Bortezomib (Monograph)

Brand name: Velcade
Drug class: Antineoplastic Agents
- Proteasome Inhibitors
VA class: AN900
Chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propanoyl]amino]butyl]boronic acid
Molecular formula: C₁₉H₂₅BN₄O₄
CAS number: 179324-69-7

Medically reviewed by Drugs.com on Jul 27, 2023. Written by ASHP.

Introduction

Antineoplastic agent; inhibitor of 26S proteasome.^{1 5}

Uses for Bortezomib

Previously Untreated Multiple Myeloma

In combination with melphalan and prednisone for previously untreated multiple myeloma.^{1 20 24}

Relapsed Multiple Myeloma

Treatment of multiple myeloma in patients who have received at least 1 prior therapy.^{1 3 7}

Retreatment of multiple myeloma in patients who previously responded to bortezomib-based therapy and relapsed ≥6 months following therapy.^{1 29}

More effective than high-dose dexamethasone in achieving complete or partial response, prolonging time to disease progression, and improving survival in patients with progressive multiple myeloma who had received 1–3 prior chemotherapy regimens.^{1 8}

Induction Therapy Prior to Stem-cell Transplantation in Newly Diagnosed Multiple Myeloma

Has been studied as a component of various induction regimens for newly diagnosed multiple myeloma in transplant-eligible patients^{† [off-label]}.^{10002 10003 10004 10005 10006 10007 10008 10012 10013 10014 10015 10016 10019 10020 10021 10022 10023 10024 10025 10026 10027 10028 10029}

Use with dexamethasone^{† [off-label]10012} may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^{† [off-label]}.¹⁰⁰³² Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.¹⁰⁰³²

Use with thalidomide and dexamethasone^{† [off-label]10013 10014 10016 10027} may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^{† [off-label]};¹⁰⁰³³ however, use of a modified bortezomib-thalidomide-dexamethasone^† regimen using reduced bortezomib and thalidomide dosages¹⁰⁰¹⁵ is not fully established because of unclear risk/benefit and/or inadequate experience.¹⁰⁰³³ Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.¹⁰⁰³³

Use with doxorubicin (or pegylated liposomal doxorubicin) and dexamethasone^{†10023 10024 10025} may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^†;¹⁰⁰³⁴ however, in the absence of longer follow-up data, use of a modified bortezomib-pegylated liposomal doxorubicin-dexamethasone^† regimen using reduced bortezomib and pegylated liposomal doxorubicin dosages¹⁰⁰²⁶ is not fully established because of unclear risk/benefit and/or inadequate experience.¹⁰⁰³⁴ Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.¹⁰⁰³⁴

Use with cyclophosphamide and dexamethasone^{†10019 10021 10022 10028 10029} may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients^†.¹⁰⁰³⁵ Consider cytogenetic features, performance status, preexisting conditions (e.g., peripheral neuropathy), and tolerability when selecting a combination chemotherapy regimen.¹⁰⁰³⁵

Mantle Cell Lymphoma

In combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for previously untreated mantle cell lymphoma.^{1 26}

Treatment of mantle cell lymphoma in patients who have received at least 1 prior chemotherapy regimen.^{1 13 14 21}

Bortezomib Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics including use of gloves and protective clothing.¹

Antiviral Prophylaxis

• Consider initiating antiviral prophylaxis.¹ (See Herpes Virus Infection under Cautions.)

Administration

For solution and drug compatibility information, see Compatibility under Stability.

Dispensing and Administration Precautions

Administer only by IV or sub-Q injection (see Contraindications under Cautions); sub-Q injection may be considered in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.¹

When dispensing, label syringe holding the individual dose with sticker provided by the manufacturer indicating route of administration.¹

IV Administration

Reconstitution

To reconstitute, add 3.5 mL of 0.9% sodium chloride injection to vial containing 3.5 mg of bortezomib to yield final concentration of 1 mg/mL.¹

Administer within 8 hours after reconstitution.¹ (See Storage under Stability.)

