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BORTEZOMIB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Bortezomib is an antineoplastic agent and a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells.

Specific Substances

    1) Bortezomibum
    2) LDP-341
    3) PS-341
    4) Boronic acid, ((1R)-3-methyl-1-(((2S)-1-oxo-3-phenyl-2-((pyrazinylcarbonyl)amino)propyl)amino)butyl)-
    5) CAS 179324-69-7
    1.2.1) MOLECULAR FORMULA
    1) C19-H25-B-N4-O4 (Prod Info VELCADE(R) IV injection, 2006)

Available Forms Sources

    A) FORMS
    1) Bortezomib injection is available in the US as individually packaged 10-mL vials containing 3.5 mg of bortezomib (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).
    B) USES
    1) Bortezomib is FDA-approved for patients with multiple myeloma or mantle cell lymphoma who have received at least one prior therapy (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Bortezomib is used to treat patients with multiple myeloma or mantle cell lymphoma.
    B) PHARMACOLOGY: Bortezomib reversibly inhibits the chymotrypsin-like activity of the 26S proteasome, a large protein complex in mammalian cells that breaks down ubiquitinated proteins. The ubiquitin-proteasome pathway is responsible for regulating intracellular concentration of specific proteins, and maintaining homeostasis within cells. Proteasome inhibition prevents this targeted proteolysis and affects multiple signaling cascades within the cell. Therefore, cell death occurs with the disruption of normal homeostatic mechanisms. Studies have reported that bortezomib is cytotoxic to many types of cancer cells in vitro.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (20% or greater): Nausea, vomiting, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, lymphopenia, rash, fever, and anorexia. OTHER EFFECTS: Abdominal pain, decreased appetite, asthenia (fatigue, malaise, weakness), hypotension, hyponatremia, hypokalemia, paralytic ileus, hyperbilirubinemia, increases in liver enzymes, hepatitis, bone pain, myalgia, rhabdomyolysis, leukoencephalopathy, headache, dizziness, paresthesia and dysesthesia, psychiatric disorders, cough, dyspnea, nasopharyngitis, and tumor lysis syndrome. In postmarketing experience, complete atrioventricular block, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, bilateral deafness, disseminated intravascular coagulation, acute pancreatitis, and toxic epidermal necrolysis have also occurred.
    E) WITH POISONING/EXPOSURE
    1) Limited data. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Twice the recommended dose has resulted in an acute onset of hypotension and thrombocytopenia resulting in fatal outcomes.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever, with or without other constitutional symptoms (eg, rigors, malaise, anorexia), has been reported in patients receiving bortezomib.
    0.2.20) REPRODUCTIVE
    A) Bortezomib is classified as FDA pregnancy category D.
    0.2.21) CARCINOGENICITY
    A) Carcinogenicity studies have not been performed with bortezomib (Prod Info VELCADE(R) IV injection, 2006).

