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Bortezomib

Pronunciation

(bore TEZ oh mib)

Index Terms

  • LDP-341
  • MLN341
  • PS-341

Dosage Forms

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

Solution Reconstituted, Injection:

Velcade: 3.5 mg (1 ea)

Brand Names: U.S.

  • Velcade

Pharmacologic Category

  • Antineoplastic Agent, Proteasome Inhibitor

Pharmacology

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.

Distribution

498 to 1884 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%

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 Cmax than those ≥65 years of age.

Use: Labeled Indications

Mantle cell lymphoma: Treatment of mantle cell lymphoma

Multiple myeloma: Treatment of multiple myeloma

Use: Unlabeled

Treatment of relapsed/refractory cutaneous T-cell lymphomas (mycosis fungoides), relapsed/refractory follicular lymphoma, relapsed/refractory peripheral T-cell lymphoma, relapsed/refractory Waldenström’s macroglobulinemia, systemic light-chain amyloidosis

Contraindications

Hypersensitivity (excluding local reactions) to bortezomib, boron, mannitol, or any component of the formulation; administration via the intrathecal route

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.

Transplant-eligible patients (first-line therapy; in combination with other chemotherapy agents) (Canadian labeling): IV: 1.3 mg/m2 days 1, 4, 8, and 11 followed by a rest period of up to 20 days (equals one treatment cycle); administer 3 to 6 cycles.

Alternative first-line therapy (off-label dosing):

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)

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)

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) (Kumar 2012; Richardson 2010)

Patients ≥65 years: 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): IV, SubQ: 1.3 mg/m2 twice weekly for 2 weeks 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.

Alternative relapsed therapy (off-label dosing): IV: 1.3 mg/m2 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)

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

Mantle cell lymphoma (relapsed): IV, SubQ: 1.3 mg/m2 twice weekly for 2 weeks 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).

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 twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle (Zinzani 2007); additional data may be necessary to further define the role of bortezomib in this condition.

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 (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 (in combination with rituximab) (Ghobrial 2010)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment is necessary. The International Myeloma Working Group (IMWG) recommendations suggest that bortezomib may be safely administered to patients with renal impairment, including those on dialysis (Dimopoulos 2016). The IMWG recommends the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine. Dialysis may reduce bortezomib concentrations; administer postdialysis (Leal 2011).

Dosing: Hepatic Impairment

Mild impairment (bilirubin ≤1 times ULN and AST >ULN or bilirubin >1 to 1.5 times ULN): No initial dose adjustment is necessary (LoRusso, 2012).

Moderate (bilirubin >1.5 to 3 times ULN) and severe impairment (bilirubin >3 times ULN): Reduce initial dose to 0.7 mg/m2 in the first cycle; based on patient tolerance, may consider dose escalation to 1 mg/m2 (LoRusso, 2012) or further dose reduction to 0.5 mg/m2 in subsequent cycles

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 or motor 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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]). Reconstitute only with normal saline (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: 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 (3-5 seconds). When administering in combination with rituximab for first-line therapy of mantle cell lymphoma, administer bortezomib prior to rituximab.

SubQ: 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 IV or SubQ 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.

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

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 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Once reconstituted, the manufacturer recommends use within 8 hours of reconstitution. However, stability studies have demonstrated 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. Monitor therapy

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

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

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

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

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

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

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

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

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging 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

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering 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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

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

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

Incidences reported are associated with monotherapy. Additional adverse reactions reported with mono- or combination therapy; frequency not defined.

Cardiovascular: Hypotension (8% to 9%; grades 3/4: ≤2%), cardiac disease (treatment emergent; 8%), acute pulmonary edema (≤1%), cardiac failure (≤1%), cardiogenic shock (≤1%), pulmonary edema (≤1%), aggravated atrial fibrillation, angina pectoris, atrial flutter, atrioventricular block, bradycardia, cerebrovascular accident, deep vein thrombosis, edema, embolism (peripheral), facial edema, hemorrhagic stroke, 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: Peripheral neuropathy (IV: 35% to 54%; SubQ: 37%; grade ≥2: 24% to 39%; grade ≥3: SubQ: 5% to 6%; IV: 7% to 15%; grade 4: <1%), fatigue (7% to 52%), neuralgia (23%), headache (10% to 19%), paresthesia (7% to 19%), dizziness (10% to 18%; excludes vertigo), 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: Skin rash (12% to 23%), pruritus, urticaria

Endocrine & metabolic: Dehydration (2%), amyloid heart disease, hyperglycemia (diabetic patients), hyperkalemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia (diabetic patients), hypokalemia, hyponatremia, weight loss

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%), 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: 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%), hemorrhage (≥grade 3: 2%), disseminated intravascular coagulation, febrile neutropenia, lymphocytopenia, oral mucosal petechiae

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

Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity, hypersensitivity angiitis

Infection: Herpes zoster (reactivation; 6% to 11%), herpes simplex infection (1% to 3%), herpes zoster (1% to 2%), aspergillosis, bacteremia, listeriosis, toxoplasmosis

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

Neuromuscular & skeletal: Weakness (7% to 16%), 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: Dyspnea (11%), pneumonia (1% to 3%), adult 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

Miscellaneous: Fever (8% to 23%)

<1% (Limited to important or life-threatening): Acute ischemic stroke, amyloidosis, autonomic neuropathy, blindness, cardiac tamponade, chalazion (Fraunfelder 2016), deafness (bilateral), decreased left ventricular ejection fraction, dysgeusia, dyspepsia, hemolytic-uremic syndrome, herpes meningoencephalitis, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, 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, SIADH, Stevens-Johnson syndrome, subarachnoid hemorrhage, Sweet syndrome, syncope, tachycardia, 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 severe thrombocytopenia may occur; risk is increased in patients with pretreatment platelet counts <75,000/μL; frequent monitoring is required throughout treatment; may require dosage or schedule adjustments; withhold treatment for platelets <30,000/μL. Management with platelet transfusions and supportive care 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.

• Cardiovascular effects: Has been associated with the development or exacerbation of heart failure (HF) and decreased left ventricular ejection fraction (LVEF); monitor closely in patients with risk factors for HF or existing heart disease, although HF and decreased LVEF have been observed in patients without risk factors. Has also been associated with isolated reports of QTc prolongation.

• 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.

• Hepatic effects: 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.

• Hypotension: 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: 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).

• 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 (PML): 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.

• 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 1]).

Other warnings/precautions:

• Appropriate administration: For IV or SubQ 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.

Monitoring Parameters

CBC with differential and platelets (monitor frequently throughout therapy); liver function tests (in patients with existing hepatic impairment); 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 Risk Factor

D

Pregnancy Considerations

Adverse effects (fetal loss and decreased fetal weight) were observed in animal reproduction studies at doses less than the equivalent human dose (based on BSA). Women of reproductive potential should avoid becoming pregnant and should use effective contraception during treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, lack of appetite, insomnia, or headache. Have patient report immediately to prescriber signs of infection, signs of heart problems (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), signs of posterior reversible encephalopathy syndrome (illogical thinking, not alert, vision changes, seizures, or severe headache), signs of nerve problems (sensitivity to heat or cold; decreased sense of touch; burning, numbness, or tingling; pain, or weakness in the arms, hands, legs, or feet), signs of progressive multifocal leukoencephalopathy (confusion, not alert, vision changes, seizures, or severe headache), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), injection site irritation, severe dizziness, severe abdominal pain, severe constipation, severe loss of strength and energy, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), or signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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