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Special Alerts
Fatalities Associated with Intrathecal Bortezomib Administration
January 2012
Janssen Inc, in conjunction with Health Canada, is alerting healthcare professionals of deaths associated with inadvertent intrathecal administration of bortezomib. Three cases of accidental intrathecal administration resulting in death have been reported; all three patients were scheduled to receive intrathecal chemotherapy at the same time as I.V. bortezomib. In Canada, bortezomib is approved for I.V. administration only. Clinicians are encouraged to schedule any intrathecal chemotherapy at a different time than the scheduled bortezomib therapy. Additional recommendations include the use of different connectors for intravenous and intrathecal medications and clear labeling with the product name and intended route of administration.
In the U.S., bortezomib is approved for I.V. or SubQ administration only; intrathecal administration of bortezomib is contraindicated.
For additional information, please refer to http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/velcade_hpc-cps-eng.php.
Pronunciation
(bore TEZ oh mib)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Use: Labeled Indications
Treatment of multiple myeloma; treatment of relapsed or refractory mantle cell lymphoma
Use: Unlabeled
Treatment of cutaneous T-Cell lymphomas (mycosis fungoides), peripheral T-cell lymphoma, systemic light-chain amyloidosis, Waldenström's macroglobulinemia
Pregnancy Risk Factor
D
Pregnancy Considerations
Adverse effects (fetal loss and decreased fetal weight) were observed in animal reproduction studies. Women of childbearing potential should avoid becoming pregnant and should use effective contraception during treatment.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
Contraindications
Hypersensitivity to bortezomib, boron, mannitol, or any component of the formulation; administration via the intrathecal route
Warnings/Precautions
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: Hematologic toxicity, including 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 adjustments; withhold treatment for platelets <30,000/μL. 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.
• 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; may be reversible when discontinued. 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 pre-existing peripheral neuropathy (in patients with pre-existing 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 I.V.); consider subQ administration in patients with pre-existing 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).
• 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.
• Reversible posterior leukoencephalopathy syndrome (RPLS): Has been reported (rarely). Symptoms of RPLS include confusion, headache, hypertension, lethargy, seizure, blindness and/or other vision, or neurologic disturbances; discontinue bortezomib if RPLS occurs. MRI is recommended to confirm RPLS diagnosis. The safety of reinitiating bortezomib in patients previously experiencing RPLS is unknown.
• Tumor lysis syndrome: May cause tumor lysis syndrome; 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.
Other warnings/precautions:
• Appropriate administration: For I.V. or SubQ administration only. Inadvertent intrathecal administration has resulted in death and is contraindicated.
Adverse Reactions
>10%:
Cardiovascular: Edema (11% to 23%), cardiac disorder (treatment emergent; 15%), hypotension (13%; grades 3/4: 3%)
Central nervous system: Psychiatric disturbance (≤35%), fever (16% to 34%), dysesthesia (22% to 27%), headache (3% to 22%), insomnia (11% to 20%), dizziness (17%; excludes vertigo), fatigue (12% to 20%)
Dermatologic: Rash (18%)
Gastrointestinal: Nausea (18% to 55%), diarrhea (24% to 52%), constipation (14% to 41%), anorexia (36%), vomiting (12% to 33%), abdominal pain (2% to 15%), weight loss (3% to 15%), abnormal taste, dyspepsia
Hematologic: Thrombocytopenia (35% to 36%; grade 4: 5% to 8%; nadir: day 11; recovery: by day 21), anemia (29% to 36%; grade 4: ≤3%), neutropenia (17% to 29%; grade 4: 3% to 4%; nadir: day 11; recovery: by day 21), leukopenia (20% to 22%; grade 4: ≤1%)
Neuromuscular & skeletal: Weakness (16% to 64%; grades 3/4: 16%), peripheral neuropathy (38% to 53%; grade ≥2: SubQ 24%, I.V. 41%; grade ≥3: SubQ 6%, I.V. 16%; grade 4: ≤1%), neuralgia (23% to 24%; grade 3: SubQ 3%, I.V. 9%), paresthesia (22%), arthralgia (17%), limb pain (5% to 15%), bone pain (14%), back pain (11% to 13%), myalgia (12%), muscle cramps (11%), rigors (≤11%)