Rate of Administration

Administer by IV injection over 3–5 seconds.¹

Sub-Q Administration

Administer by sub-Q injection in thigh or abdominal region; rotate injection sites.¹

Give new injections ≥1 inch from previous injection site; do not give injections into areas where skin is tender, erythematous, bruised, or indurated.¹

Reconstitution

To reconstitute, add 1.4 mL of 0.9% sodium chloride injection to vial containing 3.5 mg of bortezomib to yield final concentration of 2.5 mg/mL.¹ If local injection site reactions occur, the manufacturer recommends reconstituting the drug to a final concentration of 1 mg/mL or considering IV administration.¹

Administer within 8 hours after reconstitution.¹ (See Storage under Stability.)

Dosage

Consult specialized references and published protocols for dosage (including dosage adjustments in special populations), method of administration, and administration sequence of drugs in combination regimens.¹

Use caution when calculating dose and respective volume of bortezomib to prevent overdosage; drug quantity contained in one 3.5-mg vial may exceed usual single dose required.¹

Adults

Previously Untreated Multiple Myeloma

Bortezomib, Melphalan, and Prednisone (VMP regimen)

IV or Sub-Q

Cycles 1–4 (of the recommended nine 6-week cycles): Bortezomib 1.3 mg/m² IV or sub-Q twice weekly during weeks 1, 2, 4, and 5 (days 1, 4, 8, 11, 22, 25, 29, and 32 of the 6-week cycle) followed by a 10-day rest period (days 33–42).^{1 20}

Cycles 5–9: Bortezomib 1.3 mg/m² IV or sub-Q once weekly during weeks 1, 2, 4, and 5 (days 1, 8, 22, and 29) followed by a 13-day rest period.^{1 20}

In all 9 cycles: Administer oral melphalan 9 mg/m² and oral prednisone 60 mg/m² once daily on days 1–4.¹

At least 72 hours should elapse between consecutive doses of bortezomib.¹

Dosage Modification for Toxicity for VMP Regimen

IV or Sub-Q

Before administering any VMP cycle, platelet counts should be ≥70,000/mm³, ANC should be ≥1000/mm³, and any nonhematologic toxicities should have resolved to grade 1 or baseline.¹

Relapsed Multiple Myeloma

IV or Sub-Q

Standard regimen: 1.3 mg/m² IV or sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21).^{1 4 5}

For extended therapy of >8 treatment cycles, continue standard 21-day regimen or initiate 35-day maintenance regimen of 1.3 mg/m² IV or sub-Q once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period (days 23–35).¹

Retreatment following prior response to bortezomib therapy and disease progression ≥6 months following last therapy: Administer last tolerated dose of bortezomib IV or sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21) for up to 8 cycles.¹ May be administered with or without dexamethasone.¹

At least 72 hours should elapse between consecutive doses.¹

Dosage Modification for Peripheral Neuropathy in Relapsed Multiple Myeloma

IV or Sub-Q

Adjust dose and/or frequency of administration if new or worsening peripheral neuropathy occurs.^{1 6} (See Table 2.)

Dosage Modification for Other Nonhematologic or Hematologic Effects in Relapsed Multiple Myeloma

IV or Sub-Q

Temporarily discontinue therapy if grade 3 nonhematologic (other than peripheral neuropathy) or grade 4 hematologic toxicities (e.g., grade 4 thrombocytopenia [platelet count <25,000/mm³]) occur.^{1 6}

Once manifestations of toxicity resolve, reinitiate but reduce bortezomib dosage by 25% (i.e., reduce from 1.3 mg/m² per dose to 1 mg/m² per dose; reduce from 1 mg/m² per dose to 0.7 mg/m² per dose).¹

Administer the adjusted regimen for 2 weeks, followed by a 10-day rest period.⁶

Induction Therapy Prior to Stem-cell Transplantation in Newly Diagnosed Multiple Myeloma†

Bortezomib and Dexamethasone†

IV

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 during cycles 1 and 2 and then on days 1–4 during cycles 3 and 4.^{10002 10012} Treatment cycles repeated every 21 days for 4 cycles.^{10002 10012}

