients <65 years of age have about 25% lower mean dose-normalized AUC and C_max than those ≥65 years of age.

Use: Labeled Indications

Mantle cell lymphoma: Treatment of mantle cell lymphoma in adults.

Multiple myeloma: Treatment of multiple myeloma in adults.

Use: Off Label

Antibody-mediated rejection in cardiac transplantation (treatment)yes

Based on the American Heart Association's Scientific Statement for Antibody-Mediated Rejection in Cardiac Transplantation, bortezomib, in combination with other immune therapies, may be a reasonable agent for the secondary treatment of patients with antibody-mediated rejection (AMR) of the cardiac allograft. There are currently no large randomized trials evaluating treatments for AMR in cardiac transplantation; recommendations are based on consensus.

Cutaneous T-cell lymphomas (mycosis fungoides), relapsed/refractoryc

Data from a small single-center, single-agent phase II trial suggest that bortezomib may be beneficial for the treatment of relapsed/refractory cutaneous T-cell lymphomas such as mycosis fungoides Zinzani 2007.

Follicular lymphoma, relapsed/refractoryb

Data from two phase II studies support the use of bortezomib (in combination with bendamustine and rituximab) in the treatment of relapsed or refractory follicular non-Hodgkin lymphoma Fowler 2011, Friedberg 2011.

Peripheral T-cell lymphoma, relapsed/refractoryc

Data from a small single-center, single-agent phase II trial suggest that bortezomib may be beneficial for the treatment of relapsed/refractory peripheral T-cell lymphoma Zinzani 2007.

Systemic light-chain amyloidosisc

Data from a retrospective analysis suggest that bortezomib, with or without dexamethasone, may be beneficial in the management of systemic light-chain amyloidosis Kastritis 2010.

Waldenström macroglobulinemia, relapsed/refractorybyes

Data from a small phase II trial support the use of single-agent bortezomib in the management of relapsed/refractory Waldenström macroglobulinemia Chen 2007. Additional phase II trials suggest that bortezomib, either in combination with rituximab Ghobrial 2010 or dexamethasone and rituximab Treon 2009 may be beneficial for treatment of Waldenström macroglobulinemia.

Based on recommendations from the Eighth International Workshop on Waldenström Macroglobulinemia, bortezomib therapy is recommended in patients with Waldenström macroglobulinemia with high IgM levels, symptomatic hyperviscosity, cryoglobulinemia, cold agglutinemia, renal impairment, or in patients where chemotherapy with alkylators or nucleoside analog should be avoided.

Contraindications

Hypersensitivity (excluding local reactions) to bortezomib, boron, boric acid (generic product), glycine (generic product), mannitol (Velcade), or any component of the formulation; administration via the intrathecal route

Dosage and Administration

Dosing: Adult

Note: Consecutive doses should be separated by at least 72 hours.

Multiple myeloma (first-line therapy; in combination with melphalan and prednisone): IV, SubQ: 1.3 mg/m² days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42-day treatment cycle for 4 cycles, followed by 1.3 mg/m² days 1, 8, 22, and 29 of a 42-day treatment cycle for 5 cycles.

Retreatment may be considered for multiple myeloma patients who had previously responded to bortezomib (either as monotherapy or in combination) and who have relapsed at least 6 months after completing prior bortezomib therapy; initiate at the last tolerated dose.

First-line therapy off-label dosing/combinations:

CyBorD regimen: IV: 1.5 mg/m² days 1, 8, 15, and 22 of a 28-day treatment cycle for 4 cycles (may continue beyond 4 cycles) in combination with cyclophosphamide and dexamethasone (Khan 2012).

Daratumumab-containing regimens: SubQ: 1.3 mg/m² on days 1, 4, 8, and 11 of a 28-day cycle (in combination with daratumumab, thalidomide, and dexamethasone; DVTd regimen) for up to 4 pretransplant induction cycles and 2 posttransplant consolidation cycles (Moreau 2019) or 1.3 mg/m² two times a week during weeks 1, 2, 4, and 5 of the first 6-week cycle (cycle 1; 8 doses/cycle), followed by 1.3 mg/m² once a week during weeks 1, 2, 4, and 5 for eight 6-week cycles (cycles 2 to 9; 4 doses/cycle) in combination with daratumumab, melphalan, and prednisone; after cycle 9, daratumumab is continued as a single agent (Mateos 2018).