Respiratory: Dyspnea (7% to 21%), cough (20%), respiratory tract infection (12% to 15%), nasopharyngitis (12%), pneumonia (12%)
Miscellaneous: Herpesvirus infections (2% to 12%)
1% to 10%:
Cardiovascular: Hypertension (4% to 10%), heart failure (5%; includes acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema)
Central nervous system: Anxiety (10%)
Endocrine & metabolic: Dehydration (10%), hypercalcemia (grade 4: 2%)
Gastrointestinal: Appetite decreased (9% to 10%)
Hematologic: Bleeding events (≥grade 3: 4%)
Local: Injection site irritation (SubQ: 6%; resolved in 6 days on average; severe: 1%; I.V.: 5%)
Frequency not defined (including postmarketing and/or case reports; limited to important or life-threatening): Acute diffuse infiltrative pulmonary disease, acute respiratory distress syndrome, alkaline phosphatase increased, amyloidosis, anaphylaxis, angina, angioedema, ascites, aspergillosis, atelectasis, atrial fibrillation, atrial flutter, AV block, bacteremia, blindness, blurred vision, bronchitis, cardiac amyloidosis, cardiac arrest, cardiac tamponade, cardiopulmonary arrest, cerebral hemorrhage, cerebrovascular accident, cholestasis, coma, confusion, conjunctival infection/irritation, cranial palsy, deep venous thrombosis, diplopia, disseminated intravascular coagulation (DIC), duodenitis (hemorrhagic), DVT, dysautonomia, dysphagia, encephalopathy, embolism, epistaxis, fecal impaction, fracture, gastritis (hemorrhagic), gastroenteritis, GGT increased, glomerular nephritis, hearing impairment, hematemesis, hematuria, hemoptysis, hemorrhagic cystitis, hepatic failure, hepatic hemorrhage, hepatitis, hepatocellular damage, herpes meningoencephalitis, hyperbilirubinemia, hyper-/hypoglycemia, hyper-/hypokalemia, hyper-/hyponatremia, hypersensitivity, hyperuricemia, hypocalcemia, hypoxia, ileus, immune complex hypersensitivity, inappropriate ADH secretion, injection site reaction, interstitial pneumonia, intestinal obstruction, intestinal perforation, intracerebral hemorrhage, ischemic colitis, ischemic stroke, laryngeal edema, left ventricular ejection fraction decreased, leukocytoclastic vasculitis, leukopenia, listeriosis, lymphopenia, melena, mental status change, MI, myocardial ischemia, neuralgia, neutropenic fever, ophthalmic herpes, optic neuritis, oral candidiasis, pancreatitis, paralytic ileus, pericardial effusion, pericarditis, peritonitis, pleural effusion, pneumonitis, portal vein thrombosis, proliferative glomerular nephritis, pruritus, psychosis, pulmonary embolism, pulmonary hypertension, pulmonary infiltrate, QTc prolongation, renal calculus, renal failure, respiratory failure, respiratory insufficiency, reversible posterior leukoencephalopathy syndrome (RPLS), seizure, septic shock, sepsis, sinus arrest, spinal cord compression, Stevens-Johnson syndrome, stomatitis, stroke (hemorrhagic), subarachnoid hemorrhage, subdural hematoma, suicidal ideation, Sweet's syndrome (acute febrile neutrophilic dermatosis), syncope, tachycardia, torsade de pointes, toxic epidermal necrolysis, toxoplasmosis, transaminases increased, transient ischemic attack, tumor lysis syndrome, urinary incontinence, urinary retention, urinary tract infection, urticaria, ventricular tachycardia
Metabolism/Transport Effects
Substrate of CYP1A2 (minor), CYP2C19 (major), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak), CYP2C19 (moderate), CYP2C9 (weak), CYP2D6 (weak), CYP3A4 (weak)
Drug Interactions
ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole systemic exposure/affects with concomitant use of a weak CYP3A4 inhibitor. Decrease aripiprazole dose to 25% of the usual dose in patients receiving both a CYP3A4 and a CYP2D6 inhibitor (regardless of potencies). Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult product labeling for specific recommendations. Risk C: 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.). Risk D: 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.). Risk D: Consider therapy modification
Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Bortezomib. Exceptions: Dexamethasone; Dexamethasone (Systemic). Risk X: Avoid combination
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Bortezomib. Risk C: Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Green Tea: May diminish the antineoplastic effect of Bortezomib. Risk X: Avoid combination
Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Risk X: Avoid combination
St Johns Wort: May decrease the serum concentration of Bortezomib. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Food: Avoid grapefruit juice (may increase bortezomib levels).