Bortezomib, Dexamethasone, and Thalidomide†

IV

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 and thalidomide 200 mg orally daily (after initial dosage escalation during cycle 1 with 100 mg on days 1–14 followed by 200 mg orally daily thereafter).¹⁰⁰¹³ Treatment cycles repeated every 21 days for 3 cycles.¹⁰⁰¹³

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 and thalidomide 200 mg orally daily (after initial dosage escalation during cycle 1 with 50 mg orally on days 1–14 followed by 100 mg orally on days 15–28).¹⁰⁰¹⁴ Treatment cycles repeated every 4 weeks for 6 cycles.¹⁰⁰¹⁴

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 and thalidomide 100 mg orally daily.^{10016 10027} Treatment cycles repeated every 3 weeks for 4 cycles.^{10016 10027}

Sub-Q

Bortezomib 1.3 mg/m² sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 and thalidomide 100 mg orally daily.^{10016 10027} Treatment cycles repeated every 3 weeks for 4 cycles.^{10016 10027}

Bortezomib, Dexamethasone, and Doxorubicin (or Pegylated Liposomal Doxorubicin)†

IV

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with doxorubicin hydrochloride 9 mg/m² IV per day on days 1–4 and dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 of each 28-day cycle for 3 cycles.¹⁰⁰²³

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with pegylated liposomal doxorubicin hydrochloride 30 mg/m² IV on day 4 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during cycle 1.¹⁰⁰²⁴ During cycles 2–6, same dosages of bortezomib and pegylated liposomal doxorubicin administered along with dexamethasone 20 mg orally daily.¹⁰⁰²⁴ Treatment cycles repeated every 3 weeks for a total of 6 cycles.¹⁰⁰²⁴

Bortezomib, Dexamethasone, and Cyclophosphamide†

IV

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m² orally on days 1, 8, 15, and 22 and dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 of each 28-day cycle for 4 cycles.¹⁰⁰¹⁹

Bortezomib 1.5 mg/m² IV once weekly (days 1, 8, 15, and 22) along with cyclophosphamide 300 mg/m² orally on days 1, 8, 15, and 22 of each 28-day cycle for 4 cycles, with dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 during cycles 1 and 2 and then once weekly during cycles 3 and 4.¹⁰⁰²¹

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m² IV on days 1 and 8 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 1–3) followed by bortezomib 1 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 4–6).¹⁰⁰²⁹

Bortezomib 1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 900 mg/m² IV on day 1 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles.¹⁰⁰²⁸

Sub-Q

Bortezomib 1.3 mg/m² sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 900 mg/m² IV on day 1 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles.¹⁰⁰²⁸

Previously Untreated Mantle Cell Lymphoma

Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP regimen)

IV

1.3 mg/m² IV twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12–21); rituximab 375 mg/m², cyclophosphamide 750 mg/m², and doxorubicin hydrochloride 50 mg/m² IV on day 1; and prednisone 100 mg/m² orally on days 1–5 of each 3-week cycle.^{1 26}

If response is first observed at cycle 6, manufacturer recommends 2 additional cycles.¹

At least 72 hours should elapse between consecutive doses of bortezomib.¹

Dosage Modification for Toxicity for VR-CAP Regimen

IV

Before administering cycles 2–6 of VR-CAP, platelet counts should be ≥100,000/mm³, ANC should be ≥1500/mm³, hemoglobin concentration should be ≥8 g/dL, and nonhematologic toxicities should have resolved to grade 1 or baseline.¹

Relapsed Mantle Cell Lymphoma

IV or Sub-Q

Standard regimen: 1.3 mg/m² IV or sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21).¹

For extended therapy of >8 treatment cycles, continue standard 21-day regimen.¹

At least 72 hours should elapse between consecutive doses.¹

In clinical studies, patients who responded to therapy received a median of 8 treatment cycles.¹

Dosage Modification for Peripheral Neuropathy in Relapsed Mantle Cell Lymphoma

IV or Sub-Q

Adjust dose and/or frequency of administration if new or worsening peripheral neuropathy occurs.¹ (See Table 4.)⁶