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor CBC with differential and platelet count.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Monitor for clinical evidence of peripheral neuropathy or encephalopathy.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Myelosuppression has been reported. Monitor serial CBC with differential. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    C) INTRATHECAL INJECTION
    1) Intrathecal administration of bortezomib is contraindicated; fatal events have occurred with intrathecal administration. Aggressive treatment is essential. This information is derived from experience with antineoplastic agents. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours or more). Add fresh frozen plasma (25 mL FFP/liter NS of LR) or 5% albumin to the fluid used for perfusion to increase elimination from the CSF, as bortezomib is highly protein bound. Dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    E) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect their airway.
    F) ANTIDOTE
    1) None
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors to patients who develop severe neutropenia following a significant overdose. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia or anemia. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUROPATHY
    1) Treatment of neuropathy is symptomatic and supportive.
    I) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol).
    J) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding and large volume of distribution.
    K) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    L) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of bortezomib. Some toxic effects of overdose may be delayed (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking bortezomib may have severe co-morbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression).
    M) PHARMACOKINETICS
    1) Protein binding: 83%. Vd: Approximately 498 to 1884 L/m(2). Metabolism: Primarily oxidatively metabolized by cytochrome P-450 enzymes (3A4, 2C19, and 1A2). Elimination half-life: With multiple dosing, 40 to 193 hours after the 1 mg/m(2) dose and 76 to 108 hours after the 1.3 mg/m(2) dose.
    N) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression or neuropathy.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Overdoses of twice the recommended dose have resulted in rapid symptomatic hypotension and thrombocytopenia leading to fatal outcomes.
    B) THERAPEUTIC DOSE: ADULT: Initial dose of 1.3 mg/m(2) given as a 3 to 5 second bolus IV injection (concentration of 1 mg/mL) or SubQ injection (concentration of 2.5 mg/mL) twice weekly for 2 weeks followed by a 10-day rest period. CHILD: Safety and effectiveness in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Bortezomib is used to treat patients with multiple myeloma or mantle cell lymphoma.
    B) PHARMACOLOGY: Bortezomib reversibly inhibits the chymotrypsin-like activity of the 26S proteasome, a large protein complex in mammalian cells that breaks down ubiquitinated proteins. The ubiquitin-proteasome pathway is responsible for regulating intracellular concentration of specific proteins, and maintaining homeostasis within cells. Proteasome inhibition prevents this targeted proteolysis and affects multiple signaling cascades within the cell. Therefore, cell death occurs with the disruption of normal homeostatic mechanisms. Studies have reported that bortezomib is cytotoxic to many types of cancer cells in vitro.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) MOST COMMON (20% or greater): Nausea, vomiting, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, lymphopenia, rash, fever, and anorexia. OTHER EFFECTS: Abdominal pain, decreased appetite, asthenia (fatigue, malaise, weakness), hypotension, hyponatremia, hypokalemia, paralytic ileus, hyperbilirubinemia, increases in liver enzymes, hepatitis, bone pain, myalgia, rhabdomyolysis, leukoencephalopathy, headache, dizziness, paresthesia and dysesthesia, psychiatric disorders, cough, dyspnea, nasopharyngitis, and tumor lysis syndrome. In postmarketing experience, complete atrioventricular block, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, bilateral deafness, disseminated intravascular coagulation, acute pancreatitis, and toxic epidermal necrolysis have also occurred.
    E) WITH POISONING/EXPOSURE
    1) Limited data. Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Twice the recommended dose has resulted in an acute onset of hypotension and thrombocytopenia resulting in fatal outcomes.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever, with or without other constitutional symptoms (eg, rigors, malaise, anorexia), has been reported in patients receiving bortezomib.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER - In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade pyrexia occurred in 35% (2% grade 3 events) of patients receiving bortezomib versus 16% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006; Cibeira et al, 2006).
    2) RIGORS - In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade rigors occurred in 11% of patients receiving bortezomib versus 2% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    3) Fever, with or without other constitutional symptoms (eg, rigors, malaise, anorexia), was reported with intravenous bortezomib in a small phase I study involving patients with hematologic malignancies (Orlowski et al, 2002a). Considering the underlying condition of these patients, causality is speculative.