Herb/Nutraceutical: Avoid St John's wort (may decrease bortezomib levels). Avoid green tea and green tea extracts (may diminish the therapeutic effect of bortezomib) (Golden, 2009). Avoid 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 at room temperature of 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Once reconstituted, although the manufacturer recommends use within 8 hours of reconstitution, solutions of 1 mg/mL may be stored at room temperature for up to 3 days, or under refrigeration for up to 5 days, in vial or syringe (Andre, 2005). Protect form light.
Reconstitution
Note: The reconstituted concentrations for I.V. and SubQ administration are different; the manufacturer provides stickers to facilitate identification of the concentration/route for reconstituted vials. The amount contained in each vial may exceed the prescribed dose; use care with dosage and volume calculations.
Use appropriate precautions for handling and disposal. Reconstitute only with normal saline (NS). Reconstituted solutions should be clear and colorless.
I.V.: 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.
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.
Pharmacodynamics/Kinetics
Distribution: 498-1884 L/m2; distributes widely to peripheral tissues
Protein binding: ~83%
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: I.V.: 9-15 hours; multiple dosing: 1 mg/m2: 40-193 hours; 1.3 mg/m2: 76-108 hours
Dosage
Details concerning dosing in combination regimens should also be consulted. Note: Consecutive doses should be separated by at least 72 hours: Adults:
Multiple myeloma (first-line therapy; in combination with melphalan and prednisone): I.V., 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.
Alternative first-line therapy (studied in patients ≥65 years of age; unlabeled dosing): I.V.: 1.3 mg/m2/dose days 1, 8, 15, and 22 of a 5-week treatment cycle, in combination with either melphalan and prednisone or melphalan, prednisone, and thalidomide (Boccadoro, 2010; Bringhen, 2010; Palumbo, 2009)
Relapsed multiple myeloma and mantle cell lymphoma: I.V., 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).
Cutaneous and peripheral T-cell lymphoma (unlabeled use): I.V.: 1.3 mg/m2 twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle (Zinzani, 2007)
Systemic light-chain amyloidosis (unlabeled use): I.V.: 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 (unlabeled use): I.V.: 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)
Dosage adjustment in renal impairment: Dosage adjustment not necessary. Note: Dialysis may reduce bortezomib concentrations; administer postdialysis.
Dosage adjustment in hepatic impairment:
Mild impairment (bilirubin ≤1 times ULN and AST >UNL or bilirubin >1-1.5 times ULN): No initial dose adjustment necessary.
Moderate (bilirubin >1.5-3 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 or further dose reduction to 0.5 mg/m2 in subsequent cycles
Dosage 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.
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 or motor neuropathy:
Note: Consider subQ administration in patients with pre-existing 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; self-care limiting 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): Discontinue therapy
Dosage: Combination Regimens
Amyloidosis: Bortezomib-Dexamethasone (Amyloidosis)
Multiple myeloma:
Bortezomib-Dexamethasone (Multiple Myeloma)
Bortezomib-Doxorubicin-Dexamethasone
Bortezomib-Doxorubicin (Liposomal)
Bortezomib-Doxorubicin (Liposomal)-Dexamethasone
Bortezomib-Melphalan-Prednisone-Thalidomide
Melphalan-Prednisone-Bortezomib (Multiple Myeloma)
Waldenstrom's Macroglobulinemia:
Bortezomib-Dexamethasone-Rituximab (Waldenstrom's Macroglobulinemia)
Bortezomib-Rituximab (Waldenstrom's Macroglobulinemia)
Bortezomib (Waldenstrom's Macroglobulinemia)
Administration: I.V.