Dosage Modification for Other Nonhematologic or Hematologic Effects in Relapsed Mantle Cell Lymphoma

IV or Sub-Q

Temporarily discontinue therapy if grade 3 nonhematologic (other than peripheral neuropathy) or grade 4 hematologic toxicities (e.g., grade 4 thrombocytopenia [platelet count <25,000/mm³]) occur.^{1 6}

Once manifestations of toxicity resolve, reinitiate but reduce bortezomib dosage by 25% (i.e., reduce 1.3-mg/m² dose to 1-mg/m² dose; reduce 1-mg/m² dose to 0.7-mg/m² dose).¹

Administer the adjusted regimen for 2 weeks, followed by a 10-day rest period.⁶

Special Populations

Hepatic Impairment

Moderate (i.e., bilirubin concentrations >1.5–3 times ULN with any AST concentrations) or severe (i.e., bilirubin concentrations >3 times ULN with any AST concentrations) hepatic impairment: Reduce bortezomib dose during first cycle to 0.7 mg/m².¹ Based on patient tolerance, either increase dosage in subsequent cycles to 1 mg/m² or further reduce to 0.5 mg/m².¹

Mild hepatic impairment (i.e., bilirubin concentrations at or below ULN with AST concentrations exceeding ULN or bilirubin concentrations >1 to 1.5 times ULN with any AST concentrations): Administer usual recommended initial dose.¹

Renal Impairment

Dosage adjustment not required.¹

Dialysis may decrease bortezomib concentrations; administer after a dialysis procedure.¹ (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations at this time.¹ (See Geriatric Use under Cautions.)

Cautions for Bortezomib

Contraindications

• Known hypersensitivity (except for local reactions) to bortezomib, boron, or mannitol.¹ Anaphylactic reactions reported.¹

• Intrathecal administration.¹ Fatal if administered intrathecally.¹

Warnings/Precautions

Peripheral Neuropathy

Risk of severe (grade 3 or greater) new-onset peripheral neuropathy or exacerbation of preexisting peripheral neuropathy.¹ Occurs predominantly as peripheral sensory neuropathy, but severe peripheral motor neuropathy also reported.¹ Manifestations improved or returned to baseline in some patients with relapsed multiple myeloma following dosage reduction or discontinuance of bortezomib; long-term outcome of peripheral neuropathy not evaluated in patients with mantle cell lymphoma.¹

Incidence of peripheral neuropathy reportedly higher in patients with relapsed multiple myeloma receiving bortezomib by IV injection compared with those receiving the drug by sub-Q injection.¹ Consider sub-Q administration in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.¹

Monitor patients for manifestations of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, weakness).¹ Adjust dose and/or frequency of administration if new onset or exacerbation of peripheral neuropathy occurs.¹ (See Dosage under Dosage and Administration.)

Use in patients with preexisting severe neuropathy only after careful assessment of the risks and benefits for the individual patient.¹

Hypotension

Risk of severe (grade 3) hypotension, orthostatic hypotension, and syncope.¹

Use with caution in patients with history of syncope or who are dehydrated or receiving drugs associated with hypotension.¹

Orthostatic hypotension may be managed with adjustment of antihypertensive therapy, hydration, or administration of mineralocorticoids and/or sympathomimetics.¹

Cardiovascular Effects

Acute development or exacerbation of CHF and/or new onset of decreased left ventricular ejection fraction reported, including in patients with no risk factors for decreased left ventricular ejection fraction.¹ Events including acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, and cardiogenic shock reported.¹ Risk of death from cardiogenic shock, CHF, or cardiac arrest.¹ Closely monitor patients with existing heart disease and patients with increased risk for heart disease.¹

Prolongation of QT_c interval reported; however, causal relationship with bortezomib not established.¹

Pulmonary Effects

Fatal respiratory insufficiency/failure reported.¹ Pneumonitis, interstitial pneumonia, lung infiltration, and ARDS reported; sometimes fatal.¹ Pulmonary hypertension (in absence of left heart failure or significant pulmonary disease) also reported.¹