PAD regimen: IV: Induction: 1.3 mg/m² days 1, 4, 8, and 11 of a 28-day treatment cycle for 3 cycles (in combination with doxorubicin and dexamethasone), followed by conditioning/stem cell transplantation, and then maintenance bortezomib 1.3 mg/m² once every 2 weeks for 2 years (Sonneveld 2012).

VD regimen: IV: Induction: 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle (in combination with dexamethasone) for 4 cycles, followed by autologous stem cell transplantation (Harousseau 2010)

VRd regimen: IV: 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle for 8 cycles (in combination with lenalidomide and dexamethasone) (Durie 2017)

VTd regimen: IV: 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle for 3 induction cycles (in combination with thalidomide and dexamethasone), followed by tandem transplant, then (3 months after second transplant) 1.3 mg/m² days 1, 8, 15, and 22 every 35 days for 2 consolidation cycles (in combination with thalidomide and dexamethasone) (Cavo 2010)

Patients ≥65 years of age: IV: 1.3 mg/m² days 1, 8, 15, and 22 of a 35-day treatment cycle, in combination with either melphalan and prednisone or melphalan, prednisone, and thalidomide (Boccadoro 2010; Bringhen 2010; Palumbo 2009)

Multiple myeloma (relapsed/refractory): IV, SubQ: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle. Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest (days 23 through 35).

Retreatment may be considered for multiple myeloma patients who had previously responded to bortezomib (either as monotherapy or in combination) and who have relapsed at least 6 months after completing prior bortezomib therapy; initiate at the last tolerated dose. Administer twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle (either as a single-agent or in combination with dexamethasone) for a maximum of 8 cycles.

Off-label dosing/combinations for relapsed/refractory disease:

DVd regimen: SubQ: 1.3 mg/m² on days 1, 4, 8, and 11 every 21 days (in combination with daratumumab and dexamethasone) for 8 cycles (Palumbo 2016).

VRd regimen: IV: 1 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for 8 cycles (in combination with lenalidomide and dexamethasone), followed by maintenance therapy (if response or stable disease) of 1 mg/m² (or the dose tolerated in cycle 8) on days 1 and 8 of a 21-day treatment cycle (± lenalidomide and/or dexamethasone) until disease progression or unacceptable toxicity (Richardson 2014).

Bendamustine/Bortezomib/Dexamethasone regimen: IV: 1.3 mg/m² on days 1, 4, 8, and 11 of a 28-day treatment cycle for 4 cycles (if no response) or for up to a maximum of 8 cycles (in combination with bendamustine and dexamethasone) (Ludwig 2014).

Bortezomib/Doxorubicin (liposomal) regimen: IV: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for at least 8 cycles or until disease progression or unacceptable toxicity (in combination with liposomal doxorubicin) (Orlowski 2007).

CyBorD regimen: IV: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for up to 8 cycles, followed by 1.3 mg/m² on days 1, 8, 15, and 22 of a 35-day treatment cycle for up to 3 cycles (in combination with cyclophosphamide and dexamethasone) (Kropff 2007).

Panobinostat/Bortezomib/Dexamethasone regimen: IV: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for 8 cycles, followed by (if deriving benefit) 1.3 mg/m² on days 1, 8, 22, and 29 of a 42-day treatment cycle for 4 cycles (in combination with panobinostat and dexamethasone) (San-Miguel 2014).

VPd regimen: IV, SubQ: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for 8 cycles, followed by 1.3 mg/m² on days 1 and 8 of a 21-day treatment cycle until disease progression or unacceptable toxicity (in combination with pomalidomide and dexamethasone) (Richardson 2019).

Mantle cell lymphoma (first-line therapy): VcR-CAP regimen: IV: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for 6 cycles (in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone). If response first documented at cycle 6, treatment for an additional 2 cycles is recommended (Roback 2015).

Mantle cell lymphoma (relapsed): IV, SubQ: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for up to 17 cycles (Fisher 2006).

Antibody-mediated rejection in cardiac transplantation, treatment (off-label use): IV: 1.3 to 1.5 mg/m² typically given on days 1, 4, 8, and 11 (treatment frequency varies) for a total of 4 doses (treatment duration may vary) (AHA [Colvin 2015]).