Heent

    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) In postmarketing experience, bilateral deafness has occurred (Prod Info VELCADE(R) IV injection, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Cases of acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction have been reported. The incidence of heart failure events, including acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, and pulmonary edema, was 5% in the bortezomib arm versus 4% in the dexamethasone arm in a phase 3 clinical trial (Prod Info VELCADE(R) IV injection, 2006).
    b) CASE REPORT - A 47-year-old man, with no previous history of cardiac disease, experienced severe abdominal pain and weakness one day after receiving the second regimen of bortezomib for treatment of myeloma. Two weeks later, the patient also experienced dyspnea. A chest radiograph revealed an increase in the cardiothoracic ratio, and an echocardiography showed the left and right ventricle ejection fractions to be 10% and 20%, respectively, with left ventricular hypertrophy and diastolic dysfunction, and global hypokinesia, indicating cardiac failure. The patient's brain natriuretic peptide (BNP) level was estimated to be 1170 pg/mL (control < 100 pg/mL, at normal control 120 pg/mL). Although the BNP level and echocardiographic findings gradually improved following discontinuation of bortezomib therapy, the LVEF had not returned to pretreatment levels at 6 months follow-up (Hacihanefioglu et al, 2008).
    B) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) Isolated cases of QT-interval prolongations occurred in clinical trials. Causality has not been established (Prod Info VELCADE(R) IV injection, 2006).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In clinical trials, hypotension (postural, orthostatic, and hypotension NOS) occurred in 13% of patients (Prod Info VELCADE(R) IV injection, 2006).
    b) Symptomatic postural hypotension was described in one patient with hematologic malignancy (undefined) during the second cycle of bortezomib therapy (twice weekly for 4 of 6 weeks) in a phase I study; the patient responded to discontinuation of the drug and steroid therapy, but was not rechallenged, precluding assessment of causality (Orlowski et al, 2002a).
    c) CHILDREN - In a phase I study, 12 patients (median age 11 years; range 1 to 18 years; 9 with acute lymphoblastic leukemia, 3 with acute myelogenous leukemia) received bortezomib twice weekly for 2 consecutive weeks at 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Two patients had dose-limiting toxicities at the 1.7 mg/m(2) dose level. One patient developed grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine elevation (Horton et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) Overdoses of twice the recommended dose have resulted in rapid symptomatic hypotension and thrombocytopenia leading to fatal outcomes (Prod Info VELCADE(R) IV injection, 2006).
    D) ATRIOVENTRICULAR BLOCK
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, complete atrioventricular block has occurred (Prod Info VELCADE(R) IV injection, 2006).
    E) CARDIAC TAMPONADE
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, cardiac tamponade has occurred (Prod Info VELCADE(R) IV injection, 2006).
    F) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade edema of the lower limbs occurred in 11% of patients receiving bortezomib versus 13% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CARDIOVASCULAR FINDING
    a) In animal studies (monkeys and dogs), increases in heart rate, decreases in contractility, hypotension, and death occurred following IV bortezomib doses as low as 2 times the recommended clinical dose. A slight increase in the corrected QT interval was noted in dogs with doses resulting in death. Hypotension developed in monkeys after bortezomib doses of 3 mg/m(2) and greater (approximately twice the recommended clinical dose). Death occurred in these monkeys 12 to 14 hours after drug administration (Prod Info VELCADE(R) IV injection, 2006).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DIFFUSE INFILTRATIVE LUNG DISEASE
    1) WITH THERAPEUTIC USE
    a) Manufacturer post marketing surveillance has revealed reports (incidence unknown) of acute diffuse infiltrative pulmonary disease in patients treated with bortezomib (Prod Info VELCADE(R) IV injection, 2006).
    B) LOWER RESPIRATORY TRACT INFECTION
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 clinical trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade lower respiratory/lung infections occurred in 15% (4% grade 3 events; less than 1% grade 4 events) of patients receiving bortezomib versus 21% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    C) ACUTE PNEUMONITIS
    1) WITH THERAPEUTIC USE
    a) There have been rare reports, some fatal, of acute infiltrative pulmonary disease such as pneumonitis, or acute lung injury, in patients receiving bortezomib; the etiology is unknown (Prod Info VELCADE(R) IV injection, 2006).
    D) COUGH
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade cough occurred in 21% (less than 1% grade 3 events) of patients receiving bortezomib versus 11% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    E) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade dyspnea occurred in 20% (5% grade 3 events and less than 1% grade 4 events) of patients receiving bortezomib versus 17% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    b) Dyspnea and pleural effusions were described in some hematologic malignancy patients in a phase I study (Orlowski et al, 2002a). A direct causal relationship to bortezomib has not been established.