If new or worsening cardiopulmonary symptoms occur, promptly conduct comprehensive diagnostic evaluation; consider temporarily withholding bortezomib therapy pending evaluation.¹

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS reported.¹ May manifest as seizures, hypertension, headache, lethargy, confusion, blindness, and other visual and neurologic disturbances.¹ Brain imaging, preferably MRI, necessary to confirm diagnosis.¹

If RPLS develops, discontinue bortezomib.¹ Safety of reinitiating bortezomib in patients previously experiencing RPLS not known.¹

GI Effects

Risk of nausea, diarrhea, constipation, vomiting, loss of appetite, dyspepsia, and dysgeusia; ileus also may occur.¹

Adverse GI effects may be severe and require use of antiemetics and antidiarrheals.¹ Fluid and electrolyte replacement recommended to prevent dehydration.¹ If severe adverse GI effects occur, temporarily interrupt bortezomib therapy.¹

Hematologic Effects

Risk of severe (grade 3 or 4) thrombocytopenia.¹ Platelet count nadir typically occurs following last dose of each treatment cycle and recovers before initiation of next cycle.¹ Platelet count nadir averages approximately 40% of baseline.¹ Risk of GI and intracerebral hemorrhage associated with thrombocytopenia.¹

Risk of severe (grade 3 or 4) neutropenia.¹ Neutrophil count nadir typically occurs following last dose of each treatment cycle and recovers before initiation of next cycle.¹

No evidence of cumulative thrombocytopenia or neutropenia with the treatment regimens evaluated for multiple myeloma or mantle cell lymphoma.¹

Monitor platelet count prior to each dose.¹ In addition, regularly monitor CBC during treatment and adjust dosage as appropriate.¹ (See Dosage under Dosage and Administration.) Administer supportive care (e.g., transfusions) according to published guidelines.¹

Tumor Lysis Syndrome

Tumor lysis syndrome reported.¹ Increased risk in patients with large tumor burden; closely monitor such patients and take appropriate precautions.¹

Hepatic Effects

Acute liver failure reported in patients with serious underlying medical conditions who were receiving bortezomib with multiple concomitant drugs.¹ Increases in hepatic enzyme concentrations, hyperbilirubinemia, and hepatitis also reported.^{1 16}

The manufacturer recommends temporary interruption of bortezomib therapy for assessment of reversibility of adverse hepatic effects.¹ Information on results of rechallenge in these patients is limited.¹ (See Hepatic Impairment under Dosage and Administration.)

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; embryolethality and decreased fetal weight demonstrated in animals.¹ Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Herpes Virus Infection

Risk of reactivation of varicella zoster virus infection.¹ In phase 3 study, antiviral prophylaxis appeared to reduce risk of reactivation in patients receiving VMP regimen.¹ Consider antiviral prophylaxis in patients receiving bortezomib.¹

Similar frequencies of herpes simplex virus infection reported with bortezomib and comparator therapies in clinical studies in multiple myeloma patients.¹

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether bortezomib is distributed into milk.¹ Discontinue nursing or the drug because of potential risk to nursing infants; consider importance of drug to the woman.¹

Pediatric Use

Efficacy not established in pediatric patients with relapsed pre-B acute lymphoblastic leukemia (ALL).¹ In pediatric and young adult patients, the addition of bortezomib to intensive reinduction chemotherapy did not alter complete remission rates at day 36 compared with a historical control.¹ No new safety concerns identified.¹

Clearance (normalized to body surface area [BSA]) similar to clearance in adults.¹

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹ In clinical studies, patients ≥65 years of age with relapsed multiple myeloma had longer median time to progression, longer median duration of response, higher overall response rates, and higher incidence of grade 3 or 4 adverse effects compared with younger adults.¹

Exposure may be increased in geriatric patients compared with younger adults.¹ (See Geriatric Patients under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Hepatic Impairment