Cutaneous or peripheral T-cell lymphoma, relapsed/refractory (off-label use): IV: 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day treatment cycle for up to 6 cycles (Zinzani 2007).

Follicular lymphoma, relapsed/refractory (off-label use): IV: 1.3 mg/m² days 1, 4, 8, and 11 of a 28-day treatment cycle, in combination with bendamustine and rituximab for 6 cycles (Friedberg 2011) or 1.6 mg/m² days 1, 8, 15, and 22 of a 35-day treatment cycle, in combination with bendamustine and rituximab for 5 cycles (Fowler 2011).

Systemic light-chain amyloidosis (off-label use): IV: 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle (with or without dexamethasone) (Kastritis 2010).

Waldenström's macroglobulinemia, relapsed/refractory (off-label use): IV: 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle; continue until disease progression or until 2 cycles after achieving a complete response (Chen 2007) or 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle (in combination with dexamethasone and rituximab) (Treon 2009) or 1.6 mg/m² days 1, 8, and 15 of a 28-day treatment cycle for 6 cycles (in combination with rituximab) (Ghobrial 2010). The Eighth International Workshop on Waldenström Macroglobulinemia recommends administering bortezomib subcutaneously (if possible) and as a once weekly regimen; if urgent IgM level reduction is necessary, may initiate with a twice weekly regimen for 1 to 2 cycles followed by once weekly dosing (Leblond 2016).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Myeloma (first-line therapy):

Platelets should be ≥70,000/mm³, ANC should be ≥1000/mm³, and nonhematologic toxicities should resolve to grade 1 or baseline prior to therapy initiation.

Platelets ≤30,000/mm³ or ANC ≤750/mm³ on bortezomib day(s) (except day 1): Withhold bortezomib; if several bortezomib doses in consecutive cycles are withheld, reduce dose 1 level (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose)

Grade ≥3 nonhematological toxicity (other than neuropathy): Withhold bortezomib until toxicity resolves to grade 1 or baseline. May reinitiate bortezomib at 1 dose level reduction (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose).

Neuropathic pain and/or peripheral sensory or motor neuropathy: See "Neuropathic pain and/or peripheral sensory, motor, or autonomic neuropathy" toxicity adjustment guidelines below.

Mantle cell lymphoma (first-line therapy):

Platelets should be ≥100,000/mm³, ANC should be ≥1,500/mm³, hemoglobin should be ≥8 g/dL, and nonhematologic toxicities should resolve to grade 1 or baseline prior to each cycle (cycle 2 and beyond).

Platelets <25,000/mm³ or ≥ grade 3 neutropenia on bortezomib day(s) (except day 1): Withhold bortezomib for up to 2 weeks until platelets are ≥25,000/mm³ and/or ANC ≥750/mm³, then reduce dose 1 level (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose). If hematologic toxicity does not resolve after withholding therapy, discontinue bortezomib.

Grade ≥3 nonhematological toxicity (other than neuropathy): Withhold bortezomib until toxicity resolves to ≤ grade 2. May reinitiate bortezomib at 1 dose level reduction (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose).

Neuropathic pain and/or peripheral sensory or motor neuropathy: See "Neuropathic pain and/or peripheral sensory or motor neuropathy" toxicity adjustment guidelines below.

Relapsed multiple myeloma and mantle cell lymphoma:

Grade 3 nonhematological (excluding neuropathy) or grade 4 hematological toxicity: Withhold until toxicity resolved; may reinitiate with a 25% dose reduction (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose)

Neuropathic pain and/or peripheral sensory, motor, or autonomic neuropathy:

Note: Consider subQ administration in patients with preexisting or at high risk for peripheral neuropathy.

Grade 1 (asymptomatic; deep tendon reflex loss or paresthesia) without pain or loss of function: No action needed

Grade 1 with pain or grade 2 (moderate symptoms; limiting instrumental activities of daily living): Reduce dose to 1 mg/m²

Grade 2 with pain or grade 3 (severe symptoms; limiting self-care activities of daily living): Withhold until toxicity resolved, may reinitiate at 0.7 mg/m² once weekly

Grade 4 (life-threatening consequences with urgent intervention indicated) and/or severe autonomic neuropathy: Discontinue therapy.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012).