    F) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade nasopharyngitis occurred in 14% (less than 1% grade 3 events) of patients receiving bortezomib versus 7% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    G) PULMONARY HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Pulmonary hypertension, in the absence of left heart failure or significant pulmonary disease, has been reported rarely in patients treated with bortezomib (Prod Info VELCADE(R) IV injection, 2006).
    H) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 65-year-old man with Waldenstrom's macroglobulinemia developed severe pulmonary complications after receiving 3 doses of bortezomib (1.3 mg/m(2)) on day 10 of the first cycle. Physical examination showed a febrile patient in moderate-to-severe respiratory distress. Auscultation showed widespread crackles in both lung fields in a clinically dehydrated patient. Chest x-ray showed bilateral increased diffuse interstitial markings. CT scan of the patient's chest showed a diffuse ground glass opacification in both lung fields but no filling defect in main and subsegmental pulmonary arteries. Arterial blood gas revealed hypoxia (O2 sat 73% with pH 7.5 and pCO2 28%). Test results for bacterial infection were negative. Following supportive therapy for several days, he improved clinically and radiographically (Ohri & Arena, 2006).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Fatigue is common during therapy and appears to be drug-related and dose-dependent, occurring more often with doses exceeding 1 mg/m(2) (Adams, 2002ba; Orlowski et al, 2002a; Anon, 2002).
    b) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade asthenia including fatigue, malaise, and weakness occurred in 61% (12% grade 3 events; less than 1% grade 4 events) of patients receiving bortezomib versus 45% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006; Dicato et al, 2006).
    B) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy has been reported relatively frequently during therapy (19 to 37% of patients); in most instances, patients had received prior therapy with agents known to be neurotoxic (eg, thalidomide, taxanes), suggesting enhanced susceptibility to neuropathy from bortezomib (Adams, 2002aa; Orlowski et al, 2002a; Anon, 2002). Only a few patients without symptoms prior to therapy have developed neuropathic symptoms.
    b) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade peripheral neuropathy occurred in 36% (7% grade 3 events; less than 1% grade 4 events) of patients receiving bortezomib versus 9% in the dexamethasone group. Cases of severe sensory and motor peripheral neuropathy have also been reported. Patients with pre-existing symptoms and/or signs of peripheral neuropathy may experience worsening of signs and symptoms with bortezomib. Dose adjustments have improved or resolved peripheral neuropathy in 51% of patients with grades 2 to 4 peripheral neuropathy. In a phase 2 study, improvement or resolution of peripheral neuropathy occurred in 73% of patients who discontinued bortezomib use (Prod Info VELCADE(R) IV injection, 2006; Dicato et al, 2006).
    c) In a retrospective study of 78 patients with multiple myeloma, the highest risk and grade of bortezomib neurotoxicity was noted in patients who had peripheral neuropathy and diabetes mellitus at baseline (Badros et al, 2007).
    C) DISORDER OF AUTONOMIC NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, dysautonomia has occurred (Prod Info VELCADE(R) IV injection, 2006).
    D) DISORDER OF BRAIN
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, encephalopathy has occurred (Prod Info VELCADE(R) IV injection, 2006).
    E) LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) Reversible posterior leukoencephalopathy syndrome has been reported rarely in patients receiving bortezomib. Patients may present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances (Prod Info VELCADE(R) IV injection, 2006).
    F) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade headache occurred in 26% (less than 1% grade 3 events) of patients receiving bortezomib versus 13% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    G) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade dizziness occurred in 14% (less than 1% grade 3 events) of patients receiving bortezomib versus 10% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    H) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade paresthesia and dysesthesia occurred in 27% (2% grade 3 events) of patients receiving bortezomib versus 11% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    I) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) CHILDREN - In a phase I study, 12 patients (median age 11 years; range 1 to 18 years; 9 with acute lymphoblastic leukemia, 3 with acute myelogenous leukemia) received bortezomib twice weekly for 2 consecutive weeks at 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Two patients had dose-limiting toxicities at the 1.7 mg/m(2) dose level. One patient developed grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine (Horton et al, 2007).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade nausea occurred in 57% (2% grade 3 events) of patients receiving bortezomib versus 14% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006; Dicato et al, 2006).