Increased exposure to bortezomib in patients with moderate or severe hepatic impairment; reduce dosage and monitor closely for adverse effects.^{1 23} (See Hepatic Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not affected by renal impairment.¹ (See Renal Impairment under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

IV bortezomib in combination with melphalan and prednisone (VMP) in patients with previously untreated multiple myeloma: Thrombocytopenia,^{1 24} neutropenia,^{1 24} peripheral neuropathy,^{1 24} nausea,¹ diarrhea,¹ neuralgia,¹ anemia,^{1 24} leukopenia,^{1 24} vomiting,¹ fatigue,¹ constipation,¹ lymphopenia,^{1 24} anorexia,¹ asthenia,¹ pyrexia,¹ paresthesia,¹ herpes zoster,¹ rash,¹ abdominal pain (upper quadrant),¹ insomnia.¹

IV bortezomib monotherapy in patients with relapsed multiple myeloma: Nausea,¹ diarrhea,¹ fatigue,¹ peripheral neuropathy,¹ thrombocytopenia,¹ constipation,¹ vomiting,¹ anorexia,¹ pyrexia,¹ paresthesia,¹ anemia,¹ headache,¹ neutropenia,¹ rash,¹ decreased appetite,¹ dyspnea,¹ abdominal pain,¹ dizziness (excluding vertigo),¹ weakness.¹

IV bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma: Neutropenia,^{1 26} thrombocytopenia,^{1 26} leukopenia,^{1 26} anemia,^{1 26} peripheral neuropathy,^{1 26} lymphopenia,^{1 26} diarrhea,^{1 26} nausea,^{1 26} pyrexia,^{1 26} cough,²⁶ constipation,^{1 26} fatigue,^{1 26} febrile neutropenia,^{1 26} loss of appetite,^{1 26} peripheral edema,²⁶ alopecia,¹ asthenia,^{1 26} pneumonia,²⁶ neuralgia,¹ vomiting.¹

IV bortezomib monotherapy in patients with relapsed mantle cell lymphoma: Peripheral neuropathy,¹ fatigue,¹ diarrhea,¹ nausea,¹ constipation,¹ rash,¹ vomiting,¹ dizziness (excluding vertigo),¹ thrombocytopenia,¹ anorexia,¹ anemia,¹ weakness,¹ headache,¹ pyrexia.¹

Sub-Q bortezomib monotherapy in patients with relapsed multiple myeloma: Peripheral neuropathy,^{1 27} thrombocytopenia,^{1 27} neuralgia,^{1 27} neutropenia,^{1 27} anemia,^{1 27} diarrhea,^{1 27} leukopenia,^{1 27} nausea,^{1 27} pyrexia,^{1 27} vomiting,²⁷ asthenia,²⁷ weight loss,²⁷ constipation,²⁷ fatigue.²⁷

Drug Interactions

Metabolized principally by CYP isoenzymes 1A2, 2C19, and 3A4; metabolism by CYP2C9 and CYP2D6 is minor.^{1 5} May inhibit CYP2C19; poor inhibitor of CYP isoenzymes 1A2, 2C9, 2D6, and 3A4.¹ Does not induce CYP1A2 or CYP3A4 in vitro.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased systemic exposure of bortezomib.¹ Closely monitor patients for potential toxicities and consider reducing bortezomib dosage.¹

Potent CYP3A4 inducers: Possible decreased systemic exposure and reduced efficacy of bortezomib.¹ Avoid concomitant use.¹

Weak CYP3A4 inducers: Pharmacokinetic interaction not observed to date.¹

Potent CYP2C19 inhibitors: Pharmacokinetic interaction not observed to date.¹

Specific Drugs

Bortezomib Pharmacokinetics

Absorption

Bioavailability

Systemic exposure of bortezomib was comparable following repeated IV or sub-Q administration.^{1 27 31}

Mean dose-normalized peak plasma concentration and AUC of bortezomib are comparable between male and female patients.¹

Onset

Maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood observed 5 minutes following administration.¹ Maximum inhibition of 20S proteasome activity is comparable following administration of bortezomib doses of 1 mg/m² (70–84%) and 1.3 mg/m² (73–83%).¹