Reconstitution

Note: The reconstituted concentrations for IV and SubQ administration are different; the manufacturer provides stickers to facilitate identification of the route for reconstituted vials. The amount contained in each vial may exceed the prescribed dose; use care with dosage and volume calculations.

Reconstitute only with NS. Reconstituted solutions should be clear and colorless.

IV: Reconstitute each 3.5 mg vial with 3.5 mL NS to a concentration of 1 mg/mL.

SubQ [Velcade only]: Reconstitute each 3.5 mg vial with 1.4 mL NS to a concentration of 2.5 mg/mL (Moreau 2011). If injection site reaction occurs, the more dilute 1 mg/mL concentration may be used SubQ.

Administration

Note: The reconstituted concentrations for IV and SubQ administration are different; use caution when calculating the volume for each route and dose. Consider SubQ administration in patients with preexisting or at high risk for peripheral neuropathy.

IV: Administer via rapid IV push (3 to 5 seconds). When administering in combination with rituximab for first-line therapy of mantle cell lymphoma, administer bortezomib prior to rituximab.

SubQ (Velcade only): Subcutaneous administration of bortezomib 1.3 mg/m² days 1, 4, 8, and 11 of a 21-day treatment cycle has been studied in a limited number of patients with relapsed multiple myeloma; doses were administered subcutaneously (concentration of 2.5 mg/mL) into the thigh or abdomen, rotating the injection site with each dose; injections at the same site within a single cycle were avoided (Moreau 2010; Moreau 2011). Response rates were similar to IV administration; decreased incidence of grade 3 or higher adverse events were observed with SubQ administration. Administer at least 1 inch from an old site and never administer to tender, bruised, erythematous, or indurated sites. If injection site reaction occurs, the more dilute 1 mg/mL concentration may be used SubQ (or IV administration of 1 mg/mL concentration may be considered).

For SubQ (Velcade) or IV administration only; fatalities have been reported with inadvertent intrathecal administration. Bortezomib should NOT be delivered to the patient at the same time with any medications intended for central nervous system administration.

Note: The generic product (Fresenius Kabi) is NOT approved for subcutaneous administration.

Dietary Considerations

Green tea and green tea extracts may diminish the therapeutic effect of bortezomib and should be avoided (Golden 2009). Avoid grapefruit juice. Avoid additional, nondietary sources of ascorbic acid supplements, including multivitamins containing ascorbic acid (may diminish bortezomib activity) during treatment, especially 12 hours before and after bortezomib treatment (Perrone 2009).

Storage

Prior to reconstitution, store intact vials at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F). Once reconstituted, the manufacturers recommend use within 8 hours of reconstitution. However, stability studies (using Velcade) have demonstrated that solutions of 1 mg/mL (vial or syringe) may be stored at room temperature for up to 3 days, or under refrigeration for up to 5 days (Andre 2005); or refrigerated in the original vial for up to 15 days (Vanderloo 2010). Protect from light. After preparation, keep bortezomib in a location away from the separate storage location recommended for intrathecal medications.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Ascorbic Acid: May diminish the therapeutic effect of Bortezomib. Management: Patients should avoid taking vitamin C supplements and vitamin C-containing multivitamins during their bortezomib therapy. It is probably unnecessary to advise patients to avoid foods/beverages that contain vitamin C (e.g., citrus fruits, etc.). Consider therapy modification

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

CYP2C19 Inducers (Moderate): May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Bortezomib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bortezomib. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Green Tea: May diminish the antineoplastic effect of Bortezomib. Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May diminish the therapeutic effect of Bortezomib. Specifically, the vitamin C (ascorbic acid) found in many multivitamins may impair the clinical effects of bortezomib. Management: Patients should avoid taking extra vitamin C supplements and vitamin C-containing multivitamins during their bortezomib therapy. It is likely unnecessary, though, to advise patients to avoid dietary sources of vitamin C. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May diminish the therapeutic effect of Bortezomib. Management: Patients should avoid taking extra vitamin C supplements and vitamin C-containing multivitamins with bortezomib. It is probably unnecessary to restrict or limit vitamin C-containing foods/beverages. Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May diminish the therapeutic effect of Bortezomib. Specifically, vitamin C may decrease bortezomib therapeutic effects. Management: Patients should avoid taking extra vitamin C supplements and vitamin C-containing multivitamins during their bortezomib therapy. It is likely unnecessary, though, to advise patients to avoid dietary sources of vitamin C. Consider therapy modification