    b) In a phase I study involving patients with hematologic malignancies treated with 1.04 to 1.38 mg/m(2) twice weekly for 4 weeks, then 2 weeks of rest (n=27), the most frequent GI effects during the first cycle were nausea (52% of patients), diarrhea (37%), and vomiting and constipation (each in 30%); severity data were not provided (Orlowski et al, 2002a). There was some evidence of dose-dependency for nausea in this study (50%, 57%, and 80% of patients at doses of 1.04, 1.2, and 1.38 mg/m(2), respectively).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade vomiting occurred in 35% (3% grade 3 events) of patients receiving bortezomib versus 6% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade diarrhea occurred in 57% (7% grade 3 events) of patients receiving bortezomib versus 21% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006; Dicato et al, 2006).
    b) In a phase I study involving patients with hematologic malignancies treated with 1.04 to 1.38 mg/m(2) twice weekly for 4 weeks, then 2 weeks of rest (n=27), the most frequent GI effects during the first cycle were nausea (52% of patients), diarrhea (37%), and vomiting and constipation (each in 30%); severity data were not provided (Orlowski et al, 2002a). There was some evidence of dose-dependency for nausea in this study (50%, 57%, and 80% of patients at doses of 1.04, 1.2, and 1.38 mg/m(2), respectively).
    D) DECREASE IN APPETITE
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade anorexia and decreased appetite occurred in 34% (3% grade 3 events) of patients receiving bortezomib versus 9% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    E) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade constipation occurred in 42% (2% grade 3 events) of patients receiving bortezomib versus 15% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006; Dicato et al, 2006).
    b) In a phase I study involving patients with hematologic malignancies treated with 1.04 to 1.38 mg/m(2) twice weekly for 4 weeks, then 2 weeks of rest (n=27), the most frequent GI effects during the first cycle were nausea (52% of patients), diarrhea (37%), and vomiting and constipation (each in 30%); severity data were not provided (Orlowski et al, 2002a).
    F) ISCHEMIC COLITIS
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, ischemic colitis has occurred (Prod Info VELCADE(R) IV injection, 2006).
    G) ACUTE PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, acute pancreatitis has occurred (Prod Info VELCADE(R) IV injection, 2006).
    H) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade abdominal pain occurred in 16% (2% grade 3 events) of patients receiving bortezomib versus 4% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    b) CASE REPORT - A 47-year-old man with no previous history of cardiac disease, experienced severe abdominal pain and weakness one day after receiving the second regimen of bortezomib for treatment of myeloma. Two weeks later, the patient also experienced dyspnea. A chest radiograph revealed an increase in the cardiothoracic ratio, and an echocardiography showed the left and right ventricle ejection fractions to be 10% and 20%, respectively, with left ventricular hypertrophy and diastolic dysfunction, and global hypokinesia, indicating cardiac failure. Following discontinuation of bortezomib therapy, the patient's condition gradually improved. It is speculated that the patient's abdominal pain may have either been due to mesenteric ischemia resulting from the cardiac failure, or was secondary to a sub-ileus associated with bortezomib neuropathy (Hacihanefioglu et al, 2008).
    I) PARALYTIC ILEUS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 63-year-old man with multiple myeloma (stage III, IgA) developed severe paralytic ileus during the third cycle of bortezomib (standard treatment: 1.3 mg/m(2) IV bolus injection on days 1, 4, 8, 11, to be repeated every 3 weeks). He presented with constipation, burning dysesthesia of hands and feet, nausea, vomiting, and modest abdominal pain. Evaluation revealed normal vital signs, marked abdominal distension, absence of bowel movements, no herniations, and acral hypesthesia. Abdominal radiography revealed distension of small and large intestine with multiple air-fluid levels. Following supportive treatment, his symptoms improved gradually and he was discharged 3 days after admission (Perfetti et al, 2007).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ACUTE HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) Rare cases of acute liver failure have occurred in patients receiving bortezomib with multiple concomitant medications and serious underlying conditions (Prod Info VELCADE(R) IV injection, 2006).
    B) HYPERBILIRUBINEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperbilirubinemia has been reported in patients taking bortezomib and may be reversible upon discontinuation (Prod Info VELCADE(R) IV injection, 2006).