Note: The reconstituted concentrations for I.V. and SubQ administration are different; use caution when calculating the volume for each dose. Consider SubQ administration in patients with pre-existing or at high risk for peripheral neuropathy.
Administer via rapid I.V. push (3-5 seconds).
Administration: Other
Note: The reconstituted concentrations for I.V. and SubQ administration are different; use caution when calculating the volume for each dose.
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 I.V. administration; decreased incidence of grade 3 or higher adverse events were observed with SubQ administration. If injection site reaction occurs, the more dilute 1 mg/mL concentration may be used subQ (or I.V. administration of the 1 mg/mL concentration may be considered).
Administration: I.V. Detail
pH: 2-6.5
Monitoring Parameters
Signs/symptoms of peripheral neuropathy, dehydration, hypotension, or RPLS; CBC with differential and platelets (monitor frequently throughout therapy); renal function, pulmonary function (with new or worsening pulmonary symptoms), liver function tests (in patients with existing hepatic impairment)
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).
Patient Education
Avoid grapefruit juice, green tea, and ascorbic acid supplements. This medication can be administered intravenously or subcutaneously; you will be monitored during and following infusion. Maintain adequate hydration, unless instructed to restrict fluid intake. If you have diabetes, monitor blood sugars closely; may cause alterations in glycemic control. May cause headache, dizziness, anxiety, sleep disturbances, fever, fatigue, nausea, vomiting, loss of appetite, abnormal taste, constipation, or diarrhea. You may be more susceptible to infection. Report immediately any chest pain, respiratory difficulty, itching, rash, acute headache, throat tightness, pain, redness, or swelling at infusion site. Report swelling in extremities; weight gain; persistent headache; muscle, bone, or back pain; abdominal pain; cramping or loss of sensation or tingling of extremities; unusual bleeding; or changes in vision.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Abnormal taste and stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Insomnia, dizziness, and anxiety are common; may cause agitation, confusion, psychosis, and suicidal ideation
Mental Health: Effects on Psychiatric Treatment
Gastrointestinal side effects are common; use caution with SSRIs. May cause neutropenia and thrombocytopenia; use caution with clozapine, carbamazepine, and valproic acid. Fluoxetine, fluvoxamine, and nefazodone may increase bortezomib serum levels, while carbamazepine and barbiturates may decrease its serum levels.
Nursing: Physical Assessment/Monitoring
Monitor for peripheral neuropathy, postural hypotension, dehydration, heart failure, and infections. Be alert to the potential for reactivation of herpes.
Oncology: Emetic Potential
Low (10% to 30%)
Oncology: Vesicant
May be an irritant; extravasation has not been associated with tissue damage
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution:
Velcade®: 3.5 mg [contains mannitol]
References
Agathocleous A, Rohatiner A, Rule S, et al, “Weekly Versus Twice Weekly Bortezomib Given in Conjunction With Rituximab, in Patients With Recurrent follicular Lymphoma, Mantle Cell Lymphoma and Waldenström Macroglobulinaemia,” Br J Haematol, 2010, 151(4):346-53.
Andre P, Cisternino S, Chiadmi F, et al, “Stability of Bortezomib 1-mg/mL Solution in Plastic Syringe and Glass Vial,” Ann Pharmacother, 2005, 39(9):1462-6.
Boccadoro M, Bringhen S, Gaidano G, et al, “Bortezomib, Melphalan, Prednisone, and Thalidomide (VMPT) Followed by Maintenance With Bortexomib and Thalidomide (VT) for Initial Treatment of Elderly Multiple Myeloma Patients,” J Clin Oncol, 2010, 28(7s):8013 [abstract 8013 from 2010 ASCO Annual Meeting].