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

St John's Wort: May decrease the serum concentration of Bortezomib. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Peripheral neuropathy (IV: 35% to 54%; SubQ: 37%; grade ≥2: 24% to 39%; grade ≥3: IV: 7% to 15%; SubQ: 5% to 6%; grade 4: <1%), fatigue (7% to 52%), neuralgia (23%), headache (10% to 19%), paresthesia (7% to 19%), dizziness (10% to 18%; excludes vertigo)

Dermatologic: Skin rash (12% to 23%)

Gastrointestinal: Diarrhea (19% to 52%), nausea (14% to 52%), constipation (24% to 34%), vomiting (9% to 29%), anorexia (14% to 21%), abdominal pain (11%), decreased appetite (11%)

Hematologic & oncologic: Thrombocytopenia (16% to 52%; grade 3: 5% to 24%; grade 4: 3% to 7%; nadir: Day 11; recovery: By day 21), neutropenia (5% to 27%; grade 3: 8% to 18%; grade 4: 2% to 4%; nadir: Day 11; recovery: By day 21), anemia (12% to 23%; grade 3: 4% to 6%; grade 4: <1%), leukopenia (18% to 20%; grade 3: 5%; grade 4: ≤1%)

Infection: Herpes zoster infection (reactivation; 6% to 11%)

Neuromuscular & skeletal: Asthenia (7% to 16%)

Respiratory: Dyspnea (11%)

Miscellaneous: Fever (8% to 23%)

1% to 10%:

Cardiovascular: Hypotension (8% to 9%), cardiac disease (treatment emergent; 8%), acute pulmonary edema (≤1%), cardiac failure (≤1%), cardiogenic shock (≤1%), pulmonary edema (≤1%)

Endocrine & metabolic: Dehydration (2%)

Hematologic & oncologic: Hemorrhage (≥ grade 3: 2%)

Infection: Herpes simplex infection (1% to 3%), herpes zoster (1% to 2%)

Local: Injection site reaction (mostly redness; SubQ: 6%), irritation at injection site (IV: 5%)

Respiratory: Pneumonia (1% to 3%)

Frequency not defined:

Cardiovascular: Aggravated atrial fibrillation, angina pectoris, atrial flutter, atrioventricular block, bradycardia, cerebrovascular accident, deep vein thrombosis, edema, embolism (peripheral), facial edema, hemorrhagic stroke, hypersensitivity angiitis, hypertension, ischemic heart disease, myocardial infarction, pericardial effusion, pericarditis, peripheral edema, phlebitis, portal vein thrombosis, pulmonary embolism, septic shock, sinoatrial arrest, subdural hematoma, torsades de pointes, transient ischemic attacks, ventricular tachycardia

Central nervous system: Agitation, anxiety, ataxia, brain disease, cerebral hemorrhage, chills, coma, confusion, cranial nerve palsy, dysarthria, dysautonomia, dysesthesia, insomnia, malaise, mental status changes, motor dysfunction, paralysis, psychosis, seizure, spinal cord compression, suicidal ideation, vertigo

Dermatologic: Pruritus, urticaria

Endocrine & metabolic: Amyloid heart disease, hyperglycemia (diabetic patients), hyperkalemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia (diabetic patients), hypokalemia, hyponatremia, weight loss

Gastrointestinal: Cholestasis, duodenitis (hemorrhagic), dysphagia, fecal impaction, gastritis (hemorrhagic), gastroenteritis, gastroesophageal reflux disease, hematemesis, intestinal obstruction, intestinal perforation, melena, oral candidiasis, pancreatitis, paralytic ileus, peritonitis, stomatitis

Genitourinary: Bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, urinary tract infection

Hematologic & oncologic: Disseminated intravascular coagulation, febrile neutropenia, lymphocytopenia, oral mucosal petechiae

Hepatic: Ascites, hepatic failure, hepatic hemorrhage, hepatitis, hyperbilirubinemia

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction

Infection: Aspergillosis, bacteremia, listeriosis, toxoplasmosis

Local: Catheter infection

Neuromuscular & skeletal: Arthralgia, back pain, bone fracture, limb pain, myalgia, ostealgia

Ophthalmic: Blurred vision, conjunctival infection, conjunctival irritation, diplopia