    b) A patient in a phase I study with normalized hepatitis C prior to therapy developed grade 4 increases in AST and ALT with hyperbilirubinemia during the second cycle with 1.2 mg/m(2) (twice weekly for 4 of 6 weeks); however, the patient was also receiving high-dose acetaminophen at this time, lending doubt to bortezomib causality. The patient recovered with supportive care but was not rechallenged with bortezomib (Orlowski et al, 2002a).
    C) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) Increases in liver enzymes have been reported in patients taking bortezomib and may be reversible upon discontinuation (Prod Info VELCADE(R) IV injection, 2006; Cibeira et al, 2006).
    b) Rises in ALT and alkaline phosphatase were observed in a phase I study (15% or less of patients). One patient in this latter study with normalized hepatitis C prior to therapy developed grade 4 increases in AST and ALT with hyperbilirubinemia during the second cycle with 1.2 mg/m(2) (twice weekly for 4 of 6 weeks); however, the patient was also receiving high-dose acetaminophen at this time, lending doubt to bortezomib causality. The patient recovered with supportive care but was not rechallenged with bortezomib (Orlowski et al, 2002a).
    D) INFLAMMATORY DISEASE OF LIVER
    1) WITH THERAPEUTIC USE
    a) Hepatitis has been reported in patients taking bortezomib and may be reversible upon discontinuation (Prod Info VELCADE(R) IV injection, 2006).
    b) In postmarketing experience, hepatitis has occurred (Prod Info VELCADE(R) IV injection, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) SERUM CREATININE RAISED
    1) WITH THERAPEUTIC USE
    a) CHILDREN - In a phase I study, 12 patients (median age 11 years; range 1 to 18 years; 9 with acute lymphoblastic leukemia, 3 with acute myelogenous leukemia) received bortezomib twice weekly for 2 consecutive weeks at 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Two patients had dose-limiting toxicities at the 1.7 mg/m(2) dose level. One patient developed grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine (Horton et al, 2007).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia has been common with all regimens of bortezomib (Prod Info VELCADE(R) IV injection, 2006; Dicato et al, 2006; Adams, 2002aa; Anon, 2002; Orlowski et al, 2002a).
    b) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade thrombocytopenia occurred in 35% of patients (26% reported grade 3 events, 4% reported grade 4 events) during bortezomib dosing versus 11% of patients in the dexamethasone treatment arm. Platelet counts returned toward baseline values during the 10-day rest period in each bortezomib treatment cycle. Bortezomib therapy should be held when the platelet count is less than 25,000 per microliter and reinitiated at a reduced dose (Prod Info VELCADE(R) IV injection, 2006)
    c) Although not dose-limiting, it has influenced dosing. Patients with low baseline platelet counts have been at greater risk of thrombocytopenia (Orlowski et al, 2002a).
    d) In a phase I study in patients with hematologic malignancies treated with 1.04 to 1.38 mg/m(2) twice weekly for 4 weeks, then 2 weeks of rest (n=27), thrombocytopenia (any grade) occurred at some point during the first cycle in 74% of patients; corresponding grade 3 incidences were 37%. At the maximum tolerated dose (1.04 mg/m(2)), nadir platelet counts were seen in 3 to 4 weeks, and these nadirs tended to extend to the start of the 2-week rest period; recovery was evident by day 38 (Orlowski et al, 2002a).
    2) WITH POISONING/EXPOSURE
    a) Overdoses of twice the recommended dose have resulted in rapid symptomatic hypotension and thrombocytopenia leading to fatal outcomes (Prod Info VELCADE(R) IV injection, 2006).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade neutropenia occurred in 19% of patients (12% reported grade 3 events and 2% reported grade 4 events) during bortezomib dosing versus 2% in the dexamethasone group. Neutrophils count returned toward baseline values during the rest period in each bortezomib treatment cycle(Prod Info VELCADE(R) IV injection, 2006).
    b) In a phase I study in patients with hematologic malignancies treated with 1.04 to 1.38 mg/m(2) twice weekly for 4 weeks, then 2 weeks of rest (n=27), neutropenia (any grade) occurred at some point during the first cycle in 37% of patients; corresponding grade 3 incidences were 15%. The neutropenia was not dose-limiting (Orlowski et al, 2002a).
    c) CHILDREN - In a phase I study, 12 patients (median age 11 years; range 1 to 18 years; 9 with acute lymphoblastic leukemia, 3 with acute myelogenous leukemia) received bortezomib twice weekly for 2 consecutive weeks at 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Two patients had dose-limiting toxicities at the 1.7 mg/m(2) dose level. One patient developed grade 3 confusion and the other patient had grade 4 febrile neutropenia (absolute neutrophil count, 560) associated with grade 4 hypotension and grade 3 creatinine (Horton et al, 2007).
    C) ANEMIA
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade anemia occurred in 26% of patients (9% reported grade 3 events and less than 1% reported grade 4 events) during bortezomib dosing versus 22% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    b) In a phase I study in patients with hematologic malignancies treated with 1.04 to 1.38 mg/m(2) twice weekly for 4 weeks, then 2 weeks of rest (n=27), thrombocytopenia, neutropenia, and anemia (any grade) occurred at some point during the first cycle in 74%, 37%, and 48%, respectively; corresponding grade 3 incidences were 37%, 15%, and 19%. At the maximum tolerated dose (1.04 mg/m(2)), nadir platelet counts were seen in 3 to 4 weeks, and these nadirs tended to extend to the start of the 2-week rest period; recovery was evident by day 38 (Orlowski et al, 2002a).