Bringhen S, Larocca A, Rossi D, et al, “Efficacy and Safety of Once-Weekly Bortezomib in Multiple Myeloma Patients,” Blood, 2010, 116(23):4745-53.
Cavo M, Tacchetti P, Patriarca F, et al, “Bortezomib With Thalidomide Plus Dexamethasone Compared With Thalidomide Plus Dexamethasone as Induction Therapy Before, and Consolidation Therapy After, Double Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Randomised Phase 3 Study,” Lancet, 2010, 376(9758):2075-85.
Chanan-Khan AA, Kaufman JL, Mehta J, et al, “Activity and Safety of Bortezomib in Multiple Myeloma Patients With Advanced Renal Failure: A Multicenter Retrospective Study,” Blood, 2006, 109(9):2604-6.
Chanan-Khan A, Sonneveld P, Schuster MW, et al, "Analysis of Herpes Zoster Events Among Bortezomib-Treated Patients in the Phase III APEX Study," J Clin Oncol, 2008, 26(29):4784-90.
Chen CI, Kouroukis CT, White D, et al, “Bortezomib is Active in Patients With Untreated or Relapsed Waldenstrom's Macroglobulinemia: A Phase II Study of the National Cancer Institute of Canada Clinical Trials Group,” J Clin Oncol, 2007, 25(12):1570-5.
Dimopoulos MA, Mateos MV, Richardson PG, et al, “Risk Factors for, and Reversibility of, Peripheral Neuropathy Associated With Bortezomib-Melphalan-Prednisone in Newly Diagnosed Patients With Multiple Myeloma: Subanalysis of the Phase 3 VISTA Study,” Eur J Haematol, 2011, 86(1):23-31.
Dimopoulos MA, Richardson PG, Schlag R, et al, “VMP (Bortezomib, Melphalan, and Prednisone) is Active and Well Tolerated in Newly Diagnosed Patients With Multiple Myeloma With Moderately Impaired Renal Function, and Results in Reversal of Renal Impairment: Cohort Analysis of the Phase III VISTA Study,” J Clin Oncol, 2009, 27(36):6086-93.
Engelhardt M, Udi J, Kleber M, et al, “European Myeloma Network: The 3rd Trialist Forum Consensus Statement from the European Experts Meeting on Multiple Myeloma,” Leuk Lymphoma, 2010, 51(11):2006-11.
Fisher RI, Bernstein SH, Kahl BS, et al, “Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma,” J Clin Oncol, 2006, 24(30):4867-74.
Ghobrial IM, Hong F, Padmanabhan S, et al, “Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenstrom Macroglobulinemia,” J Clin Oncol, 2010, 28(8):1422-8.
Golden EB, Lam PY, Kardosh A, et al, “Green Tea Polyphenols Block the Anticancer Effects of Bortezomib and Other Boronic Acid-Based Proteasome Inhibitors,” Blood, 2009, 113(23):5927-37.
Harousseau JL, Attal M, Avet-Loiseau H, et al, “Bortezomib Plus Dexamethasone is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone as Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial,” J Clin Oncol, 2010, 28(30):4621-9.
Harousseau JL, Palumbo A, Richardson PG, et al, “Superior Outcomes Associated With Complete Response in Newly Diagnosed Multiple Myeloma Patients Treated With Nonintensive Therapy: Analysis of the Phase 3 VISTA Study of Bortezomib Plus Melphalan-Prednisone Versus Melphalan-Prednisone,” Blood, 2010, 116(19):3743-50.
Iwamoto T, Ishibashi M, Fujieda A, et al, “Drug Interaction Between Itraconazole and Bortezomib: Exacerbation of Peripheral Neuropathy and Thrombocytopenia Induced by Bortezomib,” Pharmacotherapy, 2010, 30(7):661-5.
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International Brand Names
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Last full review/revision February 2012
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