Otic: Auditory impairment

Renal: Bilateral hydronephrosis, nephrolithiasis, proliferative glomerulonephritis, renal failure

Respiratory: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, bronchitis, chronic obstructive pulmonary disease (exacerbation), cough, epistaxis, hemoptysis, hypoxia, laryngeal edema, nasopharyngitis, pleural effusion, pneumonitis, pulmonary hypertension, pulmonary infiltrates (including diffuse), respiratory tract infection, sinusitis

<1%, postmarketing, and/or case reports: Amyloidosis, blepharitis, blindness, cardiac tamponade, chalazion (Fraunfelder 2016), deafness (bilateral), decreased left ventricular ejection fraction, dysgeusia, dyspepsia, hemolytic-uremic syndrome, herpes meningoencephalitis, increased serum transaminases, interstitial pneumonitis, intestinal obstruction, ischemic colitis, ocular herpes simplex, optic neuritis, optic neuropathy, progressive multifocal leukoencephalopathy, prolonged Q-T interval on ECG, pulmonary disease, respiratory insufficiency, reversible posterior leukoencephalopathy syndrome, sepsis, Stevens-Johnson syndrome, Sweet syndrome, syncope, thrombotic microangiopathy, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, tumor lysis syndrome

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Hematologic toxicity, including grade 3 and 4 neutropenia and thrombocytopenia may occur; risk is increased in patients with pretreatment platelet counts <75,000/mm³. Monitor frequently throughout treatment; may require treatment interruption, or dosage reduction. Management with platelet transfusions, supportive care, and/or myeloid growth factors may be necessary. Nadirs generally occur following the last dose of a cycle and recover prior to the next cycle. Hemorrhage (gastrointestinal and intracerebral) due to low platelet count has been observed. Neutropenic fever has been observed.
• Cardiovascular effects: Acute development or exacerbation of HF and new onset decreased left ventricular ejection fraction (LVEF) have been reported with bortezomib; some cases have occurred in patients without risk factors for HF and/or decreased LVEF. Monitor closely in patients with risk factors for HF or existing heart disease. Isolated case of QTc prolongation have been reported with bortezomib.
• Gastrointestinal effects: Nausea, vomiting, diarrhea, or constipation may occur; may require antiemetics or antidiarrheals. Ileus may occur. Administer fluid and electrolytes to prevent dehydration; interrupt therapy for severe symptoms.
• Hepatotoxicity: Acute liver failure has been reported (rarely) in patients receiving multiple concomitant medications and with serious underlying conditions. Hepatitis, transaminase increases, and hyperbilirubinemia have also been reported; interrupt therapy to assess reversibility. Use caution in patients with hepatic dysfunction; reduced initial doses are recommended for moderate and severe hepatic impairment (exposure is increased); closely monitor for toxicities. Limited data exists for patients that have been rechallenged.
• Herpes reactivation: Herpes (zoster and simplex) reactivation has been reported with bortezomib; consider antiviral prophylaxis during therapy.
• Hypersensitivity: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, and laryngeal edema have been reported with bortezomib.
• Hypotension: Bortezomib may cause hypotension (including postural and orthostatic); use caution with dehydration, history of syncope, or medications associated with hypotension (may require adjustment of antihypertensive medication, hydration, and mineralocorticoids and/or sympathomimetics).
• Peripheral neuropathy: Bortezomib may cause or worsen peripheral neuropathy (usually sensory but may be mixed sensorimotor); risk may be increased with previous use of neurotoxic agents or preexisting peripheral neuropathy (in patients with preexisting neuropathy, use only after risk versus benefit assessment); monitor for signs and symptoms; adjustment of dose and/or schedule may be required. The incidence of grades 2 and 3 peripheral neuropathy may be lower with SubQ route (compared to IV); consider SubQ administration in patients with preexisting or at high risk for peripheral neuropathy. The majority of patients with ≥ grade 2 peripheral neuropathy have improvement in or resolution of symptoms with dose adjustments or discontinuation. In a study of elderly patients receiving a weekly bortezomib schedule with combination chemotherapy, the incidence of peripheral neuropathy was significantly reduced without an effect on outcome (Boccadoro 2010; Palumbo 2009). The generic product (by Fresenius Kabi) is NOT approved for subcutaneous administration.
• Posterior reversible leukoencephalopathy syndrome: Posterior reversible leukoencephalopathy syndrome (PRES, formerly RPLS) has been reported (rarely). Symptoms of PRES include confusion, headache, hypertension, lethargy, seizure, blindness and/or other vision, or neurologic disturbances; discontinue bortezomib if PRES occurs. MRI is recommended to confirm PRES diagnosis. The safety of reinitiating bortezomib in patients previously experiencing PRES is unknown.
• Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) has been rarely observed; evaluate promptly any new onset or worsening neurologic symptoms (eg, confusion, loss of balance, vision disturbances, reduced strength or weakness in an arm/leg).
• Pulmonary toxicity: Pulmonary disorders (some fatal) including pneumonitis, interstitial pneumonia, lung infiltrates, and acute respiratory distress syndrome (ARDS) have been reported. Pulmonary hypertension (without left heart failure or significant pulmonary disease) has been reported rarely. Promptly evaluate with new or worsening cardiopulmonary symptoms; therapy interruption may be required.
• Thrombotic microangiopathy: Cases (some fatal) of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported. Discontinue and further evaluate if TTP/HUS is suspected; may resume bortezomib if diagnosis of TTP/HUS excluded. The safety of reinitiating bortezomib therapy in patients previously experiencing TTP/HUS is unknown.
• Tumor lysis syndrome: Tumor lysis syndrome has been reported with bortezomib; risk is increased in patients with high tumor burden prior to treatment; monitor closely.