    D) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH THERAPEUTIC USE
    a) In postmarketing experience, disseminated intravascular coagulation has occurred (Prod Info VELCADE(R) IV injection, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) Manufacturer post marketing surveillance has revealed reports (incidence unknown) of toxic epidermal necrolysis in patients treated with bortezomib (Prod Info VELCADE(R) IV injection, 2006).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade rash occurred in 18% (1% grade 3 events) of patients receiving bortezomib versus 6% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    b) In one patient, a maculopapular rash with a superficial perivascular lymphocytic/eosinophilic infiltrate occurred during the first cycle of therapy (twice weekly for 4 of 6 weeks), resolving spontaneously; the rash recurred during the second cycle, with attendant dyspnea and arthritis symptoms, suggestive of systemic hypersensitivity (Orlowski et al, 2002a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BONE PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade bone pain occurred in 16% (4% grade 3 events) of patients receiving bortezomib versus 15% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade arthralgia occurred in 14% (less than 1% grade 3 events) of patients receiving bortezomib versus 11% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    C) BACKACHE
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade back pain occurred in 14% (3% grade 3 events) of patients receiving bortezomib versus 10% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    D) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade myalgia occurred in 12% (less than 1% grade 3 events) of patients receiving bortezomib versus 5% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    E) CRAMP
    1) WITH THERAPEUTIC USE
    a) In a randomized phase 3 trial (n=331 bortezomib-treated; n=332 dexamethasone-treated), all grade muscle cramps occurred in 12% of patients receiving bortezomib versus 15% in the dexamethasone group (Prod Info VELCADE(R) IV injection, 2006).
    F) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 46-year-old man with IgG/k stage IIIA multiple myeloma developed chills, high fever (up to 39 degrees C), and severe generalized muscle pain 12 hours after receiving bortezomib (a conventional schedule of 1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks). Laboratory values showed CPK at 519 International Units(IU)/L, serum creatinine at 1.4 mg/dL, LDH at 4634 IU/L, AST at 554 IU/L, and ALT at 46 IU/L. Following bortezomib discontinuation and supportive therapy, all symptoms resolved 3 days after the onset of rhabdomyolysis. For the next three courses, he was treated with bortezomib (0.7 mg/m(2), 1 mg/m(2), 1.3 mg/m(2), respectively) without complications. On day 9 of cycle 5, he developed high fever (39 degrees C) and generalized muscle pain 6 hours after receiving bortezomib (1.3 mg/m(2)). Laboratory values showed elevated LDH 951 IU/L and CPK 205 IU/L. Following supportive therapy, his symptoms resolved after a few hours. Bortezomib was continued at a reduced dose of 1 mg/m(2) (Cibeira et al, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Bortezomib is classified as FDA pregnancy category D.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS, RABBITS: No teratogenicity was noted in rats and rabbits following exposures approximately 0.5 times the clinical dose of 1.3 mg/m(2) during organogenesis (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified bortezomib as FDA pregnancy category D. There is insufficient clinical experience with bortezomib to confirm its safety in pregnancy. Until additional data are available, women of childbearing potential should avoid becoming pregnant while undergoing treatment with bortezomib. If a patient is exposed to bortezomib during pregnancy, advise the patient of the potential hazard to the fetus (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).
    B) ANIMAL STUDIES
    1) RABBITS: Significant post-implantation losses and reductions in live fetuses occurred with doses approximately 0.5 times the clinical dose of 1.3 mg/m(2) during organogenesis. Surviving fetuses were significantly underweight (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether bortezomib is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Until additional data are available, a decision whether to discontinue nursing or discontinue the drug should be made, taking into account the importance of the drug to the mother (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Degenerative effects in the ovaries and testes occurred in rats with 6 months of exposure to bortezomib at doses one-fourth the recommended clinical dose and 1.2 mg/m(2), respectively (Prod Info VELCADE(R) intravenous subcutaneous injection powder, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS179324-69-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Carcinogenicity studies have not been performed with bortezomib (Prod Info VELCADE(R) IV injection, 2006).