Special Populations

Exposure increased about 60% in patients with moderate (i.e., bilirubin concentrations >1.5–3 times ULN with any AST concentrations) or severe (i.e., bilirubin concentrations >3 times ULN with any AST concentrations) hepatic impairment.^{1 23}

In patients with varying degrees of renal impairment or normal renal function, exposure (based on dose-normalized AUC and peak plasma concentrations) was comparable among all the groups.¹ Dialysis may decrease concentrations; administer after a dialysis procedure.¹ (See Renal Impairment under Dosage and Administration.)

Mean dose-normalized peak plasma concentration and AUC of bortezomib are 25% lower in patients <65 years of age than in those ≥65 years of age.¹

Distribution

Extent

Distributed extensively to peripheral tissues.¹

Not known whether bortezomib is distributed into milk.¹

Plasma Protein Binding

83%.¹

Elimination

Metabolism

Metabolized principally by CYP1A2, 2C19, and 3A4 to inactive metabolites; metabolism by CYP2C9 and 2D6 is minor.^{1 5}

Elimination Route

Elimination pathways have not been characterized in humans.¹

Half-life

40–193 or 76–108 hours following multiple dosing with 1- or 1.3-mg/m² regimen, respectively.¹

Special Populations

Clearance (normalized to BSA) in pediatric patients similar to clearance in adults.¹

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C) in original package.¹ Protect from light.¹

Store reconstituted solution at 25°C in the original vial⁶ or in the syringe for up to 8 hours.¹

Compatibility

Parenteral

Solution Compatibility

Actions

• A modified dipeptidyl boronic acid.^{1 4 5}

• Reversibly inhibits the 26S proteasome, a large protein complex that degrades ubiquitinated proteins, preventing targeted proteolysis and causing disruption of normal homeostatic mechanisms, which can lead to cell death.^{1 5}

• Cytotoxic to a variety of cancer cell types in vitro.^{1 5}

• Has been shown to delay tumor growth in tumor models, including multiple myeloma.¹

Advice to Patients

• Risk of fatigue, dizziness, syncope, or orthostatic hypotension; avoid driving or operating machinery if these symptoms occur.¹

• Importance of taking appropriate measures to avoid dehydration caused by vomiting and/or diarrhea.¹ Importance of informing clinician if dizziness, light-headedness, fainting spells, or muscle cramps develop.¹

• Advise women to use an effective method of contraception and to avoid breast-feeding while receiving bortezomib therapy.¹ Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.¹ Advise pregnant women of risk to the fetus.¹

• For patients with diabetes receiving oral antidiabetic agents, importance of monitoring blood glucose concentrations frequently and informing clinician of any unusual change.¹

• Importance of informing clinician of new-onset or worsening symptoms of peripheral neuropathy (e.g., tingling, numbness, pain, burning sensation in hands or feet, weakness in arms or legs).¹

• Risk of RPLS.¹ Importance of reporting any possible manifestations of RPLS (e.g., seizure, persistent headache, reduced eyesight, blurred vision, confusion, lethargy, inability to think, difficulty walking).¹

• Risk of cardiac effects.¹ Importance of informing clinician if swelling (of the feet, ankles, or legs) or other cardiac-related problems occur.¹

• Risk of pulmonary effects.¹ Importance of informing clinician if shortness of breath, cough, or other pulmonary problems occur.¹

• Risk of hepatotoxicity.¹ Importance of reporting any possible manifestations of hepatotoxicity (e.g., jaundice, abdominal pain [particularly in the right upper quadrant]).¹

• Importance of informing clinician if rash, severe injection site reactions, or dermatologic pain occurs.¹

• Risk of reactivation of latent varicella zoster virus infection.¹ Importance of discussing with clinician whether to initiate antiviral prophylaxis.¹

• Importance of informing clinician if increase in BP, bleeding, fever, constipation, or loss of appetite occurs.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Frequently asked questions

• Ninlaro vs Velcade, which is better?

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