Disease-related concerns:

• Diabetes: Hyper- and hypoglycemia may occur in diabetic patients receiving oral hypoglycemics; monitor; may require adjustment of diabetes medications.

Concurrent drug therapy issues:

• Drug-drug/drug-food interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Coadministration of strong CYP3A4 inhibitors may increase bortezomib exposure; monitor for toxicity and consider dose reduction if concurrent therapy cannot be avoided. Efficacy may be reduced when administered with strong CYP3A4 inducers; concomitant use is not recommended.

Other warnings/precautions:

• Appropriate administration: For SubQ (Velcade only) or IV administration only. Intrathecal administration is contraindicated; inadvertent intrathecal administration has resulted in death. Bortezomib should NOT be prepared during the preparation of any intrathecal medications. After preparation, keep bortezomib in a location away from the separate storage location recommended for intrathecal medications. Bortezomib should NOT be delivered to the patient at the same time with any medications intended for central nervous system administration. The reconstituted concentrations for IV and SubQ administration are different; use caution when calculating the volume for each route and dose. The manufacturer provides stickers to facilitate identification of the route for reconstituted vials. The generic product (by Fresenius Kabi) is approved for IV administration only.

Monitoring Parameters

CBC with differential and platelets (monitor frequently throughout therapy); liver function tests (in patients with existing hepatic impairment); verify pregnancy status in women of reproductive potential prior to therapy initiation; signs/symptoms of peripheral neuropathy, dehydration, hypotension, PRES, or PML; renal function, baseline chest x-ray and then periodic pulmonary function testing (with new or worsening pulmonary symptoms)

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and on findings in animal reproduction studies, bortezomib may cause fetal harm if administered during pregnancy.

Evaluate pregnancy status in women of reproductive potential prior to initiating therapy; women of reproductive potential should avoid becoming pregnant during bortezomib treatment. Females of reproductive potential should use effective contraception during therapy and for 7 months following bortezomib treatment. Males with female partners of reproductive potential should use effective contraception during and for 4 months following bortezomib treatment.

Bortezomib may potentially affect male or female fertility (based on the mechanism of action).

Patient Education

What is this drug used for?

• It is used to treat multiple myeloma.
• It is used to treat a type of lymphoma.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Nausea
• Vomiting
• Constipation
• Abdominal pain
• Diarrhea
• Lack of appetite
• Trouble sleeping

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome like bruising or bleeding; severe loss of strength and energy; dark urine or yellow skin; pale skin; change in amount of urine passed; vision changes; change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance; or fever
• Posterior reversible encephalopathy syndrome like illogical thinking, not alert, vision changes, seizures, or severe headache
• Nerve problems like sensitivity to heat or cold; decreased sense of touch; burning, numbness, or tingling; pain, or weakness in the arms, hands, legs, or feet
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• Injection site irritation
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Severe loss of strength and energy
• Severe pulmonary disorder like lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.