Genotoxicity

    A) There was no evidence of genotoxicity when bortezomib was tested in the in vitro mutagenicity assay (Ames test), and in vivo micronucleus assay in mice; however, bortezomib showed clastogenic activity in the Chinese hamster ovary chromosomal aberration assay (Prod Info VELCADE(R) IV injection, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor CBC with differential and platelet count.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Monitor for clinical evidence of peripheral neuropathy or encephalopathy.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs, mental status, and liver enzymes following significant overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    D) Monitor CBC with differential and platelet count.
    E) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    F) Monitor for clinical evidence of peripheral neuropathy or encephalopathy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Overdoses of twice the recommended dose have resulted in rapid symptomatic hypotension and thrombocytopenia leading to fatal outcomes.
    B) THERAPEUTIC DOSE: ADULT: Initial dose of 1.3 mg/m(2) given as a 3 to 5 second bolus IV injection (concentration of 1 mg/mL) or SubQ injection (concentration of 2.5 mg/mL) twice weekly for 2 weeks followed by a 10-day rest period. CHILD: Safety and effectiveness in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) The recommended initial dose is 1.3 mg/m(2) administered as a 3 to 5 second IV bolus or subQ injection (Prod Info VELCADE(R) subcutaneous, intravenous injection, 2014).
    1) PREVIOUSLY UNTREATED MULTIPLE MYELOMA: 1.3 mg/m(2) IV bolus or SUBQ twice weekly for cycles 1 to 4; then once weekly for 6 weeks for cycles 5 through 9; administer in combination with oral melphalan and oral prednisone. Allow for at least 72 hours to pass between consecutive bortezomib doses (Prod Info VELCADE(R) subcutaneous, intravenous injection, 2014).
    2) RELAPSED MULTIPLE MYELOMA OR MANTLE CELL LYMPHOMA: 1.3 mg/m(2) IV bolus or SUBQ twice weekly for 2 weeks. Allow for at least 72 hours to pass between consecutive bortezomib doses (Prod Info VELCADE(R) subcutaneous, intravenous injection, 2014; Prod Info VELCADE(R) intravenous, subcutaneous injection, 2012).
    3) RETREATMENT IN RELAPSED MULTIPLE MYELOMA: treatment may be initiated at the last tolerated dose administered twice weekly every 3 weeks for a maximum of 8 cycles. Allow for at least 72 hours to pass between consecutive bortezomib doses (Prod Info VELCADE(R) subcutaneous, intravenous injection, 2014).
    7.2.2) PEDIATRIC
    A) Safety and effectiveness in pediatric patients have not been established (Prod Info VELCADE(R) subcutaneous, intravenous injection, 2014).

Minimum Lethal Exposure

    A) A toxic dose has not been established. Overdoses of twice the recommended dose have resulted in rapid symptomatic hypotension and thrombocytopenia leading to fatal outcomes (Prod Info VELCADE(R) IV injection, 2006).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) Plasma level monitoring is of little usefulness to guide dosing or monitor therapy as bortezomib has a short elimination half-life and most of a dose is rapidly and extensively distributed outside of the circulation (Elliott & Ross, 2001; Nix et al, 2001; Adams, 2002). A bioassay to determine whole-blood, white-cell, or tissue levels of residual proteasome activity has been developed to more adequately monitor therapy (Adams, 2002b; Elliott & Ross, 2001; Nix et al, 2001); however, this will probably not be used in clinical practice as proteasome inhibition has been shown to be dose-dependent with minimal variation, even in differing patient populations (Adams, 2002b). The optimal extent of proteasome inhibition for clinical studies is considered to be 80%, for short periods (Wright et al, 2000).

Workplace Standards

    A) ACGIH TLV Values for CAS179324-69-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS179324-69-7 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS179324-69-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS179324-69-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Bortezomib reversibly inhibits the chymotrypsin-like activity of the 26S proteasome, a large protein complex in mammalian cells that breaks down ubiquitinated proteins. The ubiquitin-proteasome pathway is responsible for regulating intracellular concentration of specific proteins, and maintaining homeostasis within cells. Proteasome inhibition prevents this targeted proteolysis and affects multiple signaling cascades within the cell. Therefore, cell death occurs with the disruption of normal homeostatic mechanisms. Studies have reported that bortezomib is cytotoxic to many types of cancer cells in vitro (Prod Info VELCADE(R) IV injection, 2006).

Physicochemical

Physical Characteristics

    A) As the monomeric boronic acid, the solubility in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5 (Prod Info VELCADE(R) IV injection, 2006).

Molecular Weight

    A) 384.24 (Prod Info VELCADE(R) IV injection, 2006)

References

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